Helsinki University of Technology

Organic Chemistry Report 1/2008

Espoo 2008

CHIRAL BIDENTATE OXAZOLINE LIGANDS ON DIFFERENT

SUPPORTS: PREPARATION AND APPLICATION

Markku Oila

Dissertation for the degree of Doctor of Science in Technology to be presented with

due permission of the Department of Chemical Technology for public examination

and debate in Auditorium Ke 2 (Komppa) at Helsinki University of Technology

(Espoo, Finland) on the 16th of February, 2008, at 12 noon.

Helsinki University of Technology

Department of Chemical Technology

Laboratory of Organic Chemistry

2

Distribution:

Helsinki University of Technology

Laboratory of Organic Chemistry

P.O. Box 6100

FIN-02015 TKK

© Markku Oila

ISBN 978-951-22-8959-2

ISSN 1236-2999

Dissertation also available as pdf:

http://lib.tkk.fi/Diss/2008/isbn9789512289608/

ISBN 978-951-22-8960-8

Multiprint Oy

Espoo 2008

3

Oila, Markku. Chiral Bidentate Oxazoline Ligands on Different Supports: Preparation and Application. Espoo 2008. Helsinki University of Technology, Organic Chemistry Report 1/2008. 90 pages. ISBN 978-951-22-8959-2 (printed) 978-951-22-8960-2 (electronic) ISSN 1236-2999 Keywords PyOX-ligand, IndOX-ligand, solid-phase chemistry, supramolecular chemistry, gold nanoparticle, asymmetric catalysis, enantioselectivity.

ABSTRACT The oxazoline core is found in many active pharmaceuticals. It has for some decades been recognized as a useful synthon in chemical synthesis and, more recently, as a ligand in catalysis. The PyOX-core (2-(2´-pyridyl)oxazoline), consisting of two heteroatom rings, was accidentally formed for the first time in the early 1970’s. The excellence of PyOX-structures as metal catalyst ligands was recognized from the late 1980’s onwards, an observation generating a need for more efficient syntheses of enantiopure, functionalized PyOX-ligands. In the first part of this thesis, an efficient synthesis route to form an enantiopure PyOX-based thiolate compound was optimized. This method was then applied in the synthesis of a series of enantiopure solid-supported compounds. The novel PyOX-derived thiolate was used to form a novel chiral gold nanoligand. Its gold core was to the best of our knowledge smaller than before in experimental chemistry. This nanoparticle was used as a ligand in a known asymmetric test reaction, giving a reasonable selectivity. Novel PyOX-ligands, synthesized in this thesis, were also used as chiral ligands in the asymmetric Henry reaction, an application previously unknown for PyOX-ligands. Finally, the methodology used to prepare substituted and chiral PyOX-ligands was applied to the synthesis of a new, enantiopure ligand family, the IndOX (2-(2´-indolyl)oxazoline). This thesis has yielded an optimized methodology to form substituted enantiopure bidentate oxazoline ligands (PyOX and IndOX) in a simple and efficient way. The methodology was also applied on ligand formation on solid polymer and semi-soluble nano supports. These ligands were tested for known asymmetric test reactions and a new test reaction for PyOX-ligands (Henry reaction) was introduced.

4

Oila, Markku. Kiraalisia kaksihampaisia oksatsoliiniligandeja eri kantajilla: Valmistus ja sovellus. Espoo 2008. Teknillinen korkeakoulu, Organic Chemistry Report 1/2008. 90 sivua. ISBN 978-951-22-8959-2 (painettu) 978-951-22-8960-2 (elektroninen) ISSN 1236-2999 Asiasanat PyOX-ligandi, IndOX-ligandi, kiinteäfaasikemia, supramolekulaarinen kemia, kultananopartikkeli, asymmetrinen katalyysi, enantioselektiivisyys.

TIIVISTELMÄ Moni aktiivinen lääkeaine sisältää oksatsoliinirungon. Tätä runkoa on muutaman vuosikymmenen ajan pidetty hyödyllisenä syntonina kemiallisessa synteesissä sekä myöhemmin myös katalyyttiligandina. Kahdesta heteroatomirenkaasta koostuva PyOX-runko (2-(2´-pyridyyli)oksatsoliini) valmistettiin vahingossa ensi kertaa 1970-luvun alussa. Sen erinomaiset ominaisuudet metallikatalyytin ligandina opittiin tuntemaan 1980-luvun lopulla, mikä kasvatti tarvetta kehittää tehokkaampia synteesimenetelmiä enantiopuhtaiden, funktionalisoitujen PyOX-ligandien valmistamiseksi. Työni ensimmäisessä osassa optimoitiin tehokas synteesireitti, jonka tavoitteena oli valmistaa enantiopuhdas PyOX-pohjainen tiolaattiyhdiste. Tätä menetelmää sovellettiin sen jälkeen enantiopuhtaan PyOX-kiinteäfaasiligandisarjan synteesissä. Kehittämääni PyOX-pohjaista tiolaattia käytettiin uuden, kiraalisen kultananoligandin muodostuksessa. Partikkelin kultaydin oli tietääkseeni pienempi kuin koskaan aikaisemmin kokeellisessa kemiassa. Tätä nanopartikkelia käytettiin myös ligandina tunnetussa asymmetrisessä koereaktiossa, jolloin saavutettiin lupaava selektiivisyys. Työssäni valmistettuja PyOX-ligandeja käytettiin kiraalisina ligandeina asymmetrisessä Henry-reaktiossa, joka oli PyOX-ligandeilla ennen kokeilematon koereaktio. Lopuksi kiraalisten PyOX-ligandien valmistusmenetelmää käytettiin täysin uuden, enantiopuhtaan ligandiperheen (IndOX, 2-(2´-indolyyli)oksatsoliini) synteesissä. Tässä väitöskirjassa on saavutettu optimoitu menetelmä valmistaa helposti ja tehokkaasti enantiopuhtaita, kaksihampaisia oksatsoliiniligandeja (PyOX ja IndOX). Menetelmää sovellettiin myös näiden ligandien valmistukseen sekä polymeeri- että nanokantajilla. Ligandeja kokeiltiin tunnetuissa asymmetrisissä koereaktioissa ja PyOX-ligandeille kehitettiin uusi koereaktio (Henry-reaktio).

5

Acknowledgments

This work was carried out in the Laboratory of Organic Chemistry, Helsinki University of Technology, during the years 2001-2006. It was funded by the Finnish Funding Agency for Technology and Innovation (TEKES) and the Academy of Finland. Financial support for this thesis was also granted by Petter and Margit Forsström Foundation, the technology promotion foundation TES and the Emil Aaltonen Foundation. Every piece of funding is gratefully acknowledged. I would firstly like to thank Professor Ari Koskinen, not only for giving me the opportunity to work and do my thesis in his research group, but also for being an excellent supervisor, particularly when hard decisions had to be made. Professors Robert Franzén and Leiv K. Sydnes are greatly acknowledged for their careful inspection of this thesis. I am also grateful to my first instructor Päivi Koskinen, particularly for the valuable practical aid she offered me during the early stages of my thesis. My later instructor Jan Tois is really worth a great thank. Not only did you share your outstanding knowledge and enthusiasm in synthetic chemistry your excellent way, but also turned out to be a great friend, as well inside as outside the lab! I would also like to thank all of the people I have had the pleasure to meet and work with during these years. Besides your valuable help, I remember nice coffee room chatting and partying! Special thanks go to Anna-Maija for CHN analysis, Jari for his expertise in NMR and MS issues, Aapo and Vesa for computer logics, Mikko P. and Reetta for making my course teaching easier and Mikko M. for the fruitful discussions as a long-term roommate! Very special and warm thanks I send to my parents Kirsti and Kari and my sister Heidi, as they always were equally supportive and gave me belief in what I was doing. Last, but definitively not least, I would like to thank my wife Outi for her everlasting love and support, not to mention the superior patience she showed during all these years. Outi, thank you! You are the one, whom I shared my thoughts and sometimes bad mood with. This has been the key to carry on and complete this thesis. I would also like to thank our son Eelis for offering me a counterpart in life to completion of this thesis. Lohja January 2008 Markku Oila

6

Original publications

I Oila, M.J., Tois, J.E. and Koskinen, A.M.P., Tetrahedron Lett., 2005, 46,

967-969. II Oila, M.J., Tois, J.E. and Koskinen, A.M.P., Tetrahedron, 2005, 61,

10748-10756. III Oila, M.J. and Koskinen, A.M.P., Arkivoc, 2006, XV, 76-83. IV Oila, M.J., Tois, J.E. and Koskinen, A.M.P., Lett.Org.Chem. 2008, 5, in press. V Oila, M.J., Tois, J.E. and Koskinen, A.M.P., Synth.Commun., 2008, 38 (3), in

press.

The author´s contribution in the attended publications I Markku Oila designed the synthesis plan with the co-authors. He carried out

the experimental work and interpreted the achieved data. He also wrote the manuscript with the co-authors.

II Markku Oila designed the research plan with the co-authors, carried out the experimental work and interpreted the experimental data. The manuscript was written with co-authors.

III Markku Oila designed the strategy and carried out the nanoparticle syntheses. Analysis was performed and interpreted by him, assisted by collaborators. The manuscript was written with the co-author.

IV Markku Oila discovered the reported application, designed the experimental plan with co-authors. Experimental work, analysis and interpretation of results were performed by Oila.

V Markku Oila with co-authors designed the ligand synthesis plan. Experimental work was carried out by Oila and collaborators and analysis made and results interpreted by Oila himself.

7

Abbreviations

Ac acetyl

aq aqueous

AuNP gold nanoparticle

Bn benzyl

Boc t-butoxycarbonyl

BOP (Benzotriazol-1-yloxy)tris(dimethylamino)phosphonium-

hexafluorophosphate

BTMSA = BSA bis-N,O-trimethylsilylacetamide

BuLi n-butyllithium

Bz benzoyl

cat. catalytic amount

COD 1,4-cyclooctadiene

DAST diethylaminosulfur trifluoride

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

DIC diisopropylcarbodiimide

DIPEA diisopropylethylamine

DMAP 4-N,N-dimethylaminopyridine

DMF N,N-dimethylformamide

DMSO dimethylsulfoxide

ee enantiomeric excess

ESCA = XPS X-ray Photoelectron Spectroscopy

Et ethyl

HOBt 2-hydroxybenzotriazole

IndOX 2-(2´-indolyl)oxazoline

i-Pr isopropyl

mCPBA m-chloroperbenzoic acid

Me methyl

Ms methanesulfonyl (mesyl)

Ph phenyl

Pr propyl

py pyridine

8

PyOX 2-(2´-pyridyl)oxazoline

PyrOX 2-(2´-pyrrolyl)oxazoline

rt room temperature

TBS t-butyldimethylsilyl

t-Bu tert-butyl = 1,1-dimethylethyl

TEM transmission electron microscopy

Tf trifluoromethanesulfonyl (triflyl)

TFA trifluoroacetic acid

THF tetrahydrofuran

TLC thin layer chromatography

TMS trimethylsilyl

Tr triphenylmethyl (trityl)

Ts p-toluenesulfonyl (tosyl)

XPS see ESCA

9

Table of Contents 1 Introduction ................................................................................................................ 10

1.1 2-Oxazolines .................................................................................................................. 10 1.2 Synthesis in heterogeneous systems ............................................................................. 11

1.2.1 Solid supported synthesis ...................................................................................................... 11 1.2.2 Synthesis on semi-solid supports: nanoparticles ................................................................... 12

2 Preparation of oxazoline ligands ................................................................................ 14 2.1 PyOX preparation procedures from nitriles .................................................................... 14

2.1.1 Copper activation ................................................................................................................... 14 2.1.2 Zinc activation ........................................................................................................................ 14 2.1.3 Cadmium activation ............................................................................................................... 15

2.2 Substituted PyOX-ligands via nitriles ............................................................................. 15 2.3 PyOX preparation by condensation from imidates ......................................................... 16 2.4 Preparation of oxazolines from carboxylic acids ............................................................. 17

2.4.1 Chlorination of amido alcohol................................................................................................. 17 2.4.2 Other amido alcohol activators in oxazoline synthesis .......................................................... 18

2.5 Preparation of other bidentate N, N-oxazolines .............................................................. 19 2.5.1 2-Pyrrolidinyl 2´-oxazoline (PyrOX) ....................................................................................... 19 2.5.2 2-indolyl-2´-oxazoline (IndOX) ............................................................................................... 21

3 Catalytic Applications of PyOX-compounds ............................................................... 22 3.1 Hydrosilylation: Asymmetric Reduction of Ketones ........................................................ 22 3.2 Diels-Alder-reaction ....................................................................................................... 23 3.3 Meerwein arylation ......................................................................................................... 23 3.4 Asymmetric epoxidation ................................................................................................. 24 3.5 Nucleophilic 1,2-attack on carbonyls .............................................................................. 25

3.5.1 Addition of diethylzinc to aromatic aldehydes ........................................................................ 25 3.5.2 Addition of allyltrialkylsilanes to aromatic aldehydes ............................................................. 26

3.6 Nucleophilic conjugate addition ...................................................................................... 27 3.6.1 Michael addition ..................................................................................................................... 27 3.6.2 Allylic substitution ................................................................................................................... 28

3.7 Cyclopropanation of olefins ............................................................................................ 30

4 Aim of the study ......................................................................................................... 32 5 Results and Discussion .............................................................................................. 33

5.1 Synthesis of a mercapto derived soluble PyOX-ligand (I) ............................................... 33 5.2 Ligand preparation via linking: A new approach to solid-phase synthesis (II) ................. 36 5.3 Chirally modified gold nanoparticles (III) ........................................................................ 41 5.4 The asymmetric Henry reaction – a new Application for PyOX (IV) ................................ 43 5.5 Preparation of a Novel Ligand Family: The IndOX (V) .................................................... 46

6 Conclusions ............................................................................................................... 48 7 References ................................................................................................................. 49

10

1 Introduction

1.1 2-Oxazolines

The 2-oxazoline core (Figure 1) is a well-known functional group in organic synthesis. It is

a five-membered ring including both the nitrogen and the oxygen atom, with one double

bond located at the 2-position.

N

O1

2

3 4

5

Figure 1. The 2-oxazoline ring with its substituent numbering.

The oxazoline structure is a functional group of several drug species inhibiting e.g. sex

pheromone production of bacteria1 or enzymes like chymotrypsin,2 cathepsin B3 and

thrombin.4 Oxazoline compounds have also been recognized as antibacterials5 or active

species against colon,6 ovarian or prostate cancer cells 7.

To its synthetic utility, the oxazoline structure is known as a protective group of

carboxylates.8 Furthermore, there have been lots of other synthetic purposes for oxazoline

compounds9 as e.g. ligands in asymmetric catalysis.10

Synthesis of 2-oxazolines is a well understood and frequently reported topic and a number

of preparation methods have been reported.11 On the other hand, these methods are

rather case-sensitive, when it comes to the substrate used, which occasionally makes

oxazoline synthesis challenging.12

11

1.2 Synthesis in heterogeneous systems

In modern chemistry, not all reactions are performed in solution. From the late 1900s, it

has been more and more popular and more advantageous to involve a totally insoluble or,

later on, under some conditions soluble reagents. This kind of synthesis on supports offers

new benefits and drawbacks, unaccessible in solution chemistry. So far the drawback of

supported synthesis has been the need of reagent excesses and sometimes extended

reaction times. The major benefit is the ease of use, as the insoluble agents can be

washed with all kinds of solvents and supported species isolated by simple filtration. This

is of interest for industrial processes. The latest fashion, developed particularly from the

1990s, is the use of semi-solid supports, e.g. nanoparticles13 or sol-gels14 (Figure 2). The

new feature of these species is that they are dissolved in the reaction mixture, eliminating

the need for reagents excesses as mass transfer is eased. The supported species is then

removed by precipitation from a suitable solvent and removed by filtration.

Si

O

O

O

SiSi

Si

Figure 2. Simplified structures of nanoparticles (left) and sol-gels (right). The matrices

around the central metal species represent an organic cover for nanoparticles and a silica

cover for sol-gels.

1.2.1 Solid supported synthesis

The concept of “solid supported synthesis” means in short chemical reactions performed

on the surface of an insoluble support material or the use of immobilized, insoluble

reagents. Examples of solid support materials are glass,15 metal surfaces16 and

polymers.17 Nowadays, a very common support in synthetic chemistry is insoluble

polymer, of which the polystyrene derived Merrifield resin 1, introduced in the 1960s for

peptide synthesis, is the leading example18 (Figure 3)

12

n

Cl Cl

= Cl

1

Figure 3. The Merrifield resin 1. In solid-phase synthesis, the only difference to solution chemistry is the utilization of one

insoluble component, either a reagent or the substrate itself. In the latter case, the

chemical modifications are performed as in solution chemistry and the product isolated by

filtration. In Scheme 1, a typical procedure is illustrated. It is formation of a peptide chain, a

procedure developed by Merrifield.18 Selected amino acids are coupled with the Merrifield

resin 1 to form the polymer-bound 2. After deprotection, another amino acid is coupled to 3

to form the protected, immobilized dipeptide 4. The desired product 5 is then cleaved from

the resin to the solution by a suitable chemical modification (basic hydrolysis).

Cl O

O

R1

HN

O

OO

O

R1

NH2

O

O

R1

HN

O

NH

R2 O

OHO

O

R1

HN

O

NH2

R2

1 2 3

45

Scheme 1. Formation of a dipeptide 5 on polymer support.18

1.2.2 Synthesis on semi-solid supports: nanoparticles

During the last decade, there has been an increasing trend towards “semi-solid” supports,

i.e. support materials soluble in reaction solvents, but separable by precipitation from

certain solvent mixtures. A well-known application of catalyst immobilization on semi-solid

13

support is the sol-gel technique, originally introduced 1984.19 In this technique, the active

agent, e.g. the catalyst metal is added to a solution of silicon tetraalkoxides or

methyltrialkoxysilicates and the resulting silicate hydrolyzed to form a solid SiO2-cage on

the catalyst.20

An application of synthesis on semi-solid support is the utilization of metallic nanoparticles.

Nanoparticles have been defined as metal clusters (e.g. gold, Figure 4) in the range of 1-

10 nm, often passivated with organic compounds.21 Within this range, the particles have

features differing from small molecules and the bulk metal itself. One example of this

exceptional behaviour is the solubility of the particles: they can be dissolved in some

organic solvents, but precipitate from some others. Even though nanoparticles have been

known from the early 1980s (“Schmid´s cluster” 6, Figure 4),22 they have only recently

gained a huge interest due to the exceptional properties.23

Aun

P

P P

P

6

Figure 4. Simplified image of Schmid´s cluster 6.22

14

2 Preparation of oxazoline ligands

2.1 PyOX (2-(2´-pyridyl)oxazoline) preparation procedures from nitriles

2.1.1 Copper activation

A pioneering discovery was made in 1971, as picolinonitrile hydrolysis was examined by

Breslow et al.24 Copper complexing agent 8 was used as ligand, and the rate of hydrolysis

from 7 to 10 was examined (Scheme 2). No 10 was observed, but instead compound 9

was formed exclusively. Furthermore, it was observed that 10 could not be converted into

9 under these conditions.

NN

NH2

HO

HO

OH iN

N

O

HO

OH7 8 9

N

O

NH2

i

10

i

Scheme 2. Picolinonitrile hydrolysis attempt and the unexpected PyOX-ligand 9.24 i.

CuCl2, aq. EtOH.

2.1.2 Zinc activation

After the discovery of Breslow, as the interest towards asymmetric metal catalysis was

growing, the easy synthetic access to PyOX-ligands was examined more thoroughly. An

intensive study towards the formation of a large number of PyOX-ligands using simple zinc

activation was introduced by Bolm, two decades after Breslow (Scheme 3).25 This

procedure has grown to become the most popular preparation method of PyOX-

15

compounds catalyzed by Lewis acids and gives a simple access to oxazolines. The major

drawback of zinc activation is the need for harsh reaction conditions, as the risk of by-

products is a considerable one.

NN

OHNH2

R*

7

N

N

O

R*

i

11a, R = i-Pr 11b, R = Ph11c, R = t-Bu

12a, R = i-Pr 12b, R = Ph12c, R = t-Bu

Scheme 3. PyOX preparation by Bolm.25 i. ZnCl2, PhCl, 130 °C.

2.1.3 Cadmium activation

As always in heterocyclic chemistry, problems occur if the activating metal firmly

coordinates to heteroatoms. This was the case in the study of Aggarwal,26 as zinc

activation was less successful, probably due to the sulphide group on methioninol salt 13.

Instead, replacing zinc chloride with cadmium acetate facilitated the synthesis of 14.

SOH

NH3

Cl

13

N

N

O

S14

i

NN

7

Scheme 4. The cadmium-promoted cyclisation by Aggarwal et al.26 i. Cd(OAc)2.H2O, PhCl,

reflux.

2.2 Substituted PyOX-ligands via nitriles

In chapter 2.1, all approaches towards PyOX-ligands were based on the unsubstituted

pyridine ring and were performed with picolinonitrile 7. For synthetic purposes and a

broadened range of use, it is also essential to consider functionalisation at the pyridine

16

ring. Moberg and co-workers27 and Chelucci et al.28 prepared 6-alkylsubstituted

picolinonitriles using the modified Reissert-Henze-reaction to form the corresponding

PyOX-ligands (Scheme 5). This modification by Fife was a selective method in

functionalizing the 2-position of the pyridine ring with the nitrile group.29

NR

15, R = H16, R = Me17, R = p-Tol18, R = t-Bu19, R = CH(OH)C10H1920, R = C(OH)(Me)t-Bu

NR

7, R = H21, R = Me22, R = p-Tol23, R = t-Bu24, R = CH(OH)C10H1925, R = C(OH)(Me)t-Bu

N

NR

N

O

R1

i

*

ii

12a, R1 = i-Pr12b, R1 = Ph26a-k

Scheme 5. Preparation of substituted PyOX-ligands. i. a) mCPBA, CH2Cl2, 1 d; b)

Me2NCOCl, TMSCN, CH2Cl2, 6 d.27,28 ii. Amino alcohols, metal activation.

2.3 PyOX preparation by condensation from imidates

In the previous chapters, the used nitriles were activated by metal salts to improve the

electrophilicity of nitrile 7. Another way of activating the electrophile is to form the

corresponding alkyl imidate from the nitrile using a modified Nef reaction.30

Picolinoimidates have turned out to be electrophilic enough for direct condensation with an

amino alcohol. This transformation can be done simply by fusing the imidate and the

amino alcohol neat at 130 °C for some hours (Scheme 6).31

NN

7

N

NH

O

27

N

N

O

28

i ii

Scheme 6. Condensation of imidate 27 with ethanolamine.31 i. Na, MeOH; ii. 2-

ethanolamine (neat), 130 °C.

17

2.4 Preparation of oxazolines from carboxylic acids

Carboxylic acids are readily available, often cheaper reagents than the corresponding

nitriles. Furthermore, the known activation methods of nitriles are not always compatible

with the substrates used. This is probably why carboxylic acids also are of interest in

oxazoline syntheses. It is, however, noteworthy that these procedures are not applied on

PyOX syntheses. In all of these routes, the strategy lies on routine formation of a β-amido

alcohol from the acid and amino alcohol and cyclisation of it to the oxazoline using various

activation methods. Preparation of phenyloxazolines has been widely reported, and some

of the methods will be presented here.11

2.4.1 Chlorination of amido alcohol

Treatment of an amido alcohol with thionyl chloride was first discovered by Bergmann in

1923.32 He, however, did not notice the rearrangement of oxazolinium salt back to the

corresponding β-haloamide under certain conditions. The equilibria in oxazoline formation

using thionyl chloride were examined by Fry in the late 1940s.33 (Scheme 7) The biggest

outcome of his discovery was the need for a basic work-up to avoid the formation of by-

products V and VI, the latter also rearranging to I.

18

O

R´´ NH

R´

OH

R

O

R´´ NH

R´

O

R

S

O

Cl

O

NR´´

R

R´

.HCl

i

I II

III

O

NR´´

R

R´

ii

IV

O

R´´ NH

R´

Cl

R

ii

Viii

O

R´´ O

R

NH3Cl

R´

VI

Iii

iii

Scheme 7. Equilibria in oxazoline formation.33 i. SOCl2; ii. base; iii. H2O, heat.

Since Fry’s discovery, there have been many new chlorination methods, e.g. thionyl

chloride / silver triflate34, phosphorus oxychloride35 or the Vilsmeier reagent12, but no

general chlorinating reagent is yet found in oxazoline synthesis.

2.4.2 Other amido alcohol activators in oxazoline synthesis

Chlorination of the hydroxyl group of amido alcohols is not always the best choice in

oxazoline synthesis, as e.g. the nucleophilicity of the chloride ion causes side reactions,

like elimination to form N-vinyl amides particularly in the case of peptide structures.36

Cyclisation to the corresponding carbonyl aziridine may occur,37 even very selectively if

Mitsunobu conditions are applied in ring formation.38 This is why several alternative routes

have been developed for alcohol activation. These include formation of sulfonates like p-

toluenesulfonate,39 methanesulfonate40 or trifluoromethanesulfonate.41 Triphenylphosphine

is claimed to be a good reagent in some oxazoline ring closing reactions,42,43 contrary to

the studies by Wipf.38 Salts used to improve the leaving tendency of the hydroxyl group in

oxazoline synthesis are the Burgess reagent44 or diethylaminosulphur trifluoride (DAST).45

19

Dehydrating agents like phosphorus pentoxide46 or diisopropylcarbodiimide (DIC) with

copper(II) triflate47 have been reported, as well as sulphuric acid,48 hydrobromic acid49 or

perchloric acid.50 Convential heating (280 °C) is used for preparation of small oxazolines.46

2.5 Preparation of other bidentate N,N-oxazolines

2.5.1 2-Pyrrolidinyl 2´-oxazoline (PyrOX)

An interesting family of bidentate N,N-ligands is the PyrOX. It differs from PyOX-ligands

mostly by the relatively acidic pyrrolidine proton (29, Figure 5), which affects the chemistry

of this ligand family compared to the PyOX.

NH N

O

29

Figure 5. The PyrOX-core 29.

The first preparation of PyrOX-ligands was reported in 1977, as the unsubstituted PyrOX

was prepared from the corresponding N-ethylcarboxythioamide 3051 and ethanolamine by

liberation of hydrogen sulphide and ethyl carbamate to form the unsubstituted compound

29 (Scheme 8).

20

NH S

HN

O

O

H2NOH

NH

HN

O

O

NHHS

OH

-H2S

NH O

HN

HN

O O

-H2NCO2Et

NH N

O

3031

3229

Scheme 8. The first PyrOX synthesis.51

It was soon found out that the PyrOX-core was so much like the PyOX, that it could also

be synthesized from the corresponding β-amido alcohol 33 (Scheme 9) using the well-

known chlorination procedure reported for PyOX-ligands (chapter 2.4.1).52,53 The formed

β-chloroamide 34 is spontaneously cyclised to oxazoline 35 at room temperature.

Noteworthy about this synthesis is, however, that the pyrrole nitrogen is methylated,

eliminating e.g. proton transfers from the free pyrrole nitrogen.

N O

HN

HO N O

HN

ClN

N

O

33 34 35

i

Scheme 9. PyrOX formation from amido alcohol 33.52,53 i. SOCl2, benzene or toluene, 16

h, rt.

The first one to introduce chiral PyrOX-ligands using free pyrrole nitrogen (39) was

Brunner in 1998.54 These ligands were synthesized from amino alcohols to be tested in an

21

asymmetric cyclopropanation reaction (Scheme 10), yielding selectivities of below 15% ee.

(product 40 up to 7% ee). This discovery, however, gave indications of the possibilities of

this kind of ligands.

R

N2CHCO2Et

Ri CO2Et

*36, R = H37, R = Ph

40, R = H41, R = Ph

38

NH N

O

HO39

Scheme 10. The asymmetric cyclopropanation reaction by Brunner.54 i. CuOTf, PyrOX-

ligand (e.g. 39).

2.5.2 2-indolyl-2´-oxazoline (IndOX)

As the PyrOX was found out to be a potent catalyst ligand, the search for new analogous

structures was introduced. A couple of years after Brunner´s discovery,54 the first attempt

on constructing a chiral IndOX-compound was made.55 The strategy was to cyclise the

corresponding amido alcohol using the DAST method (Scheme 11).

NH

F

O

HN

HO

O

O

NH

F

N

O

O

HN

OH

ii, iii

43 44

NH

F

O

OH i

42

H2N OH

OO

Scheme 11. Preparation of a racemic IndOX-compound 44.55 i. HATU, HOAt, DIPEA,

DMF; ii. DAST, CH2Cl2, -20 °C; iii. NH2OH.HCl, NaOMe, MeOH.

22

The outcome of the reaction in Scheme 11 was, however, racemic 44. Nevertheless, it

was found out that rac-44 was a potential antibacterial (inhibition of deacetylase LpxC: IC50

= 1.6 µM).55

Up to date, racemisation of the oxazoline ring has been a problem in the rare IndOX

syntheses reported and the first synthesis of enantiopure IndOX-compounds is presented

in this thesis.

3 Catalytic Applications of PyOX-compounds

3.1 Hydrosilylation: Asymmetric Reduction of Ketones

One of the most interesting catalytic applications from an industrial point of view is the

asymmetric reduction of ketones. This reaction has been performed by a rhodium (I)56,57-

or cobalt (I)58-catalyzed hydrosilylation of e.g. acetophenone (39, Scheme 12). The

needed mildness of this reaction is achieved by using diphenylsilane as the hydrogen

source,59 facilitating good selectivities. Selectivities of up to 80% ee and yields of almost

100 % were reached using this protocol.

O OH

*

45 47

N

N

O

R1

R2

46a-i

i

Scheme 12. Asymmetric hydrosilylation.56 i. a) [Rh(COD)Cl]2, 46a-i, Ph2SiH2, 0 °C -> rt. b)

p-TsOH, MeOH.

23

3.2 Diels-Alder-reaction

The Diels-Alder-reaction is a very useful tool in the formation of six-membered rings.60 Its

synthetic utility lies in the formation of four contiguous stereocenters, offering a great deal

of challenge. This is why stereocontrol of this reaction has become a big issue within

organic chemistry.61 A major discovery within this reaction was made in 1960, as it was

discovered that Lewis acids (AlCl3) significantly speeded up Diels-Alder-reactions.62 This

was the basis for the development of asymmetric metal-catalyzed Diels-Alder-reactions,

originally presented by Koga two decades later.63 The first report of asymmetric Diels-

Alder-reaction using PyOX-ligands dates back to the late 1990s.64 This group reported

ruthenium-catalyzed cyclisation of methacrolein 48 and cyclopentadiene 49 (Scheme 13).

Using this protocol, the exo : endo ratio of 50 was at about 95 : 5, moderate to good yields

and enantioselectivities of 70 - 80% ee were obtained.

O

O

50

i

N

N

O

12a

48 49

Scheme 13. Asymmetric Diels-Alder-reaction, using PyOX-ligand.64 i. a) 12a, [RuCl2(η6-

mes)]2, NaSbF6 or KPF6, MeOH; b) 48, 49, 2,6-di-t-butylpyridine, CH2Cl2.

3.3 Meerwein arylation

The reaction known as the Meerwein arylation65 is an efficient way of functionalizing

double bonds with aryl substituents. Its mechanism is, however, not fully understood yet.66

The Meerwein arylation means activation of aryl diazonium salts (e.g. 52) with copper (I)

and coupling the liberated aryl radical to an activated double bond (e.g. 51, Scheme 14).

The reaction reported by Brunner66 is the first reported asymmetric Meerwein arylation,

with moderate yields and selectivities of 55 in the range of 2-6% ee.

24

O

O

N2 BF4

51 52

i

O

OCl

*

55

N

N

O

R

53 : R = n-Pr54 : R = n-Bu

*

Scheme 14. Asymmetric Meerwein arylation.66 i. a) 53 or 54, CuOTf.0.5 PhH, 51, MeCN;

b) Bu4NCl, 52, MeCN.

3.4 Asymmetric epoxidation

Asymmetric epoxidations have gained a huge interest due to the possibility of controlling

two stereocenters. Henbest reported the first asymmetric epoxidation in 1965, oxidising

double bonds with percamphoric acid.67 The breakthrough in efficient asymmetric

epoxidation was, however, the contributions of Sharpless.68 He invented the epoxidation of

allylic alcohols using the titanium tetraisopropoxide-diethyl tartrate-combination as catalyst.

Among other efforts, this gave Sharpless the Nobel Prize in 2001. Since the 1980s,

asymmetric epoxidations have been developed to a large extent.69 Asymmetric

epoxidations on unfunctionalized olefins have also been made with PyOX-ligands.

Ruthenium(III)-catalyzed oxidations using sodium periodate as oxidant was reported by

Dai.70 In this study, asymmetric epoxidation of trans-stilbene 56 and 1-phenylcyclohexene

57 were oxidized using PyOX-ligands as sources of chirality (Scheme 15). The results

were moderate yields and not very high ee:s (6-21% ee), mainly due to lack of functionality

in the olefins.

25

56

57

60

61

O

O

*

*

N

N

O

R

i

12a, R = iPr12b, R = Ph58, R = iBu59, R = Bn

Scheme 15. Asymmetric epoxidation with PyOX-ligands.70 i. a) 12, 58 or 59, RuCl3.3H2O,

H2O; b) 56 or 57, CH2Cl2; c) NaIO4.

3.5 Nucleophilic 1,2-attack on carbonyls

3.5.1 Addition of diethylzinc to aromatic aldehydes

One of the most popular test reactions in asymmetric synthesis has been the addition

reaction of diethylzinc to aldehydes, mostly benzaldehyde. The first asymmetric ligand,

called DAIB was introduced for this reaction (62, Figure 6) in 1986 by Noyori.71

OH

N

62

Figure 6. DAIB (62) introduced by Noyori.71

Enantioselectivities of up to 98% ee could be reached using DAIB. Since this discovery,

there has been a large number of applications involving this reaction.72 A decade later

Moberg introduced tridentate PyOX-carbinols as enantioselective ligands for this

26

reaction.73 This reaction gave good yields and enantioselectivities for the non-substituted

product 66 and the p-chloro adduct 67 (Scheme 16).

R

O

Zn

R

OH

63, R = H64, R = Cl

66, R = H67, R = Cl

i

N

N

O

R

OH

*

26j, R = iPr26k, R = Ph

*

65

Scheme 16. Addition of diethylzinc to benzaldehydes.73 i. PyOX-carbinol, 63 or 64, 65,

hexane, PhMe.

3.5.2 Addition of allyltrialkylsilanes to aromatic aldehydes

Stereoselective formation of homoallylic alcohols is a challenge in organic synthesis, partly

due to the chemical features of this functionality.74 The most popular way of constructing

homoallylic alcohols is the nucleophilic allylation on aldehydes, which can be

accomplished using a variety of organometal species.75 One of the species used is the

allyltrialkylsilane family. The PyOX was found to be a promising ligand in this reaction.

Barrett screened different PyOX-ligands and aldehydes to achieve good yields (up to 91%)

and selectivities (up to 74% ee) using crotyltrichlorosilane 68 as the nucleophile (Scheme

17).76

27

SiCl3

68

Ar

O

Ar

OH

**

N

N

O

R

63, R = Ph69, R = p-MePh70, R = p-OMePh71, R = p-NO2Ph72, R = p-FPh73, R = PhCH=CH

74, R = Ph75, R = p-MePh76, R = p-OMePh77, R = p-NO2Ph78, R = p-FPh79, R = PhCH=CH

i

12

Scheme 17. Enantioselective crotylation of aldehydes 63, 69-73.76 i. 12, CH2Cl2,

-78 °C.

3.6 Nucleophilic conjugate addition

3.6.1 Michael addition

Addition of soft nucleophiles to enones via conjugate addition is a widespread reaction

within synthesis of complex molecules.77 The basic concept was introduced in the early

1940s, as enones were alkylated with Grignard reagents at the 4-position, using copper

(I)-salts as carbonyl activators.78 The concept itself is unchanged to our days, with the

exception of the nucleophile species. Chirality is achieved using asymmetric copper

ligands. A PyOX-ligand was used for this reaction, as trimethylalane was used as the

nucleophile.79 According to this study, a slight excess of TBSOTf was needed for a

successful and efficient reaction. The reason was claimed to be formation of intermediate

82 (Scheme 18). This reaction was carried out under the same conditions with ligand 12a,

but no mechanistic explanation for the use of TBSOTf with that bidentate N,N-ligand was

presented. With ligand 11a, a chemical yield of 33% and 12% ee was achieved.

28

O

O

O

N

CuTfO

SiO

82

N

O

80

O

81

iO

O

N

N

O

12aO

*

83

Scheme 18. i. Conjugate addition with mechanism for ligand 82.79 i. Me3Al (200 mol-%),

CuOTf.0.5 PhH (5 mol-%), TBSOTf (120 mol-%), 80 (20 mol-%), 81 (100 mol-%), THF,

Yields 0-66 %, 0-63 % ee.

Another case of Michael-additions with PyOX-ligands is an approach made by PyOX-

ligands with a thioether tail (86), making 86 a tridentate ligand.80 Scheme 19 shows this

approach, giving 87 a selectivity of maximally 19% ee.

O O

O

84

O

85

O

87

O

CO2Et

*

N

N

O

S

86

i

Scheme 19. Michael addition with the optimized threedentate PyOX-ligand.80 i. a) MXn, (M

= transition metals, best selectivity using Ni(OAc)2.4H2O), 86, 84, CH2Cl2; b) 85. Yields 10 -

above 95 %, 6 – 19 % ee.

3.6.2 Allylic substitution

The most explored asymmetric reaction type using PyOX-ligands is probably allylic

substitution.81 Among the early examples of these was the Kharasch-Sosnovsky-reaction,

29

that is about oxidizing olefins (e.g. 88, Scheme 20) with t-butyl peresters using copper

activation.82,83 In a more recent study, PyOX-ligands were used with copper(I) salts in this

reaction to give selectivities in the range of 20-30% ee.84

O

O

Ph

*

88 89i

N

N

O

R*

12b, 58

Scheme 20. Asymmetric Kharasch-Sosnovsky-reaction.84 i. Cu(MeCN)4PF6, 12b or 58,

PhCO3tBu, MeCN.

A newer asymmetric substitution reaction performed with PyOX is the Pd-catalyzed allylic

substitution reaction by Trost.85 It is about alkylating chalconol acetate 90 with dimethyl

malonate (Scheme 21). It was used for bidentate and some tridentate PyOX-ligands27 or

for polymer-bound tridentate ligands86 by Moberg and for fused pyridine ring PyOX-

ligands28 or 4,6-substituted pyridine ring ligands87 by Chelucci, all of these with good to

excellent enantioselectivities (up to 99% ee for tridentate PyOX-ligands)27. This procedure

was performed by deprotonating dimethyl malonate and adding it to the solution of the

formed complex of the allylpalladium catalyst and 90 (Scheme 21).

OAc

rac-90

O O

O O

*

91

N

N

OR1

R2

i

Scheme 21. Asymmetric alkylation of chalconol acetate using PyOX-ligands.27 i. a) PyOX-

ligand (14 different), [(η-C3H5)PdCl]2, CH2Cl2; b) 90; c) Dimethyl malonate, BTMSA, AcOK.

30

Chelucci87 reasoned with the possible mechanism of palladium-catalyzed reactions with

PyOX-ligands. Since PyOX is a non-C2-symmetric species, it can form two Pd-allyl-

complexes (Scheme 22). Configurations 92 and 93 are at equilibrium via the π-σ-π-

mechanism at the olefinic bond. This equilibrium is substrate-sensitive and dependent on

steric and electronic factors. There can thus be four possible sites for the nucleophile to

attack. Since the reactive allylic intermediate of substrate 90 (1,3-diphenylallyl cation) is

symmetric, these four reacting centers (Scheme 22) can only form two products.

N

N

O

R

Pd

Ph

Ph

R´ N

N

O

R

Pd

R´

Ph

Ph

Nu

Nu

NuNu

i

92 93

Scheme 22. Possible sites for nucleophilic attack.87 i. π-σ-π-equilibrium.

3.7 Cyclopropanation of olefins

One of the most successful introductions of asymmetric test reactions has been the

introduction of cyclopropanation of olefins, as splendid results were achieved in the very

first report by Evans in his study of Cu-1,3-BOX-catalyzed cyclopropanations of styrene

derivatives.88 The best results were, however, achieved with 1,1-disubstituted olefins 37

and 94 (Scheme 23), and nearly enantiopure products 41 and 96 (>99% ee) were

obtained in excellent yields (>90%). The protocol gave, however, low selectivities (3-8%

ee) in the case of 1,2-bisoxazoline ligand and styrene as substrate (cf. Scheme 24).

31

R

37, R = Ph94, R = Me

R

EtO2C N2

38

R

R

CO2Et

N

O

N

O

95

41, R = Ph96, R = Me

i

Scheme 23. Asymmetric cyclopropanation by Evans.88 i. CuOTf.

The Evans procedure has been applied on more hindered olefins and more electron-poor

olefins to find the limitations of this reaction.89 Bi- and tridentate P,N- and P,N,N-ligands

with ruthenium catalysts have also been used for cyclopropanation.90

Chelucci examined the use of PyOX-catalysts (e.g. 97) in asymmetric cyclopropanation of

styrene 36 using ethyl diazoacetate (38, Scheme 23).91 Like Evans,88 he used copper (I)

triflate as the catalyst metal salt to achieve moderate selectivities (up to 60% ee) with

PyOX-ligands. This was a remarkable improvement to the Evans C2-symmetric BOX-

catalyst in the case of styrene (Scheme 24).

36

EtO2C N2

38

CO2Et

N

O

trans-40cis-40

i

N

97Ph

Scheme 24. Asymmetric cyclopropanation with PyOX-ligands.91 i. CuOTf.

32

4 Aim of the study

Due to an increasing demand for enantiopure compounds, it is essential to develop new

methods to induce this purity in an efficient manner. Reaction efficiency is not, however,

the only criterion in this field, including e.g. pharmaceuticals. The development of new

synthesis routes also includes the problems of isolating the pure product, making the

entire process cost worthy and environmentally friendly with a minimal amount of waste

and solvents related to the amount of desired products. In this thesis, the strategy was

firstly to prepare bidentate chiral PyOX-ligands in an efficient manner for inducing chiral

information in an asymmetric test reaction. The PyOX was chosen as the target compound

family, because of its promising and yet rather unexplored ligand activity. The point of

preparing known types of ligands was, however, the second stage of this project: to

efficiently immobilize this chiral ligand on a support for the reasons stated above: improved

efficiency in industrial processes. A modern approach to supported catalyst ligands are the

semi-soluble supports, e.g. gold nanoparticles, soluble in some organic solvents but strictly

insoluble in others. For this reason, the target was also set in preparing novel gold nano

ligands with the PyOX functionality and testing their catalytic activity.

To ensure the efficiency of all PyOX-ligands, their selectivity impact required testing in a

known, efficient asymmetric reaction, applicable for all PyOX-compounds. Finally, to tackle

the problems with a general oxazoline formation procedure, my procedure was used to

develop an efficient synthesis route for a previously never enantiopurely synthesized

bidentate N,N-oxazoline compound family, the 2-indolyloxazolines (IndOX). The results

achieved in this thesis have been partitioned and published in five scientific publications:

I: Preparation of a soluble mercapto derived PyOX-ligand.

II: Preparation of PyOX-ligands on solid support: Simultaneous linking and oxazoline

formation.

III: Preparation of a chiral gold nanoparticle by linking a novel PyOX-ligand on passivated

gold surface.

IV: The asymmetric Henry reaction – a new application for PyOX-ligands.

V: Preparation of a novel compound family: the IndOX.

33

5 Results and Discussion

5.1 Synthesis of a mercapto derived soluble PyOX-ligand (I)

In the first publication of this thesis, an efficient and simple procedure to form the PyOX-

core and, further on, modify the 5-position of the pyridine ring was obtained. The designed

mercapto ester with the chiral PyOX-core (98, Scheme 25) was prepared to be used in the

preparation of gold nanoparticles (chapter 5.3.). The retrosynthetic analysis of the key

steps of the synthesis of 98 is presented in Scheme 25. The acid group in 99 was

introduced for further functionalization of the 5-position of the pyridine ring.

N

O

OHS

N

ON

O

HO

N

O

N

O

O

O

HN

HO

N

O

OH

O

HO

NH2

OH+

98 99

100101102

Scheme 25. Retrosynthetic analysis of the preparation of mercapto ester 98.

Diacid 102 was chosen as the starting material because of its clean and efficient reactions

in our hands, contrary to substituted picolinonitriles in known reactions with zinc chloride25

or the isolation problems of picolinoimidates.30 Diacid 102 was set for exhaustive

esterification to form diester 103 (Scheme 26), which in turn was set for selective

hydrolysis of the more electrophilic 2-position to form monoacid 104.92 Acid 104 was

coupled with phenylalaninol 101 by formation of the corresponding acid chloride 105 with

thionyl chloride to form amido alcohol 100. The amido alcohol was then cyclised to the

34

corresponding PyOX-structure 107 in two steps. Amido alcohol 100 was mesylated to form

the isolable mesylate precursor 106.12 To our knowledge, a one-step cyclisation using

tosylation has only been presented by Meyers, using prolonged reaction times and

mixtures.93 Mesylate 106 was then cyclised to oxazoline 107 by DBU treatment at

elevated temperature12 to achieve a clean reaction. The methyl ester group of 107 was

hydrolyzed to give the key intermediate 99 (Scheme 26).

N

O

OH

O

HO

NH2

OH

101

102

N

O

O

O

O

103

N

O

OH

O

O

104

N

O

Cl

O

O

105

i ii iii

iv

N

O

O

O

HN

HO100

N

O

O

O

HN

MsO106

v

N

O

O

N

O

107

N

O

HO

N

O

99

vi

vii

Scheme 26. Synthesis of key intermediate 99. i. MeOH, H2SO4, reflux, 17.5 h, 91 %; ii. a)

NaOH, MeOH, reflux, 2.5 h, 90 %; b) concentrated aq. HCl; iii. SOCl2, reflux; iv. 105, NEt3,

CH2Cl2, rt, 64 %; v. MsCl, NEt3, DMAP, CH2Cl2, rt, 3 min, 92 %; vi. DBU, THF, 50 °C, 8 h,

84 %; vii. a) NaOH, aq. MeOH, reflux, 4 h, 71 %; b) concentrated aq. HCl.

To acid 99 was added S-tritylprotected mercaptoethanol 10994 according to standard

esterification procedures to form the protected target molecule 110 (Scheme 27). The final

target 98 was reached by deprotection of the trityl group of 110. It was accomplished using

TFA with triethylsilane as scavenger of the formed trityl cation.95 Addition of Et3SiH had to

35

be done carefully, since an excess or a rapid addition immediately decomposed the

oxazoline group in 110.

N

O

OHS

N

O

N

O

HO

N

O

98

99

HSOH

108

i SOH

109

N

O

N

O

110

SO

ii

iii

Scheme 27. Final steps in the synthesis of 98. i. Ph3COH, conc. aq. HCl, MeCN, 10 min,

rt; ii. 109, DIC, DMAP, CH2Cl2 / DMF, rt, 22 h, 72 %; iii. TFA, Et3SiH, CH2Cl2, rt, 10 min, 91

%.

The outcome of this synthesis is of great value because of the combination of efficient

preparation of a chiral ligand and the new approach to form the mercapto terminus on a

ligand like 98. Mercapto adducts are of great interest because of their well-known

attachment on gold surfaces96 or nanoparticles.97 Applications involving such complexes

are examined at a growing rate,98 making mercapto derived efficient ligands valuable in

e.g. nano sciences.

36

5.2 Ligand preparation via linking: A new approach to solid-phase synthesis (II)

Traditional soluble ligands have turned out to be efficient in catalysis, but cause severe

purification problems in processes because of the need for extraction and possibly even

other purifications to avoid the existence of the valuable and harmful catalyst metals in the

products. A method nowadays commonly used in industrial processes is the use of non-

soluble catalysts or ligands. The advantage of solid supports is the ease of purification, as

the product mixture can be separated by simple filtration and washing of the non-soluble

agent. In this part of my thesis, an efficient and simple method to form PyOX-ligands on

insoluble polystyrene support was introduced. The novelty of this method was the

synthesis of a novel, chiral amino alcohol linker that could be used for a simultaneous

attachment of an acid and ligand formation on the support.

The major discovery of this study was the chiral amino alcohol linker 111 (Scheme 28).

This tyrosine analogue was chosen based on the knowledge on benzylic amino alcohols

presented in chapter 5.1. Furthermore, the phenolic functionality of tyrosine (114) could be

used for linking onto Merrifield resin18 (1, Schemes 1 and 28). Preparation of 111 was

rapidly accomplished by protection of tyrosine, coupling to support 1, reduction of the ester

and deprotection, as shown in Scheme 28.

37

ONH2

OH

111

ONHBoc

O

112

O

Cl

1

HONHBoc

O

113

O

HO

OH

114

O

NH2

Scheme 28. Retrosynthesis of amino alcohol linker 111.

Synthesis of 111 was started by examining the corresponding solution phase reactions

(Scheme 29) by IR analysis as reference for solid-phase follow-up. Furthermore, the

absence of racemisation was verified (Scheme 30). The crucial step from this point of view

was the reduction of 115 (Scheme 29). The model reaction path was set up by replacing

the insoluble polymer tail by the benzyl group and optimizing the reaction conditions for

that path. The protocol for Boc removal is originally tailored for solid-phase synthesis and

thus used in this model test also.99

38

HO

OH

114

O

NH2HO

NHBoc

O

113

O

ONHBoc

O

115

O

ONHBoc

OH

116

ONH2

OH

117

i, ii iii

iv

v

Scheme 29. Synthesis of the soluble analogue 117. i. (i) SOCl2, MeOH, -72 °C -> reflux,

20 h; (ii) NEt3, Boc2O, MeOH, rt, 17 h, 89 % (2 steps); (iii) BnBr, K2CO3, KI, acetone,

reflux, 4 h, 100 %; (iv) NaBH4, LiI, THF, reflux, 3 h, 87 %; (v) p-TsOH, CH2Cl2, THF, rt, 20

h, 68 %.

The major observation in the presented synthesis route was the benzylation step, as it

turned out that the use of cesium carbonate in step (iii) (Scheme 29) instead of potassium

carbonate decomposed 113 and the formed 115, giving a complex mixture of products.100

The use of potassium carbonate correspondingly gave a clean conversion in acetone, as

reported earlier.80 Since acetone is not a compatible solvent with the Merrifield resin due to

poor swelling, racemisation and decomposition with potassium carbonate in DMF were

also tested in my study and found to cause none of these. Racemisation was examined by

preparing proline-derived diastereomeric derivatives101 of 116 and its corresponding (D)-

isomer 118 (Scheme 30). Derivatives 120 and 121 could be separated by achiral HPLC

and no racemisation could be detected.

39

ONHBoc

OH

116

ONHBoc

OH

118

N

119

i

ONHBoc

O

120

121

O

N

PhO2SSO2Ph

O

Cl

ONHBoc

O

O

N

PhO2S

Scheme 30. Preparation of diastereomeric derivatives 120 and 121 for HPLC analysis. i.

a) 116 or 118, DIPEA, 119, CH2Cl2, rt, 120: 18 h, 121: 20 min.

Preparation on solid support followed the optimized synthesis route from phenol 113 for

soluble adducts (Scheme 29). Each of the reactions were followed and monitored by FTIR

analysis after isolation of an analytical sample to form the novel amino alcohol linker 111

(Scheme 31).

HONHBoc

O

113

O Cl

1

iO

NHBoc

O

O

112

ONHBoc

OH

122

ii

ONH2

OH

111

iii

Scheme 31. Synthesis of the novel amino alcohol linker 111. i. 1 (1.59 mmol Cl / g),

K2CO3, KI, DMF, 70 °C, 19 h; ii. NaBH4, LiI, THF, reflux, 7 h; iii. p-TsOH, CH2Cl2, THF, rt,

1.5 h.

40

Resin 111 was used in PyOX-preparation according to procedures optimized in chapter

5.1. A variety of picolinic acids were attached to 111 to form the supported ligands 131-

133 (Scheme 32). Further functionalization at the pyridine ring was done by designing acid

124 by Sonogashira-type coupling of compounds 135 and 136.102 A noteworthy issue was

that the use of copper (original Sonogashira-conditions)103 at different ratios inhibited this

coupling totally, contrary to previous studies.104

ONH2

OH

111N

O

OH

R

123, R = H104, R = CO2Me124, R = OTBS

i

OHN

OH

O

N

R

125, R = H126, R = CO2Me127, R = OTBS

OHN

OMs

O

N

R

128, R = H129, R = CO2Me130, R = OTBS

ON

O

N

R131, R = H132, R = CO2Me133, R = OTBS

ii

iii

N

Br

Br N

Br

O

O

N

O

OH

TBSO

134 135 124

iv, vvi, vii

OTBS

136

Scheme 32. Synthesis of solid-supported PyOX-ligands 131-133 and acid 124. i. HOBt,

DIC, CH2Cl2, DMF, rt; ii. MsCl, NEt3, DMAP, CH2Cl2, rt; iii. DBU, THF, 50 °C; iv. BuLi,

PhMe, -77°C, 3 h, quench by CO2; v. SOCl2, reflux, 4 h; quench MeOH/NEt3, rt; vi. 136,

Pd(PPh3)2Cl2, NEt3, THF, reflux, 24 h; vii. NaOH, aq. MeOH, reflux, 6 h.

41

The approach presented in Scheme 32 is to the best of my knowledge the first approach to

form PyOX-ligands via simultaneous linking and ligand formation. The common way of

preparing solid-supported ligands is to prepare the soluble ligand first and then attach it

onto the support.

5.3 Chirally modified gold nanoparticles (III)

Solution chemistry has always been the most popular approach to synthesis (e.g. in

chapter 5.1.). This is mainly because of its superior efficiency, as kinetics of reactions is

practically limited by diffusion of the used components only. Synthesis on solid supports

(e.g. chapter 5.2.) is somewhat less efficient because of phase differences, but offers the

advantage of much easier isolation. A modern way of combining the advantages of these

methods is the use of semi-soluble nanoparticles, as presented in chapter 1.2.2. The

major problem with early nanoparticles was their instability to air, moisture and light. This

was the fact that made the relatively stable alkylthiolate-passivated gold nanoparticles

(Brust-Schiffrin-particles, 137, Scheme 33)105 a breakthrough in this field.

In this part of my thesis, particle 137 was prepared according to the original procedure105

and used to synthesize a chiral PyOX-derived nanoparticle 138 via simple ligand

exchange (Scheme 33). The ligand used for this purpose was the soluble 98, the synthesis

of which is presented in chapter 5.1. (Scheme 27)

42

SS

S

S

Au32

S

S

S

S

S S

S

S

SS

S

S

Aun

S

S

S

S S

S

S

S

S

S

S

SS

S

S

S

SO

S

S

S

Au32

O

S

O

S

O

S

O

O

S

O

O

S S

S

S

SS

S

S

OO

O

O

OO

O

O

Au32

S

S

S

S S

S

S

S

S

S

S

SS

S

S

S

O

N

ON

O

N

ON

O

NO

N

O

N

O

N

ON

O

N

O

N

O

NO

N

O

N

O

N

O N

O

N

O N

O

N

ON

O

NO

N

O

NO

N

O

N

O

N

O

N

O

N

ON

O

N O

N

O

N

SHO

O

N

O

N

137 138

i

98

Scheme 33. Preparation of the chiral nanoligand 138. i. 98, PhMe, 25 d, rt.

The long reaction time was a surprise in this synthesis, and at 20 days particle 138 could

not even be isolated, indicating the presence of larger and more soluble particles or

conglomerates in the solution. After precipitation of 138, its composition was analyzed by

CHN-analysis and a ratio of Au : S : N = 1 : 1 : 1 was obtained, indicating that half of the

original hexanethiolate ligands of 137 were substituted with 98. Further on, this would

mean that all thiolates were at the surface of the hollow gold core, an observation that was

supported by ESCA analysis of the compound. The big observation was, however, the size

of 138: TEM images of these particles (b, Figure 7) revealed that a diameter of 1.2 ± 0.2

nm was achieved, i.e. smaller than ever in this field! Earlier modelling studies106 predicted

that this would correspond to a fullerene-like core, consisting of 32 gold atoms.

43

Figure 7. Low resolution TEM images of a) particle 137; b) particle 138; c) High resolution

TEM image of 138.

As 138 was a chiral ligand, it was used in an asymmetric test reaction by Trost (Scheme

21)85 and gave selectivities somewhat poorer than the soluble analogues, but better than

the corresponding polymer-bound adduct (presented in chapter 5.2.). Conclusively, this

paper yielded a chiral PyOX-derived gold nanoparticle 138 of, to my knowledge, a

magnitude never achieved in experimental chemistry. Its ligand activity was successfully

tested in a metal-catalyzed asymmetric test reaction.

5.4 The asymmetric Henry reaction – a new Application for PyOX (IV)

Bidentate N,N-oxazoline ligands are potent ligands for metal catalysis, as frequent reports

have shown.10 A subunit of these ligands is the chiral PyOX-ligand family, also widely used

in catalytic applications (Chapter 3).

In this paper, a new application for chiral PyOX-ligands was presented: the asymmetric

Henry reaction, i.e. coupling of a nitroalkane (II, Scheme 34) to aldehydes (I).107 The

synthetic value of the Henry reaction is the formation of a C-C-bond with a chiral

environment combined with excellent synthetic potential of the formed nitroalcohol III, like

44

easy access to amino alcohols (IV). In addition to this, the reactions were quite clean and

cheap starting materials and solvents were used, which is of industrial interest.

R

O

NO

O

R

OH

N

O

O* R

OH

*NH2

I III IV

i

R'

R'

*

R'

II [H]

Scheme 34. General reaction scheme of the Henry reaction. i. metal salt, ligand, solvent,

heating.

The asymmetric Henry reaction involves somewhat more consideration, since the

mechanism is not yet fully known. In Scheme 35, a mechanism proposed by Evans108 is

presented.

N

NO

R

X

Cu

OAc

OAcN

O

O-AcOH

+AcOHN

NO

R

X

Cu

OAc

O N

O

R1

O

N

N

O

R

X

CuAcO

O

N OR1

O

+AcOH

R1

OH

NO

O

*

139 141

142

140

III

I

Scheme 35. The proposed mechanism by Evans,108 the PyOX-ligand used for clarity.

In Scheme 35, it can be noticed that the formation of the intermolecular ring in 142 is

essential for product formation. At the same stage (141 à 142), the oxazoline substituent

seems to block the other face and prevent aldehyde attack selectively.

45

To test the Henry reaction with PyOX-ligands, an electron-poor aldehyde (p-

nitrobenzaldehyde, 71) was selected for good reactivity to effectively monitor the selectivity

of the different PyOX-ligands (Scheme 36).

O2N

O NO

O

71

140

O2N

OH

143

NO2

N

N

O

R

12b, R = Ph12c, R = t-Bu12d, R = Bn144, R = CHPh2

N

N

O

145

N

N

O

146

N

N

O

R

O

O

107, R = Bn147, R = t-Bu

i

Scheme 36. The asymmetric Henry reaction with p-nitrobenzaldehyde 71 and

nitromethane (140). i. a) 12, 107, 144-147, Cu(OAc)2, EtOH, 70°C, 1 h; b) 71, 140, rt , 3-24

h.

Yields and selectivities were monitored in these test reactions and the best ligand (147, full

conversion, 70% ee) was selected and fixed for the next reaction series, where aldehydes

were varied (Scheme 37). The used aldehydes (63, 70 and 148) were selected for

monitoring of the electronic impact of substituents and the compatibility on aliphatic

aldehydes (148). Selectivities of as high as 78% ee were achieved for alcohol 138, but

required a long (48 h) reaction time and yielded a little amount of by-products, probably

due to the enolizable aldehyde (148).

46

R

O

63, R = Ph70, R = (p-OMe)Ph148, R = c-Hex

R

OH

NO2

N

N

O

O

O

i

147

149, R = Ph150, R = (p-OMe)Ph151, R = c-Hex

Scheme 37. Screening of aldehydes. i. a) 147, Cu(OAc)2, EtOH, 70°C, 1 h; b) Aldehyde

(63, 70 or 148), 140, rt , 20-48 h.

In conclusion, a new application for chiral PyOX-ligands was explored in this paper. The

best ligand was found by careful screening of my novel PyOX-ligands. This is of synthetic

use in the synthesis of e.g. amino alcohols, if different nitroalkanes from 140 are used to

prepare diastereomeric adducts.

5.5 Preparation of a Novel Ligand Family: The IndOX (V)

As mentioned previously (e.g. chapter 3.6.), the dissymmetric oxazoline ligands can form

two different metal complexes, a selectivity feature absent in e.g. corresponding PyBOX

cores. Some other chiral bidentate N,N-oxazoline ligands than PyOX are also known,

though not as common, in synthetic chemistry. A group of compounds with these features

is the pyrrolyl oxazoline ligand family (PyrOX), the core of which was originally introduced

in the 1970s.51 Chiral PyrOX-ligands were prepared by Pfaltz109 some years ago using the

zinc activated condensation procedure for nitriles25 (chapter 2.1.2.). A catalytic application

for PyrOX-ligands was found recently by Brunner, as selective ruthenium-catalyzed Diels-

Alder reactions with the isolated catalyst 153110 (Scheme 38) were reported with

comparable results (50 exo : endo 98 : 2, 60% ee), with PyOX-ligands in chapter 3.2.64

47

NH N

O

152

i, ii

N

N

O

RuCl

153

CHO

CHO

iii

5048 49

Scheme 38. Diels-Alder-reaction with PyrOX-catalyst 153. i. t-BuOK, CH2Cl2, rt; ii. [(η6-p-

cymol)RuCl2]2, CH2Cl2, 0°C -> rt; iii. a) 153, AgSbF6, acetone, CH2Cl2, rt; b) 48, 49, rt.

In the study by Pfaltz,109 attempts to form the corresponding indolyl ligand species (IndOX)

were made. Another attempt to form chiral IndOX-species was made in 2002, giving the

racemate as outcome, as mentioned in chapter 2.5.2.55 This species turned, nevertheless,

out to be an active pharmaceutical compound.

In the final part of my thesis, a protocol to form a chiral IndOX-compound family was

reported. The preparation procedure followed the same strategy as in the preparation of

my substituted PyOX-compounds. The indolyl-2-carboxylic acids 154-156 (Scheme 39)

were selected to vary the substituent at the 5-position of the indolyl ring from electron

donating to withdrawing. The oxazoline ring substituents were introduced by careful

selection of amino alcohols (101, 157-159) to give structural variety.

48

NH O

OHX

NH O

HN

X

HO

R

154, X = H155, X = OMe156, X = Cl

NH2

OHR

160, X = H, R = t-Bu161, X = H, R = Bn162, X = H, R = (R)-Ph163, X = H, R = i-Bu164, X = OMe, R = t-Bu165, X = Cl, R = t-Bu

NH

X

N

O

R166, X = H, R = t-Bu167, X = H, R = Bn168, X = H, R = (R)-Ph169, X = H, R = i-Bu170, X = OMe, R = t-Bu171, X = Cl, R = t-Bu

i

ii

101, R = Bn157, R = t-Bu158, R = (R)-Ph159, R = i-Bu

Scheme 39. Preparation of the IndOX-compound family. i. 154-156, amino alcohol 101 or

157-159, BOP, DIPEA, CH2Cl2, rt, pH = 9, 40-84 %; ii. 160-165, MsCl, NEt3, DMAP,

CH2Cl2, rt, 41-68 %.

As Scheme 39 shows, the reaction route consisted of two simple reaction steps performed

at room temperature. The ease of this reaction turned out to be a fact, because no

chromatographic purifications were needed in the formation of oxazolines 166-171. To

ensure the optical purity of the oxazoline ligands, the (S)-enantiomer of 168 was also

prepared and the purity ensured by chiral HPLC. All the products were obtained in

moderate to good yields in clean reactions, indicating that even better yields could be

achieved on laboratory scale using column chromatography.

In conclusion, a novel chiral compound family, the IndOX, is introduced. The target

molecules 166-171 could be reached in two simple steps without column chromatography.

The synthesis is tailored to facilitate modification of as well the indole as the oxazoline

ring, thus tuneable for many synthetic purposes.

6 Conclusions

In this thesis, the focus was on the preparation of chiral bidentate N,N-oxazoline ligands

(PyOX and IndOX) on different supports and in different applications. The key issue was

thus to develop an efficient method, mild enough not to racemize the formed oxazolines

and also offering the opportunity to modify both rings of the compound core. This thesis

was introduced by tailoring a mercapto ester derived chiral PyOX-ligand for attachment on

49

a gold surface. As this tailored species was attached on a gold nanoparticle, the result was

a selective catalyst ligand on a gold nanoparticle smaller than ever achieved in synthetic

chemistry! Another method to form supported PyOX-ligands was also created, as a novel

polymer-bound amino alcohol linker was synthesized. On this linker, picolinic acids could

be attached and the corresponding polymer-bound PyOX-ligands could be formed

simultaneously, contrary to earlier studies to first form the ligand and then attach it on the

support. A new catalytic application with promising results was also found for PyOX-

ligands, i.e. the Henry reaction. To further expand the synthetic value of the optimized

PyOX-formation protocol, the pyridine ring was substituted with the indole ring and a novel

chiral ligand family, the IndOX, was synthesized by varying the substituents of both rings

of its core.

The major contribution of this thesis is the optimization of a synthetic procedure to be

applied on conventional ligand synthesis, solid phase synthesis and nanochemistry, very

important fields of chemistry nowadays. In addition to this, a new catalytic asymmetric

application for most of the new oxazoline compounds, i.e. all PyOX-ligands, was found,

broadening the scope of bidentate oxazoline compounds even further to meet the strict

demands of synthesis in our days.

7 References

1 Hirashima, A., Eiraku, T., Shigeta, Y. and Kuwano, E. Bioorg. Med. Chem. 2003, 11, 95-

104.

2 Annedi, S.C., Majumder, K., Wei, L., Oyiliagu, C.E., Samson, S. and Kotra, L.P. Bioorg.

Med. Chem. 2005, 13, 2943-2958.

3 Götz, M.G., Caffrey, C.R., Hansell, E., McKerrow, J.H. and Powers, J.C. Bioorg. Med.

Chem. 2004, 12, 5203-5212.

4 Zhang, P., Bao, L., Zuckett, J.F., Jia, Z.J., Woolfrey, J., Arfsten, A., Edwards, S., Sinha,

U., Hutchaleelaha, A., Lambing, J.L., Hollenbach, S.J., Scarborough, R.M. and Zhu, B.-

Y. Bioorg. Med. Chem. Lett. 2004, 14, 989-994.

5 Pirrung, M.C., Turney, L.N., McClerren, A.L. and Raetz, C.R.H., J. Am. Chem. Soc.,

2003, 125, 1575-1586.

50

6 Mahler, G., Serra, G., Dematteis, S., Saldaña, J., Dominguez, L. and Manta, E. Bioorg.

Med. Chem. Lett. 2006, 16, 1309-1311.

7 Wipf, P., Reeves, J.T., Balachandran, R. and Day, B.W. J. Med. Chem. 2002, 45, 1901-

1917.

8 Protective groups in Organic Synthesis, 3rd. ed.; Greene, T. W., Wuts, P. G. M., Eds.;

Wiley: New York, 1999.

9 Reviews: a) Gant, T. G. and Meyers, A. I. Tetrahedron 1994, 50, 2297-2360.; b) Meyers,

A. I. J. Org. Chem. 2005, 70, 6137-6151.

10 McManus, H.A. and Guiry, P.J. Chem. Rev. 2004, 104, 4151-4202.

11 Frump, J.A. Chem. Rev. 1971, 71, 483-505 and references cited therein.

12 Wuts, P.G.M., Northuis, J.M. and Kwan, T.A. J. Org. Chem. 2000, 65, 9223-9225.

13 Chen, M. and Goodman, D.W. Acc. Chem. Res. 2006, 39, 739-746. 14 Applications: Ciriminna, R. and Pagliaro, M. Org. Process Res. Dev. 2006, 10, 320-326.

15 MacBeath, G., Koehler, A.N. and Schreiber, S.L. J. Am. Chem. Soc. 1999, 121, 7967-

7968.

16 Application on gold surface: Nuzzo, R.G. and Allara, D.L. J. Am. Chem. Soc. 1983, 105,

4481-4483.

17 Gladysz, J. A. (Ed.), Chem. Rev. 2002, 102, 3215–3892 (the whole issue).

18 Merrifield, R.B. J. Am. Chem. Soc. 1963, 85, 2149-2154.

19 Avnir, D., Levy, D. and Reisfeld, R. J. Chem. Phys. 1984, 88, 5956-5959. 20 Sol-gel catalysis: Pagliaro, M and Ciriminna, R. Tetrahedron Lett. 2001, 42, 4511-4514.;

Kawasaki, T., Ishikawa, K., Sekibata, H., Sato, I. and Soai, K. Tetrahedron Lett. 2004,

45, 7939-7941.

21 Alivisatos, A. P. Science 1996, 271, 933-937.

22 Schmid, G.; Pfeil, R.; Boese, R; Bandermann, F.; Meyer, S.; Calis, G. H. M.; van der

Velden, J. W. A. Chem. Ber. 1981, 114, 3634-3642.

23 Daniel, M.-C.; Astruc, D. Chem. Rev. 2004, 104, 293-346.

24 Breslow, R. and Schmir, M. J. Am. Chem. Soc. 1971, 93, 4960-4961.

25 Bolm, C.;Veickhardt, K.;Zehnder, M. and Ranff, T. Chem. Ber. 1991, 124, 1173–1180.

26 Aggarwal, V.K., Bell, L., Coogan, M.P. and Jubault, P. J. Chem. Soc., Perkin Trans. 1,

1998, 2037–2042 and references therein.

27 Nordström, K., Macedo, E. and Moberg, C. J. Org. Chem. 1997, 62, 1604-1609.

28 Chelucci, G., Medici, S. and Saba, A. Tetrahedron: Asymmetry, 1999, 10, 543-550.

51

29 Fife, W.K. J. Org. Chem. 1983, 48, 1375-1377.

30 Imidate preparation: Nef, J.U. Ann. 1895, 287, 265; Schaefer, F.C. and Peters, G.A. J.

Org. Chem. 1961, 26, 412-418.

31 Orellana, G., Alvarez-Ibarra, C. and Quiroga, M.L. Bull. Soc. Chim. Belg. 1988, 97, 731-

742.

32 Bergmann, M. and Brand, E., Chem. Ber. 1923, 56, 1280-1283.

33 Fry, E.M. J. Org. Chem. 1949, 14, 887-894.

34 Hamada, Y., Shibat, M. and Shioiri, T. Tetrahedron Lett. 1985, 26, 6501-6504.

35 Langlois, N. and Wang, H.-S. Synth. Commun. 1997, 27, 3133-3144.

36 a) Yonezawa, Y., Tani, N. and Shin, C. Bull. Chem. Soc. Jpn. 2005, 78, 1492-1499; b)

Andruszkiewicz, R. and Czerwiński, A. Synthesis, 1982, 968-969. 37 Krook, M.A. and Miller, M.J. J. Org. Chem. 1985, 50, 1126-1128.

38 Wipf, P. and Miller, C.P. Tetrahedron Lett. 1992, 33, 6267-6270.

39 Boyd, R.N. and Hansen, R.H. J. Am. Chem .Soc. 1953, 75, 5896-5897.

40 Krook, M.A. and Miller, M.J. J. Org. Chem. 1985, 50, 1126-1128.

41 Trost, B.M. and Lee, C.B. J. Am. Chem. Soc. 1998, 120, 6818-6819.

42 Bunnage, M.E., Davies, S.G. and Goodwin, C.J. J. Chem. Soc., Perkin Trans. 1, 1994,

2385-2391.

43 Chesney, A., Bryce, M.R., Chubb, R.W.J., Batsanov, A.S. and Howard, J.A.K.

Synthesis, 1998, 413-416.

44 Wipf, P. and Venkatraman, S. Tetrahedron Lett. 1996, 37, 4659-4662.

45 Brown, T.H., Campbell, C.A., Chan, W.N., Evans, J.M., Martin, R.T., Stean, T.O.,

Stemp, G., Stevens, N.C., Thompson, M., Upton, N. and Vong, A.K. Bioorg. Med.

Chem. Lett. 1995, 5, 2563-2566.

46 Wenker, H. J. Am. Chem. Soc. 1935, 57, 1079-1080.

47 Crosignani, S., Young, A.C. and Linclau, B. Tetrahedron Lett. 2004, 45, 9611-9616.

48 de Benneville, P.L., Luskin, L.S. and Sims, H.J. J. Org. Chem. 1958, 23, 1355-1357.

49 Reynard, E., Reymond, J.-L. and Vogel. P. Synlett, 1991, 469-471.

50 Leonard, N.J., Conrow, K. and Sauers, R.R. J. Am. Chem. Soc. 1958, 80, 5185-5193.

51 George, B. and Papadopoulos, E.P. J. Org. Chem. 1977, 42, 441-443.

52 Chadwick, D.J., McKnight, M.V. and Ngochindo, R. J. Chem. Soc., Perkin Trans 1,

1982, 1343-1348.

53 Chadwick, D.J. and Ennis, D.S. Tetrahedron, 1991, 47, 9901-9914.

52

54 Brunner, H. and Hassler, B. Z. Naturforsch. 1998, 53b, 476-480.

55 Kline, T., Andersen, N.H., Harwood, E.A., Bowman, J., Malanda, A., Endsley, S., Erwin,

A.L., Doyle, M., Fong, S., Harris, A.L., Mendelsohn, B., Mdluli, K., Raetz, C.R.H.,

Stover, C.K., Witte, P.R., Yabannavar, A. and Zhu, S. J. Med. Chem. 2002, 45, 3112-

3129.

56 Brunner, H., Störiko, R. and Nuber, B. Tetrahedron: Asymmetry, 1998, 9, 407-422.

57 Brunner, H. and Obermann, U. Chem. Ber. 1989, 122, 499-507.

58 Brunner, H. and Amberger, K. J. Organomet. Chem. 1991, 417, C63-C65.

59 Brunner, H. and Riepl, G. Chem. Ber. 1985, 118, 3380-3395.

60 Diels, O. and Alder, K. Ann. 1928, 460, 98-122.

61 Kagan, H.B. and Riant, O. Chem. Rev. 1992, 92, 1007-1019.

62 Yates, P. and Eaton, P. J. Am. Chem. Soc. 1960, 82, 4436-4437.

63 Hashimoto, S., Komeshima, N. and Koga, K. J. Chem. Soc., Chem. Commun. 1979,

437-438.

64 Davies, D.L., Fawcett, J., Garratt, S.A. and Russell, D.R. Chem. Commun. 1997, 1351-

1352.

65 Meerwein, H., Buchner, E. and van Emster, K. J. Prakt. Chem. 1939, 152, 237-266.

66 Brunner, H., Blüchel, C. and Doyle, M.P. J. Organomet. Chem. 1997, 541, 89-95.

67 Henbest, H.B. Chem. Soc. Spec. Publ. 1965, 19, 83-92.

68 Katsuki, T. and Sharpless, K.B. J. Am. Chem. Soc. 1980, 102, 5974-5976.

69 Xia, Q.-H., Ge, H.-Q., Ye, C.-P., Liu, Z.-M. and Su, K.X. Chem. Rev. 2005, 105, 1603-

1662.

70 Yang, R.-Y. and Dai, L.-X. J. Mol. Catal. A. 1994, 87, L1-L4.

71 Kitamura, M., Suga, S., Kawai, K. and Noyori, R. J. Am. Chem. Soc. 1986, 108, 6071-

6072.

72 Pu, L. and Yu, H.-B. Chem. Rev. 2001, 101, 757-824.

73 Macedo, E. and Moberg, C. Tetrahedron: Asymmetry, 1995, 6, 549-558.

74 Denmark, S.E. and Fu, J. Chem. Rev. 2003, 103, 2763-2793.

75 Hosomi, A. Acc. Chem. Res. 1988, 21, 200-206.

76 Angell, R.M., Barrett, A.G.M., Braddock, D.C., Swallow, S. and Vickery, B.D. Chem.

Commun. 1997, 919-920.

77 Rossiter, B.E and Swingle, N.M. Chem. Rev. 1992, 92, 771-806.

78 Kharasch, M.S. and Tawney, P.O. J. Am. Chem. Soc. 1941, 63, 2308-2316.

53

79 Takemoto, Y., Kuraoka, S., Hamaue, N., Aoe, K., Hiramatsu, H. and Iwata, C.

Tetrahedron, 1996, 52, 14177-14188.

80 Christoffers, J., Mann, A. and Pickardt, J. Tetrahedron, 1999, 55, 5377-5388.

81 Review: Trost, B.M. and van Vranken, D.L. Chem. Rev. 1996, 96, 395-422.

82 Review: Rawlinson, D.J. and Sosnovsky, G. Synthesis, 1972, 1-28.

83 Denney, D.B., Napier, R. and Cammarata, A. J. Org. Chem. 1965, 30, 3151-3153.

84 Clark, J.S., Tolhurst, K.F., Taylor, M. and Swallow, S. J. Chem. Soc., Perkin Trans 1,

1998, 1167-1169.

85 Trost, B.M. and Murphy, D.J. Organometallics, 1985, 4, 1143-1145.

86 Bremberg, U., Larhed, M., Moberg, C. and Hallberg, A. J. Org. Chem. 1999, 64, 1082-

1083.

87 Chelucci, G., Deriu, S.P., Saba, A. and Valenti, R. Tetrahedron: Asymmetry, 1999, 10,

1457-1464.

88 Evans, D.A., Woerpel, K.A., Hinman, M.M. and Faul, M.M. J. Am. Chem. Soc. 1991,

113, 726-728.

89 Review on these studies: Desimoni, G., Faita, G. and Jorgensen, K.A. Chem. Rev.

2006, 106, 3561-3651.

90 Chelucci, G., Gianmauro, O. and Pinna, G.A. Tetrahedron, 2003, 59, 9471-9515.

91 Chelucci, G., Sanna, M.G. and Gladiali, S. Tetrahedron, 2000, 56, 2889-2893.

92 Faul, M.M., Ratz, A.M., Sullivan, K.A., Trankle, W.G. and Winneroski, L.L. J. Org. Chem.

2001, 66, 5772-5782.

93 Meyers, A.I., Robichaud, A.J. and McKennon, M.J. Tetrahedron Lett. 1992, 33, 1181-

1184.

94 Maltese, M. J. Org. Chem. 2001, 66, 7615-7625.

95 Rao, V.S. Synth. Commun. 1993, 23, 2915-2920.

96 Nuzzo, R.G. and Allara, D.L. J. Am. Chem. Soc. 1983, 105, 4481-4483.

97 Thomas, K.G. and Kamat, P.V. Acc. Chem. Res. 2003, 36, 888-898.

98 Ciszek, J.W., Stewart, M.P. and Tour, J.M. J. Am. Chem. Soc. 2004, 126, 13172-13173

and references cited therein.

99 Brinkman, H.R., Landi, J.J., Paterson, J.B. and Stone, P.J. Synth. Commun. 1991, 459-

465.

100 Report on racemisation with Cs2CO3: Richter, L.S. and Gadek, T.R. Tetrahedron Lett.

1994, 35, 4705-4706.

54

101 Compound 105: Maurer, P.J., Takahata, H. and Rapoport, H. J. Am. Chem. Soc. 1984,

106, 1095-1098.

102 Preparation of compound 136: Krafft, M.E., Cheung, Y.Y. and Abboud, K.A. J. Org.

Chem. 2001, 66, 7443-7448.

103 Sonogashira, K., Tohda, Y. and Hagihara, N. Tetrahedron Lett. 1975, 16, 4467-4470.

104 Hartner, F. W.; Hsiao, Y.; Eng, K. K.; Rivera, N. R.; Palucki, M.; Tan, L.; Yasuda, N.;

Hughes, D. L.; Weissman, S.; Zewge, D.; King, T.; Tschaen, D. and Volante, R. P. J.

Org. Chem. 2004, 69, 8723–8730.

105 Brust, M.; Walker, M.; Bethell, D.; Schiffrin, D. J.; Whyman, R.J. Chem. Commun. 1994,

801-802.

106 Johansson, M. P.; Sundholm, D.; Vaara, J. Angew. Chem. Int. Ed. Engl. 2004, 43,

2678-2681.

107 The original Henry reaction: Henry, L. C. R. Acad. Sci. Ser. C. 1895, 1265; Henry, L.

Bull. Soc .Chim. Fr. 1895, 13, 999.

108 Evans, D. A.; Seidel, D.; Rueping, M.; Lam, H. W.; Shaw, J. T.; Downey, C. W. J. Am.

Chem. Soc. 2003, 125, 12692 - 12693.

109 Gozzi, P.G., Zimmerman, N., Hilgraf, R., Schaffner, S. and Pfaltz, A. Adv. Synth. Cat.

2001, 343, 450-454.

110 Brunner, H., Henning, F. and Zabel, M. Z. Anorg. Allg. Chem. 2004, 630, 91-96.