OFF-TEMPLATE FUNCTIONALISATION OF CARBOHYDRATES

A thesis submitted to The University Manchester for the degree of Doctor of Philosophy in the Faculty of Engineering and Physical Sciences

2012

DAYANA ISMAIL

SCHOOL OF CHEMISTRY

2

CONTENTS

Abstract 4

Declaration 5

Copyright Statement 6

Acknowledgements 7

List of Abbreviations 8

1 Introduction 10

1.1 Studies Toward the Synthesis of Gilvocarcin M 10

1.1.1 The ‘BHQ’ Benzannulation Reaction 10

1.2 Model Studies 12

1.3 Previous Work Within the Group 13

1.3.1 Cross-metathesis Reaction 13

1.3.2 SN2’ Reaction 16

1.3.3 Heck Reaction 17

1.3.4 Conjugate Addition Reaction 19

1.3.4.1 Aim of the Project 20

2 Results and Discussion 21

2.1 Off-template Studies 21

2.1.1 Organocopper Reaction 21

2.1.2 Rhodium(I)-catalysed Conjugate Addition Reactions 23

2.1.3 α,β-Unsaturated Esters 28

2.1.3.1 Effect of the Nature of the C-3 Protecting Group on the Stereochemical

Outcome of Conjugate Addition Reactions 36

2.1.4 Organolithium Reaction 41

2.1.5 Conjugate Addition Reaction of Ylide and N-Heterocycle Compounds 43

2.1.6 α,β-Unsaturated Aldehyde 48

2.1.7 α,β-Unsaturated Ketones 51

3

2.1.8 α,β-Unsaturated Nitro Alkenes 54

2.1.9 α,β-Unsaturated 2-Pyridylsulfones 61

2.1.10 Palladium(II)-catalysed Conjugate Addition Reactions 64

2.2 Stereochemical Rationale 66

3 Conclusions 68

4 Future Work 69

5 Experimental 71

5.1 General Procedures 71

5.1.1 Purification of Solvents and Reagents 71

5.1.2 Chromatography 71

5.1.3 Spectroscopic and Physical Data 72

5.2 Experimental Procedures 73

6 References 171

7 Appendix 176

4

ABSTRACT

The conjugate addition of organometallic reagents to α,β-unsaturated carbonyl compounds

has been studied extensively and is now one of the most important methods for carbon-

carbon bond formation. In devising a novel approach to the synthesis of C-glycosides such

as gilvocarcin M, we had occasion to investigate the conjugate addition reactions of a

diverse range of nucleophilic reagents (i.e. cuprate, RMgX, R-Li, NR2 and ylides) with a

number of γ-alkoxy-α,β-unsaturated compounds (esters, ketones, aldehydes, nitro and

sulfones): a sequence which hitherto has received scant attention. The stereochemical

outcome of these conjugate addition reactions has been elucidated and the stereochemical

rationale for the observed sense of asymmetric induction is also discussed.

5

DECLARATION

No portion of the work referred to in the thesis has been submitted in support of an

application for another degree or qualification of this or any other university or other institute

of learning.

6

COPYRIGHT STATEMENT

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certain copyright or related rights in it (the “Copyright”) and s/he has given The University of

Manchester certain rights to use such Copyright, including for administrative purposes.

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property (the “Intellectual Property”) and any reproductions of copyright works in the thesis,

for example graphs and tables (“Reproductions”), which may be described in this thesis, may

not be owned by the author and may be owned by third parties. Such Intellectual Property

and Reproductions cannot and must not be made available for use without the prior written

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http://www.campus.manchester.ac.uk/medialibrary/policies/intellectual-property.pdf), in any

relevant Thesis restriction declarations deposited in the University Library, The University

Library’s regulations (see http://www.manchester.ac.uk/library/aboutus/regulations) and in

The University’s policy on presentation of Theses.

7

ACKNOWLEDGEMENTS

I would like to acknowledge and extend my sincere gratitude to the following people who

have supported and made possible the completion of this research project. First and

foremost, I wish to express my gratitude to my supervisor, Dr Peter Quayle who has been

abundantly helpful and offered endless assistance and guidance throughout this project.

I would also like to thank the members of the Quayle group: Dr Cristina Luján Barroso, Dr

Amy Lawrence, Andreas Economou, Jakir Hussain, Mark Little and Omer Rasheed for their

knowledge, support and friendship over the past three years making the whole research

experience more exciting (and bearable!). I am also grateful for the friendship of many

people at the Department who have enlightened and entertained me over the years, as well

as helping me to adjust to a new country.

Not to forget, my special thank you to Dr Stephen Snee who has always supported and

believed in me. His constant patience and tolerance of my occasional mood swings are most

admirable and greatly appreciated.

Additionally, I wish to express my gratitude to the University of Manchester technical staff,

especially to Jim Raftery and Madeleine Helliwell for their help in X-ray crystallography

analysis, and also Rehana Sung and Gareth Smith for all the mass spectrometry

measurements.

Finally, and most importantly, my deepest gratitude goes to my beloved parents for their

never-ending support and encouragement to pursue this degree and providing the financial

means through the duration of my studies.

8

LIST OF ABBREVIATIONS

Ac Acyl

Ar Aromatic

ATRC Atom Transfer Radical Cyclisation

BHQ Bull-Hutchings-Quayle

Bn Benzyl

13C NMR Carbon-13 nuclear magnetic resonance

Cat. Catalytic

cod 1,5-Cyclooctadiene

d Doublet

δ Chemical shift

DBU 1,8-Diazabicyclo[5.4.0]undec-7-ene

DCC N,N’-Dicyclohexylcarbodiimide

DCE 1,2-Dichloroethane

DCM Dichloromethane

DIAD Di-isopropyl azodicarboxylate

DIBAL-H Di-isobutylaluminium hydride

DMAP 4-(Dimethylamino)pyridine

DMF N,N-Dimethylformamide

DMS Dimethyl sulfide

DMSO Dimethyl sulfoxide

d.r. Diastereomeric ratio

ES+/-

Electrospray (positive or negative mode)

Et Ethyl

eq. Equivalence

EWG Electron-withdrawing group

FT-IR Fourier transform-infrared spectroscopy

g Grams

h Hour(s)

1H NMR Proton nuclear magnetic resonance

Hz Hertz

(i-Pr) 1,3-Bis-(2,6,diisopropylphenyl)imidazolium

IR Infrared

m Multiplet

M Molarity

Me Methyl

mg Milligrams

MHz Megahertz

9

min Minute(s)

mmol Millimoles

mol Moles

mp Melting point

m/z Mass-to-charge ratio

MW Microwave

NHC N-Heterocyclic carbenes

nOe Nuclear Overhauser effect

Nu Nucleophile

31P NMR Phosphorus-31 (proton decoupled) nuclear magnetic

resonance

31P NMR [

1H] Phosphorus-31 (proton coupled) nuclear magnetic

resonance

Petrol Petroleum ether (40 – 60 °C)

PG Protecting group

Ph Phenyl

ppm Parts-per-million

PTC Phase-transfer-catalysis

q Quartet

R General alkyl/alkenyl/aryl group

Rf Retention factor

R-M Main group organometallic reagent

r.t. Room temperature

s Singlet

SN2 Bimolecular nucleophilic substitution

SN2’ Anti-bimolecular nucleophilic substitution

T Temperature

TBAB Tetra-n-butylammonium bromide

TBAF Tetra-n-butylammonium fluoride

TBS tert-Butyldimethylsilyl

TEBAC Benzyltriethylammonium chloride

THF Tetrahydrofuran

TLC Thin layer chromatography

TM Transition metal

TMS Trimethylsilyl

X Halide

ZnCl2·TMEDA N,N,N’,N’-Tetramethylethylenediamine

10

1 INTRODUCTION

1.1 STUDIES TOWARD THE SYNTHESIS OF GILVOCARCIN M

1.1.1 THE ‘BHQ’ BENZANNULATION REACTION

Recently, the Quayle group has been investigating the application of Atom Transfer Radical

Cyclisation (ATRC) reactions in organic synthesis,1-5

which led to the discovery of a new

synthesis of naphthalene derivatives from ortho-allylaryl trichloroacetates6,7

- the BHQ

reaction (figure 1).

R = OMe, Halogen, NO2, CO2Me, CHO, COMe etc. [M] = Redox-active TM catalyst.

Figure 1: Synthesis of naphthalene derivatives via the BHQ reaction.

Further investigations showed that this new benzannulation reaction is compatible with a

wide range of common functional groups, such as esters, aldehydes, ketones and nitro

groups. The BHQ reaction can be promoted using a variety of transition metal catalysts8

under either microwave irradiation or purely thermal reaction conditions.9 Within the group, it

had been shown that the BHQ reaction could be promoted effectively using a variety of

transition metal catalysts, although the combination of ligand 1 with CuCl or the preformed

copper(I)-NHC complex 2 (figure 2) were commonly adopted in standard reaction protocols.9

Figure 2: Ligand 1 and complex 2 for BHQ reaction.

Having proven the generality of the BHQ reaction for the synthesis of relatively simple

naphthalene derivatives, its application to more challenging targets, such as the synthesis of

the 6H-benzo[d]naphtha[1,2-b]pyran-6-one ring system present in gilvocarcin M (figure 3),

became the focus of the group’s efforts.

11

Figure 3: Proposed synthesis of gilvocarcin M 4 by the BHQ reaction.

The gilvocarcins (figure 4) were isolated from a group of Streptomyces and have been

reported to present significant antitumor activity with low toxicity.10,11

The structure of the

gilvocarcins consist of a C-glycoside unit attached directly to a highly functionalised aromatic

skeleton and thus the total syntheses of gilvocarcins remain a challenging problem.12,13

Figure 4: Core structure of the gilvocarcins.

We envisaged that gilvocarcin M 4 could be synthesised from trichloroacetate 3 via the BHQ

reaction. Claisen rearrangement of allyl ether 6 would afford phenol 5, which would then

undergo trichloroacetylation to give the necessary BHQ precursor 3 (figure 5).

Figure 5: Proposed retrosynthesis of gilvocarcin M 4 via the BHQ reaction.

12

1.2 MODEL STUDIES

Model studies within the group focused on the ortho-Claisen rearrangement of an allyl ether

containing a pre-functionalised carbohydrate residue. The group envisaged that phenol 9,

which could be synthesised from allyl ether (E)-10 via Claisen rearrangement, would

undergo acetylation to obtain the trichloroacetate 8. This substrate could then be used to test

the BHQ reaction to afford the chloronaphthalene 7 (figure 6).

Figure 6: Retrosynthesis of chloronaphthalene 7.

Previous studies in the group had shown that the allyl ether (E)-10 could be prepared in a

two-step sequence from ester (E)-11 (scheme 1).9

Scheme 1: Synthesis of allyl ether (E)-10. i. DIBAL-H (1.0 M in hexane, 2.5 eq.), DCM, -78 ºC, 2 h,

95%. ii. Phenol (1 eq.), PPh3 (1 eq.), Et3N (1 eq.), DIAD (1 eq.), THF, r.t., 16 h, 49%.

The ortho-Claisen rearrangement of allyl ether (E)-10 had also been investigated briefly

within the group: these studies showed that thermolysis of ether (E)-10 at 220 °C in Ph2O for

16 h did indeed afford the phenol 9, as a single diastereoisomer (unknown configuration),

albeit in low isolated 8% yield (scheme 2). Unfortunately this reaction proved to be highly

capricious and did not provide a reproducible route to the desired intermediate 9. Therefore

13

this route was abandoned and alternate approaches to the synthesis intermediates such as

phenol 9 were investigated.

Scheme 2: Synthesis of allyl phenol 9 via Claisen rearrangement. i. Ph2O, 220 ºC, 16 h, 8%.

1.3 PREVIOUS WORK WITHIN THE GROUP

1.3.1 CROSS-METATHESIS REACTION

An alternate approach to generic structures such as naphthalene 13 has also been

investigated within the group. Here it was envisaged that the chloronaphthalene 13 could be

prepared from vinyl sugar 15 via an olefin cross-metathesis reaction (figure 7).

Figure 7: Retrosynthesis of naphthalene 13 via cross-metathesis reaction of alkene 15.

Aldehyde 19 was prepared from commercially available 1,2:5,6-di-O-isopropylidene-α-D-

glucofuranose 16 as reported in the literature.14

Protection of furanose 16 (NaH, 60%

dispersion in mineral oil and benzyl bromide in DMF at room temperature; 98% yield) as its

benzyl ether and selective deprotection of the 5,6-acetonide (65% aqueous acetic acid at 40

°C) afforded diol 18 in 87% yield. Oxidative cleavage of diol 18 (NaIO4 in 1,4-dioxane at

room temperature) afforded aldehyde 19, which was used immediately as this compound

was sensitive to column chromatography (scheme 3).

14

Scheme 3: Synthesis of aldehyde 19. i. NaH (60% dispersion in mineral oil, 1.5 eq.), benzyl bromide

(1.1 eq.), DMF, r.t., 16 h, 98%. ii. Acetic acid, water, 40 °C, 20 h, 87%. iii. NaIO4 (1.2 eq.), 1,4-dioxane,

r.t., 16 h, 100% (crude yield).

Unfortunately, attempts9 to prepare alkene 15 from aldehyde 19 using Wittig chemistry

(scheme 4) was unsuccessful, affording a myriad of products.

Scheme 4: Attempted synthesis of alkene 15 from aldehyde 19 via Wittig reaction. i. Ph3PMeBr (1.5

eq.), KOtBu (1.5 eq.), THF, 0 ºC, 30 min, addition of aldehyde 19 then r.t., 12 h.

Fortunately, Turner et al.15

developed a direct method for the conversion of diol 18 into

alkene 15, a process which afforded the desired olefin in 96% yield (scheme 5).

Scheme 5: Synthesis of alkene 15 from diol 18. i. Imidazole (4 eq.), PPh3 (4 eq.), toluene, 50 °C, then

I2 (4 eq.), reflux, 24 h, followed by EtOAc (8 mol%) and I2 (4 eq.), r.t., 15 min, 96%.

Having successfully repeated Turner’s preparation of alkene 15, its cross-metathesis

reaction with the allyl phenol 20, using Grubbs’ I catalyst, was attempted. Unfortunately this

reaction afforded a complex mixture of products, where it was apparent that self-metathesis

of phenol 20 occurred predominantly, rather than the desired cross metathesis reaction

(scheme 6).

15

Scheme 6: Attempted cross-metathesis reaction of vinyl sugar 15 with allyl phenol 20. i. Grubbs’ I (5

mol%), DCM, 24 h, reflux.

The effect of phenol protecting groups on the metathesis reaction was investigated next.

Unfortunately the cross-metathesis of the vinyl sugar 15 with the TBS-ether 22, in the

presence of Grubbs’ I catalyst only gave some conversion to the desired product despite

being heated to reflux for more than 30 h in DCM. Encouragingly, the metathesis reaction, in

the presence of Grubbs’ II catalyst, afforded the desired product 23 as a single trans-isomer

in 44% yield (scheme 7).9

Scheme 7: Cross-metathesis reaction of vinyl sugar 15 with TBS-ether 22. i. Grubbs’ II (1 mol% or 5

mol%), DCM, 20 h, reflux, 44%.

Deprotection of alkene 23 (KOH in ethanol at 25 °C) gave allyl phenol 24 in 91% yield.

Acylation of phenol 24 (ClC(O)CCl3 and Et3N in diethyl ether at 25 °C) afforded the

trichloroacetate 25 in 88% yield. With a route to the key intermediate 25 in hand, its

conversion to the chloronaphtalene 13 using the BHQ reaction was investigated (scheme 8).

Scheme 8: Deprotection and acylation. i. KOH (1.5 eq.), EtOH, 25 ºC, 16 h, 91%. ii. ClC(O)CCl3 (3.8

eq.), Et3N (3.8 eq.), Et2O, 25 ºC, 16 h, 88%.

Due to time constraints, the benzannulation reaction of trichloroacetate 25 was attempted

only on a single occasion, an attempt which proved to be wholly unsuccessful (scheme 9).

16

Scheme 9: Attempted benzannulation reaction of trichloroacetate 25. i. (i-Pr)CuCl 2 (5 mol%) DCE,

200 ºC, 2 h, MW.

1.3.2 SN2’ REACTION

Another approach employed by the group for the synthesis of allyl phenol 9 involved SN2’

displacement of allyl picolinate 26 with a Grignard reagent (figure 8).

Figure 8: Retrosynthesis of allyl phenol 9 from allyl picolinate 26 via SN2’ reaction.

The reduction of trans-ester (E)-27 with excess DIBAL-H afforded trans-alcohol (E)-12,

which upon treatment with 2-picolinic acid, in the presence of DMAP and DCC, gave trans-

allyl picolinate 26 in 65% yield (scheme 10).

Scheme 10: Synthesis of allylic picolinate 26. i. DIBAL-H (1.0 M in hexane, 2.5 eq.), DCM, -78 ºC, 2 h,

89%. ii. 2-Picolinic acid (1.2 eq.), DMAP (1 eq.), DCC (1 eq.), DCM, r.t., 8 h, 65%.

Unfortunately, it was observed that displacement of picolinate 26 with phenylmagnesium

bromide in the presence of CuBr.DMS afforded the linear alkene 28 (i.e. SN2 displacement)

in good yield rather than the desired branched alkene 9 (SN2’) (scheme 11).

17

Scheme 11: Direct SN2 displacement of picolinate 26. i. PhMgBr (1.0 M in THF, 2 eq.), CuBr.Me2S (1.0

eq.), THF, -40 ºC to -60 ºC, 1.5 h, 56%.

1.3.3 HECK REACTION

Another approach employed by the group for the synthesis of allyl phenol 9 was via a Heck

reaction. It was postulated that Heck reaction of α,β-unsaturated ester (E)-27 with ortho-

iodophenol would give phenol 30, which would then undergo reduction followed by

elimination of the corresponding alcohol 29 to produce the desired allyl phenol 9 (figure 9).

Figure 9: Retrosynthetic approach to allyl phenol 9 via Heck reaction.

The Heck reaction was attempted on a cis/trans mixture of esters (Z)-27 and (E)-27 with

ortho-iodophenol. However, instead of the desired product 30 the reaction afforded coumarin

31, presumably via cyclisation of the intermediate 30 (scheme 12).

Scheme 12: Heck reaction of esters (Z)-27 and (E)-27. i. o-iodophenol (1 eq.), Et3N (3.4 eq.), TBAB

(3.4 eq.), Pd(OAc)2 (0.1 eq.), DMF, 100 °C, 48 h, 37%.

18

To convert the coumarin 31 into allyl phenol 9 would then involve the reduction of olefin in

the coumarin ring to give dihydrocoumarin 33, which could then be ring-opened to give ester

32. Reduction of the ester to the corresponding alcohol, followed by elimination reaction

would lead to the synthesis of the allyl phenol 9 (figure 10).

Figure 10: Retrosynthetic approach to allyl phenol 9 from coumarin 31.

Attempted reduction of coumarin 31 using an H-cube® failed to produce the desired

dihydrocoumarin 33 and merely resulted in the removal of the benzyl ether (figure 11).

Figure 11: Attempted hydrogenation of coumarin 31 to synthesise dihydrocoumarin 33.

The use of protected ortho-iodophenols 34 and 35 in the Heck reaction of cis/trans mixture of

esters (Z)-27 and (E)-27 was also investigated in order to suppress the in situ formation of

coumarin 31. Unfortunately, the reaction with iodide 34 afforded a complex mixture of

products while the reaction with iodide 35 once again afforded the coumarin 31, this time in

33% overall yield (scheme 13).

19

Scheme 13: Heck reaction with protected phenols 34 and 35. i. Iodide 34 or 35 (1 eq.), Et3N (3.4 eq.),

TBAB (3.4 eq.), Pd(OAc)2 (0.1 eq.), CH3CN, reflux, 24 h.

1.3.4 CONJUGATE ADDITION REACTION

As a continuation of the work previously carried out within the group, we envisaged that a

possible alternative to the Heck reaction for the synthesis of ester 32 involved a Michael

addition reaction. The conjugate addition reaction of an aryl organometallic species to an

α,β-unsaturated ester (E)-27 would give ester 32, which could be reduced to the alcohol and

then eliminated to afford the desired allyl phenol 9 (figure 12).

Figure 12: Retrosynthetic approach to allyl phenol 9 via Michael addition reaction.

Conjugate addition reactions of organocopper reagents with α,β-unsaturated carbonyl

compounds has been studied extensively and is one of the most general methods for

carbon-carbon bond formation.16,17

In 1941, Kharasch and Tawney18

reported that the

conjugate addition reaction often proceeds with no regioselectivity, the reaction led to either

1,2- or 1,4-addition products depending on the structure of the substrate. It was also

reported that the conjugate addition of Grignard reagents would predominantly favour 1,4-

over 1,2-addition when using a catalytic amount of cuprous chloride.19

The reaction of

isophorone 38 with MeMgBr in the presence of 1 mol% CuCl resulted in 1,4-adduct 39 (82%)

and diene 41 (7%), formed from 1,2-addition product 40 due to its tendency to dehydrate

(scheme 14). The use of 1 mol% of copper powder in the reaction afforded mainly the 1,2-

addition product, in the form of diene 41 (78%) and 1,4-product 39 in only 8% yield.

20

However, without the addition of metallic catalyst, the reaction gave exclusively the 1,2-

addition products, alcohol 40 (67%) and diene 41 (24%).

Scheme 14: Conjugate addition reaction of ketone 38. i. MeMgBr (2.1 M in Et2O), CuCl (1 mol%),

Et2O, r.t., overnight, 39 (82%) and 41 (7%).

1.3.4.1 Aim of the project

Recently, we embarked upon a systematic study of the factors affecting the stereochemical

outcome observed in the addition of organometallic reagents to α,β-unsaturated

carbohydrate derivatives (figure 13).

EWG = Ester, aldehyde, ketone, nitro and sulfone.

Figure 13: Effect of organometallic reagents on α,β-unsaturated carbohydrate derivates.

The aim of the project was to investigate the conjugate addition reactions of a diverse range

nucleophilic reagents (i.e. cuprate, RMgX, R-Li, NR2 and ylides) with a number of α,β-

unsaturated carbohydrate derivatives (such as esters, aldehyde, ketones, nitro alkene and

sulfone). The effects of geometry of the olefin and the nature of the oxygen protecting group

on the stereochemical outcomes of the conjugate addition reactions were also studied.

We initiated this study by investigating the stereochemical course observed in the copper-

catalysed addition reactions of Grignard reagents to γ-alkoxy-α,β-unsaturated esters where

the oxygen substituent was constrained within a ring system. Although there are a myriad of

publications detailing the application of copper reagents in conjugate addition reactions, this

particular variant has, to the best of our knowledge, not been reported.

21

2 RESULTS AND DISCUSSION

2.1 OFF-TEMPLATE STUDIES

2.1.1 ORGANOCOPPER REACTION

In this initial investigation, the Michael acceptors, α,β-unsaturated esters (Z)-43 and (E)-43

were synthesised from commercially available (±)-2-tetrahydrofurfuryl alcohol 42 via in situ

oxidation-Wittig reaction using manganese dioxide as the oxidant.20

The reaction afforded a

cis/trans mixture in 1:1 ratio with an overall yield of 56% (scheme 15).

Scheme 15: Synthesis of α,β-unsaturated esters (Z)-43 and (E)-43 via in situ oxidation-Wittig reaction.

i. Activated MnO2 (10 eq.), Ph3PCHCOOEt (1.2 eq.), DCM, reflux, 24 h, 56% (1:1, Z:E).

We also considered an alternative route to the synthesis of these Michael acceptors, which

involved the use of a Swern oxidation21

in the preparation of the aldehyde 44 (figure 14).

Figure 14: Retrosynthesis of α,β-unsaturated esters (Z)-43 and (E)-43 via Swern oxidation.

We carried out the Swern oxidation with alcohol 42 using oxalyl chloride, dimethyl sulfoxide

and in the presence of triethylamine as a base. The reaction was carried out at -60 °C,

before being slowly brought to room temperature and stirred for over 2 h to ensure total

conversion to the aldehyde 44. The corresponding aldehyde was then proceeded through

the Wittig reaction to afford a 1:1 mixture of esters (Z)-43 and (E)-43, but in only 31% yield

(scheme 16).

Scheme 16: Synthesis of α,β-unsaturated esters (Z)-43 and (E)-43 via Swern oxidation. i. Oxalyl

chloride (2.0 M in DCM, 1.2 eq.), DMSO (2 eq.), Et3N (5 eq.), DCM, -60 °C to r.t., 2 h, 100% (crude

yield). ii. Ph3PCHCOOEt (1.1 eq.), DCM, r.t., 16 h, 31% (1:1, Z:E).

22

With a viable route to the substrates (Z)-43 and (E)-43 in hand (via in situ oxidation-Wittig

reaction), their reaction with organometallic reagents was investigated. Initial optimisation of

the reaction was achieved by varying the nature of the copper(I) precursor and the

substrate:Grignard concentrations. The standard conditions for the Michael reactions

employed THF as solvent and were carried out at -78 °C then slowly warmed to -40 °C over

a period of 3 h. The performance of CuCl, CuI, CuBr.DMS and (i-Pr)CuCl 2 were examined.

The highest yield obtained was 45%, where 5 eq. PhMgBr and 5 mol% CuCl were used.

Substituting CuCl with CuI resulted in a lower yield of the Michael adduct (33% isolated

yield). When the reactions were carried out using 2 eq. PhMgBr instead of 5 eq., we

observed a drop in yields (18% - 20%). No product was observed when 5 mol% (i-Pr)CuCl 2

and 1 eq. PhMgBr were used in the reaction (table 1).

Entry PhMgBr (x eq.) Cu(I) species Cu(I) (x eq.) Yield, %

1 5 CuCl 5 mol% 45

2 5 CuI 5 mol% 33

3 2 CuBr.DMS 10 mol% 20

4 2 CuBr.DMS 1 18

5 2 CuCl 1 18

6 1 (i-Pr)CuCl 5 mol% -

i. Cu(I), PhMgBr (1.0 M in THF), THF, -78 °C to -40 °C, 3 h.

Table 1: Michael reaction of ester (E)-43.

Interestingly, we managed to isolate compound 46 (Z-configuration) in 4% yield as one of the

products in the reaction with 10 mol% CuBr.DMS and 2 eq. PhMgBr (entry 3, table 1).

Scheme 17: Cuprate reaction of ester (E)-43. i. CuBr.DMS (10 mol%), PhMgBr (1.0 M in THF, 2 eq.),

THF, -78 °C to -40 °C, 3 h, 46 (4%) and 45 (20%).

During the optimisation of the Michael reaction, we found this reaction also gave two by-

products, phenol 48 and biphenyl 49 with yields ranging from 14% to 18%. Blank reactions

were carried out to determine the source of these by-products and phenol was found to be

23

present in phenylmagnesium bromide reagent which was used directly as supplied from

Sigma Aldrich. Since the Rf of both phenol and the resulting product were very similar,

separating them by flash column chromatography was difficult. On the other hand, biphenyl

was thought to form during the course of the reaction, via homo-coupling of the phenyl MgBr.

Compound 47 was isolated in 1% yield as another by-product of the reaction (scheme 18).

Scheme 18: Blank reaction. i. THF, -78 °C to -40 °C, 3 h, 47 (1%), 48 and 49 (14 -18%).

2.1.2 RHODIUM(I)-CATALYSED CONJUGATE ADDITION REACTIONS

Among the different types of conjugate addition reactions, the Hayashi-Miyaura reaction22

has become increasingly popular.23,24

This rhodium-catalysed conjugate addition of

organoboronic acids to γ-alkoxy-α,β-unsaturated esters can be carried out in aqueous

solvents and is known to be environmentally-friendly due to the low toxicity of the boron

reagents and their side-products. The Hayashi-Miyaura reaction is tolerant of a wide range of

functional groups and can be used in the presence of unprotected hydroxyl groups.25,26

In our study, [RhCl(1,5-cod)]2 50 and [Rh(OH)(1,5-cod)]2 50a were used as catalyst

precursors in the asymmetric conjugate addition of organoboronic acids to α,β-unsaturated

carbonyl compounds. It was reported that [Rh(OH)(1,5-cod)]2 50a exhibited excellent catalyst

activities compared to those of the corresponding RhCl or Rh(acac) complexes.27

Reaction

between rhodium trichloride and 1,5-cyclooctadiene (cod) in the presence of sodium

carbonate gave chloro–rhodium(I) complex 50 (65%) as yellow-orange solid. Hydroxo-

rhodium(I) complex 50a can be synthesised from the rhodium(I) complex 50 by reaction with

KOH in benzene (scheme 19).

Scheme 19: Synthesis of dimer rhodium(I) complex 50a. i. Na2CO3 (1 eq.), cod (3 eq.), EtOH:H2O

(5:1), reflux, 18 h, 65%. ii. KOH (0.2 M), TEBAC (34 mol%), benzene, r.t., 15 min.

24

Itooka et al.27

reported that the presence of a base (i.e. Et3N) is vital in generating an active

species, Rh(OH) for transmetallation with ArB(OH)2 when [RhCl(1,5-cod)]2 50 is used as the

catalyst precursor. Catalyst [Rh(OH)(1,5-cod)]2 50a or the [Rh]-OH species A generated in

situ from [RhCl(1,5-cod)]2 50 and Et3N was reported to be the most efficient system in the

asymmetric conjugate addition of organoboronic acids to α,β-unsaturated carbonyl

compounds. The Rh-catalysed conjugate addition reaction is initiated through

transmetallation of an aryl group from boron to [Rh]-OH species A to form the [Rh]-Ar

species B. Then, insertion of α,β-unsaturated carbonyl compounds into [Rh]-Ar bond of

species B generates the thermodynamically stable oxa-π-allylrhodium (rhodium enolate)

species C. Hydrolysis of the rhodium enolate species C regenerates [Rh]-OH A and liberates

the desired conjugate addition product (figure 15).28

Figure 15: Catalytic cycle of rhodium-catalysed conjugate addition of organoboronic acids to α,β-

unsaturated carbonyl compounds.

Initially, we investigated the Hayashi-Miyaura reaction of trans-ester (E)-43 with

phenylboronic acid and in the presence of a catalytic amount of [Rh(OH)(1,5-cod)]2 50a

which was found to afford the 1,4-adduct esters 45 and 45a in an overall yield of 81% as an

4:1 mixture of diastereomers. The reaction was carried out in 1,4-dioxane:H2O (10:1) at 50

°C for 18 h (scheme 20).

Scheme 20: Hayashi-Miyaura reaction of ester (E)-43. i. PhB(OH)2 (2 eq.), [Rh(OH)(1,5-cod)]2 50a (5

mol%), Et3N (1 eq.), 1,4-dioxane:H2O (10:1), 50 °C, 18 h, 81% (d.r. 4:1, 45:45a).

25

The assignment of relative stereochemistry at the newly generated chiral centre was

determined by comparing the 13

C NMR spectral data of the alcohols 51/51a (figure 16) to

that provided by Kiyoshi Tomioka et al.29

(table 2). DIBAL-H reduction of mixture 45 and 45a

in THF gave the known alcohols 51 and 51a in 85% yield (d.r. 4:1) (scheme 21).

Scheme 21: Reduction of esters 45 and 45a. i. DIBAL-H (1.0 M in hexane, 3.5 eq.), THF, -78 ºC to 0

°C, 3 h, 85% (d.r. 4:1, 51:51a).

As reported by Kiyoshi Tomioka et al.,29

the relative configuration of alcohol 51a was

undoubtedly determined by its conversion into known lactone 5430

with established

stereochemistry (scheme 22). Alcohol 51a underwent sequential Swern and Pinnick

oxidations to give the corresponding carboxylic acid, which was then converted into acyl

chloride 52 upon treatment with oxalyl chloride. Acyl chloride 52 was treated with aluminium

chloride at room temperature to afford chloro lactone 53 via acylative tetrahydrofuran ring

opening31

(40% over four steps), which was then dehalogenated to give the known lactone

54 (49% over two steps) to determine the relative configuration of alcohol 51a.

Scheme 22: Conversion of alcohol 51a into lactone 54. i. Oxalyl chloride (0.4 M in DCM, 1.8 eq.),

DMSO (4.2 eq.), Et3N (5.1 eq.), DCM, -72 °C to r.t., 4.5 h, 100% (crude yield). ii. 2-methyl-2- butene

(2.0 M in THF, 18.2 eq.), NaH2PO4/H2O (2.7 M, 9.1 eq.), NaClO2/H2O (2.7 M, 9.1 eq.), 0 °C to r.t., 1 h,

100% (crude yield). iii. Oxalyl chloride (9.8 eq.), r.t., 30 min, 100% (crude yield). iv. AlCl3 (1.6 eq.),

benzene, 0 °C to r.t., 3 h, 40%. v. NaI (5 eq.), acetone, 50 °C, 36 h. vi. Bu3SnH (7.3 eq.), Et3B (1.0 M in

hexane, 0.2 eq.), benzene, r.t., 1 h. 49%.

According to 13

C NMR spectral data presented by Kiyoshi Tomioka et al.,29

there are distinct

differences in chemical shifts observed between the two isomeric compounds 51 and 51a.

For instance, the peaks of C-4, C-5 and C-6 of alcohol 51 appear at δ 83.4, 49.6 and 37.9

26

ppm, respectively, whilst the peaks of C-4, C-5 and C-6 of isomer 51a appear at δ 82.7, 47.1

and 35.3 ppm, respectively (table 2).

13C NMR (125 MHz, CDCl3) δ 143.2 (C, Ar-

C), 128.6 (CH, Ar-C), 128.0 (CH, Ar-C), 126.6 (CH, Ar-C), 83.4 (CH, C-4), 68.1 (CH2, C-1), 61.5 (CH2, C-7), 49.6 (CH, C-5), 37.9 (CH2, C-6), 30.7 (CH2, C-3), 25.4 (CH2, C-2) ppm.

13C NMR (125 MHz, CDCl3) δ 141.9 (C, Ar-

C), 128.7 (CH, Ar-C), 128.3 (CH, Ar-C), 126.6 (CH, Ar-C), 82.7 (CH, C-4), 68.1 (CH2, C-1), 60.9 (CH2, C-7), 47.1 (CH, C-5), 35.3 (CH2, C-6), 29.0 (CH2, C-3), 25.7 (CH2, C-2) ppm.

Table 2: 13

C NMR spectral data of alcohols 51 and 51a presented by Kiyoshi Tomioka et al.

The relative configuration of the major product from DIBAL-H reduction of diastereoisomeric

mixture 45/45a (d.r. 4:1) was found to be consistent with alcohol 51 based on literature 13

C

NMR data. The chemical shifts of carbons C-4, C-5 and C-6, which appear at δ 83.4, 49.6

and 37.9 ppm, respectively (figure 16).

27

CH, Ar-C

2011-08-15-paq-8_013001r

144 136 128 120 112 104 96 88 80 72 64 56 48 40 32 24

Figure 16: 13

C NMR spectrum for alcohols 51 and 51a measured in CDCl3 at 125 MHz.

CH2, C-2

CH2, C-3

CH2, C-6 CH, C-5

CH2, C-7

CH2, C-1

CH, C-4

C, Ar-C

28

Having been able to correlate the stereochemical outcome of the conjugate addition

reactions for the simple unsaturated ester (E)-43 with Grignard reagents, we proceeded with

our investigation on a more complicated carbohydrate system to study the effects of different

electron-withdrawing groups, geometry of the olefin and also the nature of organometallic

reagents on the stereochemical outcome of the conjugate addition reactions (figure 17).

EWG = Ester, aldehyde, ketone, nitro and sulfone.

Figure 17: Effect of organometallic reagents on unsaturated carbohydrate derivates.

2.1.3 α,β-UNSATURATED ESTERS

We focused our study on optimising reaction conditions of Michael reactions on

hexofuranosyl carbohydrates. Aldehyde 19 was subjected to Wittig reaction with commercial

Ph3PCHCOOMe to afford α,β-unsaturated esters (Z)-27 and (E)-27 in 85% overall yield

(1:1.3, Z:E). The analogous α,β-unsaturated esters (Z)-11 and (E)-11 were also synthesised

using Ph3PCHCOOEt in 72% overall yield (1:2, Z:E) (scheme 23).

Scheme 23: Synthesis of α,β-unsaturated esters. i. Ph3PCHCOOMe (1.1 eq.), DCM, r.t., 16 h, 85%

(1:1.3, Z:E). ii. Ph3PCHCOOEt (1.0 eq.), DCM, r.t., 16 h, 72% (1:2, Z:E).

In the first instance, Michael reactions of esters (Z)-27 and (E)-27 were studied

independently using 2 eq. PhMgBr and 1 eq. CuBr.DMS at -78 °C. Unfortunately, both

reactions afforded no product, instead only the starting materials, phenol and biphenyl were

recovered. Nevertheless, when 1 eq. CuI was used, in the reaction with cis-ester (Z)-27 in

THF at -78 °C, we observed an inseparable mixture of the starting material and the 1,4-

adduct ester 55. Unfortunately, no product was observed in the reaction with trans-ester (E)-

27 when CuI was used (table 3).

29

Entry Isomer PhMgBr (x eq.) Cu(I) Cu(I) (x eq.) Yield, %

1 (E)-27 2 CuBr.DMS 1 -

2 (Z)-27 2 CuBr.DMS 1 -

3 (E)-27 2 CuI 1 -

4 (Z)-27 2 CuI 1 (Z)-27 and 55

i. Cu(I) (1 eq.), PhMgBr (1.0 M in THF, 2 eq.), THF, -78 °C, 2 days.

Table 3: Michael reactions of esters (Z)-27 and (E)-27.

We increased the amount of PhMgBr used in the reaction from 2 eq. to 5 eq. and in the

presence of 1 eq. CuI. The reaction was carried out at -78 °C and stirred for over 3 h in THF

to give a mixture of the 1,4-adduct ester 55 and phenyl ketone 56 (scheme 24). The

assignments of relative stereochemistry of 1,4-adduct 55 and ketone 56 are discussed later

in the chapter.

Scheme 24: Cuprate reaction of ester (E)-27. i. CuI (1 eq.), PhMgBr (1.0 M in THF, 5 eq.), THF, -78

°C, 3 h.

After several attempts, we found that the use of TMSCl as an additive was crucial in the

organocopper reactions in order to afford the desired product in high yield. It was also

necessary to use an excess of TMSCl in order to force the reaction to completion. Initially,

we attempted cuprate reactions using 1 eq. CuBr.DMS, 5 eq. PhMgBr and 2 eq. TMSCl, but

the reaction failed to go to completion, despite allowing a longer reaction time (> 24 h). As a

result, we carried out the Michael reaction using 1 eq. CuI, 5 eq. PhMgBr and 15 eq. TMSCl

to give 1,4-adduct ester 55 in good yield (reaction with trans-ester (E)-27 gave 69% yield,

whilst reaction with cis-ester (Z)-27 gave 84% yield) (table 4).

30

Entry Isomer PhMgBr (x eq.) Cu(I) Cu(I) (x eq.) TMSCl (x eq.) Yield, %

1 (E)-27 5 CuI 1 15 69

2 (Z)-27 5 CuI 1 15 84

i. CuI (1 eq.), PhMgBr (1.0 M in THF, 5 eq.), TMSCl (15 eq.), THF, -78 °C, 3 h

Table 4: Michael reactions of esters (Z)-27 and (E)-27 in the presence of TMSCl.

Having established the optimum conditions for the reaction of PhMgBr with α,β-unsaturated

esters (Z)-27 and (E)-27, these conditions (CuI (1 eq.), RMgBr (5 eq.), TMSCl (15 eq.), THF,

-78 °C to room temperature) were used for the rest of the study. In addition to aryl cuprates,

we also examined the conjugate addition reactions with vinyl and alkyl-derived cuprates. We

observed that these reactions proceeded with high levels of diastereoselectivity (d.r. > 13:1

in the case of aryl cuprates and d.r. 6:1 in the case of vinyl cuprates). However, simple alkyl

cuprates proved to be capricious and often afforded complex mixtures of products. In the

case of EtMgBr, we observed a 1:1 diastereomeric mixture of the products 60 and 60a in an

overall yield of 42%. The ratios of isomers were determined on the basis of 1H NMR spectra

where H-1 and H-3 have different chemical shifts in the major and minor isomers (table 5).

Entry R Product Yield, % d.r.†

1 Phenyl-

55 + 55a 84 55:55a, 1:0

2 4-Methoxyphenyl 57 + 57a 63 57:57a, 13:1

3 Isopropenyl- 58 + 58a 65 58:58a, 1:0

4 Vinyl- 59 + 59a 80 59:59a, 6:1

5 Ethyl- 60 + 60a 42 60:60a, 1:1

6 Ethyl- 60 + 60a 78a

60:60a, 6:1

7 Methyl- - - -

i. CuI (1 eq.), RMgBr (in THF solution) (5 eq.), TMSCl (15 eq.), THF, -78 °C to r.t., 3 h.

aYield based on reduction of vinyl product.

†Determined from

1H NMR of crude reaction mixtures.

Table 5: Michael reactions of (E)-27 with aryl, vinyl and alkyl-derived cuprates.

31

Guobi Chai et al.32

reported the use of ferric chloride hexahydrate as an efficient catalyst for

highly regio- and stereoselective conjugate addition reaction of 2,3-allenoates with various

Grignard reagents for the synthesis of β,γ-unsaturated alkenoates (table 6).

Entry Substrate Time, h Product Yield, %

1 61 2.5 63 64

2 62 3 64 60

i. 2,3-allenoates (0.4 mmol), PhMgCl (in THF solution) (3 eq.), FeCl3·6H2O (2 mol%), toluene, -78 °C.

Table 6: Conjugate addition reaction of 2,3-allenoates in the presence of FeCl3·6H2O.

We attempted the reaction with α,β-unsaturated ester (E)-27 by using 2 mol% FeCl3·7H2O

and a 1.0 M solution of PhMgBr in THF to observe FeCl3·7H2O on the addition reaction to

α,β-unsaturated ester (E)-27. Unfortunately, the reaction failed to give any product after

stirring for 4 h at -78 °C (scheme 25).

Scheme 25: Conjugate addition reaction using FeCl3·7H2O. i. PhMgBr (1.0 M in THF, 5 eq.),

FeCl3·7H2O (2 mol%), THF, -78 °C.

Thereafter, we examined the Hayashi-Miyaura reactions of α,β-unsaturated ester (E)-27 with

several arylboronic acids by using catalytic amounts of [RhCl(1,5-cod)]2 50 in 1,4-

dioxane:H2O (10:1) and in the presence of Et3N. The reactions proceeded with high levels of

diastereoselectivity (d.r. > 9:1 for compounds 55, 57, 66 and 67 and d.r. > 4:1 for compounds

68, 69 and 70). The reaction of ester (E)-27 with 4-vinylphenylboronic acid was carried out at

room temperature and took about 72 h for total consumption of the starting material to give

adducts 65 and 65a in only 2% yield (d.r. 2:1). Unfortunately, no reaction was observed with

3-thienyboronic acid, and starting materials were recovered. We also carried out the

Hayashi-Miyaura reaction of ester (E)-27 with PhB(OH)2 in the presence of [Rh(OH)(1,5-

cod)]2 50a which afforded the adduct 55 in 71% yield (d.r. 17:1). Some of the reactions were

32

quite sluggish and required heating up to 50 °C to ensure 100% consumption of starting

material. In the case of reaction with 4-acetylphenylboronic acid, 4 eq. of boronic acid and 2

eq. Et3N were added to consume all the substrate (table 7).

Entry R Product Time, h T, °C Yield, % d.r.†

1 Phenyl- 55 + 55a 48 r.t. 90a

55:55a, 12:1

2 4-Vinylphenyl- 65 + 65a 72 r.t. 2b

65:65a, 2:1

3 4-Methoxyphenyl- 57 + 57a 12 50 47c

57:57a, 13:1

4 1-Naphthyl- 66 + 66a 5 50 97 66:66a, 9:1

5 2-Naphthyl- 67 + 67a 4 r.t. 76 67:67a, 14:1

6

4-Acetylphenyl- 68 + 68a 5 r.t. 57d

68:68a, 7:1

7 4-Fluorophenyl- 69 + 69a 5 r.t. 71 69:69a, 8:1

8 3-Nitrophenyl- 70 + 70a 48 50 29 70:70a, 4:1

9 3-Thienyl- - 24 r.t. - -

10 3-Thienyl- - 7 50 - -

i. [RhCl(1,5-cod)]2 50 (5 mol%), RB(OH)2 (2 eq.), Et3N (1 eq.), 1,4-dioxane:H2O (10:1).

aReaction with [Rh(OH)(1,5-cod)]2 50a afforded 55 in 71% (d.r. 17:1, 55:55a).

bNon-optimised condition.

cStarting material recovered.

d4 eq. boronic acid and 2 eq. Et3N used.

†Determined by

1H NMR of crude reaction mixtures.

Table 7: Hayashi-Miyaura reaction of ester (E)-27 with various boronic acids.

The relative stereochemistry of the newly generated stereocentre at C-5 was deduced by

nOe studies on the derived lactones 71 – 74 (scheme 26). The lactones 71, 72, 73 and 74

were readily obtained, in two steps from the adducts 66, 55, 58 and 60 respectively; via

debenzylation (H-Cube®)33

followed by lactonisation under basic conditions.

33

Scheme 26: Synthesis of lactones 71, 72, 73 and 73. i. 0.05 M in MeOH, 10% Pd/C, 1 bar, 50 °C, 1

mL/min, full H2. ii. K2CO3 (1 eq.), DCM, r.t., 30 min, 71 (8%), 72 (58%), 73 (62%), 74 (34%).

Lactones 71 – 74 exhibited characteristic nOe enhancements for H-3 – H-4, H-4 – H-5 and

H-5 – H-6equatorial

, as shown in table 8.

Entry Lactone 1H NMR data of relevant protons, J (Hz)

H-4 H-5 H-6 (axial) H-6 (equatorial)

1 71 4.81 ppm

(m)

4.26 ppm (dd, J

= 14 and 5)

3.14 ppm (dd, J =

18 and 14)

2.90 ppm (dd, J =

18 and 5)

2 72 4.63 ppm

(br. s.)

3.43 – 3.37 ppm

(m)

3.02 ppm (dd, J =

17 and 14)

2.75 ppm (dd, J =

18 and 5)

3 73 4.51 ppm

(br. s.)

1.79 – 1.68 ppm

(m)

2.62 ppm (dd, J =

18 and 13)

2.41 ppm (dd, J =

18 and 5)

4 74 4.42 ppm

(m)

2.07 – 1.96 ppm

(m)

2.54 ppm (dd, J =

18 and 13)

2.42 ppm (dd, J =

18 and 5)

Table 8: 1H NMR data of relevant protons for lactones 71, 72, 73 and 74.

The assignment of the relative stereochemistry at the C-5 in the adduct 55 was also

confirmed by a single crystal X-ray crystallographic analysis of lactone 72 (figure 18). This

analysis revealed that the lactone adopted a chair-like conformation which correlated well

with the coupling constant and nOe NMR data for this compound in solution.

34

Figure 18: ORTEP projection of lactone 72.

The substituted lactone 72 could be readily prepared from the D-glucose derivative 16 in a

three step sequence, involving a sequential hydrolysis-oxidation-Wittig olefination protocol,

as reported by Elsie Ramirez et al (scheme 27).34

However, contrary to the literature report,

we observed that hemiacetal 7635

is produced in good yield (60%) (scheme 28), rather than

the β-hydroxyaldehyde 75.

Scheme 27: Ramirez synthesis of β-hydroxyaldehyde 75 from alcohol 16. i. H5IO6 (0.4 eq.), AcOEt, 0

°C to r.t., 2 h.

Stereochemical assignments of compound 76 were based initially on the magnitude of the

3JH3-H4 coupling constant (J = 2 Hz) and eventually corroborated by X-ray crystal analysis

(figure 19). Acetylation of alcohol 76 with acetic anhydride and pyridine gave acetate 77,

whose structure was assigned from the spectral data (scheme 28).

Scheme 28: Synthesis of hemiacetal 76 and acetate 77. i. H5IO6 (1.3 eq.), AcOEt, r.t., 5 h, 60%. ii.

Pyridine (1 eq.), Ac2O (1 eq.), DCM, 0 °C to r.t., 24 h, 79%.

35

Figure 19: ORTEP projection of hemiacetal 76.

Reaction of the hemiacetal 76 with the Wittig reagent afforded the α,β-unsaturated esters

(Z)-79 and (E)-79 which could only be partially separated by column chromatography. The

reaction afforded a mixture of cis- and trans-isomers (1:3, Z:E) in 8% yield, and the α,β-

unsaturated lactone 78 in 45% yield, which presumably arose from cyclisation of the Z-

isomer (scheme 29).34,36

Scheme 29: Synthesis of lactone 78 and esters (Z)-79 and (E)-79. i. Ph3PCHCOOMe (2.5 eq.), DCM,

r.t., 20 h, 45% (78), 8% ((Z/E)-79) (1:3, Z:E).

The rhodium-catalysed conjugate addition reaction of α,β-lactone 78 with PhB(OH)2 afforded

the phenyl adduct lactone 80 in 71% yield as a single diastereoisomer (scheme 30). Based

on 1H and

13C NMR data as well as nOe studies, we concluded that this reaction had

proceeded with the opposite facial selectivity to that resulting in lactone 72 from the α,β-

unsaturated ester (E)-27. In particular the 1H NMR spectrum of lactone 80 exhibits a

resonance attributed to H-3 at δ 4.62 ppm (d, J = 3 Hz) and multiplet for H-5 at δ 3.59 – 3.54

ppm. This is to be compared with resonances for H-3 at δ 4.87 ppm (d, J = 3 Hz) and H-5 at

δ 3.43 – 3.37 ppm which are observed for lactone 72.

Scheme 30: Hayashi-Miyaura reaction of lactone 78. i. [RhCl(1,5-cod)]2 50 (5 mol%), PhB(OH)2 (2

eq.), Et3N (1 eq.), 1,4-dioxane:H2O (10:1), r.t., 6 h, 71%.

36

2.1.3.1 Effect of the nature of the C-3 protecting group on the stereochemical

outcome of the conjugate addition reactions

We envisaged the C-3 protecting group as one of the factors that may affect the

stereochemical outcome of the conjugate addition reactions. We studied the steric effect of

O-tert-butylsilyl and the electronic effect of O-picolyl protecting groups on the rate and

stereochemical outcome of the conjugate addition reactions.

Firstly, we investigated the organocopper conjugate additions to Michael acceptors (Z)-84

and (E)-84. Commercially available D-glucose diacetonide 16 was reacted with TBSCl and

imidazole in DMF to give the TBS-protected diacetonide 81 in only 32% yield. Reaction of

TBS-ether 81 with 75% aqueous acetic acid at room temperature for 24 h afforded diol 82 in

41% yield, which was submitted to oxidative cleavage with aqueous sodium periodate to give

94% yield of crude aldehyde 83. Treatment with Ph3PCHCOOMe in DCM gave the α,β-

unsaturated esters (Z)-84 and (E)-84 in an overall yield of 52% (1:1, Z:E) (scheme 31).

Scheme 31: Synthesis of esters (Z)-84 and (E)-84. i. TBSCl (1 eq.), imidazole (2 eq.), DMF, r.t., 18 h,

32%. ii. 75% aqueous acetic acid, r.t., 24 h, 41%. iii. NaIO4 (1.2 eq.), THF, r.t., 5 h, 94% (crude yield).

iv. Ph3PCHCOOMe (1 eq.), DCM, r.t., 16 h, 52% (1:1, Z:E).

We observed that the rate of 1,4-additions to esters (Z)-84 and (E)-84 were much slower to

those of benzyl-protected esters (Z)-27 and (E)-27. The cuprate reaction of mixture (Z)-84

and (E)-84 with PhMgBr took about 17 h for total consumption of the starting material and

resulted in poor 29% yield of the 1,4-adduct 85. Meanwhile, the rhodium-catalysed conjugate

addition reaction of trans-ester (E)-84 with PhB(OH)2 took 4 days at room temperature, but

37

gave a higher yield (62%) of product 85. Nevertheless, both of the reactions proceeded with

high levels of diastereoselectivity (d.r. > 12:1) (scheme 32).

Scheme 32: Conjugate addition reactions of esters (Z)-84 and (E)-84. i. CuI (1 eq.), PhMgBr (1.0 M in

THF, 5 eq.), TMSCl (15 eq.), THF, -78 °C to r.t., 17 h, 29%. ii. [RhCl(1,5-cod)]2 50 (5 mol%), PhB(OH)2

(2 eq.), Et3N (1 eq.), 1,4-dioxane:H2O (10:1), r.t., 4 d, 62% (d.r. 12:1).

The influence of an O-picolyl group at C-3 was examined next. Esters (Z)-89 and (E)-89

were conveniently prepared in four steps from 1,2:5,6-di-O-isopropylidene-α-D-

glucofuranose 16. Phase-transfer-catalysed (PTC)37

alkylation of alcohol 16 with 2-picolyl

chloride hydrochloride in the presence of tetra-n-butylammonium hydrogensulfate afforded

ether 86 in excellent yield (93%). Selective deprotection of the 5,6-acetonide moiety, with

aqueous acetic acid, followed by oxidative cleavage of diol 87 with sodium periodate

afforded aldehyde 88 in good overall yield. Homologation of the crude aldehyde 88 afforded

esters (Z)-89 and (E)-89 in 76% yield as a 1:2 mixture (Z:E) of geometric isomers (scheme

33).

Scheme 33: Synthesis of esters (Z)-89 and (E)-89. i. NBu4HSO4 (0.1 eq.), 2-picolyl chloride

hydrochloride (1.5 eq.), tamyl-OH, NaOH, H2O/toluene, r.t., overnight, 93%. ii. Acetic acid, water, 40

°C, 24 h, 87%. iii. NaIO4 (1.2 eq.), 1,4-dioxane:H2O, r.t.,16 h, 85% (crude yield). iv. Ph

3PCHCOOMe

(1.1 eq.), DCM, r.t., 16 h, 76% (1:2, Z:E).

38

Whereas the copper-promoted Michael reaction of phenyl Grignard with the Z/E isomeric

mixture of esters (Z)-89 and (E)-89 (1:2, Z:E) afforded phenyl adduct ester 90 in 84% yield

as a single diastereoisomer, the Hayashi-Miyaura reaction of the same substrate mixture,

using [RhCl(1,5-cod)]2 50 and PhB(OH)2, afforded the adduct 90 (d.r. 9:1) in low yield (33%)

after 4 days at 50 °C (scheme 34). The rate of cuprate reaction of picolyl-protected esters

(Z)-89 and (E)-89 was the similar to those of benzyl-protected esters (Z)-27 and (E)-27,

however the Hayashi-Miyaura reaction was much slower.

Scheme 34: Conjugate addition reactions of esters (Z)-89 and (E)-89. i. CuI (1 eq.), PhMgBr (1.0 M in

THF, 5 eq.), TMSCl (15 eq.), THF, -78 °C to r.t., 3 h, 84%. ii. [RhCl(1,5-cod)]2 50 (5 mol%), PhB(OH)2

(2 eq.), Et3N (1 eq.), 1,4-dioxane:H2O (10:1), 50 °C, 4 d, 33% (d.r. 9:1).

At this point we had yet to determine the stereochemistry at C-5 in adducts 85 and 90. We

proposed that this stereochemical correlation could be achieved using a hydrogenolysis-

lactonisation sequence, which would ultimately result in the isolation of the known lactones

72 and 80. Comparison of the spectral data for lactones 72 and 80 with authentic samples

would then enable the stereochemical course of the initial conjugate addition to be made

(figure 20).

Figure 20: An approach to determine the relative C-5 stereochemistry in esters 85 and 90.

39

Another factor that we considered may affect the stereochemical outcome of the conjugate

addition reactions was the stereocentre at the C-3 position of α,β-unsaturated ester (E)-95.

The initial synthetic step involved pyridinium dichromate oxidation of commercially available

1,2:5,6-di-O-isopropylidene-α-D-glucofuranose 16, followed by reduction with sodium

borohydride in EtOH:H2O (24:19) to afford allofuranose 91 in 90% yield. Protection of alcohol

91 as its tert-butyldimethylsilyl ether (TBSCl/imidazole, 97%), followed by selective

deprotection of the 5,6-acetonide 92 and periodate cleavage of diol 93 (NaIO4, ca. 100%)

afforded the crude aldehyde 94 which was sufficiently pure to be used in the next step. Wittig

olefination of aldehyde 94 afforded enoate (E)-95 as a single geometric isomer (3JH5-H6 = 16

Hz) in good yield (86%) (scheme 35).

Scheme 35: Synthesis of ester (E)-95. i (a) PDC (0.75 eq.), Ac2O (2.6 eq.), DCM, reflux, 2 h. i (b)

NaBH4 (1.3 eq.), EtOH:H2O (24:19), r.t., 3 h, 90%. ii. TBSCl (1 eq.), imidazole (2 eq.), DMF, r.t., 18 h,

97%. iii. 75% aqueous acetic acid, r.t., 24 h, 49%. iv. NaIO4 (1.2 eq.), 1,4-dioxane:H2O, r.t., 6 h, 100%

(crude yield). v. Ph3PCHCOOMe (1 eq.), DCM, r.t., 16 h, 86%.

The rate of the conjugate addition reactions to the TBS-protected ester (E)-95 was much

slower than that of ester 27. Under our optimised organocopper-catalysed reaction

conditions, the Michael reaction on the benzyl protected esters (Z)-27 and (E)-27 took about

3 h to go to completion compared to 20 h for the TBS-protected ester (E)-95. The copper-

catalysed reaction afforded the 1,4-adduct 96 as a single diastereoisomer in 97% yield, while

the Hayashi-Miyaura reaction afforded the same product in 55%, also as a single

diastereoisomer (scheme 36).

40

Scheme 36: Conjugate addition reactions of ester (E)-95. i. CuI (1 eq.), PhMgBr (1.0 M solution in

THF) (5 eq.), TMSCl (15 eq.), THF, -78 °C to r.t., 20 h, 97%. ii. [RhCl(1,5-cod)]2 50 (5 mol%), PhB(OH)2

(2 eq.), Et3N (1 eq.), 1,4-dioxane:H2O (10:1), r.t., 48 h, 55%.

TBS deprotection of ester 96 with TBAF afforded the alcohol 97 in 79% yield (scheme 37).

Fortunately, alcohol 97 was a crystalline solid, which was amenable to X-ray analysis, and

enabled a direct determination of the relative stereochemistry at C-5 in compound 96 (figure

21). This analysis enabled us to conclude that the conjugate addition to (E)-95 had occurred

with the same facial selectivity as observed with esters (Z)-27 and (E)-27, thereby indicating

that neither the nature of the oxygen protecting group at C-3 nor the stereochemistry at C-3

had any effect on the stereochemical outcome of the conjugate addition reaction at the C-5 –

C-6 double bond.

Scheme 37: Deprotection of TBS-group. i. TBAF (1.0 M solution in THF) (1.5 eq.), 0 °C to r.t., 2 h,

79%.

Figure 21: ORTEP projection of alcohol 97.

41

2.1.4 ORGANOLITHIUM REACTION

In 1977, Minoru Isobe et al.38

introduced lithium triorganozincates (R3ZnLi) as a new reagent

to undergo conjugate addition reactions to α,β-unsaturated carbonyl compounds. This

reagent can be prepared from ZnCl2 or ZnCl2·TMEDA complex in THF (scheme 38).

Scheme 38: Preparation of lithium triorganozincates from zinc chloride.

According to Kjonaas et al.39

the use of ZnCl2·TMEDA, despite being only slightly soluble in

ether, is more convenient since it is non-hygroscopic. As part of our investigation, we also

examined the reaction with ZnCl2·TMEDA and PhLi, with and without the addition of TMSCl,

at -78 °C. In the absence of TMSCl, we observed the formation of ester 55 and phenyl

ketone 56 that we previously saw during the optimisation of the organocuprate Michael

reaction (scheme 24). However, in the presence of TMSCl, under the same conditions, the

reaction failed to give any product (scheme 39).

Scheme 39: Reaction of ester (E)-27 with organozincate. i. ZnCl2·TMEDA (1.3 eq.), PhLi (2.0 M in n-

dibutyl ether) (3 eq.), THF, 0 °C to -78 °C, 4 h, 21% (56) (1:7, 55:56).

Not surprisingly, reaction of α,β-unsaturated ester (E)-27 with 2 eq. PhLi at -78 °C for 4 h

resulted in the isolation of the 1,2-addition product 98 in 36% yield (d.r. 12:1) (scheme 40).

Scheme 40: Reaction of ester (E)-27 with organolithium. i. PhLi (2.0 M in n-dibutyl ether, 2 eq.), THF, -

78 °C, 4 h, 36% (d.r. 12:1).

42

As we had determined successfully the C-5 stereochemistry of the phenyl adduct 55

(scheme 26), it was reacted with 1 eq. PhLi at -78 °C for 4 h to give the tertiary alcohol 99 in

13% yield, although 27% starting material was also recovered (scheme 41).

Scheme 41: Reaction of ester 55 with organolithium. i. PhLi (2.0 M in n-dibutyl ether, 1 eq.), THF, -78

°C, 4 h, 13% (99).

To establish the relative stereochemistry of phenyl ketone 56, a sample of the mixture of

products 55 and 56 that had been isolated previously was subjected to a reaction with 1 eq.

PhLi in THF at -78 °C to give the tertiary alcohol 99, but in only 15% yield as a single

diastereoisomer (scheme 42). The identity of the compound was confirmed by comparing the

1H and

13C NMR data to those obtained from the reaction above (scheme 41).

Scheme 42: Reaction of mixture 55 and 56 with organolithium. i. PhLi (2.0 M in n-dibutyl ether, 1 eq.),

THF, -78 °C, 4 h, 15%.

Gilman et al.40,41

reported the formation of organocuprates (R2CuLi) upon treatment of Cu(I)

species with organolithium compounds (R-Li) and its application in conjugate addition

reactions.17

Ph2CuLi was prepared in situ from 2 eq. PhLi and CuI in THF at -78 °C (scheme

43).

Scheme 43: Preparation of aryl lithiated cuprate.

Conjugate addition of Ph2CuLi to α,β-unsaturated ester (E)-11 was carried out in the

presence of TMSCl. Unfortunately, the reaction gave no product (scheme 44).

43

Scheme 44: Reaction of ester (E)-11 with aryl lithiated cuprate. i. PhLi (2.0 M in n-dibutyl ether, 5 eq.),

CuI (1 eq.), TMSCl (15 eq.), THF, -78 °C to r.t., 3 h.

At this stage we wondered whether ester (E)-27 would also be susceptible to Michael

reactions with furyllithium reagents.42

Reaction of α,β-unsaturated ester (E)-27 with 2-

furyllithium (formed in situ by metalation of furan with n-butyllithium) afforded alcohol 101 as

the major product in 15% yield together with small amounts of ketone 102 (2.5% yield). At

that point we had yet to determine the extent of stereochemical induction in adduct 102, but

presumed it to be the same as that of adduct 56 (scheme 45).

Scheme 45: Reaction of ester (E)-27 with organolithium via halogen-lithium exchange. i. Furan (2 eq.),

n-BuLi (1.6 M in hexane, 2 eq.), THF, -78 °C, 1.5 h, 15% (101) and 2.5% (102).

2.1.5 CONJUGATE ADDITION REACTIONS OF YLIDE AND N-HETEROCYCLE

COMPOUNDS

We also investigated the cyclopropanation reactions of α,β-unsaturated ester (E)-27, which,

in certain cases, can be thought of as proceeding via an initial conjugate addition reaction.

Cyclopropane containing compounds are important in bioorganic chemistry and has been of

great general interest.43

The Corey-Chaykovsky cyclopropanation44

reaction of α,β-

unsaturated ester (E)-27 with trimethylsulfoxonium iodide in DMSO in the presence of

sodium hydride afforded cyclopropyl ester 103 as a single diastereoisomer, but in poor yield

(20%) (scheme 46).45

X-ray crystallography of ester 103 confirmed the stereochemistry at C-

5 and C-6 (figure 22).

44

Scheme 46: Corey-Chaykovsky cyclopropanation reaction of ester (E)-27. i. NaH (60% dispersion in

mineral oil, 1.1 eq.), (CH3)3S(I)O (1.1 eq.), DMSO, r.t., 1 h, 20%.

Figure 22: ORTEP projection of cyclopropyl ester 103.

Khan and co-workers46

described the conjugate addition reactions of amines to sugar

derived olefinic esters (E)-11 and (E)-104 leading to formation of glycosylated amino esters.

A study of the effective steric bulk of the amine using n-butylamine, benzylamine, pyrrolidine,

piperidine, morpholine and N-methylpiperazine, with both 3-O-benzyl and 3-O-methyl

substituted ester derivatives (E)-11 and (E)-104, indicated that both amine as well as the 3-

O-substituent of the olefinic esters are important in diastereoselectivity (scheme 47).

Scheme 47: Michael reaction of amines. i. R1R2NH (2 eq.), NaHCO3 (0.6 eq.), EtOH, r.t., 16 - 18 h.

We studied the addition of dimethylamine to α,β-unsaturated ester (E)-27 in the presence of

(CH3)2NH·HCl and triethylamine in DCM (scheme 48). The reaction in anhydrous DCM at

room temperature led to the isolation of 105 and 105a as a diastereomeric mixture in a 5:1

ratio, but the reaction was found to be extremely sluggish (~ 33% conversion). The use of an

45

excess of reagent did not improve the degree of conversion or the diastereoselectivity even

after prolonged reaction times (~ 96 h).

Scheme 48: Michael reaction of dimethylamine to ester (E)-27. i. (CH3)2NH·HCl (2 eq.), Et3N (2 eq.),

DCM, r.t., 24 h, 16% (d.r. 5:1, 105:105a).

The synthesis of β-amino acids has attracted much attention due to its usefulness for the

synthesis of several classes of bioactive compounds, such as β-peptides which have been

targeted as potential peptidomimetics.47

Sharma and co-workers47

described the application

of TBAF as an efficient base for the Michael reaction of benzylamine to α,β-unsaturated

esters (E)-11 and (E)-104 for the synthesis of glycosyl β-amino acid esters 106 and 107

(scheme 49).

Scheme 49: Sharma Michael reaction of benzylamine. i. BnNH2, TBAF (1.0 M in THF, 1 eq.), r.t.

Accordingly, the reaction of α,β-unsaturated ester (E)-27 with imidazole in the presence of

TBAF (1.0 M in THF) at room temperature was attempted. Intriguingly, in our hands, the

addition of TBAF as a promoter in this case led to the generation of the diene 108 (47%) as

a colourless oil (scheme 50). The formation of diene 108 was clearly evident from its 1H

NMR spectrum which exhibited a resonance for H-3 at δ 5.53 ppm (d, J = 3 Hz), which was

coupled to H-2 at δ 5.35 ppm (dd, J = 5 and 3 Hz), but was devoid of a resonance peak for

H-4 confirming the introduction of the C-3 – C-4 double bond. A resonance peak for H-5 at δ

6.32 ppm (d, J = 15 Hz), which coupled to H-6 at δ 7.08 ppm (d, J = 16 Hz) indicated trans-

geometry about the double bond.

46

Scheme 50: Synthesis of diene 108. i. Imidazole (1 eq.), TBAF (1.0 M in THF, 1 eq.), THF, r.t., 24 h,

47%.

Tiwari et al.48

reported the use of DBU as a catalyst for addition of heterocyclic bases to α,β-

unsaturated esters (E)-11 and (E)-104. Their findings showed the formation of 1,4-addition

products 109 - 112 as well as the unexpected (E)-β,γ-unsaturated esters 113 and 114

(scheme 51). Interestingly, the β,γ-unsaturated esters 113 and 114 were obtained as sole

products by reaction of α,β-unsaturated esters (E)-11 and (E)-104, respectively, with only

DBU at 80 – 90 °C.49

Scheme 51: Conjugate addition reactions of heterocyclic bases. i. Imidazole (1.7 eq.), DBU (25 mol%),

THF, r.t., 12 h.

In our hands, reaction of ester (E)-27 with imidazole and DBU at room temperature in THF,

as reported by Tiwari and Tripathi,48

led to the isolation of (Z)-β,γ-unsaturated ester (Z)-115

(17%) and a mixture of 1,4-addition products 116 and 116a (d.r. 2:1) (scheme 52).

Scheme 52: i. DBU (25 mol%), imidazole (1.7 eq.), THF, r.t., 20 h, 17% ((Z)-115), 116/116a (d.r. 2:1).

47

However, heating ester (E)-27 with imidazole and DBU in THF at 80 °C for 5 h resulted in the

(Z)-β,γ-unsaturated ester (Z)-115 in 61% yield and ester 116 (15%) as a single

diasteroisomer (scheme 53). The Z-geometry of the double bond in ester (Z)-115 was

determined from nOe experiments and assignment of the C-5 stereochemistry of imidazole

derivative 116 was determined by a single crystal X-ray analysis (figure 23).

Scheme 53: i. DBU (25 mol%), imidazole (1.7 eq.), THF, 80 °C, 5 h, 61% ((Z)-115), 15% (116) (4:1,

(Z)-115:116).

Figure 23: ORTEP projection of ester 116.

During the course of this work, we were also interested in the efficient synthesis of (Z)- and

(E)-β,γ-unsaturated esters. In the presence of DBU (25 mol%), at 80 °C in THF for 2 h, a

mixture of (Z)- and (E)-β,γ-unsaturated esters (Z)-115 and (E)-115 were obtained in 75% and

5% yields, respectively (scheme 54).

Scheme 54: i. DBU (25 mol%), THF, 80 °C, 2 h, 75% ((Z)-115) and 5% ((E)-115) (15:1, Z:E).

48

In a blank reaction we also made the observation that reaction of α,β-unsaturated ester (E)-

27 with DBU (2 eq.) in DCM at reflux afforded ester (Z)-115 in 50% yield (scheme 55).

Scheme 55: i. DBU (2 eq.), DCM, reflux, 10 h, 50%.

Reduction of (Z)-β,γ-unsaturated ester (Z)-115 with DIBAL-H gave the corresponding (Z)-

β,γ-unsaturated alcohol 117 (79%), which upon exposure to amberlyst-15 ion-exchange

resin in DCM resulted in the formation of a diastereoisomeric mixture of spiroketal 118 (d.r.

1:1) in 22% overall yield (scheme 56).

Scheme 56: i. DIBAL-H (1.0 M in hexane, 3.5 eq.), THF, -78 °C, 3 h, 79%. ii. Amberlyst-15 ion-

exchange resin (cat.), DCM, r.t., 24 h, 22% (d.r. 1:1).

2.1.6 α,β-UNSATURATED ALDEHYDE

α,β-Unsaturated aldehyde 119 was also studied as a substrate for the Michael reaction.

Aldehyde 119 was synthesised from trans-ester (E)-27 by first reduction, using DIBAL-H, to

give the allylic alcohol (E)-12 in 89% yield, followed by re-oxidation of the alcohol with PDC

in DCM (81%). The 1H NMR spectrum of aldehyde 119 exhibited characteristic resonances

at δ 6.76 ppm (H-5; dd, J = 16 and 5 Hz) and δ 6.38 ppm (H-6; dd, J = 16 and 8 Hz)

indicating the introduction of a polarised trans-olefinic double bond (scheme 57).

Scheme 57: Synthesis of α,β-unsaturated aldehyde 119. i. DIBAL-H (1.0 M in hexane, 2.5 eq.), DCM, -

78 ºC, 2 h, 89%. ii. PDC (1 eq.), DCM, r.t., 6.5 h, 81%.

49

The Michael reaction of α,β-unsaturated aldehyde 119 using 1 eq. CuI and 5 eq. PhMgBr in

the presence of TMSCl afforded predominantly the 1,2-addition product 120 in 57% yield

(unknown C-7 configuration) and also the 1,4-product 121 as a single diastereoisomer in

13% yield (scheme 58).

Scheme 58: Michael reaction of aldehyde 119. i. CuI (1 eq.), PhMgBr (1.0 M in THF, 5 eq.), TMSCl (15

eq.), THF, -78 °C to r.t., 2 h, 57% (120) and 13% (121).

Again, when reacted with 1 eq. PhMgBr in THF at -78 °C for 2 h, without the use of CuI or

TMSCl, we observed only the 1,2-addition product 120 in 71% yield (as a single

diastereoisomer). The formation of alcohol 120 was also observed in the organolithium

reaction with high level of diastereoselectivity (d.r. 11:1) (scheme 59).

Scheme 59: Reactions of aldehyde 119 with Grignard and organolithium. i. PhMgBr (1.0 M in THF, 1

eq.), THF, -78 °C, 2 h, 71%. ii. PhLi (2.0 M in n-dibutyl ether, 1 eq.), THF, -78 °C, 1 h, 82% (d.r. 11:1).

We also applied our standard Hayashi-Miyaura reaction conditions to substrate 119 (2 eq.

PhB(OH)2, 5 mol% [Rh(OH)(1,5-cod)]2 50a and 1 eq. Et3N in 1,4-dioxane:H2O). The reaction

lead to the isolation of a mixture of products; 1,4-adduct 121, alcohol 122 (as a single

diastereoisomer) as well as compound 123 as a mixture of diastereoisomers. Compared to

the esters, the reaction only took about 30 min at room temperature for total consumption of

the starting material (scheme 60).

50

Scheme 60: Hayashi-Miyaura reaction of aldehyde 119. i. PhB(OH)2 (2 eq.), [Rh(OH)(1,5-cod)]2 50a (5

mol%), Et3N (1 eq.), 1,4-dioxane:H2O (10:1), r.t., 30 min.

The rhodium-catalysed conjugate addition reaction took as long as 16 h when only 1 eq.

PhB(OH)2 was used. Nevertheless, it was interesting that the 1,4-adduct 121 was obtained

with high diastereoselectivity (d.r. 8:1), although the yield was poor (47%) (scheme 61).

Scheme 61: Hayashi-Miyaura reaction of aldehyde 119. i. PhB(OH)2 (1 eq.), [Rh(OH)(1,5-cod)]2 50a (5

mol%), Et3N (1 eq.), 1,4-dioxane:H2O (10:1), r.t., 16 h, 47% (d.r. 8:1, 121:121a).

The stereochemistry of the newly generated centre at C-5 was assigned by reduction of the

aldehyde 121 to the corresponding alcohol 124 (scheme 62).

Scheme 62: Reduction of aldehyde 121. i. NaBH4 (2 eq.), MeOH, r.t., 30 min, 87%.

The 1H and

13C NMR data of the resulting compound were compared to those obtained for

the alcohol derived from ester 55, which has known C-5 configuration, and were found to be

identical (scheme 63).

51

Scheme 63: Reduction of ester 55. i. DIBAL-H (1.0 M in toluene, 2.5 eq.), toluene, -78 °C, 3 h, 62%.

2.1.7 α,β-UNSATURATED KETONES

The conjugate addition reactions of α,β-unsaturated ketones (Z)-125 and (E)-125 were also

investigated. These compounds were synthesised from aldehyde 19 via Wittig reaction

affording 76% yield of a 1:1 mixture of cis- and trans-isomers (scheme 64).

Scheme 64: Synthesis of α,β-unsaturated ketones (Z)-125 and (E)-125. i. Ph3PCHCOMe

50 (1.1 eq.),

DCM, r.t., 5 h, 76% (1:1, Z:E).

To understand the effect of double bond geometry on the stereoselectivity of the Hayashi-

Miyaura reactions, the reactions were performed with ketones (Z)-125 and (E)-125

independently. Under identical reaction conditions (PhB(OH)2 (2 eq.), [Rh(OH)(1,5-cod)]2

50a (5 mol%), Et3N (1 eq.) in 1,4-dioxane:H2O (10:1) at room temperature for 1 h), both

reactions afforded the 1,4-adduct 126 in excellent isolated yields (90 – 92%) and with high

levels of diastereocontrol (d.r. > 14:1) (scheme 65).

Scheme 65: Hayashi-Miyaura reactions of (Z)-125 and (E)-125. i. PhB(OH)2 (2 eq.), [Rh(OH)(1,5-

cod)]2 50a (5 mol%), Et3N (1 eq.), 1,4-dioxane:H2O (10:1), r.t., 1 h., (Z)-125 → 126 90% (d.r. 16:1,

126:126a), (E)-125 → 126 92% (d.r. 14:1, 126:126a).

52

The C-5 stereochemistry of 1,4-addition product 126 was unambiguously determined by 1H

and 13

C NMR spectra. Aldehyde 121, of known C-5 configuration (scheme 62), was

subjected to Grignard reaction with methylmagnesium bromide to afford alcohol 127 as a

mixture of diastereoisomers. The compounds were oxidised with PDC to give the

corresponding ketone. The 1H and

13C NMR spectral data were identical to those of 1,4-

addition product 126 (scheme 66).

Scheme 66: Synthesis of ketone 126 from aldehyde 121. i. MeMgBr (1.4 M in toluene/THF, 1 eq.),

THF, -78 °C, 3 h. ii. PDC (1 eq.), DCM, r.t., 6 h.

The Michael reaction of ketone (Z)-125 using 1 eq. CuI and 5 eq. vinyl MgBr in the presence

of TMSCl afforded 1,4-adduct 128 (as a single diastereoisomer), however the yield was poor

(45%). The relative stereochemistry of the product had yet to be determined (scheme 67).

Scheme 67: Michael reaction of ketone (Z)-125. i. CuI (1 eq.), CH2=CHMgBr (1.0 M in THF, 5 eq.),

TMSCl (15 eq.), THF, -78 °C to r.t., 3 h, 45%.

As we had seen with the aldehyde (scheme 59), reaction of ketone (E)-125 with vinyl MgBr

resulted in a 3:1 diastereomeric mixture of 1,2-addition product 129 in an overall yield of 36%

(unknown C-7 configuration) (scheme 68).

Scheme 68: Grignard reaction of ketone (E)-125. CH2=CHMgBr (1.0 M in THF, 1 eq.), THF, -78 °C, 2.5

h, 36% (d.r. 1:1).

When trans-ketone (E)-125 was reacted with CuI and PhMgBr in the presence of TMSCl, we

observed the formation of 1,2-addition product 130 in 26% yield as a mixture of

53

diastereoisomers (d.r. 1:1). The reaction of (E)-125 with 1 eq. PhLi at -78 °C also resulted in

the isolation of alcohol 130 as a mixture of diastereoisomers (d.r. 2:1), but in an excellent

yield of 98% (scheme 69). At that stage, the C-7 stereochemistry of the alcohol had yet to be

determined.

Scheme 69: Conjugate addition reactions of ketone (E)-125. i. CuI (1 eq.), PhMgBr (1.0 M in THF, 5

eq.), TMSCl (15 eq.), THF, -78 °C to r.t., 3 h, 26% (d.r. 1:1). ii. PhLi (2.0 M in n-dibutyl ether, 1 eq.),

THF, -78 °C, 4 h, 98% (d.r. 2:1).

Meanwhile, reaction of cis-ketone (Z)-125 with 1 eq. PhLi at -78 °C afforded 3:1

diastereomeric mixture of 1,2-product 131 in a combined yield of 33% with the cis-geometry

of the double bond retained (scheme 70).

Scheme 70: Reaction of ketone (Z)-125 with organolithium. i. PhLi (2.0 M in n-dibutyl ether, 1 eq.),

THF, -78 °C, 4 h, 33% (d.r. 3:1).

The relative configurations of the products from the reactions with PhLi had yet to be

determined. However, the products were submitted to catalytic hydrogenation using 10%

Pd/C, independently, to determine if they both have the same C-7 stereochemistry. Catalytic

hydrogenation of mixture 131 resulted in alcohol 132, based on the 1H NMR spectrum of the

crude reaction mixture. However, the compound appeared to have decomposed on

purification on silica gel chromatography (scheme 71).

Scheme 71: Catalytic hydrogenation of mixture 131. i. 10% Pd/C (10 mol%), MeOH, r.t., 3 h.

It is noteworthy that in the case of alcohol 130, catalytic hydrogenation afforded an

inseparable mixture of at least two compounds, the major of which were assigned as alcohol

2 × H-3

54

132 and deoxygenated alkene 133, based on the 1H NMR spectrum of the crude reaction

mixture (scheme 72).

Scheme 72: Catalytic hydrogenation of mixture 130. i. 10% Pd/C (10 mol%), MeOH, r.t., 3 h.

Unfortunately, the phenylcuprate reaction of cis-ketone (Z)-125 in the presence of TMSCl

failed to give any product; 1H NMR spectrum of the crude product shows unreacted starting

material.

2.1.8 α,β-UNSATURATED NITRO ALKENE

Next, we studied the conjugate addition reactions of α,β-unsaturated nitro compound 135,

which was prepared from the aldehyde precursor 19 via a Henry reaction, followed by

elimination of the resulting nitro alcohol 134 (d.r. 9:1) affording predominantly the trans-

alkene derivative 135, as confirmed by the 1H NMR spectrum (scheme 73).

51

Scheme 73: Synthesis of α,β-unsaturated nitro 135. i. CH3NO

2 (10.2 eq.), NaOMe (1.2 eq.), MeOH, r.t.,

1.5 h, 85% (d.r. 9:1). ii. MsCl (3.2 eq.), Et3N (4.3 eq.), DCM, 0 °C, 45 min, 95% (25:1, E:Z).

Nitro olefins are versatile synthetic intermediates since the nitro group can be converted into

a variety of useful functional groups.43

Rhodium-catalysed reactions of various arylboronic

acids to nitro alkene 135 were examined under the standard conditions, (5 mol% [RhCl(1,5-

cod)]2 50, Et3N, 1,4-dioxane:H2O (10:1) at room temperature), and the results are

summarised in table 9. In all cases, complete consumption of starting material was observed

within 3 h, affording adducts with good levels of stereocontrol (d.r. > 6:1), except for 140 (d.r.

2:1) and 141 (d.r. 3:1). The yields of the products ranged from 52% to 91%.

55

Entry R Product Time, h Yield, % d.r.†

1 Phenyl- 136 + 136a 3 91a 136:136a, 10:1

2 4-Fluorophenyl- 137 + 137a 1 78 137:137a, 10:1

3 4-Acetylphenyl- 138 + 138a 1 52 138:138a, 10:1

4

4-Methyoxyphenyl- 139 + 139a 1 74 139:139a, 6:1

5

3-Nitrophenyl- 140 + 140a 2 57 140:140a, 2:1

6 2-Methoxyphenyl- 141 + 141a 1 84 141:141a, 3:1

7 3-Thienyl- 142 + 142a 3 60 142:142a, 6:1

8 1-Naphthyl- 143 + 143a 1 89 143:143a, 7:1

9 2-Naphthyl- 144 + 144a 1 80 144:144a, 10:1

i. [RhCl(1,5-cod)]2 50 (5 mol%), RB(OH)2 (2 eq.), Et3N (1 eq.), 1,4-dioxane:H2O (10:1), r.t., 1 – 3 h.

aReaction with [Rh(OH)(1,5-cod)]2 50a afforded 136 in 89% (d.r. 10:1, 136:136a).

†Determined by

1H NMR of crude reaction mixtures.

Table 9: Hayashi-Miyaura reactions of various arylboronic acids to nitro compound 135.

56

Compounds 139, 141, 143 and 144 were confirmed by X-ray analysis (figure 24).

Figure 24: ORTEP projections of nitro compounds 139, 141, 143 and 144, respectively.

The chemical shifts of the relevant peaks in the 1H NMR of compounds 136, 136a, 138 and

138a are summarised in table 10. We observe a trend in which H-3 chemical shifts in the 1H

NMR spectra of 136 and 138 at δ 3.54 ppm (d, J = 3 Hz), whilst shifts for the H-3 in

compounds 136a and 138a are at δ 3.82 ppm (d, J = 3 Hz). The structure of the major

diastereomer in compound 138 was identified unambiguously with the aid of X-ray analysis,

thus the minor diastereomer compound 138a was identified as bearing the opposite epimer

at C-5.

57

Entry Substrate H-1 H-2 H-3 H-4 H-5 H-6 H-6’

1

5.97 ppm (d, J = 4 Hz)

4.55 ppm (d, J = 4 Hz)

3.54 ppm (d, J = 3 Hz)

4.41 ppm (dd, J = 10, 3 Hz)

4.05 ppm (td, J = 10, 4 Hz)

5.02 ppm (dd, J = 13, 4 Hz)

4.74 ppm (dd, J = 13, 11

Hz)

2

5.93 ppm (d, J = 4 Hz)

4.64 ppm (d, J = 4 Hz)

3.82 ppm (d, J = 3 Hz)

4.39 ppm (dd, J = 8, 3 Hz)

4.10 ppm (ddd, J = 10, 8, 4

Hz)

4.83 – 4.76 ppm (m, J = 12, 8 Hz)

4.67 – 4.64 ppm (m, J = 8, 4 Hz)

3

5.98 ppm (d, J = 4 Hz)

4.58 ppm (d, J = 4 Hz)

3.54 ppm (d, J = 3 Hz)

4.40 ppm (dd, J = 9.5, 3

Hz)

4.09 ppm (td, J = 10, 4 Hz)

5.05 ppm (dd, J = 13, 4 Hz)

4.75 ppm (dd, J = 13, 11

Hz)

4

5.91 ppm (d, J = 4 Hz)

4.66 ppm (d, J = 4 Hz)

3.82 ppm (d, J = 3 Hz)

4.37 ppm (dd, J = 8, 3 Hz)

4.13 ppm (ddd, J = 10, 8, 4

Hz)

4.72 ppm (d, J = 10 Hz)

4.60 – 4.54 ppm (m, J = 8, 4 Hz)

Table 10: Relevant 1H NMR peaks for compounds 136, 136a, 138 and 138a.

58

Interestingly, we observed divergent stereochemical outcomes in the copper-catalysed

conjugate addition reactions depending on the presence of copper in the reaction mixture.

Cuprate reaction of PhMgBr to α,β-unsaturated nitro alkene 135, without the use of TMSCl,

afforded nitro compound 136 (61%) with excellent diastereoselectivity (d.r. 13:1) (scheme

74). The stereochemical outcome was established by analysis of 1H and

13C NMR spectra

and it was found to undergo the same facial selectivity as those in the Hayashi-Miyaura

reaction.

Scheme 74: Cuprate reaction of nitro alkene 135. i. CuI (1 eq.), PhMgBr (1.0 M in THF, 5 eq.), THF, -

78 °C to r.t., 2 h, 61% (d.r. 13:1, 136:136a).

Reaction of p-methoxyphenylmagnesium bromide in THF at -78 °C for 4 h resulted in nitro

compound 139a in 29% yield (d.r. 3:1). This reaction only proceeded to 50% conversion,

hence the poor yield. Reaction of vinylmagnesium bromide with alkene 135, and under the

same conditions, produced nitro compound 145 in 66% yield as a single diastereoisomer

and the structure was confirmed by X-ray analysis (figure 25). The stereochemical

assignment is also in agreement with literature data.52

The facial selectivity of the products

obtained from the Grignard reactions was found to be the opposite to those of the cuprate

and Hayashi-Miyaura reactions. Catalytic hydrogenation of the nitro vinyl compound 145

using 10% Pd/C in MeOH at room temperature gave nitro ethyl compound 146. The

Grignard reaction of EtMgBr with nitro alkene-135 afforded nitro compound 146 and 146a

(d.r. 1:1) in a combined yield of 42% (scheme 75).

59

Scheme 75: Grignard reactions of nitro alkene 135. i. 4-MeOPhMgBr (0.5 M in THF, 1 eq.), THF, -78

°C, 4 h, 29% (d.r. 3:1, 139:139a). ii. CH2=CHMgBr (1.0 M in THF, 1 eq.), THF, -78 °C, 4 h, 66%. iii.10%

Pd/C (10 mol%), MeOH, r.t., 2 h, 100% (crude yield). iv. EtMgBr (1.0 M in THF, 1 eq.), THF, -78 °C, 4

h, 42% (d.r. 1:1, 146:146a).

Figure 25: ORTEP projection of nitro vinyl compound 145.

Results of the reaction between the nitro alkene 135 and various aryllithiums are

summarised in scheme 76. The conjugate addition reaction of PhLi to the α,β-unsaturated

nitro compound 135 afforded product 136a in 49% yield (d.r. 3:1). Alternatively, the reaction

of 2-lithioanisole (prepared in situ from 2-bromoanisole and n-butyllithium) led to product

141a (d.r. 3:2) in 32% yield. However, the reaction at -78 °C for 4 h only gave 65%

conversion. Higher yield of naphthalene 143a (76%) was observed with d.r. 5:1. The relative

configurations of adducts 136a, 141a and 143a were the same as those in the Grignard

reaction.

60

Scheme 76: Reactions of nitro alkene 135 with organolithium. i. PhLi (2.0 M in n-dibutyl ether, 1 eq.),

THF, -78 °C, 4 h, 49% (d.r. 3:1, 136:136a). ii. 2-bromoanisole (1.1 eq.), n-BuLi (1.6 M in hexane, 1.1

eq.), THF, -78 °C, 4 h, 32% (d.r. 3:2, 141:141a). iii. 1-bromonaphthalene (1.1 eq.), n-BuLi (1.6 M in

hexane, 1.1 eq.), THF, -78 °C, 4 h, 76% (d.r. 5:1, 143:143a).

Interestingly, the reaction of 4-lithioanisole did not give the expected 1,4-addition product

139a, but instead we observed the addition of n-butoxide to the nitro alkene 135. The ether

147 (22%) arose presumably via conjugate addition reaction of n-butoxide, as an impurity in

the batch of (commercial) n-BuLi used in this particular case. 1H NMR spectrum exhibited

signals for H-7 at δ 3.74 ppm (dt, J = 9 and 6 Hz) and 3.53 ppm (dt, J = 9 and 7 Hz), H-8 at δ

1.54 – 1.46 ppm (m) and H-9 at δ 1.33 – 1.25 ppm (m). Meanwhile, a resonance peak for H-

10 is observed at 0.89 ppm (t, J = 7 Hz). We also recovered 4-bromoanisole from the

reaction, which suggested that the halogen-lithium exchange did not occur (scheme 77). The

assignment of the C-5 stereochemistry is currently the focus of further work within the group.

Scheme 77: Reaction of nitro alkene 135. i. 4-bromoanisole (1.2 eq.), n-BuLi (1.6 M in hexane, 1.2

eq.), THF, -78 °C, 4 h, 22% (d.r. 13:1).

61

2.1.9 α,β-UNSATURATED 2-PYRIDYLSULFONES

Asymmetric conjugate addition reaction of organometallic reagents to α,β-unsaturated

sulfones has been an area of intensive research and sulfones bearing β-stereocentres are

highly versatile synthons in organic chemistry.53,54

Wittig olefination of aldehyde 19 with

diethyl (2-pyridylsulfonyl)methyl phosphonate 15255,56

in the presence of K2CO3 in DCM at

room temperature for 20 h resulted in α,β-unsaturated 2-pyridylsulfone 148 in 71% yield

(scheme 78). The configuration about the double bond was assigned as trans, according to

the 1H NMR spectrum of 148, which shows the H-5 at δ 7.14 ppm (dd, J = 15 and 4 Hz) and

H-6 at δ 6.94 ppm (dd, J = 15 and 2 Hz).

Scheme 78: Synthesis of α,β-unsaturated pyridylsulfone 148. i. K2CO3 (1 eq.), diethyl (2-

pyridylsulfonyl)methyl phosphonate 152 (0.9 eq.), DCM, r.t., 20 h, 71%.

Diethyl (2-pyridylsulfonyl)methyl phosphonate 152 was synthesised from commercially

available chloromethylphosphonic acid dichloride 149 via three simple steps. Treatment of

149 with Et3N and EtOH afforded diethyl 1-chloromethylphosphonate 150. The α-(pyridin-2-

ylsulfonyl)alkylphosphonate ester 152 was prepared from phosphate 150 and 2-

mercaptopyridine in the presence of NaH, followed by m-CPBA oxidation of the resulting α-

(pyridin-2-ylthio)alkylphosphonate 151 (scheme 79).

Scheme 79: Synthesis of diethyl (2-pyridylsulfonyl)methyl phosphonate 152. i. Et3N (2.2 eq.), EtOH

(2.2 eq.), THF, 0 °C to r.t., 2 h, 100% (crude yield). ii. NaH (60% dispersion in mineral oil, 1.7 eq.), 2-

mercaptopyridine (1 eq.), DMF, 0 °C to r.t., 18 h, 47%. iii. m-CPBA (75% reagent, 3.2 eq.), CHCl3/DCM

(1:1), 0 °C to r.t., 18 h, 100% (crude yield).

Bos et al.53

described a highly efficient method for the asymmetric copper-catalysed

conjugate addition of Grignard reagents to α,β-unsaturated 2-pyridylsulfones by using

62

CuI/TolBinap 153 complex in DCM or t-BuOMe. The procedure provides β-substituted 2-

pyridylsulfones with excellent enantioselectivities (88 – 94% ee) and yields (88 – 97%)

(scheme 80).

Scheme 80: Bos catalytic asymmetric conjugate addition of Grignard reagents. i. CuCl or CuI (5

mol%), ligand 153 (6 mol%), R2MgBr (1.2 eq.), DCM or t-BuOMe, -40 °C, 16 h, 88 – 97%.

Initially, we studied the addition of PhMgBr to α,β-unsaturated pyridylsulfone 148 using CuI

and TMSCl in THF, our standard conditions. Unfortunately, the reaction afforded a complex

mixture of products, which were inseparable. Thereafter, we attempted the addition of

EtMgBr to α,β-unsaturated pyridylsulfone 148 using CuI in DCM at -40 °C for 24 h, under the

conditions described by Bos and co-workers, however without the use of the bidentate

phosphine ligand. Unfortunately, the reaction did not undergo any conversion overnight.

Thus, unsurprisingly, the reaction of α,β-unsaturated pyridylsulfone 148 with PhLi also failed

to give any product, only starting material was recovered after 4 h stirring in THF at -78 °C

(scheme 81).

Scheme 81: Conjugate addition reactions of sulfone 148. i. CuI (5 mol%), EtMgBr (1.0 M in THF, 1.2

eq.), DCM, -40 °C, 24 h. ii. PhLi (2.0 M in n-dibutyl ether, 1 eq.), THF, -78 °C, 4 h.

Mauleón et al.54,57

described an efficient method for the rhodium-catalysed enantioselective

catalytic conjugate addition of organoboronic acids to α,β-unsaturated sulfones, which relies

63

on the use of α,β-unsaturated 2-pyridyl sulfones as Michael acceptors and (S,S)-chiraphos

155 as chiral ligand to provide the best asymmetric induction The procedure provides β-

substituted sulfones in good yields (84 – 98%) and enantioselectivities (70 – 92% ee)

(scheme 82).

Scheme 82: Mauleón catalytic asymmetric conjugate addition of organoboronic acids. i. R2B(OH)2 (5

eq.), [Rh(acac)(C2H4)2 (3 mol%), ligand 155 (3 mol%), 1,4-dioxane:H2O (10:1), 100 °C, 12 h, 84 – 98%.

On using α,β-unsaturated 2-pyridylsulfone 148 as a substrate for the rhodium-catalysed

addition with PhB(OH)2 and [Rh(OH)(1,5-cod)]2 50a at 100 °C for 24 h, but without the use of

a ligand, we observed the formation of (Z)-β,γ-unsaturated sulfone 156 (35%). The Z-

configuration was determined by evidenced by nOe experiments (scheme 83).

Scheme 83: Hayashi-Miyaura reaction of sulfone 148. i. PhB(OH)2 (2 eq.), [Rh(OH)(1,5-cod)]2 50a (5

mol%), Et3N (1 eq.), 1,4-dioxane:H2O (10:1), 100 °C, 24 h, 35%.

The 1,4-addition of organometallics to α,β-unsaturated carbonyl compounds can be

achieved successfully by using organocuprate (CuI and RMgBr) and rhodium(I) complexes

([RhCl(1,5-cod)]2 50 or [Rh(OH)(1,5-cod)]2 50a and RB(OH)2) with high diastereoselectivities

(d.r. > 6:1) in moderate to high yields, in most cases. Rhodium-catalysed conjugate addition

reactions appear to have a major advantage over organocuprates and organolithium

reactions, whereby the reaction can be carried out in an aqueous solvent due to the relative

stability of boronic acids to air and moisture, thus providing more facile implementation.

However, the Hayashi-Miyaura reaction is not very cost effective due to the high cost of

rhodium reagents.

64

2.1.10 PALLADIUM(II)-CATALYSED CONJUGATE ADDITION REACTIONS

In 2007, Bedford et al.58

reported the use of palladacyclic catalyst 157 (figure 26) as an

excellent catalyst in the coupling of arylboronic acids with a range of Michael acceptors.

Figure 26: Bedford’s catalyst 157.

The effectiveness of Bedford’s catalyst in conjugate addition reactions of PhB(OH)2 to α,β-

unsaturated carbonyl compounds (E)-27, 119, (E)-125 and 135 were studied and are

summarised in table 11. The Pd-catalysed reaction was performed in toluene at 40 °C using

K3PO4 as the base to activate the boronic acid. As can be seen, the phosphine-based

palladacycle complex 157 efficiently catalyses the coupling of PhB(OH)2 with α,β-

unsaturated aldehyde 119 in 2.5 h, with essentially quantitative conversion to 1,4-product

121 with excellent diastereoselectivity (d.r. 15:1). In the first instance, the reaction was

carried out at room temperature with a 5 mol% loading of complex 157, but slow conversion

was observed within 6 h and by increasing the reaction time further did not lead to improved

results. The use of complex 157 with slightly more electron-deficient olefins, α,β-unsaturated

ester (E)-27, ketone (E)-125 and nitro compound 135 showed lower activity of the Pd-

catalyst, giving only 50% to 75% conversion to the desired 1,4-products 55, 126 and 136,

respectively, but in poor yields (14% - 50%). It is noteworthy that, at temperature of 40 °C,

the Bedford’s catalyst underwent rapid decomposition in the presence of PhB(OH)2 and

K3PO4, liberating inactive black palladium(0) species.

65

Entry Substrate Product Time, h Conversion,

% Yield,

% d.r.

†

1 (E)-27 55 + 55a 48 75 31 55:55a, 15:1

2 119 121 + 121a 2.5 > 99 65 121:121a, 15:1

3 (E)-125 126 + 126a 6 50 14 126:126a, 7:1

4 135 136 + 136a 48 > 60 50 136:136a, 18:1

i. PhB(OH)2 (2 eq.), K3PO4 (1 eq.), Bedford’s catalyst 157 (5 mol%), toluene, 40 °C.

†Determined by

1H NMR of crude reaction mixtures.

Table 11: Reaction with Bedford’s catalyst.

Catalytic cycle for Pd-catalysed conjugate addition reaction is reported to be closely related

to that shown for rhodium (figure 17).28

Transmetallation between dicationic species A and

ArB(OH)2 generates cationic Pd–Ar species B, which subsequently adds to a solution of α,β-

unsaturated carbonyl compounds. This produces an α-palladate species C, which is in

equilibrium with palladium enolate species D. Hydrolysis of the species D leads to the

regeneration of dicationic species A and liberates the asymmetric conjugate addition

product. However, slow hydrolysis of the enolate species D can afford Heck product E via β-

hydride elimination (figure 27).

Figure 27: Catalytic cycle of palladium-catalysed conjugate addition of organoboronic acids to α,β-

unsaturated carbonyl compounds.

66

2.2 STEREOCHEMICAL RATIONALE

Over the past years, there have been many reports16,59,60

in the literature to explain the

stereochemical outcome observed in conjugate addition reactions of organometallic reagents

(i.e. cuprate, RMgX, R-Li, NR2 and ylides) to γ-alkoxyenones and related systems. However,

to date, there is no unifying mechanism that can be used to predict the stereochemical

outcome of these reactions. It was reported that the stereochemical outcome may be finely

balanced, dependent on the substrate, nucleophile and reaction conditions.

Roush and co-workers61,62

explained the predominance of the anti-selectivity in

organocuprate addition reactions by using a modified Felkin-Anh model, which suggests that

nucleophilic attack by an organocuprate takes place from the face opposite to the γ-alkoxy

substituent via a C-C π-complex system with the R-[M] species (figure 28). Csákÿ et al.25

and Kurosawa et al.63

described that the Rh(I)- and Pd(II)-catalysed conjugate addition

reactions of organoboronic acids to α,β-unsaturated carbonyl compounds also occurred with

high diastereoselectivity to afford the anti-products.

Figure 28: Modified Felkin-Anh model via an initial π-complex. EWG = CO2Me, CHO, COMe, NO2.

The stereoselectivity of conjugate addition of R-Li, RMgX, ylides and N-heterocycles to γ-

alkoxy-α,β-unsaturated systems can be explained by modified Yamamoto model,64,65

which

suggests coordination of the R-[M] species with the σ-oxygen (figure 29).66

In our study,

additions of R-Li/RMgX reagent and nitro alkene 135 afforded the syn-isomer predominantly.

67

The reactions of trans-α,β-unsaturated ester (E)-27 with ylide (i.e. oxosulfoxonium) and N-

heterocycle compound (i.e. imidazole) also resulted the syn-selectivity.

Figure 29: Modified Yamamoto model via an initial σ-complex. EWG = CO2Me, NO2.

68

3 CONCLUSIONS

We have investigated the reactions of a diverse range nucleophilic reagents (i.e. cuprate,

RMgX, R-Li, NR2 and ylides) with a number of α,β-unsaturated carbohydrate derivatives

(such as esters (Z)-27 and (E)-27, aldehyde 119, ketones (Z)-125 and (E)-125, nitro alkene

135 and 2-pyridylsulfone 148); the stereochemical outcomes of these conjugate addition

reactions have been elucidated. Reactions of RMgX and R-Li with α,β-unsaturated esters,

ketones (Z)-125 and (E)-125, and aldehyde 119 afforded the product of 1,2-addition, in the

case of nitro olefin 135, the reaction with RMgX and R-Li led to syn-addition with high

diastereoselectivities. Cuprate addition reactions to these unsaturated carbohydrates

generally afforded the anti-1,4-addition products, except in the case of α,β-unsaturated

aldehyde 119 where the products of 1,2-addition predominated. The additions of ylide (i.e.

oxosulfoxonium) and N-heterocycle compound (i.e. imidazole) to α,β-unsaturated ester (E)-

27 resulted in syn-selectivity. The Rh(I) and Pd(II)-catalysed conjugate addition reactions

with the α,β-unsaturated carbohydrates also afforded 1,4-addition products with anti-

selectivity, such reactions are highly chemoselective (except in the case of α,β-unsaturated

2-pyridylsulfone 148, where (Z)-β,γ-unsaturated 2-pyridylsulfone 156 was observed. It was

investigated that conjugate addition reactions to (Z)- and (E)-isomers did not affect the

stereochemical outcomes of the conjugate addition reactions. This is also true as the nature

of the oxygen protecting group and stereochemistry at C-3 were examined. We also

observed no major differences in rate of reaction and levels of diastereoselectivity when

[RhCl(1,5-cod)]2 50 or [Rh(OH)(1,5-cod)]2 50a used as catalyst precursors in the asymmetric

conjugate addition of organoboronic acids to α,β-unsaturated carbonyl compounds.

Stereochemical rationale for the observed sense of asymmetric induction is discussed.

69

4 FUTURE WORK

During the course of our study, we had successfully proven that the 3-O-substituents on the

furanose did not affect the stereochemical outcome of conjugate addition reactions.

However, it would be interesting to investigate the C-3 deoxy compound to the 1,4-addition

reactions (figure 30).

Figure 30: Conjugate addition reactions of deoxygenated olefins.

Future studies on the conjugate addition reactions of organometallic reagents to electron

deficient alkenes will involve the use of α,β:γ,δ-unsaturated ester 158 in such reactions. The

factors which control 1,6- versus 1,4-addition reaction will be investigated. The extensions of

this chemistry to pyrano-sugars could have synthetic applications as depicted below (figure

31).

Figure 31: Diene 158 as a potential Michael acceptor and a retrosynthetic approach to aloin via

conjugate addition reaction.

70

The use of α,β-unsaturated nitro sugars as Michael acceptors will be applied to the

development of a new approach to the synthesis polyhydroxylated azepanes.67

Here, it is

proposed that the synthesis of polyhydroxyazepanes could be achieved via reduction of the

adduct, followed by an intramolecular reductive amination (figure 32).

Figure 32: An approach to synthesis of trihydroxyazepane via conjugate addition reaction to α,β-nitro

alkenes.

In 2010, Sawamura et al.68

reported a Pd(II)-catalysed allyl-aryl coupling reaction between

acyclic E-allylic acetates and arylboronic acids with excellent γ- and E-selectivity (scheme

84).

Scheme 84: Sawamura coupling reaction. i. Pd(OAc)2 (10 mol%), Phen 159 (12 mol%), AgSbF6 (10

mol%), PhB(OH)2 (1.5 eq.), DCE, 60 °C, 6 h, 80% (99:1, γ:α).

Thus, the methodology can be applied for the synthesis of allyl phenol 9 from acetate 160 as

a model study directed towards the synthesis of gilvocarcin M 4 via BHQ reaction (figure 33).

Figure 33: Retrosynthetic approach to chloronaphthalene 7 via acetate 160.

71

5 EXPERIMENTAL

5.1 GENERAL PROCEDURES

All reactions were carried out under an atmosphere of dry nitrogen, unless otherwise stated.

The reaction vessels used were dried either in an oven or flame-dried whilst under vacuum

prior to use.

Bedford’s catalyst, 2-[Bis(2,4-di-tert-butyl-phenoxy)phosphinooxy]-3,5-di(tert-butyl)phenyl-

palladium(II) chloride dimer 157 was supplied by Thomas Pell (preparation as described by

Robin B. Bedford et al.69

).

5.1.1 PURIFICATION OF SOLVENTS AND REAGENTS

Dichloromethane (DCM) and trimethylsilylchloride (TMSCl) were dried over calcium hydride

and freshly distilled under an atmosphere of nitrogen prior to use. Tetrahydrofuran (THF)

was dried over sodium, using benzophenone as indicator, and distilled prior to use.

Anhydrous toluene, Et2O, THF and DCM were obtained from the PureSolv MD 5 Solvent

Purification System. Acetone and EtOAc were dried and stored over 4 Å molecular sieves

under nitrogen atmosphere. All other reagents and solvents were used as purchased without

further purification, unless otherwise stated.

5.1.2 CHROMATOGRAPHY

Flash column chromatography was carried out using Merck 60 Å (40 – 60 micron, 230 – 300

mesh) silica gel. Thin layer chromatography (TLC) was carried out using Polygram® SIL

G/UV254 silica gel from Macherey-Nagel GmbH & Co. Detection was made under ultraviolet

absorption (254 nm) and/or developed by treatment with potassium permanganate solution,

followed by heating.

72

5.1.3 SPECTROSCOPIC AND PHYSICAL DATA

Infrared spectra were recorded on a Genesis FT-IR as evaporated films on sodium chloride

plates, Perkin Elmer Spectrum BX FT-IR spectrometer or Bruker Optics Alpha-P FT-IR

spectrometer and are quoted in cm-1

.

Melting points were obtained on a Sanyo Gallenkamp melting point apparatus and are

uncorrected.

Optical rotations were measured using an Optical Activity Ltd. AA-100 automatic polarimeter

with a 0.25 dm cell. The concentration is measured in g/100 mL and α values are given in

deg dm−1

cm3 g

−1.

Mass spectra were recorded as follows: Micromass Platform II for electrospray (ES), Waters

QTOF for electrospray and/or high resolution accurate mass measurements, Thermo

Finnigan MAT95XP was also used for accurate mass measurements and Hewlet Packard

5971 MSD for electron impact (EI) and GC/MS (gas chromatography/mass spectrometry).

Nuclear magnetic resonance (NMR) spectra were recorded by using deuterated chloroform

(CDCl3) as solvent, unless otherwise stated. Proton NMR spectra (1H NMR) were recorded

on either a Bruker AMX 500 (500 MHz) spectrometer, Bruker AMX 400 (400 MHz)

spectrometer or a Varian INOVA Unity 300 (300 MHz) spectrometer, as stated. Residual

non-deuterated solvent was used as internal standard. Carbon NMR spectra (13

C NMR)

were recorded on either a Bruker AMX 500 (125 MHz) spectrometer, Bruker AMX 400 (100

MHz) spectrometer or a Varian INOVA unity 300 (75 MHz) spectrometer, using deuterated

solvents as the internal standard. Chemical shifts (δ) are quoted in parts-per-million (ppm)

downfield from tetramethylsilane (TMS). Signal splitting patterns are described as singlet (s),

doublet (d), triplet (t), quartet (q), broad singlet (br. s), multiplet (m), or combinations thereof.

Coupling constants (J) are quoted in hertz (Hz). Diastereomeric ratio (d.r.) is determined by

integration of the 1H NMR signals of the crude reaction mixtures.

73

5.2 EXPERIMENTAL PROCEDURES

(Z)-Ethyl 3-O-benzyl-5,6-dideoxy-1,2-O-isopropylidene-α-D-xylo-hept-5-enfuranuronate (Z)-

11 and (E)-Ethyl 3-O-benzyl-5,6-dideoxy-1,2-O-isopropylidene-α-D-xylo-hept-5-

enfuranuronate70

(E)-11

To a solution of the crude aldehyde 19 (5.00 g, 18.0 mmol) in anhydrous DCM (70 mL), was

added commercially available Ph3PCHCOOEt (6.61 g, 19.0 mmol) at room temperature.

After stirring for 16 h, the solvent was evaporated and the crude product was purified by

flash column chromatography (silica gel; eluent 10% EtOAc/petrol) to afford an overall yield

of 4.54 g (72%) of the title compounds as white oil (1:2, Z:E). IR max (thin film) 2984 (C-H

stretch), 2936 (C-H stretch), 1715 (C=O stretch), 1663 (C=C stretch), 1373, 1164, 1072 (C-O

stretch), 1023 (C-O stretch) cm-1

.

Z-isomer (Z)-11

Isolated yield: 457 mg (7% as Z-isomer). α -68.3 (c 1.0, CHCl3).

1H NMR (400 MHz,

CDCl3) δ 7.38 - 7.25 (5 H, m, Ar-H), 6.40 (1 H, dd, J = 12 Hz, J = 7 Hz, H-5), 6.02 (1 H, d, J =

4 Hz, H-1), 5.93 (1 H, dd, J = 12 and 2 Hz, H-6), 5.64 (1 H, ddd, J = 7, 3 and 1 Hz, H-4), 4.65

(1 H, d, J = 4 Hz, H-2), 4.62 (1 H, d, J = 12 Hz, CHxHyAr), 4.47 (1 H, d, J = 12 Hz, CHxHyAr),

4.29 (1 H, d, J = 3 Hz, H-3), 4.12 (2 H, m, OCH2CH3), 1.52 (3 H, s, CH3), 1.34 (3 H, s, CH3),

1.26 (3 H, t, J = 7 Hz, OCH2CH3) ppm. 13

C NMR (125 MHz, CDCl3) δ 165.47 (C, C=O),

145.14 (CH, C-5), 137.40 (C, Ar-C), 128.33 (CH, Ar-C), 127.82 (CH, Ar-C), 127.69 (CH, Ar-

C), 121.15 (CH, C-6), 111.75 (C, C-Me2), 105.10 (CH, C-1), 83.72 (CH, C-3), 83.05 (CH, C-

2), 78.13 (CH, C-4), 72.12 (CH2, OCH2Ar), 60.35 (CH2, OCH2CH3), 26.89 (CH3, C(CH3)2),

26.36 (CH3, C(CH3)2), 14.14 (CH3, OCH2CH3) ppm. MS (ES+) m/z [M+NH4]+ 366.0, [M+Na]

+

371.0. Accurate Mass C19H24O6Na, [M+Na]+ requires 371.1465, measured 371.1466.

74

E-isomer (E)-11

Isolated yield: 1.29 g (21% as E-isomer) (3.87 g (62%) as Z/E mixture). 1H NMR (400 MHz,

CDCl3) δ 7.46 - 7.23 (5 H, m, Ar-H), 6.98 (1 H, dd, J = 16 and 5 Hz, H-5), 6.18 (1 H, dd, J =

16 and 2 Hz, H-6), 6.01 (1 H, d, J = 4 Hz, H-1), 4.80 (1 H, ddd, J = 5, 3 and 2 Hz, H-4), 4.65

(1 H, d, J = 4 Hz, H-2), 4.64 (1 H, d, J = 12 Hz, CHxHyAr), 4.51 (1 H, d, J = 12 Hz, CHxHyAr),

4.23 (2 H, q, J = 7 Hz, OCH2CH3), 3.98 (1 H, d, J = 3 Hz, H-3), 1.50 (3 H, s, CH3), 1.34 (3 H,

s, CH3), 1.31 (3 H, t, J = 7 Hz, OCH2CH3) ppm. 13

C NMR (75 MHz, CDCl3) δ 165.89 (C,

C=O), 141.33 (CH, C-5), 137.06 (C, Ar-C), 128.44 (CH, Ar-C), 127.98 (CH, Ar-C), 127.72

(CH, Ar-C), 123.26 (CH, C-6), 111.84 (C, C-Me2), 104.97 (CH, C-1), 82.90 (CH, C-3), 82.77

(CH, C-2), 79.42 (CH, C-4), 72.17 (CH2, OCH2Ar), 60.34 (CH2, OCH2CH3), 26.75 (CH3,

C(CH3)2), 26.15 (CH3, C(CH3)2), 14.19 (CH3, OCH2CH3) ppm.

(E)-3-O-benzyl-5,6-dideoxy-1,2-O-isopropylidene-α-D-xylo-hept-5-enfuranose71

(E)-12

To a solution of ester (E)-27 (85.5 mg, 0.21 mmol) in anhydrous THF (5 mL) at -78 °C was

added dropwise a 1.0 M solution of DIBAL-H in hexane (0.74 mL, 0.74 mmol) and the

mixture was stirred at -78 °C for 40 min, then slowly warmed up to room temperature over 2

h. The reaction mixture was quenched slowly with methanol (6 mL) at -78 °C, followed by

Rochelle salt (2 mL) at -10 °C. The mixture was allowed to warm up to room temperature

and then extracted with diethyl ether (3 × 10 mL), dried over anhydrous magnesium sulfate,

filtered and concentrated in vacuo. The crude product was purified by flash column

chromatography (silica gel; eluent 40% EtOAc/petrol) to afford the title compound as

colourless oil as trans-isomer. Rf (50% EtOAc/petrol): 0.20. IR max (thin film) 3437 (O-H

stretch), 2987 (C-H stretch), 2925 (C-H stretch), 2863 (C-H stretch), 1452, 1372, 1215, 1163,

1075 (C-O stretch), 1013 (C-O stretch) cm-1

. 1H NMR (500 MHz, CDCl3) δ 7.37 - 7.30 (5 H,

m, Ar-H), 6.06 – 6.00 (1 H, m, H-6), 5.97 (1 H, d, J = 4 Hz, H-1), 5.90 (1 H, dd, J = 16 and 7

Hz, H-5), 4.69 – 4.65 (2 H, m, CHxHyAr, H-4), 4.64 (1 H, d, J = 4 Hz, H-2), 4.54 (1 H, d, J =

12 Hz, CHxHyAr), 4.20 (2 H, d, J = 4 Hz, 2 × H-7), 3.88 (1 H, d, J = 3 Hz, H-3), 1.51 (3 H, s,

75

CH3), 1.33 (3 H, s, CH3) ppm. 13

C NMR (100 MHz, CDCl3) δ 137.47 (C, Ar-C), 134.10 (CH,

C-5), 128.44 (CH, Ar-C), 127.91 (CH, Ar-C), 127.66 (CH, Ar-C), 125.08 (CH, C-6), 111.57

(C, C-Me2), 104.78 (CH, C-1), 83.30 (CH, C-3), 82.85 (CH, C-2), 80.53 (CH, C-4), 72.15

(CH2, OCH2Ar), 63.03 (CH2, C-7), 26.74 (CH3, C(CH3)2), 26.17 (CH3, C(CH3)2) ppm. MS

(ES+) m/z [M+Na]+ 329.0, [2M+Na]

+ 635.0. Accurate Mass C17H22O5Na, [M+Na]

+ requires

329.1361, measured 329.1360.

3-O-benzyl-1,2:5,6-di-O-isopropylidene-α-D-glucofuranose72

17

A solution of 1,2:5,6-di-O-isopropylidene-α-D-glucofuranose (5.00 g, 19.2 mmol) in

anhydrous DMF (13 mL) was added dropwise at 0 °C to a suspension of sodium hydride

(60% dispersion in mineral oil, 692 mg, 28.8 mmol) in anhydrous DMF (13 mL). The resulting

mixture was stirred for fifteen minutes at 0 °C and then it was allowed to warm to room

temperature and stirred for 1 h. On re-cooling to 0 °C, benzyl bromide (2.51 mL, 21.2 mmol)

was added dropwise and the resulting reaction mixture was then stirred for 16 h at room

temperature. The mixture was quenched by the addition of saturated aqueous NH4Cl (15

mL) and then extracted with diethyl ether (3 × 15 mL). The combined organic extracts were

washed with water (2 × 15 mL) and brine (15 mL), respectively, then dried over anhydrous

magnesium sulfate, filtered and concentrated in vacuo. The crude product was purified by

flash column chromatography (silica gel; eluent 5% EtOAc/petrol) to afford 6.59 g (98%) of

the title compound as colourless oil. Rf (30% EtOAc/petrol): 0.57. α -24.1 (c 1.4, CHCl3)

lit.72

-29.8 (c 1.0, CHCl3). IR max (thin film) 2987 (C-H stretch), 2936 (C-H stretch),

2887 (C-H stretch), 1455 (aromatic C=C stretch), 1374, 1255, 1215, 1165, 1126, 1077 (C-O

stretch), 1024 (C-O stretch) cm-1

. 1

H NMR (400 MHz, CDCl3) δ 7.28 - 7.19 (5 H, m, Ar-H),

5.83 (1 H, d, J = 4 Hz, H-1), 4.63 (1 H, d, J = 12 Hz, CHxHyAr), 4.56 (1 H, d, J = 12 Hz,

CHxHyAr), 4.52 (1 H, d, J = 4 Hz, H-2), 4.30 (1 H, dt, J = 8 and 6 Hz, H-5), 4.07 (1 H, dd, J =

8 and 3 Hz, H-3), 4.04 (1 H, dd, J = 8 and 6 Hz, H-4), 3.95 - 3.91 (2 H, m, H-6), 1.42 (3 H, s,

76

CH3), 1.36 (3H, s, CH3), 1.30 (3 H, s, CH3), 1.24 (3 H, s, CH3) ppm. 13

C NMR (100 MHz,

CDCl3) δ 137.61 (C, Ar-C), 128.39 (CH, Ar-C), 127.84 (CH, Ar-C), 127.64 (CH, Ar-C), 111.78

(C, C-Me2), 108.98 (C, C-Me2), 105.28 (CH, C-1), 82.62 (CH, C-2), 81.66 (CH, C-3), 81.29

(CH, C-4), 72.50 (CH, C-5), 72.36 (CH2, OCH2Ar), 67.38 (CH2, C-6), 26.82 (CH3, C(CH3)2),

26.77 (CH3, C(CH3)2), 26.23 (CH3, C(CH3)2), 25.42 (CH3, C(CH3)2) ppm. MS (ES+) m/z

[M+Na]+ 373.3. Accurate Mass C19H2606Na, [M+Na]

+ requires 373.1611, measured

373.1622.

3-O-benzyl-1,2-di-O-isopropylidene-α-D-glucofuranose73

18

Acetic acid (36 mL) and water (20 mL) were added, at room temperature, to furanose 17

(6.50 g, 18.5 mmol). The resulting reaction mixture was stirred for 20 h at 40 °C. The mixture

was then neutralised with saturated Na2CO3 solution and extracted with DCM (3 × 35 mL).

The combined organic extracts were washed with water (35 mL), dried over anhydrous

magnesium sulfate, filtered and concentrated in vacuo. The crude product was purified by

flash column chromatography (silica gel; eluent 30% EtOAc/petrol) to afford 5.01 g (87%) of

the title compound as white oil. Rf (EtOAc): 0.51. -15.1 (c 1.0, CHCl3) lit.

74

-39.4 (c

1.0, CHCl3). IR max (thin film) 3347 (O-H stretch), 2357 (C-H stretch), 2337 (C-H stretch),

1648, 1559, 1267, 1099 (C-O stretch) cm-1

. 1H NMR (400 MHz, CDCl3) δ 7.40 - 7.33 (5 H, m,

Ar-H), 5.95 (1 H, d, J = 4 Hz, H-1), 4.76 (1 H, d, J = 11 Hz, CHxHyAr), 4.65 (1 H, d, J = 4 Hz,

H-2), 4.55 (1 H, d, J = 12 Hz, CHxHyAr), 4.13 (1 H, m, H-4), 4.13 (1 H, s, OH), 4.11 (1 H, s,

OH), 4.10 (1 H, d, J = 3 Hz, H-3), 4.05 - 4.02 (1 H, m, H-5), 3.81 (1 H, dd, J = 12 and 3, H-6),

3.70 (1 H, dd, J = 12 and 6 Hz, H-6), 1.49 (3 H, s, CH3), 1.33 (3 H, s, CH3) ppm. 13

C NMR

(100 MHz, CDCl3) δ 137.06 (C, Ar-C), 128.75 (CH, Ar-C), 128.31 (CH, Ar-C), 127.91 (CH,

Ar-C), 111.83 (C, C-Me2), 105.11 (CH, C-1), 82.04 (CH, C-2), 81.96 (CH, C-3), 79.88 (CH,

C-4), 72.06 (CH2, OCH2Ar), 69.17 (CH, C-5), 64.17 (CH2, C-6), 26.69 (CH3, C(CH3)2), 26.19

(CH3, C(CH3)2) ppm. MS (ES+) m/z [M+Na]+ 333.2. Accurate Mass C16H2206Na, [M+Na]

+

requires 333.1309, measured 333.1314.

77

3-O-benzyl-1,2-di-O-isopropylidene-α-D-xylo-pentadialdo-1,4-furanose14

19

Diol 18 (5.00 g, 16.1 mmol) was dissolved in 1,4-dioxane (42 mL) and a solution of sodium

metaperiodate (4.13 g, 19.3 mmol) in water (42 mL) was added. The reaction mixture was

stirred for 16 h at room temperature and then filtered. The filtrate was extracted with DCM (3

× 40 mL). The combined organic extracts were washed with water (25 mL), dried over

anhydrous magnesium sulfate, filtered and concentrated in vacuo to afford 4.55 g (100%)

crude of the title compound as yellow oil. -40.2 (c 1.7, CHCl3) lit.

75 -86.5 (c 2.7,

CHCl3). IR max (thin film) 2924 (C-H stretch), 2857 (C-H stretch), 1730 (C=O stretch), 1646,

1458, 1379, 1260, 1213, 1166, 1077 (C-O stretch), 1025 (C-O stretch) cm-1

. 1H NMR (400

MHz, CDCl3) δ 9.70 (1 H, d, J = 1.5 Hz, CHO), 7.39 - 7.25 (5 H, m, Ar-H), 6.15 (1 H, d, J = 3

Hz, H-1), 4.69 (1 H, d, J = 3 Hz, H-2), 4.62 (1 H, d, J = 12 Hz, CHxHyAr), 4.59 (1 H, dd, J = 4

and 1.5 Hz, H-4), 4.51 (1 H, d, J = 12 Hz, CHxHyAr), 4.36 (1 H, d, J = 4 Hz, H-3), 1.49 (3 H,

s, CH3), 1.35 (3 H, s, CH3) ppm. 13

C NMR (100 MHz, CDCl3) δ 199.97 (CH, CHO), 136.59

(C, Ar-C), 128.56 (CH, Ar-C), 128.19 (CH, Ar-C), 127.73 (CH, Ar-C), 112.59 (C, C-Me2),

106.20 (CH, C-1), 84.59 (CH, C-2), 83.69 (CH, C-3), 82.15 (CH, C-4), 72.38 (CH2, OCH2Ar),

26.97 (CH3, C(CH3)2), 26.35 (CH3, C(CH3)2) ppm. MS (ES+) m/z [M+Na]+ 301.2. Accurate

Mass C15H1805Na, [M+Na]+ requires 301.1054, measured 301.1046.

(E)-Methyl 3-O-benzyl-5,6-dideoxy-1,2-O-isopropylidene-α-D-xylo-hept-5-enfuranuronate76

(E)-27 and (Z)-Methyl 3-O-benzyl-5,6-dideoxy-1,2-O-isopropylidene-α-D-xylo-hept-5-

enfuranuronate (Z)-27

To a solution of the crude aldehyde 19 (10.6 g, 38.2 mmol) in anhydrous DCM (140 mL) was

added commercially available Ph3PCHCOOMe (14.0 g, 42.0 mmol) at room temperature.

78

After stirring for 16 h, the solvent was evaporated and the crude product was purified by

flash column chromatography (silica gel; eluent 10% EtOAc/petrol) to afford an overall yield

of 10.9 g (85%) of the title compounds as white oil (1:1.3, Z:E).

E-isomer (E)-27

Isolated yield: 7.04 g (55% as E-isomer) (1.36 g (11%) as Z/E mixture). -21.6 (c 0.8,

CHCl3). IR max (thin film) 2987 (C-H stretch), 2952 (C-H stretch), 1723 (C=O stretch), 1663

(C=C stretch), 1500, 1436, 1375, 1167, 1074 (C-O stretch), 1024 (C-O stretch) cm-1

. 1H

NMR (400 MHz, CDCl3) δ 7.34 - 7.24 (5 H, m, Ar-H), 6.95 (1 H, dd, J = 16 and 5 Hz, H-5),

6.16 (1 H, dd, J = 16 and 2 Hz, H-6), 5.98 (1 H, d, J = 4 Hz, H-1), 4.78 (1 H, dt, J = 3, 2 and 2

Hz, H-4), 4.62 (1 H, d, J = 3.5 Hz, H-2), 4.61 (1 H, d, J = 12 Hz, CHxHyAr), 4.48 (1 H, d, J =

12 Hz, CHxHyAr), 3.96 (1 H, d, J = 3 Hz, H-3), 3.74 (3 H, s, OCH3), 1.47 (3 H, s, CH3), 1.31

(3 H, s, CH3) ppm. 13

C NMR (100 MHz, CDCl3) δ 166.44 (C, C=O), 141.70 (CH, C-5), 137.02

(C, Ar-C), 128.50 (CH, Ar-C), 128.05 (CH, Ar-C), 127.78 (CH, Ar-C), 122.75 (CH, C-6),

111.90 (C, C-Me2), 104.96 (CH, C-1), 82.79 (CH, C-3), 82.72 (CH, C-2), 79.40 (CH, C-4),

72.18 (CH2, OCH2Ar), 51.65 (CH3, OCH3), 26.78 (CH3, C(CH3)2), 26.16 (CH3, C(CH3)2) ppm.

Z-isomer (Z)-27

Isolated yield: 2.49 g (19% as Z-isomer). -84.6 (c 1.2, CHCl3) lit.

77 -165.5 (c 1.5,

CHCl3). IR max (thin film) 2988 (C-H stretch), 2951 (C-H stretch), 1721 (C=O stretch), 1651

(C=C stretch), 1497, 1439, 1375, 1203, 1165, 1028 (C-O stretch) cm-1

. 1H NMR (400 MHz,

CDCl3) δ 7.32 - 7.25 (5 H, m, Ar-H), 6.41 (1 H, dd, J = 12 and 7 Hz, H-5), 6.02 (1 H, d, J = 4

Hz, H-1), 5.94 (1 H, dd, J = 12 and 2 Hz, H-6), 5.65 (1 H, ddd, J = 5, 3 and 2 Hz, H-4), 4.65

(1 H, d, J = 4 Hz, H-2), 4.62 (1 H, d, J = 12 Hz, CHxHyAr), 4.46 (1 H, d, J = 12 Hz, CHxHyAr),

4.30 (1 H, d, J = 3 Hz, H-3), 3.68 (3 H, s, OCH3), 1.53 (3 H, s, CH3), 1.34 (3 H, s, CH3) ppm.

13C NMR (100 MHz, CDCl3) δ 165.88 (C, C=O), 145.68 (CH, C-5), 137.37 (C, Ar-C), 128.33

(CH, Ar-C), 127.82 (CH, Ar-C), 127.71 (CH, Ar-C), 120.58 (CH, C-6), 111.81 (C, C-Me2),

105.11 (CH, C-1), 83.69 (CH, C-3), 83.04 (CH, C-2), 78.08 (CH, C-4), 72.14 (CH2, OCH2Ar),

51.41 (CH3, OCH3), 26.91 (CH3, C(CH3)2), 26.39 (CH3, C(CH3)2) ppm. MS (ES+) m/z

79

[M+NH4]+ 352.2, [M+Na]

+ 357.2. Accurate Mass C18H22O6Na, [M+Na]

+ requires 357.1309,

measured 357.1323.

(±)-(Z)-3-(Tetrahydro-furan-2-yl)-acrylic acid ethyl ester20

(Z)-43 and (±)-(E)-3-(Tetrahydro-

furan-2-yl)-acrylic acid ethyl ester (E)-43

To a stirred solution of commercially available (±)-2-tetrahydrofurfuryl alcohol (1.00 g, 9.80

mmol) and commercially available Ph3PCHCOOEt (4.09 g, 11.8 mmol) in anhydrous DCM

(80 mL) was added activated manganese dioxide (8.51 g, 97.9 mmol) in three equal portions

over the first hour while heated to reflux. The reaction mixture was then left to stir at reflux for

24 h. The manganese dioxide was removed by filtration through Celite and washed well with

DCM. The filtrate was dried over anhydrous magnesium sulfate, filtered and concentrated in

vacuo. The crude product was purified by flash column chromatography (silica gel; eluent

10% EtOAc/petrol) to afford an overall yield of 930 mg (56%) of the title compounds as

colourless oil (1:1, Z:E).

Z-isomer (Z)-43

Rf (10% EtOAc/petrol): 0.63. IR max (thin film) 3121 (C-H stretch), 2980 (C-H stretch), 1716

(C=O stretch), 1646 (C=C stretch), 1300, 1031 (C-O stretch) cm-1

. 1H NMR (300 MHz,

CDCl3) δ 1H NMR (300 MHz, CDCl3) δ 6.30 (1 H, dd, J = 12 and 7 Hz, H-5), 5.76 (1 H, dd, J

= 12 and 1.5 Hz, H-6), 5.25 - 5.32 (1 H, m, H-4), 4.17 (2 H, q, J = 7 Hz, OCH2CH3), 3.88 -

3.96 (1 H, m, H-1), 3.78 - 3.85 (1 H, m, H-1), 2.35 (1 H, dq, J = 13 and 7 Hz, H-3), 1.88 -

1.98 (2 H, m, H-2), 1.51 - 1.63 (1 H, m, H-3), 1.28 (3 H, t, J = 7 Hz, OCH2CH3) ppm. 13

C

NMR (75 MHz, CDCl3) δ 166.25 (C, C=O), 151.63 (CH, C-5), 119.62 (CH, C-6), 76.34 (CH,

C-4), 68.74 (CH2, C-1), 60.56 (CH2, OCH2CH3), 32.58 (CH2, C-3), 26.48 (CH2, C-2), 14.60

(CH3, OCH2CH3) ppm. MS (ES+) m/z [M+H]+

171.0, [M+Na]+ 193.0, [2M+Na]

+ 363.1.

Accurate Mass C9H14O3Na, [M+Na]+ requires 193.0835, measured 193.0839.

80

E-isomer (E)-43

Rf (10% EtOAc/petrol): 0.47. IR max (thin film) 3123 (C-H stretch), 2978 (C-H stretch), 1720

(C=O stretch), 1659 (C=C stretch), 1299, 1043 (C-O stretch) cm-1

. 1H NMR (300 MHz,

CDCl3) δ 6.91 (1 H, dd, J = 16 and 5 Hz, H-5), 6.01 (1 H, dd, J = 16 and 1 Hz, H-6), 4.47 -

4.55 (1 H, m, H-4), 4.19 (2 H, q, J = 7 Hz, OCH2CH3), 3.90 - 3.97 (1 H, m, H-1), 3.80 - 3.87

(1 H, m, H-1), 2.08 - 2.19 (1 H, m, H-3), 1.92 (2 H, quin, J = 7 Hz, H-2), 1.63 - 1.75 (1 H, m,

H-3), 1.28 (3 H, t, J = 7 Hz, OCH2CH3) ppm. 13

C NMR (75 MHz, CDCl3) δ 166.51 (C, C=O),

148.34 (CH, C-5), 120.19 (CH, C-6), 77.48 (CH, C-4), 68.46 (CH2, C-1), 60.31 (CH2,

OCH2CH3), 31.57 (CH2, C-3), 25.52 (CH2, C-2), 14.20 (CH3, OCH2CH3) ppm.

(3R)-ethyl 3-phenyl-3-(tetrahydrofuran-2-yl)propanoate 45 and (3S)-ethyl 3-phenyl-3-

(tetrahydrofuran-2-yl)propanoate 45a

CUPRATE REACTION

CuBr.DMS (“Aldrich”) (48.0 mg, 10 mol%) was dissolved in anhydrous THF (1 mL) and the

resulting solution was cooled to -78 °C. A 1.0 M solution of PhMgBr in THF (4.70 mL, 4.70

mmol) was added dropwise. After stirring for 30 min at the same temperature, a solution of

ester (E)-43 (0.40 g, 2.40 mmol) in anhydrous THF (5 mL) was added dropwise and the

resultant solution was stirred at the same temperature for 10 min and then at -40 °C for 3 h.

The reaction mixture was quenched by the addition of saturated aqueous NH4Cl (10 mL) and

extracted with diethyl ether (3 × 10 mL). The combined organic extracts were washed with

brine (10 mL), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo.

The crude product was purified by flash column chromatography (silica gel; eluent 15%

EtOAc/petrol) and the elution gave the title compounds as yellow oil with an overall yield of

118 mg (20%) (d.r. 8:1, 45:45a) and 18.3 mg (4%) of ester 46. Rf (30% EtOAc/petrol): 0.58.

IR max (thin film) 3029 (C-H stretch), 2977 (C-H stretch), 2871 (C-H stretch), 1733 (C=O

stretch), 1602 (C=C stretch), 1257 (C-O stretch), 1034 (C-O stretch) cm-1

. 1

H NMR (400

81

MHz, CDCl3) δ 7.31 -7.20 (5 H, m, Ar-H), 4.05 – 3.97 (3 H, m, OCH2CH3, H-4), 3.90 – 3.83 (1

H, m, H-1), 3.81 – 3.75 (1 H, m, H-1), 3.12 (1 H, td, J = 9 and 6 Hz, H-5), 3.03 (1 H, dd, J =

15 and 5.5 Hz, H-6), 2.61 (1 H, dd, J = 15 and 9 Hz, H-6), 1.94 - 1.75 (2 H, m, 2 × H-2), 1.72

- 1.62 (1 H, m, H-3), 1.54 - 1.44 (1 H, m, H-3), 1.11 (3 H, t, J = 7 Hz, OCH2CH3) ppm. 13

C

NMR (100 MHz, CDCl3) δ 172.59 (C, C=O), 141.42 (C, Ar-C), 128.42 (CH, Ar-C), 128.11

(CH, Ar-C), 126.79 (CH, Ar-C), 82.59 (CH, C-4), 68.07 (CH2, C-1), 60.13 (CH2, OCH2CH3),

47.80 (CH, C-5), 38.73 (CH2, C-6), 30.08 (CH2, C-3), 25.61 (CH2, C-2), 14.06 (CH3,

OCH2CH3) ppm. MS (ES+) m/z [M+Na]+ 271.1, [2M+Na]

+ 519.4. Accurate Mass

C15H20O3Na, [M+Na]+ requires 271.1305, measured 271.1306.

HAYASHI-MIYAURA REACTION25

To a mixture of phenylboronic acid (394 mg, 3.23 mmol) and commercially available

[RhCl(1,5-cod)]2 50 (36.8 mg, 5 mol%) under nitrogen were added a solution of α,β-

unsaturated ester (E)-43 (275 mg, 1.61 mmol) in 1,4-dioxane:H2O (10:1; 1.65 mL), followed

by triethylamine (0.22 mL, 1.61 mmol). The reaction mixture was stirred for 18 h at 50 °C,

then the products were isolated by evaporation of volatiles under reduced pressure and

purified by flash column chromatography (silica gel; eluent 5% EtOAc/petrol). The elution

gave the title compounds as yellow oil with an overall yield of 325 mg (81%) (d.r. 4:1,

45:45a). 1H NMR (500 MHz, CDCl3) δ 7.31 -7.19 (10 H, m, Ar-Hmajor, Ar-Hminor), 4.12 – 4.08 (1

H, m, Hminor-4), 4.04 – 3.98 (5 H, m, OCH2majorCH3, OCH2minorCH3, Hmajor-4), 3.86 (1 H, q, J =

7 Hz, Hmajor-1), 3.80 – 3.75 (1 H, m, Hmajor-1), 3.73 – 3.67 (2 H, m, 2 × Hminor-1), 3.29 (1 H, td,

J = 9 and 6 Hz, Hminor-5), 3.13 (1 H, td, J = 9 and 6 Hz, Hmajor-5), 3.01 (1 H, dd, J = 15 and 5.5

Hz, Hmajor-6), 2.82 (1 H, dd, J = 15 and 5 Hz, Hminor-6), 2.72 (1 H, dd, J = 15 and 10 Hz,

Hminor-6), 2.61 (1 H, dd, J = 15 and 9 Hz, Hmajor-6), 1.93 - 1.74 (6 H, m, 2 × Hmajor-2, 2 × Hminor-

2, 2 × Hminor-3), 1.71 - 1.65 (1 H, m, Hmajor-3), 1.55 - 1.45 (1 H, m, Hmajor-3), 1.16 – 1.08 (6 H,

overlapped t, J = 7 Hz, OCH2CH3major, OCH2CH3minor) ppm. 13

C NMR (100 MHz, CDCl3) δ

172.60 (C, Cmajor=O), 172.36 (C, Cminor=O), 141.40 (C, Ar-C), 128.68 (CH, Ar-Cminor), 128.42

(CH, Ar-Cmajor), 128.15 (CH, Ar-Cminor), 128.10 (CH, Ar-Cmajor), 126.79 (CH, Ar-Cmajor), 126.70

(CH, Ar-Cminor), 82.58 (CH, Cmajor-4), 81.68 (CH, Cminor-4), 68.29 (CH2, Cminor-1), 68.07 (CH2,

Cmajor-1), 60.29 (CH2, OCminorH2CH3), 60.14 (CH2, OCmajorH2CH3), 47.79 (CH, Cmajor-5), 46.31

82

(CH, Cminor-5), 38.72 (CH2, Cmajor-6), 37.50 (CH2, Cminor-6), 30.07 (CH2, Cmajor-3), 28.89 (CH2,

Cminor-3), 25.81 (CH2, Cminor-2), 25.60 (CH2, Cmajor-2), 14.06 (CH3, OCH2CH3) ppm.

(Z)-ethyl 7-hydroxyhept-3-enoate78

46

Isolated yield: 18.3 mg (4%). IR max (thin film) 3460 (O-H stretch), 2977 (C-H stretch), 2937

(C-H stretch), 2868 (C-H stretch), 1731 (C=O stretch), 1031 (C-O stretch) cm-1

. 1H NMR (400

MHz, CDCl3) δ 5.59 (2 H, m, H-2, H-3), 4.15 (2 H, q, J = 7 Hz, OCH2CH3), 3.67 (2 H, t, J = 6

Hz, 2 × H-6), 3.04 (2 H, m, 2 × H-1), 2.18 – 2.13 (2 H, m, 2 × H-4), 1.70 – 1.63 (2 H, m, 2 ×

H-5), 1.27 (3 H, t, J = 7 Hz, OCH2CH3) ppm. 13

C NMR (125 MHz, CDCl3) δ 172.41 (C, C=O),

134.30 (CH, C-2), 122.56 (CH, C-3), 62.66 (CH2, C-6), 60.86 (CH2, OCH2CH3), 38.27 (CH2,

C-1), 32.21 (CH2, C-5), 29.19 (CH2, C-4), 14.43 (CH3, OCH2CH3) ppm. MS (ES+) m/z

[M+Na]+ 195.1, [2M+Na]

+ 367.3. Accurate Mass C9H16O3Na, [M+Na]

+ requires 195.0992,

measured 195.0998.

(±)-1-phenylbutane-1,4-diol79

47

To a 1.0 M solution PhMgBr in THF (14 mL, 14.10 mmol) was added anhydrous THF (14

mL) and the solution was stirred at -78 °C for 30 min, then for 50 min at -40 °C. The solution

was quenched quenched by the addition of saturated aqueous NH4Cl (5 mL) and extracted

with diethyl ether (3 × 5 mL). The combined organic extracts were washed with brine (5 mL),

dried over anhydrous magnesium sulfate and concentrated in vacuo. The crude product was

purified by flash column chromatography (silica gel; eluent 10% → 20% → 50%

EtOAc/petrol) to afford 29.0 mg (1%) of the title compound as yellow oil. 1H NMR (400 MHz,

CDCl3) δ 7.30 - 7.17 (5 H, m, Ar-H), 4.63 (1 H, t, J = 6 Hz, H-4), 3.63 – 3.52 (2 H, m, 2 × H-

1), 2.95 (2 H, br. s, 2 × OH), 1.77 (2 H, q, J = 7 Hz, 2 × H-3), 1.65 – 1.53 (2 H, m, 2 × H-2)

ppm. 13

C NMR (100 MHz, CDCl3) δ 144.65 (C, Ar-C), 128.37 (CH, Ar-C), 128.06 (CH, Ar-C),

127.39 (CH, Ar-C), 126.06 (CH, Ar-C), 125.74 (CH, Ar-C), 74.25 (CH, C-4), 62.70 (CH2, C-

83

1), 36.30 (CH2, C-3), 29.12 (CH2, C-2) ppm. MS (ES+) m/z [M+Na]+ 189.0. Accurate Mass

C10H14O2Na, [M+Na]+ requires 189.0886, measured 189.0892.

Bis(η4-1,5-cyclooctadiene)-di-µ-chloro-dirhodium(I)

80 50

To a mixture of RhCl3 (2.00 g, 9.56 mmol) and Na2CO3 (1.01 g, 9.56 mmol) in deoxygenated

EtOH:H2O (5:1; 25 mL) was added 1,5-cyclooctadiene (4 mL, 28.68 mmol) and the resulting

solution was stirred at reflux for 18 h. The reaction mixture was then cooled and immediately

filtered. The solid was washed with pentane (25 mL), and then with MeOH:H2O (1:5; 25 mL)

until the washings no longer contained chloride ions. The crude product was recrystallised

from DCM to afford 1.53 g (65%) of the title compound as yellow-orange solid. mp 245 - 250

°C (lit.81

mp 256 °C). IR max (thin film) 2909 (C-H stretch), 2871 (C-H stretch), 2827 (C-H

stretch), 1467 (CH2 bending), 1322 (C-H bending), 959 cm-1

. 1H NMR (500 MHz, CDCl3) δ

4.24 (8 H, br. s, vinylic protons), 2.52 – 2.50 (8 H, m, allylic protons), 1.76 (8 H, dd, J = 7 Hz,

allylic protons) ppm.

Bis(η4-1,5-cyclooctadiene)-di-µ-hydroxo-dirhodium(I)

82,83 50a

To a vigorously stirred solution of [RhCl(1,5-cod)]2 50 (0.24 g, 0.47 mmol) in benzene (10

mL), was added a solution of 0.2 M of aqueous potassium hydroxide (16 mL) containing

benzyltriethylammonium chloride (36.0 mg, 0.16 mmol) over a period of 10 minutes. The

reaction mixture was stirred for 15 minutes and the yellow precipitate was filtered and dried

in vacuo to afford the title compound as yellow solid. 1H NMR (500 MHz, CDCl3) δ 3.85 (8 H,

br. s, vinylic protons), 2.46 (10 H, br. s, allylic protons and hydroxides), 1.67 (8 H, br. m,

allylic protons) ppm.

84

(4S,5R)-3-phenyl-3-(tetrahydrofuran-2-yl)propan-1-ol 51 and (4S,5S)-3-phenyl-3-

(tetrahydrofuran-2-yl)propan-1-ol29

51a

To a solution of a mixture of esters 45 and 45a (d.r. 4:1, 45:45a) (194 mg, 0.78 mmol) in

anhydrous THF (5 mL) was added dropwise a 1.0 M solution of DIBAL-H in hexane (2.73

mL, 2.73 mmol) at -78 °C and the mixture was slowly warmed up to 0 °C over 3 h. Upon

completion, the reaction mixture was quenched slowly with methanol (2 mL) at -78 °C,

followed by Rochelle salt (2 mL) at -10 °C. The mixture was allowed to warm up to room

temperature and then extracted with diethyl ether (3 × 10 mL), dried over anhydrous

magnesium sulfate, filtered and concentrated in vacuo. The crude product was purified by

flash column chromatography (silica gel; eluent 15% → 20% EtOAc/petrol) and the elution

gave the title compounds as colourless oil with an overall yield of 138 mg (85%) (d.r. 4:1,

51:51a). Rf (40% EtOAc/petrol): 0.27. IR max (thin film) 3382 (O-H stretch), 3060 (C-H

stretch), 3027 (C-H stretch), 2946 (C-H stretch), 2871 (C-H stretch), 1494, 1453, 1051 (C-O

stretch) cm-1

. 1

H NMR (500 MHz, CDCl3) δ 7.35 -7.11 (5 H, m, Ar-Hmajor), 4.01 (1 H, td, J =

8.5 and 6 Hz, Hmajor-4), 3.95 – 3.89 (1 H, m, Hmajor-1), 3.83 (1 H, td, J = 8 and 6 Hz, Hmajor-1),

3.69 – 3.63 (1 H, m, Hmajor-7), 3.61 – 3.53 (1 H, m, Hmajor-7), 2.77 (1 H, br. s, OHmajor), 2.69 (1

H, dt, J = 9 and 7 Hz, Hmajor-5), 2.28 – 2.18 (1 H, m, Hmajor-6), 1.97 - 1.89 (1 H, m, Hmajor-6),

1.87 – 1.75 (2 H, m, 2 × Hmajor-2), 1.66 – 1.55 (1 H, m, Hmajor-3), 1.41 (1 H, dq, J = 13 and 8

Hz, Hmajor-3) ppm. 13

C NMR (125 MHz, CDCl3) δ 143.16 (C, Ar-Cmajor), 141.88 (C, Ar-Cminor),

128.68 (CH, Ar-Cminor), 128.53 (CH, Ar-Cmajor), 128.29 (CH, Ar-Cminor), 127.93 (CH, Ar-Cmajor),

126.54 (CH, Ar-Cmajor), 126.51 (CH, Ar-Cminor), 83.44 (CH, Cmajor-4), 82.70 (CH, Cminor-4),

68.16 (CH2, Cmajor-1), 68.07 (CH2, Cminor-1), 61.54 (CH2, Cmajor-7), 60.96 (CH2, Cminor-7), 49.58

(CH, Cmajor-5), 47.16 (CH, Cminor-5), 37.88 (CH2, Cmajor-6), 35.35 (CH2, Cminor-6), 30.78 (CH2,

Cmajor-3), 29.10 (CH2, Cminor-3), 25.74 (CH2, Cminor-2), 25.48 (CH2, Cmajor-2) ppm. MS (ES+)

m/z [M+H]+ 207.0, [M+Na]

+ 229.0. Accurate Mass C13H19O2, [M+H]

+ requires 207.1381,

measured 207.1380.

85

(5S)-Methyl 3-O-benzyl-5-phenyl-1,2-O-isopropylidene-α-D-xylo-hept-5-enfuranuronate59,84

55

CUPRATE REACTION

Reaction with E-isomer: To a suspension of CuI (171 mg, 0.90 mmol) in anhydrous THF (9

mL) was added, at -78 °C, a 1.0 M solution of PhMgBr in THF (4.50 mL, 4.50 mmol). After 40

min at -78 °C, TMSCl (1.71 mL, 13.5 mmol) was added to the reaction mixture, followed by

dropwise addition of a solution of α,β-unsaturated ester (E)-27 (300 mg, 0.90 mmol) in

anhydrous THF (13 mL). The reaction mixture was then allowed to slowly warm to room

temperature over 3 h. The reaction mixture was then quenched, at -78 °C, by the addition of

saturated aqueous NH4OH:NH4Cl (1:9; 35 mL) and extracted with diethyl ether (3 × 35 mL).

The combined organic extracts were washed with brine (30 mL), dried over anhydrous

magnesium sulfate, filtered and concentrated in vacuo. The crude product was purified by

flash column chromatography (silica gel; eluent 5% EtOAc/petrol) to afford 311 mg (84%) of

the title compound as white oil as a single diastereoisomer. Rf (30% EtOAc/petrol): 0.57.

-52.4 (c 1.6, CHCl3) lit.

84

-29.5 (c 2.0, CHCl3). IR max (thin film) 3063 (C-H

stretch), 3031 (C-H stretch), 2987 (C-H stretch), 2929 (C-H stretch), 2873 (C-H stretch),

1739 (C=O stretch), 1496, 1454, 1374, 1256, 1165, 1079 (C-O stretch), 1027 (C-O stretch)

cm-1

. 1H NMR (400 MHz, CDCl3) δ 7.36 - 7.24 (10 H, m, Ar-H), 5.97 (1 H, d, J = 4 Hz, H-1),

4.54 (1 H, d, J = 4 Hz, H-2), 4.41 (1 H, d, J = 11 Hz, CHxHyAr), 4.37 (1 H, dd, J = 10 and 3

Hz, H-4), 4.12 (1 H, d, J = 11 Hz, CHxHyAr), 3.71 (1 H, td, J = 11 and 4 Hz, H-5), 3.52 (3 H,

s, OCH3), 3.44 (1 H, d, J = 3 Hz, H-3), 3.12 (1 H, dd, J = 16 and 4 Hz, H-6), 2.70 (1 H, dd, J

= 16 and 11 Hz, H-6), 1.54 (3 H, s, CH3), 1.32 (3 H, s, CH3) ppm. 13

C NMR (100 MHz, CDCl3)

δ 172.53 (C, C=O), 140.24 (C, Ar-C), 137.28 (C, Ar-C), 128.41 (CH, Ar-C), 128.39 (CH, Ar-

C), 128.19 (CH, Ar-C), 127.79 (CH, Ar-C), 127.68 (CH, Ar-C), 126.99 (CH, Ar-C), 111.41 (C,

C-Me2), 105.00 (CH, C-1), 83.31 (CH, C-4), 81.85 (CH, C-2), 81.51 (CH, C-3), 71.95 (CH2,

OCH2Ar), 51.38 (CH3, OCH3), 40.79 (CH, C-5), 38.72 (CH2, C-6), 26.72 (CH3, C(CH3)2),

86

26.11 (CH3, C(CH3)2) ppm. MS (ES+) m/z [M+Na]+ 413.0. Accurate Mass C24H28O6Na,

[M+Na]+ requires 413.1959, measured 413.1953.

Reaction with Z-isomer: To a suspension of CuI (171 mg, 0.90 mmol) in anhydrous THF (9

mL) was added, at -78 °C, a 1.0 M solution of PhMgBr in THF (4.50 mL, 4.50 mmol). After 40

min at -78 °C, TMSCl (1.71 mL, 13.5 mmol) was added to the reaction mixture, followed by

dropwise addition of a solution of α,β-unsaturated ester (Z)-27 (300 mg, 0.90 mmol) in

anhydrous THF (13 mL). The reaction mixture was then allowed to slowly warm to room

temperature over 3 h. The reaction mixture was then quenched, at -78 °C, by the addition of

saturated aqueous NH4OH:NH4Cl (1:9; 35 mL) and extracted with diethyl ether (3 × 35 mL).

The combined organic extracts were washed with brine (30 mL), dried over anhydrous

magnesium sulfate, filtered and concentrated in vacuo. The crude product was purified by

flash column chromatography (silica gel; eluent 5% EtOAc/petrol) to afford 257 mg (69%) of

the title compound as white oil as a single diastereoisomer (data as described above).

HAYASHI-MIYAURA REACTION25

Reaction with [RhCl(1,5-cod)]2 catalyst: To a mixture of phenylboronic acid (0.22 g, 1.80

mmol) and [RhCl(1,5-cod)]2 50 (24.6 mg, 5 mol%) under nitrogen were added a solution of

α,β-unsaturated ester (E)-27 (0.30 g, 0.90 mmol) in 1,4-dioxane:H2O (10:1; 2.25 mL),

followed by triethylamine (0.13 mL, 0.90 mmol). The reaction mixture was stirred for two

days at room temperature, then the products were isolated by evaporation of volatiles under

reduced pressure and purified by flash column chromatography (silica gel; eluent 5%

EtOAc/petrol). The elution gave the title compound as colourless oil with an overall yield of

0.35 g (90%) (d.r. 12:1, 55:55a) (data of major diastereoisomer as described above).

Reaction with [Rh(OH)(1,5-cod)]2 catalyst: To a mixture of phenylboronic acid (73.1 mg,

0.60 mmol) and [Rh(OH)(1,5-cod)]2 50a (6.84 mg, 5 mol%) under nitrogen were added a

solution of α,β-unsaturated ester (E)-27 (100 mg, 0.30 mmol) in 1,4-dioxane:H2O (10:1; 0.76

mL), followed by triethylamine (42 μL, 0.30 mmol). The reaction mixture was stirred for two

days at room temperature, then the products were isolated by evaporation of volatiles under

87

reduced pressure and purified by flash column chromatography (silica gel; eluent 20%

EtOAc/petrol). The elution gave the title compound as colourless oil with an overall yield of

88.4 mg (71%) (d.r. 17:1, 55:55a) (data of major diastereoisomer as described above).

PALLADIUM-CATALYSED REACTION58

To a stirred solution of α,β-unsaturated ester (E)-27 (0.15 g, 0.45 mmol) in toluene (2 mL)

were added phenylboronic acid (109 mg, 0.90 mmol), potassium phosphate (95.5 mg, 0.45

mmol) and the Bedford’s catalyst 157 (34.4 mg, 5 mol%). The reaction mixture was stirred

for 48 h at 40 °C, then quenched with water (5 mL), extracted with DCM (3 × 5 mL) and dried

over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The crude product

was purified by flash column chromatography (silica gel; eluent 5% EtOAc/petrol) to afford

47.9 mg (26%) of the title compound as yellow oil (d.r. 15:1, 55:55a) (data of major

diastereoisomer as described above).

(S)-3-((3aR,5R,6S,6aR)-6-(benzyloxy)-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-5-yl)-1,3-

diphenylpropan-1-one38

56

ZnCl2·TMEDA (68.2 mg, 0.27 mmol) was stirred in THF (4 mL) at 0 °C for 15 min. To the

resulting suspension, was added a 2.0 M solution of phenyllithium in n-dibutyl ether (1.26

mL, 0.45 mmol) at 0 °C and stirred for further 15 min. The reaction mixture was then cooled

to -78 °C and was added a solution of α,β-unsaturated ester (E)-27 (70.0 mg, 0.21 mmol) in

THF (2 mL) dropwise. The reaction mixture was stirred at -78 °C for 4 h, then quenched with

saturated aqueous NH4Cl (5 mL) and extracted with diethyl ether (3 × 5 mL). The combined

organic extracts were washed with brine (5 mL), dried over anhydrous magnesium sulfate,

filtered and concentrated in vacuo. The crude product was purified by flash column

chromatography (silica gel; eluent 5% EtOAc/petrol) to afford 20.0 mg (21%) of the title

compound as colourless oil as a single diastereoisomer (7:1, 56:55). Rf (15% EtOAc/petrol):

88

0.14. 1H NMR (500 MHz, CDCl3) δ 7.90 (2 H, overlapped d, J = 7 Hz, 2 × Ar-H), 7.52 – 7.46

(1 H, m, Ar-H), 7.42 – 7.16 (12 H, m, Ar-H), 5.98 (1 H, d, J = 4 Hz, H-1), 4.55 (1 H, d, J = 4

Hz, H-2), 4.45 (1 H, dd, J = 10 and 3 Hz, H-4), 4.41 (1 H, d, J = 11 Hz, CHxHyAr), 4.15 (1 H,

d, J = 11 Hz, CHxHyAr), 3.99 (1 H, td, J = 11 and 3 Hz, H-5), 3.76 (1 H, dd, J = 17 and 3 Hz,

H-6), 3.51 – 3.43 (1 H, m, H-6), 3.46 (1 H, d, J = 3 Hz, H-3), 1.56 (3 H, s, CH3), 1.32 (3 H, s,

CH3) ppm.

(5S)-Methyl 3-O-benzyl-5-(4-methoxyphenyl)-1,2-O-isopropylidene-α-D-xylo-hept-5-

enfuranuronate 57

CUPRATE REACTION59

To a suspension of CuI (284 mg, 1.49 mmol) in anhydrous THF (14 mL) was added, at -78

°C, a 0.5 M solution of p-methoxyphenymagnesium bromide in THF (15 mL, 7.48 mmol).

After 40 min at -78 °C, freshly distilled TMSCl (2.84 mL, 22.3 mmol) was added to the

reaction mixture, followed by dropwise addition of a solution of α,β-unsaturated ester (E)-27

(0.50 g, 1.49 mmol) in anhydrous THF (21 mL). The reaction mixture was then allowed to

slowly warm to room temperature over 3 h. The reaction mixture was then quenched, at -78

°C, by the addition of saturated aqueous NH4OH:NH4Cl (1:9; 25 mL) and extracted with

diethyl ether (3 × 25 mL). The combined organic extracts were washed with brine (25 mL),

dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The crude

product was purified by flash column chromatography (silica gel; eluent 10% EtOAc/petrol) to

afford 418 mg (63%) of the title compounds as yellow oil (d.r. 13:1, 57:57a). Rf (40%

EtOAc/petrol): 0.65. -47.3 (c 1.0, CHCl3). IR max (thin film) 2923 (C-H stretch), 1732

(C=O stretch), 1611 (aromatic C=C stretch), 1512, 1372, 1245, 1162, 1070 (C-O stretch),

1025 (C-O stretch) cm-1

. 1H NMR (400 MHz, CDCl3) δ 7.30 - 7.38 (3 H, m, Ar-H), 7.25 - 7.29

(2 H, m, Ar-H), 7.12 - 7.17 (2 H, m, Ar-H), 6.79 - 6.82 (2 H, m, Ar-H), 5.95 (1 H, d, J = 4 Hz,

89

H-1), 4.52 (1 H, d, J = 4 Hz, H-2), 4.41 (1 H, d, J = 11 Hz, CHxHyAr), 4.31 (1 H, dd, J = 10

and 3 Hz, H-4), 4.14 (1 H, d, J = 11 Hz, CHxHyAr), 3.79 (3 H, s, C(O)CH3), 3.64 (1 H, td, J =

11 and 4 Hz, H-5), 3.51 (3 H, s, OCH3), 3.43 (1 H, d, J = 3 Hz, H-3), 3.08 (1 H, dd, J = 16

and 4 Hz, H-6), 2.65 (1 H, dd, J = 16 and 11 Hz, H-6), 1.53 (3 H, s, CH3), 1.31 (3 H, s, CH3)

ppm. 13

C NMR (100 MHz, CDCl3) δ 172.65 (C, C=O), 158.37 (C, Ar-C-OCH3), 137.39 (C, Ar-

C), 132.19 (CH, Ar-C), 129.17 (CH, Ar-C), 128.42 (CH, Ar-C), 127.80 (CH, Ar-C), 127.70

(CH, Ar-C), 113.79 (CH, Ar-C), 111.42 (C, C-Me2), 105.05 (CH, C-1), 83.49 (CH, C-4), 81.87

(CH, C-2), 81.57 (CH, C-3), 71.96 (CH2, OCH2Ar), 55.19 (CH3, OCH3), 51.39 (CH3,

C(O)CH3), 39.99 (CH, C-5), 38.84 (CH2, C-6), 26.76 (CH3, C(CH3)2), 26.15 (CH3, C(CH3)2)

ppm. MS (ES+) m/z [M+Na]+ 465.0. Accurate Mass C25H30O7Na, [M+Na]

+ requires

465.1884, measured 465.1877.

HAYASHI-MIYAURA REACTION25

To a mixture of 4-methoxyphenylboronic acid (0.45 g, 2.98 mmol) and [RhCl(1,5-cod)]2 50

(36.7 mg, 5 mol%) under nitrogen were added a solution of α,β-unsaturated ester (E)-27

(0.50 g, 1.49 mmol) in 1,4-dioxane:H2O (10:1; 3.72 mL), followed by triethylamine (0.21 mL,

1.49 mmol). The reaction mixture was stirred for 12 h at 50 °C, then the products were

isolated by evaporation of volatiles under reduced pressure and the crude product (50%

conversion) was purified by flash column chromatography (silica gel; eluent 5%

EtOAc/petrol) to afford 0.31 g (47%) of the title compounds as yellow oil (d.r. 13:1, 57:57a)

(data of major diastereoisomer as described above).

(5S)-Methyl 3-O-benzyl-5-isopropenyl-1,2-O-isopropylidene-α-D-xylo-hept-5-

enfuranuronate59

58

To a suspension of CuI (57.1 mg, 0.30 mmol) in anhydrous THF (3 mL) was added, at -78

°C, a 0.5 M solution of isopropenylmagnesium bromide in THF (3.00 mL, 1.50 mmol). After

90

40 min at -78 °C, TMSCl (0.57 mL, 4.50 mmol) was added to the reaction mixture, followed

by dropwise addition of a solution of α,β-unsaturated ester (E)-27 (100 mg, 0.30 mmol) in

anhydrous THF (4 mL). The reaction mixture was then allowed to slowly warm to room

temperature over 4 h. The reaction mixture was then quenched, at -78 °C, by the addition of

saturated aqueous NH4OH:NH4Cl (1:9; 10 mL) and extracted with diethyl ether (3 × 10 mL).

The combined organic extracts were washed with brine (10 mL), dried over anhydrous

magnesium sulfate, filtered and concentrated in vacuo. The crude product was purified by

flash column chromatography (silica gel; eluent 5% EtOAc/petrol) to afford 74.0 mg (65%) of

the title compound as yellow oil as a single diastereoisomer. IR max (thin film) 2961 (C-H

stretch), 1736 (C=O stretch), 1646 (C=C stretch), 1075 (C-O stretch), 1021 (C-O stretch) cm-

1.

1H NMR (500 MHz, CDCl3) δ 7.39 - 7.30 (5 H, m, Ar-H), 5.91 (1 H, d, J = 4 Hz, H-1), 4.85

(2 H, overlapped d, J = 9 Hz, 2 × H-7), 4.61 (1 H, d, J = 11 Hz, CHxHyAr), 4.57 (1 H, d, J = 4

Hz, H-2), 4.47 (1 H, d, J = 11 Hz, CHxHyAr), 4.15 (1 H, dd, J = 10 and 3 Hz, H-4), 3.81 (1 H,

d, J = 3 Hz, H-3), 3.63 (3 H, s, OCH3), 3.19 - 3.14 (1 H, m, H-5), 2.86 (1 H, dd, J = 15 and 4

Hz, H-6), 2.49 (1 H, dd, J = 15 and 10 Hz, H-6), 1.74 (3 H, s, H-8), 1.51 (3 H, s, CH3), 1.32 (3

H, s, CH3) ppm. 13

C NMR (125 MHz, CDCl3) δ 172.90 (C, C=O), 143.82 (C, C-9), 137.37 (C,

Ar-C), 128.56 (CH, Ar-C), 128.38 (CH, Ar-C), 127.80 (CH, Ar-C), 127.64 (CH, Ar-C), 126.97

(CH, Ar-C), 113.82 (CH2, C-7), 111.36 (C, C-Me2), 104.74 (CH, C-1), 81.86 (CH, C-4), 81.82

(CH, C-2), 81.59 (CH, C-3), 72.09 (CH2, OCH2Ar), 51.42 (CH3, OCH3), 41.68 (CH, C-5),

36.79 (CH2, C-6), 26.70 (CH3, C(CH3)2), 26.15 (CH3, C(CH3)2), 20.56 (CH3, C-8) ppm. MS

(ES+) m/z [M+Na]+ 399.0. Accurate Mass C21H28O6Na, [M+Na]

+ requires 399.1778,

measured 399.1781.

(5S)-Methyl 3-O-benzyl-5-vinyl-1,2-O-isopropylidene-α-D-xylo-hept-5-enfuranuronate59

59

To a suspension of CuI (28.6 mg, 0.15 mmol) in anhydrous THF (1 mL) was added, at -78

°C, a 0.7 M solution of vinylmagnesium bromide in THF (1.07 mL, 0.75 mmol). After 40 min

91

at -78 °C, TMSCl (0.28 mL, 2.25 mmol) was added to the reaction mixture, followed by

dropwise addition of a solution of α,β-unsaturated ester (E)-27 (50.0 mg, 0.15 mmol) in

anhydrous THF (2 mL). The reaction mixture was then allowed to slowly warm to room

temperature over 4 h. The reaction mixture was then quenched, at -78 °C, by the addition of

saturated aqueous NH4OH:NH4Cl (1:9; 10 mL) and extracted with diethyl ether (3 × 10 mL).

The combined organic extracts were washed with brine (10 mL), dried over anhydrous

magnesium sulfate, filtered and concentrated in vacuo. The crude product was purified by

flash column chromatography (silica gel; eluent 5% EtOAc/petrol) and the elution gave the

title compound as yellow oil with an overall yield of 43.7 mg (80%) (d.r. 6:1, 59:59a). IR max

(thin film) 2961 (C-H stretch), 1734 (C=O stretch), 1654 (C=C stretch), 1073 (C-O stretch),

1031 (C-O stretch) cm-1

. 1H NMR (500 MHz, CDCl3) δ 7.41 - 7.28 (5 H, m, Ar-H), 5.92 (1 H,

d, J = 4 Hz, H-1), 5.67 (1 H, ddd, J = 17, 10 and 8 Hz, H-8), 5.15 (1 H, d, J = 17 Hz, H-7),

5.08 (1 H, dd, J = 10 and 1 Hz, H-7), 4.64 (1 H, d, J = 11 Hz, CHxHyAr), 4.59 (1 H, d, J = 4

Hz, H-2), 4.47 (1 H, d, J = 11 Hz, CHxHyAr), 4.04 (1 H, dd, J = 10 and 3 Hz, H-4), 3.83 (1 H,

d, J = 3 Hz, H-3), 3.64 (3 H, s, OCH3), 3.14 - 3.21 (1 H, m, H-5), 2.84 (1 H, dd, J = 15 and 4

Hz, H-6), 2.43 (1 H, dd, J = 15 and 10 Hz, H-6), 1.50 (3 H, s, CH3), 1.32 (3 H, s, CH3) ppm.

13C NMR (125 MHz, CDCl3) δ 172.72 (C, C=O), 137.34 (CH, C-8), 136.32 (C, Ar-C), 128.42

(CH, Ar-C), 127.87 (CH, Ar-C), 127.76 (CH, Ar-C), 117.68 (CH2, C-7), 111.45 (C, C-Me2),

104.75 (CH, C-1), 81.88 (CH, C-4), 81.82 (CH, C-2), 81.67 (CH, C-3), 72.04 (CH2, OCH2Ar),

51.41 (CH3, OCH3), 38.97 (CH, C-5), 36.81 (CH2, C-6), 26.69 (CH3, C(CH3)2), 26.18 (CH3,

C(CH3)2) ppm. MS (ES+) m/z [M+Na]+ 385.1. Accurate Mass C20H26O6Na, [M+Na]

+ requires

385.1622, measured 385.1619.

(5S)-Methyl 3-O-benzyl-5-ethyl-1,2-O-isopropylidene-α-D-xylo-hept-5-enfuranuronate 60

Using a 30 × 4 mm catalyst cartridge (CatCart®) of 10% Pd/C (TH01111), a 0.05 M solution

of 63 (39.5 mg, 0.10 mmol) in MeOH (0.79 mL) was passed through the CatCart® four times

92

at a flow rate of 1 mL/min and the product was continuously eluted out of the CatCart® and

into a collection vial. The pressure of the system was set to 1 bar and the temperature to 50

°C, with a constant flow of hydrogen (full H2 mode). The crude product was then purified by

flash column chromatography (silica gel; eluent 5% EtOAc/petrol) and the elution gave the

title compound as yellow oil with an overall yield of 31.4 mg (78%) (d.r. 6:1, 60:60a). -

27.8 (c 0.2, CHCl3). IR max (thin film) 2956 (C-H stretch), 2927 (C-H stretch), 1734 (C=O

stretch), 1073 (C-O stretch), 1026 (C-O stretch) cm-1

. 1H NMR (500 MHz, CDCl3) δ 7.29 -

7.40 (5 H, m, Ar-H), 5.90 (1 H, d, J = 4 Hz, H-1), 4.71 (1 H, d, J = 12 Hz, CHxHyAr), 4.63 (1

H, d, J = 4 Hz, H-2), 4.46 (1 H, d, J = 12 Hz, CHxHyAr), 4.05 (1 H, dd, J = 9 and 3 Hz, H-4),

3.85 (1 H, d, J = 3 Hz, H-3), 3.65 (3 H, s, OCH3), 2.64 - 2.69 (1 H, m, H-6), 2.43 - 2.45 (1 H,

m, H-6), 2.35 - 2.42 (1 H, m, H-5), 1.50 (3 H, s, CH3), 1.33 (3 H, s, CH3), 1.19 - 1.31 (5 H, m,

H-7, H-8) ppm. 13

C NMR (125 MHz, CDCl3) δ 173.61 (C, C=O), 137.29 (C, Ar-C), 128.42

(CH, Ar-C), 127.95 (CH, Ar-C), 127.88 (CH, Ar-C), 111.30 (C, C-Me2), 104.44 (CH, C-1),

81.93 (CH, C-4), 81.85 (CH, C-2), 81.26 (CH, C-3), 71.59 (CH2, OCH2Ar), 51.35 (CH3,

OCH3), 35.05 (CH2, C-6), 29.69 (CH, C-5), 26.70 (CH3, C(CH3)2), 26.28 (CH3, C(CH3)2),

22.98 (CH2, C-8), 10.65 (CH3, C-7) ppm. MS (ES+) m/z [M+Na]+ 387.0. Accurate Mass

C20H28O6Na, [M+Na]+

requires 387.1778, measured 387.1771.

(5S)-Methyl 3-O-benzyl-5-(4-vinylphenyl)-1,2-O-isopropylidene-α-D-xylo-hept-5-

enfuranuronate25

65

To a mixture of 4-vinylphenylboronic acid (0.27 g, 1.80 mmol) and [RhCl(1,5-cod)]2 50 (24.6

mg, 5 mol%) under nitrogen were added a solution of α,β-unsaturated ester (E)-27 (0.30 g,

0.90 mmol) in 1,4-dioxane:H2O (10:1; 2.25 mL), followed by triethylamine (0.13 mL, 0.90

mmol). The reaction mixture was stirred for two days at room temperature, then the products

were isolated by evaporation of volatiles under reduced pressure and purified by flash

93

column chromatography (silica gel; eluent 5% EtOAc/petrol) to afford 8.10 mg (2%) of the

title compound as yellow oil (d.r. 2:1, 65:65a). IR max (thin film) 2925 (C-H stretch), 1736

(C=O stretch), 1604 (C=C stretch), 1163, 1071 (C-O stretch), 1023 (C-O stretch) cm-1

. 1

H

NMR (400 MHz, CDCl3) δ 7.54 - 7.20 (9 H, m, Ar-H), 6.73 (1 H, dd, J = 18 and 11 Hz, H-8),

5.97 (1 H, d, J = 4 Hz, H-1), 5.78 (1 H, d, J = 18 Hz, H-7), 5.26 (1 H, d, J = 11 Hz, H-7), 4.54

(1 H, d, J = 4 Hz, H-2), 4.43 (1 H, d, J = 11 Hz, CHxHyAr), 4.36 (1 H, dd, J = 10 and 3 Hz, H-

4), 4.15 (1 H, d, J = 12 Hz, CHxHyAr), 3.75 – 3.68 (1 H, m, H-5), 3.52 (3 H, s, OCH3), 3.46 (1

H, d, J = 3 Hz, H-3), 3.12 (1 H, dd, J = 16 and 4 Hz, H-6), 2.70 (1 H, dd, J = 16 and 11 Hz, H-

6), 1.54 (3 H, s, CH3), 1.31 (3 H, s, CH3) ppm. 13

C NMR (100 MHz, CDCl3) δ 172.49 (C,

C=O), 137.28 (C, Ar-C), 136.84 (C, Ar-C), 136.39 (CH, C-8), 136.02 (C, Ar-C), 128.54 (CH,

Ar-C), 128.41 (CH, Ar-C), 128.21 (CH, Ar-C), 128.05 (CH, Ar-C), 127.80 (CH, Ar-C), 127.67

(CH, Ar-C), 126.62 (CH, Ar-C), 126.56 (CH, Ar-C), 126.53 (CH, Ar-C), 113.74 (CH2, C-7),

111.44 (C, C-Me2), 105.01 (CH, C-1), 83.21 (CH, C-2), 81.82 (CH, C-3), 81.49 (CH, C-4),

71.92 (CH2, OCH2Ar), 51.43 (CH3, OCH3), 40.59 (CH2, C-6), 29.69 (CH, C-5), 26.74 (CH3,

C(CH3)2), 26.11 (CH3, C(CH3)2) ppm. MS (ES+) m/z [M+Na]+ 461.0 Accurate Mass

C26H30O6Na, [M+Na]+

requires 461.1940, measured 461.1937.

(5S)-Methyl 3-O-benzyl-5-(1-naphthyl)-1,2-O-isopropylidene-α-D-xylo-hept-5-

enfuranuronate25

66

To a mixture of 1-naphthylboronic acid (51.6 mg, 0.30 mmol) and [RhCl(1,5-cod)]2 50 (3.70

mg, 5 mol%) under nitrogen were added a solution of α,β-unsaturated ester (E)-27 (50.0 mg,

0.15 mmol) in 1,4-dioxane:H2O (10:1; 0.38 mL), followed by triethylamine (21 µL, 0.15

mmol). The reaction mixture was stirred for 3 h at 50 °C, then the products were isolated by

evaporation of volatiles under reduced pressure and purified by flash column

chromatography (silica gel; eluent 5% EtOAc/petrol). The elution gave the title compound as

yellow oil with an overall yield of 67.2 mg (97%) (d.r. 9:1, 66:66a). +2.5 (c 1.6, CHCl3).

94

IR max (thin film) 2924 (C-H stretch), 1734 (C=O stretch), 1373, 1212, 1163, 1073 (C-O

stretch), 1024 (C-O stretch) cm-1

. 1H NMR (500 MHz, CDCl3) δ 8.28 (1 H, d, J = 8.5 Hz, Ar-

H), 7.84 (1 H, d, J = 8 Hz, Ar-H), 7.75 (1 H, dd, J = 7 and 2.5 Hz, Ar-H), 7.47 – 7.40 (3 H, m,

Ar-H), 7.33 (1 H, t, J = 8 Hz, Ar-H), 7.20 – 7.15 (1 H, m, Ar-H), 7.12 (2 H, t, J = 7 Hz, Ar-H),

6.76 (2 H, d, J = 7.5 Hz, Ar-H), 6.01 (1 H, d, J = 4 Hz, H-1), 4.69 (1 H, dd, J = 10 and 3 Hz,

H-4), 4.58 (1 H, td, J = 9 and 5 Hz, H-5), 4.49 (1 H, d, J = 4 Hz, H-2), 4.04 (1 H, d, J = 11 Hz,

CHxHyAr), 3.60 (1 H, d, J = 11 Hz, CHxHyAr), 3.45 (1 H, d, J = 3 Hz, H-3), 3.41 (3 H, s,

OCH3), 3.18 (1 H, dd, J = 15 and 5 Hz, H-6), 2.82 (1 H, dd, J = 15 and 9 Hz, H-6), 1.58 (3 H,

s, CH3), 1.32 (3 H, s, CH3) ppm. 13

C NMR (100 MHz, CDCl3) δ 172.48 (C, C=O), 137.43 (C,

Ar-C), 136.81 (C, Ar-C), 133.84 (C, Ar-C), 131.67 (C, Ar-C), 128.40 (CH, Ar-C), 128.02 (CH,

Ar-C), 127.93 (CH, Ar-C), 127.66 (CH, Ar-C), 127.50 (CH, Ar-C), 127.39 (CH, Ar-C), 125.95

(CH, Ar-C), 125.56 (CH, Ar-C), 125.17 (CH, Ar-C), 124.15 (CH, Ar-C), 123.89 (CH, Ar-C),

111.47 (C, C-Me2), 105.01 (CH, C-1), 83.86 (CH, C-4), 81.94 (CH, C-2), 81.22 (CH, C-3),

71.66 (CH2, OCH2Ar), 51.33 (CH3, OCH3), 39.79 (CH2, C-6), 34.47 (CH, C-5), 26.81 (CH3,

C(CH3)2), 26.16 (CH3, C(CH3)2) ppm. MS (ES+) m/z [M+Na]+ 485.0 Accurate Mass

C28H30O6Na, [M+Na]+

requires 485.1935, measured 485.1937.

(5S)-Methyl 3-O-benzyl-5-(2-naphthyl)-1,2-O-isopropylidene-α-D-xylo-hept-5-

enfuranuronate25

67

To a mixture of 2-naphthylboronic acid (51.6 mg, 0.30 mmol) and [RhCl(1,5-cod)]2 50 (3.70

mg, 5 mol%) under nitrogen were added a solution of α,β-unsaturated ester (E)-27 (50.0 mg,

0.15 mmol) in 1,4-dioxane:H2O (10:1; 0.37 mL), followed by triethylamine (21 µL, 0.15

mmol). The reaction mixture was stirred for 4 h at room temperature, then the products were

isolated by evaporation of volatiles under reduced pressure and purified by flash column

chromatography (silica gel; eluent 5% EtOAc/petrol). The elution gave the title compound as

95

yellow oil with an overall yield of 52.7 mg (76%) (d.r. 14:1, 67:67a). -37.4 (c 2.0,

CHCl3). IR max (thin film) 2936 (C-H stretch), 1735 (C=O stretch), 1375, 1164, 1071 (C-O

stretch), 1016 (C-O stretch) cm-1

. 1H NMR (500 MHz, CDCl3) δ 7.82 - 7.64 (4 H, m, Ar-H),

7.48 - 7.35 (4 H, m, Ar-H), 7.31 - 7.18 (5 H, m, Ar-H), 5.97 (1 H, d, J = 4 Hz, H-1), 4.52 (1 H,

d, J = 4 Hz, H-2), 4.45 (1 H, dd, J = 10 and 3 Hz, H-4), 4.37 (1 H, d, J = 11 Hz, CHxHyAr),

4.02 (1 H, d, J = 11 Hz, CHxHyAr), 3.85 (1 H, td, J = 10 and 4 Hz, H-5), 3.45 (3 H, s, OCH3),

3.40 (1 H, d, J = 3 Hz, H-3), 3.17 (1 H, dd, J = 16 and 4 Hz, H-6), 2.79 (1 H, dd, J = 16 and

11 Hz, H-6), 1.53 (3 H, s, CH3), 1.29 (3 H, s, CH3) ppm. 13

C NMR (125 MHz, CDCl3) δ 172.47

(C, C=O), 137.78 (C, Ar-C), 137.20 (C, Ar-C), 133.33 (C, Ar-C), 132.55 (C, Ar-C), 128.34

(CH, Ar-C), 128.08 (CH, Ar-C), 128.01 (CH, Ar-C), 127.76 (CH, Ar-C), 127.66 (CH, Ar-C),

127.06 (CH, Ar-C), 126.99 (CH, Ar-C), 126.39 (CH, Ar-C), 125.93 (CH, Ar-C), 125.63 (CH,

Ar-C), 111.43 (C, C-Me2), 105.04 (CH, C-1), 83.27 (CH, C-4), 81.79 (CH, C-2), 81.55 (CH,

C-3), 71.80 (CH2, OCH2Ar), 51.36 (CH3, OCH3), 40.87 (CH, C-5), 38.66 (CH2, C-6), 26.70

(CH3, C(CH3)2), 26.13 (CH3, C(CH3)2) ppm. MS (ES+) m/z [M+H]+ 463.0, [M+Na]

+ 485.0.

Accurate Mass C28H31O6, [M+H]+

requires 463.2116, measured 463.2129.

(5S)-Methyl 3-O-benzyl-5-(4-acetylphenyl)-1,2-O-isopropylidene-α-D-xylo-hept-5-

enfuranuronate25

68

To a mixture of 4-acetylphenylboronic acid (49.2 mg, 0.30 mmol) and [RhCl(1,5-cod)]2 50

(3.70 mg, 5 mol%) under nitrogen were added a solution of α,β-unsaturated ester (E)-27

(50.0 mg, 0.15 mmol) in 1,4-dioxane:H2O (10:1; 0.37 mL), followed by triethylamine (21 µL,

0.15 mmol). The reaction mixture was stirred for 5 h at room temperature, then the products

were isolated by evaporation of volatiles under reduced pressure and purified by flash

column chromatography (silica gel; eluent 20% EtOAc/petrol) to afford 40.0 mg (57%) of the

title compound as colourless oil (d.r. 7:1, 68:68a). Rf (25% EtOAc/petrol): 0.20. -42.1 (c

96

1.5, CHCl3). IR max (thin film) 2924 (C-H stretch), 1735 (C=O stretch), 1615 (aromatic C=C

stretch), 1070 (C-O stretch), 1028 (C-O stretch) cm-1

. 1H NMR (500 MHz, CDCl3) δ 7.85 (2

H, d, J = 8 Hz, Ar-H), 7.38 - 7.30 (5 H, m, Ar-H), 7.26 - 7.23 (2 H, m, Ar-H), 5.96 (1 H, d, J =

4 Hz, H-1), 4.55 (1 H, d, J = 4 Hz, H-2), 4.44 (1 H, d, J = 11 Hz, CHxHyAr), 4.35 (1 H, dd, J =

10 and 3 Hz, H-4), 4.10 (1 H, d, J = 11 Hz, CHxHyAr), 3.75 (1 H, td, J = 11 and 4 Hz, H-5),

3.51 (3 H, s, OCH3), 3.41 (1 H, d, J = 3 Hz, H-3), 3.15 (1 H, dd, J = 16 and 4 Hz, H-6), 2.71

(1 H, dd, J = 16 and 11 Hz, H-6), 2.59 (3 H, s, C(O)CH3), 1.53 (3 H, s, CH3), 1.31 (3 H, s,

CH3) ppm. 13

C NMR (125 MHz, CDCl3) δ 196.94 (C(O)CH3), 166.61 (C, C=O), 137.05 (C, Ar-

C), 135.97 (C, Ar-C), 128.52 (CH, Ar-C), 128.46 (CH, Ar-C), 128.14 (CH, Ar-C), 127.94 (CH,

Ar-C), 127.92 (CH, Ar-C), 127.74 (CH, Ar-C), 111.56 (C, C-Me2), 104.99 (CH, C-1), 82.85

(CH, C-4), 81.73 (CH, C-2), 81.44 (CH, C-3), 71.87 (CH2, OCH2Ar), 51.48 (CH3, OCH3),

40.87 (CH, C-5), 38.32 (CH2, C-6), 26.74 (CH3, C(CH3)2), 26.57 (CH3, C(O)CH3), 26.10 (CH3,

C(CH3)2) ppm. MS (ES+) m/z [M+Na]+ 477.0. Accurate Mass C26H30O7Na, [M+Na]

+ requires

477.1887, measured 477.1884.

(5S)-Methyl 3-O-benzyl-5-(4-fluorophenyl)-1,2-O-isopropylidene-α-D-xylo-hept-5-

enfuranuronate25

69

To a mixture of 4-fluorophenylboronic acid (42.0 mg, 0.30 mmol) and [RhCl(1,5-cod)]2 50

(3.70 mg, 5 mol%) under nitrogen were added a solution of α,β-unsaturated ester (E)-27

(50.0 mg, 0.15 mmol) in 1,4-dioxane:H2O (10:1; 0.37 mL), followed by triethylamine (21 µL,

0.15 mmol). The reaction mixture was stirred for 5 h at room temperature, then the products

were isolated by evaporation of volatiles under reduced pressure and purified by flash

column chromatography (silica gel; eluent 5% EtOAc/petrol) to afford 45.7 mg (71%) of the

title compound as yellow oil (d.r. 8:1, 69:69a). Rf (20% EtOAc/petrol): 0.28. -52.4 (c 1.9,

CHCl3). IR max (thin film) 2987 (C-H stretch), 2933 (C-H stretch), 1735 (C=O stretch), 1604

97

(C=C stretch), 1509, 1373, 1219, 1160, 1071 (C-O stretch), 1014 (C-O stretch) cm-1

. 1H

NMR (400 MHz, CDCl3) δ 7.38 – 7.31 (3 H, m, Ar-H), 7.26 - 7.23 (2 H, m, Ar-H), 7.21 - 7.16

(2 H, m, Ar-H), 6.95 (2 H, t, J = 9 Hz, Ar-H), 5.96 (1 H, d, J = 4 Hz, H-1), 4.54 (1 H, d, J = 4

Hz, H-2), 4.44 (1 H, d, J = 11 Hz, CHxHyAr), 4.30 (1 H, dd, J = 10 and 3 Hz, H-4), 4.10 (1 H,

d, J = 11 Hz, CHxHyAr), 3.67 (1 H, td, J = 11 and 4 Hz, H-5), 3.51 (3 H, s, OCH3), 3.42 (1 H,

d, J = 3 Hz, H-3), 3.10 (1 H, dd, J = 16 and 4 Hz, H-6), 2.64 (1 H, dd, J = 16 and 11 Hz, H-6),

1.53 (3 H, s, CH3), 1.31 (3 H, s, CH3) ppm. 13

C NMR (100 MHz, CDCl3) δ 172.40 (C, C=O),

151.48 (C, Ar-C-F), 137.13 (C, Ar-C), 129.72 (CH, Ar-C), 129.64 (CH, Ar-C), 128.44 (CH, Ar-

C), 127.89 (CH, Ar-C), 127.69 (CH, Ar-C), 115.36 (CH, Ar-C), 115.15 (CH, Ar-C), 111.47 (C,

C-Me2), 105.00 (CH, C-1), 83.19 (CH, C-4), 81.71 (CH, C-2), 81.43 (CH, C-3), 71.87 (CH2,

OCH2Ar), 51.43 (CH3, OCH3), 40.11 (CH, C-5), 38.68 (CH2, C-6), 26.72 (CH3, C(CH3)2),

26.09 (CH3, C(CH3)2) ppm. MS (ES+) m/z [M+Na]+ 453.0. Accurate Mass C26H28FO6Na,

[M+Na]+

requires 431.1877, measured 431.1865.

(5S)-Methyl 3-O-benzyl-5-(3-nitrophenyl)-1,2-O-isopropylidene-α-D-xylo-hept-5-

enfuranuronate25

70

To a mixture of 3-nitrophenylboronic acid (75.1 mg, 0.45 mmol) and [RhCl(1,5-cod)]2 50

(3.70 mg, 5 mol%) under nitrogen were added a solution of α,β-unsaturated ester (E)-27

(50.0 mg, 0.15 mmol) in 1,4-dioxane:H2O (10:1; 0.37 mL), followed by triethylamine (21 µL,

0.15 mmol). The reaction mixture was stirred for 42 h at 50 °C resulting in only > 60%

consumption of the starting material, then were further added 3-nitrophenylboronic acid (25.0

mg, 0.15 mmol) and Et2N (21 μL, 0.115 mmol). The reaction mixture was left to stir for

further 6 h at 50 °C and the products were then isolated by evaporation of volatiles under

reduced pressure and purified by flash column chromatography (silica gel; eluent 5%

EtOAc/petrol). The elution gave the title compound as colourless oil with an overall yield of

20.0 mg (29%) (d.r. 4:1, 70:70a). Rf (30% EtOAc/petrol): 0.60. -24.8 (c 0.1, CHCl3). IR

98

max (thin film) 2991 (C-H stretch), 2918 (C-H stretch), 1736 (C=O stretch), 1531 (NO2 asym.

stretch), 1349 (NO2 sym. stretch), 1130, 1073 (C-O stretch), 1027 (C-O stretch) cm-1

. 1H

NMR (400 MHz, CDCl3) δ 8.16 - 8.05 (2 H, m, Ar-H), 7.55 (1 H, d, J = 8 Hz, Ar-H), 7.44 -

7.38 (1 H, m, Ar-H), 7.38 - 7.28 (3 H, m, Ar-H), 7.26 - 7.20 (2 H, m, Ar-H), 5.97 (1 H, d, J = 4

Hz, H-1), 4.59 (1 H, d, J = 4 Hz, H-2), 4.48 (1 H, d, J = 11 Hz, CHxHyAr), 4.34 (1 H, dd, J =

10 and 3 Hz, H-4), 4.11 (1 H, d, J = 11 Hz, CHxHyAr), 3.83 - 3.75 (1 H, m, H-5), 3.52 (3 H, s,

OCH3), 3.42 (1 H, d, J = 3 Hz, H-3), 3.18 (1 H, dd, J = 16 and 4 Hz, H-6), 2.72 (1 H, dd, J =

16 and 11 Hz, H-6), 1.53 (3 H, s, CH3), 1.32 (3 H, s, CH3) ppm. 13

C NMR (100 MHz, CDCl3) δ

171.96 (C, C=O), 148.20 (C, Ar-C-NO2), 142.47 (C, Ar-C), 136.61 (C, Ar-C), 134.71 (CH, Ar-

C), 129.30 (CH, Ar-C), 128.49 (CH, Ar-C), 128.07 (CH, Ar-C), 127.92 (CH, Ar-C), 123.09

(CH, Ar-C), 122.18 (CH, Ar-C), 111.65 (C, C-Me2), 104.94 (CH, C-1), 82.60 (CH, C-4), 81.91

(CH, C-2), 81.51 (CH, C-3), 71.82 (CH2, OCH2Ar), 51.56 (CH3, OCH3), 40.56 (CH, C-5),

38.04 (CH2, C-6), 26.72 (CH3, C(CH3)2), 26.04 (CH3, C(CH3)2) ppm. MS (ES+) m/z [M+Na]+

480.0. Accurate Mass C24H28NO8, [M+H]+

requires 458.1820, measured 458.1810.

(5S)-5,6-Dideoxy-1,2-O-isopropylidene-α-D-xylo-hept-5-naphthyl-7,3-lactone 71

To a solution of ester 66 (46.2 mg, 0.10 mmol) in MeOH (0.75 mL) was added a slurry

suspension of 10% Pd/C (10 mol%) in toluene (0.50 mL). H2 gas was passed through the

reaction mixture and stirred for 3 days at room temperature. The crude product was filtered

through Celite, washed with MeOH (5 mL), concentrated in vacuo and purified by flash

column chromatography (silica gel; eluent 5% EtOAc/petrol) to afford 3.80 mg (8%) of the

title compound as yellow oil as a single diastereoisomer. Rf (30% EtOAc/petrol): 0.38. IR max

(thin film) 2960 (C-H stretch), 1750 (C=O stretch), 1257, 1159, 1078 (C-O stretch), 1015 (C-

O stretch) cm-1

. 1

H NMR (400 MHz, CDCl3) δ 7.98 – 7.49 (7 H, m, Ar-H), 6.07 (1 H, d, J = 4

Hz, H-1), 5.00 (1 H, d, J = 3 Hz, H-3), 4.81 (1 H, m, H-4), 4.78 (1 H, d, J = 4 Hz, H-2), 4.26 (1

H, dd, J = 14 and 5 Hz, H-5), 3.14 (1 H, dd, J = 18 and 14 Hz, H-6), 2.90 (1 H, dd, J = 18 and

99

5 Hz, H-6), 1.46 (3 H, s, CH3), 1.35 (3 H, s, CH3) ppm. 13

C NMR (100 MHz, CDCl3) δ 168.83

(C, C=O), 136.50 (C, Ar-C), 134.38 (C, Ar-C), 133.91 (C, Ar-C), 130.78 (CH, Ar-C), 129.42

(CH, Ar-C), 128.22 (CH, Ar-C), 126.63 (CH, Ar-C), 125.82 (CH, Ar-C), 125.71 (CH, Ar-C),

125.03 (CH, Ar-C), 112.54 (C, C-Me2), 105.27 (CH, C-1), 84.69 (CH, C-3), 83.30 (CH, C-2),

74.62 (CH,C-4), 33.71 (CH, C-5), 31.21 (CH2, C-6), 26.57 (CH3, C(CH3)2), 26.22 (CH3,

C(CH3)2) ppm. MS (ES+) m/z [M+Na]+ 363.0. Accurate Mass C20H24O5N, [M+NH4]

+ requires

358.1649, measured 358.1651.

(5S)-5,6-Dideoxy-1,2-O-isopropylidene-α-D-xylo-hept-5-phenyl-7,3-lactone 72

Using a 30 × 4 mm catalyst cartridge (CatCart®) of 10% Pd/C (TH01111), a 0.05 M solution

of ester 55 (20.0 mg, 0.05 mmol) in MeOH (0.40 mL) was passed through the CatCart® four

times at a flow rate of 1 mL/min and the product was continuously eluted out of the CatCart®

and into a collection vial. The pressure of the system was set to 1 bar and the temperature to

50 °C, with a constant flow of hydrogen (full H2 mode). The crude product was then stirred

with potassium carbonate in DCM for 30 min at room temperature to ensure complete

cyclisation of the lactone. The crude lactone was filtered through a sintered funnel and

purified by flash column chromatography (silica gel; eluent 5% EtOAc/petrol) to afford 8.50

mg (58%) of the title compound as colourless oil as a single diastereoisomer. -44.3 (c

0.3, CHCl3). IR max (thin film) 2956 (C-H stretch), 2927 (C-H stretch), 1746 (C=O stretch),

1605, 1073 (C-O stretch), 1022 (C-O stretch) cm-1

. 1H NMR (500 MHz, CDCl3) δ 7.40 - 7.29

(5 H, m, Ar-H), 6.03 (1 H, d, J = 3 Hz, H-1), 4.87 (1 H, d, J = 3 Hz, H-3), 4.73 (1 H, d, J = 3

Hz, H-2), 4.63 (1 H, br. s, H-4), 3.43 – 3.37 (1 H, m, H-5), 3.02 (1 H, dd, J = 17 and 14 Hz, H-

6), 2.75 (1 H, dd, J = 18 and 5 Hz, H-6), 1.48 (3 H, s, CH3), 1.34 (3 H, s, CH3) ppm. 13

C NMR

(125 MHz, CDCl3) δ 168.65 (C, C=O), 138.95 (C, Ar-C), 128.87 (CH, Ar-C), 127.66 (CH, Ar-

C), 127.63 (CH, Ar-C), 112.45 (C, C-Me2), 105.15 (CH, C-1), 84.47 (CH, C-3), 83.39 (CH, C-

2), 74.78 (CH, C-4), 38.72 (CH, C-5), 31.30 (CH2, C-6), 26.56 (CH3, C(CH3)2), 26.19 (CH3,

100

C(CH3)2) ppm. MS (GC/MS) m/z [M+] 290, [M-CH3] 275. Accurate Mass C16H18O5, [M+]

requires 290.1149, measured 290.1148.

(5S)-5,6-Dideoxy-1,2-O-isopropylidene-α-D-xylo-hept-5-propyl-7,3-lactone 73

Using a 30 × 4 mm catalyst cartridge (CatCart®) of 10% Pd/C (TH01111), a 0.05 M solution

of ester 58 (74.0 mg, 0.20 mmol) in MeOH (1.48 mL) was passed through the CatCart® four

times at a flow rate of 1 mL/min and the product was continuously eluted out of the CatCart®

and into a collection vial. The pressure of the system was set to 1 bar and the temperature to

50 °C, with a constant flow of hydrogen (full H2 mode). The crude product was then stirred

with potassium carbonate in DCM for 30 min at room temperature to ensure complete

cyclisation of the lactone. The crude lactone was filtered through a sintered funnel and

purified by flash column chromatography (silica gel; eluent 5% EtOAc/petrol) to afford 31.5

mg (62%) of the title compound as colourless oil as a single diastereoisomer. Rf (20%

EtOAc/petrol): 0.19. -64.6 (c 1.1, CHCl3). IR max (thin film) 2954 (C-H stretch), 2930 (C-

H stretch), 1750 (C=O stretch), 1611, 1070 (C-O stretch), 1027 (C-O stretch) cm-1

. 1H NMR

(400 MHz, CDCl3) δ 5.90 (1 H, d, J = 4 Hz, H-1), 4.66 (2 H, t, J = 4 Hz, H-2, H-3), 4.51 (1 H,

br. s., H-4), 2.62 (1 H, dd, J = 18 and 5 Hz, H-6), 2.41 (1 H, dd, J = 18 and 13 Hz, H-6), 1.79

– 1.68 (2 H, m, H-5, H-8), 1.51 (3 H, s, CH3), 1.33 (3 H, s, CH3), 1.03 (3 H, d, J = 6 Hz, H-7),

0.95 (3 H, d, J = 6 Hz, H-9) ppm. 13

C NMR (100 MHz, CDCl3) δ 169.06 (C, C=O), 111.95 (C-

C-Me2), 104.48 (CH, C-1), 83.77 (CH, C-3), 83.30 (CH, C-2), 71.73 (CH, C-4), 39.05 (CH, C-

5), 29.33 (CH2, C-6), 28.79 (CH, C-8), 26.38 (CH3, C(CH3)2), 25.92 (CH3, C(CH3)2), 19.76

(CH3, C-7), 19.69 (CH3, C-7) ppm. MS (ES+) m/z [M+Na]+ 279.0. Accurate Mass

C13H20O5Na, [M+Na]+

requires 279.1207, measured 279.1209.

101

(5S)-5,6-Dideoxy-1,2-O-isopropylidene-α-D-xylo-hept-5-ethyl-7,3-lactone 74

Using a 30 × 4 mm catalyst cartridge (CatCart®) of 10% Pd/C (TH01111), a 0.05 M solution

of ester 60 (39.5 mg, 0.11 mmol) in MeOH (0.79 mL) was passed through the CatCart® four

times at a flow rate of 1 mL/min and the product was continuously eluted out of the CatCart®

and into a collection vial. The pressure of the system was set to 1 bar and the temperature to

50 °C, with a constant flow of hydrogen (full H2 mode). The crude product was then stirred

with potassium carbonate in DCM for 2 h at room temperature to ensure complete cyclisation

of the lactone. The crude lactone was filtered through a sintered funnel and purified by flash

column chromatography (silica gel; eluent 5% EtOAc/petrol) to afford 9.10 mg (34%) of the

title compound as colourless oil as a single diastereoisomer. IR max (thin film) 2955 (C-H

stretch), 2927 (C-H stretch), 1752 (C=O stretch), 1601, 1070 (C-O stretch), 1021 (C-O

stretch) cm-1

. 1

H NMR (400 MHz, CDCl3) δ 5.92 (1 H, d, J = 4 Hz, H-1), 4.71 (1 H, d, J = 3

Hz, H-3), 4.68 (1 H, d, J = 4 Hz, H-2), 4.42 (1 H, m, H-4), 2.54 (1 H, dd, J = 18 and 5 Hz, H-

6), 2.42 (1 H, dd, J = 18 and 13 Hz, H-6), 2.07 – 1.96 (1 H, m, H-5), 1.53 (3 H, s, CH3), 1.69

– 1.44 (2 H, m, H-8), 1.34 (3 H, s, CH3), 0.99 (3 H, t, J = 7 Hz, H-7) ppm. 13

C NMR (100 MHz,

CDCl3) δ 169.44 (C, C=O), 112.62 (C, C-Me2), 105.11 (CH-C-1), 84.36 (CH, C-3), 84.18

(CH, C-2), 73.56 (CH, C-4), 34.89 (CH, C-5), 30.76 (CH2, C-6), 26.99 (CH3, C(CH3)2), 26.54

(CH3, C(CH3)2), 25.36 (CH2, C-8), 11.37 (CH3, C-7) ppm. MS (ES+) m/z [M+Na]+ 265.0.

Accurate Mass C12H18O5Na, [M+Na]+ requires 265.1036, measured 265.1047.

102

1,2-O-isopropylidene-3,5-O-methylidene-5-hydroxy-α-D-xylofuranose35

76

To a solution of furanose 16 (0.50 g, 1.92 mmol) in anhydrous ethyl acetate (36 mL) was

added periodic acid (0.57 g, 2.50 mmol) at 0 °C and the reaction mixture was allowed to stir

for 5 h at room temperature. The resulting mixture was then filtered and the solvent was

evaporated under reduced pressure. The crude product was purified by column

chromatography (silica gel; eluent 15% EtOAc/petrol) to afford 0.25 g (60%) of the title

compound as white solid as a single diastereoisomer. The purified product was recrystallised

from EtOAc to obtain colourless crystals. Rf (30% EtOAc/petrol): 0.25. +41.6 (c 1.8,

CHCl3). mp 68 – 71 °C. IR max (thin film) 3382 (O-H stretch), 2992 (C-H stretch), 2938 (C-H

stretch), 1086 (C-O stretch), 1071 (C-O stretch) cm-1

. 1H NMR (400 MHz, CDCl3) δ 6.03 (1 H,

d, J = 4 Hz, H-1), 5.40 (1 H, d, J = 3 Hz, H-5), 5.21 (1 H, d, J = 6 Hz, H-6), 4.70 (1 H, d, J = 6

Hz, H-6), 4.55 (1 H, d, J = 3.5 Hz, H-2), 4.35 (1 H, d, J = 2 Hz, H-3), 3.98 (1 H, d, J = 2 Hz,

H-4), 2.79 (1 H, d, J = 3.5 Hz, OH), 1.51 (3 H, s, CH3), 1.34 (3 H, s, CH3) ppm. 13

C NMR (100

MHz, CDCl3) δ 112.17 (C, C-Me2), 105.22 (CH, C-1), 89.81 (CH, C-5), 83.44 (CH, C-2),

83.34 (CH2, C-6), 75.88 (CH, C-3), 73.92 (CH, C-4), 26.70 (CH3, C(CH3)2), 26.22 (CH3,

C(CH3)2) ppm. MS (ES+) m/z [M+Na]+ 241.0. Accurate Mass C9H14O6Na, [M+Na]

+ requires

241.0655, measured 241.0653.

1,2-O-isopropylidene-3,5-O-methylidene-5-acetoxy-α-D-xylofuranose85

77

To a solution of alcohol 76 (0.24 g, 1.10 mmol) in DCM (6 mL), anhydrous pyridine (0.10 mL,

1.10 mmol) was added at 0 °C, followed by the addition of acetic anhydride (0.10 mL, 1.10

mmol). The reaction mixture was stirred at room temperature for 24 h, then extracted with

DCM (3 × 10 mL) and washed with water (10 mL). The combined organic extracts were dried

over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The crude product

103

was purified by column chromatography (silica gel; eluent 6% EtOAc/petrol) to afford 0.23 g

(79%) of the title compound as colourless oil as a single diastereoisomer. Rf (20%

EtOAc/petrol): 0.23. +42.7 (c 1.6, CHCl3). IR max (thin film) 2921 (C-H stretch), 1755

(C=O stretch), 1373, 1216, 1178, 1136, 1085 (C-O stretch), 1002 (C-O stretch) cm-1

. 1

H

NMR (500 MHz, CDCl3) δ 6.25 (1 H, s, H-5), 6.04 (1 H, d, J = 3 Hz, H-1), 5.02 (1 H, d, J = 6

Hz, H-6), 4.78 (1 H, d, J = 7 Hz, H-6), 4.58 (1 H, d, J = 4 Hz, H-2), 4.35 (1 H, d, J = 2 Hz, H-

3), 3.91 (1 H, s, H-4), 2.16 (3 H, s, C(O)CH3), 1.50 (3 H, s, CH3), 1.35 (3 H, s, CH3) ppm. 13

C

NMR (100 MHz, CDCl3) δ 168.50 (C, C(O)CH3), 112.22 (C, C-Me2), 105.23 (CH, C-1), 88.13

(CH, C-5), 85.14 (CH2, C-6), 83.20 (CH, C-2), 76.13 (CH, C-3), 72.93 (CH, C-4), 26.63 (CH3,

C(CH3)2), 26.08 (CH3, C(CH3)2), 20.86 (CH3, C(O)CH3) ppm. MS (ES+) m/z [M+Na]+ 283.0.

Accurate Mass C11H16O7Na, [M+Na]+

requires 283.0788, measured 283.0782.

5,6-dideoxy-1,2-O-isopropylidene-α-D-xylo-hept-5-enofuranurono-7,3-lactone34

78

To a solution of alcohol 76 (100 mg, 0.46 mmol) in DCM (5 mL), Ph3PCHCOOMe (384 mg,

1.15 mmol) was added at room temperature. After stirring for 20 h, the solvent was

evaporated and the crude product was purified by flash column chromatography (silica gel;

eluent 10% EtOAc/petrol) to afford 44.2 mg (45%) of the title compound as yellow oil as Z-

isomer. Rf (30% EtOAc/petrol): 0.25. -131.0 (c 0.8, CHCl3) lit.

34

+15.0 (c 1.0,

CHCl3). IR max (thin film) 2987 (C-H stretch), 1720 (C=O stretch), 1650 (C=C stretch), 1375,

1207, 1162, 1071 (C-O stretch), 1006 (C-O stretch) cm-1

. 1

H NMR (400 MHz, CDCl3) δ 6.97

(1 H, dd, J = 10 and 6 Hz, H-5), 6.25 (1 H, d, J = 10 Hz, H-6), 6.03 (1 H, d, J = 4 Hz, H-1),

4.83 (2 H, t, J = 4 Hz, H-3, H-2), 4.64 (1 H, dd, J = 6 and 3 Hz, H-4), 1.54 (3 H, s, CH3), 1.37

(3 H, s, CH3) ppm. 13

C NMR (100 MHz, CDCl3) δ 160.83 (C, C=O), 138.64 (CH, C-5), 125.39

(CH, C-6), 112.57 (C, C-Me2), 105.30 (CH, C-1), 83.91 (CH, C-3), 82.42 (CH, C-2), 67.58

(CH, C-4), 26.73 (CH3, C(CH3)2), 26.17 (CH3, C(CH3)2) ppm. MS (ES+) m/z [M+Na]+ 235.0.

Accurate Mass C10H12O5Na, [M+Na]+

requires 235.0586, measured 235.0577.

104

5,6-Dideoxy-1,2-O-isopropylidene-α-D-xylo-hept-5-phenyl-7,3-lactone25

80

To a mixture of phenylboronic acid (0.10 g, 0.84 mmol) and [RhCl(1,5-cod)]2 50 (10.3 mg, 5

mol%) under nitrogen, a solution of α,β-unsaturated lactone 78 (90.0 mg, 0.42 mmol) in 1,4-

dioxane:H2O (10:1; 1.05 mL) was added, followed by triethylamine (58 µL, 0.42 mmol). The

reaction mixture was stirred for 6 h at room temperature, then the products were isolated by

evaporation of volatiles under reduced pressure and purified by flash column

chromatography (silica gel; eluent 20% EtOAc/petrol) to afford an overall yield of 86.9 mg

(71%) of the title compound as yellow oil as a single diastereoisomer. Rf (30% EtOAc/petrol):

0.75. -9.9 (c 1.4, CHCl3). IR max (thin film) 2985 (C-H stretch), 1747 (C=O stretch),

1374, 1209, 1158, 1071 (C-O stretch), 1016 (C-O stretch) cm-1

. 1H NMR (500 MHz, CDCl3) δ

7.42 – 7.37 (2 H, m, Ar-H), 7.35 – 7.31 (1 H, m, Ar-H), 7.23 (2 H, d, J = 7 Hz, Ar-H), 6.02 (1

H, d, J = 4 Hz, H-1), 4.76 (1 H, d, J = 4 Hz, H-2), 4.62 (1 H, d, J = 3 Hz, H-3), 4.50 (1 H, t, J =

3 Hz, H-4), 3.59 – 3.54 (1 H, m, H-5), 3.01 (1 H, dd, J = 17 and 6 Hz, H-6), 2.75 (1 H, dd, J =

17 and 6 Hz, H-6), 1.48 (3 H, s, CH3), 1.33 (3 H, s, CH3) ppm. 13

C NMR (125 MHz, CDCl3) δ

169.48 (C, C=O), 139.34 (C, Ar-C), 129.27 (CH, Ar-C), 127.79 (CH, Ar-C), 126.94 (CH, Ar-

C), 112.32 (C, C-Me2), 104.89 (CH, C-1), 83.57 (CH, C-3), 81.86 (CH, C-2), 78.21 (CH, C-4),

39.62 (CH, C-5), 31.04 (CH2, C-6), 26.54 (CH3, C(CH3)2), 26.10 (CH3, C(CH3)2) ppm. MS

(ES+) m/z [M+H]+ 291.0, [M+Na]

+ 313.0. Accurate Mass C16H19O5, [M+H]

+ requires

291.1220, measured 291.1227.

105

3-O-(tert-butyldimethylsilyl)-1,2:5,6-di-O-isopropylidene-α-D-glucofuranose86

81

t-Butyldimethylsilyl chloride (1.16 g, 7.68 mmol) and imidazole (1.05 g, 15.36 mmol) were

added to a solution of commercially available 1,2:5,6-di-O-isopropylidene-α-D-glucofuranose

(2.00 g, 7.68 mmol) in DMF (10 mL). After 18 h, the reaction mixture was poured into water

(20 mL) and then extracted with ethyl acetate (2 × 20 mL). The combined organic extracts

were washed sequentially with water (2 × 10 mL) and brine (10 mL), dried over anhydrous

magnesium sulfate, filtered and then concentrated in vacuo to afford 0.92 g (32%) of the title

compound as colourless oil. -16.2 (c 1.2, CHCl3). IR max (thin film) 2933 (C-H stretch),

1371, 1245, 1211, 1077 (C-O stretch), 1049 (C-O stretch) cm-1

. 1

H NMR (500 MHz, CDCl3) δ

5.88 (1 H, d, J = 3 Hz, H-1), 4.35 (1 H, d, J = 3 Hz, H-2), 4.25 (1 H, d, J = 3 Hz, H-3), 4.24 –

4.21 (1 H, m, H-5), 4.11 (1 H, dd, J = 8.5 and 6 Hz, H-6), 4.03 (1 H, dd, J = 8 and 2.5 Hz, H-

4), 3.96 (1 H, dd, J = 8 and 6 Hz, H-6), 1.50 (3 H, s, CH3), 1.41 (3 H, s, CH3), 1.33 (3 H, s,

CH3), 1.32 (3 H, s, CH3), 0.91 (9 H, s, SiC(CH3)3), 0.14 (3 H, s, SiCH3), 0.13 (3 H, s, SiCH3)

ppm. 13

C NMR (125 MHz, CDCl3) δ 111.82 (C, C-Me2), 108.93 (C, C-Me2), 105.28 (CH, C-1),

85.59 (CH, C-2), 82.26 (CH, C-4), 75.47 (CH, C-3), 72.15 (CH, C-5), 67.71 (CH2, C-6), 26.95

(CH3, C(CH3)2), 26.74 (CH3, C(CH3)2), 26.35 (CH3, C(CH3)2), 25.69 (3 × CH3, SiC(CH3)3),

25.30 (CH3, C(CH3)2), 18.11 (C, SiC(CH3)3), -5.01 (CH3, SiCH3), -5.21 (CH3, SiCH3) ppm. MS

(ES+) m/z [M+H]+ 375.0, [M+Na]

+ 397.0. Accurate Mass C18H34O6NaSi, [M+Na]

+ requires

397.2031, measured 397.2017.

106

3-O-(tert-butyldimethylsilyl)-1,2-O-isopropylidene-α-D-glucofuranose86

82

A solution of furanose 81 (920 mg, 2.46 mmol) in 75% aqueous acetic acid (10 mL) was

stirred at room temperature for 24 h. The reaction mixture was concentrated and then dried

by azeotropic coevaporation with toluene (3 × 5 mL), and the resulting diol was dried

overnight under high vacuum to remove any trace of acetic acid. The crude product was

purified by flash column chromatography (silica gel; eluent 20% EtOAc/petrol) to afford 340

mg (41%) of the title compound as yellow oil. -45.2 (c 0.8, CHCl3). IR max (thin film)

3432 (O-H stretch), 2929 (C-H stretch), 1373, 1250, 1217, 1077 (C-O stretch), 1040 (C-O

stretch), 1005 (C-O stretch) cm-1

. 1

H NMR (500 MHz, CDCl3) δ 5.90 (1 H, d, J = 4 Hz, H-1),

4.38 (1 H, d, J = 4 Hz, H-2), 4.33 (1 H, d, J = 2.5 Hz, H-3), 4.08 (1 H, dd, J = 8 and 3 Hz, H-

4), 3.96 – 3.92 (1 H, m, H-5), 3.87 – 3.83 (1 H, m, H-6), 3.80 – 3.75 (1 H, m, H-6), 1.50 (3 H,

s, CH3), 1.32 (3 H, s, CH3), 0.92 (9 H, s, SiC(CH3)3), 0.17 (3 H, s, SiCH3), 0.15 (3 H, s,

SiCH3) ppm. 13

C NMR (125 MHz, CDCl3) δ 111.83 (C, C-Me2), 104.98 (CH, C-1), 85.30 (CH,

C-2), 80.93 (CH, C-4), 75.89 (CH, C-3), 68.90 (CH, C-5), 64.58 (CH2, C-6), 26.85 (CH3,

C(CH3)2), 26.30 (CH3, C(CH3)2), 25.67 (3 × CH3, SiC(CH3)3), 17.99 (C, SiC(CH3)3), -4.75

(CH3, SiCH3), -5.10 (CH3, SiCH3) ppm. MS (ES+) m/z [M+Na]+ 357.0. Accurate Mass

C15H30O6NaSi, [M+Na]+

requires 357.1704, measured 357.1693.

3-O-(tert-butyldimethylsilyl)-1,2-O-isopropylidene-α-D-xylo-pentadialdo-1,4-furanose86

83

A solution of sodium periodate (260 mg, 1.22 mmol) in water (2 mL) was added to a solution

of the crude diol 82 (340 mg, 1.02 mmol) in THF (5 mL). The resulting slurry was stirred at

room temperature for 5 h and then filtered. The filtrate was extracted with DCM (3 × 5 mL)

and the combined organic extracts were washed with water (5 mL), dried over anhydrous

107

magnesium sulfate and concentrated in vacuo to afford 290 mg (94%) crude of the title

compound as yellow oil. -61.2 (c 0.8, CHCl3). IR max (thin film) 2927 (C-H stretch),

1711 (C=O stretch), 1373, 1250, 1075 (C-O stretch), 1012 (C-O stretch) cm-1

. 1

H NMR (500

MHz, CDCl3) δ 9.64 (1 H, d, J = 1.5 Hz, CHO), 6.13 (1 H, d, J = 3 Hz, H-1), 4.55 (1 H, d, J =

3 Hz, H-3), 4.50 (1 H, dd, J = 3 and 1.5 Hz, H-4), 4.41 (1 H, d, J = 3 Hz, H-2), 1.48 (3 H, s,

CH3), 1.35 (3 H, s, CH3), 0.85 (9 H, s, SiC(CH3)3), 0.11 (3 H, s, SiCH3), 0.05 (3 H, s, SiCH3)

ppm. 13

C NMR (125 MHz, CDCl3) δ 201.07 (CH, CHO), 112.63 (C, C-Me2), 106.24 (CH, C-1),

85.46 (CH, C-2), 85.37 (CH, C-4), 77.98 (CH, C-3), 27.09 (CH3, C(CH3)2), 26.47 (CH3,

C(CH3)2), 25.50 (3 × CH3, SiC(CH3)3), 17.90 (C, SiC(CH3)3), -4.87 (CH3, SiCH3), -5.37 (CH3,

SiCH3) ppm. MS (ES+) m/z [M+Na]+ 325.0. Accurate Mass C14H26O5NaSi, [M+Na]

+ requires

325.1442, measured 325.1451.

(Z)-Methyl 3-O-tert-butyldimethylsilanyl-5,6-dideoxy-1,2-O-isopropylidene-α-D-xylo-hept-5-

enfuranuronate (Z)-84 and (E)-Methyl 3-O-tert-butyldimethylsilanyl-5,6-dideoxy-1,2-O-

isopropylidene-α-D-xylo-hept-5-enfuranuronate86

(E)-84

To a solution of the crude aldehyde 83 (290 mg, 0.96 mmol) in anhydrous DCM (3 mL), was

added commercially available Ph3PCHCOOMe (320 mg, 0.96 mmol) at room temperature.

After stirring for 16 h, the solvent was evaporated and the crude product was purified by

flash column chromatography (silica gel; eluent 10% EtOAc/petrol) to afford an overall yield

of 180 mg (52%) of the title compound as yellow oil (1:1, Z:E). IR max (thin film) 2929 (C-H

stretch), 1721 (C=O stretch), 1653 (C=C stretch), 1437, 1372, 1251, 1198, 1163, 1117, 1076

(C-O stretch), 1018 (C-O stretch) cm-1

. MS (ES-) m/z [M-H]

- 357.0, [M] 358.0. Accurate

Mass C17H29O6Si, [M-H]- requires 357.1736, measured 357.1738.

108

Z-isomer (Z)-84

Isolated yield: 50.0 mg (14% as Z-isomer). Rf (10% EtOAc/petrol): 0.31. -154.1 (c 2.0,

CHCl3). 1H NMR (500 MHz, CDCl3) δ 6.30 (1 H, dd, J = 12 and 7 Hz, H-5), 6.00 (1 H, d, J = 4

Hz, H-1), 5.93 (1 H, dd, J = 12 and 1.5 Hz, H-6), 5.65 – 5.60 (1 H, m, H-4), 4.49 (1 H, d, J =

3 Hz, H-3), 4.41 (1 H, d, J = 3 Hz, H-2), 3.74 (3 H, s, OCH3), 1.53 (3 H, s, CH3), 1.34 (3 H, s,

CH3), 0.86 (9 H, s, SiC(CH3)3), 0.06 (3 H, s, SiCH3), -0.02 (3 H, s, SiCH3) ppm. 13

C NMR

(125 MHz, CDCl3) δ 164.98 (C, C=O), 145.53 (CH, C-5), 119.53 (CH, C-6), 110.86 (C, C-

Me2), 104.17 (CH, C-1), 85.07 (CH, C-2), 77.83 (CH, C-3), 76.95 (CH, C-4), 50.46 (CH3,

OCH3), 26.04 (CH3, C(CH3)2), 25.53 (3 × CH3, SiC(CH3)3), 24.64 (CH3, C(CH3)2), 17.00 (C,

SiC(CH3)3), -5.93 (CH3, SiCH3), -6.14 (CH3, SiCH3) ppm.

E-isomer (E)-84

Isolated yield: 50.0 mg (14% as E-isomer) (80.0 mg (23%) as Z/E mixture). Rf (10%

EtOAc/petrol): 0.25. -130.9 (c 1.5, CHCl3).

1H NMR (500 MHz, CDCl3) δ 6.88 (1 H, dd,

J = 16 and 5 Hz, H-5), 6.15 (1 H, dd, J = 16 and 1 Hz, H-6), 5.98 (1 H, d, J = 4 Hz, H-1), 4.80

– 4.75 (1 H, m, H-4), 4.42 (1 H, d, J = 4 Hz, H-2), 4.22 (1 H, d, J = 3 Hz, H-3), 3.75 (3 H, s,

OCH3), 1.51 (3 H, s, CH3), 1.34 (3 H, s, CH3), 0.87 (9 H, s, SiC(CH3)3), 0.09 (3 H, s, SiCH3),

0.04 (3 H, s, SiCH3) ppm. 13

C NMR (125 MHz, CDCl3) δ 166.36 (C, C=O), 142.51 (CH, C-5),

123.01 (CH, C-6), 111.98 (C, C-Me2), 105.12 (CH, C-1), 85.70, (CH, C-2) 80.33 (CH, C-4),

77.44 (CH, C-3), 51.59 (CH3, OCH3), 26.95 (CH3, C(CH3)2), 26.34 (CH3, C(CH3)2), 25.59 (3 ×

CH3, SiC(CH3)3), 18.06 (C, SiC(CH3)3), -4.91 (CH3, SiCH3), -5.06 (CH3, SiCH3) ppm.

Methyl 3-O-tert-butyldimethylsilanyl-5-phenyl-1,2-O-isopropylidene-α-D-xylo-hept-5-

enfuranuronate25

85

To a mixture of phenylboronic acid (26.8 mg, 0.22 mmol) and [RhCl(1,5-cod)]2 50 (2.46 mg, 5

mol%) under nitrogen were added a solution of α,β-unsaturated esters (E)-84 (40.0 mg, 0.11

109

mmol) in 1,4-dioxane:H2O (10:1; 0.27 mL), followed by triethylamine (15 µL, 0.11 mmol). The

reaction mixture was stirred for 4 days at room temperature, then the products were isolated

by evaporation of volatiles under reduced pressure and purified by flash column

chromatography (silica gel; eluent 5% EtOAc/petrol). The elution gave the title compound as

yellow oil with an overall yield of 30.0 mg (62%) (d.r. 12:1). Rf (15% EtOAc/petrol): 0.44.

-19.2 (c 1.9, CHCl3). IR max (thin film) 2928 (C-H stretch), 1739 (C=O stretch), 1252,

1214, 1163, 1074 (C-O stretch), 1015 (C-O stretch) cm-1

. 1H NMR (500 MHz, CDCl3) δ 7.32 -

7.20 (5 H, m, Ar-H), 5.95 (1 H, d, J = 4 Hz, H-1), 4.51 (1 H, dd, J = 10 and 2 Hz, H-4), 4.37 (1

H, d, J = 4 Hz, H-2), 3.91 (1 H, d, J = 2 Hz, H-3), 3.59 – 3.56 (1 H, m, H-5), 3.54 (3 H, s,

OCH3), 3.09 (1 H, dd, J = 15 and 4 Hz, H-6), 2.63 (1 H, dd, J = 16 and 10 Hz, H-6), 1.57 (3

H, s, CH3), 1.34 (3 H, s, CH3), 0.91 (9 H, s, SiC(CH3)3), -0.04 (3 H, s, SiCH3), -0.32 (3 H, s,

SiCH3) ppm. 13

C NMR (125 MHz, CDCl3) δ 172.59 (C, C=O), 140.56 (C, Ar-C), 128.42 (CH,

Ar-C), 128.25 (CH, Ar-C), 126.98 (CH, Ar-C), 111.42 (C, C-Me2), 104.54 (CH, C-1), 85.43

(CH, C-2), 85.41 (CH, C-4), 82.89 (CH, C-3), 51.28 (CH3, OCH3), 40.44 (CH2, C-6), 39.78

(CH, C-5), 26.87 (CH3, C(CH3)2), 26.31 (CH3, C(CH3)2), 25.78 (3 × CH3, SiC(CH3)3), 17.91

(C, SiC(CH3)3), -4.61 (CH3, SiCH3), -5.68 (CH3, SiCH3) ppm. MS (ES+) m/z [M+H]+ 437.0,

[M+Na]+ 459.0. Accurate Mass C23H37O6Si, [M+H]

+ requires 437.2361, measured 437.2354.

3-O-pyridyl-1,2:5,6-di-O-isopropylidene-α-D-glucofuranose37

86

To a solution of commercially available1,2:5,6-di-O-isopropylidene-α-D-glucofuranose (5.00

g, 19.2 mmol) in anhydrous toluene (45 mL) were added tert-amyl alcohol (0.64 mL), 50%

sodium hydroxide solution (32 mL), tetra-n-butylammonium hydrogensulfate (652 mg, 1.92

mmol) and 2-picolyl chloride hydrochloride (4.73 g, 28.8 mmol). The resulting mixture was

stirred vigorously overnight at room temperature. Then, water (50 mL) and DCM (50 mL)

were added and the organic layer was decanted. The aqueous phase was extracted with

DCM (2 × 50 mL) and the combined organic extracts were dried over anhydrous magnesium

110

sulfate, filtered and concentrated in vacuo. The crude product was purified by column

chromatography (silica gel; eluent 10% EtOAc/petrol) to afford 6.26 g (93%) of the title

compound as colourless oil. Rf (100% EtOAc): 0.47. -32.2 (c 1.1, CHCl3). IR max (thin

film) 2985 (C-H stretch), 2935 (C-H stretch), 1372, 1213, 1070 (C-O stretch), 1015 (C-O

stretch) cm-1

. 1

H NMR (400 MHz, CDCl3) δ 8.56 (1 H, ddd, J = 5, 2 and 1 Hz, H-11), 7.70 (1

H, td, J = 8 and 2 Hz, H-9), 7.51 (1 H, d, J = 8 Hz, H-8), 7.23 - 7.19 (1 H, m, H-10), 5.93 (1 H,

d, J = 3.5 Hz, H-1), 4.83 (1 H, app. d, J = 12 Hz, CHxHyAr), 4.77 (1 H, app. d, J = 12 Hz,

CHxHyAr), 4.67 (1 H, d, J = 4 Hz, H-2), 4.41 (1 H, dt, J = 8 and 6 Hz, H-5), 4.19 – 4.10 (3 H,

m, H-3, H-4, H-6), 4.03 (1 H, dd, J = 8.5 and 5.5 Hz, H-6), 1.51 (3 H, s, CH3), 1.44 (3 H, s,

CH3), 1.37 (3 H, s, CH3), 1.33 (3 H, s, CH3) ppm. 13

C NMR (125 MHz, CDCl3) δ 157.92 (C, C-

7), 149.05 (CH, C-11), 136.62 (CH, C-9), 122.49 (CH, C-10), 121.34 (CH, C-8), 111.86 (C,

C-Me2), 109.07 (C, C-Me2), 105.27 (CH, C-1), 82.45 (CH, C-2), 82.31 (CH, C-3), 81.25 (CH,

C-4), 73.07 (CH2, OCH2Ar), 72.42 (CH, C-5), 67.48 (CH2, C-6), 26.80 (2 × CH3, C(CH3)2),

26.21 (CH3, C(CH3)2), 25.40 (CH3, C(CH3)2) ppm. m/z [M+H]+ 352.0, [M+Na]

+ 374.0.

Accurate Mass C18H26NO6, [M+H]+

requires 352.1758, measured 352.1755.

3-O-pyridyl-1,2-di-O-isopropylidene-α-D-glucofuranose73

87

Acetic acid (34 mL) and water (11 mL) were added, at room temperature, to furanose 86

(4.99 g, 14.2 mmol). The resulting reaction mixture was stirred for 24 h at 40 °C. The mixture

was then neutralised with saturated Na2CO3 solution and extracted with DCM (3 × 35 mL).

The combined organic extracts were washed with water (35 mL), dried over anhydrous

magnesium sulfate, filtered and concentrated in vacuo. The crude product was purified by

flash column chromatography (silica gel; eluent 100% EtOAc) to afford 3.83 g (87%) of the

title compound as colourless oil. Rf (100% EtOAc): 0.08. -76.7 (c 1.0, CHCl3). IR max

(thin film) 3206 (O-H stretch), 2985 (C-H stretch), 2933 (C-H stretch), 1215, 1077 (C-O

stretch), 1012 (C-O stretch) cm-1

. 1H NMR (500 MHz, CDCl3) δ 8.56 (1 H, d, J = 5 Hz, H-11),

7.73 (1 H, td, J = 8 and 1 Hz, H-9), 7.32 – 7.24 (1 H, m, H-8), 7.19 (1 H, d, J = 7.5 Hz, H-10),

111

6.01 (1 H, d, J = 4 Hz, H-1), 4.98 (1 H, d, J = 15 Hz, CHxHyAr), 4.72 (1 H, d, J = 15 Hz,

CHxHyAr), 4.65 (1 H, d, J = 4 Hz, H-2), 4.26 – 4.20 (1 H, m, H-4), 4.15 – 4.10 (2 H, m, H-3,

H-5), 3.99 – 3.90 (1 H, m, H-6), 3.74 (1 H, dt, J = 11 and 6 Hz, H-6), 2.41 (1 H, t, J = 6 Hz,

OH), 1.48 (3 H, s, CH3), 1.33 (3 H, s, CH3) ppm. 13

C NMR (125 MHz, CDCl3) δ 156.55 (C, C-

7), 148.80 (CH, C-11), 137.40 (CH, C-9), 123.07 (CH, C-8), 121.44 (CH, C-10), 111.82 (C,

C-Me2), 105.77 (CH, C-1), 82.90 (CH, C-3), 82.19 (CH, C-2), 80.67 (CH, C-4), 69.75 (CH2,

C-6), 68.59 (CH, C-5), 64.80 (CH2, C-6), 26.77 (CH3, C(CH3)2), 26.34 (CH3, C(CH3)2) ppm.

MS (ES+) m/z [M+H]+ 312.0, [M+Na]

+ 334.0. Accurate Mass C15H22NO6, [M+H]

+ requires

312.1445, measured 312.1442.

3-O-pyridyl-1,2-di-O-isopropylidene-α-D-xylo-pentadialdo-1,4-furanose14

88

Diol 87 (2.90 g, 9.31 mmol) was dissolved in 1,4-dioxane (24 mL) and a solution of sodium

metaperiodate (2.39 g, 11.2 mmol) in water (24 mL) was added. The reaction mixture was

stirred for 16 h at room temperature and then filtered. The filtrate was extracted with DCM (3

× 25 mL). The combined organic extracts were washed with water (10 mL), dried over

anhydrous magnesium sulfate and concentrated in vacuo to afford 2.22 g (85%) crude of the

title compound as yellow oil. Rf (100% EtOAc): 0.31. -188.7 (c 0.7, CHCl3). IR max (thin

film) 2985 (C-H stretch), 2935 (C-H stretch), 1737 (C=O stretch), 1374, 1215, 1075 (C-O

stretch), 1007 (C-O stretch) cm-1

. 1

H NMR (500 MHz, CDCl3) δ 9.73 (1 H, d, J = 1.5 Hz,

CHO), 8.54 (1 H, dt, J = 5 and 1 Hz, H-9), 7.70 (1 H, td, J = 8 and 2 Hz, H-7), 7.30 – 7.26 (1

H, m, H-6), 7.23 - 7.20 (1 H, m, H-8), 6.14 (1 H, d, J = 3 Hz, H-1), 4.77 – 4.72 (2 H, m, H-2,

CHxHyAr), 4.65 – 4.60 (2 H, m, H-4, CHxHyAr), 4.44 (1 H, d, J = 4 Hz, H-3), 1.49 (3 H, s,

CH3), 1.34 (3 H, s, CH3) ppm. 13

C NMR (125 MHz, CDCl3) δ 199.82 (CH, CHO), 156.81 (C,

C-5), 149.06 (CH, C-9), 136.89 (CH, C-7), 122.81 (CH, C-8), 121.46 (CH, C-6), 112.63 (C,

C-Me2), 106.13 (CH, C-1), 84.57 (CH, C-3), 84.45 (CH, C-4), 81.92 (CH, C-2), 72.95 (CH2,

OCH2Ar), 26.94 (CH3, C(CH3)2), 26.31 (CH3, C(CH3)2) ppm. MS (ES+) m/z [M+H]+ 280.0,

[M+Na]+ 312.0. Accurate Mass C14H18NO5, [M+H]

+ requires 280.1173, measured 280.1180.

112

(Z)-Methyl 3-O-pyridyl-5,6-dideoxy-1,2-O-isopropylidene-α-D-xylo-hept-5-enfuranuronate

and (Z)-89 (E)-Methyl 3-O-pyridyl-5,6-dideoxy-1,2-O-isopropylidene-α-D-xylo-hept-5-

enfuranuronate76

(E)-89

To a solution of the crude aldehyde 88 (2.20 g, 7.88 mmol) in anhydrous DCM (30 mL),

Ph3PCHCOOMe (2.90 g, 8.66 mmol) was added at room temperature. After stirring for 16 h,

the solvent was evaporated and the crude product was purified by flash column

chromatography (silica gel; eluent 35% EtOAc/petrol). The elution gave a mixture of esters

(Z)-89 and (E)-89 (1:2, Z:E) with an overall yield of 2.01 g (76%) as yellow oil. Rf (100%

EtOAc): 0.54. IR max (thin film) 2987 (C-H stretch), 2950 (C-H stretch), 1719 (C=O stretch),

1436 (C=C stretch), 1164, 1074 (C-O stretch), 1011 (C-O stretch) cm-1

. 1H NMR (400 MHz,

CDCl3) δ 8.54 – 8.46 (2 H, m, Hcis-11, Htrans-11), 7.73 – 7.57 (2 H, m, Hcis-9, Htrans-9), 7.36 –

7.30 (2 H, m, Hcis-8, Htrans-8), 7.21 - 7.14 (2 H, m, Hcis-10, Htrans-10), 6.99 (1 H, dd, J = 16 and

5 Hz, Htrans-5), 6.41 (1 H, dd, J = 12 and 7 Hz, Hcis-5), 6.19 (1 H, dd, J = 16 and 2 Hz, Htrans-

6), 6.01 (1 H, d, J = 4 Hz, Hcis-1), 6.00 (1 H, d, J = 4 Hz, Htrans-1), 5.95 (1 H, dd, J = 12 and 2

Hz, Hcis-6), 5.67 (1 H, ddd, J = 7 and 3 and 2 Hz, Hcis-4), 4.75 – 4.68 (4 H, m, Hcis-2, Htrans-2,

CHxcisHyAr, CHxtransHyAr), 4.64 – 4.60 (1 H, app. d, J = 12 Hz, CHxHytransAr), 4.60 – 4.57 (1 H,

app. d, J = 12 Hz, CHxHycisAr), 4.34 (1 H, d, J = 3 Hz, Hcis-3), 4.07 (1 H, d, J = 3 Hz, Htrans-3),

3.73 (3 H, s, OCH3trans), 3.68 (3 H, s, OCH3cis), 1.52 (3 H, s, CH3cis), 1.49 (3 H, s, CH3trans),

1.32 (6 H, s, CH3cis, CH3trans) ppm. 13

C NMR (100 MHz, CDCl3) δ 166.32 (C, Ctrans=O), 165.83

(C, Ccis=O), 157.63 (C, Ccis-7), 157.33 (C, Ctrans-7), 148.92 (CH, Ccis-11, Ctrans-11), 145.33

(CH, Ccis-5), 141.44 (CH, Ctrans-5), 136.77 (CH, Ctrans-9), 136.53 (CH, Ccis-9), 122.87 (CH,

Ctrans-5), 122.61 (CH, Ctrans-10), 122.44 (CH, Ccis-10), 121.40 (CH, Ctrans-8), 121.19 (CH, Ccis-

8), 120.80 (CH, Ccis-6), 111.91 (C, C(CtransH3)2), 111.81 (C, C(CcisH3)2), 105.00 (CH, Ccis-1),

104.87 (CH, Ctrans-1), 84.54 (CH, Ccis-3), 83.79 (CH, Ctrans-3), 82.82 (CH, Ccis-2), 82.43 (CH,

Ctrans-2), 79.27 (CH, Ctrans-4), 77.89 (CH, Ccis-4), 72.90 (2 × CH2, OCcisH2Ar, OCtransH2Ar),

51.61 (CH3, OCtransH3), 51.43 (CH3, OCcisH3), 26.82 (CH3, C(CcisH3)2), 26.70 (CH3,

C(CtransH3)2), 26.31 (CH3, C(CcisH3)2), 26.08 (CH3, C(CtransH3)2) ppm. MS (ES+) m/z [M+H]+

113

336.0, [M+Na]+ 358.0. Accurate Mass C17H22NO6, [M+H]

+ requires 336.1439, measured

336.1442.

Methyl 3-O-pyridyl-5-phenyl-1,2-O-isopropylidene-α-D-xylo-hept-5-enfuranuronate 90

CUPRATE REACTION59

To a suspension of CuI (85.2 mg, 0.45 mmol) in anhydrous THF (4 mL) was added, at -78

°C, a 1.0 M solution of phenylmagnesium bromide in THF (2.25 mL, 2.25 mmol). After 40

min at -78 °C, freshly distilled TMSCl (0.86 mL, 6.75 mmol) was added to the reaction

mixture, followed by dropwise addition of a solution of Z/E isomeric mixture α,β-unsaturated

esters (Z)-89 and (E)-89 (150 mg, 0.45 mmol) in anhydrous THF (6 mL). The reaction

mixture was then allowed to slowly warm to room temperature over 3 h. The reaction mixture

was then quenched, at -78 °C, by the addition of saturated aqueous NH4OH:NH4Cl (1:9; 5

mL) and extracted with diethyl ether (3 × 5 mL). The combined organic extracts were washed

with brine (5 mL), dried over anhydrous magnesium sulfate, filtered and concentrated in

vacuo. The crude was purified by flash column chromatography (silica gel; eluent 20% →

30% EtOAc/petrol) to afford 157 mg (84%) of the title compound as orange oil as a single

diastereoisomer. Rf (EtOAc): 0.57. -53.7 (c 1.7, CHCl3). IR max (thin film) 3029 (C-H

stretch), 2986 (C-H stretch), 2935 (C-H stretch), 1734 (C=O stretch), 1163, 1074 (C-O

stretch), 1013 (C-O stretch) cm-1

. 1

H NMR (500 MHz, CDCl3) δ 8.52 (1 H, d, J = 5 Hz, H-11),

7.70 (1 H, t, J = 7.5 Hz, H-9), 7.40 (1 H, d, J = 7.5 Hz, H-8), 7.30 - 7.17 (6 H, m, H-10, Ar-H),

5.97 (1 H, d, J = 4 Hz, H-1), 4.58 (1 H, d, J = 4 Hz, H-2), 4.54 (1 H, d, J = 13 Hz, CHxHyAr),

4.39 (1 H, dd, J = 10 and 2.5 Hz, H-4), 4.24 (1 H, d, J = 13 Hz, CHxHyAr), 3.74 (1 H, td, J =

10 and 4 Hz, H-5), 3.52 (3 H,s, OCH3), 3.51 (1 H, d, J = 3 Hz, H-3), 3.12 (1 H, dd, J = 16 and

4 Hz, H-6), 2.71 (1 H, dd, J = 16 and 10.5 Hz, H-6), 1.53 (3 H, s, CH3), 1.31 (3 H, s, CH3)

ppm. 13

C NMR (100 MHz, CDCl3) δ 172.57 (C, C=O), 157.45 (C, C-7), 148.95 (CH, C-11),

140.10 (C, Ar-C), 136.78 (CH, C-9), 128.51 (CH, Ar-C), 128.05 (CH, Ar-C), 127.08 (CH, Ar-

114

C), 122.53 (CH, C-10), 121.398 (CH, C-8), 111.48 (C, C-Me2), 105.01 (CH, C-1), 83.30 (CH,

C-4), 81.76 (CH, C-3), 81.65 (CH, C-2), 72.45 (CH2, OCH2Ar), 51.42 (CH3, OCH3), 40.87

(CH, C-5), 38.66 (CH2, C-6), 26.69 (CH3, C(CH3)2), 26.07 (CH3, C(CH3)2) ppm. MS (ES+)

m/z [M+H]+ 414.0, [M+Na]

+ 436.0. Accurate Mass C23H28NO6, [M+H]

+ requires 414.1922,

measured 414.1912.

HAYASHI-MIYAURA REACTION25

To a mixture of phenylboronic acid (218 mg, 1.79 mmol) and commercially available

[RhCl(1,5-cod)]2 50 (20.3 mg, 5 mol%) under nitrogen were added a solution of Z/E isomeric

mixture α,β-unsaturated esters (Z)-89 and (E)-89 (300 mg, 0.89 mmol) in 1,4-dioxane:H2O

(10:1; 1.68 mL), followed by triethylamine (0.12 mL, 0.89 mmol). The reaction mixture was

stirred for 24 h at 50 °C resulting in only > 33% consumption of the starting material, then

were further added phenylboronic acid (218 mg, 1.79 mmol) and [RhCl(1,5-cod)]2 54 (20.3

mg, 5 mol%). The reaction mixture was left to stir for further 4 d at 50 °C. The products were

isolated by evaporation of volatiles under reduced pressure and purified by flash column

chromatography (silica gel; eluent 20% → 25% EtOAc/petrol). The elution gave the title

compound as orange oil with an overall yield of 121 mg (33%) (d.r. 9:1) (data of major

diastereoisomer as described above).

1,2:5,6-di-O-isopropylidene-α-D-allofuranose87

91

To a suspension of pyridinium dichromate (5.42 g, 14.4 mmol) and acetic anhydride (4.72

mL, 49.9 mmol) in DCM (37 mL) was added a solution of commercially available 1,2:5,6-di-

O-isopropylidene-α-D-glucofuranose (5.00 g, 19.2 mmol) in DCM (13 mL). After 2 h reflux,

the mixture was evaporated, the residue taken up in ethyl acetate and the solution filtered

through a pad of silica gel and Celite. The filtrate was evaporated, the residue dissolved in

EtOH:H2O (24:19; 22 mL), and treated with sodium borohydride (940 mg, 25.0 mmol) in

water (13 mL). After stirring for 3 h at room temperature, the mixture was extracted with

115

DCM (3 × 20 mL), dried over anhydrous magnesium sulfate, filtered and concentrated in

vacuo. The residue was crystallised from Et2O to afford 4.15 g (90%) of the title compound

as white solid. +41.0 (c 0.9, CHCl3) lit.

87

+37.0 (c 1.0, CHCl3). mp 70 - 72 °C (lit.87

mp 76 °C). IR max (thin film) 3260 (O-H stretch), 2949 (C-H stretch), 1381, 1223, 1118, 1079

(C-O stretch), 1017 (C-O stretch) cm-1

. 1

H NMR (400 MHz, CDCl3) δ 5.82 (1 H, d, J = 4 Hz,

H-1), 4.62 (1 H, dd, J = 5 and 4 Hz, H-2), 4.35 – 4.28 (1 H, m, H-5), 4.12 – 3.99 (3 H, m, H-6,

H-6, H-3), 3.82 (1 H, dd, J = 8.5 and 5 Hz, H-4), 2.56 (1 H, br. s., OH), 1.58 (3 H, s, CH3),

1.47 (3 H, s, CH3), 1.39 (3 H, s, CH3), 1.37 (3 H, s, CH3) ppm. 13

C NMR (100 MHz, CDCl3) δ

112.81 (C, C-Me2), 109.83 (C, C-Me2), 103.88 (CH, C-1), 79.63 (CH, C-4), 78.91 (CH, C-2),

75.51 (CH, C-3), 72.42 (CH, C-5), 65.81 (CH2, C-6), 26.53 (CH3, C(CH3)2), 26.47 (CH3,

C(CH3)2), 26.27 (CH3, C(CH3)2), 25.23 (CH3, C(CH3)2) ppm. MS (ES+) m/z [M+Na]+ 283.0.

Accurate Mass C12H20O6Na, [M+Na]+

requires 283.1152, measured 283.1144.

3-O-(tert-butyldimethylsilyl)-1,2:5,6-di-O-isopropylidene-α-D-allofuranose86

92

t-Butyldimethylsilyl chloride (1.16 g, 7.68 mmol) and imidazole (1.05 g, 15.4 mmol) were

added to a solution of furanose 91 (2.00 g, 7.68 mmol) in DMF (10 mL). After 18 h, the

reaction mixture was poured into water (20 mL) and then extracted with ethyl acetate (2 × 20

mL). The combined organic extracts were washed sequentially with water (2 × 10 mL) and

brine (10 mL), dried over anhydrous magnesium sulfate, filtered and then concentrated in

vacuo to afford 2.79 g (97%) of the title compound as yellow oil. IR max (thin film) 2937 (C-H

stretch), 1375, 1255, 1217, 1077 (C-O stretch), 1014 (C-O stretch) cm-1

. 1

H NMR (400 MHz,

CDCl3) δ 5.76 (1 H, d, J = 4 Hz, H-1), 4.46 (1 H, t, J = 4 Hz, H-2), 4.36 (1 H, dt, J = 7 and 3

Hz, H-5), 4.06 (1 H, dd, J = 4 and 8 Hz, H-3), 4.01 – 3.98 (3 H, m, H-6, H-6, H-4), 1.55 (3 H,

s, CH3), 1.46 (3 H, s, CH3), 1.37 (3 H, s, CH3), 1.33 (3 H, s, CH3), 0.92 (9 H, s, SiC(CH3)3),

0.14 (3 H, s, SiCH3), 0.13 (3 H, s, SiCH3) ppm. 13

C NMR (100 MHz, CDCl3) δ 112.47 (C, C-

Me2), 109.51 (C, C-Me2), 103.72 (CH, C-1), 79.61 (CH, C-2), 79.11 (CH, C-4), 74.89 (CH, C-

116

3), 72.52 (CH, C-5), 64.90 (CH2, C-6), 26.71 (CH3, C(CH3)3), 26.68 (CH3, C(CH3)3), 26.31

(CH3, C(CH3)3), 25.68 (3 × CH3, SiC(CH3)3), 25.01 (CH3, C(CH3)3), 18.08 (C, SiC(CH3)3), -

4.41 (CH3, SiCH3), -4.84 (CH3, SiCH3) ppm. MS (ES+) m/z [M+Na]+ 397.0. Accurate Mass

C18H34O6NaSi, [M+Na]+

requires 397.2022, measured 397.2025.

3-O-(tert-butyldimethylsilyl)-1,2-O-isopropylidene-α-D-allofuranose86

93

A solution of furanose 92 (2.79 g, 7.45 mmol) in 75% aqueous acetic acid (20 mL) was

stirred at room temperature for 24 h. The reaction mixture was concentrated and then dried

by azeotropic coevaporation with toluene (3 × 10 mL), and the resulting diol was dried

overnight under high vacuum to remove any trace of acetic acid. The crude product was

purified by flash column chromatography (silica gel; eluent 30% EtOAc/petrol) to afford 1.23

g (49%) of the title compound as yellow oil. +12.2 (c 0.1, CHCl3). IR max (thin film)

3422 (O-H stretch), 2931 (C-H stretch), 1354, 1249, 1215, 1077 (C-O stretch), 1034 (C-O

stretch), 1017 (C-O stretch) cm-1

. 1

H NMR (500 MHz, CDCl3) δ 5.74 (1 H, d, J = 4 Hz, H-1),

4.47 (1 H, t, J = 4 Hz, H-2), 4.10 (1 H, dd, J = 9 and 4.5 Hz, H-3), 4.03 (1 H, m, H-5), 3.99 (1

H, m, H-4), 3.75 (1 H, m, H-6), 3.69 (1 H, m, H-6), 1.55 (3 H, s, CH3), 1.34 (3 H, s, CH3), 0.92

(9 H, s, SiC(CH3)3), 0.17 (3 H, s, SiCH3), 0.15 (3 H, s, SiCH3) ppm. 13

C NMR (125 MHz,

CDCl3) δ 112.84 (C, C-Me2), 103.93 (CH, C-1), 79.77 (CH, C-2), 79.28 (CH, C-4), 72.25 (CH,

C-3), 71.35 (CH, C-5), 63.14 (CH2, C-6), 26.66 (CH3, C(CH3)3), 26.52 (CH3, C(CH3)3), 25.69

(CH3, SiC(CH3)3), 25.62 (CH3, SiC(CH3)3), 18.06 (C, SiC(CH3)3), -4.24 (CH3, SiCH3), -4.81

(CH3, SiCH3) ppm. MS (ES+) m/z [M+Na]+ 357.0. Accurate Mass C15H30O6NaSi, [M+Na]

+

requires 357.1704, measured 357.1693.

117

3-O-(tert-butyldimethylsilyl)-1,2-O-isopropylidene-α-D-allo-pentadialdo-1,4-furanose86

94

A solution of sodium periodate (0.94 g, 4.42 mmol) in water (5 mL) was added to a solution

of diol 93 (1.23 g, 3.68 mmol) in THF (20 mL). The resulting slurry was stirred at room

temperature for 6 h and then filtered. The filtrate was extracted with DCM (3 × 10 mL) and

the combined organic extracts were washed with water (5 mL), dried over anhydrous

magnesium sulfate and concentrated in vacuo to afford 1.14 g (100%) crude of the title

compound as yellow oil. IR max (thin film) 2929 (C-H stretch), 1713 (C=O stretch), 1371,

1247, 1074 (C-O stretch), 1011 (C-O stretch) cm-1

. 1H NMR (500 MHz, CDCl3) δ 9.67 (1 H, d,

J = 2 Hz, CHO), 5.85 (1 H, d, J = 3 Hz, H-1), 4.50 (1 H, t, J = 4 Hz, H-2), 4.35 (1 H, dd, J = 9

and 2 Hz, H-4), 4.07 (1 H, dd, J = 9 and 4 Hz, H-3), 1.57 (3 H, s, CH3), 1.37 (3 H, s, CH3),

0.92 (9 H, s, SiC(CH3)3), 0.12 (3 H, s, SiCH3), 0.10 (3 H, s, SiCH3) ppm. 13

C NMR (125 MHz,

CDCl3) δ 198.60 (C, C=O), 113.52 (C, C-Me2), 104.62 (CH, C-1), 83.33 (CH, C-2), 79.33

(CH, C-4), 73.55 (CH, C-3), 26.80 (CH3, C(CH3)3), 26.71 (CH3, C(CH3)3), 25.61 (3 × CH3,

SiC(CH3)3), 18.12 (C, SiC(CH3)3), -4.73 (CH3, SiCH3), -4.93 (CH3, SiCH3) ppm. MS (ES+) m/z

[M+Na]+ 325.0, [M+Na+MeOH]

+ 357.0.

(E)-Methyl 3-O-(tert-butyldimethylsilyl)-5,6-dideoxy-1,2-O-isopropylidene-α-D-allo-hept-5-

enfuranuronate86

(E)-95

To a solution of the crude aldehyde 94 (1.14 g, 3.77 mmol) in DCM (13 mL) was added

commercially available Ph3PCHCOOMe (1.26 g, 3.77 mmol) at room temperature. After

stirring for 16 h, the solvent was evaporated and the crude product was purified by flash

column chromatography (silica gel; eluent 20% EtOAc/petrol) to afford 1.16 g (86%) of the

title compound as yellow oil as trans- isomer. +63.2 (c 0.9, CHCl3). IR max (thin film)

118

2929 (C-H stretch), 1731 (C=O stretch), 1652 (C=C stretch), 1434, 1370, 1251, 1197, 1164,

1115, 1070 (C-O stretch), 1006 (C-O stretch) cm-1

. 1

H NMR (500 MHz, CDCl3) δ 6.94 (1 H,

dd, J = 16 and 5 Hz, H-5), 6.12 (1 H, dd, J = 16 and 1 Hz, H-6), 5.79 (1 H, d, J = 3 Hz, H-1),

4.51 – 4.45 (2 H, m, H-2, H-4), 3.75 (3 H, s, OCH3), 3.70 (1 H, dd, J = 9 and 4 Hz, H-3), 1.57

(3 H, s, CH3), 1.35 (3 H, s, CH3), 0.91 (9 H, s, SiC(CH3)3), 0.11 (3 H, s, SiCH3), 0.09 (3 H, s,

SiCH3) ppm. 13

C NMR (125 MHz, CDCl3) δ 166.49 (C, C=O), 144.28 (CH, C-5), 121.55 (CH,

C-6), 112.89 (C, C-Me2), 103.88 (CH, C-1), 79.24 (2 × CH, C-2, C-4), 78.31 (H, C-3), 51.64

(CH3, OCH3), 26.67 (CH3, C(CH3)2), 26.54 (CH3, C(CH3)2), 25.69 (3 × CH3, SiC(CH3)3), 18.16

(C, SiC(CH3)3), -4.64 (CH3, SiCH3), -4.78 (CH3, SiCH3) ppm. MS (ES+) m/z [M+Na]+ 381.0.

Accurate Mass C17H30O6NaSi, [M+Na]+

requires 381.1704, measured 381.1707.

(5S)-Methyl 3-O-(tert-butyldimethylsilyl)-5-phenyl-1,2-O-isopropylidene-α-D-allo-hept-5-

enfuranuronate 96

CUPRATE REACTION59

To a suspension of CuI (265 mg, 1.39 mmol) in anhydrous THF (13 mL) was added, at -78

°C, a 1.0 M solution of phenylmagnesium bromide in THF (6.97 mL, 6.97 mmol). After 40

min at -78 °C, TMSCl (2.65 mL, 20.85 mmol) was added to the reaction mixture, followed by

dropwise addition of a solution of α,β-unsaturated ester (E)-95 (500 mg, 1.39 mmol) in

anhydrous THF (20 mL). The reaction mixture was then allowed to slowly warm to room

temperature over 24 h. The reaction mixture was then quenched, at -78 °C, by the addition

of saturated aqueous NH4OH:NH4Cl (1:9; 35 mL) and extracted with diethyl ether (3 × 35

mL). The combined organic extracts were washed with brine (35 mL), dried over anhydrous

magnesium sulfate, filtered and concentrated in vacuo. The crude product was purified by

flash column chromatography (silica gel; eluent 5% EtOAc/petrol) to afford 590 mg (97%) of

the title compound as yellow as a single diastereoisomer. Rf (10% EtOAc/petrol): 0.39. -

1.2 (c 1.2, CHCl3). IR max (thin film) 2928 (C-H stretch), 1739 (C=O stretch), 1254, 1216,

119

1154, 1078 (C-O stretch), 1005 (C-O stretch) cm-1

. 1H NMR (500 MHz, CDCl3) δ 7.29 - 7.19

(5 H, m, Ar-H), 5.67 (1 H, d, J = 4 Hz, H-1), 4.36 (1 H, t, J = 4 Hz, H-2), 4.14 (1 H, dd, J = 8

and 5 Hz, H-4), 3.69 (1 H, dd, J = 8.5 and 5 Hz, H-3), 3.54 (3 H, s, OCH3), 3.41 (1 H, dt, J =

10 and 5 Hz, H-5), 2.86 (1 H, dd, J = 16 and 5 Hz, H-6), 2.68 (1 H, dd, J = 16 and 10 Hz, H-

6), 1.51 (3 H, s, CH3), 1.30 (3 H, s, CH3), 0.84 (9 H, s, SiC(CH3)3), 0.05 (3 H, s, SiCH3), -0.07

(3 H, s, SiCH3) ppm. 13

C NMR (125 MHz, CDCl3) δ 172.76 (C, C=O), 140.85 (C, Ar-C),

128.58 (CH, Ar-C), 128.31 (CH, Ar-C), 126.79 (CH, Ar-C), 112.44 (C, C-Me2), 103.67 (CH,

C-1), 82.01 (CH, C-2), 79.34 (CH, C-4), 74.61 (CH, C-3), 51.49 (CH3, OCH3), 43.45 (CH2, C-

6), 36.71 (CH, C-5), 29.70 (CH3, C(CH3)2), 26.71 (CH3, C(CH3)2), 25.72 (3 × CH3,

SiC(CH3)3), 18.01 (C, SiC(CH3)3), -4.40 (CH3, SiCH3), -4.98 (CH3, SiCH3) ppm. MS (ES+) m/z

[M+Na]+ 459.0. Accurate Mass C23H36O6NaSi, [M+Na]

+ requires 459.2173, measured

459.2180.

HAYASHI-MIYAURA REACTION25

To a mixture of phenylboronic acid (34.1 mg, 0.28 mmol) and [RhCl(1,5-cod)]2 50 (3.45 mg, 5

mol%) under nitrogen, a solution of α,β-unsaturated ester (E)-95 (50.0 mg, 0.14 mmol) in

1,4-dioxane:H2O (10:1; 0.35 mL) was added, followed by triethylamine (20 µL, 0.14 mmol).

The reaction mixture was stirred for 48 h at room temperature, then the products were

isolated by evaporation of volatiles under reduced pressure and purified by flash column

chromatography (silica gel; eluent 5% EtOAc/petrol) to afford an overall yield of 33.5 mg

(55%) of the title compound as yellow oil as a single diastereoisomer (data as described

above).

(5S)-Methyl 3-hydroxyl-5-phenyl-1,2-O-isopropylidene-α-D-allo-hept-5-enfuranuronate88

97

To a stirred solution of ester 96 (0.58 g, 1.33 mmol) in THF (20 mL) was added a 1.0 M

solution of TBAF in THF (1.99 mL, 1.99 mmol) at 0 °C and the reaction mixture was left to

stir at room temperature for 2 h. The mixture was concentrated in vacuo and the residue was

120

dissolved in DCM (5 mL), washed with water (2 × 5 mL). The combined organic extracts

were dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The

crude product was purified by column chromatography (silica gel; eluent 20% EtOAc/petrol)

to afford 0.34 g (79%) of the title compound as yellow solid as a single diastereoisomer. The

purified product was recrystallised from ethyl acetate to obtain colourless crystals.

+43.6 (c 0.6, CHCl3). mp 82 - 85 °C. IR max (thin film) 3443 (O-H stretch), 2938 (C-H

stretch), 1724 (C=O stretch), 1453 (C=C stretch), 1374, 1268, 1220, 1165, 1091, 1060 (C-O

stretch), 1022 (C-O stretch), 1002 (C-O stretch) cm-1

. 1H NMR (500 MHz, CDCl3) δ 7.38 -

7.22 (5 H, m, Ar-H), 5.75 (1 H, d, J = 4 Hz, H-1), 4.52 – 4.49 (1 H, m, H-2), 3.94 (1 H, dd, J =

8.5 and 6 Hz, H-4), 3.73 (1 H, td, J = 9 and 5 Hz, H-3), 3.57 (3 H, s, OCH3), 3.44 (1 H, dt, J =

9 and 6 Hz, H-5), 2.98 (1 H, dd, J = 16 and 5.5 Hz, H-6), 2.76 (1 H, dd, J = 16 and 9 Hz, H-

6), 1.93 (1 H, d, J = 9 Hz, OH), 1.55 (3 H, s, CH3), 1.30 (3 H, s, CH3) ppm. 13

C NMR (125

MHz, CDCl3) δ 172.58 (C, C=O), 139.64 (C, Ar-C), 128.56 (CH, Ar-C), 128.53 (CH, Ar-C),

127.25 (CH, Ar-C), 112.60 (C, C-Me2), 103.43 (CH, C-1), 82.47 (CH, C-2), 78.82 (CH, C-4),

73.97 (CH, C-3), 51.62 (CH3, OCH3), 44.14 (CH2, C-6), 36.71 (CH, C-5), 26.54 (CH3,

C(CH3)2), 26.51 (CH3, C(CH3)2) ppm. MS (ES+) m/z [M+Na]+ 345.0. Accurate Mass

C17H22O6Na, [M+Na]+

requires 345.1309, measured 345.1313.

(E)-3-((3aR,5R,6S,6aR)-6-(benzyloxy)-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-5-yl)-1,1-

diphenylprop-2-en-1-ol 98

To a solution of α,β-unsaturated ester (E)-27 (0.30 g, 0.90 mmol) in THF (10 mL) was added

a 2.0 M solution of phenyllithium in n-dibutyl ether (0.90 mL, 1.79 mmol) dropwise at -78 °C.

The reaction mixture was stirred at -78 °C for 4 h, then quenched with saturated aqueous

NH4Cl (10 mL) and extracted with diethyl ether (3 × 10 mL). The combined organic extracts

were washed with brine (10 mL), dried over anhydrous magnesium sulfate, filtered and

concentrated in vacuo. The crude product was purified by flash column chromatography

121

(silica gel; eluent 8% EtOAc/petrol) to afford 150 mg (36%) of the title compound as

colourless oil (d.r. 12:1). Rf (30% EtOAc/petrol): 0.53. -24.4 (c 1.6, CHCl3). IR max (thin

film) 3468 (O-H stretch), 3060 (C-H stretch), 3029 (C-H stretch), 2985 (C-H stretch), 2934

(C-H stretch), 1069 (C-O stretch), 981 cm-1

. 1H NMR (400 MHz, CDCl3) δ 7.42 - 7.17 (15 H,

m, Ar-H), 6.51 (1 H, dd, J = 16 and 1 Hz, H-6), 5.98 (1 H, d, J = 4 Hz, H-1), 5.90 (1 H, dd, J =

16 and 7 Hz, H-5), 4.77 (1 H, ddd, J = 7, 3 and 1 Hz, H-4), 4.64 (1 H, d, J = 4 Hz, H-2), 4.60

– 4.55 (1 H, m, J = 12 Hz, CHxHyAr), 4.48 – 4.43 (1 H, m, J = 12 Hz, CHxHyAr), 3.86 (1 H, d,

J = 3 Hz), 2.32 (1 H, s, OH), 1.50 (3 H, s, CH3), 1.33 (3 H, s, CH3) ppm. 13

C NMR (100 MHz,

CDCl3) δ 145.62 (C, Ar-C), 139.69 (C, C-6), 137.40 (C, Ar-C), 128.41 (CH, Ar-C), 128.14

(CH, Ar-C), 128.12 (CH, Ar-C), 127.80 (CH, Ar-C), 127.58 (CH, Ar-C), 127.34 (CH, Ar-C),

127.19 (CH, Ar-C), 127.09 (CH, Ar-C), 126.81 (CH, Ar-C), 124.09 (CH, C-5), 111.54 (C, C-

Me2), 104.80 (CH, C-1), 83.09 (CH, C-3), 82.93 (CH, C-2), 80.58 (CH, C-4), 79.01 (C, C-7),

72.02 (CH2, OCH2Ar), 26.72 (CH3, C(CH3)2), 26.16 (CH3, C(CH3)2) ppm. MS (ES+) m/z

[M+Na]+ 481.0. Accurate Mass C29H30O5Na, [M+Na]

+ requires 481.1982, measured

481.1986.

(S)-3-((3aR,5R,6S,6aR)-6-(benzyloxy)-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-5-yl)-

1,1,3-triphenylpropan-1-ol 99

To a mixture of ester 55 and ketone 56 (550 mg, 1.33 mmol) in THF (20 mL) was added a

2.0 M solution of phenyllithium in n-dibutyl ether (0.67 mL, 1.33 mmol) dropwise at -78 °C.

The reaction mixture was stirred at -78 °C for 4 h, then quenched with saturated aqueous

NH4Cl (10 mL) and extracted with diethyl ether (3 × 10 mL). The combined organic extracts

were washed with brine (10 mL), dried over anhydrous magnesium sulfate, filtered and

concentrated in vacuo. The crude product was purified by flash column chromatography

(silica gel; eluent 5% → 7% EtOAc/petrol) to afford 108 mg (15%) of the title compound as

white crystalline solid as a single diastereoisomer. Rf (30% EtOAc/petrol): 0.61. -43.1 (c

122

1.2, CHCl3). mp 65 – 67 °C. IR max (thin film) 3431 (O-H stretch), 3026 (C-H stretch), 2981

(C-H stretch), 2931 (C-H stretch), 1071 (C-O stretch), 1021 (C-O stretch) cm-1

. 1H NMR (500

MHz, CDCl3) δ 7.39 (2 H, d, J = 8 Hz, Ar-H), 7.32 (2 H, d, J = 8 Hz, Ar-H), 7.23 – 7.07 (12 H,

m, Ar-H), 6.99 (2 H, dd, J = 7 and 2 Hz, Ar-H), 6.86 (2 H, dd, J = 7 and 2 Hz, Ar-H), 5.89 (1

H, d, J = 4 Hz, H-1), 4.37 (1 H, d, J = 4 Hz, H-2), 4.34 (1 H, dd, J = 10 and 3 Hz, H-4), 4.19

(1 H, d, J = 12 Hz, CHxHyAr), 3.89 (1 H, d, J = 12 Hz, CHxHyAr), 3.32 (1 H, dt, J = 11 and 5

Hz, H-5), 3.20 (1 H, d, J = 3 Hz, H-3), 2.98 (1 H, dd, J = 15 and 5 Hz, H-6), 2.72 (1 H, dd, J =

15 and 5 Hz, H-6), 1.45 (1 H, s, CH3), 1.21 (3 H, s, CH3) ppm. 13

C NMR (125 MHz, CDCl3) δ

147.98 (C, Ar-C), 146.96 (C, Ar-C), 142.98 (C, Ar-C), 137.44 (C, Ar-C), 128.65 (CH, Ar-C),

128.64 (CH, Ar-C), 128.30 (CH, Ar-C), 128.13 (CH, Ar-C), 127.95 (CH, Ar-C), 127.79 (CH,

Ar-C), 127.51 (CH, Ar-C), 126.96 (CH, Ar-C), 126.70 (CH, Ar-C), 126.43 (CH, Ar-C), 126.31

(CH, Ar-C), 126.09 (CH, Ar-C), 111.74 (C, C-Me2), 104.86 (CH, C-1), 84.99 (CH, C-4), 81.83

(CH, C-2), 81.17 (CH, C-3), 78.11 (C, C-7), 71.50 (CH2, OCH2Ar), 47.03 (CH2, C-6), 40.01

(CH, C-5), 26.77 (CH3, C(CH3)2), 26.14 (CH3, C(CH3)2) ppm. MS (ES+) m/z [2M+Na]+ 1096.0.

Accurate Mass C35H36O5Na, [M+Na]+ requires 559.2449, measured 559.2455.

(E)-3-((3aR,5R,6S,6aR)-6-(benzyloxy)-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-5-yl)-1,1-

di(furan-2-yl)prop-2-en-1-ol 101

To a solution of furan (78 μL, 1.08 mmol) in THF (3.55 mL) was added a 1.6 M solution of n-

butyllithium in hexane (0.67 mL, 1.08 mmol) dropwise at -78 °C. The reaction mixture was

allowed to warm up to 0 °C tor 20 min, resulting in the formation of the yellow lithium

intermediate. At -78 °C, a solution of α,β-unsaturated ester (E)-27 (180 mg, 0.54 mmol) in

THF (1 mL) was added to the reaction mixture and the resulting mixture was stirred for 1.5 h

at -78 °C. Upon completion, it was quenched with saturated aqueous NH4Cl (5 mL) and

extracted with diethyl ether (3 × 3 mL). The combined organic extracts were washed with

brine (3 mL), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo.

123

The crude product was purified by flash column chromatography (silica gel; eluent 10% →

20% EtOAc/petrol) to afford 34.7 mg (15%) of the title compound as brown oil as a single

diastereoisomer and also 6.00 mg (2.5%) of ketone 102 as yellow oil as a single

diasteroisomer. Rf (30% EtOAc/petrol): 0.39. -83.6 (c 0.4, CHCl3). IR max (thin film)

3436 (O-H stretch), 2977 (C-H stretch), 2929 (C-H stretch), 2863 (C-H stretch), 1453, 1373,

1152, 1070 (C-O stretch), 1009 (C-O stretch) cm-1

. 1H NMR (500 MHz, CDCl3) δ 7.40 (1 H,

dd, J = 1.5 and 0.6 Hz, H-11), 7.38 – 7.37 (1 H, m, H-11), 7.33 – 7.25 (5 H, m, Ar-H), 6.41 (1

H, dd, J = 16 and 1 Hz, H-6), 6.35 (1 H, dd, J = 3 and 2 Hz, H-10), 6.32 (1 H, dd, J = 3 and 2

Hz, H-10), 6.29 (1 H, d, J = 3 Hz, H-9), 6.26 (1 H, d, J = 3 Hz, H-9), 6.03 – 5.97 (2 H, m, H-1,

H-5), 4.79 – 4.76 (1 H, m, H-4), 4.65 (1 H, d, J = 4 Hz, H-2), 4.63 – 4.60 (1 H, m, J = 15 Hz,

CHxHyAr), 4.55 – 4.52 (1 H, m, J = 15 Hz, CHxHyAr), 3.91 (1 H, d, J = 3 Hz, H-3), 2.79 (1 H,

s, OH), 1.51 (1 H, s, CH3), 1.33 (3 H, s, CH3) ppm. 13

C NMR (125 MHz, CDCl3) δ 154.61 (C,

C-8), 142.61 (CH, C-11), 142.58 (CH, C-11), 137.44 (C, Ar-C), 134.09 (CH, C-5), 128.39

(CH, Ar-C), 127.77 (CH, Ar-C), 127.61 (CH, Ar-C), 125.95 (CH, C-6), 111.59 (C, C-Me2),

110.27 (CH, C-10), 110.24 (CH, C-10), 107.89 (CH, C-9), 107.70 (CH, C-9), 104.82 (CH, C-

1), 83.14 (CH, C-2), 82.97 (CH, C-3), 80.27 (CH, C-4), 72.11 (C, C-7), 71.96 (CH2, OCH2Ar),

26.73 (CH3, C(CH3)2), 26.17 (CH3, C(CH3)2) ppm. MS (ES+) m/z [M+Na]+ 461.0. Accurate

Mass C25H26O7Na, [M+Na]+ requires 461.1567, measured 461.1571.

3-((3aR,5R,6S,6aR)-6-(benzyloxy)-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-5-yl)-1,3-

di(furan-2-yl)propan-1-one 102

(procedure as described above)

Isolated yield: 6.00 mg (2.5%). Rf (30% EtOAc/petrol): 0.47. 1H NMR (500 MHz, CDCl3) δ

7.54 (1 H, d, J = 1.5 Hz, H-12), 7.38 – 7.29 (6 H, m, H-9, Ar-H), 7.14 (1 H, d, J = 3 Hz, H-10),

6.48 (1 H, dd, J = 3 and 1.5 Hz, H-11), 6.21 (1 H, dd, J = 3 and 2 Hz, H-8), 6.05 (1 H, d, J = 3

Hz, H-7), 5.94 (1 H, d, J = 4 Hz, H-1), 4.58 (1 H, d, J = 4 Hz, H-2), 4.53 (1 H, d, J = 11 Hz,

124

CHxHyAr), 4.46 (1 H, dd, J = 10 and 3 Hz, H-4), 4.37 (1 H, d, J = 11 Hz, CHxHyAr), 4.09 (1 H,

td, J = 10 and 4 Hz, H-5), 3.68 (1 H, d, J = 3 Hz, H-3), 3.49 – 3.42 (1 H, m, H-6), 3.41 – 3.31

(1 H, m, H-6), 1.54 (1 H, s, CH3), 1.32 (3 H, s, CH3) ppm. MS (ES+) m/z [M+Na]

+ 461.0.

Accurate Mass C25H26O7Na, [M+Na]+

requires 461.1573, measured 461.1571.

Methyl 3-O-benzyl-5,6,7-trideoxy-1,2-O-isopropylidene-α-D-gluco-heptofuranuronate45

103

To a suspension of sodium hydride (60% dispersion in mineral oil, 7.92 mg, 0.33 mmol) and

trimethylsulfoxonium iodide (72.6 mg, 0.33 mmol) in DMSO (3 mL) under nitrogen at room

temperature was added dropwise a solution of α,β-unsaturated ester (E)-27 (100 mg, 0.30

mmol) in DMSO (3 mL). The reaction mixture was allowed to stir for an hour before

quenching with ice-cold water and extracted with ethyl acetate (3 × 5 mL). The combined

organic extracts were washed with water (5 mL), dried over anhydrous magnesium sulfate,

filtered and concentrated in vacuo. The crude product was purified by flash column

chromatography (silica gel; eluent 20% EtOAc/petrol) to afford 21.9 mg (21%) of the title

compound as white solid as a single diastereoisomer. The purified product was recystallised

from Et2O/petrol to obtain white cystals. Rf (20% EtOAc/petrol): 0.22. IR max (thin film) 2961

(C-H stretch), 2915 (C-H stretch), 2847 (C-H stretch), 1726 (C=O stretch), 1600 (aromatic

C=C stretch), 1452, 1437, 1372, 1259, 1207, 1163, 1073 (C-O stretch), 1026 (C-O stretch),

796 cm-1

. 1H NMR (400 MHz, CDCl3) δ 7.38 - 7.26 (5 H, m, Ar-H), 5.92 (1 H, d, J = 4 Hz, H-

1), 4.70 (1 H, d, J = 12 Hz, CHxHyAr), 4.62 (1 H, d, J = 4 Hz, H-2), 4.56 (1 H, d, J = 12 Hz,

CHxHyAr), 3.86 (1 H, d, J = 3 Hz, H-3), 3.68 (3 H, s, OCH3), 3.63 (1 H, dd, J = 8 and 3 Hz, H-

4), 1.97 – 1.91 (1 H, m, H-5), 1.64 - 1.57 (1 H, m, H-7), 1.45 (1 H, s, CH3), 1.38 (1 H, dt, J =

9 and 5 Hz, H-6), 1.31 (3 H, s, CH3), 1.14 (1 H, ddd, J = 9, 6 and 5 Hz, H-7) ppm. 13

C NMR

(100 MHz, CDCl3) δ 173.80 (C, C=O), 137.37 (C, Ar-C), 128.45 (CH, Ar-C), 127.85 (CH, Ar-

C), 127.51 (CH, Ar-C), 111.39 (C, C-Me2), 104.77 (CH, C-1), 82.63 (CH, C-2), 82.50 (CH, C-

3), 82.01 (CH, C-4), 71.99 (CH2, OCH2Ar), 51.80 (CH3, OCH3), 26.67 (CH3, C(CH3)2), 26.06

(CH3, C(CH3)2), 19.65 (CH, C-5), 17.16 (CH, C-6), 13.87 (CH2, C-7) ppm. MS (ES+) m/z

125

[M+NH4]+ 366.0, [M+Na]

+ 371.0. Accurate Mass C19H24O6Na, [M+Na]

+ requires 371.1461,

measured 371.1466.

(5R)-Methyl 3-O-benzyl-5,6-dideoxy-5-dimethylamino-1,2-O-isopropylidene-α-D-gluco-

heptofuranuronate46

105 and (5S)-Methyl 3-O-benzyl-5,6-dideoxy-5-dimethylamino-1,2-

O-isopropylidene-α-D-gluco-heptofuranuronate 105a

To a solution of α,β-unsaturated ester (E)-27 (350 mg, 1.05 mmol) in DCM (5 mL) were

added dimethylamine hydrochloride (171 mg, 2.10 mmol) and triethylamine (0.29 mL, 2.10

mmol), sequentially. The reaction mixture was stirred for 24 h at room temperature, and then

washed with water (3 × 5 mL). The combined organic extracts were dried over anhydrous

magnesium sulfate, filtered and concentrated in vacuo. The crude product was purified by

flash column chromatography (silica gel; eluent 10% → 20% EtOAc/petrol) and the elution

gave the title compounds as white oil with an overall yield of 60.0 mg (16%) (d.r. 5:1,

105:105a). -42.0 (c 1.3, CHCl3). IR max (thin film) 2995 (C-H stretch), 1750 (C=O

stretch), 1377, 1211, 1153, 1071 (C-O stretch), 1006 (C-O stretch) cm-1

. 1H NMR (400 MHz,

CDCl3) δ 7.39 - 7.33 (10 H, m, Ar-Hmajor, Ar-Hminor), 5.96 (1 H, d, J = 4 Hz, Hmajor-1), 5.89 (1 H,

d, J = 4 Hz, Hminor-1), 4.70 (1 H, d, J = 12 Hz, CHxmajorHyAr), 4.67 (1 H, d, J = 12 Hz,

CHxminorHyAr), 4.62 (1 H, d, J = 4 Hz, H-2), 4.58 (1 H, d, J = 12 Hz, CHxHyminorAr), 4.55 (1 H,

d, J = 4 Hz, Hminor-2), 4.42 (1 H, d, J = 12 Hz, CHxHymajorAr), 4.21 (2 H, dd, J = 10 and 3 Hz,

Hmajor-4, Hminor-4), 3.95 (1 H, d, J = 3 Hz, Hminor-3), 3.78 (1 H, d, J = 3 Hz, Hmajor-3), 3.65 (3 H,

s, OCH3minor), 3.62 (3 H, s, OCH3major), 3.57 (2 H, td, J = 10 and 4 Hz, Hmajor-5, Hminor-5), 2.60

(2 H, dd, J = 10 and 5 Hz, 2 × Hminor-6), 2.32 (1 H, dd, J = 15 and 9 Hz, Hmajor-6), 1.94 (1 H,

dd, J = 15 and 4 Hz, Hmajor-6), 1.50 (6 H, s, CH3major, CH3minor), 1.33 (3 H, s, CH3major), 1.31 (3

H, s, CH3minor) ppm. MS (ES+) m/z [M+H]

+ 380.0, [M+Na]

+ 402.0. Accurate Mass C20H30NO6,

[M+H]+ requires 380.2065, measured 380.2068.

126

Methyl 3,5,6-trideoxy-3,5-(E)-dieno-1,2-O-isopropylidene-α-D-glycero-heptofuranouronate47

108

To a solution of α,β-unsaturated ester (E)-27 (0.05 g, 0.15 mmol) in THF (5 mL) and

imidazole (10.2 mg, 0.15 mmol) was added dropwise a 1.0 M solution of TBAF in THF (0.15

mL, 0.15 mmol) at 0 °C. The mixture was stirred at room temperature for 24 h and then

quenched with saturated aqueous Na2CO3 and extracted with diethyl ether (3 × 5 mL). The

combined organic extracts were dried over anhydrous magnesium sulfate, filtered and

concentrated in vacuo. The crude product was purified by column chromatography (silica

gel; eluent 5% EtOAc/petrol) to afford 15.9 mg (47%) of the title compound as colourless oil.

Rf (20% EtOAc/petrol): 0.40. 1H NMR (500 MHz, CDCl3) δ 7.08 (1 H, d, J = 16 Hz, H-6), 6.32

(1 H, d, J = 15 Hz, H-5), 6.14 (1 H, d, J = 5 Hz, H-1), 5.53 (1 H, d, J = 3 Hz, H-3), 5.35 (1 H,

dd, J = 5 and 3 Hz, H-2), 3.78 (3 H, s, OCH3), 1.46 (3 H, s, CH3), 1.41 (3 H, s, CH3) ppm. 13

C

NMR (125 MHz, CDCl3) δ 166.69 (C, C=O), 155.70 (C, C-4), 131.51 (CH, C-5), 122.72 (CH,

C-6), 112.59 (C, C-Me2), 108.39 (CH, C-1), 105.83 (CH, C-3), 83.27 (CH, C-2), 52.00 (CH3,

OCH3), 27.95 (CH3, C(CH3)2), 27.74 (CH3, C(CH3)2) ppm.

(4Z)-Methyl (3-O-benzyl-1,2-O-isopropylidene-β-L-threo)-hept-4-enofuranuronate48

(Z)-115

To a solution of α,β-unsaturated ester (E)-27 (180 mg, 0.54 mmol) in DCM (3 mL) was

added DBU (0.16 mL, 1.08 mmol) and the reaction mixture was heated at reflux for 10 h.

The reaction mixture was extracted with DCM (3 × 5 mL) and washed with water (3 × 5 mL).

The organic extracts were dried over anhydrous magnesium sulfate, filtered and

concentrated in vacuo. The crude product was purified by flash column chromatography

(silica gel; eluent 3% EtOAc/petrol) to afford 90.0 mg (50%) of the title compound as

colourless oil. Rf (30% EtOAc/petrol): 0.60. -3.0 (c 0.5, CHCl3). IR max (thin film) 2951

127

(C-H stretch), 1747 (C=O stretch), 1373, 1209, 1146, 1077 (C-O stretch), 1009 (C-O stretch)

cm-1

. 1H NMR (400 MHz, CDCl3) δ 7.39 - 7.28 (5 H, m, Ar-H), 6.12 (1 H, d, J = 3 Hz, H-1),

4.83 (1 H, t, J = 7 Hz, H-5), 4.69 (1 H, dd, J = 12 Hz, CHxHyAr), 4.59 (1 H, d, J = 3 Hz, H-2),

4.50 (1 H, d, J = 12 Hz, CHxHyAr), 4.27 (1 H, s, H-3), 3.70 (3 H, s, OCH3), 3.24 (2 H, dd, J =

7 and 5 Hz, H-6), 1.41 (3 H, s, CH3), 1.38 (3 H, s, CH3) ppm. 13

C NMR (100 MHz, CDCl3) δ

172.29 (C, C=O), 153.52 (C, C-4), 137.18 (C, Ar-C), 128.54 (CH, Ar-C), 128.00 (CH, Ar-C),

127.96 (CH, Ar-C), 113.96 (C, C-Me2), 106.78 (CH, C-1), 97.02 (CH, C-5), 83.20 (CH, C-2),

80.18 (CH, C-3), 70.18 (CH2, OCH2Ar), 51.87 (CH3, OCH3), 30.69 (CH2, C-6), 27.88 (CH3,

C(CH3)2), 27.25 (CH3, C(CH3)2) ppm. MS (ES+) m/z [M+Na]+ 357.0, [2M+Na]

+ 691.0.

Accurate Mass C18H22O6Na, [M+Na]+ requires 357.1309, measured 357.1307.

(5R)-Methyl 3-O-benzyl-5-imidazol-1,2-O-isopropylidene-α-D-xylo-hept-5-enfuranuronate

116 and (5S)-Methyl 3-O-benzyl-5-imidazol-1,2-O-isopropylidene-α-D-xylo-hept-5-

enfuranuronate48

116a

PROCEDURE 1

To a solution of α,β-unsaturated ester (E)-27 (500 mg, 1.49 mmol) in THF (3 mL) were

added DBU (50 µL, 25 mol%) and imidazole (173 mg, 2.54 mmol). The reaction mixture was

stirred at 80 °C for 5 h. The reaction mixture was allowed to cool and the solvent evaporated

in vacuo. The crude product was dissolved in ethyl acetate (2 × 5 mL) and washed with

water (2 × 5 mL). The organic layer was dried over anhydrous magnesium sulfate, filtered

and concentrated in vacuo. The crude product was purified by flash column chromatography

(silica gel; eluent 20% EtOAc/petrol → 100% EtOAc) to afford 91.3 mg (15%) of the title

compound 116 as yellow solid as a single diastereoisomer, which was then recystallised

from DCM/petrol to obtain yellow crystalline solid for X-ray crystallography. The elution also

afforded 302 mg (61%) of ester (Z)-115 as colourless oil (1:4, 116:(Z)-115). Rf (80%

EtOAc/petrol): 0.11. -38.2 (c 1.0, CHCl3). mp 133 - 135 °C. IR max (thin film) 2951 (C-H

128

stretch), 2919 (C-H stretch), 1723 (C=O stretch), 1442, 1377, 1361, 1225, 1211, 1162, 1073

(C-O stretch), 1038 (C-O stretch) cm-1

. 1H NMR (500 MHz, CDCl3) δ 7.55 (1 H, s, H-7), 7.42

- 7.33 (5 H, m, Ar-H), 7.03 (1 H, s, H-9), 6.94 (1 H, s, H-8), 5.89 (1 H, d, J = 4 Hz, H-1), 4.92

– 4.86 (1 H, m, H-5), 4.77 (1 H, d, J = 12 Hz, CHxHyAr), 4.66 (1 H, d, J = 4 Hz, H-2), 4.45 (1

H, d, J = 12 Hz, CHxHyAr), 4.37 (1 H, dd, J = 9 and 3 Hz, H-4), 3.94 (1 H, d, J = 3 Hz, H-3),

3.58 (3 H, s, OCH3), 2.67 (1 H, dd, J = 16 and 10 Hz, H-6), 2.45 (1 H, dd, J = 16 and 3 Hz,

H-6), 1.46 (3 H, s, CH3), 1.32 (3 H, s, CH3) ppm. 13

C NMR (100 MHz, CDCl3) δ 169.78 (C,

C=O), 137.13 (CH, C-7), 136.28 (C, Ar-C), 129.43 (CH, C-9), 128.67 (CH, Ar-C), 128.49

(CH, Ar-C), 128.29 (CH, Ar-C), 116.97 (CH, C-8) 111.95 (C, C-Me2), 104.86 (CH, C-1), 81.53

(CH, C-2), 80.63 (CH, C-3), 80.50 (CH, C-4), 71.53 (CH2, OCH2Ar), 53.44 (CH, C-5), 52.04

(CH3, OCH3), 36.35 (CH2, C-6), 26.77 (CH3, C(CH3)2), 26.17 (CH3, C(CH3)2) ppm. MS (ES+)

m/z [M+H]+ 403.0. Accurate Mass C21H27N2O6, [M+H]

+ requires 403.1863, measured

403.1864.

PROCEDURE 2

To a solution of α,β-unsaturated ester (E)-27 (520 mg, 1.55 mmol) in THF (3 mL) were

added DBU (60 µL, 25 mol%) and imidazole (180 mg, 2.64 mmol). The reaction mixture was

stirred for 20 h at room temperature. The mixture was extracted with ethyl acetate (2 × 5 mL)

and washed with water (2 × 5 mL). The organic layer was dried over anhydrous magnesium

sulfate, filtered and concentrated in vacuo. The crude was purified by flash column

chromatography (silica gel; eluent 10% → 50% EtOAc/petrol → 100% EtOAc) to afford the

title compounds as yellow oil (d.r. 2:1, 116:116a). The elution also afforded 90 mg (17%) of

ester (Z)-115 as colourless oil (data of major diastereomer as described above).

(4E)-Methyl (3-O-benzyl-1,2-O-isopropylidene-β-L-threo)-hept-4-enofuranuronate49

(E)-115

To a solution of α,β-unsaturated ester (E)-27 (560 mg, 1.67 mmol) in THF (3 mL) was added

DBU (60 µL, 25 mol%) and the reaction mixture was stirred at 80 °C for 2 h. The reaction

129

mixture was allowed to cool and the solvent evaporated in vacuo. The residue was extracted

with ethyl acetate (2 × 5 mL) and washed with water (2 × 5 mL). The organic layer was dried

over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The crude product

was purified by flash column chromatography (silica gel; eluent 3% EtOAc/petrol) to afford

30.0 mg (5%) of the title compound as colourless oil and also 420 mg (75%) of ester (Z)-115

as colourless oil (15:1, Z:E). -3.5 (c 0.2, CHCl3). IR max (thin film) 3032 (C-H stretch),

2952 (C-H stretch), 1722 (C=O stretch), 1454, 1439, 1373, 1206, 1163, 1071 (C-O stretch),

1023 (C-O stretch) cm-1

. 1H NMR (500 MHz, CDCl3) δ 7.41 - 7.26 (5 H, m, Ar-H), 6.06 (1 H,

d, J = 3 Hz, H-1), 5.28 (1 H, t, J = 8 Hz, H-5), 4.71 (1 H, d, J = 4 Hz, CHxHyAr), 4.66 (1 H, d,

J = 3 Hz, H-2), 4.59 (1 H, d, J = 5 Hz, CHxHyAr), 4.54 (1 H, s, H-3), 3.67 (3 H, s, OCH3), 2.99

(2 H, d, J = 8 Hz, 2 × H-6), 1.45 (3 H, s, CH3), 1.40 (3 H, s, CH3) ppm. 13

C NMR (75 MHz,

CDCl3) δ 171.91 (C, C=O), 155.07 (C, C-4), 137.00 (C, Ar-C), 128.52 (CH, Ar-C), 127.92

(CH, Ar-C), 126.94 (CH, Ar-C), 113.73 (C, C-Me2), 106.03 (CH, C-1), 97.40 (CH, C-5), 82.68

(CH, C-2), 77.98 (CH, C-3), 71.00 (CH2, OCH2Ar), 51.84 (CH3, OCH3), 32.29 (CH2, C-6),

27.87 (CH3, C(CH3)2), 27.25 (CH3, C(CH3)2) ppm. MS (ES+) m/z [M+Na]+ 357.0, [2M+Na]

+

691.0.

(4Z)-(3-O-benzyl-1,2-O-isopropylidene-β-L-threo)-hept-4-enofuranuronose 117

To a solution of (Z)-115 (0.50 g, 1.49 mmol) in anhydrous THF (10 mL) at -78 °C was added

dropwise a 1.0 M solution of DIBAL-H in hexane (5.21 mL, 5.21 mmol) and the mixture was

stirred for 4 h at that temperature. The reaction mixture was quenched slowly with methanol

(6 mL) at -78 °C, followed by Rochelle salt (2 mL) at -10 °C. The mixture was allowed to

warm up to room temperature and then extracted with diethyl ether (3 × 10 mL), dried over

anhydrous magnesium sulfate and concentrated in vacuo. The crude product was purified by

flash column chromatography (silica gel; eluent 10% EtOAc/petrol) to afford an overall yield

of 0.35 g (77%) of the title compound as colourless oil as a single geometric isomer. Rf (30%

130

EtOAc/petrol): 0.25. IR max (thin film) 3445 (O-H stretch), 2947 (C-H stretch), 1450, 1370,

1211, 1145, 1060 (C-O stretch), 1017 (C-O stretch) cm-1

. 1H NMR (400 MHz, CDCl3) δ 7.40 -

7.28 (5 H, m, Ar-H), 6.11 (1 H, d, J = 3 Hz, H-1), 4.68 (1 H, overlapped d, J = 15 Hz, H-5),

4.67 (1 H, overlapped d, J = 13 Hz, CHxHyAr), 4.59 (1 H, d, J = 4 Hz, H-2), 4.49 (1 H, d, J =

12 Hz, CHxHyAr), 4.24 (1 H, s, H-3), 3.70 (2 H, q, J = 6 Hz, H-7), 2.53 - 2.33 (2 H, m, H-6),

1.58 (1 H, t, J = 5 Hz, OH), 1.44 (3 H, s, CH3), 1.38 (3 H, s, CH3) ppm. 13

C NMR (100 MHz,

CDCl3) δ 153.21 (C, C-4), 137.26 (C, Ar-C), 128.51 (CH, Ar-C), 127.89 (CH, Ar-C), 113.70

(C, C-Me2), 106.56 (CH, C-1), 101.58 (CH, C-5), 83.00 (CH, C-2), 80.52 (CH, C-3), 70.16

(CH2, OCH2Ar), 62.28 (CH2, C-7), 29.01 (CH2, C-6), 27.88 (CH3, C(CH3)2), 27.14 (CH3,

C(CH3)2) ppm. MS (ES+) m/z [M+Na]+ 329.0. Accurate Mass C17H22O5Na, [M+Na]

+ requires

329.1350, measured 329.1360.

(3a'S,6'R,6a'R)-6'-(benzyloxy)-2',2'-dimethyltetrahydro-3H,3a'H-spiro[furan-2,5'-furo[2,3-

d][1,3]dioxole] 118

The alcohol 117 (0.25 g, 0.83 mmol) was stirred in DCM (5 mL) in the presence of a catalytic

amount of Amberlyst-15 ion exchange resin for 24 h at room temperature. The solution was

then filtered and the filtrate was concentrated in vacuo. The crude product was purified by

flash column chromatography (silica gel; eluent 10% EtOAc/petrol) to afford an overall yield

of 56.9 mg (22%) of the title compounds as yellow oil (d.r. 1:1).

Isomer 1

Isolated yield: 38.6 mg (15%). Rf (20% EtOAc/petrol): 0.40. -124.8 (c 1.5, CHCl3). IR

max (thin film) 2979 (C-H stretch), 2937 (C-H stretch), 1215, 1096 (C-O stretch), 1002 (C-O

stretch) cm-1

. 1H NMR (500 MHz, CDCl3) 7.41 - 7.28 (5 H, m, Ar-H), 5.92 (1 H, d, J = 4 Hz,

H-1), 4.75 (1 H, d, J = 12 Hz, CHxHyAr), 4.67 (1 H, d, J = 4 Hz, H-2), 4.56 (1 H, d, J = 12 Hz,

CHxHyAr), 4.14 - 4.03 (1 H, m, H-7), 3.97 (1 H, s, H-3), 3.94 - 3.84 (1 H, m, H-7), 2.18 - 2.06

(2 H, m, H-5), 2.06 – 1.97 (1 H, m, H-6), 1.90 - 1.78 (1 H, m, H-6), 1.59 (3 H, s, CH3), 1.34 (3

131

H, s, CH3) ppm. 13

C NMR (125 MHz, CDCl3) δ 137.31 (C, Ar-C), 128.51 (CH, Ar-C), 127.96

(CH, Ar-C), 127.71 (CH, Ar-C), 117.85 (C, C-4), 113.29 (C, C-Me2), 105.65 (CH, C-1), 85.85

(CH, C-3), 85.49 (CH, C-2), 72.06 (CH2, OCH2Ar), 68.55 (CH2, C-7), 32.90 (CH2, C-5), 27.13

(CH3, C(CH3)2), 26.92 (CH3, C(CH3)2), 26.21 (CH2, C-6) ppm. MS (ES+) m/z [M+Na]+ 329.0.

Accurate Mass C17H22O5Na, [M+Na]+ requires 329.1357, measured 329.1360.

Isomer 2

Isolated yield: 10.0 mg (4%). Rf (20% EtOAc/petrol): 0.34. 1H NMR (500 MHz, CDCl3) 7.41 -

7.29 (5 H, m, Ar-H), 5.84 (1 H, d, J = 5 Hz, H-1), 4.84 (1 H, d, J = 12 Hz, CHxHyAr), 4.78 (1

H, t, J = 3 Hz, H-2), 4.65 (1 H, d, J = 12 Hz, CHxHyAr), 4.07 (1 H, td, J = 8 and 5 Hz, H-7),

4.01 – 3.96 (1 H, m, H-7), 3.94 (1 H, d, J = 3 Hz, H-3), 2.10 – 2.01 (2 H, m, H-5), 1.97 – 1.88

(2 H, m, H-6), 1.48 (3 H, s, CH3), 1.41 (3 H, s, CH3) ppm. 13

C NMR (125 MHz, CDCl3) δ

137.31 (C, Ar-C), 128.37 (CH, Ar-C), 128.18 (CH, Ar-C), 127.89 (CH, Ar-C), 114.03 (C, C-4),

113.23 (C, C-Me2), 103.24 (CH, C-1), 85.21 (CH, C-3), 84.16 (CH, C-2), 72.18 (CH2,

OCH2Ar), 68.61 (CH2, C-7), 34.05 (CH2, C-5), 27.81 (CH3, C(CH3)2), 27.50 (CH3, C(CH3)2),

23.97 (CH2, C-6) ppm.

(E)-5,6-didehydro-5,6-dideoxy-3-O-benzyl-1,2-O-isopropylidene-α-D-xylo-heptodialdo-1,4-

furanose89

119

To a solution of pyridinium dichromate (1.47 g, 3.92 mmol) in DCM (20 mL) was added a

solution of alcohol (E)-12 (1.20 g, 3.92 mmol) in DCM (20 mL) and the reaction mixture was

stirred for 6.5 hours. Celite was added to the reaction mixture and it was filtered through a

pad of silica, washed with DCM (20 mL) and concentrated in vacuo to afford 970 mg (81%)

of the title compound as yellow oil as trans-isomer. Rf (30% EtOAc/petrol): 0.45. +8.7 (c

1.6, CHCl3) lit.90

-34.0 (c 0.9, DCM). IR max (thin film) 3023 (C-H stretch), 2995 (C-H

stretch), 2976 (C-H stretch), 2925 (C-H stretch), 2839 (C-H stretch), 2753 (C-H stretch),

2359 (C-H stretch), 1675 (C-O stretch), 1375 (C=C stretch), 1146, 1109, 1074 (C-O stretch),

132

1037, 1014, 983 (=C-H bend) cm-1

. 1H NMR (500 MHz, CDCl3) δ 9.58 (1 H, d, J = 7.5 Hz,

CHO), 7.38 - 7.29 (3 H, m, Ar-H), 7.26 (2 H, d, J = 7 Hz, Ar-H), 6.76 (1 H, dd, J = 16 and 5

Hz, H-5), 6.38 (1 H, dd, J = 16 and 8 Hz, H-6), 6.03 (1 H, d, J = 4 Hz, H-1), 4.90 (1 H, t, J = 4

Hz, H-4), 4.71 – 4.65 (2 H, m, H-2, CHxHyAr), 4.48 (1 H, d, J = 12 Hz, CHxHyAr), 4.04 (1 H, d,

J = 3 Hz, H-3), 1.51 (3 H, s, CH3), 1.35 (3 H, s, CH3) ppm. 13

C NMR (125 MHz, CDCl3) δ

193.03 (C, CHO), 150.10 (CH, C-5), 136.84 (C, Ar-C), 133.41 (CH, C-6), 128.58 (CH, Ar-C),

128.24 (CH, Ar-C), 127.81 (CH, Ar-C), 112.09 (C, C-Me2), 105.11 (CH, C-1), 83.06 (CH, C-

3), 82.52 (CH, C-2), 79.42 (CH, C-4), 72.15 (CH2, OCH2Ar), 26.79 (CH3, C(CH3)2), 26.17

(CH3, C(CH3)2) ppm. MS (ES+) m/z [M+Na]+ 327.0. Accurate Mass C17H20O5Na, [M+Na]

+

requires 327.1197, measured 327.1203.

(E)-3-((3aR,5R,6S,6aR)-6-(benzyloxy)-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-5-yl)-1-

phenylprop-2-en-1-ol 120

CUPRATE REACTION59

To a suspension of CuI (38.1 mg, 0.20 mmol) in anhydrous THF (2 mL) was added, at -78

°C, a 1.0 M solution of phenylmagnesium bromide in THF (0.98 mL, 0.98 mmol). After 40

min at -78 °C, freshly distilled TMSCl (0.38 mL, 3.00 mmol) was added to the reaction

mixture, followed by dropwise addition of a solution of α,β-unsaturated aldehyde 119 (60.0

mg, 0.20 mmol) in anhydrous THF (3 mL). The reaction mixture was then allowed to slowly

warm to room temperature over 2 h. The reaction mixture was then quenched, at -78 °C, by

the addition of saturated aqueous NH4OH:NH4Cl (1:9; 5 mL) and extracted with diethyl ether

(3 × 5 mL). The combined organic extracts were washed with brine (5 mL), dried over

anhydrous magnesium sulfate, filtered and concentrated in vacuo. The crude product was

purified by flash column chromatography (silica gel; eluent 10% EtOAc/petrol) to afford 43.8

mg (57%) of the title compound as white oil as a single diasteroisomer and 10.4 mg (13%) of

aldehyde 121 as yellow oil. Rf (40% EtOAc/petrol): 0.43. -12.8 (c 1.8, CHCl3). IR max

133

(thin film) 3449 (O-H stretch), 3030 (C-H stretch), 2987 (C-H stretch), 2932 (C-H stretch),

2864 (C-H stretch), 1454 (aromatic C=C stretch), 1375, 1214, 1164, 1070 (C-O stretch),

1014 (C-O stretch) cm-1

. 1H NMR (400 MHz, CDCl3) δ 7.43 – 7.50 (10 H, m, Ar-H), 6.13 –

6.04 (1 H, m, H-6), 6.00 – 5.90 (2 H, m, H-1, H-5), 5.27 (1 H, d, J = 6 Hz, H-7), 4.71 – 4.60 (3

H, m, H-2, H-4, CHxHyAr), 4.55 – 4.47 (1 H, m, CHxHyAr), 3.90 – 3.83 (1 H, m, H-3), 1.49 (3

H, s, CH3), 1.33 (3 H, s, CH3) ppm. 13

C NMR (100 MHz, CDCl3) δ 142.27 (C, Ar-C), 137.38

(C, Ar-C), 136.88 (CH, C-6), 128.54 (CH, Ar-C), 128.42 (CH, Ar-C), 127.84 (CH, Ar-C),

127.74 (CH, Ar-C), 127.67 (CH, Ar-C), 127.52 (CH, Ar-C), 126.37 (CH, Ar-C), 125.16 (CH,

C-5), 111.55 (C, C-Me2), 104.78 (CH, C-1), 83.18 (CH, C-3), 82.81 (CH, C-2), 80.53 (CH, C-

4), 74.50 (CH, C-7), 71.97 (CH2, OCH2Ar), 26.71 (CH3, C(CH3)2), 26.17 (CH3, C(CH3)2) ppm.

MS (ES+) m/z [M+Na]+ 405.0. Accurate Mass C23H26O5Na, [M+Na]

+ requires 405.1663,

measured 405.1673.

GRIGNARD REACTION

To a solution of α,β-unsaturated aldehyde 119 (100 mg, 0.33 mmol) in anhydrous THF (5

mL) was added a 1.0 M solution of phenylmagnesium bromide in THF (0.33 mL, 0.33 mmol)

at -78 °C. The reaction mixture was stirred at -78 °C for 2 h, then quenched with saturated

aqueous NH4Cl (5 mL) and extracted with diethyl ether (3 × 5 mL). The combined organic

extracts were washed with brine (5 mL), dried over anhydrous magnesium sulfate and

concentrated in vacuo. The crude product was purified by flash column chromatography

(silica gel; eluent 5% → 7% → 10% → 20% EtOAc/petrol) to afford 89.8 mg (71%) of the title

compound as colourless oil as a single diastereoisomer (data as described above).

ORGANOLITHIUM REACTION

To a solution of α,β-unsaturated aldehyde 119 (0.10 g, 0.33 mmol) in THF (5 mL) was added

a 2.0 M solution of phenyllithium in n-dibutyl ether (0.16 mL, 0.33 mmol) dropwise at -78 °C.

The reaction mixture was stirred at -78 °C for 1 h, then quenched with saturated aqueous

NH4Cl (5 mL) and extracted with diethyl ether (3 × 5 mL). The combined organic extracts

were washed with brine (5 mL), dried over anhydrous magnesium sulfate, filtered and

concentrated in vacuo. The crude product was purified by flash column chromatography

134

(silica gel; eluent 20% EtOAc/petrol) to afford 103 mg (82%) of the title compound as white

oil (d.r. 11:1) (data of major diastereoisomer as described above).

(5S)-3-((3aR,5R,6S,6aR)-6-(benzyloxy)-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-5-yl)-3-

phenylpropanal 121

HAYASHI-MIYAURA REACTION25

To a mixture of phenylboronic acid (40.2 mg, 0.33 mmol) and [Rh(OH)(1,5-cod)]2 50a (7.53

mg, 5 mol%) under nitrogen were added a solution of α,β-unsaturated aldehyde 119 (100

mg, 0.33 mmol) in 1,4-dioxane:H2O (10:1; 0.76 mL), followed by triethylamine (46 µL, 0.33

mmol). The reaction mixture was stirred for 16 hours at room temperature, then the products

were isolated by evaporation of volatiles under reduced pressure and purified by flash

column chromatography (silica gel; eluent 8% EtOAc/petrol). The elution gave the title

compound as white oil with an overall yield of 59.8 mg (47%) (d.r. 8:1, 121:121a). Rf (30%

EtOAc/petrol): 0.47. -48.8 (c 1.0, CHCl3). IR max (thin film) 3031 (C-H stretch), 2987 (C-

H stretch), 2926 (C-H stretch), 2873 (C-H stretch), 1722 (C=O stretch), 1455 (aromatic C=C

stretch), 1375, 1164, 1071 (C-O stretch), 1022 (C-O stretch) cm-1

. 1H NMR (500 MHz,

CDCl3) δ 9.68 (1 H, t, J = 2 Hz, CHO), 7.39 - 7.21 (10 H, m, Ar-H), 5.95 (1 H, d, J = 4 Hz, H-

1), 4.54 (1 H, d, J = 4 Hz, H-2), 4.44 (1 H, d, J = 11 Hz, CHxHyAr), 4.36 (1 H, dd, J = 10 and

3 Hz, H-4), 4.16 (1 H, d, J = 11 Hz, CHxHyAr), 3.81 (1 H, td, J = 10 and 5 Hz, H-5), 3.46 (1 H,

d, J = 3 Hz, H-3), 3.13 (1 H, ddd, J = 17, 5 and 2 Hz, H-6), 2.78 (1 H, ddd, J = 17, 9 and 2

Hz, H-6), 1.52 (3 H, s, CH3), 1.31 (3 H, s, CH3) ppm. 13

C NMR (125 MHz, CDCl3) δ 201.49

(C, CHO), 140.24 (C, Ar-C), 137.23 (C, Ar-C), 128.68 (CH, Ar-C), 128.47 (CH, Ar-C), 128.16

(CH, Ar-C), 127.91 (CH, Ar-C), 127.76 (CH, Ar-C), 127.15 (CH, Ar-C), 111.48 (C, C-Me2),

104.96 (CH, C-1), 83.66 (CH, C-4), 81.88 (CH, C-2), 81.43 (CH, C-3), 72.00 (CH2, OCH2Ar),

47.98 (CH2, C-6), 38.92 (CH, C-5), 26.73 (CH3, C(CH3)2), 26.10 (CH3, C(CH3)2) ppm. MS

135

(ES+) m/z [M+Na]+ 405.0. Accurate Mass C23H26O5Na, [M+Na]

+ requires 405.1660,

measured 405.1673.

CUPRATE REACTION59

To a suspension of CuI (38.1 mg, 0.20 mmol) in anhydrous THF (2 mL) was added, at -78

°C, a 1.0 M solution of phenylmagnesium bromide in THF (0.98 mL, 0.98 mmol). After 40

min at -78 °C, freshly distilled TMSCl (0.38 mL, 3.00 mmol) was added to the reaction

mixture, followed by dropwise addition of a solution of α,β-unsaturated aldehyde 119 (60.0

mg, 0.20 mmol) in anhydrous THF (3 mL). The reaction mixture was then allowed to slowly

warm to room temperature over 2 h. The reaction mixture was then quenched, at -78 °C, by

the addition of saturated aqueous NH4OH:NH4Cl (1:9; 5 mL) and extracted with diethyl ether

(3 × 5 mL). The combined organic extracts were washed with brine (5 mL), dried over

anhydrous magnesium sulfate and concentrated in vacuo. The crude product was purified by

flash column chromatography (silica gel; eluent 10% EtOAc/petrol) to afford 10.4 mg (13%)

of the title compound as yellow oil as a single diastereoisomer (data as described above)

and also 43.8 mg (57%) of alcohol 120 as yellow oil as a single diasteroisomer.

PALLADIUM-CATALYSED REACTION58

To a stirred solution of α,β-unsaturated aldehyde 119 (0.30 g, 0.98 mmol) in toluene (6 mL)

were added phenylboronic acid (0.24 g, 1.97 mmol), potassium phosphate (0.07 g, 0.98

mmol) and the Bedford’s catalyst 157 (77.2 mg, 5 mol%). The reaction mixture was stirred

for 2.5 hours at 40 °C. Upon completion, the reaction mixture was quenched with water (10

mL), extracted with DCM (3 × 10 mL) and dried over anhydrous magnesium sulfate, filtered

and concentrated in vacuo. The crude product was purified by flash column chromatography

(silica gel; eluent 5% EtOAc/petrol) to afford 81.6 mg (65%) of the title compound as white oil

(d.r. 15:1, 121:121a) (data of major diastereoisomer as described above).

136

(5S)-3-O-benzyl-5-phenyl-1,2-O-isopropylidene-α-D-xylo-hept-5-enfuranuronose 124

REDUCTION OF ESTER TO PRIMARY ALCOHOL

To a solution of ester 55 (270 mg, 0.66 mmol) in dry toluene (5 mL) at -78 °C was added

dropwise a 1.0 M solution of DIBAL-H in toluene (1.65 mL, 1.65 mmol) and the mixture was

stirred for 4 h at that temperature. The reaction mixture was quenched slowly with methanol

(2 mL) at -78 °C, followed by Rochelle salt (2 mL) at -10 °C. The mixture was allowed to

warm up to room temperature and then extracted with diethyl ether (3 × 5 mL), dried over

anhydrous magnesium sulfate and concentrated in vacuo. The crude product was purified by

flash column chromatography (silica gel; eluent 10% EtOAc/petrol) to afford 160 mg (62%) of

the title compound as colourless oil. Rf (60% EtOAc/petrol): 0.49. -26.7 (c 1.8, CHCl3).

IR max (thin film) 3451 (O-H stretch), 2932 (C-H stretch), 1453, 1372, 1212, 1163, 1069 (C-O

stretch), 1019 (C-O stretch) cm-1

. 1H NMR (500 MHz, CDCl3) δ 7.36 - 7.19 (10 H, m, Ar-H),

5.97 (1 H, d, J = 4 Hz, H-1), 4.50 (1 H, d, J = 4 Hz, H-2), 4.40 (1 H, dd, J = 10 and 3 Hz, H-

4), 4.32 (1 H, d, J = 11 Hz, CHxHyAr), 4.01 (1 H, d, J = 11 Hz, CHxHyAr), 3.64 – 3.59 (1 H, m,

H-7), 3.56 – 3.51 (1 H, m, H-7), 3.40 (1 H, d, J = 3 Hz, H-3), 3.26 (1 H, td, J = 10 and 6 Hz,

H-5), 2.32 – 2.25 (1 H, m, H-6), 1.96 – 1.91 (1 H, m, H-6), 1.54 (3 H, s, CH3), 1.31 (3 H, s,

CH3) ppm. 13

C NMR (125 MHz, CDCl3) δ 141.65 (C, Ar-C), 137.36 (C, Ar-C), 128.52 (CH, Ar-

C), 128.39 (CH, Ar-C), 128.18 (CH, Ar-C), 127.80 (CH, Ar-C), 127.74 (CH, Ar-C), 126.75

(CH, Ar-C), 111.51 (C, C-Me2), 105.02 (CH, C-1), 84.24 (CH, C-4), 81.85 (CH, C-3), 81.67

(CH, C-2), 72.03 (CH2, OCH2Ar), 61.23 (CH2, C-7), 41.86 (CH, C-5), 37.87 (CH2, C-6), 26.77

(CH3, C(CH3)2), 26.15 (CH3, C(CH3)2) ppm. MS (ES+) m/z [M+Na]+ 407.0. Accurate Mass

C23H28O5Na, [M+Na]+

requires 407.1829, measured 407.1822.

REDUCTION OF ALDEHYDE TO PRIMARY ALCOHOL

To a solution of aldehyde 121 (37.6 mg, 0.10 mmol) in MeOH (1 mL) was added sodium

borohydride (7.57 mg, 0.20 mmol) and the reaction mixture was stirred for 30 minutes at

137

room temperature. Upon completion, water (2 mL) was added, extracted with EtOAc (3 × 2

mL) and washed with brine (2 mL). The combined organic extracts were dried over

anhydrous magnesium sulfate and concentrated in vacuo. The crude product was purified by

flash column chromatography (silica gel; eluent 20% EtOAc/petrol) to afford 33.3 mg (87%)

of the title compound as white oil (data as described above).

(Z)-3-O-benzyl-5,6,8-trideoxy-1,2-O-isopropylidene-α-D-xylo-oct-5-enfuranos-7-ulose (Z)-125

and (E)-3-O-benzyl-5,6,8-trideoxy-1,2-O-isopropylidene-α-D-xylo-oct-5-enfuranos-7-ulose91

(E)-125

To a solution of the crude aldehyde 19 (2.13 g, 7.65 mmol) in anhydrous DCM (77 mL) was

added freshly prepared acetylmethylene-triphenylphosphorane50

(2.68 g, 8.41 mmol) and

stirred for 5 h at room temperature. The reaction mixture was then evaporated and the

resulting crude product was purified by flash column chromatography (silica gel; eluent 10%

EtOAc/petrol) to afford an overall yield of 1.85 g (76%) of the title compounds as yellow oil

(1:1, Z:E).

Z-isomer (Z)-125

Isolated yield: 851 mg (35% as Z-isomer). Rf (30% EtOAc/petrol): 0.55. -87.3 (c 1.2,

CHCl3). IR max (thin film) 2988 (C-H stretch), 1694 (C=O stretch), 1164, 1072 (C-O stretch),

1017 (C-O stretch) cm-1

. 1H NMR (400 MHz, CDCl3) δ 7.35 - 7.23 (5 H, m, Ar-H), 6.34 - 6.29

(1 H, m, J = 12 and 1 Hz, H-6), 6.27 - 6.21 (1 H, m, J = 12 and 6 Hz, H-5), 6.01 (1 H, d, J = 4

Hz, H-1), 5.48 (1 H, ddd, J = 6, 3 and 1 Hz, H-4), 4.63 (1 H, d, J = 4 Hz, H-2), 4.59 - 4.56 (1

H, d, J = 12 Hz, CHxHyAr), 4.46 - 4.42 (1 H, d, J = 12 Hz, CHxHyAr), 4.37 (1 H, d, J = 3 Hz,

H-3), 2.22 (3 H, s, C(O)CH3), 1.52 (3 H, s, CH3), 1.33 (3 H, s, CH3) ppm. 13

C NMR (100 MHz,

CDCl3) δ 198.30 (C, C(O)CH3), 143.45 (CH, C-5), 137.53 (C, Ar-C), 128.30 (CH, Ar-C),

127.78 (CH, Ar-C), 127.62 (CH, C-6), 127.53 (CH, Ar-C), 111.79 (C, C-Me2), 105.16 (CH, C-

1), 84.33 (CH, C-3), 83.25 (CH, C-2), 78.80 (CH, C-4), 72.29 (CH2, OCH2Ar), 31.12 (CH3,

138

C(O)CH3), 26.89 (CH3, C(CH3)2), 26.40 (CH3, C(CH3)2) ppm. MS (ES+) m/z [M+Na]+ 341.0.

Accurate Mass C18H23O5, [M+H]+

requires 319.1540, measured 319.1540.

E-isomer (E)-125

Isolated yield: 867 mg (35% as E-isomer) (131 mg (5%) as Z/E mixture). Rf (30%

EtOAc/petrol): 0.42. -30.7 (c 0.9, CHCl3). IR max (thin film) 2986 (C-H stretch), 1675

(C=O stretch), 1164, 1071 (C-O stretch), 1019 (C-o stretch) cm-1

. 1H NMR (400 MHz, CDCl3)

δ 7.38 - 7.25 (5 H, m, Ar-H), 6.78 (1 H, dd, J = 16 and 5 Hz, H-5), 6.39 (1 H, dd, J = 16 and 1

Hz, H-6), 6.02 (1 H, d, J = 4 Hz, H-1), 4.81 (1 H, ddd, J = 5, 3 and 1 Hz, H-4), 4.68 - 4.63 (2

H, m, H-2, CHxHyAr), 4.48 (1 H, d, J = 12 Hz, CHxHyAr), 4.00 (1 H, d, J = 3 Hz, H-3), 2.28 (3

H, s, C(O)CH3), 1.50 (3 H, s, CH3), 1.34 (3 H, s, CH3) ppm. 13

C NMR (100 MHz, CDCl3) δ

197.84 (C, C(O)CH3), 140.23 (CH, C-5), 136.96 (C, Ar-C), 131.76 (CH, C-6), 128.54 (CH, Ar-

C), 128.14 (CH, Ar-C), 127.73 (CH, Ar-C), 111.99 (C, C-Me2), 105.04 (CH, C-1), 83.08 (CH,

C-3), 82.65 (CH, C-2), 79.60 (CH, C-4), 72.17 (CH2, OCH2Ar), 27.56 (CH3, C(O)CH3), 26.78

(CH3, C(CH3)2), 26.17 (CH3, C(CH3)2) ppm.

(5S)-4-((3aR,5R,6S,6aR)-6-(benzyloxy)-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-5-yl)-4-

phenylbutan-2-one 126

HAYASHI-MIYAURA REACTION25

Reaction with Z-ketone: To a mixture of phenylboronic acid (38.3 mg, 0.31 mmol) and

[RhCl(1,5-cod)]2 50 (3.94 mg, 5 mol%) under nitrogen were added a solution of α,β-

unsaturated ketone (Z)-125 (50.0 mg, 0.16 mmol) in 1,4-dioxane:H2O (10:1; 0.37 mL)

followed by triethylamine (22 µL, 0.16 mmol). The reaction mixture was stirred for 1 h at

room temperature, then the products were isolated by evaporation of volatiles under reduced

pressure and purified by flash column chromatography (silica gel; eluent 10% EtOAc/petrol).

The elution gave a 18:1 diastereomeric mixture of the title compound as yellow oil with an

139

overall yield of 67.7 mg (90%) (d.r. 16:1, 126:126a). Rf (20% EtOAc/petrol): 0.19. -17.4

(c 1.3, CHCl3). IR max (thin film) 2934 (C-H stretch), 1713 (C=O stretch), 1374, 1213, 1164,

1070 (C-O stretch), 1019 (C-O stretch) cm-1

. 1H NMR (400 MHz, CDCl3) δ 7.41 - 7.17 (10 H,

m, Ar-H), 5.94 (1 H, d, J = 4 Hz, H-1), 4.52 (1 H, d, J = 4 Hz, H-2), 4.41 (1 H, d, J = 11 Hz,

CHxHyAr), 4.32 (1 H, dd, J = 10 and 3 Hz, H-4), 4.14 (1 H, d, J = 11 Hz, CHxHyAr), 3.76 (1 H,

td, J = 10 and 4 Hz, H-5), 3.41 (1 H, d, J = 3 Hz, H-3), 3.18 (1 H, dd, J = 17 and 4 Hz, H-6),

2.85 (1 H, dd, J = 17 and 10 Hz, H-6), 2.01 (3 H, s, C(O)CH3), 1.52 (3 H, s, CH3), 1.30 (3 H,

s, CH3) ppm. 13

C NMR (100 MHz, CDCl3) δ 206.88 (C, C(O)CH3), 140.46 (C, Ar-C), 136.97

(C, Ar-C), 128.13 (CH, Ar-C), 128.10 (CH, Ar-C), 127.93 (CH, Ar-C), 127.50 (CH, Ar-C),

127.39 (CH, Ar-C), 126.54 (CH, Ar-C), 111.06 (C, C-Me2), 104.60 (CH, C-1), 83.28 (CH, C-

4), 81.55 (CH, C-2), 81.13 (CH, C-3), 71.63 (CH2, OCH2Ar), 47.47 (CH2, C-6), 39.45 (CH, C-

5), 30.18 (CH3, C(O)CH3), 26.39 (CH3, C(CH3)2), 25.76 (CH3, C(CH3)2) ppm. MS (ES+) m/z

[M+Na]+ 419.0. Accurate Mass C24H29O5, [M+H]

+ requires 397.2015, measured 397.2010.

Reaction with E-ketone: To a mixture of phenylboronic acid (38.3 mg, 0.31 mmol) and

[RhCl(1,5-cod)]2 50 (3.94 mg, 5 mol%) under nitrogen were added a solution of α,β-

unsaturated ketone (E)-125 (50.0 mg, 0.16 mmol) in 1,4-dioxane:H2O (10:1; 0.37 mL),

followed by triethylamine (22 µL, 0.16 mmol). The reaction mixture was stirred for 1 h at

room temperature, then the products were isolated by evaporation of volatiles under reduced

pressure and purified by flash column chromatography (silica gel; eluent 10% EtOAc/petrol).

The elution gave the title compound as yellow oil with an overall yield of 58.7 mg (92%) (d.r.

14:1, 126:126a) (data of major diastereoisomer as described above).

PALLADIUM-CATALYSED REACTION58

To a stirred solution of α,β-unsaturated ketone (E)-125 (141 mg, 0.44 mmol) in toluene (2

mL) were added phenylboronic acid (108 mg, 0.89 mmol), potassium phosphate (93.4 mg,

0.44 mmol) and the Bedford’s catalyst 157 (34.7 mg, 5 mol%). The reaction mixture was

stirred for 6 h at 40 °C, then quenched with water (10 mL), extracted with DCM (3 × 10 mL)

and dried over anhydrous magnesium sulfate and concentrated in vacuo. The crude product

was purified by flash column chromatography (silica gel; eluent 5% EtOAc/petrol) to afford

140

16.8 mg (14%) of the title compound as yellow oil (d.r. 7:1, 126:126a) (data of major

diastereoisomer as described above).

4-((3aR,5R,6S,6aR)-6-(benzyloxy)-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-5-yl)hex-5-

en-2-one59

128

To a suspension of CuI (89.7 mg, 0.47 mmol) in anhydrous THF (5 mL) was added, at -78

°C, a 1.0 M solution of vinylmagnesium bromide in THF (2.35 mL, 2.35 mmol). After 40 min

at -78 °C, freshly distilled TMSCl (0.75 mL, 5.87 mmol) was added to the reaction mixture,

followed by dropwise addition of a solution of α,β-unsaturated ketone (Z)-125 (150 mg, 0.47

mmol) in anhydrous THF (7 mL). The reaction mixture was then allowed to slowly warm to

room temperature over 3 h. The reaction mixture was then quenched, at -78 °C, by the

addition of saturated aqueous NH4OH:NH4Cl (1:9; 15 mL) and extracted with diethyl ether (3

× 10 mL). The combined organic extracts were washed with brine (10 mL), dried over

anhydrous magnesium sulfate, filtered and concentrated in vacuo. The crude product was

purified by flash column chromatography (silica gel; eluent 10% EtOAc/petrol) to afford 73.1

mg (45%) of the title compound as yellow oil as a single diastereoisomer. Rf (30%

EtOAc/petrol): 0.49. -63.0 (c 1.2, CHCl3). IR max (thin film) 2984 (C-H stretch), 2933 (C-

H stretch), 2359 (C-H stretch), 2340 (C-H stretch), 1713 (C=O stretch), 1213, 1162, 1070 (C-

O stretch), 1019 (C-O stretch) cm-1

. 1H NMR (400 MHz, CDCl3) δ 7.44 – 7.31 (5 H, m, Ar-H),

5.93 (1 H, d, J = 4 Hz, H-1), 5.67 (1 H, ddd, J = 17, 10 and 8 Hz, H-7), 5.26 (1 H, dt, J = 17

and 1 Hz, H-8), 5.21 (1 H, dt, J = 10 and 1 Hz, H-8), 4.71 (1 H, d, J = 12 Hz, CHxHyAr), 4.64

(1 H, d, J = 4 Hz, H-2), 4.49 – 4.40 (3 H, m, 2 × H-6, CHxHyAr), 4.18 (1 H, dd, J = 8 and 3 Hz,

H-4), 3.90 (1 H, d, J = 3 Hz, H-3), 3.49 (1 H, quin., J = 8 Hz, H-5), 2.12 (3 H, s, C(O)CH3),

1.50 (3 H, s, CH3), 1.33 (3 H, s, CH3) ppm. 13

C NMR (100 MHz, CDCl3) δ 207.62 (C,

C(O)CH3), 137.31 (C, Ar-C), 136.77 (CH, C-7), 128.44 (CH, Ar-C), 127.91 (CH, Ar-C),

127.82 (CH, Ar-C), 117.31 (CH2, C-8), 111.44 (C, C-Me2), 104.67 (CH, C-1), 82.04 (CH, C-

4), 81.92 (CH, C-2), 81.58 (CH, C-3), 72.05 (CH2, OCH2Ar), 45.94 (CH2, C-6), 37.94 (CH, C-

141

5), 30.14 (CH3, C(O)CH3), 26.68 (CH3, C(CH3)2), 26.15 (CH3, C(CH3)2) ppm. MS (ES+) m/z

[M+Na]+ 372.0. Accurate Mass C18H23NO6Na, [M+Na]

+ requires 372.1404, measured

372.1418.

(R,E)-1-((3aR,5R,6S,6aR)-6-(benzyloxy)-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-5-yl)-3-

methylpenta-1,4-dien-3-ol and (S,E)-1-((3aR,5R,6S,6aR)-6-(benzyloxy)-2,2-

dimethyltetrahydrofuro[2,3-d][1,3]dioxol-5-yl)-3-methylpenta-1,4-dien-3-ol 129

To a solution of α,β-unsaturated ketone (E)-125 (0.30 g, 0.94 mmol) in anhydrous THF (10

mL) was added a 1.0 M solution of vinylmagnesium bromide in THF (1.88 mL, 1.88 mmol) at

-78 °C. The reaction mixture was allowed to slowly warm up to room temperature over 2.5

hours. The reaction mixture was then quenched, at -78 °C, by the addition of saturated

aqueous NH4Cl (10 mL) and extracted with diethyl ether (3 × 10 mL). The combined organic

extracts were washed with brine (10 mL), dried over anhydrous magnesium sulfate, filtered

and concentrated in vacuo. The crude product was purified by flash column chromatography

(silica gel; eluent 10% EtOAc/petrol) and the elution gave the title compounds as yellow oil

with an overall yield of 119 mg (36%) (d.r. 1:1). Rf (30% EtOAc/petrol): 0.33. -80.1 (c

1.9, CHCl3). IR max (thin film) 3450 (O-H stretch), 2979 (C-H stretch), 2932 (C-H stretch),

1454, 1373, 1213, 1163, 1071 (C-O stretch), 1016 (C-O stretch) cm-1

. 1H NMR (500 MHz,

CDCl3) δ 7.35 – 7.28 (10 H, m, Ar-H, Ar-H*), 6.01 – 5.93 (8 H, m, H-1, H*-1, H-5, H*-5, H-6,

H*-6, H-8, H*-8), 5.29 – 5.24 (2 H, overlapped d, J = 17 Hz, H-9, H*-9), 5.09 (2 H,

overlapped d, J = 11 Hz, H-9, H*-9), 4.68 – 4.64 (6 H, m, H-2, H*-2, H-4, H*-4, CHxHyAr,

CHx*HyAr), 4.52 (2 H, overlapped d, CHxHyAr, CHxHy*Ar), 3.86 (2 H, overlapped d, J = 3 Hz,

H-3, H*-3), 1.50 (6 H, s, CH3, CH3*), 1.40 (6 H, s, C(OH)CH3, C(OH)CH3*), 1.33 (6 H, s, CH3,

CH3*) ppm. 13

C NMR (125 MHz, CDCl3) δ 143.31 (2 × CH, C-8, C*-8), 140.19 (CH, C-6),

140.13 (CH, C-6), 137.47 (2 × C, Ar-C, Ar-C*), 128.41 (CH, Ar-C), 128.39 (CH, Ar-C), 127.86

(2 × CH, Ar-C, Ar-C*), 127.62 (CH, Ar-C), 127.56 (CH, Ar-C), 122.46 (CH2, C-5), 122.33

(CH2, C-5), 112.58 (CH, C-9), 112.48 (CH, C-9), 111.54 (2 × C, C-Me2, C*-Me2), 104.77 (2 ×

142

CH, C-1, C*-1), 83.22 (CH, C-3), 83.19 (CH, C-3), 82.89 (CH, C-2), 82.88 (CH, C-2), 80.68

(CH, C-4), 80.66 (CH, C-4), 73.05 (C, C-7), 73.03 (C, C-7), 72.01 (2 × CH2, OCH2Ar,

OC*H2Ar), 27.74 (CH3, C(OH)(CH3)2), 27.69 (CH3, C(OH)(CH3)2), 26.71 (2 × CH3, C(CH3)2,

C(C*H3)2), 26.16 (2 × CH3, C(CH3)2, C(C*H3)2) ppm. MS (ES+) m/z [M+Na]+ 369.0. Accurate

Mass C20H26O5Na, [M+Na]+

requires 369.1669, measured 369.1673.

(S,E)-4-((3aR,5R,6S,6aR)-6-(benzyloxy)-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-5-yl)-2-

phenylbut-3-en-2-ol and (R,E)-4-((3aR,5R,6S,6aR)-6-(benzyloxy)-2,2-

dimethyltetrahydrofuro[2,3-d][1,3]dioxol-5-yl)-2-phenylbut-3-en-2-ol 130

ORGANOLITHIUM REACTION

To a solution of α,β-unsaturated ketone (E)-125 (110 mg, 0.34 mmol) in THF (5 mL) was

added a 2.0 M solution of phenyllithium in n-dibutyl ether (0.17 mL, 0.34 mmol) dropwise at -

78 °C. The reaction mixture was stirred at -78 °C for 4 h, then quenched with saturated

aqueous NH4Cl (5 mL) and extracted with diethyl ether (3 × 5 mL). The combined organic

extracts were washed with brine (5 mL), dried over anhydrous magnesium sulfate, filtered

and concentrated in vacuo. The crude product was purified by flash column chromatography

(silica gel; eluent 25% EtOAc/petrol) and the elution gave the title compounds as colourless

oil with an overall yield of 134 mg (98%) (d.r. 1:1). Rf (30% EtOAc/petrol): 0.40. -39.4 (c

1.0, CHCl3). IR max (thin film) 3478 (O-H stretch), 3031 (C-H stretch), 2981 (C-H stretch),

2933 (C-H stretch), 2864 (C-H stretch), 1374, 1213, 1164, 1070 (C-O stretch), 1023 (C-O

stretch), 978 (=C-H bend) cm-1

. 1H NMR (500 MHz, CDCl3) δ 7.46 - 7.25 (20 H, m, Ar-Hmajor,

Ar-Hminor), 6.17 (1 H, d, J = 16 Hz, Hmajor-6), 6.16 (1 H, d, J = 16 Hz, Hminor-6), 5.96 – 5.94 (2

H, overlapped d, J = 4 Hz, Hmajor-1, Hminor-1), 5.91 (1 H, overlapped dd, J = 16 and 7 Hz,

Hminor-5), 5.87 (1 H, dd, J = 16 and 7 Hz, Hmajor-5), 4.66 (2 H, overlapped dd, J = 7 and 2 Hz,

Hmajor-4, Hminor-4), 4.64 – 4.61 (4 H, m, Hmajor-2, Hminor-2, CHxmajorHyAr, CHxminorHyAr), 4.51 –

4.46 (2 H, overlapped d, CHxHymajorAr, CHxHyminorAr), 3.85 – 3.84 (2 H, overlapped d, J = 3

143

Hz, Hmajor-3, Hminor-3), 1.67 (3 H, s, C(OH)CH3major), 1.66 (3 H, s, C(OH)CH3minor), 1.48 (6 H, s,

CH3major, CH3minor), 1.31 (6 H, s, CH3major, CH3minor) ppm. 13

C NMR (125 MHz, CDCl3) δ 146.10

(2 × C, Ar-Cmajor, Ar-Cminor), 141.38 (CH, Cminor-6), 141.42 (CH, Cmajor-6), 137.47 (2 × C, Ar-

Cmajor, Ar-Cminor), 128.45 (2 × CH, Ar-Cmajor, Ar-Cminor), 128.24 (2 × CH, Ar-Cmajor, Ar-Cminor),

127.87 (2 × CH, Ar-Cmajor, Ar-Cminor), 127.62 (CH, Ar-Cmajor), 127.59 (CH, Ar-Cminor), 127.02

(CH, Ar-Cmajor), 126.99 (CH, Ar-Cminor), 125.25 (CH, Ar-Cmajor), 125.13 (CH, Ar-Cminor), 122.47

(CH, Cmajor-5), 122.29 (CH, Cminor-5), 111.57 (C, Cmajor-Me2, Cminor-Me2), 104.83 (CH, Cminor-1),

104.81 (CH, Cmajor-1), 83.29 (CH, Cminor-3), 83.22 (CH, Cmajor-3), 82.69 (2 × CH, Cmajor-2,

Cminor-2), 80.74 (CH, Cminor-4), 80.68 (CH, Cmajor-4), 74.31 (C, Cmajor-7, Cminor-7), 72.05 CH2,

OCminorH2Ar), 72.02 (CH2, OCmajorH2Ar), 29.67 (CH3, C(OH)CminorH3), 29.50 (CH3,

C(OH)CmajorH3), 26.73 (CH3, C(CmajorH3)2, C(CminorH3)2), 26.20 (CH3, C(CmajorH3)2, C(CminorH3)2)

ppm. MS (ES+) m/z [M+Na]+ 419.0, [2M+Na]

+ 815.0. Accurate Mass C24H28O5Na, [M+Na]

+

requires 419.1815, measured 419.1829.

CUPRATE REACTION

To a suspension of CuI (59.8 mg, 0.31 mmol) in anhydrous THF (3 mL) was added, at -78

°C, a 1.0 M solution of phenylmagnesium bromide in THF (1.55 mL, 1.55 mmol). After 40

min at -78 °C, freshly distilled TMSCl (0.59 mL, 4.65 mmol) was added to the reaction

mixture, followed by dropwise addition of a solution of α,β-unsaturated ketone (E)-125 (100

mg, 0.31 mmol) in anhydrous THF (4 mL). The reaction mixture was then allowed to slowly

warm to room temperature over 3 h. The reaction mixture was then quenched, at -78 °C, by

the addition of saturated aqueous NH4OH:NH4Cl (1:9; 15 mL) and extracted with diethyl

ether (3 × 10 mL). The combined organic extracts were washed with brine (10 mL), dried

over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The crude product

was purified by flash column chromatography (silica gel; eluent 5% → 10% → 20%

EtOAc/petrol) and the elution gave the title compounds with an overall yield of 63.6 mg

(26%) as yellow oil (d.r. 1:1) (data as described above).

144

(R,Z)-4-((3aR,5R,6S,6aR)-6-(benzyloxy)-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-5-yl)-2-

phenylbut-3-en-2-ol and (S,Z)-4-((3aR,5R,6S,6aR)-6-(benzyloxy)-2,2-

dimethyltetrahydrofuro[2,3-d][1,3]dioxol-5-yl)-2-phenylbut-3-en-2-ol 131

To a solution of α,β-unsaturated ketone (Z)-125 (0.05 g, 0.16 mmol) in THF (3 mL) was

added a 2.0 M solution of phenyllithium in n-dibutyl ether (80 μL, 0.16 mmol) dropwise at -78

°C. The reaction mixture was stirred at -78 °C for 4 h, then quenched with saturated aqueous

NH4Cl (5 mL) and extracted with diethyl ether (3 × 5 mL). The combined organic extracts

were washed with brine (5 mL), dried over anhydrous magnesium sulfate, filtered and

concentrated in vacuo. The crude product was purified by flash column chromatography

(silica gel; eluent 10% EtOAc/petrol) and the elution gave the title compound as white oil with

an overall yield of 20.7 mg (33%) (d.r. 3:1). Rf (30% EtOAc/petrol): 0.46. -50.2 (c 1.0,

CHCl3). IR max (thin film) 3470 (O-H stretch), 2980 (C-H stretch), 2928 (C-H stretch), 1373,

1214, 1164, 1071 (C-O stretch), 1025 (C-O stretch) cm-1

. 1H NMR (400 MHz, CDCl3) δ 7.50 -

7.18 (20 H, m, Ar-Hmajor, Ar-Hminor), 6.20 (1 H, dd, J = 12 and 2 Hz, Hmajor-6), 6.08 (1 H, dd, J

= 12 and 1.5 Hz, Hminor-6), 5.91 (1 H, d, J = 4 Hz, Hmajor-1), 5.86 (1 H, d, J = 4 Hz, Hminor-1),

5.78 (1 H, dd, J = 12 and 7 Hz, Hmajor-5), 5.70 (1 H, dd, J = 12 and 7 Hz, Hminor-5), 5.04 – 5.01

(1 H, overlapped ddd, J = 7, 3 and 1.5 Hz, Hminor-4), 4.99 (1 H, ddd, J = 7, 3 and 1 Hz, Hmajor-

4), 4.68 (1 H, d, J = 12 Hz, CHxminorHyAr), 4.59 – 4.56 (2 H, overlapped d, J = 12 Hz,

CHxmajorHyAr, Hminor-2), 4.54 (1 H, d, J = 4 Hz, Hmajor-2), 4.50 (1 H, d, J = 12 Hz, CHxHyminorAr),

4.40 (1 H, d, J = 12 Hz, CHxHymajorAr), 3.79 (1 H, d, J = 3 Hz, Hminor-3), 3.52 (1 H, d, J = 3 Hz,

Hmajor-3), 3.04 (1 H, br. s, OHmajor), 2.46 (1 H, br. s, OHminor), 1.66 (3 H, s, C(OH)CH3major),

1.64 (3 H, s, C(OH)CH3minor), 1.37 (3 H, s, CH3major), 1.35 (3 H, s, CH3minor), 1.28 (3 H, s,

CH3major), 1.27 (3 H, s, CH3minor) ppm. 13

C NMR (125 MHz, CDCl3) δ 147.84 (C, Ar-Cmajor),

147.26 (C, Ar-Cminor), 142.57 (CH, Cmajor-6), 140.55 (CH, Cminor-6), 137.62 (C, Ar-Cminor),

137.46 (C, Ar-Cmajor), 128.42 (CH, Ar-Cmajor), 128.21 (CH, Ar-Cminor), 128.15 (CH, Ar-Cmajor),

127.96 (CH, Ar-Cminor), 127.93 (CH, Ar-Cminor), 127.87 (CH, Ar-Cmajor), 127.66 (CH, Ar-Cmajor),

145

126.94 (CH, Ar-Cminor), 126.67 (CH, Ar-Cmajor), 125.14 (CH, Ar-Cminor), 124.97 (CH, Ar-Cmajor),

124.73 (CH, Ar-Cminor), 124.55 (CH, Ar-Cmajor), 111.71 (C, Cmajor-Me2), 111.66 (C, Cminor-Me2),

104.59 (CH, Cminor-1), 104.50 (CH, Cmajor-1), 82.62 (CH, C-3), 82.57 (CH, C-2), 76.29 (CH,

Cminor-4), 75.59 (CH, Cmajor-4), 74.56 (C, Cminor-7), 74.12 (C, Cmajor-7), 71.85 (CH2,

OCmajorH2Ar), 71.79 (CH2, OCminorH2Ar), 32.97 (CH3, C(OH)CmajorH3), 31.74 (CH3,

C(OH)CminorH3), 26.79 (CH3, C(CminorH3)2), 26.70 (CH3, C(CmajorH3)2), 26.44 (CH3,

C(CminorH3)2), 26.38 (CH3, C(CmajorH3)2) ppm. MS (ES+) m/z [M+Na]+ 419.0. Accurate Mass

C24H28O5Na, [M+Na]+

requires 419.1828, measured 419.1829.

(R)-3-O-benzyl-1,2-O-isopropylidene-5,6-dideoxy-5-hydroxyl-6-nitro-D-glucofuranose51

and

(S)-3-O-benzyl-1,2-O-isopropylidene-5,6-dideoxy-5-hydroxyl-6-nitro-D-glucofuranose 134

To a solution of aldehyde 19 (5.00 g, 17.97 mmol) in anhydrous methanol (38 mL) was

added nitromethane (10 mL, 183 mmol), followed by sodium methoxide (1.16 g, 21.56 mmol)

and the reaction mixture was stirred for 1.5 h. The pH of the mixture was brought to 2 by the

addition of glacial acetic acid and the solvent was evaporated under pressure. The residue

was dissolved in DCM (20 mL) and washed with brine (20 mL). The organic extract was

dried over anhydrous magnesium sulfate and concentrated in vacuo. The crude product was

purified by flash column chromatography (silica gel; eluent 15% EtOAc/petrol) to afford an

overall yield of 5.20 g (85%) of the title compound as yellow oil (d.r. 9:1).

Isomer 1

Isolated yield: 2.97 g (49%). Rf (30% EtOAc/petrol): 0.49. -52.0 (c 1.4, CHCl3). IR max

(thin film) 3465 (O-H stretch), 3037 (C-H stretch), 2987 (C-H stretch), 2935 (C-H stretch),

1552 (NO2 asym. stretch), 1376 (NO2 sym. stretch), 1164, 1070 (C-O stretch), 1023 (C-O

stretch) cm-1

. 1H NMR (400 MHz, CDCl3) δ 7.43 - 7.33 (5 H, m, Ar-H), 5.93 (1 H, d, J = 4 Hz,

H-1), 4.77 (1 H, d, J = 12 Hz, CHxHyAr), 4.70 - 4.75 (1 H, m, H-6), 4.65 (2 H, m, H-2, H-5),

4.53 (1 H, d, J = 12 Hz, CHxHyAr), 4.44 - 4.51 (1 H, m, H-6), 4.06 - 4.17 (2 H, m, H-3, H-4),

146

2.49 (1 H, d, J = 5 Hz, OH), 1.49 (3 H, s, CH3), 1.34 (3 H, s, CH3) ppm. 13

C NMR (100 MHz,

CDCl3) δ 136.82 (C, Ar-C), 128.88 (CH, Ar-C), 128.51 (CH, Ar-C), 128.00 (CH, Ar-C), 112.20

(C, C-Me2), 105.30 (CH, C-1), 82.02 (CH, C-2), 80.87 (CH, C-3), 79.86 (CH, C-4), 78.51

(CH2, C-6), 72.19 (CH2, OCH2Ar), 66.38 (CH, C-5), 26.93 (CH3, C(CH3)2), 26.21 (CH3,

C(CH3)2) ppm. MS (ES+) m/z [M+Na]+ 362.0. Accurate Mass C16H21NO7Na, [M+Na]

+

requires 362.1228, measured 362.1211.

Isomer 2

Isolated yield: 482 mg (8%) (1.75 g (27%) as R/S mixture). Rf (30% EtOAc/petrol): 0.43.

-62.3 (c 1.5, CHCl3). IR max (thin film) 3465 (O-H stretch), 2984 (C-H stretch), 2935 (C-

H stretch), 1553 (NO2 asym. stretch), 1376 (NO2 sym. stretch), 1164, 1070 (C-O stretch),

1022 (C-O stretch) cm-1

. 1H NMR (400 MHz, CDCl3) δ 7.43 - 7.31 (5 H, m, Ar-H), 6.02 (1 H,

d, J = 4 Hz, H-1), 4.77 (1 H, d, J = 12 Hz, CHxHyAr), 4.74 - 4.69 (1 H, m, H-5), 4.68 (1 H, d, J

= 4 Hz, H-2), 4.57 - 4.48 (2 H, m, H-6, CHxHyAr), 4.37 – 4.32 (1 H, m, H-6), 4.19 - 4.09 (2 H,

m, H-3, H-4), 3.32 (1 H, dd, J = 2.5 and 1 Hz, OH), 1.48 (3 H, s, CH3), 1.35 (3 H, s, CH3)

ppm. 13

C NMR (125 MHz, CDCl3) δ 136.05 (C, Ar-C), 128.86 (CH, Ar-C), 128.65 (CH, Ar-C),

128.13 (CH, Ar-C), 112.35 (C, C-Me2), 105.03 (CH, C-1), 82.64 (C-2), 82.21 (CH, C-3),

79.02 (CH, C-4), 77.58 (CH2, C-6), 72.07 (CH2, OCH2Ar), 67.76 (CH, C-5), 26.83 (CH3,

C(CH3)2), 26.28 (CH3, C(CH3)2) ppm.

(E)-3-O-benzyl-1,2-O-isopropylidene-5,6-dideoxy-5,6-dehydro-6-nitro-D-glucofuranose51

135

To a stirred solution of nitro alcohol 134 (2.13 g, 6.27 mmol) in DCM (16 mL) at 0 °C were

added mesyl chloride (1.55 mL, 20.08 mmol) and triethylamine (3.76 mL, 26.98 mmol). The

reaction mixture was stirred further for 45 min and, after completion, washed with

bicarbonate (3 × 10 mL). The combined organic extracts were dried over anhydrous

magnesium sulfate and concentrated in vacuo. The crude product was purified by flash

column chromatography (silica gel; eluent 10% EtOAc/petrol) to afford an overall yield of

147

1.92 g (95%) of the title compound as yellow oil (25:1, E:Z). Rf (20% EtOAc/petrol): 0.28.

-16.1 (c 1.0, CHCl3) lit.

52

-29.1 (c 1.0, CHCl3). IR max (thin film) 2987 (C-H

stretch), 2935 (C-H stretch), 2869 (C-H stretch), 1660, 1523 (NO2 asym. stretch), 1351 (NO2

sym. stretch), 1214, 1074 (C-O stretch), 1023 (C-O stretch) cm-1

. 1H NMR (500 MHz, CDCl3)

δ 7.39 - 7.31 (3 H, m, Ar-H), 7.28 – 7.25 (2 H, m, Ar-H), 7.23 (1 H, d, J = 2 Hz, H-6), 7.20 –

7.13 (1 H, m, H-5), 6.01 (1 H, d, J = 4 Hz, H-1), 4.96 – 4.84 (1 H, m, H-4), 4.68 -4.66 (2 H, m,

H-2, CHxHyAr), 4.48 (1 H, d, J = 12 Hz, CHxHyAr), 4.06 (1 H, d, J = 3 Hz, H-3), 1.50 (1 H, s,

CH3), 1.31 (3 H, s, CH3) ppm. 13

C NMR (125 MHz, CDCl3) δ 140.95 (CH, C-6), 136.55 (C, Ar-

C), 135.82 (CH, C-5), 128.70 (CH, Ar-C), 128.37 (CH, Ar-C), 127.89 (CH, Ar-C), 112.37 (C,

C-Me2), 105.08 (CH, C-1), 82.46 (CH, C-2), 82.29 (CH, C-3), 77.04 (CH, C-4), 72.27 (CH2,

OCH2Ar), 26.83 (CH3, C(CH3)2), 26.16 (CH3, C(CH3)2) ppm. MS (ES+) m/z [M+Na]+ 344.0.

Accurate Mass C16H19NO6Na, [M+Na]+

requires 344.1118, measured 344.1105.

(5S)-3-O-benzyl-5,6-dideoxy-1,2-O-isopropylidene-6-C-nitro-5-C-phenyl-α-D-idofuranose84

136

CUPRATE REACTION59

To a suspension of CuI (89.5 mg, 0.47 mmol) in anhydrous THF (4 mL) was added, at -78

°C, a 1.0 M solution of phenylmagnesium bromide in THF (2.33 mL, 2.33 mmol). After 40

min at -78 °C, a solution of α,β-unsaturated nitro alkene 135 (150 mg, 0.47 mmol) in

anhydrous THF (6 mL) was added. The reaction mixture was then allowed to slowly warm to

room temperature over 4 h, then quenched, at -78 °C, by the addition of saturated aqueous

NH4OH:NH4Cl (1:9; 10 mL) and extracted with diethyl ether (3 × 10 mL). The combined

organic extracts were washed with brine (10 mL), dried over anhydrous magnesium sulfate,

filtered and concentrated in vacuo. The crude product was purified by flash column

chromatography (silica gel; eluent 5% EtOAc/petrol) to afford 101 mg (61%) of the title

compound as yellow oil (d.r. 13:1, 136:136a). Rf (20% EtOAc/petrol): 0.34. -68.6 (c 0.9,

148

CHCl3) lit.84

-26.8 (c 2.0, CHCl3). IR max (thin film) 2934 (C-H stretch), 1550 (NO2

asym. stretch), 1376 (NO2 sym. stretch), 1071 (C-O stretch), 1024 (C-O stretch) cm-1

. 1H

NMR (500 MHz, CDCl3) δ 7.44 - 7.20 (10 H, m, Ar-H), 5.97 (1 H, d, J = 4 Hz, H-1), 5.02 (1 H,

dd, J = 13 and 4 Hz, H-6), 4.74 (1 H, dd, J = 13 and 11 Hz, H-6), 4.55 (1 H, d, J = 4 Hz, H-2),

4.46 (1 H, d, J = 11 Hz, CHxHyAr), 4.41 (1 H, dd, J = 10 and 3 Hz, H-4), 4.17 (1 H, d, J = 11

Hz, CHxHyAr), 4.05 (1 H, td, J = 10 and 4 Hz, H-5), 3.54 (1 H, d, J = 3 Hz, H-3), 1.52 (3 H, s,

CH3), 1.32 (3 H, s, CH3) ppm. 13

C NMR (125 MHz, CDCl3) δ 136.91 (C, Ar-C), 136.55 (C, Ar-

C), 128.89 (CH, Ar-C), 128.54 (CH, Ar-C), 128.13 (CH, Ar-C), 128.05 (CH, Ar-C), 127.79

(CH, Ar-C), 111.77 (C, C-Me2), 105.15 (CH, C-1), 81.60 (CH, C-2), 81.56 (CH, C-3), 81.22

(CH, C-4), 78.79 (CH2, C-6), 72.17 (CH2, OCH2Ar), 43.07 (CH, C-5), 26.74 (CH3, C(CH3)2),

26.07 (CH3, C(CH3)2) ppm. MS (ES+) m/z [M+Na]+ 422.0. Accurate Mass C22H25NO6Na,

[M+Na]+

requires 422.1583, measured 422.1575.

HAYASHI-MIYAURA REACTION25

Reaction with [RhCl(1,5-cod)]2 catalyst: To a mixture of phenylboronic acid (46.3 mg, 0.38

mmol) and [RhCl(1,5-cod)]2 50 (4.68 mg, 5 mol%) under nitrogen were added a solution of

α,β-unsaturated nitro alkene 135 (60.0 mg, 0.19 mmol) in 1,4-dioxane:H2O (10:1; 0.39 mL),

followed by triethylamine (26 µL, 0.16 mmol). The reaction mixture was stirred for 3 h at

room temperature, then the products were isolated by evaporation of volatiles under reduced

pressure and purified by flash column chromatography (silica gel; eluent 10% EtOAc/petrol).

The elution gave the title compound as yellow oil with an overall yield of 68.8 mg (91%) (d.r.

10:1, 136:136a) (data of major diastereoisomer as described above).

Reaction with [Rh(OH)(1,5-cod)]2 catalyst: To a mixture of phenylboronic acid (37.9 mg,

0.31 mmol) and [Rh(OH)(1,5-cod)]2 50a (3.56 mg, 5 mol%) under nitrogen were added a

solution of α,β-unsaturated nitro alkene 135 (50.0 mg, 0.15 mmol) in 1,4-dioxane:H2O (10:1;

0.39 mL), followed by triethylamine (22 µL, 0.15 mmol). The reaction mixture was stirred for

2 h at room temperature, then the products were isolated by evaporation of volatiles under

reduced pressure and purified by flash column chromatography (silica gel; eluent 10%

149

EtOAc/petrol). The elution gave the title compound as yellow oil with an overall yield of 53.3

mg (89%) (d.r. 10:1, 136:136a) (data of major diastereoisomer as described above).

PALLADIUM-CATALYSED REACTION58

To a stirred solution of α,β-unsaturated nitro alkene 135 (150 mg, 0.36 mmol) in toluene (3

mL) were added phenylboronic acid (87.6 mg, 0.72 mmol), potassium phosphate (76.4 mg,

0.36 mmol) and the Bedford’s catalyst 157 (28.4 mg, 5 mol%). The reaction mixture was

stirred for 48 h at 40 °C, then quenched with water (10 mL), extracted with DCM (3 × 10 mL)

and dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The crude

product was purified by flash column chromatography (silica gel; eluent 5% EtOAc/petrol) to

afford 72.4 mg (50%) of the title compound as yellow oil (d.r. 18:1, 136:136a) (data of major

diastereoisomer as described above).

(5R)-3-O-benzyl-5,6-dideoxy-1,2-O-isopropylidene-6-C-nitro-5-C-phenyl-α-D-idofuranose

136a

ORGANOLITHIUM REACTION

To a solution of nitro alkene 135 (0.10 g, 0.31 mmol) in THF (5 mL) at -78 °C was added a

2.0 M solution of phenyllithium in n-dibutyl ether (0.16 mL, 0.31 mmol). The reaction mixture

was stirred at the same temperature for 4 h, then quenched with saturated aqueous NH4Cl

(5 mL) and extracted with diethyl ether (3 × 5 mL). The combined organic extracts were

washed with brine (5 mL), dried over anhydrous magnesium sulfate, filtered and

concentrated in vacuo. The crude product was purified by flash column chromatography

(silica gel; eluent 10% EtOAc/petrol) and the elution gave the title compound as white solid

with an overall yield of 61.4 mg (49%) (d.r. 3:1, 136a:136). Rf (20% EtOAc/petrol): 0.25.

-102.8 (c 0.8, CHCl3). mp 146 - 148 °C. IR max (thin film) 2910 (C-H stretch), 1544 (NO2

asym. stretch), 1375 (NO2 sym. stretch), 1071 (C-O stretch), 1035 (C-O stretch) cm-1

. 1H

150

NMR (400 MHz, CDCl3) δ 7.35 - 7.46 (5 H, m, Ar-H), 7.19 - 7.35 (5 H, m, Ar-H), 5.93 (1 H, d,

J = 4 Hz, H-1), 4.76 - 4.83 (1 H, dd, J = 13 and 10 Hz, H-6), 4.73 (1 H, d, J = 12 Hz,

CHxHyAr), 4.65 (2 H, dt, J = 9 and 4 Hz, H-6, H-2), 4.46 (1 H, d, J = 12 Hz, CHxHyAr), 4.39 (1

H, dd, J = 8 and 3 Hz, H-4), 4.10 (1 H, ddd, J = 10, 8 and 4 Hz, H-5), 3.82 (1 H, d, J = 3 Hz,

H-3), 1.48 (3 H, s, CH3), 1.31 (3 H, s, CH3) ppm. 13

C NMR (75 MHz, CDCl3) δ 136.64 (C, Ar-

C), 136.54 (C, Ar-C), 128.93 (CH, Ar-C), 128.82 (CH, Ar-C), 128.48 (CH, Ar-C), 128.18 (CH,

Ar-C), 127.93 (CH, Ar-C), 127.84 (CH, Ar-C), 111.71 (C, C-Me2), 104.56 (CH, C-1), 81.31

(CH, C-2, C-3), 80.73 (CH, C-4), 76.18 (CH2, C-6), 71.57 (CH2, OCH2Ar), 43.53 (CH, C-5),

26.68 (CH3, C(CH3)2), 26.11 (CH3, C(CH3)2) ppm.

(5S)-3-O-benzyl-5,6-dideoxy-1,2-O-isopropylidene-6-C-nitro-5-C-(4-fluorophenyl)-α-D-

idofuranose 137

HAYASHI-MIYAURA REACTION25

To a mixture of 4-fluorophenylboronic acid (43.4 mg, 0.31 mmol) and [RhCl(1,5-cod)]2 50

(3.84 mg, 5 mol%) under nitrogen were added a solution of α,β-unsaturated nitro alkene 135

(50.0 mg, 0.15 mmol) in 1,4-dioxane:H2O (10:1; 0.37 mL), followed by triethylamine (22 µL,

0.15 mmol). The reaction mixture was stirred for 1 h at room temperature, then the products

were isolated by evaporation of volatiles under reduced pressure and purified by flash

column chromatography (silica gel; eluent 10% EtOAc/petrol). The elution gave the title

compound as yellow oil with an overall yield of to afford 48.6 mg (78%) (d.r. 10:1, 137:137a).

Rf (30% EtOAc/petrol): 0.53. -64.0 (c 1.8, CHCl3). IR max (thin film) 2934 (C-H stretch),

1551 (NO2 asym. stretch), 1376 (NO2 sym. stretch), 1222, 1162, 1071 (C-O stretch), 1024

(C-O stretch) cm-1

. 1H NMR (500 MHz, CDCl3) δ 7.42 - 7.32 (3 H, m, Ar-H), 7.27 – 7.23 (2 H,

m, Ar-H), 7.19 (2 H, dd, J = 9 and 5 Hz, Ar-H), 6.99 (2 H, t, J = 9 Hz, Ar-H), 5.97 (1 H, d, J =

4 Hz, H-1), 5.01 (1 H, dd, J = 13 and 4 Hz, H-6), 4.69 (1 H, dd, J = 13 and 11 Hz, H-6), 4.58

(1 H, d, J = 4 Hz, H-2), 4.50 (1 H, d, J = 11 Hz, CHxHyAr), 4.36 (1 H, dd, J = 10 and 3 Hz, H-

151

4), 4.18 (1 H, d, J = 11 Hz, CHxHyAr), 4.02 (1 H, td, J = 10 and 4 Hz, H-5), 3.55 (1 H, d, J = 3

Hz, H-3), 1.52 (3 H, s, CH3), 1.32 (3 H, s, CH3) ppm. 13

C NMR (125 MHz, CDCl3) δ 162.27

(C, d, JCF = 246 Hz, Ar-C-F), 136.72 (C, Ar-C), 132.30 (C, Ar-C), 129.75 (CH, Ar-C), 129.69

(CH, Ar-C), 128.54 (CH, Ar-C), 128.11 (CH, Ar-C), 127.79 (CH, Ar-C), 115.89 (CH, Ar-C),

115.72 (CH, Ar-C), 111.80 (C, C-Me2), 105.11 (CH, C-1), 81.43 (CH, C-2, C-3), 81.08 (CH,

C-4), 78.71 (CH2, C-6), 72.05 (CH2, OCH2Ar), 42.38 (CH, C-5), 26.69 (CH3, C(CH3)2), 26.01

(CH3, C(CH3)2) ppm. MS (ES+) m/z [M+Na]+ 440.0, [2M+Na]

+ 857.0. Accurate Mass

C22H24NO6FNa, [M+Na]+

requires 440.1463, measured 440.1480.

(5S)-3-O-benzyl-5,6-dideoxy-1,2-O-isopropylidene-6-C-nitro-5-C-(4-acetylphenyl)-α-D-

idofuranose 138

HAYASHI-MIYAURA REACTION25

To a mixture of 4-acetylphenylboronic acid (102 mg, 0.62 mmol) and [RhCl(1,5-cod)]2 50

(7.64 mg, 5 mol%) under nitrogen were added a solution of α,β-unsaturated nitro alkene 135

(100 mg, 0.31 mmol) in 1,4-dioxane:H2O (10:1; 0.74 mL), followed by triethylamine (43 µL,

0.31 mmol). The reaction mixture was stirred for 1 h at room temperature, then the products

were isolated by evaporation of volatiles under reduced pressure and purified by flash

column chromatography (silica gel; eluent 20% EtOAc/petrol) to afford 71.3 mg (52%) of the

title compound as white oil (d.r. 10:1, 138:138a). The purified product was slowly crystallised

from hot ethanol to obtain white solid. Rf (40% EtOAc/petrol): 0.51. -40.7 (c 1.1,

CHCl3). mp 115 - 119 °C. IR max (thin film) 3032 (C-H stretch), 2986 (C-H stretch), 2922 (C-

H stretch), 2852 (C-H stretch), 1682 (C=O stretch), 1550 (NO2 asym. stretch), 1376 (NO2

sym. stretch), 1070 (C-O stretch), 1023 (C-O stretch) cm-1

. 1H NMR (400 MHz, CDCl3) δ 7.91

– 7.86 (2 H, m, Ar-H), 7.40 - 7.31 (5 H, m, Ar-H), 7.28 – 7.23 (2 H, m, Ar-H), 5.98 (1 H, d, J =

4 Hz, H-1), 5.05 (1 H, dd, J = 13 and 4 Hz, H-6), 4.75 (1 H, dd, J = 13 and 11 Hz, H-6), 4.58

152

(1 H, d, J = 4 Hz, H-2), 4.50 (1 H, d, J = 11 Hz, CHxHyAr), 4.40 (1 H, dd, J = 10 and 3 Hz, H-

4), 4.17 (1 H, d, J = 11 Hz, CHxHyAr), 4.09 (1 H, td, J = 10 and 4 Hz, H-5), 3.54 (1 H, d, J = 3

Hz, H-3), 2.60 (3 H, s, C(O)CH3), 1.51 (3 H, s, CH3), 1.32 (3 H, s, CH3) ppm. 13

C NMR (100

MHz, CDCl3) δ 197.47 (C, C(O)CH3), 141.94 (C, Ar-C), 136.74 (C, Ar-C), 136.61 (C, Ar-C),

128.84 (CH, Ar-C), 128.56 (CH, Ar-C), 128.41 (CH, Ar-C), 128.15 (CH, Ar-C), 127.84 (CH,

Ar-C), 111.88 (C, C-Me2), 105.10 (CH, C-1), 81.42 (CH, C-2), 81.39 (CH, C-3), 80.77 (CH,

C-4), 78.29 (CH2, C-6), 72.03 (CH2, OCH2Ar), 43.02 (CH, C-5), 26.70 (CH3, C(CH3)2), 26.58

(C(O)CH3), 26.02 (CH3, C(CH3)2) ppm. MS (ES+) m/z [M+Na]+ 464.0, [2M+Na]

+ 905.0.

Accurate Mass C24H28NO7, [M+H]+

requires 442.1854, measured 442.1861.

(5R)-3-O-benzyl-5,6-dideoxy-1,2-O-isopropylidene-6-C-nitro-5-C-(4-acetylphenyl)-α-D-

idofuranose 138a

HAYASHI-MIYAURA REACTION25

(procedure as described above)

Isolated yield: 6.00 mg (4%) as yellow oil. -274.1 (c 0.4, CHCl3). IR max (thin film)

2919 (C-H stretch), 2850 (C-H stretch), 1675 (C=O stretch), 1549 (NO2 asym. stretch), 1377

(NO2 sym. stretch), 1071, 1037 (C-O stretch), 1013 (C-O stretch) cm-1

. 1H NMR (400 MHz,

CDCl3) δ 7.91 – 7.87 (2 H, m, Ar-H), 7.46 - 7.30 (7 H, m, Ar-H), 5.91 (1 H, d, J = 4 Hz, H-1),

4.75 (1 H, d, J = 11 Hz, CHxHyAr), 4.72 (1 H, d, J = 10 Hz, H-6), 4.66 (1 H, d, J = 4 Hz, H-2),

4.60 – 4.54 (1 H, dd, J = 8 and 4 Hz, H-6), 4.44 (1 H, d, J = 11 Hz, CHxHyAr), 4.37 (1 H, dd, J

= 8 and 3 Hz, H-4), 4.13 (1 H, ddd, J = 10 and 8 and 4 Hz, H-5), 3.82 (1 H, d, J = 3 Hz, H-3),

2.58 (3 H, s, C(O)CH3), 1.47 (3 H, s, CH3), 1.32 (3 H, s, CH3) ppm. 13

C NMR (100 MHz,

CDCl3) δ 197.47 (C, C(O)CH3), 142.12 (C, Ar-C), 136.65 (C, Ar-C), 136.35 (C, Ar-C), 128.92

(CH, Ar-C), 128.88 (CH, Ar-C), 128.63 (CH, Ar-C), 128.31 (CH, Ar-C), 128.28 (CH, Ar-C),

111.84 (C, C-Me2), 104.58 (CH, C-1), 81.31 (CH, C-2), 81.01 (CH, C-3), 80.29 (CH, C-4),

153

75.83 (CH2, C-6), 71.61 (CH2, OCH2Ar), 43.36 (CH, C-5), 26.70 (CH3, C(CH3)2), 26.56 (C,

C(O)CH3), 26.11 (CH3, C(CH3)2) ppm.

(5S)-3-O-benzyl-5,6-dideoxy-1,2-O-isopropylidene-6-C-nitro-5-C-(4-methoxyphenyl)-α-D-

idofuranose 139

HAYASHI-MIYAURA REACTION25

To a mixture of 4-methoxyphenylboronic acid (94.2 mg, 0.62 mmol) and [RhCl(1,5-cod)]2 50

(7.64 mg, 5 mol%) under nitrogen were added a solution of α,β-unsaturated nitro alkene 135

(100 mg, 0.31 mmol) in 1,4-dioxane:H2O (10:1; 0.74 mL), followed by triethylamine (43 µL,

0.31 mmol). The reaction mixture was stirred for 1 h at room temperature, then the products

were isolated by evaporation of volatiles under reduced pressure and purified by flash

column chromatography (silica gel; eluent 8% EtOAc/petrol) to afford 98.1 mg (74%) of the

title compound as yellow oil (d.r. 6:1, 139:139a). The purified product was crystallised from

hot ethanol to obtain white crystals for X-ray crystallography. Rf (30% EtOAc/petrol): 0.50.

-24.1 (c 0.9, CHCl3). mp 73 - 75 °C. IR max (thin film) 2986 (C-H stretch), 2931 (C-H

stretch), 1549 (NO2 asym. stretch), 1375 (NO2 sym. stretch), 1070 (C-O stretch), 1023 (C-O

stretch) cm-1

. 1H NMR (500 MHz, CDCl3) δ 7.42 – 7.23 (5 H, m, Ar-H), 7.14 (2 H, d, J = 9 Hz,

Ar-H), 6.83 (2 H, d, J = 9 Hz, Ar-H), 5.96 (1 H, d, J = 4 Hz, H-1), 4.98 (1 H, dd, J = 13 and 4

Hz, H-6), 4.69 (1 H, dd, J = 12.5 and 11 Hz, H-6), 4.55 (1 H, d, J = 4 Hz, H-2), 4.46 (1 H, d, J

= 11 Hz, CHxHyAr), 4.37 (1 H, dd, J = 10 and 3 Hz, H-4), 4.19 (1 H, d, J = 11 Hz, CHxHyAr),

3.99 (1 H, td, J = 10 and 4 Hz, H-5), 3.79 (3 H, s, OCH3), 3.55 (1 H, d, J = 3 Hz, H-3), 1.51 (3

H, s, CH3), 1.31 (3 H, s, CH3) ppm. 13

C NMR (125 MHz, CDCl3) δ 159.19 (CH3, C-OCH3),

136.96 (C, Ar-C), 129.13 (CH, Ar-C), 128.51 (CH, Ar-C), 128.35 (CH, Ar-C), 128.01 (CH, Ar-

C), 127.76 (CH, Ar-C), 114.25 (CH, Ar-C), 111.72 (C, C-Me2), 105.15 (CH, C-1), 81.56 (CH,

C-2), 81.52 (CH, C-3), 81.33 (CH, C-4), 78.96 (CH2, C-6), 72.12 (CH2, OCH2Ar), 55.22 (CH3,

154

OCH3), 42.34 (CH, C-5), 26.70 (CH3, C(CH3)2), 26.04 (CH3, C(CH3)2) ppm. MS (ES+) m/z

[M+Na]+ 452.0. Accurate Mass C23H27NO7Na, [M+Na]

+ requires 452.1664, measured

452.1680.

(5R)-3-O-benzyl-5,6-dideoxy-1,2-O-isopropylidene-6-C-nitro-5-C-(4-methoxyphenyl)-α-D-

idofuranose 139a

HAYASHI-MIYAURA REACTION25

(procedure as described above)

Isolated yield: 10.2 mg (8%) as yellow solid. Rf (30% EtOAc/petrol): 0.44. -62.4 (c 1.0,

CHCl3). mp 130 - 133 °C. IR max (thin film) 2985 (C-H stretch), 2939 (C-H stretch), 2907 (C-

H stretch), 2867 (C-H stretch), 1543 (NO2 asym. stretch), 1376 (NO2 sym. stretch), 1065,

1031 (C-O stretch), 1011 (C-O stretch) cm-1

. 1H NMR (400 MHz, CDCl3) δ 7.46 – 7.36 (5 H,

m, Ar-H), 7.14 – 7.19 (2 H, m, Ar-H), 6.82 (2 H, d, J = 9 Hz, Ar-H), 5.92 (1 H, d, J = 4 Hz, H-

1), 4.78 – 4.71 (2 H, m, H-6, CHxHyAr), 4.65 – 4.60 (2 H, m, H-2, H-6), 4.46 (1 H, d, J = 12

Hz, CHxHyAr), 4.35 (1 H, dd, J = 8 and 3 Hz, H-4), 4.04 (1 H, ddd, J = 10, 8 and 4 Hz, H-5),

3.83 (1 H, d, J = 3 Hz, H-3), 3.78 (3 H, s, OCH3) 1.48 (3 H, s, CH3), 1.32 (3 H, s, CH3) ppm.

13C NMR (100 MHz, CDCl3) δ 159.07 (CH3, C-OCH3), 136.54 (C, Ar-C), 128.98 (CH, Ar-C),

128.81 (CH, Ar-C), 128.49 (CH, Ar-C), 128.47 (CH, Ar-C), 128.19 (CH, Ar-C), 114.32 (CH,

Ar-C), 111.66 (C, C-Me2), 104.53 (CH, C-1), 81.29 (CH, C-2), 81.24 (CH, C-3), 80.82 (CH,

C-4), 76.44 (CH2, C-6), 71.51 (CH2, OCH2Ar), 55.20 (CH3, OCH3), 42.82 (CH, C-5), 26.67

(CH3, C(CH3)2), 26.11 (CH3, C(CH3)2) ppm.

GRIGNARD REACTION

To a solution of α,β-unsaturated nitro alkene 135 (150 mg, 0.47 mmol) in anhydrous THF (5

mL) was added a 0.5 M solution of 4-methoxyphenylmagnesium bromide in THF (0.93 mL,

0.47 mmol) at -78 °C. The reaction mixture was stirred at -78 °C for 4 h, then quenched with

155

saturated aqueous NH4Cl (5 mL) and extracted with diethyl ether (3 × 5 mL). The combined

organic extracts were washed with brine (5 mL), dried over anhydrous magnesium sulfate,

filtered and concentrated in vacuo. The crude product was purified by flash column

chromatography (silica gel; eluent 5% EtOAc/petrol) to afford 59.4 mg (29%) of the title

compound as yellow solid (d.r. 3:1, 139a:139) (data of major diastereoisomer as

described above).

(5S)-3-O-benzyl-5,6-dideoxy-1,2-O-isopropylidene-6-C-nitro-5-C-(3-nitrophenyl)-α-D-

idofuranose25

140

To a mixture of 3-nitrophenylboronic acid (104 mg, 0.62 mmol) and [RhCl(1,5-cod)]2 50 (7.64

mg, 5 mol%) under nitrogen were added a solution of α,β-unsaturated nitro alkene 135 (100

mg, 0.31 mmol) in 1,4-dioxane:H2O (10:1; 0.74 mL), followed by triethylamine (43 µL, 0.31

mmol). The reaction mixture was stirred for 2 h at room temperature, then the products were

isolated by evaporation of volatiles under reduced pressure and purified by flash column

chromatography (silica gel; eluent 10% EtOAc/petrol) to afford 79.1 mg (57%) of the title

compound as yellow oil (d.r. 2:1, 140:140a). Rf (30% EtOAc/petrol): 0.45. -33.5 (c 1.3,

CHCl3). IR max (thin film) 2986 (C-H stretch), 2929 (C-H stretch), 2872 (C-H stretch), 1551

(NO2 asym. stretch), 1528, 1376 (NO2 sym. stretch), 1348, 1070 (C-O stretch), 1023 (C-O

stretch) cm-1

. 1H NMR (400 MHz, CDCl3) δ 8.15 (1 H, ddd, J = 8, 2 and 1 Hz, Ar-H), 8.13 –

8.11 (1 H, m, Ar-H), 7.55 (1 H, dt, J = 8 and 1.5 Hz, Ar-H), 7.50 – 7.44 (1 H, m, Ar-H), 7.40 -

7.32 (3 H, m, Ar-H), 7.26 – 7.23 (2 H, m, Ar-H), 5.99 (1 H, d, J = 4 Hz, H-1), 5.09 (1 H, dd, J

= 13 and 4 Hz, H-6), 4.77 (1 H, dd, J = 13 and 11 Hz, H-6), 4.62 (1 H, d, J = 4 Hz, H-2), 4.54

(1 H, d, J = 11 Hz, CHxHyAr), 4.38 (1 H, dd, J = 9 and 3 Hz, H-4), 4.18 (1 H, d, J = 11 Hz,

CHxHyAr), 4.16 – 4.10 (1 H, m, H-5), 3.56 (1 H, d, J = 3 Hz, H-3), 1.52 (3 H, s, CH3), 1.33 (3

H, s, CH3) ppm. 13

C NMR (100 MHz, CDCl3) δ 148.40 (C, Ar-C-NO2), 138.83 (C, Ar-C),

136.24 (C, Ar-C), 134.4 (CH, Ar-C), 129.90 (CH, Ar-C), 128.65 (CH, Ar-C), 128.37 (CH, Ar-

156

C), 128.07 (CH, Ar-C), 123.17 (CH, Ar-C), 123.12 (CH, Ar-C), 112.03 (C, C-Me2), 105.11

(CH, C-1), 81.26 (CH, C-2), 81.23 (CH, C-3), 80.63 (CH, C-4), 77.99 (CH2, C-6), 72.04 (CH2,

OCH2Ar), 42.79 (CH, C-5), 26.73 (CH3, C(CH3)2), 26.02 (CH3, C(CH3)2) ppm. MS (ES+) m/z

[M+Na]+ 467.0, [2M+Na]

+ 911.0. Accurate Mass C22H24N2O8Na, [M+Na]

+ requires 467.1423,

measured 467.1425.

(5S)-3-O-benzyl-5,6-dideoxy-1,2-O-isopropylidene-6-C-nitro-5-C-(2-methoxyphenyl)-α-D-

idofuranose 141

HAYASHI-MIYAURA REACTION25

To a mixture of 2-methoxyphenylboronic acid (94.2 mg, 0.62 mmol) and [RhCl(1,5-cod)]2 50

(7.64 mg, 5 mol%) under nitrogen were added a solution of α,β-unsaturated nitro alkene 135

(100 mg, 0.31 mmol) in 1,4-dioxane:H2O (10:1; 0.74 mL), followed by triethylamine (43 µL,

0.31 mmol). The reaction mixture was stirred for 1 h at room temperature, then the products

were isolated by evaporation of volatiles under reduced pressure and purified by flash

column chromatography (silica gel; eluent 10% EtOAc/petrol) to afford 112 mg (84%) of the

title compound as yellow oil (d.r. 3:1, 141:141a). The purified product was crystallised from

hot ethanol to obtain yellow crystals. Rf (30% EtOAc/petrol): 0.50. -21.0 (c 1.1, CHCl3).

mp 121 - 123 °C. IR max (thin film) 2985 (C-H stretch), 2935 (C-H stretch), 2837 (C-H

stretch), 1548 (NO2 asym. stretch), 1495, 1375 (NO2 sym. stretch), 1245, 1071 (C-O stretch),

1021 (C-O stretch) cm-1

. 1H NMR (400 MHz, CDCl3) δ 7.36 - 7.19 (6 H, m, Ar-H), 7.12 (1 H,

dd, J = 7.5 and 2 Hz, Ar-H), 6.90 – 6.83 (2 H, m, Ar-H), 5.97 (1 H, d, J = 4 Hz, H-1), 5.07 –

5.00 (1 H, m, H-6), 4.93 – 4.88 (1 H, m, H-6), 4.82 (1 H, dd, J = 10 and 3 Hz, H-4), 4.54 (1 H,

d, J = 4 Hz, H-2), 4.39 (1 H, d, J = 11 Hz, CHxHyAr), 4.17 (1 H, td, J = 10 and 4.5 Hz, H-5),

4.08 (1 H, d, J = 11 Hz, CHxHyAr), 3.80 (3 H, s, OCH3) 3.56 (1 H, d, J = 3 Hz, H-3), 1.53 (3

H, s, CH3), 1.32 (3 H, s, CH3) ppm. 13

C NMR (100 MHz, CDCl3) δ 157.48 (C, C-OCH3),

137.11 (C, Ar-C), 131.21 (C, Ar-C), 129.18 (CH, Ar-C), 128.40 (CH, Ar-C), 127.86 (CH, Ar-

157

C), 127.68 (CH, Ar-C), 123.98 (CH, Ar-C), 120.85 (CH, Ar-C), 111.67 (C, C-Me2), 111.02

(CH, Ar-C), 105.03 (CH, C-1), 81.89 (CH, C-2), 81.80 (CH, C-3), 78.95 (CH, C-4), 72.12

(CH2, OCH2Ar), 55.21 (CH3, OCH3), 26.77 (CH3, C(CH3)2), 26.26 (CH3, C(CH3)2) ppm. MS

(ES+) m/z [M+Na]+ 452.0. Accurate Mass C23H28NO7, [M+H]

+ requires 430.1865, measured

430.1861.

(5R)-3-O-benzyl-5,6-dideoxy-1,2-O-isopropylidene-6-C-nitro-5-C-(2-methoxyphenyl)-α-D-

idofuranose 141a

HAYASHI-MIYAURA REACTION25

(procedure as described above)

Isolated yield: 7.30 mg (5%) as white solid. Rf (30% EtOAc/petrol): 0.40. -50.8 (c 1.0,

CHCl3). mp 110 - 115 °C. IR max (thin film) 2918 (C-H stretch), 2849 (C-H stretch), 1550

(NO2 stretch), 1494, 1374 (NO2 stretch), 1071 (C-O stretch), 1024 (C-O stretch) cm-1

. 1H

NMR (400 MHz, CDCl3) δ 7.44 – 7.31 (5 H, m, Ar-H), 7.24 (1 H, ddd, J = 8, 7 and 2 Hz, Ar-

H), 7.14 (1 H, dd, J = 8 and 2 Hz, Ar-H), 6.90 – 6.85 (2 H, m, Ar-H), 5.90 (1 H, d, J = 4 Hz, H-

1), 4.84 (1 H, dd, J = 13 and 9 Hz, H-6), 4.71 (1 H, d, J = 12 Hz, CHxHyAr), 4.67 (1 H, dd, J =

8.5 and 3 Hz, H-4), 4.63 (1 H, d, J = 4 Hz, H-2), 4.57 (1 H, dd, J = 13 and 4 Hz, H-6), 4.44 (1

H, d, J = 12 Hz, CHxHyAr), 4.37 (1 H, td, J = 9 and 4 Hz, H-5), 3.83 (3 H, s, OCH3), 3.81 (1 H,

d, J = 3 Hz, H-3), 1.48 (3 H, s, CH3), 1.32 (3 H, s, CH3) ppm. 13

C NMR (100 MHz, CDCl3) δ

157.40 (C-OCH3), 136.77 (Ar-C), 129.30 (Ar-C), 128.87 (Ar-C), 128.74 (Ar-C), 128.35 (Ar-C),

128.14 (Ar-C), 124.43 (Ar-C), 120.84 (Ar-C), 111.63 (C-Me2), 111.05 (Ar-C), 104.59 (C-1),

81.47 (C-2), 81.27 (C-3), 78.41 (C-4), 75.20 (C-6), 71.48 (OCH2Ar), 55.37 (OCH3), 38.71 (C-

5), 26.74 (CH3), 26.31 (CH3) ppm. MS (ES+) m/z [M+Na]+ 452.0. Accurate Mass

C23H28NO7, [M+H]+

requires 430.1865, measured 430.1861.

158

ORGANOLITHIUM REACTION

To a solution of 2-bromoanisole (0.12 mL, 0.93 mmol) in anhydrous THF (0.33 mL) was

added a 1.6 M solution of n-butyllithium in hexane (0.32 mL, 0.52 mmol) dropwise at -40 °C.

The reaction mixture was warmed to up to room temperature to obtain yellow solution of 2-

lithioanisole. A solution of α,β-unsaturated nitro alkene 135 (150 mg, 0.47 mmol) in THF (5

mL) was added to the reaction mixture at -78 °C and stirred at that temperature for 3 h. The

reaction mixture was then quenched with saturated aqueous NH4Cl (5 mL) and extracted

with diethyl ether (3 × 5 mL). The combined organic extracts were washed with brine (5 mL),

dried over anhydrous magnesium sulfate and concentrated in vacuo. The crude product was

purified by flash column chromatography (silica gel; eluent 10% EtOAc/petrol) to afford 63.8

mg (32%) of the title compound as yellow solid (d.r. 3:2, 141a:141) (data of major

diastereoisomer as described above).

(5S)-3-O-benzyl-5,6-dideoxy-1,2-O-isopropylidene-6-C-nitro-5-C-(3-thienyl)-α-D-

idofuranose25

142

To a mixture of 3-thienylboronic acid (79.3 mg, 0.62 mmol) and [RhCl(1,5-cod)]2 50 (7.64 mg,

5 mol%) under nitrogen, a solution of α,β-unsaturated nitro alkene 135 (100 mg, 0.31 mmol)

in 1,4-dioxane:H2O (10:1; 0.74 mL) was added, followed by triethylamine (43 µL, 0.31 mmol).

The reaction mixture was stirred for 3 h at room temperature, then the products were

isolated by evaporation of volatiles under reduced pressure and purified by flash column

chromatography (silica gel; eluent 10% EtOAc/petrol) to afford 75.9 mg (60%) of the title

compound as yellow oil (d.r. 6:1, 142:142a). Rf (30% EtOAc/petrol): 0.54. -31.7 (c 1.8,

CHCl3). IR max (thin film) 3032 (C-H stretch), 2987 (C-H stretch), 2933 (C-H stretch), 1550

(NO2 asym. stretch), 1375 (NO2 sym. stretch), 1070 (C-O stretch), 1023 (C-O stretch) cm-1

.

1H NMR (400 MHz, CDCl3) δ 7.39 – 7.25 (5 H, m, Ar-H), 7.30 (1 H, dd, J = 5 and 3 Hz, H-8),

7.09 (1 H, dd, J = 3 and 1 Hz, H-7), 6.99 (1 H, dd, J = 5 and 1.5 Hz, H-9), 5.96 (1 H, d, J = 4

159

Hz, H-1), 4.97 (1 H, dd, J = 13 and 4 Hz, H-6), 4.68 (1 H, dd, J = 13 and 10 Hz, H-6), 4.58 (1

H, d, J = 4 Hz, H-2), 4.52 (1 H, d, J = 11 Hz, CHxHyAr), 4.40 (1 H, dd, J = 10 and 3 Hz, H-4),

4.24 (1 H, d, J = 12 Hz, CHxHyAr), 4.23 - 4.17 (1 H, m, H-5), 3.63 (1 H, d, J = 3 Hz, H-3),

1.52 (3 H, s, CH3), 1.32 (3 H, s, CH3) ppm. 13

C NMR (100 MHz, CDCl3) δ 136.89 (C, Ar-C),

136.80 (C, Ar-C), 128.55 (CH, Ar-C), 128.05 (CH, Ar-C), 127.67 (CH, Ar-C), 126.47 (CH, C-

9), 126.42 (CH, C-8), 123.08 (CH, C-7), 111.79 (C, C-Me2), 105.11 (CH, C-1), 81.56 (CH, C-

2), 81.53 (CH, C-3), 80.81 (CH, C-4), 78.66 (CH2, C-6), 72.11 (CH2, OCH2Ar), 38.56 (CH, C-

5), 26.72 (CH3, C(CH3)2), 26.06 (CH3, C(CH3)2) ppm. MS (ES+) m/z [M+Na]+ 428.0, [2M+Na]

+

833.0. Accurate Mass C20H23NO6NaS, [M+Na]+

requires 428.1130, measured 428.1139.

(5S)-3-O-benzyl-5,6-dideoxy-1,2-O-isopropylidene-6-C-nitro-5-C-naphthyl-α-D-idofuranose25

143

To a mixture of 1-naphthylboronic acid (91.0 mg, 0.53 mmol) and [RhCl(1,5-cod)]2 50 (6.41

mg, 5 mol%) under nitrogen were added a solution of α,β-unsaturated nitro alkene 135 (85.0

mg, 0.26 mmol) in 1,4-dioxane:H2O (10:1; 0.37 mL), followed by triethylamine (36 µL, 0.26

mmol). The reaction mixture was stirred for 1 h at room temperature, then the products were

isolated by evaporation of volatiles under reduced pressure and purified by flash column

chromatography (silica gel; eluent 10% EtOAc/petrol). The elution gave the title compound

as yellow solid with an overall yield of 104 mg (89%) (d.r. 7:1, 143:143a). The purified

product was recrystallised from DCM/petrol to obtain yellow crystals for X-ray

crystallography. Rf (30% EtOAc/petrol): 0.42. -4.81 (c 1.0, CHCl3). mp 129 - 132 °C. IR

max (thin film) 2982 (C-H stretch), 2931 (C-H stretch), 2881 (C-H stretch), 1555 (NO2 asym.

stretch), 1382 (NO2 sym. stretch), 1077 (C-O stretch), 1024 (C-O stretch) cm-1

. 1H NMR (500

MHz, CDCl3) δ 8.18 (1 H, d, J = 8.5 Hz, Ar-H), 7.87 (1 H, d, J = 8 Hz, Ar-H), 7.81 (1 H, dd, J

= 6 and 3 Hz, Ar-H), 7.52 – 7.35 (4 H, m, Ar-H), 7.27 – 7.13 (3 H, m, Ar-H), 6.83 (2 H, d, J =

7.5 Hz, Ar-H), 6.03 (1 H, d, J = 4 Hz, H-1), 5.10 (1 H, dd, J = 12 and 4.5 Hz, H-6), 4.99 –

160

4.93 (1 H, m, H-5), 4.91 – 4.85 (1 H, m, H-6), 4.76 – 4.70 (1 H, m, H-4), 4.54 (1 H, d, J = 4

Hz, H-2), 4.17 (1 H, d, J = 11 Hz, CHxHyAr), 4.75 (1 H, d, J = 11 Hz, CHxHyAr), 3.57 (1 H, dd,

J = 2.5 and 1 Hz, H-3), 1.57 (3 H, s, CH3), 1.33 (3 H, s, CH3) ppm. 13

C NMR (125 MHz,

CDCl3) δ 136.48 (C, Ar-C), 133.99 (C, Ar-C), 133.38 (C, Ar-C), 131.55 (C, Ar-C), 128.82

(CH, Ar-C), 128.70 (CH, Ar-C), 128.48 (CH, Ar-C), 128.17 (CH, Ar-C), 127.75 (CH, Ar-C),

126.58 (CH, Ar-C), 125.95 (CH, Ar-C), 125.14 (CH, Ar-C), 124.14 (CH, Ar-C), 123.30 (CH,

Ar-C), 111.81 (C, C-Me2), 105.11 (CH, C-1), 81.91 (CH, C-4), 81.69 (CH, C-2), 81.24 (CH,

C-3), 79.07 (CH2, C-6), 71.83 (CH2, OCH2Ar), 36.74 (CH, C-5), 26.81 (CH3, C(CH3)2), 26.13

(CH3, C(CH3)2) ppm. MS (ES+) m/z [M+Na]+ 472.0. Accurate Mass C26H27NO6Na, [M+Na]

+

requires 472.1735, measured 472.1731.

(5R)-3-O-benzyl-5,6-dideoxy-1,2-O-isopropylidene-6-C-nitro-5-C-naphthyl-α-D-idofuranose

143a

ORGANOLITHIUM REACTION

To a solution of 1-bromonaphthalene (87 μL, 0.62 mmol) in THF (0.22 mL) was added a 1.6

M solution of n-butyllithium in hexane (0.42 mL, 0.68 mmol) dropwise at -40 °C. The reaction

mixture was allowed to warm up to room temperature to obtain the yellow solution of 1-

lithionaphthalene. At -78 °C, a solution of α,β-unsaturated nitro alkene 135 (0.10 g, 0.31

mmol) in THF (5 mL) was added to the reaction mixture and the resulting mixture was stirred

for 4 h at -78 °C. Upon completion, it was quenched with saturated aqueous NH4Cl (5 mL)

and extracted with diethyl ether (3 × 5 mL). The combined organic extracts were washed

with brine (5 mL), dried over anhydrous magnesium sulfate, filtered and concentrated in

vacuo. The crude product was purified by flash column chromatography (silica gel; eluent

30% EtOAc/petrol) and the elution gave the title compound as white crystalline solid with an

overall yield of 105 mg (76%) (d.r. 5:1, 143a:143). Rf (30% EtOAc/petrol): 0.55. -61.1 (c

1.0, CHCl3). mp 60 - 65 °C. IR max (thin film) 2987 (C-H stretch), 2928 (C-H stretch), 2864

161

(C-H stretch), 2361 (C-H stretch), 2337 (C-H stretch), 1551 (NO2 asym. stretch), 1375 (NO2

sym. stretch), 1073 (C-O stretch), 1023 (C-O stretch) cm-1

. 1H NMR (400 MHz, CDCl3) δ 8.21

(1 H, d, J = 8.5 Hz, Ar-H), 7.87 (1 H, dd, J = 8 and 1.5 Hz, Ar-H), 7.78 (1 H, dd, J = 6 and 4

Hz, Ar-H), 7.58 (1 H, ddd, J = 8.5, 7 and 1.5 Hz, Ar-H), 7.54 – 7.50 (1 H, m, Ar-H), 7.50 –

7.41 (6 H, m, Ar-H), 7.35 (1 H, d, J = 2 Hz, Ar-H), 5.95 (1 H, d, J = 4 Hz, H-1), 5.13 – 5.05 (2

H, m, H-5, H-6), 5.01 – 4.94 (1 H, m, H-6), 4.72 (1 H, d, J = 12 Hz, CHxHyAr), 4.62 (1 H, d, J

= 4 Hz, H-2), 4.61 – 4.58 (1 H, m, H-4), 4.46 (1 H, d, J = 12 Hz, CHxHyAr), 3.76 (1 H, d, J = 3

Hz, H-3), 1.43 (3 H, s, CH3), 1.29 (3 H, s, CH3) ppm. 13

C NMR (100 MHz, CDCl3) δ 136.65

(C, Ar-C), 134.07 (C, Ar-C), 132.39 (C, Ar-C), 131.84 (C, Ar-C), 129.04 (CH, Ar-C), 128.85

(CH, Ar-C), 128.46 (CH, Ar-C), 128.11 (CH, Ar-C), 127.77 (CH, Ar-C), 126.74 (CH, Ar-C),

125.85 (CH, Ar-C), 125.25 (CH, Ar-C), 123.92 (CH, Ar-C), 122.52 (CH, Ar-C), 111.74 (C, C-

Me2), 104.62 (CH, C-1), 81.82 (CH, C-3), 81.23 (CH, C-2), 80.00 (CH, C-4), 75.85 (CH2, C-

6), 71.73 (CH2, OCH2Ar), 37.67 (CH, C-5), 26.68 (CH3, C(CH3)2), 26.10 (CH3, C(CH3)2) ppm.

MS (ES+) m/z [M+H]+ 450.0, [M+Na]

+ 472.0. Accurate Mass C26H31N2O6, [M+NH4]

+ requires

467.2188, measured 467.2177.

(5S)-3-O-benzyl-5,6-dideoxy-1,2-O-isopropylidene-6-C-nitro-5-C-(2-naphthyl)-α-D-

idofuranose25

144

To a mixture of 2-naphthylboronic acid (107 mg, 0.62 mmol) and [RhCl(1,5-cod)]2 50 (7.64

mg, 5 mol%) under nitrogen were added a solution of α,β-unsaturated nitro alkene 135 (0.10

g, 0.31 mmol) in 1,4-dioxane:H2O (10:1; 0.74 mL), followed by triethylamine (43 µL, 0.31

mmol). The reaction mixture was stirred for 1 h at room temperature, then the products were

isolated by evaporation of volatiles under reduced pressure and purified by flash column

chromatography (silica gel; eluent 10% EtOAc/petrol) to afford 111 mg (80%) of the title

compound as white solid (d.r. 10:1, 144:144a). The purified product was recystallised from

162

DCM/petrol to obtain white crystals. Rf (30% EtOAc/petrol): 0.49. -23.0 (c 1.5, CHCl3).

mp 140 - 141 °C. IR max (thin film) 3057 (C-H stretch), 2986 (C-H stretch), 2929 (C-H

stretch), 1545 (NO2 asym. stretch), 1375 (NO2 sym. stretch), 1070 (C-O stretch), 1022 (C-O

stretch) cm-1

. 1H NMR (500 MHz, CDCl3) δ 7.86 – 7.79 (2 H, m, Ar-H), 7.75 (1 H, dd, J = 6

and 3 Hz, Ar-H), 7.68 (1 H, s, Ar-H), 7.50 (2 H, dd, J = 6 and 3 Hz, Ar-H), 7.37 (1 H, d, J = 9

Hz, Ar-H), 7.34 – 7.30 (3 H, m, Ar-H), 7.26 – 7.22 (2 H, m, Ar-H), 6.01 (1 H, d, J = 4 Hz, H-1),

5.10 (1 H, dd, J = 13 and 4 Hz, H-6), 4.86 (1 H, dd, J = 13 and 10.5 Hz, H-6), 4.58 (1 H, d, J

= 4 Hz, H-2), 4.53 (1 H, dd, J = 10 and 3 Hz, H-4), 4.46 (1 H, d, J = 11 Hz, CHxHyAr), 4.22 (1

H, td, J = 10 and 4 Hz, H-5), 4.12 (1 H, d, J = 11 Hz, CHxHyAr), 3.55 (1 H, d, J = 3, H-3), 1.54

(3 H, s, CH3), 1.33 (3 H, s, CH3) ppm. 13

C NMR (125 MHz, CDCl3) δ 136.83 (C, Ar-C), 133.91

(C, Ar-C), 133.29 (C, Ar-C), 132.95 (C, Ar-C), 128.75 (CH, Ar-C), 128.49 (CH, Ar-C), 128.04

(CH, Ar-C), 127.85 (CH, Ar-C), 127.79 (CH, Ar-C), 127.66 (CH, Ar-C), 127.55 (CH, Ar-C),

126.36 (CH, Ar-C), 126.24 (CH, Ar-C), 125.50 (Ar-C), 111.80 (C, C-Me2), 105.17 (CH, C-1),

81.58 (CH, C-2), 81.54 (CH, C-3), 81.21 (CH, C-4), 78.74 (CH2, C-6), 72.14 (CH2, OCH2Ar),

43.26 (CH, C-5), 26.78 (CH3, C(CH3)2), 26.08 (CH3, C(CH3)2) ppm. MS (ES+) m/z [M+Na]+

472.0. Accurate Mass C26H27NO6Na, [M+Na]+

requires 472.1719, measured 472.1731.

3-O-benzyl-5,6-dideoxy-1,2-O-isopropylidene-6-C-nitro-5-C-vinyl-β-L-idofuranose52

145

To a solution of α,β-unsaturated nitro alkene 135 (156 mg, 0.48 mmol) in anhydrous THF (10

mL) was added a 1.0 M solution of vinylmagnesium bromide in THF (0.48 mL, 0.48 mmol) at

-78 °C. The reaction mixture was allowed to slowly warm to room temperature over 4 hours.

The reaction mixture was then quenched, at -78 °C, by the addition of saturated aqueous

NH4Cl (10 mL) and extracted with diethyl ether (3 × 10 mL). The combined organic extracts

were washed with brine (10 mL), dried over anhydrous magnesium sulfate, filtered and

concentrated in vacuo. The crude product was purified by flash column chromatography

(silica gel; eluent 10% EtOAc/petrol) to afford 53.2 mg (36%) of the title compound as yellow

oil as a single diastereoisomer. The purified product was recystallised from hot ethanol to

163

obtain white cystals. Rf (30% EtOAc/petrol): 0.33. -60.0 (c 0.9, CHCl3) lit.

52

-71.4

(c 1.0, CHCl3). mp 100 - 101 °C (lit.52

mp 103°C). IR max (thin film) 2985 (C-H stretch), 2932

(C-H stretch), 1548 (NO2 asym. stretch), 1373 (NO2 sym. stretch), 1211, 1070 (C-O stretch),

1017 (C-O stretch) cm-1

. 1H NMR (400 MHz, CDCl3) δ 7.44 – 7.31 (5 H, m, Ar-H), 5.93 (1 H,

d, J = 4 Hz, H-1), 5.67 (1 H, ddd, J = 17, 10 and 8 Hz, H-7), 5.26 (1 H, dt, J = 17 and 1 Hz,

H-8), 5.21 (1 H, dt, J = 10 and 1 Hz, H-8), 4.71 (1 H, d, J = 12 Hz, CHxHyAr), 4.64 (1 H, d, J =

4 Hz, H-2), 4.49 – 4.40 (3 H, m, 2 × H-6, CHxHyAr), 4.18 (1 H, dd, J = 8 and 3 Hz, H-4), 3.90

(1 H, d, J = 3 Hz, H-3), 3.49 (1 H, quin., J = 8 Hz, H-5), 1.50 (3 H, s, CH3), 1.33 (3 H, s, CH3)

ppm. 13

C NMR (100 MHz, CDCl3) δ 136.43 (C, Ar-C), 133.17 (CH, C-7), 128.72 (CH, Ar-C),

128.44 (CH, Ar-C), 128.24 (CH, Ar-C), 120.03 (CH2, C-8), 111.73 (C, C-Me2), 104.56 (CH,

C-1), 81.37 (CH, C-2), 81.18 (CH, C-3), 79.61 (CH, C-4), 75.90 (CH2, C-6), 71.61 (CH2,

OCH2Ar), 42.16 (CH, C-5), 26.64 (CH3, C(CH3)2), 26.11 (CH3, C(CH3)2) ppm. MS (ES+) m/z

[M+Na]+ 372.0. Accurate Mass C18H23NO6Na, [M+Na]

+ requires 372.1404, measured

372.1418.

3-O-benzyl-5,6-dideoxy-1,2-O-isopropylidene-6-C-nitro-5-C-ethyl-β-L-idofuranose 146

To a solution of nitro compound 145 (14.2 mg, 0.04 mmol) in MeOH (0.50 mL) was added a

slurry suspension of 10% Pd/C (10 mol%) in toluene (0.50 mL). H2 gas was passed through

the reaction mixture and stirred for 2 h at room temperature. The crude product was filtered

through Celite, washed with MeOH (5 mL) and concentrated in vacuo to afford 14.3 mg

(100%) of the title compound as white oil as a single diastereoisomer. -99.4 (c 1.3,

CHCl3). IR max (thin film) 3033 (C-H stretch), 2968 (C-H stretch), 2936 (C-H stretch), 2880

(C-H stretch), 1550 (NO2 asym. stretch), 1375 (NO2 sym. stretch), 1215, 1164, 1073 (C-O

stretch), 1026 (C-O stretch) cm-1

. 1H NMR (400 MHz, CDCl3) δ 7.57 – 7.15 (5 H, m, Ar-H),

5.92 (1 H, d, J = 4 Hz, H-1), 4.70 (1 H, d, J = 12 Hz, CHxHyAr), 4.64 (1 H, d, J = 4 Hz, H-2),

4.49 – 4.40 (2 H, m, H-6, CHxHyAr), 4.25 (1 H, dd, J = 13 and 7 Hz, H-6), 4.17 (1 H, dd, J = 8

164

and 3 Hz, H-4), 3.94 (1 H, d, J = 3 Hz, H-3), 2.74 – 2.65 (1 H, m, H-5), 1.68 – 1.55 (1 H, m,

H-7), 1.53 – 1.42 (1 H, m, H-7), 1.50 (3 H, s, CH3), 1.34 (3 H, s, CH3), 0.97 (3 H, t, J = 7 Hz,

3 × H-8) ppm. 13

C NMR (100 MHz, CDCl3) δ 136.63 (C, Ar-C), 128.65 (CH, Ar-C), 128.32

(CH, Ar-C), 128.11 (CH, Ar-C), 111.59 (C, C-Me2), 104.43 (CH, C-1), 81.49 (CH, C-2), 81.25

(CH, C-3), 79.51 (CH, C-4), 75.75 (CH2, C-6), 71.53 (CH2, OCH2Ar), 38.21 (CH, C-5), 26.67

(CH3, C(CH3)2), 26.15 (CH3, C(CH3)2), 22.02 (CH2, C-7), 10.72 (CH3, C-8) ppm. MS (ES+)

m/z [M+Na]+ 374.0, [2M+Na]

+ 725.0. Accurate Mass C18H25NO6Na, [M+Na]

+ requires

374.1567, measured 374.1575.

3-O-benzyl-5,6-dideoxy-1,2-O-isopropylidene-6-C-nitro-5-C-ethyl-α-D-idofuranose 146a

To a solution of α,β-unsaturated nitro alkene 135 (220 mg, 0.68 mmol) in anhydrous THF (10

mL) was added a 1.0 M solution of ethylmagnesium bromide in THF (0.68 mL, 0.68 mmol) at

-78 °C. The reaction mixture was stirred at -78 °C for 4 h, then quenched with saturated

aqueous NH4Cl (5 mL) and extracted with diethyl ether (3 × 5 mL). The combined organic

extracts were washed with brine (5 mL), dried over anhydrous magnesium sulfate, filtered

and concentrated in vacuo. The crude product was purified by flash column chromatography

(silica gel; eluent 5% → 10% EtOAc/petrol) to afford an overall yield of 101 mg (42%) of 1:1

diastereomeric mixture of the title compound 146a and nitro ethyl 146 as colourless oil (d.r.

1:1, 146:146a). Rf (20% EtOAc/petrol): 0.35. 1H NMR (400 MHz, CDCl3) δ 7.42 – 7.30 (5 H,

m, Ar-H), 5.90 (1 H, d, J = 4 Hz, H-1), 4.76 – 4.72 (1 H, m, H-6), 4.70 (1 H, d, J = 12 Hz,

CHxHyAr), 4.65 (1 H, d, J = 4 Hz, H-2), 4.53 (1 H, dd, J = 13 and 7 Hz, H-6), 4.49 – 4.42 (1

H, m, CHxHyAr), 4.12 (1 H, dd, J = 9 and 3 Hz, H-4), 3.89 (1 H, d, J = 3 Hz, H-3), 2.75 – 2.60

(1 H, m, H-5), 1.50 (3 H, s, CH3), 1.34 (3 H, s, CH3), 1.32 – 1.25 (2 H, m, 2 × H-7), 0.97 –

0.92 (3 H, m, 3 × H-8) ppm. 13

C NMR (100 MHz, CDCl3) δ 136.85 (C, Ar-C), 128.56 (CH, Ar-

C), 128.20 (CH, Ar-C), 128.00 (CH, Ar-C), 111.72 (C, C-Me2), 104.50 (CH, C-1), 81.65 (CH,

C-2), 81.28 (CH, C-3), 79.61 (CH, C-4), 75.76 (CH2, C-6), 71.75 (CH2, OCH2Ar), 37.53 (CH,

C-5), 26.71 (CH3, C(CH3)2), 26.25 (CH3, C(CH3)2), 21.28 (CH2, C-7), 10.39 (CH3, C-8) ppm.

165

(3aR,5R,6S,6aR)-6-(benzyloxy)-5-(1-butoxy-2-nitroethyl)-2,2-dimethyltetrahydrofuro[2,3-

d][1,3]dioxole 147

To a solution of 4-bromoanisole (94 μL, 0.75 mmol) in anhydrous THF (0.20 mL) was added

a 1.6 M solution of n-butyllithium in hexane (0.47 mL, 0.75 mmol) dropwise at -40 °C. The

reaction mixture was warmed to up to room temperature to obtain yellow solution of 2-

lithioanisole. A solution of α,β-unsaturated nitro alkene 135 (200 mg, 0.62 mmol) in THF (5

mL) was added to the reaction mixture at -78 °C and stirred at that temperature for 4 h. The

reaction mixture was then quenched with saturated aqueous NH4Cl (5 mL) and extracted

with diethyl ether (3 × 5 mL). The combined organic extracts were washed with brine (5 mL),

dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The crude

product (50% conversion) was purified by flash column chromatography (silica gel; eluent

5% EtOAc/petrol) and the elution gave the title compound as yellow oil with an overall yield

of 54.6 mg (22%) (d.r. 13:1). Rf (30% EtOAc/petrol): 0.64. -52.2 (c 1.6, CHCl3). IR max

(thin film) 2959 (C-H stretch), 2934 (C-H stretch), 2872 (C-H stretch), 1553 (NO2 asym.

stretch), 1375 (NO2 sym. stretch), 1213, 1164, 1072 (C-O stretch), 1018 (C-O stretch) cm-1

.

1H NMR (400 MHz, CDCl3) δ 7.41 - 7.32 (5 H, m, Ar-H), 5.97 (1 H, d, J = 4 Hz, H-1), 4.71 (1

H, d, J = 12 Hz, CHxHyAr), 4.63 (1 H, d, J = 4 Hz, H-2), 4.51 – 4.40 ( 3 H, m, 2 × H-6,

CHxHyAr), 4.31 – 4.26 (2 H, m, H-4, H-5), 3.93 (1 H, d, J = 4 Hz, H-3), 3.74 (1 H, dt, J = 9

and 6 Hz, H-7), 3.53 (1 H, dt, J = 9 and 7 Hz, H-7), 1.50 (3 H, s, CH3), 1.54 – 1.46 (2 H, m, 2

× H-8), 1.34 (3 H, s, CH3), 1.33 – 1.25 (2 H, m, 2 × H-9), 0.89 (3 H, t, J = 7 Hz, H-10) ppm.

13C NMR (100 MHz, CDCl3) δ 136.49 (C, Ar-C), 128.69 (CH, Ar-C), 128.40 (CH, Ar-C),

128.18 (CH, Ar-C), 112.03 (C, C-Me2), 105.02 (CH, C-1), 81.77 (CH, C-2), 81.38 (CH, C-3),

79.70 (CH, C-4), 76.28 (CH, C-5), 75.44 (CH2, C-6), 72.06 (CH2, C-7), 71.74 (CH2, OCH2Ar),

31.99 (CH2, C-8), 26.76 (CH3, C(CH3)2), 26.26 (CH3) , C(CH3)2, 19.04 (CH2, C-9), 13.08 (CH3,

C-10) ppm. MS (ES+) m/z [M+Na]+ 418.0. Accurate Mass C20H29NO7Na, [M+Na]

+ requires

418.1825, measured 418.1837.

166

2-((E)-2-((3aR,5R,6S,6aR)-6-(benzyloxy)-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-5-

yl)vinylsulfonyl)pyridine54

148

To a stirred suspension of potassium carbonate (1.36 g, 9.88 mmol) in anhydrous DCM (33

mL) under nitrogen, was added a solution of diethyl (2-pyridylsulfonyl)methyl phosphonate

152 (2.70 g, 9.20 mmol) in DCM (9 mL) at room temperature. The resulting suspension was

allowed to stir for 5 min, then was added a solution of α,β-unsatured aldehyde 19 (2.75 g,

9.88 mmol) in DCM (10 mL). The reaction mixture was stirred at room temperature for 20 h,

then quenched with saturated aqueous NH4Cl (20 mL) and extracted with DCM (3 × 20 mL).

The combined organic extracts were dried over anhydrous magnesium sulfate, filtered and

concentrated in vacuo. The crude product was purified by flash column chromatography

(silica gel; eluent 40% EtOAc/petrol) to afford 2.92 g (71%) of the title compound as yellow

oil as trans-isomer. Rf (50% EtOAc/petrol): 0.40. -1.47 (c 1.2, CHCl3). IR max (thin film)

3062 (C-H stretch), 2986 (C-H stretch), 2936 (C-H stretch), 2868 (C-H stretch), 1635 (C=C

stretch), 1349 (S=O asymmetric stretch), 1161 (S=O symmetric stretch), 1074 (C-O stretch),

1020 (C-O stretch) cm-1

. 1H NMR (400 MHz, CDCl3) δ 8.71 – 8.63 (1 H, m, H-11), 8.08 (1 H,

d, J = 8 Hz, H-8), 7.90 (1 H, td, J = 8 and 2 Hz, H-9), 7.48 (1 H, ddd, J = 8, 5 and 1 Hz, H-

10), 7.37 – 7.26 (5 H, m, Ar-H), 7.14 ( 1 H, dd, J = 15 and 4 Hz, H-5), 6.94 (1 H, dd, J = 15

and 2 Hz, H-6), 5.98 (1 H, d, J = 4 Hz, H-1), 4.91 (1 H, td, J = 3.5 and 2 Hz, H-4), 4.64 (1 H,

d, J = 4 Hz, H-2), 4.60 (1 H, d, J = 12 Hz, CHxHyAr), 4.51 (1 H, d, J = 12 Hz, CHxHyAr), 4.05

(1 H, d, J = 3 Hz, H-3), 1.47 (3 H, s, CH3), 1.32 (3 H, s, CH3) ppm. 13

C NMR (100 MHz,

CDCl3) δ 158.04 (C, C-7), 150.36 (CH, C-11), 142.55 (CH, C-5), 138.02 (CH, C-9), 136.83

(C, Ar-C), 129.89 (CH, C-6), 128.57 (CH, Ar-C), 128.07 (CH, Ar-C), 127.77 (CH, Ar-C),

127.07 (CH, C-10), 122.08 (CH, C-8), 112.20 (C, C-Me2), 104.93 (CH, C-1), 82.71 (CH, C-2),

82.29 (CH, C-3), 78.88 (CH, C-4), 72.27 (CH2, OCH2Ar), 26.82 (CH3, C(CH3)2), 26.18 (CH3,

C(CH3)2) ppm. MS (ES+) m/z [M+H]+

418.0, [M+Na]+ 440.0. Accurate Mass C21H24NO6SNa,

[M+Na]+

requires 418.1318, measured 418.1319.

167

Diethyl 1-chloromethylphosphonate55

150

To a solution of chloromethylphosphonic acid dichloride 149 (3.04 g, 1.85 mL, 18.1 mmol) in

THF (6 mL) was added a solution of triethylamine (5.56 mL, 39.9 mmol) in THF (6 mL) under

vigorous stirring. The reaction mixture was cooled to 0 °C in an ice-bath. Ethanol (2.33 mL,

39.9 mmol) was added dropwise at such a rate as to maintain the temperature below 30 °C.

The resulting suspension was stirred at room temperature for 2 h. The reaction mixture was

filtered and rinsed with THF (2 × 5 mL). The combined filtrates were concentrated under

reduced pressure. The residue was taken up in diethyl ether (10 mL) and the precipitated

triethylamine hydrochloride salt was filtered off and rinsed. The filtrate was concentrated in

vacuo to afford 3.71 g (100% crude) of the title compound as a brown liquid. IR max (thin

film) 2985 (C-H stretch), 2940 (C-H stretch), 1259, 1015 (C-O stretch) cm-1

. 1H NMR (400

MHz, CDCl3) δ 4.26 – 4.17 (4 H, m, 2 × OCH2CH3), 3.54 (2 H, d, J = 10.5 Hz, CH2Cl), 1.36 (6

H, t, J = 7 Hz, 2 × OCH2CH3) ppm. 13

C NMR (100 MHz, CDCl3) δ 63.41 (CH2, OCH2CH3),

63.34 (CH2, OCH2CH3), 33.32 (CH2, d, JCP = 160 Hz, H2C-Cl), 16.39 (CH3, OCH2CH3), 16.33

(CH3, OCH2CH3) ppm. 31

P NMR (162 MHz, CDCl3) δ 18.73 (m) ppm. 31

P NMR [1H] (162

MHz, CDCl3) δ 18.73 (s) ppm. MS (ES+) m/z [M+H]+

187.0, [M+Na]+ 209.0, [2M+Na]

+ 395.0.

Accurate Mass C5H13O3P35

Cl, [M+H]+

requires 187.0289, measured 187.0286.

Diethyl (pyridin-2-ylthio)methylphosphonate56

151

Sodium hydride (60% dispersion in mineral oil, 800 mg, 33.3 mmol) was washed with

petroleum ether and the suspended in dried DMF (100 mL) under nitrogen. 2-

mercaptopyridine (2.18 g, 19.6 mmol) was added slowly at 0 °C and the resulting solution

was stirred at room temperature for an hour. The crude phosphonate 150 (3.66 g, 19.6

mmol) was added at 0 °C and left to stir at 0 °C for an hour. The reaction mixture was

allowed to warm up to room temperature and stirred for 18 h. The residue was partitioned

168

with EtOAc:H2O (100 mL) and the organic layer was washed with saturated aqueous

NaHCO3 (50 mL), water (2 × 50 mL) and brine (50 mL). The organic extracts were dried over

anhydrous magnesium sulfate, filtered and concentrated in vacuo. The crude product was

purified by flash column chromatography (silica gel; eluent 100% EtOAc) to afford 2.41 g

(47%) of the title compound as yellow oil. Rf (100% EtOAc): 0.28. IR max (thin film) 2980 (C-

H stretch), 2909 (C-H stretch), 1577 (aromatic C=C stretch), 1454 (aromatic C=C stretch),

1250 (C-N stretch), 1017 (C-O stretch) cm-1

. 1H NMR (500 MHz, CDCl3) δ 8.36 (1 H, d, J = 5

Hz, H-1), 7.43 (1 H, td, J = 8 and 1.5 Hz, H-3), 7.23 – 7.14 (1 H, m, H-4), 6.97 – 6.92 (1 H,

m, H-2), 4.07 (4 H, td, J = 7 and 2.5 Hz, 2 × OCH2CH3), 3.60 (2 H, d, J = 13.5 Hz, 2 × H-6),

1.21 (6 H, t, J = 7 Hz, 2 × OCH2CH3) ppm. 13

C NMR (125 MHz, CDCl3) δ 156.33 (C, d, JCN =

4.5 Hz, C-5), 149.22 (CH, C-1), 136.13 (CH, C-3), 122.23 (CH, C-4), 119.94 (CH, C-2),

62.65 (CH2, OCH2CH3), 62.60 (CH2, OCH2CH3), 22.55 (CH2, d, JCP = 150 Hz, C-6), 16.33

(CH3, OCH2CH3), 16.28 (CH3, OCH2CH3) ppm. MS (ES+) m/z [M+H]

+ 262.0, [M+Na]

+ 284.0.

Accurate Mass C10H17NO3SP, [M+H]+

requires 262.0662, measured 262.0662.

Diethyl (pyridin-2-ylsulfonyl)methylphosphonate56

152

To a solution of thioether 151 (2.41 g, 9.23 mmol) in DCM (46 mL) was added dropwise m-

CPBA (75% reagent, 5.10 g, 29.54 mmol) in CHCl3:DCM (1:1, 74 mL) at 0 °C. After 2 h, the

reaction mixture was allowed to warm up to room temperature and stirred for 18 h. The

reaction mixture was quenched with saturated NaHCO3 solution (50 mL). Starch-iodide

paper was used to test for any peroxide and if any, the reaction mixture was further

quenched with 5% Na2S2O3. The organic layer was separated and the aqueous layer was

extracted with DCM (50 mL). The combined organic extracts were washed with NaHCO3

solution (50 mL), then brine (50 mL), dried over anhydrous magnesium sulfate and filtered.

The filtrate was concentrated in vacuo to afford 2.70 g (100% crude) of the title compound as

yellow oil. Rf (100% EtOAc): 0.17. 1H NMR (500 MHz, CDCl3) δ 8.75 (1 H, d, J = 4 Hz, H-1),

8.13 (1 H, dd, J = 8 and 1 Hz, H-3), 7.99 (1 H, td, J = 8 and 2 Hz, H-4), 7.62 – 7.53 (1 H, m,

169

H-2), 4.20 – 4.08 (6 H, m, 2 × OCH2CH3, 2 × H-6), 1.29 (6 H, t, J = 7 Hz, 2 × OCH2CH3)

ppm. 13

C NMR (125 MHz, CDCl3) δ 157.41 (C, C-5), 150.02 (CH, C-1), 138.12 (CH, C-3),

127.55 (CH, C-2), 121.99 (CH, C-4), 63.41 (CH2, OCH2CH3), 63.36 (CH2, OCH2CH3), 48.73

(CH2, d, JCP = 138 Hz, C-6), 16.22 (CH3, OCH2CH3), 16.17 (CH3, OCH2CH3) ppm. 31

P NMR

(162 MHz, CDCl3) δ 11.26 (m) ppm. 31

P NMR [1H] (162 MHz, CDCl3) δ 11.26 (s) ppm. MS

(ES+) m/z [M+Na]+ 316.0. Accurate Mass C10H16NO5SPNa, [M+Na]

+ requires 316.0372,

measured 316.0380.

2-((Z)-2-((3aR,6R,6aR)-6-(benzyloxy)-2,2-dimethyldihydrofuro[2,3-d][1,3]dioxol-5(3aH)-

ylidene)ethylsulfonyl)pyridine25

156

To a mixture of phenylboronic acid (175 mg, 1.44 mmol) and commercially available

[RhCl(1,5-cod)]2 50 (16.4 mg, 5 mol%) under nitrogen were added a solution of α,β-

unsaturated pyridylsulfone 148 (300 mg, 0.72 mmol) in 1,4-dioxane:H2O (10:1; 1.65 mL),

followed by triethylamine (0.10 mL, 0.72 mmol). The reaction mixture was heated at 100 °C

for 24 h, then the products were isolated by evaporation of volatiles under reduced pressure

and purified by flash column chromatography (silica gel; eluent 30% EtOAc/petrol) to afford

an overall yield of 124 mg (41%) of the title compound as yellow oil as Z-isomer. Rf (50%

EtOAc/petrol): 0.43. -43.6 (c 1.2, CHCl3). IR max (thin film) 2988 (C-H stretch), 2936 (C-

H stretch), 1694 (C=C stretch), 1314 (S=O asymmetric stretch), 1229 (C-O stretch), 1161

(S=O asymmetric stretch), 1108 (C-O stretch), 1073 (C-O stretch), 976 (=C-H bend) cm-1

. 1H

NMR (400 MHz, CDCl3) δ 8.76 – 8.73 (1 H, m, H-11), 8.06 (1 H, dt, J = 8 and 1 Hz, H-8),

7.86 (1 H, td, J = 8 and 2 Hz, H-9), 7.51 (1 H, ddd, J = 8, 5 and 1 Hz, H-10), 7.39 – 7.26 (5

H, m, Ar-H), 5.98 (1 H, d, J = 3 Hz, H-1), 4.69 (1 H, t, J = 8 Hz, H-5), 4.60 (1 H, d, J = 12 Hz,

CHxHyAr), 4.52 (1 H, d, J = 3 Hz, H-2), 4.42 (1 H, d, J = 12 Hz, CHxHyAr), 4.36 (1 H, dd, J =

14 and 8 Hz, H-6), 4.24 (1 H, s, H-3), 4.17 (1 H, dd, J = 14 and 7 Hz, H-6), 1.34 (3 H, s,

170

CH3), 1.32 (3 H, s, CH3) ppm. 13

C NMR (100 MHz, CDCl3) δ 158.14 (C, C-7), 157.07 (C, C-

4), 150.16 (CH, C-11), 137.83 (CH, C-9), 136.76 (C, Ar-C), 128.51 (CH, Ar-C), 128.01 (CH,

Ar-C), 127.87 (CH, Ar-C), 127.21 (CH, C-10), 122.66 (CH, C-8), 114.28 (C, C-Me2), 107.19

(CH, C-1), 89.62 (CH, C-5), 82.76 (CH, C-2), 79.94 (CH, C-3), 70.27 (CH2, OCH2Ar), 50.12

(CH2, C-6), 27.75 (CH3, C(CH3)2), 27.02 (CH3, C(CH3)2) ppm. MS (ES+) m/z [M+H]+

418.0,

[M+NH4]+

435.0, [M+Na]+

440.0. Accurate Mass C21H23NO6SNa, [M+Na]+

requires 440.1142,

measured 440.1139.

171

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176

7 APPENDIX

Crystal data and structure refinement for 72 (s3411m)

Empirical formula C16 H18 O5

Formula weight 290.30

Temperature 100(2) K

Wavelength 0.71073 A

Crystal system, space group Orthorhombic, P2(1)2(1)2(1)

Unit cell dimensions a = 5.8958(11) Å α = 90°

b = 9.9284(19) Å β = 90°

c = 24.493(5) Å γ = 90°

Volume 1433.7(5) Å3

Z, Calculated density 4, 1.345 Mg/m3

Absorption coefficient 0.100 mm-1

F(000) 616

Crystal size 0.60 × 0.50 × 0.30 mm

Theta range for data collection 2.21 to 26.42°

Limiting indices -4<=h<=7, -12<=k<=12, -28<=l<=30

Reflections collected / unique 8095 / 1734 [R(int) = 0.0583]

Completeness to theta = 26.42 99.5%

Absorption correction None

Refinement method Full-matrix least-squares on F2

Data / restraints / parameters 1734 / 0 / 192

Goodness-of-fit on F2

1.127

Final R indices [I>2sigma(I)] R1 = 0.0330, wR2 = 0.0612

R indices (all data) R1 = 0.0399, wR2 = 0.0627

Largest diff. peak and hole 0.182 and -0.193 e.A-3

177

Atomic coordinates [× 104] and equivalent isotropic displacement parameters [Å

2 × 10

3]

U(eq) is defined as one third of the trace of the orthogonalized Uij tensor.

_______________________________________________________________

x y z U(eq)

________________________________________________________________

O(1) -732(2) 442(1) 8764(1) 20(1)

O(2) 1160(2) 2792(1) 9468(1) 20(1)

O(3) 1082(2) 2486(2) 10351(1) 25(1)

O(4) -1890(3) 1281(2) 7924(1) 30(1)

O(5) 280(3) 3127(2) 8042(1) 29(1)

C(1) -1875(3) 1491(2) 8492(1) 21(1)

C(2) -486(3) 2784(2) 8572(1) 21(1)

C(3) 1533(3) 2344(2) 8912(1) 18(1)

C(4) 1600(3) 834(2) 8828(1) 17(1)

C(5) 2665(3) 87(2) 9306(1) 17(1)

C(6) 1341(3) 485(2) 9817(1) 20(1)

C(7) 1222(3) 1968(2) 9905(1) 19(1)

C(8) -1257(4) 2516(2) 7664(1) 28(1)

C(9) -3296(4) 3400(3) 7570(1) 39(1)

C(10) 32(4) 2203(3) 7147(1) 42(1)

C(11) 2925(3) -1420(2) 9223(1) 18(1)

C(12) 4865(3) -1896(2) 8969(1) 22(1)

C(13) 5191(4) -3266(2) 8890(1) 25(1)

C(14) 3596(3) -4170(2) 9075(1) 25(1)

C(15) 1684(4) -3711(2) 9332(1) 27(1)

C(16) 1328(3) -2342(2) 9408(1) 24(1)

_________________________________________________________________

Bond lengths [ Å ] and angles [ ° ].

____________________________________________________________

O(1)-C(1) 1.408(2)

O(1)-C(4) 1.438(2)

O(2)-C(7) 1.347(2)

O(2)-C(3) 1.449(2)

O(3)-C(7) 1.210(2)

O(4)-C(1) 1.407(2)

O(4)-C(8) 1.432(3)

O(5)-C(2) 1.415(2)

O(5)-C(8) 1.431(2)

C(1)-C(2) 1.535(3)

C(1)-H(1) 1.0000

C(2)-C(3) 1.518(3)

C(2)-H(2) 1.0000

C(3)-C(4) 1.513(3)

C(3)-H(3) 1.0000

C(4)-C(5) 1.521(3)

C(4)-H(4) 1.0000

C(5)-C(11) 1.518(3)

C(5)-C(6) 1.527(2)

C(5)-H(5) 1.0000

C(6)-C(7) 1.490(3)

C(6)-H(6A) 0.9900

C(6)-H(6B) 0.9900

C(8)-C(9) 1.506(3)

C(8)-C(10) 1.509(3)

C(9)-H(9A) 0.9800

C(9)-H(9B) 0.9800

C(9)-H(9C) 0.9800

C(10)-H(10A) 0.9800

178

C(10)-H(10B) 0.9800

C(10)-H(10C) 0.9800

C(11)-C(12) 1.386(3)

C(11)-C(16) 1.389(3)

C(12)-C(13) 1.387(3)

C(12)-H(12) 0.9500

C(13)-C(14) 1.376(3)

C(13)-H(13) 0.9500

C(14)-C(15) 1.369(3)

C(14)-H(14) 0.9500

C(15)-C(16) 1.388(3)

C(15)-H(15) 0.9500

C(16)-H(16) 0.9500

C(1)-O(1)-C(4) 108.06(14)

C(7)-O(2)-C(3) 123.76(15)

C(1)-O(4)-C(8) 108.14(15)

C(2)-O(5)-C(8) 106.81(15)

O(4)-C(1)-O(1) 111.19(16)

O(4)-C(1)-C(2) 104.65(15)

O(1)-C(1)-C(2) 107.62(15)

O(4)-C(1)-H(1) 111.1

O(1)-C(1)-H(1) 111.1

C(2)-C(1)-H(1) 111.1

O(5)-C(2)-C(3) 108.81(16)

O(5)-C(2)-C(1) 104.79(15)

C(3)-C(2)-C(1) 104.32(16)

O(5)-C(2)-H(2) 112.8

C(3)-C(2)-H(2) 112.8

C(1)-C(2)-H(2) 112.8

O(2)-C(3)-C(4) 115.81(15)

O(2)-C(3)-C(2) 107.96(15)

C(4)-C(3)-C(2) 103.38(16)

O(2)-C(3)-H(3) 109.8

C(4)-C(3)-H(3) 109.8

C(2)-C(3)-H(3) 109.8

O(1)-C(4)-C(3) 104.93(15)

O(1)-C(4)-C(5) 110.32(14)

C(3)-C(4)-C(5) 112.90(15)

O(1)-C(4)-H(4) 109.5

C(3)-C(4)-H(4) 109.5

C(5)-C(4)-H(4) 109.5

C(11)-C(5)-C(4) 114.79(15)

C(11)-C(5)-C(6) 114.56(16)

C(4)-C(5)-C(6) 107.10(15)

C(11)-C(5)-H(5) 106.6

C(4)-C(5)-H(5) 106.6

C(6)-C(5)-H(5) 106.6

C(7)-C(6)-C(5) 113.40(16)

C(7)-C(6)-H(6A) 108.9

C(5)-C(6)-H(6A) 108.9

C(7)-C(6)-H(6B) 108.9

C(5)-C(6)-H(6B) 108.9

H(6A)-C(6)-H(6B) 107.7

O(3)-C(7)-O(2) 117.19(18)

O(3)-C(7)-C(6) 123.58(18)

O(2)-C(7)-C(6) 119.16(17)

O(4)-C(8)-O(5) 103.91(14)

O(4)-C(8)-C(9) 111.03(18)

O(5)-C(8)-C(9) 110.94(18)

O(4)-C(8)-C(10) 109.16(18)

O(5)-C(8)-C(10) 108.16(18)

C(9)-C(8)-C(10) 113.19(17)

C(8)-C(9)-H(9A) 109.5

C(8)-C(9)-H(9B) 109.5

H(9A)-C(9)-H(9B) 109.5

C(8)-C(9)-H(9C) 109.5

H(9A)-C(9)-H(9C) 109.5

179

H(9B)-C(9)-H(9C) 109.5

C(8)-C(10)-H(10A) 109.5

C(8)-C(10)-H(10B) 109.5

H(10A)-C(10)-H(10B) 109.5

C(8)-C(10)-H(10C) 109.5

H(10A)-C(10)-H(10C) 109.5

H(10B)-C(10)-H(10C) 109.5

C(12)-C(11)-C(16) 118.73(19)

C(12)-C(11)-C(5) 118.66(18)

C(16)-C(11)-C(5) 122.58(18)

C(11)-C(12)-C(13) 120.75(19)

C(11)-C(12)-H(12) 119.6

C(13)-C(12)-H(12) 119.6

C(14)-C(13)-C(12) 119.95(19)

C(14)-C(13)-H(13) 120.0

C(12)-C(13)-H(13) 120.0

C(15)-C(14)-C(13) 119.8(2)

C(15)-C(14)-H(14) 120.1

C(13)-C(14)-H(14) 120.1

C(14)-C(15)-C(16) 120.8(2)

C(14)-C(15)-H(15) 119.6

C(16)-C(15)-H(15) 119.6

C(15)-C(16)-C(11) 120.0(2)

C(15)-C(16)-H(16) 120.0

C(11)-C(16)-H(16) 120.0

_____________________________________________________________

180

Crystal data and structure refinement for 76 (s3391m)

Empirical formula C9 H14 O6

Formula weight 218.20

Temperature 100(2) K

Wavelength 0.71073 A

Crystal system, space group Monoclinic, P2(1)

Unit cell dimensions a = 6.376(4) Å α = 90°

b = 19.246(11) Å β = 105.205(11)°

c = 8.688(5) Å γ = 90°

Volume 1028.8(11) Å3

Z, Calculated density 4, 1.409 Mg/m3

Absorption coefficient 0.119 mm-1

F(000 464

Crystal size 0.55 × 0.50 × 0.30 mm

Theta range for data collection 2.12 to 26.30°

Limiting indices -6<=h<=7, -23<=k<=23, -10<=l<=10

Reflections collected / unique 5680 / 2130 [R(int) = 0.0464]

Completeness to theta = 26.30 99.0%

Absorption correction None

Refinement method Full-matrix least-squares on F2

Data / restraints / parameters 2130 / 1 / 277

Goodness-of-fit on F2 0.964

Final R indices [I>2sigma(I)] R1 = 0.0328, wR2 = 0.0613

R indices (all data) R1 = 0.0385, wR2 = 0.0628

Largest diff. peak and hole 0.176 and -0.167 e.A-3

181

Atomic coordinates [× 104] and equivalent isotropic displacement parameters [A

2 × 10

3]

U(eq) is defined as one third of the trace of the orthogonalized Uij tensor.

________________________________________________________________

x y z U(eq)

________________________________________________________________

O(1) 8898(3) 663(1) -342(2) 23(1)

O(2) 9869(3) 1588(1) 1372(2) 23(1)

O(3) 9528(3) 24(1) 2039(2) 21(1)

O(4) 9446(3) -285(1) 5328(2) 24(1)

O(5) 7593(3) 735(1) 4250(2) 23(1)

O(6) 12901(3) 236(1) 6042(2) 25(1)

C(1) 9859(4) 1347(1) -191(3) 22(1)

C(2) 8138(4) 510(1) 1008(3) 20(1)

C(3) 8319(4) 1194(1) 1943(3) 19(1)

C(4) 9350(4) 980(1) 3656(3) 19(1)

C(5) 10814(4) 383(1) 3432(3) 19(1)

C(6) 11354(4) -112(1) 4837(3) 20(1)

C(7) 8338(4) 316(2) 5638(3) 26(1)

C(8) 12177(4) 1294(2) -300(4) 33(1)

C(9) 8443(5) 1815(2) -1444(3) 34(1)

O(7) 15488(3) -1420(1) 6205(2) 24(1)

O(8) 14974(3) -2360(1) 7695(2) 22(1)

O(9) 14534(3) -791(1) 8251(2) 22(1)

O(10) 16622(3) -1368(1) 11331(2) 21(1)

O(11) 14144(3) -486(1) 11510(2) 23(1)

O(12) 10997(3) -1177(1) 10765(2) 26(1)

C(10) 14792(4) -2136(1) 6095(3) 21(1)

C(11) 16150(4) -1208(1) 7811(3) 19(1)

C(12) 16302(4) -1881(1) 8782(3) 20(1)

C(13) 15123(4) -1709(1) 10046(3) 20(1)

C(14) 13384(4) -1209(1) 9147(3) 19(1)

C(15) 12450(4) -752(1) 10224(3) 21(1)

C(16) 15497(4) -1023(1) 12332(3) 24(1)

C(17) 16290(5) -2564(2) 5374(3) 33(1)

C(18) 12429(4) -2175(2) 5170(3) 29(1)

________________________________________________________________

Bond lengths [ Å ] and angles [ ° ]

_____________________________________________________________

O(1)-C(2) 1.411(3)

O(1)-C(1) 1.445(3)

O(2)-C(1) 1.433(3)

O(2)-C(3) 1.434(3)

O(3)-C(2) 1.431(3)

O(3)-C(5) 1.447(3)

O(4)-C(7) 1.418(3)

O(4)-C(6) 1.430(3)

O(5)-C(7) 1.425(3)

O(5)-C(4) 1.430(3)

O(6)-C(6) 1.406(3)

O(6)-H(6) 0.8200

C(1)-C(8) 1.509(4)

C(1)-C(9) 1.515(4)

C(2)-C(3) 1.535(4)

C(2)-H(2) 0.9800

C(3)-C(4) 1.518(3)

C(3)-H(3) 0.9800

C(4)-C(5) 1.524(3)

C(4)-H(4) 0.9800

C(5)-C(6) 1.515(3)

182

C(5)-H(5) 0.9800

C(6)-H(6A) 0.9800

C(7)-H(7A) 0.9700

C(7)-H(7B) 0.9700

C(8)-H(8A) 0.9600

C(8)-H(8B) 0.9600

C(8)-H(8C) 0.9600

C(9)-H(9A) 0.9600

C(9)-H(9B) 0.9600

C(9)-H(9C) 0.9600

O(7)-C(11) 1.408(3)

O(7)-C(10) 1.444(3)

O(8)-C(12) 1.429(3)

O(8)-C(10) 1.431(3)

O(9)-C(11) 1.435(3)

O(9)-C(14) 1.445(3)

O(10)-C(13) 1.425(3)

O(10)-C(16) 1.427(3)

O(11)-C(16) 1.415(3)

O(11)-C(15) 1.430(3)

O(12)-C(15) 1.406(3)

O(12)-H(12) 0.8200

C(10)-C(18) 1.512(4)

C(10)-C(17) 1.515(3)

C(11)-C(12) 1.534(4)

C(11)-H(11) 0.9800

C(12)-C(13) 1.521(4)

C(12)-H(12A) 0.9800

C(13)-C(14) 1.521(4)

C(13)-H(13) 0.9800

C(14)-C(15) 1.516(3)

C(14)-H(14) 0.9800

C(15)-H(15) 0.9800

C(16)-H(16A) 0.9700

C(16)-H(16B) 0.9700

C(17)-H(17A) 0.9600

C(17)-H(17B) 0.9600

C(17)-H(17C) 0.9600

C(18)-H(18A) 0.9600

C(18)-H(18B) 0.9600

C(18)-H(18C) 0.9600

C(2)-O(1)-C(1) 110.14(18)

C(1)-O(2)-C(3) 108.93(18)

C(2)-O(3)-C(5) 109.49(19)

C(7)-O(4)-C(6) 111.8(2)

C(7)-O(5)-C(4) 111.93(18)

C(6)-O(6)-H(6) 109.5

O(2)-C(1)-O(1) 106.10(19)

O(2)-C(1)-C(8) 108.7(2)

O(1)-C(1)-C(8) 109.3(2)

O(2)-C(1)-C(9) 110.0(2)

O(1)-C(1)-C(9) 108.6(2)

C(8)-C(1)-C(9) 113.9(2)

O(1)-C(2)-O(3) 111.4(2)

O(1)-C(2)-C(3) 105.5(2)

O(3)-C(2)-C(3) 106.31(19)

O(1)-C(2)-H(2) 111.1

O(3)-C(2)-H(2) 111.1

C(3)-C(2)-H(2) 111.1

O(2)-C(3)-C(4) 108.8(2)

O(2)-C(3)-C(2) 103.50(19)

C(4)-C(3)-C(2) 103.8(2)

O(2)-C(3)-H(3) 113.3

C(4)-C(3)-H(3) 113.3

C(2)-C(3)-H(3) 113.3

O(5)-C(4)-C(3) 105.4(2)

O(5)-C(4)-C(5) 111.2(2)

183

C(3)-C(4)-C(5) 101.65(18)

O(5)-C(4)-H(4) 112.6

C(3)-C(4)-H(4) 112.6

C(5)-C(4)-H(4) 112.6

O(3)-C(5)-C(6) 109.4(2)

O(3)-C(5)-C(4) 103.58(19)

C(6)-C(5)-C(4) 112.87(19)

O(3)-C(5)-H(5) 110.3

C(6)-C(5)-H(5) 110.3

C(4)-C(5)-H(5) 110.3

O(6)-C(6)-O(4) 112.00(19)

O(6)-C(6)-C(5) 105.5(2)

O(4)-C(6)-C(5) 110.8(2)

O(6)-C(6)-H(6A) 109.5

O(4)-C(6)-H(6A) 109.5

C(5)-C(6)-H(6A) 109.5

O(4)-C(7)-O(5) 111.91(19)

O(4)-C(7)-H(7A) 109.2

O(5)-C(7)-H(7A) 109.2

O(4)-C(7)-H(7B) 109.2

O(5)-C(7)-H(7B) 109.2

H(7A)-C(7)-H(7B) 107.9

C(1)-C(8)-H(8A) 109.5

C(1)-C(8)-H(8B) 109.5

H(8A)-C(8)-H(8B) 109.5

C(1)-C(8)-H(8C) 109.5

H(8A)-C(8)-H(8C) 109.5

H(8B)-C(8)-H(8C) 109.5

C(1)-C(9)-H(9A) 109.5

C(1)-C(9)-H(9B) 109.5

H(9A)-C(9)-H(9B) 109.5

C(1)-C(9)-H(9C) 109.5

H(9A)-C(9)-H(9C) 109.5

H(9B)-C(9)-H(9C) 109.5

C(11)-O(7)-C(10) 110.42(19)

C(12)-O(8)-C(10) 109.26(18)

C(11)-O(9)-C(14) 109.47(18)

C(13)-O(10)-C(16) 110.54(19)

C(16)-O(11)-C(15) 111.57(19)

C(15)-O(12)-H(12) 109.5

O(8)-C(10)-O(7) 106.20(19)

O(8)-C(10)-C(18) 108.5(2)

O(7)-C(10)-C(18) 109.2(2)

O(8)-C(10)-C(17) 109.8(2)

O(7)-C(10)-C(17) 109.3(2)

C(18)-C(10)-C(17) 113.7(2)

O(7)-C(11)-O(9) 112.1(2)

O(7)-C(11)-C(12) 105.1(2)

O(9)-C(11)-C(12) 105.75(19)

O(7)-C(11)-H(11) 111.2

O(9)-C(11)-H(11) 111.2

C(12)-C(11)-H(11) 111.2

O(8)-C(12)-C(13) 107.3(2)

O(8)-C(12)-C(11) 103.93(19)

C(13)-C(12)-C(11) 104.0(2)

O(8)-C(12)-H(12A) 113.5

C(13)-C(12)-H(12A) 113.5

C(11)-C(12)-H(12A) 113.5

O(10)-C(13)-C(14) 111.1(2)

O(10)-C(13)-C(12) 108.0(2)

C(14)-C(13)-C(12) 101.4(2)

O(10)-C(13)-H(13) 112.0

C(14)-C(13)-H(13) 112.0

C(12)-C(13)-H(13) 112.0

O(9)-C(14)-C(15) 110.3(2)

O(9)-C(14)-C(13) 103.00(19)

C(15)-C(14)-C(13) 113.7(2)

O(9)-C(14)-H(14) 109.9

184

C(15)-C(14)-H(14) 109.9

C(13)-C(14)-H(14) 109.9

O(12)-C(15)-O(11) 112.09(19)

O(12)-C(15)-C(14) 105.6(2)

O(11)-C(15)-C(14) 110.6(2)

O(12)-C(15)-H(15) 109.5

O(11)-C(15)-H(15) 109.5

C(14)-C(15)-H(15) 109.5

O(11)-C(16)-O(10) 111.7(2)

O(11)-C(16)-H(16A) 109.3

O(10)-C(16)-H(16A) 109.3

O(11)-C(16)-H(16B) 109.3

O(10)-C(16)-H(16B) 109.3

H(16A)-C(16)-H(16B) 107.9

C(10)-C(17)-H(17A) 109.5

C(10)-C(17)-H(17B) 109.5

H(17A)-C(17)-H(17B) 109.5

C(10)-C(17)-H(17C) 109.5

H(17A)-C(17)-H(17C) 109.5

H(17B)-C(17)-H(17C) 109.5

C(10)-C(18)-H(18A) 109.5

C(10)-C(18)-H(18B) 109.5

H(18A)-C(18)-H(18B) 109.5

C(10)-C(18)-H(18C) 109.5

H(18A)-C(18)-H(18C) 109.5

H(18B)-C(18)-H(18C) 109.5

_____________________________________________________________

Hydrogen bonds [Å and °]

____________________________________________________________________________

D-H...A d(D-H) d(H...A) d(D...A) <(DHA)

O(6)-H(6)...O(9) 0.82 1.96 2.762(3) 166.7

O(12)-H(12)...O(3)#1 0.82 2.08 2.827(3) 150.3

O(12)-H(12)...O(10)#2 0.82 2.49 2.979(3) 119.6

____________________________________________________________________________

Symmetry transformations used to generate equivalent atoms:

#1 x,y,z+1 #2 x-1,y,z

185

Crystal data and structure refinement for 97 (s3394m)

Empirical formula C17 H22 O6

Formula weight 322.35

Temperature 100(2) K

Wavelength 0.71073 A

Crystal system, space group Orthorhombic, P212121

Unit cell dimensions a = 7.9577(19) Å α = 90°

b = 10.118(2) Å β = 90°

c = 19.556(5) Å γ = 90°

Volume 1574.5(6) Å3

Z, Calculated density 4, 1.360 Mg/m3

Absorption coefficient 0.103 mm-1

F(000) 688

Crystal size 0.50 × 0.45 × 0.20 mm

Theta range for data collection 2.08 to 26.43°

Limiting indices -9<=h<=9, -11<=k<=12, -24<=l<=20

Reflections collected / unique 9173 / 1869 [R(int) = 0.0581]

Completeness to theta = 26.43 99.6%

Absorption correction None

Refinement method Full-matrix least-squares on F2

Data / restraints / parameters 1869 / 0 / 212

Goodness-of-fit on F2

1.005

Final R indices [I>2sigma(I)] R1 = 0.0340, wR2 = 0.0710

R indices (all data) R1 = 0.0403, wR2 = 0.0729

Largest diff. peak and hole 0.256 and -0.171 e.A-3

186

Atomic coordinates [× 104] and equivalent isotropic displacement parameters [A

2 × 10

3]

U(eq) is defined as one third of the trace of the orthogonalized Uij tensor.

________________________________________________________________

x y z U(eq)

________________________________________________________________

O(1) 7942(2) 1763(1) 2511(1) 19(1)

O(2) 5882(2) 1340(1) 3330(1) 20(1)

O(3) 4494(2) 106(1) 2561(1) 19(1)

O(4) 6104(2) -533(1) 1343(1) 20(1)

O(5) 11394(2) -2020(1) 573(1) 22(1)

O(6) 12767(2) -310(2) 1042(1) 25(1)

C(1) 6243(3) 1953(2) 2694(1) 17(1)

C(2) 5163(3) 1178(2) 2176(1) 17(1)

C(3) 6451(3) 692(2) 1661(1) 16(1)

C(4) 8050(3) 604(2) 2089(1) 15(1)

C(5) 9732(3) 589(2) 1706(1) 17(1)

C(6) 9911(3) -765(2) 1370(1) 20(1)

C(7) 11513(3) -971(2) 986(1) 17(1)

C(8) 12909(3) -2396(2) 217(1) 25(1)

C(9) 4394(3) 565(2) 3249(1) 19(1)

C(10) 4461(3) -602(2) 3725(1) 26(1)

C(11) 2832(3) 1396(2) 3350(1) 23(1)

C(12) 9906(3) 1758(2) 1223(1) 16(1)

C(13) 10684(3) 2911(2) 1448(1) 20(1)

C(14) 10824(3) 4013(2) 1032(1) 25(1)

C(15) 10166(3) 3978(2) 377(1) 26(1)

C(16) 9380(3) 2849(2) 145(1) 26(1)

C(17) 9258(3) 1745(2) 561(1) 21(1)

________________________________________________________________

Bond lengths [ Å ] and angles [ °.]

_____________________________________________________________

O(1)-C(1) 1.412(3)

O(1)-C(4) 1.437(2)

O(2)-C(1) 1.421(2)

O(2)-C(9) 1.430(3)

O(3)-C(2) 1.423(2)

O(3)-C(9) 1.427(2)

O(4)-C(3) 1.414(2)

O(4)-H(4) 0.8400

O(5)-C(7) 1.336(2)

O(5)-C(8) 1.443(3)

O(6)-C(7) 1.206(3)

C(1)-C(2) 1.542(3)

C(1)-H(1) 1.0000

C(2)-C(3) 1.520(3)

C(2)-H(2) 1.0000

C(3)-C(4) 1.526(3)

C(3)-H(3) 1.0000

C(4)-C(5) 1.534(3)

C(4)-H(4A) 1.0000

C(5)-C(12) 1.519(3)

C(5)-C(6) 1.526(3)

C(5)-H(5) 1.0000

C(6)-C(7) 1.495(3)

C(6)-H(6A) 0.9900

C(6)-H(6B) 0.9900

C(8)-H(8A) 0.9800

C(8)-H(8B) 0.9800

C(8)-H(8C) 0.9800

187

C(9)-C(10) 1.504(3)

C(9)-C(11) 1.514(3)

C(10)-H(10A) 0.9800

C(10)-H(10B) 0.9800

C(10)-H(10C) 0.9800

C(11)-H(11A) 0.9800

C(11)-H(11B) 0.9800

C(11)-H(11C) 0.9800

C(12)-C(13) 1.392(3)

C(12)-C(17) 1.395(3)

C(13)-C(14) 1.384(3)

C(13)-H(13) 0.9500

C(14)-C(15) 1.385(3)

C(14)-H(14) 0.9500

C(15)-C(16) 1.379(3)

C(15)-H(15) 0.9500

C(16)-C(17) 1.385(3)

C(16)-H(16) 0.9500

C(17)-H(17) 0.9500

C(1)-O(1)-C(4) 108.30(15)

C(1)-O(2)-C(9) 108.04(15)

C(2)-O(3)-C(9) 105.73(15)

C(3)-O(4)-H(4) 109.5

C(7)-O(5)-C(8) 116.21(17)

O(1)-C(1)-O(2) 110.80(16)

O(1)-C(1)-C(2) 107.37(16)

O(2)-C(1)-C(2) 103.91(16)

O(1)-C(1)-H(1) 111.5

O(2)-C(1)-H(1) 111.5

C(2)-C(1)-H(1) 111.5

O(3)-C(2)-C(3) 110.84(16)

O(3)-C(2)-C(1) 104.45(15)

C(3)-C(2)-C(1) 102.93(17)

O(3)-C(2)-H(2) 112.6

C(3)-C(2)-H(2) 112.6

C(1)-C(2)-H(2) 112.6

O(4)-C(3)-C(2) 116.33(17)

O(4)-C(3)-C(4) 110.68(16)

C(2)-C(3)-C(4) 102.56(16)

O(4)-C(3)-H(3) 109.0

C(2)-C(3)-H(3) 109.0

C(4)-C(3)-H(3) 109.0

O(1)-C(4)-C(3) 102.60(15)

O(1)-C(4)-C(5) 109.91(16)

C(3)-C(4)-C(5) 117.38(15)

O(1)-C(4)-H(4A) 108.9

C(3)-C(4)-H(4A) 108.9

C(5)-C(4)-H(4A) 108.9

C(12)-C(5)-C(6) 115.07(16)

C(12)-C(5)-C(4) 112.05(17)

C(6)-C(5)-C(4) 107.42(16)

C(12)-C(5)-H(5) 107.3

C(6)-C(5)-H(5) 107.3

C(4)-C(5)-H(5) 107.3

C(7)-C(6)-C(5) 114.86(18)

C(7)-C(6)-H(6A) 108.6

C(5)-C(6)-H(6A) 108.6

C(7)-C(6)-H(6B) 108.6

C(5)-C(6)-H(6B) 108.6

H(6A)-C(6)-H(6B) 107.5

O(6)-C(7)-O(5) 123.6(2)

O(6)-C(7)-C(6) 125.63(19)

O(5)-C(7)-C(6) 110.71(18)

O(5)-C(8)-H(8A) 109.5

O(5)-C(8)-H(8B) 109.5

H(8A)-C(8)-H(8B) 109.5

O(5)-C(8)-H(8C) 109.5

188

H(8A)-C(8)-H(8C) 109.5

H(8B)-C(8)-H(8C) 109.5

O(3)-C(9)-O(2) 103.72(16)

O(3)-C(9)-C(10) 109.07(16)

O(2)-C(9)-C(10) 109.40(18)

O(3)-C(9)-C(11) 110.46(17)

O(2)-C(9)-C(11) 111.16(16)

C(10)-C(9)-C(11) 112.63(18)

C(9)-C(10)-H(10A) 109.5

C(9)-C(10)-H(10B) 109.5

H(10A)-C(10)-H(10B) 109.5

C(9)-C(10)-H(10C) 109.5

H(10A)-C(10)-H(10C) 109.5

H(10B)-C(10)-H(10C) 109.5

C(9)-C(11)-H(11A) 109.5

C(9)-C(11)-H(11B) 109.5

H(11A)-C(11)-H(11B) 109.5

C(9)-C(11)-H(11C) 109.5

H(11A)-C(11)-H(11C) 109.5

H(11B)-C(11)-H(11C) 109.5

C(13)-C(12)-C(17) 117.74(19)

C(13)-C(12)-C(5) 119.81(18)

C(17)-C(12)-C(5) 122.41(19)

C(14)-C(13)-C(12) 121.72(19)

C(14)-C(13)-H(13) 119.1

C(12)-C(13)-H(13) 119.1

C(13)-C(14)-C(15) 119.5(2)

C(13)-C(14)-H(14) 120.2

C(15)-C(14)-H(14) 120.2

C(16)-C(15)-C(14) 119.8(2)

C(16)-C(15)-H(15) 120.1

C(14)-C(15)-H(15) 120.1

C(15)-C(16)-C(17) 120.4(2)

C(15)-C(16)-H(16) 119.8

C(17)-C(16)-H(16) 119.8

C(16)-C(17)-C(12) 120.8(2)

C(16)-C(17)-H(17) 119.6

C(12)-C(17)-H(17) 119.6

_____________________________________________________________

Hydrogen bonds [Å and °]

____________________________________________________________________________

D-H...A d(D-H) d(H...A) d(D...A) <(DHA)

O(4)-H(4)...O(6)#1 0.84 1.90 2.730(2) 169.6

____________________________________________________________________________

Symmetry transformations used to generate equivalent atoms:

#1 x-1,y,z

189

Crystal data and structure refinement for 103 (s3505)

Empirical formula C19 H24 O6

Formula weight 348.38

Temperature 100(2) K

Wavelength 0.68890 A

Crystal system, space group Orthorhombic, P2(1)2(1)2(1)

Unit cell dimensions a = 5.3928(14) Å α = 90°

b = 16.924(4) Å β= 90°

c = 19.706(5) Å γ = 90°

Volume 1798.6(8) Å3

Z, Calculated density 4, 1.287 Mg/m3

Absorption coefficient 0.095 mm-1

F(000) 744

Crystal size 0.30 × 0.01 × 0.01 mm

Theta range for data collection 1.54 to 31.62°

Limiting indices -8<=h<=7, -24<=k<=25, -29<=l<=29

Reflections collected / unique 23582 / 3567 [R(int) = 0.0458]

Completeness to theta = 24.20 98.7%

Absorption correction Semi-empirical from equivalents

Max. and min. transmission 1.000 and 0.885

Refinement method Full-matrix least-squares on F2

Data / restraints / parameters 3567 / 0 / 245

Goodness-of-fit on F2 1.084

Final R indices [I>2sigma(I)] R1 = 0.0347, wR2 = 0.0832

R indices (all data) R1 = 0.0396, wR2 = 0.0882

Largest diff. peak and hole 0.247 and -0.188 e.A-3

190

Atomic coordinates [× 104] and equivalent isotropic displacement parameters [A

2 × 10

3]

U(eq) is defined as one third of the trace of the orthogonalized Uij tensor.

________________________________________________________________

x y z U(eq)

________________________________________________________________

O(1) -591(2) 365(1) -505(1) 22(1)

O(2) 503(2) 1335(1) -1290(1) 21(1)

O(3) 3517(2) 1780(1) -585(1) 19(1)

O(4) 6085(2) -1642(1) 1112(1) 25(1)

O(5) 2050(2) -1957(1) 1134(1) 39(1)

O(6) 1031(2) 790(1) 873(1) 20(1)

C(1) -439(2) 1185(1) -626(1) 18(1)

C(2) 1578(2) 1519(1) -144(1) 16(1)

C(3) 2447(2) 799(1) 262(1) 17(1)

C(4) 1754(2) 114(1) -218(1) 19(1)

C(5) 1375(3) -676(1) 107(1) 22(1)

C(6) 3670(3) -1190(1) 212(1) 25(1)

C(7) 1683(4) -1419(1) -297(1) 34(1)

C(8) 3780(3) -1640(1) 859(1) 23(1)

C(9) 6384(3) -2056(1) 1747(1) 28(1)

C(10) 2429(2) 1912(1) -1241(1) 19(1)

C(11) 4365(3) 1749(1) -1775(1) 30(1)

C(12) 1344(3) 2743(1) -1280(1) 24(1)

C(13) 2303(3) 459(1) 1447(1) 20(1)

C(14) 583(3) 521(1) 2044(1) 19(1)

C(15) 771(3) 1148(1) 2499(1) 26(1)

C(16) -881(3) 1221(1) 3038(1) 33(1)

C(17) -2745(3) 663(1) 3124(1) 32(1)

C(18) -2969(3) 40(1) 2670(1) 33(1)

C(19) -1316(3) -29(1) 2131(1) 28(1)

________________________________________________________________

Bond lengths [ Å ] and angles [ ° ]

_____________________________________________________________

O(1)-C(1) 1.4095(15)

O(1)-C(4) 1.4496(16)

O(2)-C(1) 1.4273(15)

O(2)-C(10) 1.4296(16)

O(3)-C(2) 1.4291(15)

O(3)-C(10) 1.4362(14)

O(4)-C(8) 1.3394(18)

O(4)-C(9) 1.4429(15)

O(5)-C(8) 1.2042(18)

O(6)-C(3) 1.4263(14)

O(6)-C(13) 1.4363(14)

C(1)-C(2) 1.5504(17)

C(1)-H(1) 1.0000

C(2)-C(3) 1.5323(16)

C(2)-H(2) 1.0000

C(3)-C(4) 1.5404(16)

C(3)-H(3) 1.0000

C(4)-C(5) 1.4968(17)

C(4)-H(4) 1.0000

C(5)-C(7) 1.4959(19)

C(5)-C(6) 1.526(2)

C(5)-H(5) 0.935(18)

C(6)-C(8) 1.4872(18)

C(6)-C(7) 1.517(2)

C(6)-H(6) 0.95(2)

C(7)-H(7A) 1.01(2)

191

C(7)-H(7B) 0.92(2)

C(9)-H(9A) 0.9800

C(9)-H(9B) 0.9800

C(9)-H(9C) 0.9800

C(10)-C(11) 1.5084(18)

C(10)-C(12) 1.5245(18)

C(11)-H(11A) 0.9800

C(11)-H(11B) 0.9800

C(11)-H(11C) 0.9800

C(12)-H(12A) 0.9800

C(12)-H(12B) 0.9800

C(12)-H(12C) 0.9800

C(13)-C(14) 1.5023(17)

C(13)-H(13A) 0.9900

C(13)-H(13B) 0.9900

C(14)-C(15) 1.3932(17)

C(14)-C(19) 1.394(2)

C(15)-C(16) 1.391(2)

C(15)-H(15) 0.9500

C(16)-C(17) 1.390(2)

C(16)-H(16) 0.9500

C(17)-C(18) 1.387(2)

C(17)-H(17) 0.9500

C(18)-C(19) 1.392(2)

C(18)-H(18) 0.9500

C(19)-H(19) 0.9500

C(1)-O(1)-C(4) 107.68(10)

C(1)-O(2)-C(10) 108.48(9)

C(2)-O(3)-C(10) 107.23(9)

C(8)-O(4)-C(9) 115.32(12)

C(3)-O(6)-C(13) 114.40(9)

O(1)-C(1)-O(2) 110.51(9)

O(1)-C(1)-C(2) 107.27(9)

O(2)-C(1)-C(2) 104.32(10)

O(1)-C(1)-H(1) 111.5

O(2)-C(1)-H(1) 111.5

C(2)-C(1)-H(1) 111.5

O(3)-C(2)-C(3) 109.81(10)

O(3)-C(2)-C(1) 104.69(9)

C(3)-C(2)-C(1) 104.08(9)

O(3)-C(2)-H(2) 112.6

C(3)-C(2)-H(2) 112.6

C(1)-C(2)-H(2) 112.6

O(6)-C(3)-C(2) 106.57(9)

O(6)-C(3)-C(4) 112.31(10)

C(2)-C(3)-C(4) 101.79(9)

O(6)-C(3)-H(3) 111.9

C(2)-C(3)-H(3) 111.9

C(4)-C(3)-H(3) 111.9

O(1)-C(4)-C(5) 108.06(11)

O(1)-C(4)-C(3) 103.35(9)

C(5)-C(4)-C(3) 116.33(10)

O(1)-C(4)-H(4) 109.6

C(5)-C(4)-H(4) 109.6

C(3)-C(4)-H(4) 109.6

C(7)-C(5)-C(4) 120.58(12)

C(7)-C(5)-C(6) 60.25(10)

C(4)-C(5)-C(6) 117.14(12)

C(7)-C(5)-H(5) 116.3(11)

C(4)-C(5)-H(5) 115.6(11)

C(6)-C(5)-H(5) 115.6(11)

C(8)-C(6)-C(7) 117.65(13)

C(8)-C(6)-C(5) 116.10(12)

C(7)-C(6)-C(5) 58.88(9)

C(8)-C(6)-H(6) 115.4(11)

C(7)-C(6)-H(6) 119.9(11)

C(5)-C(6)-H(6) 117.0(12)

192

C(5)-C(7)-C(6) 60.87(9)

C(5)-C(7)-H(7A) 116.6(12)

C(6)-C(7)-H(7A) 113.8(14)

C(5)-C(7)-H(7B) 117.7(13)

C(6)-C(7)-H(7B) 114.1(13)

H(7A)-C(7)-H(7B) 119.6(18)

O(5)-C(8)-O(4) 123.42(12)

O(5)-C(8)-C(6) 125.62(14)

O(4)-C(8)-C(6) 110.95(12)

O(4)-C(9)-H(9A) 109.5

O(4)-C(9)-H(9B) 109.5

H(9A)-C(9)-H(9B) 109.5

O(4)-C(9)-H(9C) 109.5

H(9A)-C(9)-H(9C) 109.5

H(9B)-C(9)-H(9C) 109.5

O(2)-C(10)-O(3) 104.58(9)

O(2)-C(10)-C(11) 109.26(11)

O(3)-C(10)-C(11) 108.46(10)

O(2)-C(10)-C(12) 110.37(11)

O(3)-C(10)-C(12) 110.25(10)

C(11)-C(10)-C(12) 113.52(11)

C(10)-C(11)-H(11A) 109.5

C(10)-C(11)-H(11B) 109.5

H(11A)-C(11)-H(11B) 109.5

C(10)-C(11)-H(11C) 109.5

H(11A)-C(11)-H(11C) 109.5

H(11B)-C(11)-H(11C) 109.5

C(10)-C(12)-H(12A) 109.5

C(10)-C(12)-H(12B) 109.5

H(12A)-C(12)-H(12B) 109.5

C(10)-C(12)-H(12C) 109.5

H(12A)-C(12)-H(12C) 109.5

H(12B)-C(12)-H(12C) 109.5

O(6)-C(13)-C(14) 107.15(11)

O(6)-C(13)-H(13A) 110.3

C(14)-C(13)-H(13A) 110.3

O(6)-C(13)-H(13B) 110.3

C(14)-C(13)-H(13B) 110.3

H(13A)-C(13)-H(13B) 108.5

C(15)-C(14)-C(19) 118.88(12)

C(15)-C(14)-C(13) 120.84(12)

C(19)-C(14)-C(13) 120.19(11)

C(16)-C(15)-C(14) 120.75(14)

C(16)-C(15)-H(15) 119.6

C(14)-C(15)-H(15) 119.6

C(17)-C(16)-C(15) 119.77(13)

C(17)-C(16)-H(16) 120.1

C(15)-C(16)-H(16) 120.1

C(18)-C(17)-C(16) 120.05(14)

C(18)-C(17)-H(17) 120.0

C(16)-C(17)-H(17) 120.0

C(17)-C(18)-C(19) 119.97(15)

C(17)-C(18)-H(18) 120.0

C(19)-C(18)-H(18) 120.0

C(18)-C(19)-C(14) 120.57(13)

C(18)-C(19)-H(19) 119.7

C(14)-C(19)-H(19) 119.7

_____________________________________________________________

193

Crystal data and structure refinement for 116 (s3437m)

Empirical formula C21 H26 N2 O6

Formula weight 402.44

Temperature 100(2) K

Wavelength 0.71073 A

Crystal system, space group Orthorhombic, P2(1)2(1)2(1)

Unit cell dimensions a = 5.516(2) Å α = 90°

b = 9.311(4) Å β= 90°

c = 38.715(15) Å γ = 90°

Volume 1988.4(13) Å3

Z, Calculated density 4, 1.344 Mg/m3

Absorption coefficient 0.099 mm-1

F(000) 856

Crystal size 0.60 × 0.10 × 0.10 mm

Theta range for data collection 2.10 to 25.01°

Limiting indices -6<=h<=6, -11<=k<=11, -46<=l<=44

Reflections collected / unique 13964 / 2085 [R(int) = 0.1670]

Completeness to theta = 25.01 100.0%

Absorption correction None

Refinement method Full-matrix least-squares on F2

Data / restraints / parameters 2085 / 0 / 265

Goodness-of-fit on F2 1.081

Final R indices [I>2sigma(I)] R1 = 0.0774, wR2 = 0.0991

R indices (all data) R1 = 0.1295, wR2 = 0.1106

Largest diff. peak and hole 0.249 and -0.258 e.A^-3

194

Atomic coordinates [× 104] and equivalent isotropic displacement parameters [A

2 × 10

3]

U(eq) is defined as one third of the trace of the orthogonalized Uij tensor.

________________________________________________________________

x y z U(eq)

________________________________________________________________

O(1) 7117(8) 3333(5) 1747(1) 18(1)

O(2) -88(9) 2173(5) 692(1) 27(1)

O(3) 3772(8) 2305(5) 511(1) 30(1)

O(4) 7124(8) 4328(4) 2302(1) 19(1)

O(5) 5110(8) 6222(4) 2081(1) 20(1)

O(6) 7299(8) 5430(5) 1215(1) 19(1)

N(1) 3918(10) 1478(6) 1359(1) 13(1)

N(2) 4235(11) -860(6) 1458(1) 22(2)

C(1) 8009(12) 4476(7) 1960(2) 18(2)

C(2) 6856(12) 5861(7) 1830(2) 19(2)

C(3) 5598(11) 5432(7) 1497(1) 14(2)

C(4) 5021(13) 3871(7) 1571(2) 15(2)

C(5) 4597(12) 2925(7) 1257(2) 16(2)

C(6) 2649(12) 3556(7) 1023(2) 20(2)

C(7) 2199(15) 2629(8) 716(2) 26(2)

C(8) -623(13) 1273(7) 395(2) 29(2)

C(9) 6020(13) 5674(7) 2398(2) 21(2)

C(10) 3903(12) 5381(8) 2637(2) 27(2)

C(11) 7882(13) 6659(7) 2554(1) 21(2)

C(12) 7565(13) 6796(7) 1063(2) 22(2)

C(13) 9214(12) 6656(7) 754(2) 15(2)

C(14) 11200(12) 7542(7) 713(2) 24(2)

C(15) 12695(13) 7403(7) 432(2) 25(2)

C(16) 12233(14) 6356(7) 185(2) 26(2)

C(17) 10281(11) 5473(7) 228(2) 17(2)

C(18) 8741(11) 5613(7) 508(1) 16(2)

C(19) 1827(13) 1062(7) 1521(2) 23(2)

C(20) 2047(13) -362(8) 1583(2) 23(2)

C(21) 5319(13) 290(8) 1329(2) 20(2)

________________________________________________________________

Bond lengths [ Å ] and angles [ ° ]

_____________________________________________________________

O(1)-C(1) 1.433(7)

O(1)-C(4) 1.434(7)

O(2)-C(7) 1.334(8)

O(2)-C(8) 1.454(7)

O(3)-C(7) 1.215(7)

O(4)-C(1) 1.417(6)

O(4)-C(9) 1.442(7)

O(5)-C(2) 1.407(7)

O(5)-C(9) 1.421(7)

O(6)-C(12) 1.409(7)

O(6)-C(3) 1.439(7)

N(1)-C(21) 1.354(8)

N(1)-C(19) 1.368(8)

N(1)-C(5) 1.454(8)

N(2)-C(21) 1.324(8)

N(2)-C(20) 1.379(8)

C(1)-C(2) 1.523(8)

C(1)-H(1) 1.0000

C(2)-C(3) 1.519(8)

C(2)-H(2) 1.0000

C(3)-C(4) 1.515(8)

C(3)-H(3) 1.0000

195

C(4)-C(5) 1.519(8)

C(4)-H(4) 1.0000

C(5)-C(6) 1.524(8)

C(5)-H(5) 1.0000

C(6)-C(7) 1.487(8)

C(6)-H(6A) 0.9900

C(6)-H(6B) 0.9900

C(8)-H(8A) 0.9800

C(8)-H(8B) 0.9800

C(8)-H(8C) 0.9800

C(9)-C(11) 1.503(8)

C(9)-C(10) 1.515(8)

C(10)-H(10A) 0.9800

C(10)-H(10B) 0.9800

C(10)-H(10C) 0.9800

C(11)-H(11A) 0.9800

C(11)-H(11B) 0.9800

C(11)-H(11C) 0.9800

C(12)-C(13) 1.508(8)

C(12)-H(12A) 0.9900

C(12)-H(12B) 0.9900

C(13)-C(14) 1.380(8)

C(13)-C(18) 1.385(8)

C(14)-C(15) 1.373(8)

C(14)-H(14) 0.9500

C(15)-C(16) 1.388(8)

C(15)-H(15) 0.9500

C(16)-C(17) 1.364(8)

C(16)-H(16) 0.9500

C(17)-C(18) 1.384(8)

C(17)-H(17) 0.9500

C(18)-H(18) 0.9500

C(19)-C(20) 1.352(8)

C(19)-H(19) 0.9500

C(20)-H(20) 0.9500

C(21)-H(21) 0.9500

C(1)-O(1)-C(4) 107.0(5)

C(7)-O(2)-C(8) 115.5(5)

C(1)-O(4)-C(9) 107.5(5)

C(2)-O(5)-C(9) 105.5(5)

C(12)-O(6)-C(3) 112.6(5)

C(21)-N(1)-C(19) 106.8(6)

C(21)-N(1)-C(5) 125.9(6)

C(19)-N(1)-C(5) 127.2(6)

C(21)-N(2)-C(20) 104.7(6)

O(4)-C(1)-O(1) 110.2(5)

O(4)-C(1)-C(2) 104.3(5)

O(1)-C(1)-C(2) 107.2(5)

O(4)-C(1)-H(1) 111.6

O(1)-C(1)-H(1) 111.6

C(2)-C(1)-H(1) 111.6

O(5)-C(2)-C(3) 109.6(5)

O(5)-C(2)-C(1) 105.1(5)

C(3)-C(2)-C(1) 104.4(5)

O(5)-C(2)-H(2) 112.4

C(3)-C(2)-H(2) 112.4

C(1)-C(2)-H(2) 112.4

O(6)-C(3)-C(4) 106.2(5)

O(6)-C(3)-C(2) 110.2(5)

C(4)-C(3)-C(2) 100.9(5)

O(6)-C(3)-H(3) 112.9

C(4)-C(3)-H(3) 112.9

C(2)-C(3)-H(3) 112.9

O(1)-C(4)-C(3) 104.8(5)

O(1)-C(4)-C(5) 107.7(5)

C(3)-C(4)-C(5) 116.0(5)

O(1)-C(4)-H(4) 109.4

196

C(3)-C(4)-H(4) 109.4

C(5)-C(4)-H(4) 109.4

N(1)-C(5)-C(4) 111.0(5)

N(1)-C(5)-C(6) 109.8(5)

C(4)-C(5)-C(6) 111.2(5)

N(1)-C(5)-H(5) 108.3

C(4)-C(5)-H(5) 108.3

C(6)-C(5)-H(5) 108.3

C(7)-C(6)-C(5) 111.6(6)

C(7)-C(6)-H(6A) 109.3

C(5)-C(6)-H(6A) 109.3

C(7)-C(6)-H(6B) 109.3

C(5)-C(6)-H(6B) 109.3

H(6A)-C(6)-H(6B) 108.0

O(3)-C(7)-O(2) 123.4(6)

O(3)-C(7)-C(6) 123.1(7)

O(2)-C(7)-C(6) 113.5(6)

O(2)-C(8)-H(8A) 109.5

O(2)-C(8)-H(8B) 109.5

H(8A)-C(8)-H(8B) 109.5

O(2)-C(8)-H(8C) 109.5

H(8A)-C(8)-H(8C) 109.5

H(8B)-C(8)-H(8C) 109.5

O(5)-C(9)-O(4) 103.8(5)

O(5)-C(9)-C(11) 111.7(5)

O(4)-C(9)-C(11) 110.2(6)

O(5)-C(9)-C(10) 108.7(5)

O(4)-C(9)-C(10) 109.0(6)

C(11)-C(9)-C(10) 113.0(5)

C(9)-C(10)-H(10A) 109.5

C(9)-C(10)-H(10B) 109.5

H(10A)-C(10)-H(10B) 109.5

C(9)-C(10)-H(10C) 109.5

H(10A)-C(10)-H(10C) 109.5

H(10B)-C(10)-H(10C) 109.5

C(9)-C(11)-H(11A) 109.5

C(9)-C(11)-H(11B) 109.5

H(11A)-C(11)-H(11B) 109.5

C(9)-C(11)-H(11C) 109.5

H(11A)-C(11)-H(11C) 109.5

H(11B)-C(11)-H(11C) 109.5

O(6)-C(12)-C(13) 108.5(5)

O(6)-C(12)-H(12A) 110.0

C(13)-C(12)-H(12A) 110.0

O(6)-C(12)-H(12B) 110.0

C(13)-C(12)-H(12B) 110.0

H(12A)-C(12)-H(12B) 108.4

C(14)-C(13)-C(18) 119.3(6)

C(14)-C(13)-C(12) 121.2(6)

C(18)-C(13)-C(12) 119.5(6)

C(15)-C(14)-C(13) 120.7(7)

C(15)-C(14)-H(14) 119.6

C(13)-C(14)-H(14) 119.6

C(14)-C(15)-C(16) 120.1(7)

C(14)-C(15)-H(15) 119.9

C(16)-C(15)-H(15) 119.9

C(17)-C(16)-C(15) 119.0(7)

C(17)-C(16)-H(16) 120.5

C(15)-C(16)-H(16) 120.5

C(16)-C(17)-C(18) 121.5(6)

C(16)-C(17)-H(17) 119.3

C(18)-C(17)-H(17) 119.3

C(17)-C(18)-C(13) 119.3(6)

C(17)-C(18)-H(18) 120.3

C(13)-C(18)-H(18) 120.3

C(20)-C(19)-N(1) 106.4(7)

C(20)-C(19)-H(19) 126.8

N(1)-C(19)-H(19) 126.8

197

C(19)-C(20)-N(2) 110.3(7)

C(19)-C(20)-H(20) 124.8

N(2)-C(20)-H(20) 124.8

N(2)-C(21)-N(1) 111.8(6)

N(2)-C(21)-H(21) 124.1

N(1)-C(21)-H(21) 124.1

_____________________________________________________________

198

Crystal data and structure refinement for 139 (s3570)

Empirical formula C23 H27 N O7

Formula weight 429.46

Temperature 180(2) K

Wavelength 0.71073 A

Crystal system, space group Hexagonal, P6(5)

Unit cell dimensions a = 19.5348(9) Å α = 90°

b = 19.5348(9) Å β = 90°

c = 11.0557(10) Å γ = 120°

Volume 3653.7(4) Å3

Z, Calculated density 6, 1.171 Mg/m3

Absorption coefficient 0.087 mm-1

F(000) 1368

Crystal size 0.40 × 0.14 × 0.08 mm

Theta range for data collection 2.09 to 25.05°

Limiting indices -23<=h<=23, -23<=k<=23, -13<=l<=13

Reflections collected / unique 26430 / 2272 [R(int) = 0.0916]

Completeness to theta = 25.00 100.0%

Absorption correction None

Max. and min. transmission 0.9931 and 0.9661

Refinement method Full-matrix least-squares on F2

Data / restraints / parameters 2272 / 1 / 283

Goodness-of-fit on F2 1.150

Final R indices [I>2sigma(I)] R1 = 0.0711, wR2 = 0.1748

R indices (all data) R1 = 0.0832, wR2 = 0.1814

Absolute structure parameter 0(10)

Largest diff. peak and hole 0.462 and -0.214 e.A-3

199

Atomic coordinates [× 104] and equivalent isotropic displacement parameters [A

2 × 10

3]

U(eq) is defined as one third of the trace of the orthogonalized Uij tensor.

________________________________________________________________

x y z U(eq)

________________________________________________________________

C(1) 3516(3) 3737(3) 2310(5) 32(1)

C(2) 2681(3) 3086(4) 2673(5) 37(1)

C(3) 1703(4) 3194(4) 3713(6) 48(2)

C(4) 2148(4) 3179(4) 1784(6) 40(2)

C(5) 3342(3) 4366(3) 1833(5) 31(1)

C(6) 4071(4) 2936(4) 1720(6) 41(2)

C(7) 4650(3) 2978(3) 785(6) 34(1)

C(8) 4459(4) 2369(4) -14(6) 41(2)

C(9) 5012(4) 2406(4) -835(7) 50(2)

C(10) 5755(4) 3066(4) -882(6) 45(2)

C(11) 5950(4) 3677(4) -96(5) 38(1)

C(12) 5404(3) 3641(3) 741(5) 33(1)

C(13) 3941(3) 4947(3) 917(5) 29(1)

C(14) 4784(3) 5383(3) 1401(5) 27(1)

C(15) 5405(3) 5460(3) 702(5) 31(1)

C(16) 6176(4) 5892(3) 1087(5) 35(1)

C(17) 6344(3) 6260(3) 2219(5) 31(1)

C(18) 5734(4) 6171(3) 2951(5) 34(1)

C(19) 4971(3) 5745(3) 2537(5) 33(1)

C(20) 7323(4) 7145(4) 3595(7) 59(2)

C(21) 3677(3) 5528(3) 541(6) 35(1)

C(22) 1120(5) 2454(6) 4356(10) 84(3)

C(23) 1712(5) 3909(6) 4186(11) 85(3)

N(1) 4165(3) 6059(3) -474(5) 44(1)

O(1) 2477(2) 3300(3) 3794(4) 44(1)

O(2) 1510(3) 3093(3) 2449(5) 58(1)

O(3) 2592(2) 3935(2) 1241(4) 38(1)

O(4) 3810(2) 3484(2) 1340(3) 31(1)

O(5) 7134(2) 6705(3) 2499(4) 47(1)

O(6) 4405(3) 5784(3) -1242(5) 59(1)

O(7) 4272(3) 6731(3) -483(6) 67(2)

________________________________________________________________

Bond lengths [ Å ] and angles [ ° ]

_____________________________________________________________

C(1)-O(4) 1.418(7)

C(1)-C(5) 1.524(8)

C(1)-C(2) 1.537(8)

C(1)-H(1) 1.0000

C(2)-O(1) 1.427(7)

C(2)-C(4) 1.508(9)

C(2)-H(2) 1.0000

C(3)-O(1) 1.423(8)

C(3)-O(2) 1.435(8)

C(3)-C(23) 1.483(11)

C(3)-C(22) 1.497(11)

C(4)-O(2) 1.383(8)

C(4)-O(3) 1.419(7)

C(4)-H(4) 1.0000

C(5)-O(3) 1.432(7)

C(5)-C(13) 1.534(8)

C(5)-H(5) 1.0000

C(6)-O(4) 1.459(7)

C(6)-C(7) 1.504(9)

C(6)-H(6A) 0.9900

200

C(6)-H(6B) 0.9900

C(7)-C(8) 1.375(9)

C(7)-C(12) 1.393(8)

C(8)-C(9) 1.386(9)

C(8)-H(8) 0.9500

C(9)-C(10) 1.379(10)

C(9)-H(9) 0.9500

C(10)-C(11) 1.367(9)

C(10)-H(10) 0.9500

C(11)-C(12) 1.388(8)

C(11)-H(11) 0.9500

C(12)-H(12) 0.9500

C(13)-C(21) 1.522(7)

C(13)-C(14) 1.524(8)

C(13)-H(13) 1.0000

C(14)-C(15) 1.382(7)

C(14)-C(19) 1.397(8)

C(15)-C(16) 1.375(8)

C(15)-H(15) 0.9500

C(16)-C(17) 1.397(9)

C(16)-H(16) 0.9500

C(17)-O(5) 1.375(7)

C(17)-C(18) 1.378(8)

C(18)-C(19) 1.373(8)

C(18)-H(18) 0.9500

C(19)-H(19) 0.9500

C(20)-O(5) 1.423(9)

C(20)-H(20A) 0.9800

C(20)-H(20B) 0.9800

C(20)-H(20C) 0.9800

C(21)-N(1) 1.502(8)

C(21)-H(21A) 0.9900

C(21)-H(21B) 0.9900

C(22)-H(22A) 0.9800

C(22)-H(22B) 0.9800

C(22)-H(22C) 0.9800

C(23)-H(23A) 0.9800

C(23)-H(23B) 0.9800

C(23)-H(23C) 0.9800

N(1)-O(6) 1.215(7)

N(1)-O(7) 1.222(7)

O(4)-C(1)-C(5) 108.2(4)

O(4)-C(1)-C(2) 110.9(5)

C(5)-C(1)-C(2) 100.7(4)

O(4)-C(1)-H(1) 112.2

C(5)-C(1)-H(1) 112.2

C(2)-C(1)-H(1) 112.2

O(1)-C(2)-C(4) 102.6(5)

O(1)-C(2)-C(1) 108.7(5)

C(4)-C(2)-C(1) 103.9(5)

O(1)-C(2)-H(2) 113.5

C(4)-C(2)-H(2) 113.5

C(1)-C(2)-H(2) 113.5

O(1)-C(3)-O(2) 105.5(5)

O(1)-C(3)-C(23) 109.2(6)

O(2)-C(3)-C(23) 110.6(7)

O(1)-C(3)-C(22) 110.6(6)

O(2)-C(3)-C(22) 108.0(7)

C(23)-C(3)-C(22) 112.8(7)

O(2)-C(4)-O(3) 113.3(5)

O(2)-C(4)-C(2) 105.9(5)

O(3)-C(4)-C(2) 107.6(5)

O(2)-C(4)-H(4) 110.0

O(3)-C(4)-H(4) 110.0

C(2)-C(4)-H(4) 110.0

O(3)-C(5)-C(1) 105.0(4)

O(3)-C(5)-C(13) 108.1(4)

201

C(1)-C(5)-C(13) 115.4(5)

O(3)-C(5)-H(5) 109.4

C(1)-C(5)-H(5) 109.4

C(13)-C(5)-H(5) 109.4

O(4)-C(6)-C(7) 106.9(5)

O(4)-C(6)-H(6A) 110.3

C(7)-C(6)-H(6A) 110.3

O(4)-C(6)-H(6B) 110.3

C(7)-C(6)-H(6B) 110.3

H(6A)-C(6)-H(6B) 108.6

C(8)-C(7)-C(12) 119.1(6)

C(8)-C(7)-C(6) 121.5(6)

C(12)-C(7)-C(6) 119.4(6)

C(7)-C(8)-C(9) 120.6(6)

C(7)-C(8)-H(8) 119.7

C(9)-C(8)-H(8) 119.7

C(10)-C(9)-C(8) 120.1(6)

C(10)-C(9)-H(9) 119.9

C(8)-C(9)-H(9) 119.9

C(11)-C(10)-C(9) 119.8(6)

C(11)-C(10)-H(10) 120.1

C(9)-C(10)-H(10) 120.1

C(10)-C(11)-C(12) 120.6(6)

C(10)-C(11)-H(11) 119.7

C(12)-C(11)-H(11) 119.7

C(11)-C(12)-C(7) 119.9(6)

C(11)-C(12)-H(12) 120.0

C(7)-C(12)-H(12) 120.0

C(21)-C(13)-C(14) 110.7(4)

C(21)-C(13)-C(5) 108.3(4)

C(14)-C(13)-C(5) 113.2(4)

C(21)-C(13)-H(13) 108.2

C(14)-C(13)-H(13) 108.2

C(5)-C(13)-H(13) 108.2

C(15)-C(14)-C(19) 117.1(5)

C(15)-C(14)-C(13) 120.6(5)

C(19)-C(14)-C(13) 122.3(5)

C(16)-C(15)-C(14) 121.7(5)

C(16)-C(15)-H(15) 119.1

C(14)-C(15)-H(15) 119.1

C(15)-C(16)-C(17) 119.7(5)

C(15)-C(16)-H(16) 120.1

C(17)-C(16)-H(16) 120.1

O(5)-C(17)-C(18) 125.0(5)

O(5)-C(17)-C(16) 115.3(5)

C(18)-C(17)-C(16) 119.7(5)

C(19)-C(18)-C(17) 119.4(5)

C(19)-C(18)-H(18) 120.3

C(17)-C(18)-H(18) 120.3

C(18)-C(19)-C(14) 122.4(5)

C(18)-C(19)-H(19) 118.8

C(14)-C(19)-H(19) 118.8

O(5)-C(20)-H(20A) 109.5

O(5)-C(20)-H(20B) 109.5

H(20A)-C(20)-H(20B) 109.5

O(5)-C(20)-H(20C) 109.5

H(20A)-C(20)-H(20C) 109.5

H(20B)-C(20)-H(20C) 109.5

N(1)-C(21)-C(13) 112.5(5)

N(1)-C(21)-H(21A) 109.1

C(13)-C(21)-H(21A) 109.1

N(1)-C(21)-H(21B) 109.1

C(13)-C(21)-H(21B) 109.1

H(21A)-C(21)-H(21B) 107.8

C(3)-C(22)-H(22A) 109.5

C(3)-C(22)-H(22B) 109.5

H(22A)-C(22)-H(22B) 109.5

C(3)-C(22)-H(22C) 109.5

202

H(22A)-C(22)-H(22C) 109.5

H(22B)-C(22)-H(22C) 109.5

C(3)-C(23)-H(23A) 109.5

C(3)-C(23)-H(23B) 109.5

H(23A)-C(23)-H(23B) 109.5

C(3)-C(23)-H(23C) 109.5

H(23A)-C(23)-H(23C) 109.5

H(23B)-C(23)-H(23C) 109.5

O(6)-N(1)-O(7) 124.9(6)

O(6)-N(1)-C(21) 118.0(5)

O(7)-N(1)-C(21) 117.0(6)

C(3)-O(1)-C(2) 109.7(5)

C(4)-O(2)-C(3) 110.1(5)

C(4)-O(3)-C(5) 109.4(4)

C(1)-O(4)-C(6) 112.9(4)

C(17)-O(5)-C(20) 116.4(5)

_____________________________________________________________

Anisotropic displacement parameters [A2 × 10

3]. The anisotropic displacement factor

exponent takes the form: -2 pi2 [h

2 a*

2 U11 + ... + 2 h k a* b* U12]

_______________________________________________________________________

U11 U22 U33 U23 U13 U12

_______________________________________________________________________

C(1) 34(3) 37(3) 24(3) 0(2) -2(2) 17(3)

C(2) 38(3) 40(3) 34(3) 6(3) 7(3) 20(3)

C(3) 39(4) 69(5) 36(4) 6(3) 11(3) 26(3)

C(4) 39(3) 41(4) 34(3) 7(3) 7(3) 15(3)

C(5) 34(3) 37(3) 24(3) -1(3) 1(2) 20(3)

C(6) 47(4) 45(4) 43(4) 11(3) 5(3) 32(3)

C(7) 45(3) 35(3) 34(3) 6(3) -3(3) 29(3)

C(8) 46(4) 34(3) 49(4) -4(3) -8(3) 24(3)

C(9) 71(5) 44(4) 49(4) -18(3) -9(4) 39(4)

C(10) 61(4) 65(5) 31(3) -3(3) 2(3) 47(4)

C(11) 40(3) 52(4) 30(3) 2(3) -6(3) 29(3)

C(12) 48(4) 38(3) 24(3) -3(3) -8(3) 29(3)

C(13) 35(3) 34(3) 23(3) 1(2) 0(2) 20(3)

C(14) 38(3) 31(3) 23(3) 4(2) 3(2) 25(3)

C(15) 38(3) 34(3) 22(3) -1(2) 2(2) 20(3)

C(16) 37(3) 43(3) 31(3) 7(3) 4(3) 26(3)

C(17) 35(3) 27(3) 32(3) 10(2) -4(3) 17(3)

C(18) 45(4) 32(3) 23(3) -1(2) -7(3) 18(3)

C(19) 43(3) 37(3) 28(3) 4(3) 10(3) 26(3)

C(20) 60(5) 51(4) 46(4) 2(4) -20(4) 13(4)

C(21) 32(3) 39(3) 37(3) 4(3) 2(3) 19(3)

C(22) 58(5) 99(7) 70(6) 33(5) 15(5) 22(5)

C(23) 64(5) 98(7) 103(8) -9(6) 24(5) 48(5)

N(1) 33(3) 49(3) 48(3) 11(3) -10(3) 19(3)

O(1) 41(2) 67(3) 27(2) 6(2) 10(2) 29(2)

O(2) 34(2) 94(4) 45(3) 18(3) 8(2) 31(3)

O(3) 33(2) 42(2) 40(2) 4(2) -1(2) 19(2)

O(4) 37(2) 37(2) 26(2) 4(2) 4(2) 24(2)

O(5) 37(2) 49(3) 45(3) 2(2) -11(2) 15(2)

O(6) 68(3) 80(4) 38(3) 16(3) 11(3) 46(3)

O(7) 68(3) 44(3) 84(4) 21(3) 4(3) 24(3)

_______________________________________________________________________

203

Hydrogen coordinates [× 104] and isotropic displacement parameters [A

2 × 10

3]

________________________________________________________________

x y z U(eq)

________________________________________________________________

H(1) 3886 3929 3015 38

H(2) 2615 2544 2677 45

H(4) 1965 2757 1151 48

H(5) 3296 4668 2528 37

H(6A) 3615 2392 1773 49

H(6B) 4328 3088 2524 49

H(8) 3943 1919 -3 49

H(9) 4880 1975 -1367 60

H(10) 6131 3096 -1457 55

H(11) 6464 4129 -123 46

H(12) 5544 4068 1284 40

H(13) 3931 4641 185 35

H(15) 5297 5208 -65 37

H(16) 6593 5941 586 41

H(18) 5841 6402 3734 41

H(19) 4554 5695 3041 40

H(20A) 7113 7507 3567 89

H(20B) 7898 7449 3693 89

H(20C) 7088 6782 4279 89

H(21A) 3116 5230 286 42

H(21B) 3714 5857 1247 42

H(22A) 1107 1997 3968 125

H(22B) 594 2400 4315 125

H(22C) 1278 2483 5204 125

H(23A) 1820 3955 5057 128

H(23B) 1197 3866 4041 128

H(23C) 2125 4378 3773 128

________________________________________________________________

Torsion angles [.°.]

________________________________________________________________

O(4)-C(1)-C(2)-O(1) 168.3(4)

C(5)-C(1)-C(2)-O(1) -77.4(5)

O(4)-C(1)-C(2)-C(4) -82.9(6)

C(5)-C(1)-C(2)-C(4) 31.4(6)

O(1)-C(2)-C(4)-O(2) -24.6(6)

C(1)-C(2)-C(4)-O(2) -137.8(5)

O(1)-C(2)-C(4)-O(3) 96.9(5)

C(1)-C(2)-C(4)-O(3) -16.4(6)

O(4)-C(1)-C(5)-O(3) 80.1(5)

C(2)-C(1)-C(5)-O(3) -36.2(5)

O(4)-C(1)-C(5)-C(13) -38.8(6)

C(2)-C(1)-C(5)-C(13) -155.2(5)

O(4)-C(6)-C(7)-C(8) -108.2(6)

O(4)-C(6)-C(7)-C(12) 73.3(7)

C(12)-C(7)-C(8)-C(9) 1.3(9)

C(6)-C(7)-C(8)-C(9) -177.2(6)

C(7)-C(8)-C(9)-C(10) -1.9(10)

C(8)-C(9)-C(10)-C(11) 1.5(10)

C(9)-C(10)-C(11)-C(12) -0.6(9)

C(10)-C(11)-C(12)-C(7) 0.0(9)

C(8)-C(7)-C(12)-C(11) -0.4(8)

C(6)-C(7)-C(12)-C(11) 178.2(5)

O(3)-C(5)-C(13)-C(21) 62.8(6)

C(1)-C(5)-C(13)-C(21) -180.0(5)

O(3)-C(5)-C(13)-C(14) -174.1(4)

C(1)-C(5)-C(13)-C(14) -56.9(6)

204

C(21)-C(13)-C(14)-C(15) -103.9(6)

C(5)-C(13)-C(14)-C(15) 134.3(5)

C(21)-C(13)-C(14)-C(19) 73.7(6)

C(5)-C(13)-C(14)-C(19) -48.0(7)

C(19)-C(14)-C(15)-C(16) -1.8(8)

C(13)-C(14)-C(15)-C(16) 175.9(5)

C(14)-C(15)-C(16)-C(17) 0.7(8)

C(15)-C(16)-C(17)-O(5) -177.4(5)

C(15)-C(16)-C(17)-C(18) 1.5(8)

O(5)-C(17)-C(18)-C(19) 176.4(5)

C(16)-C(17)-C(18)-C(19) -2.4(8)

C(17)-C(18)-C(19)-C(14) 1.2(8)

C(15)-C(14)-C(19)-C(18) 0.9(8)

C(13)-C(14)-C(19)-C(18) -176.8(5)

C(14)-C(13)-C(21)-N(1) 62.8(6)

C(5)-C(13)-C(21)-N(1) -172.6(5)

C(13)-C(21)-N(1)-O(6) 35.0(7)

C(13)-C(21)-N(1)-O(7) -147.1(5)

O(2)-C(3)-O(1)-C(2) -13.4(7)

C(23)-C(3)-O(1)-C(2) -132.3(7)

C(22)-C(3)-O(1)-C(2) 103.1(7)

C(4)-C(2)-O(1)-C(3) 23.2(6)

C(1)-C(2)-O(1)-C(3) 132.9(5)

O(3)-C(4)-O(2)-C(3) -100.2(6)

C(2)-C(4)-O(2)-C(3) 17.5(7)

O(1)-C(3)-O(2)-C(4) -3.3(8)

C(23)-C(3)-O(2)-C(4) 114.6(7)

C(22)-C(3)-O(2)-C(4) -121.6(7)

O(2)-C(4)-O(3)-C(5) 109.7(5)

C(2)-C(4)-O(3)-C(5) -7.0(6)

C(1)-C(5)-O(3)-C(4) 27.9(6)

C(13)-C(5)-O(3)-C(4) 151.6(5)

C(5)-C(1)-O(4)-C(6) 174.3(5)

C(2)-C(1)-O(4)-C(6) -76.2(6)

C(7)-C(6)-O(4)-C(1) -157.3(5)

C(18)-C(17)-O(5)-C(20) -4.5(8)

C(16)-C(17)-O(5)-C(20) 174.2(5)

________________________________________________________________

Hydrogen bonds [Å and °]

____________________________________________________________________________

D-H...A d(D-H) d(H...A) d(D...A) <(DHA)

205

Crystal data and structure refinement for 141 (s3554m)

Empirical formula C23 H27 N O7

Formula weight 429.46

Temperature 100(2) K

Wavelength 0.71073 A

Crystal system, space group Orthorhombic, P2(1)2(1)2(1)

Unit cell dimensions a = 8.7895(14) Å α = 90°

b = 15.401(3) Å β = 90°

c = 15.951(3) Å γ = 90°

Volume 2159.2(6) A3

Z, Calculated density 4, 1.321 Mg/m3

Absorption coefficient 0.098 mm-1

F(000) 912

Crystal size 0.30 × 0.15 × 0.05 mm

Theta range for data collection 2.55 to 28.30°

Limiting indices -11<=h<=9, -20<=k<=16, -16<=l<=20

Reflections collected / unique 13773 / 2938 [R(int) = 0.1156]

Completeness to theta = 25.50 99.9%

Absorption correction None

Max. and min. transmission 0.9951 and 0.9712

Refinement method Full-matrix least-squares on F2

Data / restraints / parameters 2938 / 0 / 283

Goodness-of-fit on F2 0.769

Final R indices [I>2sigma(I)] R1 = 0.0589, wR2 = 0.1070

R indices (all data) R1 = 0.1100, wR2 = 0.1307

Absolute structure parameter 3(2)

Largest diff. peak and hole 0.221 and -0.233 e.A-3

206

Atomic coordinates [× 104] and equivalent isotropic displacement parameters [A

2 × 10

3]

U(eq) is defined as one third of the trace of the orthogonalized Uij tensor.

________________________________________________________________

x y z U(eq)

________________________________________________________________

C(1) 9071(5) 6187(3) 8416(3) 13(1)

C(2) 10140(5) 6720(3) 7871(3) 13(1)

C(3) 9752(5) 7575(3) 6694(3) 16(1)

C(4) 9884(4) 7664(3) 8154(3) 14(1)

C(5) 7774(4) 6840(3) 8545(3) 12(1)

C(6) 10641(5) 5222(3) 9200(3) 24(1)

C(7) 10959(5) 4971(3) 10099(3) 17(1)

C(8) 10179(5) 4303(3) 10483(3) 20(1)

C(9) 10507(6) 4068(3) 11307(3) 26(1)

C(10) 11579(5) 4524(3) 11756(3) 21(1)

C(11) 12346(5) 5201(3) 11380(3) 27(1)

C(12) 12074(5) 5413(3) 10554(3) 22(1)

C(13) 6800(5) 6685(3) 9320(3) 15(1)

C(14) 6197(4) 5755(3) 9358(3) 14(1)

C(15) 6194(5) 5315(3) 10133(3) 17(1)

C(16) 5680(5) 4468(3) 10176(3) 20(1)

C(17) 5139(5) 4054(3) 9464(3) 25(1)

C(18) 5118(5) 4473(3) 8701(3) 24(1)

C(19) 5636(5) 5327(3) 8652(3) 18(1)

C(20) 6860(6) 5337(3) 11588(3) 28(1)

C(21) 5548(4) 7378(3) 9425(3) 16(1)

C(22) 8418(5) 7744(3) 6124(3) 23(1)

C(23) 11303(5) 7672(3) 6290(3) 25(1)

N(1) 4292(4) 7260(2) 8800(3) 22(1)

O(1) 9575(3) 6712(2) 7028(2) 16(1)

O(2) 9639(3) 8138(2) 7406(2) 21(1)

O(3) 8554(3) 7660(2) 8666(2) 16(1)

O(4) 9707(3) 5988(2) 9209(2) 15(1)

O(5) 6745(4) 5777(2) 10798(2) 23(1)

O(6) 3089(4) 6951(2) 9052(2) 30(1)

O(7) 4530(4) 7486(2) 8072(2) 34(1)

________________________________________________________________

Bond lengths [ Å ] and angles [ ° ]

_____________________________________________________________

C(1)-O(4) 1.416(5)

C(1)-C(2) 1.521(6)

C(1)-C(5) 1.534(5)

C(1)-H(1) 1.0000

C(2)-O(1) 1.434(5)

C(2)-C(4) 1.539(5)

C(2)-H(2) 1.0000

C(3)-O(2) 1.431(5)

C(3)-O(1) 1.440(5)

C(3)-C(22) 1.507(6)

C(3)-C(23) 1.516(6)

C(4)-O(2) 1.416(5)

C(4)-O(3) 1.425(5)

C(4)-H(4) 1.0000

C(5)-O(3) 1.450(5)

C(5)-C(13) 1.522(6)

C(5)-H(5) 1.0000

C(6)-O(4) 1.438(5)

C(6)-C(7) 1.512(6)

C(6)-H(6A) 0.9900

207

C(6)-H(6B) 0.9900

C(7)-C(8) 1.380(6)

C(7)-C(12) 1.396(6)

C(8)-C(9) 1.393(6)

C(8)-H(8) 0.9500

C(9)-C(10) 1.376(6)

C(9)-H(9) 0.9500

C(10)-C(11) 1.380(6)

C(10)-H(10) 0.9500

C(11)-C(12) 1.378(7)

C(11)-H(11) 0.9500

C(12)-H(12) 0.9500

C(13)-C(14) 1.529(6)

C(13)-C(21) 1.542(5)

C(13)-H(13) 1.0000

C(14)-C(19) 1.395(6)

C(14)-C(15) 1.408(6)

C(15)-O(5) 1.366(5)

C(15)-C(16) 1.384(6)

C(16)-C(17) 1.387(6)

C(16)-H(16) 0.9500

C(17)-C(18) 1.378(6)

C(17)-H(17) 0.9500

C(18)-C(19) 1.393(6)

C(18)-H(18) 0.9500

C(19)-H(19) 0.9500

C(20)-O(5) 1.435(5)

C(20)-H(20A) 0.9800

C(20)-H(20B) 0.9800

C(20)-H(20C) 0.9800

C(21)-N(1) 1.498(5)

C(21)-H(21A) 0.9900

C(21)-H(21B) 0.9900

C(22)-H(22A) 0.9800

C(22)-H(22B) 0.9800

C(22)-H(22C) 0.9800

C(23)-H(23A) 0.9800

C(23)-H(23B) 0.9800

C(23)-H(23C) 0.9800

N(1)-O(6) 1.227(5)

N(1)-O(7) 1.231(5)

O(4)-C(1)-C(2) 112.5(3)

O(4)-C(1)-C(5) 108.4(3)

C(2)-C(1)-C(5) 100.5(3)

O(4)-C(1)-H(1) 111.6

C(2)-C(1)-H(1) 111.6

C(5)-C(1)-H(1) 111.6

O(1)-C(2)-C(1) 108.5(3)

O(1)-C(2)-C(4) 103.5(3)

C(1)-C(2)-C(4) 104.6(3)

O(1)-C(2)-H(2) 113.1

C(1)-C(2)-H(2) 113.1

C(4)-C(2)-H(2) 113.1

O(2)-C(3)-O(1) 105.1(3)

O(2)-C(3)-C(22) 108.7(3)

O(1)-C(3)-C(22) 107.4(3)

O(2)-C(3)-C(23) 109.9(3)

O(1)-C(3)-C(23) 110.2(3)

C(22)-C(3)-C(23) 115.2(4)

O(2)-C(4)-O(3) 111.1(3)

O(2)-C(4)-C(2) 105.1(3)

O(3)-C(4)-C(2) 106.5(3)

O(2)-C(4)-H(4) 111.3

O(3)-C(4)-H(4) 111.3

C(2)-C(4)-H(4) 111.3

O(3)-C(5)-C(13) 107.2(3)

O(3)-C(5)-C(1) 103.7(3)

208

C(13)-C(5)-C(1) 115.1(3)

O(3)-C(5)-H(5) 110.2

C(13)-C(5)-H(5) 110.2

C(1)-C(5)-H(5) 110.2

O(4)-C(6)-C(7) 107.8(3)

O(4)-C(6)-H(6A) 110.2

C(7)-C(6)-H(6A) 110.2

O(4)-C(6)-H(6B) 110.2

C(7)-C(6)-H(6B) 110.2

H(6A)-C(6)-H(6B) 108.5

C(8)-C(7)-C(12) 118.8(4)

C(8)-C(7)-C(6) 121.3(4)

C(12)-C(7)-C(6) 119.9(4)

C(7)-C(8)-C(9) 120.6(4)

C(7)-C(8)-H(8) 119.7

C(9)-C(8)-H(8) 119.7

C(10)-C(9)-C(8) 120.1(5)

C(10)-C(9)-H(9) 120.0

C(8)-C(9)-H(9) 120.0

C(9)-C(10)-C(11) 119.5(5)

C(9)-C(10)-H(10) 120.2

C(11)-C(10)-H(10) 120.2

C(10)-C(11)-C(12) 120.7(5)

C(10)-C(11)-H(11) 119.6

C(12)-C(11)-H(11) 119.6

C(11)-C(12)-C(7) 120.2(4)

C(11)-C(12)-H(12) 119.9

C(7)-C(12)-H(12) 119.9

C(5)-C(13)-C(14) 112.0(3)

C(5)-C(13)-C(21) 112.4(3)

C(14)-C(13)-C(21) 113.4(3)

C(5)-C(13)-H(13) 106.1

C(14)-C(13)-H(13) 106.1

C(21)-C(13)-H(13) 106.1

C(19)-C(14)-C(15) 118.7(4)

C(19)-C(14)-C(13) 122.2(4)

C(15)-C(14)-C(13) 119.1(4)

O(5)-C(15)-C(16) 124.6(4)

O(5)-C(15)-C(14) 115.5(4)

C(16)-C(15)-C(14) 119.9(4)

C(17)-C(16)-C(15) 120.3(4)

C(17)-C(16)-H(16) 119.9

C(15)-C(16)-H(16) 119.9

C(18)-C(17)-C(16) 120.8(4)

C(18)-C(17)-H(17) 119.6

C(16)-C(17)-H(17) 119.6

C(17)-C(18)-C(19) 119.2(4)

C(17)-C(18)-H(18) 120.4

C(19)-C(18)-H(18) 120.4

C(18)-C(19)-C(14) 121.1(4)

C(18)-C(19)-H(19) 119.5

C(14)-C(19)-H(19) 119.5

O(5)-C(20)-H(20A) 109.5

O(5)-C(20)-H(20B) 109.5

H(20A)-C(20)-H(20B) 109.5

O(5)-C(20)-H(20C) 109.5

H(20A)-C(20)-H(20C) 109.5

H(20B)-C(20)-H(20C) 109.5

N(1)-C(21)-C(13) 111.6(3)

N(1)-C(21)-H(21A) 109.3

C(13)-C(21)-H(21A) 109.3

N(1)-C(21)-H(21B) 109.3

C(13)-C(21)-H(21B) 109.3

H(21A)-C(21)-H(21B) 108.0

C(3)-C(22)-H(22A) 109.5

C(3)-C(22)-H(22B) 109.5

H(22A)-C(22)-H(22B) 109.5

C(3)-C(22)-H(22C) 109.5

209

H(22A)-C(22)-H(22C) 109.5

H(22B)-C(22)-H(22C) 109.5

C(3)-C(23)-H(23A) 109.5

C(3)-C(23)-H(23B) 109.5

H(23A)-C(23)-H(23B) 109.5

C(3)-C(23)-H(23C) 109.5

H(23A)-C(23)-H(23C) 109.5

H(23B)-C(23)-H(23C) 109.5

O(6)-N(1)-O(7) 124.4(4)

O(6)-N(1)-C(21) 117.7(4)

O(7)-N(1)-C(21) 117.9(4)

C(2)-O(1)-C(3) 107.5(3)

C(4)-O(2)-C(3) 110.2(3)

C(4)-O(3)-C(5) 108.4(3)

C(1)-O(4)-C(6) 113.2(3)

C(15)-O(5)-C(20) 117.4(3)

_____________________________________________________________

Anisotropic displacement parameters [A2 × 10

3]. The anisotropic displacement factor

exponent takes the form: -2 pi2 [h

2 a*

2 U11 + ... + 2 h k a* b* U12]

_______________________________________________________________________

U11 U22 U33 U23 U13 U12

_______________________________________________________________________

C(1) 17(2) 11(2) 9(2) -1(2) -5(2) 1(2)

C(2) 16(2) 12(2) 13(2) -1(2) -2(2) 2(2)

C(3) 21(2) 11(2) 15(2) 0(2) 1(2) 1(2)

C(4) 11(2) 15(2) 17(2) 3(2) 2(2) -1(2)

C(5) 13(2) 9(2) 14(2) 2(2) 2(2) -2(2)

C(6) 32(3) 19(2) 21(3) 2(2) 1(2) 7(2)

C(7) 19(2) 15(2) 17(3) -2(2) 4(2) 9(2)

C(8) 19(2) 20(2) 20(3) -4(2) -2(2) 2(2)

C(9) 31(3) 19(3) 27(3) 4(2) 6(2) 2(2)

C(10) 21(2) 26(3) 16(3) 3(2) -1(2) 9(2)

C(11) 19(3) 24(3) 37(3) 0(2) -2(2) 4(2)

C(12) 18(2) 17(2) 33(3) 5(2) 2(2) 4(2)

C(13) 15(2) 15(2) 14(2) -1(2) -6(2) 1(2)

C(14) 7(2) 20(2) 13(2) 2(2) 1(2) 2(2)

C(15) 11(2) 20(3) 20(3) -3(2) 2(2) 4(2)

C(16) 21(2) 18(3) 20(3) 8(2) 4(2) 5(2)

C(17) 28(3) 14(2) 33(3) 3(2) 0(2) -3(2)

C(18) 24(2) 24(3) 23(3) -2(2) -5(2) -5(2)

C(19) 13(2) 24(3) 17(3) 8(2) -2(2) -3(2)

C(20) 37(3) 29(3) 18(3) 7(2) -1(2) 12(2)

C(21) 11(2) 22(2) 15(2) 0(2) -3(2) 1(2)

C(22) 23(3) 25(3) 22(3) 4(2) -4(2) -2(2)

C(23) 23(2) 28(3) 23(3) 2(2) 9(2) -4(2)

N(1) 19(2) 21(2) 27(3) -1(2) -1(2) 8(2)

O(1) 21(2) 12(2) 14(2) 2(1) 1(1) -1(1)

O(2) 34(2) 16(2) 13(2) 2(1) 1(2) 1(1)

O(3) 17(2) 14(2) 18(2) -2(1) 5(1) -1(1)

O(4) 19(2) 12(2) 15(2) -1(1) 0(1) 4(1)

O(5) 37(2) 18(2) 13(2) 3(1) 1(2) 3(2)

O(6) 16(2) 37(2) 39(2) 6(2) -4(2) -4(2)

O(7) 33(2) 51(3) 18(2) 6(2) 1(2) 11(2)

_______________________________________________________________________

210

Hydrogen coordinates [× 104] and isotropic displacement parameters [A

2 × 10

3]

________________________________________________________________

x y z U(eq)

________________________________________________________________

H(1) 8712 5653 8120 15

H(2) 11226 6532 7915 16

H(4) 10783 7892 8469 17

H(5) 7119 6866 8033 14

H(6A) 11607 5339 8901 28

H(6B) 10106 4744 8908 28

H(8) 9411 4000 10183 23

H(9) 9991 3593 11558 31

H(10) 11788 4373 12322 25

H(11) 13069 5524 11693 32

H(12) 12646 5861 10293 27

H(13) 7494 6753 9812 18

H(16) 5696 4168 10697 24

H(17) 4778 3473 9502 30

H(18) 4756 4184 8214 28

H(19) 5607 5622 8130 22

H(20A) 5840 5181 11785 42

H(20B) 7348 5719 11999 42

H(20C) 7470 4809 11520 42

H(21A) 5123 7341 9999 19

H(21B) 6000 7962 9354 19

H(22A) 8470 7353 5640 35

H(22B) 8448 8348 5930 35

H(22C) 7468 7641 6430 35

H(23A) 12094 7503 6691 37

H(23B) 11456 8278 6123 37

H(23C) 11362 7298 5794 37

________________________________________________________________

Torsion angles [.°.]

________________________________________________________________

O(4)-C(1)-C(2)-O(1) 166.2(3)

C(5)-C(1)-C(2)-O(1) -78.7(4)

O(4)-C(1)-C(2)-C(4) -83.8(4)

C(5)-C(1)-C(2)-C(4) 31.3(4)

O(1)-C(2)-C(4)-O(2) -16.5(4)

C(1)-C(2)-C(4)-O(2) -130.0(3)

O(1)-C(2)-C(4)-O(3) 101.5(3)

C(1)-C(2)-C(4)-O(3) -12.0(4)

O(4)-C(1)-C(5)-O(3) 78.0(4)

C(2)-C(1)-C(5)-O(3) -40.2(4)

O(4)-C(1)-C(5)-C(13) -38.7(5)

C(2)-C(1)-C(5)-C(13) -156.9(3)

O(4)-C(6)-C(7)-C(8) 101.7(5)

O(4)-C(6)-C(7)-C(12) -79.0(5)

C(12)-C(7)-C(8)-C(9) -0.6(6)

C(6)-C(7)-C(8)-C(9) 178.6(4)

C(7)-C(8)-C(9)-C(10) 2.4(7)

C(8)-C(9)-C(10)-C(11) -1.4(7)

C(9)-C(10)-C(11)-C(12) -1.4(7)

C(10)-C(11)-C(12)-C(7) 3.2(7)

C(8)-C(7)-C(12)-C(11) -2.2(6)

C(6)-C(7)-C(12)-C(11) 178.5(4)

O(3)-C(5)-C(13)-C(14) -167.4(3)

C(1)-C(5)-C(13)-C(14) -52.6(5)

O(3)-C(5)-C(13)-C(21) 63.6(4)

C(1)-C(5)-C(13)-C(21) 178.4(3)

211

C(5)-C(13)-C(14)-C(19) -42.1(5)

C(21)-C(13)-C(14)-C(19) 86.4(5)

C(5)-C(13)-C(14)-C(15) 138.4(4)

C(21)-C(13)-C(14)-C(15) -93.1(4)

C(19)-C(14)-C(15)-O(5) -179.4(4)

C(13)-C(14)-C(15)-O(5) 0.1(5)

C(19)-C(14)-C(15)-C(16) 1.7(6)

C(13)-C(14)-C(15)-C(16) -178.8(4)

O(5)-C(15)-C(16)-C(17) 180.0(4)

C(14)-C(15)-C(16)-C(17) -1.2(6)

C(15)-C(16)-C(17)-C(18) 0.7(7)

C(16)-C(17)-C(18)-C(19) -0.6(7)

C(17)-C(18)-C(19)-C(14) 1.1(7)

C(15)-C(14)-C(19)-C(18) -1.7(6)

C(13)-C(14)-C(19)-C(18) 178.8(4)

C(5)-C(13)-C(21)-N(1) 73.3(4)

C(14)-C(13)-C(21)-N(1) -55.0(5)

C(13)-C(21)-N(1)-O(6) 104.9(4)

C(13)-C(21)-N(1)-O(7) -75.8(5)

C(1)-C(2)-O(1)-C(3) 138.8(3)

C(4)-C(2)-O(1)-C(3) 28.1(4)

O(2)-C(3)-O(1)-C(2) -29.3(4)

C(22)-C(3)-O(1)-C(2) -144.9(3)

C(23)-C(3)-O(1)-C(2) 89.0(4)

O(3)-C(4)-O(2)-C(3) -115.9(4)

C(2)-C(4)-O(2)-C(3) -1.1(4)

O(1)-C(3)-O(2)-C(4) 18.3(4)

C(22)-C(3)-O(2)-C(4) 133.0(4)

C(23)-C(3)-O(2)-C(4) -100.2(4)

O(2)-C(4)-O(3)-C(5) 99.9(4)

C(2)-C(4)-O(3)-C(5) -14.1(4)

C(13)-C(5)-O(3)-C(4) 156.8(3)

C(1)-C(5)-O(3)-C(4) 34.6(4)

C(2)-C(1)-O(4)-C(6) -85.5(4)

C(5)-C(1)-O(4)-C(6) 164.3(3)

C(7)-C(6)-O(4)-C(1) -167.7(3)

C(16)-C(15)-O(5)-C(20) 2.9(6)

C(14)-C(15)-O(5)-C(20) -175.9(4)

________________________________________________________________

Hydrogen bonds [Å and °]

____________________________________________________________________________

D-H...A d(D-H) d(H...A) d(D...A) <(DHA)

212

Crystal data and structure refinement for 143 (s3490bm)

Empirical formula C26 H27 N O6

Formula weight 449.49

Temperature 100(2) K

Wavelength 0.71073 A

Crystal system, space group Orthorhombic, P212121

Unit cell dimensions a = 9.183(2) Å α = 90°

b = 12.549(3) Å β = 90°

c = 19.240(4) Å γ = 90°

Volume 2217.0(8) Å3

Z, Calculated density 4, 1.347 Mg/m3

Absorption coefficient 0.096 mm-1

F(000) 952

Crystal size 0.45 × 0.30 × 0.25 mm

Theta range for data collection 2.12 to 26.40°

Limiting indices -11<=h<=11, -15<=k<=15, -23<=l<=24

Reflections collected / unique 17784 / 2584 [R(int) = 0.0424]

Completeness to theta = 26.40 99.8%

Absorption correction None

Refinement method Full-matrix least-squares on F2

Data / restraints / parameters 2584 / 0 / 300

Goodness-of-fit on F2 1.257

Final R indices [I>2sigma(I)] R1 = 0.0351, wR2 = 0.0853

R indices (all data) R1 = 0.0366, wR2 = 0.0859

Largest diff. peak and hole 0.239 and -0.163 e.A-3

213

Atomic coordinates [× 104] and equivalent isotropic displacement parameters [A

2 × 10

3]

U(eq) is defined as one third of the trace of the orthogonalized Uij tensor.

________________________________________________________________

x y z U(eq)

________________________________________________________________

O(1) 1689(2) 4222(1) 256(1) 19(1)

O(2) 1049(2) 3866(1) -888(1) 24(1)

O(3) 2488(2) 5220(1) -1248(1) 21(1)

O(4) 1579(2) 4161(1) 1962(1) 26(1)

O(5) 1077(2) 2637(1) 1499(1) 30(1)

O(6) 2647(2) 6411(1) 464(1) 18(1)

N(1) 1883(2) 3397(1) 1598(1) 20(1)

C(1) 994(2) 4619(2) -342(1) 19(1)

C(2) 1897(2) 5569(1) -605(1) 19(1)

C(3) 3111(2) 5689(1) -64(1) 17(1)

C(4) 3186(2) 4565(1) 238(1) 18(1)

C(5) 3819(2) 4438(2) 966(1) 18(1)

C(6) 3382(2) 3363(2) 1282(1) 21(1)

C(7) 1558(2) 4393(2) -1502(1) 22(1)

C(8) 2474(3) 3636(2) -1923(1) 29(1)

C(9) 283(2) 4854(2) -1900(1) 27(1)

C(10) 2935(2) 7490(2) 277(1) 21(1)

C(11) 2317(2) 8237(2) 817(1) 18(1)

C(12) 2105(2) 9300(2) 638(1) 20(1)

C(13) 1574(2) 10023(2) 1119(1) 25(1)

C(14) 1230(2) 9688(2) 1787(1) 26(1)

C(15) 1433(2) 8630(2) 1969(1) 26(1)

C(16) 1973(2) 7910(2) 1488(1) 21(1)

C(17) 5477(2) 4527(2) 964(1) 19(1)

C(18) 6284(2) 3688(2) 714(1) 23(1)

C(19) 7817(2) 3686(2) 746(1) 27(1)

C(20) 8538(2) 4533(2) 1023(1) 26(1)

C(21) 7773(2) 5428(2) 1266(1) 23(1)

C(22) 8518(2) 6335(2) 1528(1) 30(1)

C(23) 7793(3) 7214(2) 1749(1) 31(1)

C(24) 6263(3) 7223(2) 1730(1) 27(1)

C(25) 5492(2) 6369(2) 1480(1) 23(1)

C(26) 6210(2) 5443(2) 1239(1) 20(1)

________________________________________________________________

Bond lengths [ Å ] and angles [ ° ]

_____________________________________________________________

O(1)-C(1) 1.407(2)

O(1)-C(4) 1.441(2)

O(2)-C(1) 1.413(2)

O(2)-C(7) 1.434(2)

O(3)-C(2) 1.421(2)

O(3)-C(7) 1.430(2)

O(4)-N(1) 1.220(2)

O(5)-N(1) 1.223(2)

O(6)-C(3) 1.425(2)

O(6)-C(10) 1.426(2)

N(1)-C(6) 1.505(3)

C(1)-C(2) 1.538(3)

C(1)-H(1) 1.0000

C(2)-C(3) 1.532(3)

C(2)-H(2) 1.0000

C(3)-C(4) 1.527(3)

C(3)-H(3) 1.0000

C(4)-C(5) 1.524(3)

214

C(4)-H(4) 1.0000

C(5)-C(17) 1.527(3)

C(5)-C(6) 1.533(3)

C(5)-H(5) 1.0000

C(6)-H(6A) 0.9900

C(6)-H(6B) 0.9900

C(7)-C(8) 1.505(3)

C(7)-C(9) 1.513(3)

C(8)-H(8A) 0.9800

C(8)-H(8B) 0.9800

C(8)-H(8C) 0.9800

C(9)-H(9A) 0.9800

C(9)-H(9B) 0.9800

C(9)-H(9C) 0.9800

C(10)-C(11) 1.510(3)

C(10)-H(10A) 0.9900

C(10)-H(10B) 0.9900

C(11)-C(16) 1.391(3)

C(11)-C(12) 1.392(3)

C(12)-C(13) 1.384(3)

C(12)-H(12) 0.9500

C(13)-C(14) 1.389(3)

C(13)-H(13) 0.9500

C(14)-C(15) 1.385(3)

C(14)-H(14) 0.9500

C(15)-C(16) 1.386(3)

C(15)-H(15) 0.9500

C(16)-H(16) 0.9500

C(17)-C(18) 1.375(3)

C(17)-C(26) 1.433(3)

C(18)-C(19) 1.409(3)

C(18)-H(18) 0.9500

C(19)-C(20) 1.361(3)

C(19)-H(19) 0.9500

C(20)-C(21) 1.405(3)

C(20)-H(20) 0.9500

C(21)-C(22) 1.420(3)

C(21)-C(26) 1.436(3)

C(22)-C(23) 1.356(3)

C(22)-H(22) 0.9500

C(23)-C(24) 1.406(3)

C(23)-H(23) 0.9500

C(24)-C(25) 1.372(3)

C(24)-H(24) 0.9500

C(25)-C(26) 1.414(3)

C(25)-H(25) 0.9500

C(1)-O(1)-C(4) 107.92(14)

C(1)-O(2)-C(7) 108.38(14)

C(2)-O(3)-C(7) 107.07(15)

C(3)-O(6)-C(10) 111.61(14)

O(4)-N(1)-O(5) 124.30(17)

O(4)-N(1)-C(6) 117.62(16)

O(5)-N(1)-C(6) 117.98(16)

O(1)-C(1)-O(2) 110.75(15)

O(1)-C(1)-C(2) 107.40(15)

O(2)-C(1)-C(2) 104.80(14)

O(1)-C(1)-H(1) 111.2

O(2)-C(1)-H(1) 111.2

C(2)-C(1)-H(1) 111.2

O(3)-C(2)-C(3) 110.14(16)

O(3)-C(2)-C(1) 104.66(14)

C(3)-C(2)-C(1) 104.18(15)

O(3)-C(2)-H(2) 112.4

C(3)-C(2)-H(2) 112.4

C(1)-C(2)-H(2) 112.4

O(6)-C(3)-C(4) 109.26(14)

O(6)-C(3)-C(2) 109.20(15)

215

C(4)-C(3)-C(2) 101.58(15)

O(6)-C(3)-H(3) 112.1

C(4)-C(3)-H(3) 112.1

C(2)-C(3)-H(3) 112.1

O(1)-C(4)-C(5) 108.13(15)

O(1)-C(4)-C(3) 103.97(15)

C(5)-C(4)-C(3) 117.60(16)

O(1)-C(4)-H(4) 108.9

C(5)-C(4)-H(4) 108.9

C(3)-C(4)-H(4) 108.9

C(4)-C(5)-C(17) 111.72(15)

C(4)-C(5)-C(6) 110.88(16)

C(17)-C(5)-C(6) 109.03(16)

C(4)-C(5)-H(5) 108.4

C(17)-C(5)-H(5) 108.4

C(6)-C(5)-H(5) 108.4

N(1)-C(6)-C(5) 111.97(15)

N(1)-C(6)-H(6A) 109.2

C(5)-C(6)-H(6A) 109.2

N(1)-C(6)-H(6B) 109.2

C(5)-C(6)-H(6B) 109.2

H(6A)-C(6)-H(6B) 107.9

O(3)-C(7)-O(2) 104.32(14)

O(3)-C(7)-C(8) 107.93(18)

O(2)-C(7)-C(8) 109.51(16)

O(3)-C(7)-C(9) 111.00(16)

O(2)-C(7)-C(9) 109.95(17)

C(8)-C(7)-C(9) 113.69(17)

C(7)-C(8)-H(8A) 109.5

C(7)-C(8)-H(8B) 109.5

H(8A)-C(8)-H(8B) 109.5

C(7)-C(8)-H(8C) 109.5

H(8A)-C(8)-H(8C) 109.5

H(8B)-C(8)-H(8C) 109.5

C(7)-C(9)-H(9A) 109.5

C(7)-C(9)-H(9B) 109.5

H(9A)-C(9)-H(9B) 109.5

C(7)-C(9)-H(9C) 109.5

H(9A)-C(9)-H(9C) 109.5

H(9B)-C(9)-H(9C) 109.5

O(6)-C(10)-C(11) 110.23(15)

O(6)-C(10)-H(10A) 109.6

C(11)-C(10)-H(10A) 109.6

O(6)-C(10)-H(10B) 109.6

C(11)-C(10)-H(10B) 109.6

H(10A)-C(10)-H(10B) 108.1

C(16)-C(11)-C(12) 118.76(18)

C(16)-C(11)-C(10) 122.75(17)

C(12)-C(11)-C(10) 118.48(17)

C(13)-C(12)-C(11) 120.75(18)

C(13)-C(12)-H(12) 119.6

C(11)-C(12)-H(12) 119.6

C(12)-C(13)-C(14) 120.06(19)

C(12)-C(13)-H(13) 120.0

C(14)-C(13)-H(13) 120.0

C(15)-C(14)-C(13) 119.56(19)

C(15)-C(14)-H(14) 120.2

C(13)-C(14)-H(14) 120.2

C(14)-C(15)-C(16) 120.29(19)

C(14)-C(15)-H(15) 119.9

C(16)-C(15)-H(15) 119.9

C(15)-C(16)-C(11) 120.57(18)

C(15)-C(16)-H(16) 119.7

C(11)-C(16)-H(16) 119.7

C(18)-C(17)-C(26) 119.36(18)

C(18)-C(17)-C(5) 118.86(18)

C(26)-C(17)-C(5) 121.74(18)

C(17)-C(18)-C(19) 121.7(2)

216

C(17)-C(18)-H(18) 119.2

C(19)-C(18)-H(18) 119.2

C(20)-C(19)-C(18) 120.1(2)

C(20)-C(19)-H(19) 120.0

C(18)-C(19)-H(19) 120.0

C(19)-C(20)-C(21) 120.81(19)

C(19)-C(20)-H(20) 119.6

C(21)-C(20)-H(20) 119.6

C(20)-C(21)-C(22) 121.2(2)

C(20)-C(21)-C(26) 119.8(2)

C(22)-C(21)-C(26) 118.9(2)

C(23)-C(22)-C(21) 121.8(2)

C(23)-C(22)-H(22) 119.1

C(21)-C(22)-H(22) 119.1

C(22)-C(23)-C(24) 119.3(2)

C(22)-C(23)-H(23) 120.3

C(24)-C(23)-H(23) 120.3

C(25)-C(24)-C(23) 121.2(2)

C(25)-C(24)-H(24) 119.4

C(23)-C(24)-H(24) 119.4

C(24)-C(25)-C(26) 121.1(2)

C(24)-C(25)-H(25) 119.5

C(26)-C(25)-H(25) 119.5

C(25)-C(26)-C(17) 124.12(18)

C(25)-C(26)-C(21) 117.67(19)

C(17)-C(26)-C(21) 118.20(19)

_____________________________________________________________

217

Crystal data and structure refinement for 144 (s3526m)

Empirical formula C26 H27 N O6

Formula weight 449.49

Temperature 100(2) K

Wavelength 0.71073 A

Crystal system, space group Monoclinic, P2(1)

Unit cell dimensions a = 9.172(3) Å α = 90°

b = 13.659(4) Å β = 104.606(4)°

c = 9.308(3) Å γ = 90°

Volume 1128.4(5) Å3

Z, Calculated density 2, 1.323 Mg/m3

Absorption coefficient 0.094 mm-1

F(000) 476

Crystal size 0.45 × 0.20 × 0.20 mm

Theta range for data collection 2.26 to 23.26°

Limiting indices -10<=h<=10, -15<=k<=15, -10<=l<=10

Reflections collected / unique 6898 / 3236 [R(int) = 0.0656]

Completeness to theta = 23.26 99.9%

Absorption correction None

Refinement method Full-matrix least-squares on F2

Data / restraints / parameters 3236 / 98 / 300

Goodness-of-fit on F2

1.134

Final R indices [I>2sigma(I)] R1 = 0.0881, wR2 = 0.2007

R indices (all data) R1 = 0.0903, wR2 = 0.2022

Largest diff. peak and hole 0.776 and -0.284 e.A-3

218

Atomic coordinates [× 104] and equivalent isotropic displacement parameters [A

2 × 10

3]

U(eq) is defined as one third of the trace of the orthogonalized Uij tensor.

________________________________________________________________

x y z U(eq)

________________________________________________________________

O(1) 4463(5) 4986(3) 3074(4) 24(1)

O(2) 2994(4) 6048(3) 4061(5) 25(1)

O(3) 4942(5) 7066(3) 4864(5) 25(1)

O(4) 7693(4) 5298(3) 4375(5) 21(1)

O(5) 5786(7) 3187(4) -392(7) 58(2)

O(6) 5415(6) 4330(4) -2043(6) 49(2)

N(1) 5391(7) 4011(5) -824(7) 36(2)

C(1) 4272(7) 5445(5) 4384(7) 25(2)

C(2) 5582(7) 6124(5) 4978(6) 24(1)

C(3) 6584(7) 6001(4) 3872(6) 23(1)

C(4) 5416(7) 5629(4) 2493(6) 19(1)

C(5) 6060(7) 5049(5) 1388(7) 28(2)

C(6) 4765(7) 4635(5) 166(7) 29(2)

C(7) 3406(7) 6946(5) 4828(7) 27(2)

C(8) 2517(8) 7766(5) 3969(9) 38(2)

C(9) 3172(8) 6870(6) 6382(7) 36(2)

C(10) 9013(7) 5729(5) 5349(7) 28(2)

C(11) 10002(7) 4926(5) 6152(7) 24(1)

C(12) 9877(7) 4626(5) 7535(7) 26(1)

C(13) 10782(8) 3877(5) 8246(7) 32(2)

C(14) 11759(7) 3408(4) 7623(6) 21(1)

C(15) 11906(7) 3707(5) 6224(7) 28(2)

C(16) 11021(7) 4476(5) 5513(7) 29(2)

C(17) 7200(9) 5617(5) 860(7) 35(1)

C(18) 6774(10) 6347(5) -219(7) 42(2)

C(19) 7994(9) 6871(5) -733(8) 41(1)

C(20) 7518(11) 7571(6) -1799(9) 49(2)

C(21) 8660(11) 8030(7) -2233(9) 55(2)

C(22) 10213(11) 7796(7) -1687(9) 56(2)

C(23) 10665(11) 7114(6) -616(9) 54(2)

C(24) 9453(9) 6594(5) -83(8) 40(1)

C(25) 9893(10) 5913(6) 997(9) 48(2)

C(26) 8768(9) 5410(6) 1420(9) 46(2)

________________________________________________________________

Bond lengths [ Å ] and angles [ ° ]

_____________________________________________________________

O(1)-C(1) 1.421(7)

O(1)-C(4) 1.437(7)

O(2)-C(1) 1.402(8)

O(2)-C(7) 1.422(8)

O(3)-C(2) 1.406(8)

O(3)-C(7) 1.410(8)

O(4)-C(3) 1.392(7)

O(4)-C(10) 1.442(8)

O(5)-N(1) 1.219(8)

O(6)-N(1) 1.220(8)

N(1)-C(6) 1.474(9)

C(1)-C(2) 1.509(9)

C(1)-H(1) 1.0000

C(2)-C(3) 1.552(8)

C(2)-H(2) 1.0000

C(3)-C(4) 1.536(8)

C(3)-H(3) 1.0000

C(4)-C(5) 1.530(9)

219

C(4)-H(4) 1.0000

C(5)-C(17) 1.482(10)

C(5)-C(6) 1.531(9)

C(5)-H(5) 1.0000

C(6)-H(6A) 0.9900

C(6)-H(6B) 0.9900

C(7)-C(8) 1.494(10)

C(7)-C(9) 1.518(9)

C(8)-H(8A) 0.9800

C(8)-H(8B) 0.9800

C(8)-H(8C) 0.9800

C(9)-H(9A) 0.9800

C(9)-H(9B) 0.9800

C(9)-H(9C) 0.9800

C(10)-C(11) 1.498(9)

C(10)-H(10A) 0.9900

C(10)-H(10B) 0.9900

C(11)-C(16) 1.372(9)

C(11)-C(12) 1.383(9)

C(12)-C(13) 1.378(9)

C(12)-H(12) 0.9500

C(13)-C(14) 1.346(10)

C(13)-H(13) 0.9500

C(14)-C(15) 1.404(9)

C(14)-H(14) 0.9500

C(15)-C(16) 1.389(9)

C(15)-H(15) 0.9500

C(16)-H(16) 0.9500

C(17)-C(18) 1.399(11)

C(17)-C(26) 1.428(11)

C(18)-C(19) 1.504(11)

C(18)-H(18) 0.9500

C(19)-C(20) 1.367(11)

C(19)-C(24) 1.375(11)

C(20)-C(21) 1.366(12)

C(20)-H(20) 0.9500

C(21)-C(22) 1.423(13)

C(21)-H(21) 0.9500

C(22)-C(23) 1.351(13)

C(22)-H(22) 0.9500

C(23)-C(24) 1.504(11)

C(23)-H(23) 0.9500

C(24)-C(25) 1.355(11)

C(25)-C(26) 1.377(11)

C(25)-H(25) 0.9500

C(26)-H(26) 0.9500

C(1)-O(1)-C(4) 105.8(4)

C(1)-O(2)-C(7) 107.3(5)

C(2)-O(3)-C(7) 106.9(5)

C(3)-O(4)-C(10) 110.9(4)

O(5)-N(1)-O(6) 124.3(7)

O(5)-N(1)-C(6) 117.2(6)

O(6)-N(1)-C(6) 118.4(6)

O(2)-C(1)-O(1) 110.6(5)

O(2)-C(1)-C(2) 105.2(5)

O(1)-C(1)-C(2) 109.0(5)

O(2)-C(1)-H(1) 110.6

O(1)-C(1)-H(1) 110.6

C(2)-C(1)-H(1) 110.6

O(3)-C(2)-C(1) 104.8(5)

O(3)-C(2)-C(3) 110.8(5)

C(1)-C(2)-C(3) 103.9(5)

O(3)-C(2)-H(2) 112.3

C(1)-C(2)-H(2) 112.3

C(3)-C(2)-H(2) 112.3

O(4)-C(3)-C(4) 110.5(5)

O(4)-C(3)-C(2) 110.9(5)

220

C(4)-C(3)-C(2) 100.7(5)

O(4)-C(3)-H(3) 111.5

C(4)-C(3)-H(3) 111.5

C(2)-C(3)-H(3) 111.5

O(1)-C(4)-C(5) 108.1(5)

O(1)-C(4)-C(3) 104.5(4)

C(5)-C(4)-C(3) 115.2(5)

O(1)-C(4)-H(4) 109.6

C(5)-C(4)-H(4) 109.6

C(3)-C(4)-H(4) 109.6

C(17)-C(5)-C(4) 112.1(5)

C(17)-C(5)-C(6) 115.3(6)

C(4)-C(5)-C(6) 109.4(5)

C(17)-C(5)-H(5) 106.5

C(4)-C(5)-H(5) 106.5

C(6)-C(5)-H(5) 106.5

N(1)-C(6)-C(5) 109.1(5)

N(1)-C(6)-H(6A) 109.9

C(5)-C(6)-H(6A) 109.9

N(1)-C(6)-H(6B) 109.9

C(5)-C(6)-H(6B) 109.9

H(6A)-C(6)-H(6B) 108.3

O(3)-C(7)-O(2) 104.4(5)

O(3)-C(7)-C(8) 109.4(5)

O(2)-C(7)-C(8) 109.8(5)

O(3)-C(7)-C(9) 111.5(5)

O(2)-C(7)-C(9) 109.6(5)

C(8)-C(7)-C(9) 111.9(6)

C(7)-C(8)-H(8A) 109.5

C(7)-C(8)-H(8B) 109.5

H(8A)-C(8)-H(8B) 109.5

C(7)-C(8)-H(8C) 109.5

H(8A)-C(8)-H(8C) 109.5

H(8B)-C(8)-H(8C) 109.5

C(7)-C(9)-H(9A) 109.5

C(7)-C(9)-H(9B) 109.5

H(9A)-C(9)-H(9B) 109.5

C(7)-C(9)-H(9C) 109.5

H(9A)-C(9)-H(9C) 109.5

H(9B)-C(9)-H(9C) 109.5

O(4)-C(10)-C(11) 108.8(5)

O(4)-C(10)-H(10A) 109.9

C(11)-C(10)-H(10A) 109.9

O(4)-C(10)-H(10B) 109.9

C(11)-C(10)-H(10B) 109.9

H(10A)-C(10)-H(10B) 108.3

C(16)-C(11)-C(12) 119.7(6)

C(16)-C(11)-C(10) 120.3(6)

C(12)-C(11)-C(10) 119.9(6)

C(13)-C(12)-C(11) 119.1(6)

C(13)-C(12)-H(12) 120.5

C(11)-C(12)-H(12) 120.5

C(14)-C(13)-C(12) 122.2(6)

C(14)-C(13)-H(13) 118.9

C(12)-C(13)-H(13) 118.9

C(13)-C(14)-C(15) 119.4(6)

C(13)-C(14)-H(14) 120.3

C(15)-C(14)-H(14) 120.3

C(16)-C(15)-C(14) 118.7(6)

C(16)-C(15)-H(15) 120.6

C(14)-C(15)-H(15) 120.6

C(11)-C(16)-C(15) 120.8(6)

C(11)-C(16)-H(16) 119.6

C(15)-C(16)-H(16) 119.6

C(18)-C(17)-C(26) 118.4(7)

C(18)-C(17)-C(5) 121.2(7)

C(26)-C(17)-C(5) 120.3(7)

C(17)-C(18)-C(19) 118.2(8)

221

C(17)-C(18)-H(18) 120.9

C(19)-C(18)-H(18) 120.9

C(20)-C(19)-C(24) 127.5(8)

C(20)-C(19)-C(18) 115.9(8)

C(24)-C(19)-C(18) 116.6(7)

C(21)-C(20)-C(19) 114.0(9)

C(21)-C(20)-H(20) 123.0

C(19)-C(20)-H(20) 123.0

C(20)-C(21)-C(22) 124.4(9)

C(20)-C(21)-H(21) 117.8

C(22)-C(21)-H(21) 117.8

C(23)-C(22)-C(21) 120.7(9)

C(23)-C(22)-H(22) 119.6

C(21)-C(22)-H(22) 119.6

C(22)-C(23)-C(24) 117.0(9)

C(22)-C(23)-H(23) 121.5

C(24)-C(23)-H(23) 121.5

C(25)-C(24)-C(19) 126.2(8)

C(25)-C(24)-C(23) 117.5(8)

C(19)-C(24)-C(23) 116.3(7)

C(24)-C(25)-C(26) 116.7(8)

C(24)-C(25)-H(25) 121.6

C(26)-C(25)-H(25) 121.6

C(25)-C(26)-C(17) 123.7(8)

C(25)-C(26)-H(26) 118.1

C(17)-C(26)-H(26) 118.1

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222

Crystal data and structure refinement for 151 (s3553-sm)

Empirical formula C18 H23 N O6

Formula weight 349.37

Temperature 100(2) K

Wavelength 0.71073 A

Crystal system, space group Orthorhombic, P2(1)2(1)2(1)

Unit cell dimensions a = 5.2903(4) Å α = 90°

b = 17.9474(11) Å β = 90 deg.

c = 18.3933(12) Å γ = 90 deg.

Volume 1746.4(2) Å3

Z, Calculated density 4, 1.329 Mg/m3

Absorption coefficient 0.100 mm-1

F(000) 744

Crystal size 0.40 × 0.25 × 0.05 mm

Theta range for data collection 2.21 to 25.0°

Limiting indices -6<=h<=6, -20<=k<=21, -21<=l<=21

Reflections collected / unique 12784 / 3089 [R(int) = 0.0726]

Completeness to theta = 25.02 99.9%

Absorption correction Semi-empirical from equivalents

Max. and min. transmission 1.00000 and 0.86853

Refinement method Full-matrix least-squares on F2

Data / restraints / parameters 3089 / 0 / 228

Goodness-of-fit on F2 1.011

Final R indices [I>2sigma(I)] R1 = 0.0450, wR2 = 0.0752

R indices (all data) R1 = 0.0685, wR2 = 0.0824

Largest diff. peak and hole 0.177 and -0.176 e.A-3

223

Atomic coordinates [× 104] and equivalent isotropic displacement parameters [A

2 × 10

3]

U(eq) is defined as one third of the trace of the orthogonalized Uij tensor.

________________________________________________________________

x y z U(eq)

________________________________________________________________

O(1) 8429(3) 7427(1) 2337(1) 19(1)

O(2) 8733(3) 6477(1) 1482(1) 20(1)

O(3) 11509(3) 7198(1) 855(1) 17(1)

O(4) 12114(4) 9564(1) 3882(1) 42(1)

O(5) 15743(4) 9046(1) 4041(1) 44(1)

O(6) 9175(3) 8871(1) 1758(1) 20(1)

N(1) 13805(4) 9138(1) 3694(1) 26(1)

C(1) 7930(5) 7212(1) 1612(1) 18(1)

C(2) 9619(4) 7700(1) 1118(1) 18(1)

C(3) 10819(5) 8255(1) 1649(1) 18(1)

C(4) 10860(4) 7794(1) 2346(1) 18(1)

C(5) 11167(5) 8202(1) 3067(1) 19(1)

C(6) 13446(5) 8721(1) 3002(1) 24(1)

C(7) 11492(5) 7657(1) 3679(1) 23(1)

C(8) 10088(5) 7631(2) 4263(1) 30(1)

C(9) 10430(4) 6465(1) 874(1) 17(1)

C(10) 12492(5) 5908(1) 1028(1) 22(1)

C(11) 8983(4) 6307(1) 183(1) 20(1)

C(12) 9555(5) 9459(1) 1238(1) 20(1)

C(13) 7472(5) 10027(1) 1332(1) 17(1)

C(14) 6484(5) 10394(1) 729(1) 22(1)

C(15) 4551(5) 10910(1) 811(2) 27(1)

C(16) 3572(5) 11065(1) 1493(1) 24(1)

C(17) 4565(5) 10710(1) 2092(1) 22(1)

C(18) 6540(5) 10199(1) 2015(1) 22(1)

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Bond lengths [ Å ] and angles [ ° ]

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O(1)-C(1) 1.413(3)

O(1)-C(4) 1.445(3)

O(2)-C(1) 1.406(3)

O(2)-C(9) 1.435(3)

O(3)-C(2) 1.430(3)

O(3)-C(9) 1.434(3)

O(4)-N(1) 1.226(3)

O(5)-N(1) 1.220(3)

O(6)-C(3) 1.420(3)

O(6)-C(12) 1.438(3)

N(1)-C(6) 1.488(3)

C(1)-C(2) 1.547(3)

C(1)-H(1) 1.0000

C(2)-C(3) 1.534(3)

C(2)-H(2) 1.0000

C(3)-C(4) 1.526(3)

C(3)-H(3) 1.0000

C(4)-C(5) 1.525(3)

C(4)-H(4) 1.0000

C(5)-C(7) 1.501(3)

C(5)-C(6) 1.527(3)

C(5)-H(5) 1.0000

C(6)-H(6A) 0.9900

C(6)-H(6B) 0.9900

C(7)-C(8) 1.308(3)

C(7)-H(7) 0.9500

224

C(8)-H(8A) 0.9500

C(8)-H(8B) 0.9500

C(9)-C(10) 1.507(3)

C(9)-C(11) 1.510(3)

C(10)-H(10A) 0.9800

C(10)-H(10B) 0.9800

C(10)-H(10C) 0.9800

C(11)-H(11A) 0.9800

C(11)-H(11B) 0.9800

C(11)-H(11C) 0.9800

C(12)-C(13) 1.511(3)

C(12)-H(12A) 0.9900

C(12)-H(12B) 0.9900

C(13)-C(18) 1.385(3)

C(13)-C(14) 1.391(3)

C(14)-C(15) 1.388(3)

C(14)-H(14) 0.9500

C(15)-C(16) 1.384(4)

C(15)-H(15) 0.9500

C(16)-C(17) 1.377(3)

C(16)-H(16) 0.9500

C(17)-C(18) 1.398(3)

C(17)-H(17) 0.9500

C(18)-H(18) 0.9500

C(1)-O(1)-C(4) 107.53(17)

C(1)-O(2)-C(9) 109.64(17)

C(2)-O(3)-C(9) 106.97(17)

C(3)-O(6)-C(12) 113.05(18)

O(5)-N(1)-O(4) 123.4(2)

O(5)-N(1)-C(6) 119.1(2)

O(4)-N(1)-C(6) 117.5(2)

O(2)-C(1)-O(1) 111.12(18)

O(2)-C(1)-C(2) 104.86(19)

O(1)-C(1)-C(2) 106.97(18)

O(2)-C(1)-H(1) 111.2

O(1)-C(1)-H(1) 111.2

C(2)-C(1)-H(1) 111.2

O(3)-C(2)-C(3) 109.57(18)

O(3)-C(2)-C(1) 104.19(18)

C(3)-C(2)-C(1) 103.43(19)

O(3)-C(2)-H(2) 113.0

C(3)-C(2)-H(2) 113.0

C(1)-C(2)-H(2) 113.0

O(6)-C(3)-C(4) 108.24(19)

O(6)-C(3)-C(2) 109.97(19)

C(4)-C(3)-C(2) 100.85(18)

O(6)-C(3)-H(3) 112.4

C(4)-C(3)-H(3) 112.4

C(2)-C(3)-H(3) 112.4

O(1)-C(4)-C(5) 108.87(19)

O(1)-C(4)-C(3) 103.03(19)

C(5)-C(4)-C(3) 118.09(19)

O(1)-C(4)-H(4) 108.8

C(5)-C(4)-H(4) 108.8

C(3)-C(4)-H(4) 108.8

C(7)-C(5)-C(4) 110.49(19)

C(7)-C(5)-C(6) 111.5(2)

C(4)-C(5)-C(6) 108.0(2)

C(7)-C(5)-H(5) 109.0

C(4)-C(5)-H(5) 109.0

C(6)-C(5)-H(5) 109.0

N(1)-C(6)-C(5) 109.9(2)

N(1)-C(6)-H(6A) 109.7

C(5)-C(6)-H(6A) 109.7

N(1)-C(6)-H(6B) 109.7

C(5)-C(6)-H(6B) 109.7

H(6A)-C(6)-H(6B) 108.2

225

C(8)-C(7)-C(5) 125.0(3)

C(8)-C(7)-H(7) 117.5

C(5)-C(7)-H(7) 117.5

C(7)-C(8)-H(8A) 120.0

C(7)-C(8)-H(8B) 120.0

H(8A)-C(8)-H(8B) 120.0

O(3)-C(9)-O(2) 104.67(17)

O(3)-C(9)-C(10) 108.97(19)

O(2)-C(9)-C(10) 108.42(19)

O(3)-C(9)-C(11) 110.75(19)

O(2)-C(9)-C(11) 110.01(18)

C(10)-C(9)-C(11) 113.6(2)

C(9)-C(10)-H(10A) 109.5

C(9)-C(10)-H(10B) 109.5

H(10A)-C(10)-H(10B) 109.5

C(9)-C(10)-H(10C) 109.5

H(10A)-C(10)-H(10C) 109.5

H(10B)-C(10)-H(10C) 109.5

C(9)-C(11)-H(11A) 109.5

C(9)-C(11)-H(11B) 109.5

H(11A)-C(11)-H(11B) 109.5

C(9)-C(11)-H(11C) 109.5

H(11A)-C(11)-H(11C) 109.5

H(11B)-C(11)-H(11C) 109.5

O(6)-C(12)-C(13) 108.50(19)

O(6)-C(12)-H(12A) 110.0

C(13)-C(12)-H(12A) 110.0

O(6)-C(12)-H(12B) 110.0

C(13)-C(12)-H(12B) 110.0

H(12A)-C(12)-H(12B) 108.4

C(18)-C(13)-C(14) 119.0(2)

C(18)-C(13)-C(12) 120.9(2)

C(14)-C(13)-C(12) 120.2(2)

C(15)-C(14)-C(13) 120.4(2)

C(15)-C(14)-H(14) 119.8

C(13)-C(14)-H(14) 119.8

C(16)-C(15)-C(14) 120.6(3)

C(16)-C(15)-H(15) 119.7

C(14)-C(15)-H(15) 119.7

C(17)-C(16)-C(15) 119.2(2)

C(17)-C(16)-H(16) 120.4

C(15)-C(16)-H(16) 120.4

C(16)-C(17)-C(18) 120.6(2)

C(16)-C(17)-H(17) 119.7

C(18)-C(17)-H(17) 119.7

C(13)-C(18)-C(17) 120.2(2)

C(13)-C(18)-H(18) 119.9

C(17)-C(18)-H(18) 119.9

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