THE SYNTHESIS OF NATURAL PRODUCTS USING TANDEM

RADICAL SEQUENCES INVOLVING FRAGMENTATIONS

A thesis

Presented to

The Faculty of Graduate Studies

of

The University of Guelph

by

NADIA CORELLI

In partial ful filment of requirements

for the d e p e of

Master of Science

December. 2000

Q Nadia Corelli. 1000

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ABSTRACT

THE SYNTHESIS OF NATURAL PRODUCTS USING TANDEM RADICAL SEQüENCES WOLVING FRAGMENTATIONS

Nadia Corelli University of Guelph. 2000

Supervisor: Dr. G. L. Lange

Radical fragmentation is a useful methodology in the synthesis of natural products

containing medium-sized rings and tandem radical reactions allow the preparation of

complex molecules in minimal steps. In this thesis, tandem fragrnentation/oxygenation,

fragmentationlelimination and Frapentatiodhpentation radical sequences involving

[2+1] photoadduct derivatives were investigated as approaches to the synthesis of three

classes of sesquiterpenoid naturai products.

A novel ~gmentation.oxygenation sequence was attempted on a 3-43 photoadduct

derivative as an approach to the synthesis of the guaianolide skeleton. Two approaches

to the synthesis of dumortenol were attempted. The first approach was to involve the

radical fragmentation/elimination of a dihctional 5-4-6 photoadduct derivative. A

novel cyclobutylcarbinyllcyclopropylcarbinyl radical fragmentation sequence was

attempted on a 514613 ring system as a second approach. A comparable

fragmentatiodfragmentation radical sequence involving the more-strained 5141513 ring

system was then investigated as an approach to the synthesis of the lactarane skeleton.

ACKNOWLEDGEMENTS

Firstly, 1 would like to thank Dr. Gordon Lange for being a wonderhl supervisor and

a wonderful person. His encouragement and positive outlook have kept me going back to

the lab.

Thank you to my cornmittee members Dr. Adrian Schwan and Dr. William Tarn. for

a11 of their time and effort. 1 would also Iike to thank Alex Merka for helping me get

senled in the Lab the first two semesters of my Master's degree and for al1 of the valuable

advice given throughout that time.

"Thank you" goes out to al1 of the friends 1 have made in the Chemistry Deparanent.

They have made the past two years very enjoyable and unforgettable. They are also

making it difficult to leave. A special thank you goes out to my lab partner Craig Humber

who made the lab a fun place to be and for al1 of the good conversations over our coffee

breaks. 1 would also like to thank my "pseudo" iab partner Dino Alberico for keeping me

Company in the lab the past two semesters.

1 thank my wonderful parents for teaching me. from a very young age. the importance

of working hard in school so that 1 could land a good job one day. They have always

taken a sincere interest in al1 of my endeavours and encouraged me to set high goals for

myself.

Last but not least. 1 would Iike to thank my husband David for ail of his love and

ernotional support throughout my Master's degree and most of my underpd years. He

was always understanding when my schoolwork made spending time together dificult.

and encouraged me to persevere when 1 felt like giving up.

TABLE OF CONTENTS

ABSTRACT

ACKNOWLEDGEMENTS .................................................................... i

..................................................................................... List of Tables v

............................................................................ List of Abbreviations vi

CHAPTER ONE . AN INTRODUCTION TO RADICAL FRAGMENTATIONS AND TANDEM RADICAL REACTIONS

1.0Introduction .................................................................................. 1

................................................... 1 .1 Basic Principles of Radical Chemistry 1

............................................................... 1 . 1 . I Radical Chain Reactions 2

.................................................................... 1 . 1.2 Sources of Radicals 4

......................................................................... 1 .1. 1.1 Initiators 4

1 . l . 2.2 Chain Transfer Reagents ........................................................ 5

............................................................. 1.1.2.3 Sarnariurn(i1) Iodide 8

.................... .................*.**............... 1.2 Radicals in Organic Synthesis ... 10

1.2.1 Radical Cyclization Reactions ....................................................... 10

................................................................. 1.2.2 Radical Fragmentations 14

................ 1.2.2.1 Fragmentations Involving the Cyclopropylcarbinyl Radical 15

1.2.2.2 Fra-mentations Involving the Cyclobutylcarbinyl Radical ................. 20

.................................................................. 1.3 Tandem Radical Reactions 24

1.3.1 Tandem Radical Reactions Involving the Cyclopropylcarbinyl Radical ......... 24

1 .3.2 Tandem RadicaI Reactions Invdving the Cyclobutylcarbinyl Radical .......... 28

CHAPTER TWO . AN APPROACH TO Tm SYNTHESIS OF GUAIANOLIDES USINC A TANDEM RADICAL FRAGMENTATION/OXYCENATION SEQUENCE

.................................................................................... 2.0 Introduction 31

................................................................................... 2.1 Guaianolides 31

............................................... 1.2 Tandem Radical CyclizatiodOxygenation 33

.................. 2.2.1 Molecular Oxygen-Mediated Tandem Cyclization/Oxygenation 33

................................... 2.2.1.1 Cobalt-Mediated Oxygenative Cyclizations 34

........................... 2.2.1.2 Tin Hydride-Mediated Oxygenative Cyclizations 36

......................................... 2.2.2 Oxygenative Cyclizations Employing Tempo 37

2.2.2.1 Tin Hydride-Mediated Oxygenative Cyclizations Employing Tempo ..... 38

............. 2.2.2.2 Sm12-Mediated Oxygenative CycIizations Employing Tempo 39

....................................................................... 3.3 Results and Discussion 40

..................................... 2.3.1 Testing Oxygenation on Simple Model Systems 41

................................. 2.3.2 The Synthesis of a Simple Photoadduct Derivative 43

2.3.3 Radical FragmentatiodOxygenation of a Simple Photoadduct Derivative ...... 44

CHAPTER THREE . APPROACHES TO THE SYNTHESIS OF DUMORTENOL EMPLOYINC TANDEM RADICAL SEQUENCES

.................................................................................... 3.0 Introduction 50

.................................................................................... 3.1 Dumortenol 50

3.2 An Approach to the Synthesis of Dumortenol Employing a Radical Fragmentation/ . . . ......................................................................... Elimmation Sequence 52

3.3 An Approach to the Synthesis of Dumortenol Employing a Radical ............................. ............... Fragmentation/Fragmentation Sequence .... 56

CHAPTER FOUR . AN APPROACH TO THE SYNTHESIS OF THE LACTARANE SKELETON USINC A RADICAL FRAGMENTATION1 FRAGMENTATION SEQUENCE

.................................................................................... 4.0 Introduction 62

................................................................................. 4.1 The Lactaranes 62

............ 4.2 Radical Frapmentatioflragmentation of a 5 4 5 Photoadduct Derivative 63

.............................................. 4.3 5-4-5 Versus 5-4-6 Photoadduct Derivatives 67

.................................................................................... 4.4 Future Work 69

4.5 Surnmary and Conclusion .................................................................... 70

CHAPTER FIVE . EXPERIMENTAL

5.1 General Techniques. .......................................................................... 73

............................................................. 5.2 Experimental for Chapter Two 74

............................................................ 5.3 Experimental for Chapter Three 81

.............................................................. 5.4 Experimental for Chapter Four 91

REFERENCES .................................................................................... 95

LIST OF TABLES

1. Table 1 : Conditions and Percent Yields for the Oxygenation of Cholestanol iodide .............................. ... .................... . . 12

AIBN

DMPU

EtOAc

FC

FTTR

HMPA

IR

Me1

MS

NMR

NOESY

!'Pm

RT

SOM0

TEMPO

THF

TLC

LIST OF AEBREVLATIONS

azobisisobutyonimle

N.N'-dimethyl-N,N'-propylene urea

ethyl acetate

flash chromatography

Fourier transform infrared

hexamethylphosphoramide

in frared

methyl iodide

mass spectrurn

nuclear magnetic resonance

nuclear Overhauser and exchange spectroscopy

pms per million

room temperature

singly occupied molecular orbital

2.1.6.6-tetramethylpiperidinoxy radical

tetrahydrofuran

thin Iayer chromatopphy

Cha pter 1 - An Introduction to Radicai Fragmentations and Tandem Radical Reactions

1.0 Introduction

The existence of radicals was first reported by Moses Gomberg in 1900, who gnerated

the triphenylmethyl radical while attempting to prepare hexaphenylethane.' Gomberg's

discovery led to a growing interest in the pmperties of radicals, particularly their reactivity.

stûbiliry and selectivity.' Despite this progressive understanding of radical properties. the

application of radicai reactions in organic synthesis remained quite dormant until the early

1980's. The pst two decades have witnessed vast developments and advances in this m a

as an increasing nurnber of synthetic organic chemists are recognizing the value of radical

processes.3 Radical reactions are now routinely employed in organic synthesis and are

essensal steps in the prepaaion of many compaunds with complex stnicr~re.'~'

The use of radicals has many synthetic advantages including hi& reactivity, ease of

executiun. mild experimental conditions, compatibility with a wide range of functional

p u p s . and the possibility of regioselective gme~ttion.~' Radicals c m be used to

accomplish diverse mes of transformations and they c m even be used to conduct several

synthetic steps in ..one pt"? In addition. the use of neuual radicals has man? synthetic

advantages over the use of ions. They are less "bulky" and therefore not as strongly

influenced by steric effects or by the polarity of smunding groups, and solvation effects

are also much less importantt'* Unfortunately, a disadvantage of the use of radical

reactions is chat the desired reaction is ofien in cornpetition with several other pathways and

the researcher must careMly design the reaction conditions to favour the desired reaction

over rhe undesirable ones." Another drawback is that some of the popular reagents used to

generate radicals are envuonmentally and physiologicdly toxic. which Iimits their

application in industV.' However. these problems will surely be overcome in the near

future as current radical methods become more r e f d and new synthetic rnethods and

reagents are developed.

In order to comprehend the chernistry involved in the foIlowing chapters. it is necessary

to have an understanding of the bdamental concepts of radical processes. The first

chaptrr of this thesis involves a brkf overview of the basic principles of radical chemistq

followed by a discussion of two synthetically valuable radical =actions: cyclizarion and

fragmentation. This wi[l be followed by a discussion of tandem radical reactions. Tandem

reacrions involving radical fragmentations are key steps in the research described in

following chnpters and will therefore be the focus of the later part of this chapter.

1.1 Basic Principles of Radical Chemistry

1.1.1 Radical Chain Reactions

A radical can be defined as a species having one unpaired electron in a p orbital cailed a

Singly Occupied MoIecular Orbital (SOMO).' Radicals are formed by the homolytic

cleavage of a MO-electron bond? They cm also be generated through electron transfe?'

and this wili bz discussed in Section 1.1.7.3- Most radical reactions of interest to organic

chemists occur via a chain mechanism composed of three types of processes: an initiation

step. a series of propagation seps and one or more termination steps that stop the chain

rea~tion.'~ A npical radical chain is illustrateci in Scheme 1. In the first step. a bond in the

initiator undergoes homolytic cleavage to form a radical (In*) which then abstracts a

hydrogen atom h m the chah transfer reagent. in this case Bu3SnH. to give an alkyi tin

radical R3Sn-. In the first propagation step. this radical then absîracts a leaving group IX)

tiom die substnte (R'-X). The resulting radical IR'.) may absnact a hydrogen atom h m

the chah transfer reagent to fom RH. It may aiso add to another submte or undergo an

intramolecular transformation to &ord a new radical (P.) which is then reduced by the

chah transfer reagent to form R H . The easuing alkyl tin radical (R3Sn*) starts the

propagation sequence over again and the radical chah continues until ail of the substrate is

convertcd to product or until al1 of the chah tramfer reagent is consumed. Several chah

termination steps are aiso possible (Scheme 1).

Scheme 1

Initiation:

In-In - 21n* In- .i R3SnH -, R3Sw + InH

f ropagation:

R3Sn + R' -X -, R'* + R3SnX R'- + R3SnH -. R'H + R3Sn*

or R'* 4 RU*

R * + R3SnH -, R H + R3Sn*

Termination: R ' . + R ' m - R'-R'

R3Sn + R3Sn -, R3Sn - SnR3 EP + R3Snm--. R'- SnR3

1.1.2 Sources of Radicals

In the above section. it was shown that initiators and chain transtèr reagents work

together in radical chah rractions. However, some radical reactions are initiated through

electron transfer and do not proceed via a chah mechanism. This section involves a

discussion of the properties of various initiators and chah üansfer reagents and introduces

smarium(1I) iodide. an elecuon transfer reagent ofien emplayed in radical reactions.

1.1.3.1 Initiatiors

Radicals may be senerated directly by thermal or photochernical processes that result in

the homolytic cleavage of a covalent bond." A very hi& temperature is usually required

to break bonds. For exampie. the dissociation of a carbon-carbon bond requires about

670T.' Temperatures such as this are not suitable for m m o r p i c reactions. therefore an

initialor must be used. Initiators are reagents that contain a weak bond that undergoes

homolytic cleavage at reiativeiy low temperatures, thereby producing a d i c a l that can

start a chain reaction as shown in Scheme 1.

The correct choice of initiator is generaily decided by the reaction temperature and

hence by the appropriate half-Iife of the initiator decomposition teaction." Organic

peroxides. such as benzoyl peroxide 1 (Eqirarion I ) , are cornmon initiators. Berizoyl

peroxide dissociates easily with heat or ultraviolet irradiation to fonn radical 2. It has a

haIf-Iife of two hours at 90'~'' Other popular initiators are azo compunds like

azobisisobutyronitrile (AIBN) 3 (Equarion 2). AIBN dissociates with heat or light to form

radical 4 and nitrogen gas. At 80°C. its hdf-Iife is rwo heurs." Since peroxides are highiy

explosive and difficult to hancile. AJBN is o f t a the initiator ofchoicc.

Equatioa 1

Equation 2 CN

For reactions with low temperature requirements (Le. less than 25 OC). thermal initiation

is impractical. In such cases. photoinitiation may be useful." Several initiators have been

developed that generate radical species at or below room temperature. The initiator 2.2'-

azobis-(2.3-dimethsl4-rnethox~valeroni~le)(~-70)a has been shown to generate radicals

h m 0°C to 25°C and 9-borabicyclo [3.3.1] nonane (9-BBN)' is effective from 0°C to

-78°C . Another option for reactions requinng low temperatures is the use of an electron

transfer reagent. discussed in Secrion 1-2-23.

1.1.2.2 Chain Transfer Reagents

In order for a chain transfer reagent to be useful in synthesis it m u t satisfy the following

critena: First. it must possess a relatively weak bond that can be easily broken by an

initiator. it must generate radicals site-selectively and IastIy. it m u t ailow these radicals

sufficient lifetime to react. without allowing sufficient t h e to decompose through chah

termination steps.ja

5

One chah transfer reagent that meets the above requirements is tri-n-butyltin hydride

( n ~ ~ ~ ~ ~ ) . 3 c It possesses a weak Sn-H bond, is mild, tolerates many functional groups and

reaction conditions. and produces a relatively stable. long-lived radical.jd Other organotin

hydndes such as tnphenyltin hydride ph3SnH) and di-n-butyltin dihydride ("BurSnHz)

have dso been used. but they are more active hydndes and therefore cannot be used in

reactions where a radical rearrangement is de~ired. '~ '~

One disadvantage of the use of organotin compounds is that they. and their by-products.

are toxic and difficult to remove from the product mixture. This has made their use

inappropriate for the synthesis of dmgs and other products designed for human

consumption." To overcome this problem. a variety of work-up procedures that attempt to

eliminate the tin products from the reaction mixture are available in the literature."

Various Functional groups (indicated as X in Scheme 1) can be effectively abstracted by

the Bu3Sn* radical. These include (in order of decreasing reactivity) 1. Br. SePh. secondary

and tertiary xanthate esters. tertiary nitro. Cl. and SPh. Not every radical precursor will be

effective for al1 reactions. Iodie is often the precursor of choice since the rate constant for

iodine atom abstraction approaches the d i m i o n controlled limit."

One dificulty that often occurs with the use of tributyltin hydride is the premature

reduction of intermediate radicals. The lifetime of the intermediate radicals can be

extended through high dilution of the reaction or through the slow addition of tin hydride to

the reaction mixture (syringe-purnp technique)? Another usehl strategy for such cases

was deveioped by Corey wherein tributyltin hydride is employed in catalytic amounts and

relenerated in situ by sodium borohydride reduction." The mechanism of this catalytic

cycle is depicted in Scheme 2. F i tributyltin chlonde (Bu3SnCl) is reduced by NaBHJ.

6

The resulting tin hydride then reacts with an initiator or with ultraviolet light. in the usual

marner. to fiord the Bu3Sn* radical. This radical reacts with the substrate, abstracting the

halide (X). thereby regenerating a t h halide which can further propagate the chain. Stork

Scheme 2

ZBu3SnCI + 2NaBH4 2Bu3SnH + 2 NaCl + BzH6

Bu3SnH AiBN or hv Bu3Sno

BujSno + RX , Bu3SnX + Eh

has developed a procedure sirnilac to Corey's that involves catalytic tributyltin hydnde in

the presence of sodium cyanoborohydnde (N~cNBH~)." Another recently reponed

technique involves catalytic Bu3SnH bound to a soluble polymer support." The above-

mentioned cataiytic procedures sirnplify the tin purification problem. as long as other

bctionai _mups in the molecule are not reduced by borohydride.

As an alternative to [in hydrides. other chain transfer reagnts have k e n developed.'

Tributylgermanium hydride (Bu3GeH) is a less reactive hydrogen donor than üialkyltin

hydnde (by a factor of 1 O)" due to the stronger Ge-H bond. Therefore. direct substrate

reduction is usually not significant. In reactions with iodides. the gennyl radical is just as

reactive as the tin radical. Unfortunately. Bu3GeH has limited applications. often requires

long reactions f i e s and is quite e ~ ~ e n s i v e . ' ~

Various silyl hydndes have k e n reported to be effective in particular systems.'

However. the Si-H bond in most silyl hydrides is too strong to propagate radical chains."

T~s(trtmethy1silyl)silane ((Me3Si)3SiH) is the most successtùl and widely used

replacement fortin hydrides. It possesses a Si-H bond that is about 5 kcaVmol stronger than 7

the Sn-H bond of Bu3SnH and thecefore produces fewer by-products h m direct

reduction." It has low toxicity and superior chromatographie properties." Unfortwately.

the (Me;Si)3Si* radical has a tendency to add to multiple bonds which limits its use. Other

drawbacks are its hi& cost and its need to be handled under argoas

Some chain m s f e r reagents do not require an initiator, Bis-aibutyltin (Bu3-Sn-Sn-Bu3)

and phenyl disulfide (Ph-S-S-Ph) are two such reagents. When in the presence of

ultraviolet light. the weak central bond in these reagents breaks. foming radicals that can

then propagate a chain reaction.18

Despite the availability of various chain m f e r reagents. none have been able to

surpass the flexibility. predictability and hence. popularity of Bu3SnH. The quest for

superior reagents continues ioday.'

1.1 -2.3 Sarnariurn(11) Iodide

Thus far. we have only discussed the generation of radicals through the hornollic

dissociation of a covalent bond. Radicals may also result from chernical or electrochemical

oxidation or reduction of stable molecules.jd Many radid reactions initiated by such

electron transfer are mediated by transition metai ions like iron and rnanganese.lg The

lanthanide reagent, samarium(I1) iodide (Smk). is a powerfùi electron transfer reducing

agent that has been extensively investigatedO since its introduction by Kagan and

coworkers in 1980.)' Smiz promotes a number of important reactions found usehl in

organic synthesis. including radical reactions? Sarnariurn(Ii) iodide can be prepared by

the reaction of samarium with iodine or 12diiodoeihane in dry tetrahydrofuran ('MF)."

As long as Sn& is stored in an aprotic. deoxygenated environment it will remain stable for

extended periods. It has a characteristic blue colour and since the colour of the oxidized

sarnarium(II1) ion is yellow. the progress of Sm12 reactions can be followed by observing

the coIour of the reaction. Hexamethy lphosphorarnide (HMPA) is reponed to drarnaticall y

increase the reducing power of but due to its toxicity. other less effective cosohenis

such as N.N1-dimethyl-N.Nt-propyl urea (DMPU) are often used." Samacium(iI) iodide

reduces primary alkyl radicais at a rate of 7 X 106 M-~s-' when five equivalents of iiMPA

per Sm12 is used.?["

Sm12 can initiate radical reactions via the reduction of organic halides. The general

mcchanism for this process is illustrated in Scheme 3.''' Transfer of one electron h m

Sm& to the halide generates radical Re. This radical rnay undergo a transformation

(Rm+R'*) before it is reduced to fom the organosamariurn intermediate (R-Sm[?). The

organosamarium intermediate can then be trapped by a proton or a different electrophiie.

thus providing opprtunities for fûrther functionalization. Excellent yields are generally

artained and selectivity is ofien better than that achieved by the tin hydride method.

Seheme 3

However. as with the tin hydride meth06 there are limitations to this process. Any desired

radical transformation must occur fater than the reduction of the initial radical to the

corresponding anion. R-Srni2 ( K ~ ) , othenvise an undesireci product will form (R-E

instead of R'-E).''' srni2 c m generate radicais from a variety of substrates. not only

halides.lk Examples will be seen throughout the following sections.

1.2 Radicals in Organic Synthesis

Radicals can undergo a variety of reactions including reduction. coupling. substitution.

rearrangement. elimination, addition (cyclization) and fragmentation.'" Of these reactions.

cyclization and fragmentation are OC most use to synthetic organic chemists. Radicals can

add inter- or intrarnoleculariy to certain unsaturated functional groups such as double

bonds. triple bonds. ketones and aldehydes. IntramoIecuiar addition reactions may resdt in

the formation of a ring. hence the? are called radical cyclizations. The use of radical

cyclizations in synthetic organic chemistry is extremely well-docurnented.' In contrast.

synthetic applications of the reverse process. radical fragmentation. are not as welI-

developed. although the physical organic chemistry of this process ha been studied in

considerable detail. Fragmentations and cyclizations are important tools for the

construction of medium-sized rings (7 to 9 carbons) which are present in many biologically

active nanual products and phannaceuticals. Below is a discussion of both types of radical

processes dong with relevant examples of each.

1.2.1 Radical Cyclization Reactions

Radical cyclization is a widely employed methodology for the formation of carbon-

carbon bonds and offers a simple and efficient means for synthesizing complex cyclic and

10

polycyclic compounds with high regio- and stereoselectivity.jd Radical cyclizations are

eenenlly classified according to the size of the ring formed the type of carbon that u

undergoes attack by the radical (sp3 = tet, sp' = trig, sp = dig). and whether the radical

resulting from the cyclization step is outside the newly fomed ring (exo) or within

(endo)."

.4 ~vell-studied radical cyclization that demonstraies the regioselective nature of these

reactions is the 3-rxo-nig cyclization of the hex-5-enyl radical 9 (Eqrration 3). As

indicated. the eso mode of closure forrning the less thennodynarnically stable radical 10

occurs preferentially over endo closure. which results in the 6-membered ring II.?-'

Equation 3

Radical cyclization of the hex-5-enyl system (Equnrion 3) has been snidied extensively

and many properties of radical cyclization processes have been e~tablished.?~ For example.

Beckwith and chi esse? have found that the energy required for the exo ring closure is 2.8

kcaümol less than that for the endo closure. However. if the point of exo ring closure is

hindered. the more thermodynamicaily favoured endo product is fomed.

The formation of 5- and 6-membered rings by radical cyclization is most common.

These cyclizations occur rapidly. thereby limiting the production of reduced and uncyclized

by-products. Three- and four-membered rings possess hi@ ring strain. The formation of

11

these rings by radical cyclization requires the presence of substituents to stabilize the

cyclized radical. and the radical mut be trapped knmediately afier cyclization to prevent

rine reopening. The e m mode of closure is generally favoured in the formation of 3- to 6-

membered rings. however. the formation of 7- and 8-membered rings. as well as

macrocyclic structures. occurs very slowly and by endo c~osure.'~

~olande?' employed S d t (in the presence of HMPA) to prornote an efficient 8-endo-

irig radical cyciization of an olefhc ketone (Scheme 4). Samarium(I1) iodide was added

to ketone 12 to forrn ketyl radical 13. which underwent an 8-endo-rrig radical cyclization

formin_e radical 14. This intermediate was then reduced by another equivalent of Sml?

formine 15. which was protonated by rerr-butyl alcohol to give 16 as the final product.

Scheme 4

The formation of fused rings by radical cyclization is a particuiarly usehl process. Cis-

ring fusion predominates when fused 6.5 or 5.5-rings are constnicted. An illustrative

example h m an extensive study by ~eckwith'~ is outlined in Scheme 5. Tin hydride-

mediated 5-exo-nig cyclization of 17 provides an 89% yield of products 18. 19a and 19P.

al1 of which have a ci* ring fusion. The ratio of 18/19 (14:lS) indicates that the methoxy

croup has little effect on the cyclization. This iilustrates the principle that frontier b

molecular orbital interactions rather than the stabilities of product radicals control the rate

of cyclization. The ratio of 19a:19@ (3: 1) indicates that the tin hydride approaches the less

hindered face of the bicyclic ndicd to donate a hydrogen atom.

Scbeme 5

Two cyclization reactions were employed by Lee and coworkers" in their synthesis of

the guaianolides estafiatin and cladantholide (Scheme 6). Abstraction of the bromine atom

from 20 gave radical 21 which cyclizes ont0 the adjacent double bond in a 5-em-lrig

manner to afford the lactone radical 22. Radical 22 cyclizes in a 7-endo-trig mode giving

species 23 which was then reduced pducing the guaiane skeleton 24. Funher

transformations (not shown) gave the guaianolides estafiath 25 and cladantholide 26. More

applications of radical cyclization reactions in organic synthesis will be seen in Section 1.3.

Scheme 6

ROI..,.. 7-endo-trig RO- reduction

i ; :

" H i

OEt OEt 22 23

estafiatin cladantholide

1.23 Radical Fragmentations

In the previous section. it was show that radicals can be used to form rings. Radicals

can also be used to break bonds when generated adjacent to a suained ring. such as a

cyc~obutane~. cyclopropane. 29 aziridine. 30 or epxide?' Radical fragmentations are not as

wel1-docurnented as cyclizations but there is a growing interest in these processes.

In order for fragmentation to occur, there must be sufficient orbital overlap between the

SOMO of the radical and the o orbital of the strained C-C bond." The cleavage of three-

or four-mernbered rings takes place easily due to the high ring strain present in these

systems. The opening of larger rings does not usually occur at an adequate rate. however. it

has been show that l a r p rings can open as long as the resulting radical is appropriately

stabilized." The Fragmentation of cyclopropane and cyclobutane rings are critical steps in

the research presented in following chapters. and therefore. will be descnbed in

considerable détail beIow.

1 2 . 2 . i Fragmentations Involving the Cvclo~ro~vlcarbinvl Radical

The ring opening of the cyclopropylcarbinyl radical 27 to the but-knyl radical 28 is

one of the fastest unimolecular teactions known (Eqtmion 4) " with a rate constant of

4 1 3 6 about 1.7 .Y IO'S-' at 37'C3' The value for the reverse process is 10 s' .

Equation 4

The preferred regiochemistry of the fragmentation of substituted cyclopropyicarbinyl

radicals has been studied extensive1y."- " in confomationally mobiie radicais. rotation of

the goup carrying the unpaired electron usually takes place so that the SOMO overlaps the

more substituted CD-Cy bond. which then cleaves to give the more stabiiized radical? In

one notable study. Pereyre and coworkersj8 investigated the fragmentation of cis and am-

2-methylcyclopropylcarbinyl 29 (Equation 5) and found that the cis isomer of 29

hgmented to give the more thermodynamically stable secondary aky! radical 31. In

contrat. they discovered that the rrans isomer tends to give rnainly the primaq.

thermodynarnicdly less stable ring-opened radical 30. even at low temperanires. The

reason for this is not clear. However. they found that when a low concentration of tin

hydride is used the first-formed primary radical can undergo equilibration to the more

stable secondary one. Under these conditions. slow hydrogen m s f e r dlows equilibration

of ndicals through ring re-ciosing and re-opening.

Equation 5

Of particular relevance to the work presented in Chaptrrs 3 and 4. is the regiochemistry

of ring opening when the cyclopropane is fused to another cyclic structure. Literature on

bicyclic [n.1 .O] radicals reveals a preference for stereoelectronically controlled esocycIic

radical ring opening as opposed to thermod~arnicaliy favoured endocylic ring opening

when the ring containing the radical centet is five-membered or ~ a r ~ e r . ~ ' . ' ~ It appears that

the extemal bond of the cyclopropane ring overlaps best with the SOM0 and hence is

cleaved preferentially. However. if the ring containhg the radical center is three- or four-

membered. relief of ring strain via endocyclic ting-opening is the preferred route?'

The maximum overlap d e is well illustrateci in a study by Beckwith and co~orkers"~

who esamineci the Fragmentation of the isomeric steroidal radicals 32 and 34 (Eqiraiiom 6

16

and 7). They found that 32 underwent endocyclic fragmentation producing the

thermodynarnically favoured secondary radical 33 whereas fragmentation of 34 resulted in

the formation of the themiodynamicdly unfavourable primary radical 35.

Equrtion 6

Equation 7

Clive and c o w o r k e r ~ ' ~ ~ ~ have demonstrated tlwt the preference for enocyclic

hgmentation in bicyclo [4.1.0] radicals crin be used as a generai method for auaching

alkyl and substituted alkyl groups to an existing cyclic structure. ofien with stereo- and

regiochemicai control. An example of one of the reactions they carried out is illustrated in

Scheme '. They found that when the non-bridgehead carbon of the cyclopropane carries a

strongly electron-withdrawing group. as in 36. the ero ring opening can be achieved with

a tin hydride at the reflux temperature of knzene. The electron-withdrawing groups

facilitate ring openîng due to the enhanced stabiiity of the ring-opened radical. However.

in the absence of such electron-~ithdrawing groups. a low temperature (-20 to 25°C) is best

used in order to suppress ring expansion.

17

Scheme 7

SePh

.> H

Ph3SnH' benzene. *IBN reflux. - O>,wCOIEt - 1 hr

C0,Et

36 <H 37 'H 38

Kurth and coworkerd' have s h o w that the bicyclo [4.1 .O] radical cm also be made to

undergo endocyclic fragmentation to give the ring expanded product (Scheme 8) .

Treatment of xanthate 39 with tributyltin hydride under relatively hi@ temperature

conditions (13joC) resulted predorninantly in fnpentation of interna1 bond "a"

to sive cycloheptane 41. A low yield of cyclohexane 42 was also produced via

fragmentation of exocyclic bond " b .

Scheme 8

V AU1 1 J

benzene. 1 3 5°C O U

Lee and ~ u k ~ o u n ~ ' ' were able to carry out the endocyclic cleavage of various

cyclopropylcxbinyl radicals using SrnI?. One of the reactions they pursued is illustrated in

Scheme 9. Ring expansion is favoured due to stabilization of final radical 45 by the ester

group.

Scbeme 9

Cyclopropylcarbinyl radicals are usehl intermediates in natural product synthesis. An

sarly synthetic application was demonstrated by ~oreyJ ' in his rynthesis of 12-meihyl-

prostaglandin A2 49. s h o w in Scheme 10. More examples of the use of

cyclopropylcarbinyi radical fragmentations in organic synthesis will be seen in Section 1.3.

Scheme 10

4 benzene. 7û'C. 6hr

1.2.2.2 Framentations Involving. the CvclobutvlcarbinvI Radical

Four-membered rings have not been investigated as extensively as cyclopropanes but

some data on the rates and regiochemistry of the ring opening of cyclobutylcarbinyl

19

radicals are available as well as information on the effects of substituents." The

Cngmentation of a 4-membered ring (Equation 8) occurs at a rate of I~~o's-' at 600~:'

Comparing this value to that of the cyclopropylcarbinyl fragmentation (IO'S-' at WC).

suggests that the rate of ring opening is partly related to the amount of ring strain.

Equation 8

Fragmentation of the cyclobutylcarbinyl radical (Equution 8) occurs regioselectiveIy.

like the fragmentation of the cyclopropylcarbinyl radical (Eqziuiion 4. However. uniike

the cyclopropyIcarbinyl radical. the ring opening of borli cis- and rrcins-2-methyl-

çyclobuytlcarbinyl radicals 52 (Eqziarion 9) yields rnainly the secondary. more stable

radical 54. even under the most favomble conditions for kinetic control."

Equation 9

Fragmentation of the bicyclo [3.2.0] hept-2-yl radical 55 (Schrrnr II) , would be

rxpected to give the preferentially more stable product radical 57. however it has been

found that exocyclic fragmentation occurs pretèrentïally to give 56." This resuit is

consistent with those obtained for bicyclo [n.1.0] systerns discussed in Chapter 1.22 l.

thus confming that fragmentation is controlled principaily by efficient overlap between

the SOM0 of the radicd and the bond ro be broken.

Scheme 11

Polycyclic compounds containine cyclobutane units are versatile intermediates in

organic synthesis and are easily obtained fmm [2+2] photochemical or themal

cycloadditions. Crirnmins and coworkersu studied the regioselecrive nature of the

fragmentation of the cyclobutane ring in [2+2] photoadducts (Scheme 12).

Scheme 12

O

Bu;SnH. AIBN C6Hb 80°C X= H

Bu3SnH. AIBN C6H6. 80°C X= COzEt

The. discovered that the presence of a radicai stabilizing substituent (ester) adjacent to the

carbonyl on photoadduct 59 resulted in more hgmentation of bond "a" eventually giving

the spiro carbocycle 60 in 75% yield. In the absence of the ester group. bond "b"

hgmented to give 58 in 80% yield.

Lange and Gottardo have also investigated the cyclobutylcarbinyl fragmentation of

various [2+2] photoadducts.'" As s h o w in Scheme 13, a radical tiagmentation was a

critical step in the forma1 synthesis of the angular triquinane sesquiterpenoid.

pentalenene.'"c Fragmentation of an interna1 cyclobutyl bond of 61 resuited in the 5.8-

bicyclic ketone 62. The exocyclic double bond was isomerized into the ring and this

product could then be convened into pentalenene 63 in two previously reponed ~ t e ~ s . " ' ~

Scheme 13

Bu3SnH (1.leq) AIBN (catl

63

pentalenene

Lange and Gottardo also demonstrated that Smi- is an effective reducing agent in these

types of fragmentation^.^^ Treatment of iodide 64 with Sm12 resuited in fragmentation of

the cyclobutane ring yielding ailylic radical 65 (Scheme 14. This radical was then reduced

to carbanion (enolate) 66 by another equivaient of S d 2 . Protonation of 66 gave 67 and 68

in a 99:1 ratio and 93% yield. When the same reaction was canied out with Bu3SnH

instead of SmIr. a 33:67 ratio of 67 and 68 was obtained in a 53% yield. Tm hydride

selectively reduced the less hindered endo terminus.

Scheme 14

Crimmins and asc car el la"^ ernployed a cyclobuty!carbinyt radical Fragmentation in

their synthesis of silphinene 71 (Eqtrasion 15). Treatmeni of iodide 69 wih slow s@ge

pump addition of Bu3SnH (over 6 hours) resulted in fragmentation of the four-membered

ring and regioselective placement of a double bond. producinp silphinene I in a 95%

Scheme 15

7 1 silphinene

yield. They Çound that the concentration of Bu3SnH must be kept v e s Iow. othemise direct

reduction of the initial radical would occur thereby preventing hpentat ion. A review by

Dowd and Zhang gives many more examples of radical fkgmentations used in organic

So tàr it has k e n shown that individual cyclization and hgmentation reactions are

useful in organic synthesis. It is aiso possible for two or more of these processes to occur

in a variety of one-pot sequences. Such tandem radical reactions will be reviewed in the

following section.

1.3 Tandem Radical Reactions

In tandem radical reactions. hvo or more radical reactions occur in a "one-pot'' sequence

allowing minimization of synthetic steps with mi~virnization of complexity~ An example

of the most comrnon type of tandem teaction. the cyclization~cyclization sequence. was

illustrated in Scheme 6 where the radical resulting from a 5-exo-frig cyclization served as

the precursor for a 7-endo-nig ~yclization.'~ A variety of radical reactions can be carried

out in tandem sequences and numerous examples are given in a review by ~arsons? Since

we are mainly interested in tandem reactions involving cyclopropane and cyclobutane

fragmentations. these processes will be the focus of this section.

1.3.1 Tandem Radical Reactions invohiog the Cyclopropylcarbinyl Radical

Reports of tandem reactions involving the fra-gmentation of the cyclopropylcarbinyl

radical are scarce compared to their cyclobutyl counterpan. The most popular sequence.

Frapentationlcyclization. has ken exiensively investigated by ~otherwel1.J~ In one

particular study.J9 illustrated in Scheme 16. stereoelectronicaily controlled exo

Fragmentation of the cycIopropyL carbinyi radical 73 followed by a consecutive 5-e-ro-dig

radical cyclization resulted in spirocyclic system 75.

Scheme 16

O

Bu3SnWAIBN Fragmentation %, benzene, reflux

\ P

TMS TMS 72 73

TMS

Destablel and ~ i l b u r n ~ " studied a tandem cyclizatiodfragmentation sequence involving

a methylene cyclopropane (Scheme 17). Treatment of 76 with Bu3SnH elicited radical 77

which undenvent a 5-rxo-trig cyclization forming cyclopropylcarbinyl radical 78. This

was foilowed bu fn_mentation. yielding the desired methylene cyclohexane 79.

Scheme 17

fmgmentation cyclization and reduction

When a tandem radical reaction involves more than two consecutive steps. it is

considered a cascade. Pattenden and coworkers" established a new approach to the

synthesis of steroids based on a sequential radical cascade. which included a

75

cyclopropylcarbinyl fragmentation. Treatment of a solution of selenyl ester 80 in reflwing

benzene with Bu3SnH (sytinge pump addition over 4 hours) in the presence of AIBN

resulted in the genemtion of radical 81 (Scheme 18). This radicai underwent two

consecutive 6-endo-rrig cyclizations fonning the cyclopropyl carbinyl radical intermediate

82. Radical 82 subsequently fragmented to produce species 83. which then underwent a 9-

rncio-rrig macrocyclization generating 84. This was followed by a transannular cycIization.

The final radicaI 85 was reduced by Bu3SnH giving a 45% yield of the steroid ring system

86. which possessed an unusual. al1 cis-stereochemistry. Remarkably, in the absence of the

ester groups. 80 underwent a single 14-endo-nig cyclization between the initial radical and

the terminal alkene.

Scheme 18

Me02

Buts&. AIBN , benzene, reflux

PhSe

80 8 1

consecutive 6-endo-trig cyclopropylcarbinyl *

cyclizations Fragmentation

82

transannular _ cyclization

reduction

13.2 Tandem Radical Reactions Involving the Cyclobutylcarbinyl Radical

Tandem sequences involvine the fiagrnentation of the cyclobutylcarbinyl radical have

proven to be an effective strategy for the synthesis of fused medium-sized rings. Dowd and

2hang5' utilized a cyclizatiodfragmentation sequence in their 3-step synthesis of a ch-

hsed 6.7-bicyclic framework 90. Treatment of brornide 87 with Bu3SnH. generated

radical 88. which cyclized in a 5-exo-rrig mode to fom 89. The i n t e d bond of radical 89

undenvent fragmentation resulting in the ring expanded product 90.

Scheme 19

Br Bu3SnWAiBN kro-rr ig - benzene. A cyclization

Lange and ~ e r i c a " employed a fragmentation/elimination sequence in their synthesis

of (5)-dictarnnol. s h o w in Scheme 20. Diiodide 91 was treated with Sm& resulting in

abstraction of the primary iodine to give radical 92. Fragmentation of the cyclobutane ring

formed radical 93. from which the remaining iodine was eliminated. This tandem sequence

resulted in the cis-fused 517 bicyclic ring system 94 in hi& field with regioselective

introduction of two double bonds. Bicycle 94 was then converted in two seps to dictamnol

95 (28%) and its epimer % (22%). Lange and Gottardo reported earlier the h t synthesis 28

of alismol using a similar fragmentatiodelimination sequence. elicited by Bu3SnH rather

than ~ m ~ t . " '

Scheme 20

H CH+ H CH2.

Sm12 - fragmentation THF. DMPU

85% *AH- u H H

A tandem h~mentation/cyclization sequence. Scheme 71. was also recently carried out

by Lange and ~erica." Iodide 97 was treated with Sml?. generating radical 98 which

fragmentated to produce species 99. Subsequent hxo- tr ig cyclization gave the strained

intermediate 100 which was stabiIized by the ester moiety. Cyclization was followed by a

single electron transfer fiom S d r and proton transfer from the solvent to f iord the 5/7/3

fused ring system 101, characteristic of the aromadendrane family of sesquiterpenoids.

Over the past decade. the Lange group has demonstrated that the hgmentation of

cyclobutylcarbinyl radicals generated fiom various [2+2] photoadducts is a usefid strategy

in the synthesis of severai classes of natural j~roducts? Tandem radical reactions involving

Scbeme 21

H RT. 55%

1 e- transfer cyclization and protonation

U .

such fragmentation have been investigated during the past several years and so far.

h~enta r i~n le l imina t ion '~ (Scheme 0 ) and fragmentation/cyclizationss (Schmc 111

sequences have met with much success. Recently. anempts have been made at conducting

a novel tandem tiagmentation/oxygenation sequence in pursuit of generating the

guaianolide skeleton. This research will be presented in the following chapter. Tandem

fragmentatiodelimination and fngmentation/h@entation sequences involving both 5 - 4 5

and 5-46 photoadducts have also been investigated and wili be discussed in Chaprers 3

and 4.

Chapter 2 - An Approach to the Synthesis of Guaianoiides Using a Tandem Radical FragmentationIOxygenation Sequence

2.0 Introduction

The fragmentation of [2+2] photoadduct derivatives provides a convenient route to the

synthesis of a variety of natural products. The Lange group has previously employed the

fragmentation of 5 4 - 5 photoadduct derivatives in the synthesis of sesquiterpenoids such as

the guaiane alismol." the trinor-guaiane dictamnol." the angular triquinane

pentaIenenerk and the aromadendrane skeleton." in Section 1.3. tandem radical reactions

were discussed and examples were given of fragmentation reactions that occurred in

tandem with cyclization or elimination. Here, we present our attempt at canying out a

novel tandem fragrnentatiodoxygenation sequence on a 5-45 photoadduct derivative as an

approach to the guaianolide skeleton. This chapter begins with a general discussion of

guaianolides and a review of radical oxygenation. This will be followed by a presentation - and discussion of the results attained in our study.

2.1 Guaianolides

The guaianolides represent one of the Iargest groups of sesquiterpene lactones with over

200 known naturally occuning cornpo~nds.'~ The structure of guaianolides is based on

the gaiane skeleton 102. Guaianolides generally possess a cis-ring fusion. a lactone

moiety fused to the seven-membered ring at either positions C 6 4 7 as in 103 or C7-C8 as

in 104. a methylene group at C-10, a methyi or methylene substituent at C-1 1. and a methyI

or methylene at C 4 .

Guaianolides have ken shown to possess high biologicd accivity as antiturnour agents.

allergenic agents. and regdators of plant p ~ S 7 Their biologicd activities and intricate

suucture have made hem very ppular synthetic targets over the past decade." The

syntheses of two guaianolides: estafiath and cladantholide, were illustrated earlier in

Scheme 6.

guaiane guaianolide guaianolide

The radical fragmentation of 5-45 [2+2] photoadduct denvatives has already been

shown to provide two of the structurai fearures of the guaianolides: the 5.7 cis-fused

bicyclic ring system and the methylene at position 10 (se Scheme 20). The introduction of

the lactone moiety at C6-C7 or C7-CS and methylation or methylenation at C-4 would then

provide guaianolide skeletons 103 and 104. It was postulated that the lactone moiety could

be easily generated through transesterification between an alcohol functionality attached at

C-6 or C-8 and a CHzC02Et goup at C-7. A convenient way to produce an alcohol group

at positions C-6 or C-8 wouId be to carry out the fragmentation reaction of a 5 4 5

photoadduct derivative and then trap (oxygenate) the ensuing tiagmented radical with

oxygen. Numerous methods for carrying out tandem radical cyclization/oxygenation

sequences have k e n reporteci. yet tandem fiagrnentatiodoxygenation appeared to be an

unexplored methodology. In the following section is a review of the various tandem

radical cyclization/oxygenation methods found in the literature.

2.2 Tandem Radical Cyclization/Oxygenation

In Sedon 1.3 it was s h o w that tiagrnented radicals can be involved in M e r tandem

reactions such as cyclization (Scheme 21) and elimination (Scheme 20). It is also possible

for a radical reaction to be terminated by trapping of the final radical with an a l l~ene .~~ The

trapping or functionaiization of the final radical with an element other than carbon is a

valuable. yet rarely emploed, process in organic synthesis.* Direct radical transformation

of a carbon-halogen bond to a carbon-oxygen bond is possible with molecular oxygen6' or

with 2.2.6.6-teuamethylpipendinoxy radical (TEMP~).~' A discussion of these two

methodologies follows.

2.2.1 Molecular Oxygen Mediated Tandem Cyclizaiion/Oxygenation

Molecular oxygen is. by nature. a biradical. It is highly reactive towards aikyl radicals

and has low steric re~pirernents.~~ The reaction of carbon-centered radicals with rnolecular

oxygen is believed to be almost difiion-controlled with a rate of approximately 2x10'

mol"s" at 298KW Severai rnethods are available for convening organic haiides to their

corresponding alcohols by molecular oxygen-mediated radical o~y~enation.~' Of these

methods. cobalt-transfer and tin hydride-mediated oxgenation are most applicable to this

project and will be discussed in detail below. The success of both methods requires that the

concentration of dissolved oxygen be kept low and that the cyclization rate of the substrate

be very hi& otherwise the chn-centered radical will be quenched with oxygen before

cyclization has a chance to occur. For this reason, air is generally used instead of pure

oxygen and the types of substrates that may be ernployed are very limited.

2.2.1.1 Cobalt-Mediated Oxynenative Cvclizations

Cobalt fonns weak covalent bonds with carbon (-20-30 kcaL'mol) and homolysis of

these C-Co bonds with heat or light provides a rich source of carbon radicaln Cobalt is the

core transition metal in Vitamin Bir, a coenzyme that plays a crucial role in the important

biochemical reactions whereby fats, proteins, and carbohydrates are used to produce energy

in living c e l ~ s . ~ ~ For synthetic applications, ~,Ndiethylenebis<salicylidaminato~obdt

(Il)] (Co(sa1en)) 105 is often used to imitate the properties of vitamin B ~ ~ . ' C The mechanimi

for such cobalt-rnediated radical reactions has been proposed by Pattenden and coworke r~~~

but wilI not be discussed here.

Pattenden and coworkers were the first to examine the interaction between the cobalt

complex 107 and molecular oxygen (Scheme 2 2 1 . ~ ~ In the presence of Co(salen) 105. 106

cyclized to produce cobalt complex 107. Irradiation of this intermediate organic complex

in the presence of molecular oxygen led to an unstable peroxycobalt cornplex 108, which

was reduced by sodium borohydride to give the correspondmg alcohol 109 in low yield.

The cobalt-catalld radical oxygenation reaction developed by Pattenden involves a two-

step sequence. requires a stoichiometric quantity of the metal complex and gives a low

yield of product.

Scheme 22

Prandi and ~arnhaoud~' reporteci a more simple and efficient procedure for cobalt-

mediated radical cyclization/oxygenation. This procedure requires only a catalytic quantity

of metal complex. does not require irradiation and involves only one step. As illustrated in

Eqtrarion 10. unsaturated iodide 110 was reacted with 3% Co(salen) in air and smooth

conversion to the bicyclic alcohols 111 and 112 in an 80% yield and 7:l ratio was

observed. Only the products fiom 5-exo-trig cyclization with a cis ring junction were

Equation 10

3% Co( salen), NaBH4, NaOH in EtOH 1 hr. 40°C. dry air

80%

- ek,,@,& H

H H

detected and the major by-products were the compounds resulting from H-atom quench of

the cyclized radical and very minor amounts of uncyclized oxygenated material.

2.2.1 -2 Tin-Hvdride Mediated Oxvgenative Cvclization

Despite the rapid hydride t r ade r property of tin hydride to a prirnary carbon radical

(2x10%Tts-' at 25°C). a few methods have k e n developed that allow oxygenative

cyciizations to occur in the presence of tributyltin hydride. These methods depend on the

hi& reactivity of oxygen with carbon radicals and the maintenance of a low Bu3SnH

concenuation.

Nakamura et al6' developed a simple and effective one-step method for convening

organic halides to alcohols using Bu3SnH. An example of one of the oxygenative

cyclization reactions they investigated is illustrated in Scheme 23. Air was bubbled into a

Scheme 23

Bu3SnH (2.5eq) D air. toluene

O

bh J

* 'Ph

mixture of olefinic iodide 113 and Bu3SnH in toIuene at a Iow temperature. This resulted

in abstraction of the iodine to give radical 114, followed by a S-exu-trig cycLization to give

36

species 115. Radical 115 was then trapped by oxygen. produchg the peroxy radical 116.

Hydrogen transfer from Bu3SnH gave the peroxy intermediate 117, which was fùrther

reduced by Bu3SnH to give aicohol -118 in 83% yield. Small amounts of uncyclized

alcohol and cyclized reduced product were also fomed. Pnor to work-up of the reaction

mixture. a solution of N a B k in ethanol was added to ensure complete reduction of 117.

An interesting feature of Nakamura's conditions is that the radical chah reaction appears to

be initiated by oxygen. The success of this reaction depends initiaily on the slow, dropwise

addition of Bu3SnH and the maintenance of a low reaction temperature.

More recently. Prandi and ~ a ~ e r ~ ~ reported a catalytic tin hydride-mediated

oxygenative cyclization. They investigated the same reaction illustrated in Eqtrarion 10.

Iodide 110 was treated with Bu3SnCl, NaBk and AIBN in refluxing ethanoi under a

strearn of dry air. The 52% yield of products 11 1 and 112 was considerably lower than that

obtained by the cobalt method (Equation 10).

2.2.2 Ovgenative Cyclizations Employing TEMPO

2.2.6.6-tetramethylpiperidinyloxy radical (TEMPO) 119 is a stable radical and an

escient trap of carbon-centered radicals. TEMPO traps p n m w radicals at a rate

comparable to molecular oxygen (k1 09M%-' ). However. due to its bulkiness. secondary

and tertiary radicals are trapped more slowly. The trapping of a tertiary carbon-centered

radical occurs at a rate of 7.8 x ~ O ~ M ' S ~ ' at 250c.~'~ Since the N-O bond in tetramethyl-

piperidinoxyl group can be cleaved by zinc in the presence of acetic acid. this method

provides a convenient way to introduce a hydroxyl p u p in a protected form. TEMPO c m

be ernployed as a radical trap in reactions mediateci by both Bu3SnH and Sml: and a

discussion of both methods follows.

2.2.2.1 Tin Hvdride-Mediated Oxvaenative Cvclizations Ernoloyha TEMPO

The general synthetic scheme for a t h hydride-mediated reaction involving

TEMPO is given below in Scheme 24. A haiogen is abstracted fiom 120 to fonn the

corresponding radical 121. Radical 121 is trapped directly by the TEMPO radical fonning

122. Treatment of 122 with zinc in acetic acid produces aicohol 123. Like molecular

oxygen-rnediated oxygenation. this method is oniy effective when substrates with high

cyclization rates are employed. othenvise severe cornpetition with oxygenation prior to

cyclization will occur.

Scbeme 24

3 ZdAcOH RI a p - R-O-N - ROH

120 121 122 123

Boger and ~ c ~ i e ~ ~ ~ investigated the cycfzation/TEMPO trap of an aryl radical-alkene

(Scheme 75). Treatment of aryi iodide 124 with Bu3SnH in the presence of TEMPO 38

provided 125 directly in excellent conversion. The desired reaction did not proceed to

completion untiI approximately 3 equivaients of Bu3SnH had been added to the reaction

mixture. This result is presurnably a consequerice of the competing reaction of the

generated tributyltin radical and TEMPO, A very low yield of cyclized. reduced product

was observed indicating that hydrogen atom abstraction by the prirnary radical h m

Bu3SnH (k-l~~~''s-') does not effectively compete with rapid coupling of the cyclized

9 1 1 radical with TEMPO (k-10 M' s- ). Treatment of US with zinc in the presence of acetic

acid. then provided the corresponding alcoholl26.

Scheme 25

Zn-HOAc Nu TEMP0.C6H6 THF. H20

70°C \ 90%

AOC 83% BOC \

BOC

124 125

TMP = 23.6.6-Tetramethylpipend'm-1 -y1

2.2.2.2 SmIz-Mediated Oxvgenative CvcIizations Em~loving TEMPO

C- and ~a~ashirna~'' discoverai that TEMPO could also be employed in radical

reactions initiated by Smlz. The proposed mechanism for such a reaction is piven in

Scheme 26. An attractive feature of the Sm12-mediated reaction is that cyclization is

possible before TEMPO is even added to the reaction mixture. This Iimits the production

of uncyclized oxygenated matend and permits the use of a wide range of substrates. even

those with slower cyclization rates. As show in Scheme 26. the iüst step after the

c-lization reaction is the oxidation of alkyl-SmIz by TEMPO. This can either be a singie

39

electron transfer h m alkyl-Sn& to TEMPO or direct attack of TEMPO on samarium.

Either way, the corresponding alkyl radical R* is produced. The second step is the trapping

of the alkyl radical by a second TEMPO molecule.

Scheme 26

Step 1 : R-Sm12 + TEMPO* -, R* + TEMPO-Sd2

Step 2: TEMPO* + R* + TEMPO-R

Curran and ~ a ~ a s h i r n a ~ ~ ' investigated the cyclization/oxygenation reaction shown in

Equation II. A solution of iodide 127 in THF was added to a mixture of Sdz and HMPA

at room temperatm. Eight minutes later, TEMPO was added in one portion and the

reaction was lefi to air. Mer 15 minutes the reaction was quenched with diiute acid.

Chromatography revealed an 88% yield of the cyclized, oxygenated product 128. Now that

the previous studies on oxygenative cyclizations have been reviewed. we wiIl outline our

attempts at the first oxygenative fragmentation using the procedures described above.

Equation 11

1) SmIz (1.leq)MMPA 2) TEMPO (2.2eq)

88% do'"' 23 Results and Discussion

The possibility of carrying out a radical fragmentatiodoxygenation sequence was

considered as a method of introducing an alcohol functionality to a 5,7-bicyclic ring

çystem. it was hoped that this fimctionaiity would eventually be used to prepare the h o n e

40

rnoiety characteristic of the guaiamlides. Prior to preparing our fragmentationloxygenation

precursor, we tested some of tbe oxygenation procedm outlined in Section 2.2 on a

simple mode1 system. Following ttiis study, the precursor was prepared and then several

attempts were made at carrying out a hgmentation/oxygenation sequence.

2.3.1 Testing of Oxygenation on Simple Mode1 Systems

As an initiai investigation of radical oxygenation, some of the oxygenation procedures

reviewed in Seciion 2.2 were tested on a simple mode1 system in order to gain experience at

carrying out a radical oxygenation and to detemiine which procedure was best for our

system. Cholestanol (129), a derivative of the steroid cholesteml, was chosen as the

substrate suice it was readily available. As shown in Scheme 27, choiestanol (129) was

first converted h t o its conespoading iodide (IN), with invaion of contiguration, as

reported by Lange and ~onardo.'~ oxygenation was then camed out on the iodide

130. At this tirne. we were not partidarly interested in the TEMPO oxygenation

since this

Scbeme 27

cholestanol 41

wodd require purchase of the expensive EMPO reagent as weil as a second step to

produce the alcohol. We tested Prandi's cobalt tramfer oxygenation conditions (Table 1,

conditions A)~' and catalytic BqSnH method (Table I , conditions as well as

Nakamura's stoichiometric Bu3SnH conditions (Table 1, conditions B).~' M e r canying

out the W oxygenation (conditions A), TLC analysis indicated that two different products

had been forrned. One product possessed the same Rf as cholestanol and the otlier was

slightly less polar. The products were separated by flash chromatography and 'H NMR

analysis allowed their assignent to be cholestanol and its epimer 131. A 7030 ratio of

129:131 was obtained for conditions A and B, and an 80:20 ratio was achieved using

conditions C. The reaction times and yields are given in Table 1.

Table 1: Conditions and Percent Yields for the Oxygenation of Cholestanol Iodide

I (B) Bu3Sni-i (3eq), dry air, toluene, 0°C - RT, 24h.r.

Oxygenation Conditions

(A) 3%Co(salen), dry air, NaBH4, EtOH, 40" C, 5hr.

%Y ield

69%

As indicated by the yields displayed in Table 1, al1 of the procedures worked m n a b l y

well. Nakamura's stoichiometric t h procedure gave the highest yield, however, it was very

difficult to remove the tin products k m the reaction mixture and the reaction t h e was

lengthy. Method C became the procedure of choice since it gave a good yield, the reaction

- - --

(C) 10% Bu3SnC1, AIBN (1 eq), dry air, NaBb, EtOH, reflux, 3 hr. 76%

was complete in a relatively short period of time (3 hours) and t h rernovai did not pose a

problem since only a catalytic quantity of îin reagent was used.

23.2 The Synthesis of a Simple Photoadduct Derivative

Before attempting to synthesize the guaianolide skeleton, we decided to test the

feasibility of a fragmenation/oxygenation sequence on a simple 545-photoadduct

denvative. Synthesis of out simple derivative (Scheme 28) began with a [2+2]

photoaddition of cyclopentene 132 and enone ester 133 which gave the cis-anti-cis adduct

134 and the cis-syn-cis adduct 135 in 78% yield and in a 9:l ratio, as previously

reprted." The two isomers could not be separated by flash chromatography, however,

the presence of 135 did not affect the resuits of the following reactions. A methyllithium

reaction. at low temperature, was then carried out on ketone 134 to give alcohol 136 in a

61% yield. The next step, dehydration, was problematic and required considerable

investigation. Dehydration was originally atternpted using the procedure employed by

Lange and MacKinnon in their synthesis of tri~hodiene,~ which consisted of the addition

phosphorous oxychloride to a solution of the aicohol in pyridine. However, this procedure

was found to be t w vigorous for this substrate, as even at WC decomposition products and

a low yield of alkene were obtained. Mer attempting numerous other dehydration

procedures that gave low yields (-50°/0), the initial procedure was modified by reducing the

amount of pyridiie to 20 equivalents and dichloromethane was employed as the soIvent.

This gave the highest yield (74%) of an inseparable mixture of alkenes 137 and 138 in a

3.5: 1 ratio. and favourably reduced the amount of pyridine that was required. The presence

of the undesired isomer 138 did not affect the resuits of the foiiowing reactions. Following

prepmtion of 137, the ester was reduced to fcim alcohol139 using Lim a d &et. The

alcohol moiety was then iodinated using the protom1 developed by Lange a d ~ o t t a r d o ~ ~ to

form 140. Highest yields were aîtained by allowing the reaction to stir at m m temperature

overnigtit.

Scheme 28

H COîMe H CO7Me H ColMe

MeLi, ether POC13, pyridine - L

-78"C, 61% CH& OT, 74%

H CH21

L i M 4 , ether 12, PPh3, imidazole - reflux, 80% CH+&, RT, 77%

139 140

233 Radical Frngmentationlûxygenation of a Sunple Photoadduct Derivative

Once the precursor was prepared, we were ready to attempt our first

hgmentatiodoxygenation sequence. It was expected that this radical sequence would

occur as illustrated in Scheme 28' with the generation of an allylic radical 142 that could be

44

oxygenated at either of two positions to give 143 andlor 144. Oxygenation at either

position wouid allow the preparation of the two possible guaianolide skeletons 103 and

104.

Scheme 29

Abstraction of iodine

b Fragmentation

It was apparent that the rate of the 6agmentation wouid have to be faster than the rate of

oxygenation, othenvise the substrate would be oxygenated immediately after abstraction of

the iodide. This was not expected to be a problern. Studies involving oxygenative

cyclizations in the presence of Bu3SnH, revealed more of a problem with the reduction of

the initial radical rather than premature oxygenation, even though the rate of hydride

tmnsfer (106M"s") is much slower than the oxygenation rate (-IO~M-'s-'). In fact, Randi

and Mayer stated that al1 successful oxygenative cyclizations occur when the rate of

cyclization is at least IO'M's-' at 298 K and air is used instead of pure oxygen,69 To our

knowledge, the actuai fragmentation rate of 5 4 5 photoadduct derivatives is not known,

however, the Lange group has never encomtered ditficulty with premature reduction, even

at hi@ concentrations of B U ~ S ~ H . ~ This indicated that the rate of fragmentation of the

photoadduct derivatives is at leas faster than the rate of hydride transfer by Bu3SnH.

The first radical tiagmentationloxygenation sequence was attempted using Prandi's

catallc tin hydride conditions (conditions C, Table 1) and unreacted starting material

(3 1%) was recovered even afler 3 hours at reflux temperature. Three other unidentifiable

products were also obtained which, through TLC analysis, demonstrated a mater polarity

than the starting material. The proton NMR spectra of these unidentified compounds

consisted of signals only in the region h m 0.9 to 2.0 ppm and did not exhibit signais for

methylene protons, an indication that fragmentation had not occurred. The signals for the

protons of the methyl group attached to the double bond were not present as well. It was

concluded that undesired rearrangements or decomposition had occmed.

Nakamura's stoichiomemc tin procedure (conditions B, Table I ) ~ and Prandi's cobalt

procedure67 (conditions A, Table 1) were attempted and again mixtures of unidentifiable

products were received that produced proton NMR signais h m about 0.9 to 2.0 ppm.

Oxygenation was not observeci, even after manipulation of the reaction conditions for both

methods.

We were concemed îhat the system we chose would not fragment, so a regular

fragmentation (Equation 12) was attempmi using the Lange group's typical conditions

[BySnH (1 Seq), AIBN (IO%), toluene, SO"C]~ and a 58% yield of the two inseparable

hgmentation products 145 and 146 were obuïned. The 'H NMR spectrum of these

products gave a singlet at 5.2 ppm fur the alkene methine proton and two singlets at 4.5

ppm indicating the presence of the methylene protons. These singlets were of equal

46

intensity, suggesting a 1:l ratio of products 145 and 146. We decided to repeat this

procedure but with air bubbled into the reaction in h o p of synthesizing a

fiagrnentationloxygenation product. Unfortunately, a mixture of unidentifiable products

was again obtained.

Equation 12

Due to the lack of success with the above procedures, we decided to mm out attention to

the use of TEMPO. The reaction was first attempted with TEMPO and Bu3SnH according

to the procedure employed by Boger and ~ c ~ i e ~ ~ ~ ((Shme 30). It appearcd that

unfragmented oxygenated p d u c t 149 was pmduced, which was identified by the AB

system at 3.71 ppm in the proton NMR spectrum, indicative of the CHJOTMP protons.

This resuit was quite interesting as ail the previous attempts at oxygenative fragmentation

with molecuiar oxygen gave no indication of oxygenated unfrsigmented products, even

though the rate of trapping with molecdar oxygen is about the sarne as TEMPO. It was

expected that the trapping of the neopentyl radical wodd be more difficult with the bdky

TEMPO ragent. L o w e ~ g the concentration of TEMPO may reduce the possiblity of

oxygenation at the initial radical, however, it was now obvious that the rate of

fragmentation was slower than the rate of oxygenation and we decided to move on to the

last possible oxygenation method.

47

Scheme 30

We were optimistic about Curran and Nagashima's p~edure"2c since it would allow

Bu3SnH (3eq), Tempo (Seq), RT

70°C

the fragmentation step to occur pnor to the addition of TEMPO, as itlustrated eariier in

OTMP 147 148

Scheme 26. However. the only products received were the reduced hgmentacion producrs

140

145 and 146 in a 62% yield as illustrateci in Scheme 31. It was concluded that the

carbanion (organosamariurn intermediate) 150 is either protonated before the addition of

TEMPO or perhaps the TEMPO just could not react with the carbanion and therefore

protonation occurred during work-up. This question may be answered by repeating the

experiment and quenching the reaction with D20. If the signal for the proton at H-6 (146)

or H-8 (145) is not present in the 'H NMR spectm of the products, then we know that

protonation of 150 occucred during work-up of the reaction. Protons should not have been

present in the =action mixture since the HMPA and THF were distilled pmperly pnor to

use and precautions were taken to ensure that the reaction remained dry.

Scheme 31

* y + / 4+4 7

OTMP 1:1 147 148 145 146

The possibility of carrying out a fragmentationloxygenation sequence on this particular

system appeared to be unprornising, and after a concerted effort, we decided to retire this

project. We then tmed our attention to the possibility of carrying out a tandem

hgmentatiodhgmentation sequence, discussed in the next chapter. Oxygenation will be

revisited in Chapter 4.

Cbapter 3 - Approrches to the Synthesis of Dumortenol Employing Tandem Radical Sequenees

3.0 Introduction

The radical fragmentation of 5 4 5 photodduct derivaiives has been snidied extensively

in our lab, and this methodology has been successfuily applied to the synthesis of seved

se~qui te r~enoids .~~~~~ The radical fragmentation of 5-4-6 photoadduct denvatives has not

been as well-studied by our gmup and ody one naturai pmduct, pentaler~ene?'~ was

successfully ~ynthesized?~~ In this chapter, we present two approaches to the synthesis of

the novel sesquiterpenoid, dumortenol, u t i i i i the hgmentation of 5 - 4 6 photoadduct

derivatives. The chapter begins with an introduction to our target dumortenol and is

followed by a discussion of out fini approach to its synthesis, which involved a tandem

radical fiagmentatiodelimination sequerace of a dihctional derivative. The chapter will

conclude with a discussion of our second approach, which entaileci a tandem radid

hgmentatiodfrapentation sequence of a novel5/4/6/3 tetracyclic ring system.

3.1 Dumortenol

Durnortenol 151, was recently isdated h m the ether extract of the Argenthian

Iiverwort ûumorfiera hirsuta. This sesquiterpene alcohol contains a rare 518 ring system,

does not obey the isoprene nile and is believed to be derived h m the cyclization of fians-

famesylpyrophosphate." To our knowtedge, no syntheses of dumortenol have been

reported.

151 dumortenol

It was believed that dumortenol could be synthesized via the radical fragmentation of a

5-4-6 photoadduct denvative. Such a tiagmentation would provide the required 5/8

bicyclic ring system and the methylene at position 11. Both the fragmentation/elirnination

and hgmentation/hgmentation approaches to the synthesis of dumortenol would also

allow the regioselective placement of the double bond at C6-C7 and the introduction of the

rnethyl group at C-8, with correct stereochemistry. The hydroxyl and methyl groups at C-4

could be easily prepared by using ketal-protected cyclopentenone instead of cyclopentene

in the photoaddition step. Hydrolysis of the ketal followed by a Grignard or MeLi reaction

at the resulting carbonyl would then provide the required groups at C-4. The correct

stereachemistry at the ring fusion of dumortenol may also be prepared through synthesis of

the corresponding cis-syn-cis photoadduct using the asyrnmetric induction methodology

developed by Lange and ~ e c i c c o ? ~ Fragmentation followed by epimenzation of the C-5

hydrogen (in the presence of the carbonyl at C-4) would then provide the necessary tram

ring fusion with the correct stereochemistry. As an initial investigation of our approaches

to dumortenol we chose to test our radical sequences on simple cis-ad-cis derivatives

containhg no functionaiity on the 5-membered ring. Both of these approaches are

describeci in the following sections.

3.2 An Approacb to the Syatbesis of Dumortenol Employing a Radical Fragmentation/lEiimination Sequence

As a first approach to the synthesis of dmortenol, we ho@ to carry out a

fragmentatiodelimination sequence on simple dixanthate photoadduct derivative 152 as

shown below in Scheme 32. A related fiagmentatiodeLimination methodology was

employed by Lange and coworkers in their synthesis of dismol, which involved an

iodoxanthate, and their synthesis of dictamimol in which a diiodide was employed. The

radical fiagmentatiodelirnination of 152 rnay occur as shown in Scheme 32 whereby the

primary xmthate is fust abstracted to give neopentyl radical 153 which undergoes a

cyclobutylcarbinyl radical fragmentation to rtfford secoadary radical 154. The tertiary

xanthate would then l a v e resulting in the formation of a double bond as shown in 155. It

is dso possible for the tertiary xanthate to be abstracted first, either way the same product

will be obtained.

Scbeme 32

H CH7Xan & abstraction of 1 O xanthate

H CH2*

cyclobutylcarbinyl

H3 hgmentation

153

As outlined in Scheme 33, the synthesis of dixanthate photoadduct derivative 152 began

with a [2+2] photoaddition of cyclopentene 132 and enone ester 156 to give the 5-44 cis-

mi-cis adduct 157 and the ch-syn-cis adduct 1 s in an 85% yield and 87:13 ratio, as

previously reprted." Adduct 157 was then methylated to give an inseparable mixnire of

Scheme 33

hv, toluene

1) LDA basic A2O3 - 2) Me1 toluene. reflux

61% (epirnerization)

159 3 : 7 160

i-i C02Me H C02Me

MeLi LiAIH4 - C

-78OC to dO°C '"*w,cH~ ether. reflux 77% 73%

159 and 160 in a 3:7 ratio. This ratio was based on the integration of the respective methyl

proton doublets at 1 .O8 and 1 .O3 ppm in the 'H NMR spectnim of the product mixture. In

the NOESY spec tm of the product, the latger methyl doublet at 1.03 ppm did not show a

correlation with the ester protons or with H-7, suggesting that the major epimer 160 did not

possess the required stemchernistry. Epimerization was attempted by refluxing the above

mixture in a solution of basic alumina and toluene and a 6:4 mixture of 159:160 was

obtained. We were disappointed that a higher ratio of 159 was not achieved, but we

continued with the next reaction in our synthesis. A methyllithium reaction was carrieci out

on the epimerized mixture of 159 and 160 and to our delight a 77% yield of 161 and 162

was obtained in a 9:l ratio. It appeared that the higtily basic MeLi aided in the

epimerization of this compound. The methyllithium reaction was attempted on the non-

epimerized (3:7) mixture of 159 and 160 and only a 7:3 ratio of 161:162 was obtained. The

epimers were then separated by flash chromatography and 161 was subjected to reduction

conditions (LiAlh, ether, reflux) to give 163 in a 73% yield.

The precursor for the fiagmentationlelimination required the introduction of hivo radical

leaving groups, one at the tertiary alcohol position and the other at the neopentyl alcohol.

Diiodination using the protocol developed by the Lange p u p would be inappropnate,

since this procedure is selective for primary and secondary akoh~ls.'~ The synthesis of a

dixanthate was attempted ushg the procedure ernployed by Lange and Gottardo in their

.thesis of alism01.~ The single product obtained in this reaction gave a 'H NMR

specmun shoking a 3-proton singlet at 2.50 ppm representing the SC& protons of one

xanthate group as welI as a downfield AB system centered at 4.33 ppm representing the

CbXan protons. This data indicated that oniy monoxanthate 164, shown in Equation 13.

was obtained.

Equation 13

We were concemed that the methyl group at C-4 was preventing the addition of groups

at the desired position, so a study on simpler subsîrate 165 was pursued. As shown in

Equation II, a xanthate group could not be introduced to 165 as well. The MeLi reagent in

the xanthate reaction was replaced with different bases (NaH and KH) and still no reaction

was observed. Next, an attempt was made at introducing thiocarbonylimidazole at the

desired position using the method of Barton and ~c~ombie , " and again no reaction was

observed (Equation 1.5'). Finally, the introduction of an iodide at this position was pursued

using the protocol developed by OIah and coworken (Equation 16):' The 'H NMR

spectrum of the product showed a 1H singlet at 5.44 ppm and a 3H singlet at 1.55 ppm,

suggesting the presence of an alkene proton and an alkene methyl respectively. It appeared

that eiimination had resulted instead of iodination to afford alkene ester 166. Despite the

difficulty encountered in the introduction of the leaving p u p at the tertiary akohol, the

synthetic sequence carried out in Scheme 33 was succesfi and investigation of the

hgrnentation/eiimination approach to durnorieno1 should continue. A Merature search

may uncaver other radical leaving groups that could possibly be introduced at the tertiary

55

dcohol position of 163. This work was deferred and our second approach to the synthesis

of durnortenol was considered. This study is described in the following section.

Equation 14

l)MeLi, CS2, DMF - no reaction 2) Me1

Equation 15

CO-Me

1) KH, THF, reflux, 1 hr L no reaction

2) thiocarbonyldiimidazole / RT, 2hr

CH3

Equation 16

3.3 An Approach to the Synthesis of Dumortenol Employing a Radial Fragmentation/Fragmentation Sequence

In Secrion 1.2.2.1, it was shown that bicyclic [n.1.0] radicals, where 1123, prefer

stereoelectronically controlled exocyclic radicai ring opening as opposed to

thermodynamically favouced endayclic ring ~penin~. '~'~ Clive and coworkedkM

56

demonstrated that this exocyclic preference can be used as a general method for

introducing an alkyl group to an existent cyclic stmture (Inheme 7). We hoped to take

advantage of this methodology in our second appmach to the synthesis of dumortenol. As

illustrated in Scheme 31, we believed that if the hgmentation of cyclobutylcarbinyl radical

168 occurred in tandem with the exocyclic fragmentation of the cyclopropylcarbinyl radical

169, we could achieve the formation of the 518 bicyclic ring system, the methylene at C-

11, regioselective introduction of the required double bond at C W 7 , and the

stereocontrolled introduction of the methyl group at C-8, ail in one step. In 155. the 8-

Scheme 34

cyclobuty lcarbinyl - fragmentation

cyclopropylcarbinyl hgmentation

membered ring would then contain al1 of the structural features present in the same ring of

dumortenol. The methyl and hydroxyl goups attacheci to C-4 as well as the

stereochemistry at the ring f i o n could be pduced by methods mentioned earlier in

Section 3.1.

The synthesis of 167 began with the preparation of photoadduct 157, as shown

previously in Scheme 33. As illustrated in Scheme 35, a methyllithium reaction was then

canied out on adduct 157 to afEord aloohol 165 in a 63% yield. Alcohol 165 was then

dehydrated using the same procedure employed in Chapter 2 (Scheme 29), and alkene ester

166 was obtained in a 71% yield. Ester 166 was then reduced with L M - & to give

unsaturated alcohol 171 in a 93% yield.

Scheme 35

H COzMe

MeLi POCI3, pyridine -78 to dOoC CHîCI1, RT

63% i

H H 71% O

157 165 166

H CHIOH H CH->OH

LiALH,, ether, RT - 93%

90%

171

PPh?, imidazole II, CH2C12. RT

The next goal was to introduce a cyclopropane ring at the double bond of 171 with the

correct stereochemistry. This was first aitempted using a variation of the Simmons-Smith

reaction that involved the in situ preparation of the ZnlCu couple through the reaction of

zinc dust and CuCl in refluxing ether.79 Hydmxy alkene 171 was then added to the couple

followed by methylene diiodide. The results of this reaction were inconsistent. The yields

of 172 varied considerably and sometimes no reaction was observed, likely due to an

inactive Zn/Cu couple. A more convenient cyclopropanation procedure was then attempted

using diethylnnc and methylene diidide?' Using this procedure we obtained 172 as one

stereoisorner in consistent yields of 90%. The presence of the cyclopropane ring in 172

was verified through the analysis of its 'H NMR spectm. The cyclopropane methylene

protons (H-3) gave a triplet a 0.37 ppm and a multiplet at 0.01 ppm, the cyclopropane

methine proton (H-4) gave a multiplet at 0.78 ppm and the C-2 methyl group was shifted

upfield fiom 1.55 ppm in 171 to 0.88 ppm in 172. The NOESY spectnim of 172 showed a

correlation between the CEOH protons and H-3, and a correlation between H-1 and H-3.

This data suggested that 172 possessed the desired stereochernistry. This stereochernistry

may have k e n achieved thmugh a directive effect by the hydroxyl group. There is

extensive evidence that an allylic or homoallylic hydroxyl group can coordinate with the

reagents in zinc-promoted cyclopropanation reactions, thereby directing syn ring

f~mat ion .~ '

Following the cyclopropanation sep, iodination of 172 was achieved using the Lange

protocol~O giving 167 in a 63% yield. Once 167 was prepared, it was tirne to attempt the

hgmentationlhgmentation sequence outlined earlier in Scheme 34. SmIz was employed

since it was convenient to use and the product was easy to purify. Unfomately, as s h o w

in Scheme 36. reaction of 167 with SmIz in distilleci THF appeared to result in direct

reduction of the initial radical to give 173 in a 65% yield. The 'H NMR specmun of the

59

product did not possess methytene signals and the cyclopropaue proton signais were

present, indicating that fragmentation had not occurred However, the Ai3 system at 3.07

ppm, representing the CiJJ protons, was not present, indicating that the iodine had been

removed. This same product was obtained when the reaction was repeated using Bu3SnH

and AIBN in reflwing toluene. It seemed that the rate of fragmentation of 167 was too

slow to compte with reduction of the initial radical. so the reaction was agah attempted

substituting BgSnH with the less reactive hydride donor, BgGeH. Following 24 hours of

reaction time. pmduct 173 was again isolated and there was no sign of fragmentation.

Scheme 36

The result of this hgmentationlfiagmentation study was quite sucprising since the

Lange group has never encountered a dificulty with the premature reduction of the

neopentyl radical in the fragmentation of [2+2] photoadduct derivatives. Perhaps the 60

cyclobutane ring did not possess enough ring strain tu drive the hgmentation of this

system. Aithough it was not possible to achieve a tandem radical fragmentation1

hgmentation on the 5/416/3 teaacyclic ring system, it was believed that a more strained

5/4/5/3 ring system might aEod different tesults. A hgmentation/fragmentation sequence

was successfully carried out on such a system and the tesults of tbis study will lx presented

in the next chapter.

Chapter 4 - An Approach to the Spthesis of the Lactarane Skeleton Using a Radical Fngmentation/Fragmentation Sequence

4.0 Introduction

In Chapter 3, a radical bgmentationffiaginentation sequence was aîtempted on 5/4/6/3

ring system 167 as an approach to the synthesis of dumofienol. Unfortunately, the

cyclobutylcarbinyl radical did not hgment and it appeared that direct reduction of the

initial radical had occurred. In this chapter the results of a hgmentation/fragmentation

study using the correspondhg 5/4/5/3 ring system are presented as an approach to the

lactarane skeleton. This chapter begins with an introduction to the lactaranes and a

presentation of our synthetic approach to their synîhesis. This will be followed by a

discussion of our results and fùture work to be conducted in this area

4.1 The Lactaranes

The lactaranes are a group of sesquiterpenoids isolated h m the Lacturius and

Russulaceue species of mushrooms that are believed to possess antifeedant, rnutagenic and

antimicrobial activities.' The laciarmes pssess the non-isoprenoid carbon skeleton 174.

They have a 517 bicyclic ring system a methyl or methylene at C-3. a gem-dimethyl group

at C-10, and carbons attached to C-5 and Cd. Some lactaranes. such as pyrovellerofuran

175, possess a furan ring at CS46 and others. like vellemlactone 176. have a lactone ring

bndging these positions. Syntheses of pyrovellmfùran and vellemlactone have been

previously reported.83M We bdieved that the tandem f?agmentation/fragmentation

sequence applied in the previous chapter couid be used to synthesize the lactarane carbon

skeleton 174. Our attempt at this synthesis is discussed in the followiag section

174 lactarane

175 1 76 pyrovellerofuran velierolactone

4.2 Radical Fragmentation/Fragmentatioa of a 5-44 Pbotoadduct De rivative

It was anticipated that the same cyclobutylcarbinyVcyclopropylcarbinyl radical

fragmentation sequence illustrated earlier in Scheme 34 could be carried out using the

correspondmg 5-4-5 photoadduct derivative. The synthesis of the hgmentatiod

fragmentation precursor, outiined in Scheme 37, began with hydroxy alkene 139, the

synthesis of which was shown earlier in Scheme 28. Cyclopropanation using the sarne

EtzZn/CHziz procedure used for the 5-46 derivative resulted in 177 as one stereoisomer in

an 87% yield. The presence of the cyclopropane ring was c o h e d by the 'H NMR

spec tm of 177. The cyclopropyl methylene protons (H-9) gave a triplet at 0.08 ppm and

a multiplet at 0.28 ppm, The cyclopropyl methine proton (H-10) produced a multiplet at

1.09 ppm and the C-8 methyl protons gave a singiet at 1-08 ppm. considerably upfield

relative to that in 139 (1.64 ppm). Iodination of 177, ovemight at m m temperature, gave

our precursor 178 in an 80% yield. The presence of the iodide was confirmeci by the shifl

of the CEOH AB system at 3.29 ppm in the 'H NMR spectrum of cylcopropyl alcohol

63

177, to the C B I AB system at 3.01 ppm in ihe corresponding iodide. Following

preparation of precursor 178, the fiagmentationhgmentation sequence was attempted

using Smlz with six equivalents of HMPA in dry THF, and 181 was isolated in a 67%

yield. We believe the fiagmentatiodftagmentation sequence occucred as follows: iodide

178 was reduced by Sn& to p d u c e cyclobutylcarbinyl radical 179, which fiagmented

intemally to produce 180, Cyclopropylcarbmyl radical 180 then underwent the expected

exocyclic ring opening, as indicated by the amws in Scheme 37, to give the desired double

bond at C2-C3 and the methyi group at C-4. The synthesis of 181 is

Scheme 37

cyclobutylcarbinyl - THFMMPA fragmentation

67%

178 179

cyclopropylcarbinyl C

fragmentation and reduction

supported by spectral data. Two singlets, one at 4.67 ppm and the other at 4.68 ppm, in the

'H NMR spectnim of 181 confïxmed the presence of the two =C& protons and a doublet at

1 .O3 ppm indicated the presence of the C-4 methyl protons. The H-2 proton gave a doublet

at 5.12 ppm and the presence of the C-3 methyl was codbmed by the singlet at 1.61 pprn.

The NOESY spectnim of this product showed a correlation between H-4 and H-1 and H-7

suggesting that the stereochernistry indicated on structure 181 was achieved. GCMS of

the product revealed the presence of a small amount (<IO0?) of an unidentified isomer.

This isomer may be related to the presence of the exocyclic methylene in 138 produced in

the dehydration step, however the signals obsewed in the 'H and ')c NMR spectra of this

product were tw srnall to allow proper characterization. The fragmentatiodtiagmentation

sequence was repeated using the less toxic cosolvent DMPU, in place of HMPA, however

no reaction resulted suggesting that DMPU did not increase the reducing power of SmIz

enough to elicit the reaction.

It was believed that the fùran ring present in such lactaranes as 175 might be prepared if

an alcohol functionality was attached to the C-4 methyl group. Although the radical

oxygenation studies descnbed in Chapter 2 were unsuccessful. it was felt that a

hgmentationlhgmentatiodoxygenation radical sequence was worth an attempt on this

system. Since the final radical resulting h m the fragmentationlhgmentation step was

primary, it was believed that this may provide different results, particularly in the case with

TEMPO where stenc hindrance may be a factor. As outlined in Scheme 38, the

~entatiodhgmentatiodoxyge~tion sequence was first attempted using the

Sm12/TEMP0 method. This resulted in fiagmentatiodfragmentation product 181 and no

Scheme 38

1 1) S d z , THF/HMPA (2) Tempo

OTMP

H

oxygenation was observed. This result is consistent with the result presented earlier in

Scheme 31. Oxygenation was then aîtempted using the catalytic tributyltin hydridd

molecular oxygen (air) system. The 'H NMR spectrum showed that the product of this

reaction was alcohol 177. indicating that oxygenation of the primary radical had occurred.

Al1 of the oxygenation attempts described in Chapter 2 that employed rnolecufar oxygen

resulted in unidentifiable products h m which no conclusion could be made. The result

presented in this chapter proves that fragmentation/oxygenation is not feasible due to the

fast rate of radical trapping by oxygen, even under low oxygen concentrations (air).

Althou@ the oxygenation expriment was not successfbi we were gratified by the novel

tandem radical cyclobutylcarûinyi/cyclopropylcartiinyl fragmentation of substrate 178. We

are not aware of such a sequence king reported previously. In one reaction we were able to

form the desired seven-membered ring, to regioselectively introduce two double bonds in

that ring and to place two methyi groups at the appropriate positions for the lactarane

carbon skeleton.

43 5-45 Versus 5-44 Photosdduct Derivatives

The resdts of Chapers 3 and 4 show that significant differences exist between the

reactivity of 5-4-5 and 5 4 6 photoadducts. In the first appmach to dumorteno1 (Section

3.3) a leaving group could not be inaoduced to the tertiary akohol position of the 5-4-6

photoadduct derivative. This was quite surprishg since Lange and Gottardo easily

intoduced a xanthate group at this position of a 5 4 5 photoadduct derivative in their

synthesis of dismoLS It appears that the 5-4-6 adduct takes on a conformation that makes

this position more hindered. although it was anticipateci that the greater flexibility of the 6-

membered ring wodd have facilitated reaction at this hydroxyl group.

It was quite surprishg that the ti.agrnentatiodfragmentation sequence of the 5-46

cyclopropyl iodide was not successful, patticularly since the same sequence occurred

readily with the corresponding 5 4 5 system. Looking back at previous fragmentation

research done in the Lange lab, it was reaiiied that the 5 4 6 photoadduct derivatives were

consistently less reactive than their 5-4-5 counterpam. In an early fragmentation study.

Lange and ~ottardo"'~ wried out the ceactions shown in Equutions 17 and 18. The yield

Equation 17

Equation 18

of fragmentation product 184 fiom 5 4 5 photoadduct derivative 183 was 90% (Equation

17) whereas the 5-4-6 derivative 185 gave only a 60% yield of 186 (Equation 18). An in-

depth study of these two systerns will need to be undertaken in order to determine the

underlying cause(s) of this variance. We believe that the cyclobutane ring in the 546

system does not possess as rnuch ring strain as the comsponding 5 4 5 denvative.

Calculation of the ring strain energies in both the 5141613 and 5/415/3 systems may give the

answer. If so. tbese energies rnay be compared to the estimated energies of possible future

denvatives and may aiiow us to predict whether a photoadduct denvative wiIl undergo

fragmentation without having to cany out the entire synthetic sequence. It is also possible

that another factor may be involved. ~ofnnan '~ has proposed a phenornenon cailed orbita1

interactions through bonds (OITB), which is believed to disfavour cleavage in even-

rnembered rings and favors cleavage in odd-membered rings. The existence of this

phenomenon was recently supportai by Dowd and ~ o u k 8 ~ in their study of alkoxy radical

cieavage reactions. I f this phenomenon does in fact exist. it may explain the ease of radical

hgmentation of 5 4 5 photoadduct denvatives over the comsponding 5-46 derivatives.

The question stiii remains as to why the 5-46 cyclopropyl iodide did not fragment at ail

whereas the 5-46 ketone 185 fiagmented in a 60% yield. It is possible that the presence of

68

the carbonyl group weakens the internai bond of the cyclobutane ring in 185 making

hgmentation feasible or perhaps fragmentation of this system is driven by the resuiting

stabiIization of the finai radical by the carbonyl group. The a m e r to these questions lies

beyond the scope of our research.

4.4 Future Work

The fragrnentationlfragmentation methodology developed here will be utilized in the

synthesis of specific lactaranes such as pyroveiierofiuan and vellerolactone. The gem

dimethyl group at C-10 of the lactaranes can be easily prepared through the use of the

ready-prepared 4.4-dhethylcyclopentene~ instead of cyclopentene in the photoaddition

step. In order to prepare the lactone or furan ring. bctional groups must be attached at the

C-3 and C-4 methyl groups. We have already tried, unsuccessfùlly, to introduce a hydroxyl

group at the C-4 methyl via radical oxygenation. Another possibility is to use a technique

developed by ~ u r r a n ' ~ cdled a t m aansfer (Scheme 39) whereby the iodide of starting

Scheme 39

Bu3SnSnBu3 NaOH/H20 hv

H21 (hydrolysis)

H

material 178 may trap the final radical of the sequence to form iodide 187. This iodide rnay

then be converted to alcohol188 as shown.

A variety of functional groups rnay be added to C-1 1. The use of SmIr provides the

opportunity to add groups at this position since the final carbanion resdting fiom the

fragmentation step rnay be trapped by an appropriate elecmphiie. As well, functionality

rnay be introduced at the non-bridgehead carbon of the cyclopropane ring during the

cyclopropanation step. For example, the use of M ~ $ ~ < H C O O E C ~ ~ instead of

Et2Zn/CH212 will allow the pteparation of a cyclopropane ring with an ethyl ester (COOEt)

attached to C-1 1. Such a group would aiw facilitate fhgmentation of the cyclopropane

ring due to the resulting stabilization of the final radical. A hydroxyl group rnay be

introduced at the C-3 methyl group via selenium dioxide (Se@) oxidation, however this

might also result in oxidation of C-5. As discussed above, several possibilities are

available to introduce fiinctionality at the C-3 and C-4 methyl groups. Such functionality

rnay be used to synthesize a variety of lactaranes as well as other naturai products

containhg a 517 ring system.

4.5 Summary and Conclusions

The research presented in this thesis demonstrates both the challenges and rewards of

radical-based synthetic organic chernistry. As mentioned in the Section I.0, the major

drawback of radical reactions is that there are several competing pathways that the radical

may take. This problem was encountered several times during the research presented here.

in Chapter 2, an attempt at a novel radical fiagnentationloxygenation sequence resulted in

unidentifiable products when aii of the procedures using molecular oxygen were employed,

however, when the reaction was attempted with Bu3SnH and TEMPO, the initial radical

was oxygenated before fragmentation had a chance to occur. The same problem arose in

Chapter 4 when a hgment~tionlEragmentation~oxyge~tion sequence was attempted. This

time, reaction of Bu3SnK with molecular oxygen resuited in oxygenation of the initial

radical. This result proved that radical hgmentation/oxygenation of our photoadduct

derivatives is not feasible since the rate of fragmentation is not fast enough to compte with

the rate of oxygenation.

The problem of competing pathways was also demonstrated in Chaprer 3, where a

radical fragmentatiodfragmentation was attempted on the 5-46 cyclopropyl iodide. Direct

reduction of the initial radical by Sm12 occurred before fragmentation could take place. The

obvious solution to this problem was to either use a catalytic quanbty of Bu3SnH or to use a

less reactive chain transfer reagent. We attempted using Bu3GeH. which is known to have

a hydride m f e r rate 10 t i m slower than that of BgSnH. Although the reaction tirne

was much longer than with Bu3SnH, the same reduced product was obiained. Such a

problem with the premature reduction of the neopentyl radicaI has never been encountered

in the Lange lab untiI now. This result may be due to low ring main energy in the

cyclobutane ring of the 5/46/3 ring system andior to a proposeci effect called orbital

interactions through bonds.

Despite al1 of the complications that o c c m d during the research presented here, the

great synthetic utility of radical reactions was also demonstrated by the successful tandem

radical cyclopropylcarbinyl/cyclobutylcarbinyl fragmentation sequence described in

Chaprer 3. Four structural features were obtained in one step: ring expansion, the

regioselective formation of two double bonds and the regioselective introduction of a

methyl group. ALI of these structural features are found in the carbon skeleton of the

lacmes. To ow knowledge, such a radical sequence bas never been reported and we

believe this rnethodology will be usefiil in the synthesis of a variety of lactaranes and other

natural produc& containing a Y7 ring system.

Chapter 5 - Experimental

5.1 General Techniques

n ie 'H NMR and I3c NMR spectra were tecorded on either a 200 MHz Varian Gemini

or a Varian Unity 400 MHz NMR spectrometer using tetramethylsilane (MQS~) as an

interna1 standard. The multiplicities of the 13c spectra were detennined by DEPT

experiments. Infrared (IR) spectra were obtained on a Bomem FTIR spectrometer using

NaCl Iiquid cells and chioroform (CHCl3) as the solvent. Low resolution mass spectral

analyses were performed on a Finnigan 4500 quadruple mass spectrometer and high

resolution experiments were performed on a VG ZAB-R using electron ionization (En.

Analyticd thin layer chromatography (TLC) was performed on silica gel GF 254 plates

with a thickness of 0.25 mm. The solvents used for the chromatography are indicated in

parentheses in the procedure and the relative concentrations of solvents used were

calculated by volume. Components were observed using ultraviolet light and treatment

with 25% sulfuric acid followed by heating. Flash chromatography (FC) was performed

using 230-400 mesh silica gel (Merck) and the solvent systems used are indicated in

parentheses in the procedure.

Silica gel was recycled by soaking it in methanol for 1-2 days followed by washing with

water. It was then immersed in concentrated nitric acid for t h e days. The nitric acid was

removed by repeated washings 6 t h water and the silica gel was dried in a 200°C oven for

three days. The silica gel was deactivated through the addition of 10% water, by weight.

Solvents employed for extraction or chromatographie purification were used as

received. Dichloromethane (CHlCI2) was freshiy distilled fkom calcium chloride (CaC12)

and THF îrom benzophenoneketyl. Hexamethylphosphocamide (HMPA) and N.N'-

dimethyI-N'N-propylene urea (DMPU) were distilled under vacuum h m calcium hydride

(Cd2) and storeci over 4 A rnolecular sieves. Diisopropylamine @PA) was di i l led h m

CaHz and stored over 4 A molecuiar sieves, Tolwne, diethyl ether, and pyridine were dried

over 4 A rnolecular sieves prior to use. Al1 other reagents were used as commerciaily

obmined udess otherwise stated.

Al1 experiments were run under a positive pressure of argon in flasks which were flarne

or oven dried. Air and moisture sensitive reagents were transferred via syringe and

introduced into îhe reaction flasks chrough &ber septa Excess solvents were removed in

vacuo at pressures obtained by a water aspirator drawing on a Buchi rotary evapomtor. Al1

compounds were stored at -22" C in vials or flasks flushed with dry argon and seaied with

a sem cap.

5.2 Experimental for Chapter 2

Methyl & ~ ~ d n i ~ ~ m e t h ~ l h i c ~ e l o [ ~ ~ . ~ . d d ] d e r a n e - l - c a r b o ~ l a t e (136)

To a stirred solution of ketone 134 (0.401 g, 1.93 mmol) in anhydrous diethyl ether (10

mL) at -7892 was added a 1.4 M solution of methyllithium (MeLi) (1 -79 mL, 2.51 mmoi,

1.3 eq) dropwise. by syringe, over 45 min. The mixnw was lefl to stir at -78°C for 2 h.

The reaction was quenched by the slow addition of aqueous saturated ammonium chionde

(NH4Cl) (2.0 ml) foIIowed by water (2.0 ml) and ether (5.0 mi). Tfie two layers were

73

separated and the aqueous layer was extracteci with chiorofonn (CHC13) (3 x 20 ml). The

organic layers were combiied, washed with brine (1 x 5 mi,) and dried over anhydrous

magnesium d a t e (MgSO4). The solvent was removed in vucuo and the residue was

punfied by FC (20 % EtOAc in hexanes) to give alcohol 136 (0,262 g, 61 %) as a

colouriess oil.

TLC (30 % EtOAckxanes): Rf = 0.25

IR (CHCi3): 1268,1324,1722,2870,2953,3016,3606 cm-'.

I H NMR (CDCL): 6 1.12 (3H, s, CB), 1.36-1.49 (4H, m), 1.57-1.64 (4H. m), 1.69-1.79

(2H, m, H-9), 2.04 (lH, d, J = 32 Hz, K-7), 2.07 (IH, m, H-IO), 2.35 (IH, t, J = 7.2 H q H-

2). 2.45 ( 1 H, q, J = 4.4 Hz, H-6), 3.58 (3H, s, Cm&).

I3c NMR (CilCl,): 6 27.0 (C-8-C-H3), 25.3 (C4), 30.1 (C-3), 32.8 (C-5), 33.9 (C-6). 34.8

(C-9), 37.7 (C-10). 46.0 (C-2), 51.0 (C-1), 51.2 (ocH3), 53.0 (C-7) 79.2 (C-8), 175.4

E02Me).

MS m/z (rel Uitens): 225 (m+iil', a), 139 (100), 107 (38),79 (60), 67 (57), 43 (76).

HRMS calcd for C13H2003 + H 225.1479, found 225.l+ll.

Meihyl8-~etb~ltricycla(53.0.0~].8aecene-l-~~ibo~lpte (137) and Methyl8-~etb~lenehicyclo[53.0.0~]d~~~n~-l~rbo~1ate (138)

and

A solution of alcohol 136 (0.135 g, 0.603 mmol) in anhydrous CH2C12 (10 mL) was

cooled to O°C and pyridine (0.908 mL, 12.2 mmol, 20 eq) was added. The solution was lefi

to stir at O°C for 5 min then phosphorous oxychioride (POC13) (1 13 pi,, 1.22 mrnol, 2 eq )

was added dropwise by syringe over 0.5 h. The =action was left to stir at O0 C for 4h. The

reaction was quenched by the slow addition of water (2.0 mL) and the solution was

extracteci with ether (3 x 20 mL). The organic layers were combined and washed with a

5% solution of HCI (2 x 5 mL), water (lx 5 mL) and bine (1 x 3 mL). The organic layer

was dried over MgS04 and the solvent was removed in vacuo. The residue was purified

by FC (5% EtOAchexanes) to afford a 3.5 : 1 mixture of 137 : 138 (0.0924 g, 74%) as a

colourless oil.

T'LC (20% EtOAclhexanes): Rf = 0.64 (137) and 0.59 (138).

IR (CHC13): 1436,1667,1725.2855,2953,3018 cm".

I H NMR (CDCI3): 6 1.35-1.40 (2H, m), 1.59-1.64 (IH, m. H-5), 1.63 (3H. s, 8-Me 138).

1.64 (3rd. s, 8-Me 137), 1.70 (IH, m, H-3), 2.3 1 (IH, m, H-6), 2.55 (IH. d, J = 7.2 Hz H-

z), 2.58 (1H. m. H-10). 2.69-2.70 (IH, m, H-IO), 2.78 (IH, S. H-7), 3.60 (3H. S. O C b

137), 3.61 (3H, S. OC& 138). 4.66 (IH, S. =C& 138), 4.68 (1 H, S. =Ci& 138). 5.15 (1H. S.

H-9 137).

'k NMR for 137 (CDC13): S 14.2 (CS-CH3), 25.5 (C-4), 30.3 (C-3). 32.6 (C-5). 44.8 (C-6),

46.4 (C-IO), 49.4 (C-2). 51.3 (OcH3), 51.4 (C-1), 54.1 (C-7). 122.3 (C-9). 142.6 (C-8),

175.9 (C=O).

MS m/z(rel intens): 207 (w+H]', 70), 140 (41), 139 (IOO), 138 (83). 110 (36), 79 (50).

KRMS calcd for Ci3His@ + H 207.1375, found 207.1385.

To a stirred solution of ester 137 (0.0860 g, 4.19 mmol) in anhydrous ether (6 mL) was

carefully added lithium aluminum hydride ( L m ) (25 mg, 6.71 mmol, 1.6 eq). The

reaction was left to reflux for 3 h under an argon atmosphere. The reaction was quenched

by the slow addition of a saturated aqueous solution of NH&l(1.0 ml) followed by water

(1.0 mL). The solution was extracted with CHCI3 (3 x 15 mL). The organic layers were

combined and washed with bine ( l x 3 mL), dned over MgS04 and then the solvent was

removed in vacuo. The residue was purifiai by FC (20% EtOAcihexanes) and 139 (0.0603

g. 80%) was obtained as a colourless oiI.

ï L C (30% EtOAcJhexanes): Rr= 0.42

IR (CHC13): 1222.2398,2877,2943,3024.3621 cm".

'H NMR (CDC~J): 6 1.16-1.23 (2H. m), 1.40-1.47 (2H, m), 1.59-1.69 (2H, m). 1.64 (3H. S.

C3-CB). 1.78-1.82 (2H, m), 2.05 (lH, s, H-2), 234 (1 H. m. H-5). 2.40 (1 H. m. H-7). 2.67

(IH, dt, J = 16.8.2.0 Hz H-S), 3.40-3.63 (2H, AB. I = 10.4 Hz, Avm= 68.4 H z CLOH).

5.28 (1 H, S. H-4).

I3c NMR (CDC13): 6 14.4 (C-3-CH3), 26.9 (C-9). 28.4 (C-8), 32.6 (C-IO), 45.2 (C-l), 45.9

(C-5), 46.1 (C-7). 46.2 (Cd), 54.2 (C-2), 64.9 (CH20H), 124.0 (C-4), 142.8 (C-3).

MS d z (rel intens): 177 ([M-H]', 22), 161 (52), 1 10 (LOO), 95 (24), 81 (54).

HRMS calcd for Ci2Hia0 - H 177.1270, found 177.1279.

n

To dry CH2C12 (5mL) at m m temperature was added in the following order.

aiphenylphosphine (0.1 13 g, 0.432 mmol, 3 @, imidazole (0.0343 g, 0.504 mmol, 3.5 eq),

and iodine (4) (0.1 10 g, 0.432 mmol, 3 eq). The solution was allowed to stir under argon

for 5 min then a solution of alcohol 139 (0.0260 g, 0.144 mmol) in dry CHzC12 (0.2 mL)

was added dropwise by Pasteur pipette. The reaction was wrapped in foi1 and Ieft to stir

ovex-night, under argon at RT (-18 h). A 0.1 M solution of sodium thiosulfate (NatSz03)

(5 mi.) was added and the mixture became a pale yellow colour. The solution was allowed

to stir for 5 min then the two iayers were separated. The aqueous layer was extracteci with

CH2C12 (3 x 15 mL). The organic layers were combined. washed with brine (1 x 2 mL) and

dried over MgS04. The solvent was removed in vacuo, the residue was purified by FC

(100% hexane) and 140 (0.0322 g, 77%) was obtained as a colourless oil.

TLC (1 00% hexane): Rr = 0.64.

IR (CHCL): 1424,1525,2948,30 17.3021 cm".

I H NMR (CDC13): 6 1.33-1.42 (2H. m), 1.50-1.57 (IH, m. H-9). 1.58 (3H. s, H-3-CHJ).

1.58-1.61 (IH, m, H-IO), 1.73-1.78 (lH, m, H-9), 1.95 (lH, d, J = 6.0 & H-8), 2.00 (1H.

S. H-2). 2.22-233 (IH, m, H-1), 2.35 (IH, 4 J = 7.2 Hz). 2.37-2.39 (1H. m. H-5), 2.49 (1H.

dt, J = 14.8,4.0 HZ, H-5), 3.1 1-3.18 (2H, AB. J = 53 HZ, AVAB= 10.4 HZ. CbQ, 5.20 (1H.

S, H-4).

78

13 C NMR (CDCl3): 6 13.6 (C-3<H3), 15.8 (CH$), 25.8 (C-9), 27.0 (C-8), 31.4 (C-IO),

43.1 (C-l), 44.2 (C-6), 45.7 (C-7), 49.6 (C-5), 56.5 (C-2), 122.4 (C-4), 141.6 ((2-3).

MS rnk (rd intens): 161 (Fr-IJ +, 30), 105 (1 2 1 ), 93 (1 Oû), 91 (62), 77 (33), 41 (29).

HRMS calcd for ClIH171 - 1 161.1324, found 161-1330.

3-Methyl~methyknebicycI01[53.0 1-3-decene (145) and 3-Methyl&methylenebiCycb[53.0]-2d~ene (146)

To a solution of iodide 140 (0.0445 g, 0.1 54 mrnol) in toluene (5 mL), were added

tributyltin hydride (Bu3SnH) (62.4 pL, 0332 mrnol. 1.5 eq) and azobisisobutyronitrile

(AiBN) (2.5 mg, 0.0154 mmol, 0.10 a. The solution was refluxed under argon for 1 h.

On cooling, diazabicycloundecane @BU) (70.0 pi., 0.464 mmol. 3.5 eq) was added, A 0.1

M solution of Iz in diethyl ether was added dropwise until an orange precipitate formed.

The solvent was removed in vacuo and the residue was purified by FC (100% hexanes) to

afford a 1 : 1 mixture of 145: 146 (0.0 150 g, 58%).

TLC (1 00% EtOAc~hexanes): RI = 0.66

iR (CHC13): 889, 1641,2853,2948 cm".

'H NMR Partial Spectnrm (CDC13): 1.62 (3H, S. CH3), 4.62 (2H. S. =CH2), 4.68 (2H, S.

=Cl&), 5.20 (1 H, S. =CH).

To a solution of alkene iodide 140 (0.0160 g, 0.0555 mmol) in toluene (3 mL) was

added TEMPO (0.0433 g, 0.278 mrnol, 5 eq)) in toluene (0.1 mi.). A solution of Bu3Sn.H

(14.9 pL, 0.0555 mmol, 1 eq) in toluene (0.5 mi.) was added slowly dropwise. The

reaction was brought to reflux. Another equivalent of Bu3SnH (14.9 pL) was added after

the first 0.5 h then again after 1 h. AAer 2 h of refluxing, the solvent was removed in vacuo

and the residue was purified by FC (10% EtOAc, hexanes) to give 149 (0.0102 g, 55%).

TLC (20% EtOAchexanes): Rf = 0.72.

iR (CHC13): 1360,1376,1467,2855.293 lcm".

I H NMR (CDC13): 6 1.06 (3H, s, NCCb), 1.09 (3H. s, NCCh), 1.17 (3H, s, NCCh),

1.20 (3K, S. NCCS), 1.45 (4H, m, NCC&), 1.57 (2H, m), 1.67 (3H. S. C-3-CH& 1.71-

1.91 (4H. m), 2-19-2.43 (4H. m), 2.81 (IH, m, H-5), 3.64-3.78 (2H, AB. J = 8.6 Hz AVAB=

40.4 Hz, CBOTMP), 5.29 (IH, s, H-4).

MS m/z (rd intens): 3 18 (w+H]*, 25), 161 (71), 140 (67), 126 (100).

HRMS cdcd for C2iH35N0 + H 3 18.2791, found 3 18.2797.

53 Experimental for Chapter 3

Methyl 9-methyl-&oxotricyclo[5.4.0.~und~ne-1-carboxylate (159t160)

H COzMe

and

'*''*CH,

To a dry 10-ml round-bottom flask containhg 5 mL of dry THF at O°C was added DIPA

( 162 pL, I -16 rnrnol. 1.5 eq). This mixture was stirred for 10 min then a 1.6 M solution of

butyllithium (n-BuLi) (0.725 mL, 1.16 mmol, 1.5 eq) was added. This solution was stirred

for 30 min at 0°C then cooled to -78°C. Dry DMPU (0.982 ml, 8.12 rnmol, 35 eq) was

added, followed by a solution of photoadduct 157 (0.171 g, 0.774 mrnol) in THF (0.2 mL).

This mixture was stirred at -78 OC for 30 min, then at -23°C for 30 min. The reaction was

cooled again to -78°C and methyl iodide (MeI) (240 FL. 3.85 mrnoI. 5 eq) was addeci.

(The Me1 was passed through a plug of basic alumina pior to addition to the reaction

mixture). This mixture was stirred at -78°C for 15 min then at 0°C for 2.5 h. The reaction

was quenched with 0.5 rnL of a saturated aqueous solution of NKCI and extracted with

ether (3 x 15 mL). The organic layers were combined and washed with H 2 0 (3 x 1 mL)

and brine (1 x 1 mL). The organic layer was dried over MgSO4 and the solvent was

removed in vacuo. The residue was purified by FC (20% EtOAchexanes) to give an

unseparable mixture and a 3:7 ratio of 159 and 160 (0.1 11 g, 61%) in a 3:7 ratio.

IR {CHCI$: 1200,1224 1436,1452,1694,1724,2257,2866,2953 cm-'.

81

H NMR (CDCl3): S 1 .O3 (3H, d, J = 7 2 HZ, C-9-Ch ,160), 1 .O8 (3H, d, J = 6.8 Hz, C-9-

C&, 159), 1.30-1.33 (lH, m, H-IO), 1.40-1.45 (IH, m, H-5), 1.47 (2H, S, H-3),1.64-1.71

(3H, m),1.84 (IH, m, H-11), 1.99 (IH, m, H-IO), 2.25 (lH, m, H-11), 2.36 (lH, m, H-9).

2.78 (lH, q, J = 6.8 Hz, H-6), 2.53 (lH, t, J = 7.2 HZ, H-2), 2.94 (IH, 4 J = 6.8 Hz, H-7),

3.65 (3H, s, OC&).

I3c NMR for 160 (CDCS): 6 15.1 (C-9-CH3), 24.5 (C-4), 27.7 (C-IO), 28.0 (C-3), 31.2 (C-

Il), 31.5 (C-5), 39.8 ( C 4 , 41.7 (C-9), 46.7 (C-2), 47.3 (C-7), 48.4 (C-l), 50.7 (WH3),

173.7 (C02Me), 213.5 (C=O).

Procedure for Epimerization of 1591160

1591160 (3:7) (0.1 1 lg, 0.473 mrnol) was dissolved in 5 mL of toluene in a IO-mL

round-bottom flask. Basic aiumina (&O3) (20 mg) was added and the reaction was stirred

at reflux temperature for 1 h under argon. The product and alurnina was filtered through a

dass wool plug in a Pasteur pipeîte and washed through with CHrClz (3 x 2 mL). The

solvent was removed in vacuo and a 6:4 ratio of l59:l60 (0.1 1 1 g, 10W) was obtained.

Methyl8-~~drox~-8,9dimeth~ltnc~clo[5.4.0.0~]undcrnne-l-cn~x~late (1611162)

A solution of epimerized 1591160 (0.0464 g, O. 195 mmol) in anhydrous ether(5 mi.)

was cooled to -60°C. A 1.4 M solution of MeLi (1 8 1 pi,. 0.254 rnmol. 1.3 ee) was added

dropwise by syringe over 15 min and the reaction was left to stir at -60°C for 30 min. The

reaction was warmed to 40°C over 1 h then quenched with the addition of a saturated

solution of W C 1 (0.5 mL) foilowed by water (0.5 mL). The mixture was extracted with

CHC13 (3 x 10 mL), then the organic layers were combined and washed with brine (1 x 1

mi,). The organic layer was dried over MgS04 and the solvent was removed in vacuo.

82

The residue was purified by FC (10% EtOAc5exanes) to give a 9:l ratio of 161:162

(0.038 1 mg, 77%) as colouriess oils.

TLC (25%EtOAc/hexanes): Rf = 0.1 7.

IR(CHC13): 171 7,2865,2955,3019,3687 cm".

'H NMR (CDC13): 6 0.88 (3H, d, J = 6.8 Hz, C-9-CH3), 0.93-1.10 (lH, m, H-lOa),

1.04 (3H. S. C-8-CH3), 1.36-1.41 (2H, m), 1.49-1.53 (3H, m), 1.62-1.67 (3H, m), 1.73-1.89

(2H. m),2.29 (lH, s, H-S), 2.33 (lH, m, H-11), 2.40 (1H. d, J= 8.4 Hz!-1-7), 2.71 (lH.q, J

= 7.2 Hz H-6), 3.61 (3H, s, OC&).

I3c NMR (CDC13): 6 14.9 (C-9-CH3). 22.5 (C-8-CH3), 26.7 (C-4). 27.9 (C-3). 29.8 (C-10).

32.0 (C-5), 34.6 (C-1 1). 36.8 (C-6), 39.0 (C-9), 48.1 (C-1), 48.7 (C-7). 48.9 (C-2). 51.4

(OCH3), 72.3 (C-8), 176.0 (CaMe).

162

TLC (25%EtOAc/hexanes): Rf = 0.2 1.

IR(CHC13): 17 1 7,2865,2955,3019, 3687cme1.

83

'H NMR (CDCl3): 8 0.84 (3H, d, J = 6.4 H& C-9-CH3), 1 .O7 (3H, S, C-8-CH3), 1.20 (2H,

m), 1.35-1.50 (6H, m), 1.63-1.66 (2H, m, H-43, 1.94 (IH, 4 J = 7.2 Hz, H-1 lp), 2.07 (1H'

m, H-1 la), 2.18 (lH, d, J = 6.8 Hz, H-7), 2.35 (IH, 4 J = 7.2 Hz, H-2), 2.86 (IH, q, J = 6.8

HZ, H-6), 3.61 (3H, S, WH3).

I3c NMR (CDC13): 6 15.1 (C-9-CH3), 26.1 (C-4), 26.8 (C-IO), 28.5 (C-8-CH3). 28.6 (C-

l l). 28.9 (C-3), 32.8 (C-5), 34.2 (C-g), 34.7 (C-6), 46.8 (C-l), 47.0 (C-2), 47.7 (C-7), 5 l .3

(OCH3), 70.8 ( C-8), 176.4 (CaMe).

To a stirred solution of hydroxy ester 161 (0.0789 g, 0.3 13 mmol) in anhydrous ether (5

mL) was added slowly LiAIH4 (0.0190 g, 0.500 mrnol, 1.6 eq). The mixnue was stirred at

reflux under an argon atmospherg for 2 h. Excess Li- was quenched with slow addition

of a saturated aqueous solution of W C 1 (2.0 d). The produci was extracted with CHCG

(3 x 15 mi+) and the combinai organic layers were washed with brine (1 x 2.0 mL) and

dried over MgSOd. The solvent was removed in vamo and purification by FC (30%

EtOAcihexanes) afforded di01 163 (0.0536 g, 76%) as a colourless oil.

TLC (25% EtOAcihexanes): Rf = 0.21.

IR (CHC13): 1372,1448,2871,2946,301 8,3626 cm-'.

'H NMR (CDC13): 6 0.98 (3H, d, J = 6.3 Hz, C4C&), 1.07 (3H, s, C-3-Cb), 1.25 (IH,

d, J=6.8 Hz, H-2), 1.35-1.51 (7H, m), 1.66-1.80(6H, m),2.18 (lH,t, J = 8.1 Hz, H-8),

2.89(1H,q,.J=6.8H~,H-1), 3.36-3.50 (2H,AB,J=10.9Hz, AvM= 33.2Hz,C&OH).

I3c NMR (CDC13): 6 14.4 (C-8-CH3), 25.3 (C-5), 25.6 (C-IO), 26.2 (C-6), 26.5 (C-9), 28.9

(C-3-CH3), 31.6 (C-1 l), 34.7 (C-l), 34.9 (C-4), 38.7 (C-7), 43.2 (C-2), 48.4 (C-8), 63.2

(CH20H), 70.0 (C-3).

MS m/L (rd intens): 224 @f, 2), 189 (lm), 139 (30), 121 (21), 95 (34), 43 (1 1). HRMS

calcd for C14H2402 224.1 787 found 224.1776.

To a solution of ketone 157 (0.41 7 g, 1.88 rnmol) in anhydrous ether (7 mL) at -78T

was added a 1.4 M solution of MeLi (1.74 mL, 2.44 mmol, 1.3 eq) dropwise, by syringe,

over 45 min. The reaction was iefl to stir at -78'C for 6 h and then was quenched by the

addition of a saturated aqueous solution of W C 1 (2 rnL) followed by water (2 mL). The

solution was extracted with CHCb (3 x 15 mL) and the organic layers were combied,

washed with brine (1 x 2 mL) and dried on MgSO4. The solvent was removed in vacuo and

the residue was purifieci by FC (30% EtOAdhexanes) to give hydroxy ester 165 (0.283 g,

63%) as a light yellow oiI.

TLC (25% EtOAcIhexanes): Rf = 0.26

IR (CHCL): 1720,2866,2952,3002,3601cm".

'H NMR (CDC13): 6 1 .l7 (3H, s, C-&CH3), 1.40-1.43 (IH, m, H-3). 1.46-1.60 (9H. m),

1.60-1.65 (1 H, m, H-4), 1.77 (lH, m, H-4), 2.21 (2H, m, H-11)' 2.3 1 (lH, m, H-2), 1.67

(1 H. q, J = 6.8 Hz, H-6), 3.62 (3H, s, WH3).

13c NMR (CDC13): 6 20.8 (C-IO), 26.5 (Cd), 28.1 (C-3), 29.5 (C-S), 32.1 (C-5), 33.1 (C-

i l), 36.6 (C-9), 36.8 (C-6), 46.8 (C-7), 47.4 (C-l), 48.5 (C-2), 51.4 (m3), 69.8 (C-8),

176.0 ( mzMe).

MS d z (rel intens): 238 (W. 7), 221 (IOO), 163 (33,161 (93), 93 (41), 67 (36), 43 (41)

HRMS calcd for CIJH103 + H 239.1644, found 239.1647.

A solution of alcohol 165 (0.277 g, 1.22 mmol) in anhydrous CH-Ch (8 mi.) was cooled

to 0°C and pyridine (1.84 mL. 24.4 m o l , 20 eq) was added. The solution was left to stir at

0°C for 5 min then POC13 (227 jL2.44 mmol. 2 eq ) was added dropwise by syringe over

0.5 h. The reaction was lefi to stir at RT. ovemight (-15 h). The reaction was quenched by

the slow addition water (2.0 mi.) and the solution was extractecl with ether (3 x 20 mL).

The organic layers combined and washed with a 5% solution of HCl(2 x 5 mL), water (1 x

5 mL) and brine (1 x 2 mL). The organic layer was dried over M@OJ and the solvent was

removed in vacuo. The residue was pudied by FC (5% EtOAcIhexanes) to af3ord alkene

ester 166 (0.191 g, 71 %) as a colourless oil.

TLC (20% EtOAc/hexanes): Rr = 0.61

IR (CHC13): I l69,1257,1449,I712,2853,2952 cm-'.

I H NMR (CDC13): 6 1.46-1.50 (lH, H-51, t .S2 (2H, m, H-3), 1.57 (3H, s, C-WH3), 1 S9-

1.74 (5H, m), 1.88 (lH, m, H-IO), 2.20 (lH, dt, J = 12.4,2.0 Hz, H-11). 2.43-2.51 (3H. m),

3.66 (3H, s, OC&), 3.45 (lH, d, J = 5.2 Hz, H-9).

[ 3 ~ NMR (CDCI3): 6 20.3 (C-8-CH]), 22.1 (C-IO), 26.2 (CM), 28.8 (C-3), 32.3 (C-11).

32.4 (C-5), 40.3 (C-S), 41.4 (Cd), 46.8 (C-l), 47.4 (C-7), 51.4 (OCH3), 121.2 (C-9), 135.6

(C-8), 175.8 (CaMe).

MS m/z (rel intens): 22 1 (W+HJ7. 53,220 dl), 189 (40). 151 (73). 93 (71). 91 (42).

HRMS calcd for CI~Hz0@ 220.1462, found 220.1463.

To a stirred solution of unsaniriited esta 166 (0.0771 g, 0.350 mmol) in anhydrous ether

(5 mi,) was added slowly L i u (0.0190 g, 0.500 mmol. 1.6 eq). Tfie mixture was stirred

at RT under an argon atmqhere for 3 h. Excess L M - & was quenched with slow addition

of an aqueous saturated solution of W C 1 (2.0 EL). The Wuct was extracteci with

CHCI3 (3 x 15 mi.) and the cornbined organic Iayers were washed with brine (1 x 2.0 mL)

87

and dried over MgS04. The solvent was removeci in vacuo and purification by FC (30%

EtOAchexanes) afforded alcohol 171 (0.0628 g, 93%) as a colourless oil.

TLC (25% EtOAchexanes): Rr = 0.43. -

iR (CHCh): 101 1,1447,2852,2945,3017,3625 cm-'.

'H NMR (CDC13): SI .40-1.60 (6H, m), 1.55 (3H, s, C-3-Ch), 1.75-1.85 ( 3 8 m), 1.92-

1.95 (3H, m), 2.23 (lH, t, J = 8.0 Hz, H a , 2.46 (IH, q, J = 6.8 Hz, H-l), 3.40-3.51 (2H,

AB,J=11.1 Hz,Avm=23.5Hz,C&0H), 5.44(1H,s,H-4).

'k NMR (CDCI,): S 20.4 (C3-CH3), 21.3 (C-5), 27.1 (C-IO), 27.4 (C-9). 30.O(C-6).

32.I(C-1 1), 39.2 (C-7), 42.5(C-l), 44.3 (C-8). 44.4 (C-2), 63.2 (cHZOH), 121.2 (C-4),

136.4 (C-3).

MS Nz (rel intens): 192 W. 19,124 (1 00), 95 (100). 93 (83). 8 1 (61). 49 (82).

HRMS calcd for C i3H200 192.1548, found 192.15 14.

A solution of hydroxy alkene 171 (0.0822 g, 0.428 rnmol) and ether (5 mL) was cooled

to O'C. A 1.0 M soiution of diethylzinc (Et&) (1.28 mL. 1.28 mmol, 3 eq) was then

added and the reaction was lefi to stir for 5 min. Methylene iodide (CH2G) (103 pL. 1.28

mrnol, 3 eq) was then added by syringe, slowly dropwise. The reaction was left to stir at

O'C for 30 min then at m m temperature for 4 h. The reaction was quenched by the

88

addition of an aqueous saturated solution of NhCI (2 mL) and the solution was extracteci

with ether (3 x 15 mL). The organic layers were c o m b i and washed with a 0.1 M

solution of Na2S203 (2 mL) followed by brine (2 mL). The organic layers were dried over

MgS04 and the solvent was removed in vacuo. The residue was purified by FC (10%

EtOAcJhexanes) to give 172 (0.0790 g, 90%) as a colourless oil.

TLC (20% EtOAcJhexanes): Rr = 0.33.

IR (CHC13): 1005,1447,2863,2942,2999,3626 cm".

1 H NMR (CDC13): 60.01-0.04 (lH, m H-3), 0.37 (lH, t, J = 4.0 Hz, H-3), 0.78 (IH, m, H-

4). 0.88 (3H. S, C-2-CH3), 1.22-1.31 (3H, m), 1.37 (lH, d, J = 8.0 HZ, H-l), 1.40-1.48 (2H,

m. H-I 1). 1.59 (IH, m, H-IO), 1.67-1.83 (4H, m), 2.09 (lH, m, H-5). 2.14 (lH, t, J = 8.0

Hz H-8), 2.34 (IH, m, H-12), 3.25-3.38 (2H, AB, J = 12.0 Hz, AvAB = 28.0 Hz. C W H ) .

I3c NMR (CDCl3): 6 1 1.5 (C-3), 17.3 (C-2), 18.9 (C-4), 19.1 (C-5), 22.9 (C-2-CH3), 26.8

(C-IO). 27.6 (C-6),28.0 (C-9), 32.3 (C-1 l), 37.8 (C-7), 41.0 (C-12), 41.8 (C-8). 42.7 (C-1),

67.6 (CH20H).

MS d z ( r d intens): 206 (Pvf, 6), l89(6 1 ), l38( 63), 1 O7(lOO ), 95 (62). 8 l(5 1 ).

HRMS calcd for C 14HuO 206.1682, found 206.167 1.

To dry CH2C12 (5 mL) at room tempture was added in the following order.

triphenylphosphine (0.302 g, 1 .l5 mmol, 3 eq), imidazole (0.0913 g, 1.34 mmol, 3.5 eq),

and iodine (0.292 g, 1.15 mmol, 3 eq). The solution was allowed to stir under argon for 5

min then a solution of alcohol 172 (0.0790 g, 0.383 mmol) in dry CH2C12 (0.2 mL) was

added dropwise by Pasteur pipette. The reaction was wrapped in foi1 and lefi to stir

ovemight, under argon. at RT (-18 h). A 0.1 M solution of sodium thiosulfate (5 mL) was

added and the mixture became a paie yellow colour. The solution was allowed to stir for 5

min then the two layers were separated. The aqueous layer was extracted with CH2C12 (3 x

15 mL). The organic layers were combined, washed with brine (1 x 2 mL) and dried over

MgSO4. The solvent was removed in vacuo, the residue was purified by FC (100%

hexane) and 167 (0.0755 g, 63%) was obtained as a colourkss oil.

TLC (1 00% hexanes): Rr = 0.53.

IR (CHC13): 1 176,145 1,2861,2943,3002 cm".

'H NMR (CDC13): 6 0.078 (IH, m, H-3), 0.45 (IH. t, J = 4.8 Hz H-3), 0.78-0.89 (1H. m,

H-4), 1.04 (3H, s, C-2-CH3), 1.24 (IH, m. Hd), f .35-1-44 (3H. m), 1.51-1.56 (IH, m. H-

l l), 1.57-1.59 (1H. d. J = 6.4 Hz, H-l), 1.77-1.82 (2H, m), 1.92 (2H. q. J = 6.0 Hz, H-9),

2.01 (lH, m. H-5). 2.12 (IH, t, J = 8.0 Hz H-S), 2.30 ( lH, q, J = 7.2 H z H-12), 3.04-3.10

(2H. AB, J = 9.6 Hz A V ~ B = 8.0 CH2[).

13 C NMR (CDC13): 612.1 (C-3). 18.6 (C-4), 19.4 (CHiI), 19.5 (C-S), 22.7(C-&CH3), 22.9

(C-2). 26.9 (C-IO), 27.3 (C-9), 31.9(C-1 l), 33.1 (Ca), 36.2 (C-7). 40.0 (C-12), 42.6 (C-8),

45.8 (C-1).

MS d z (rel intens): 189 (Fi-I]', lm), 107 (62), 93 (74), 81 (61), 79 (62), 52 (83).

HRMS calcd for C 14H2~1- I 189.1637, found 289.1643.

90

5.4 Experimental for Chapter 4

l-~~drox~eth~1-8-meth~1[~.4.0.0~. @)undecane (177)

A solution of hydroxy alkene 139 (0.0595 g, 0.334 mmol) and ether (5 mL) was cooied

to O'C. A 1.0 M solution of Etl& (1.00 mL, 1.00 mmol, 3 eq) was then added and the

reaction was iefi to stir for 5 min. Methylene iodide (CH212) (81.0 pi.. 1.00 mmol, 3 eq)

was then added by syringe, slowly dropwise. The reaction was lefi to stir at O'C for 30

min then at RT for 4 h. The reaction was quenched by the addition of an aqueaus saturated

soiution of W C 1 (2 mL) and the solution was extracted with ether (3 x 15 mL). The

organic layers were combined and washed with a 0.1 M solution of Na2S203 (2 mL)

followed by brine (2 mL). The o r p i c layers were dried over MgSOj and the solvent was

removed in vaczto. The residue was purifid by FC (t5% EtOAdhexanes) ta give 175

(0.0555 g, 87%) as a colourless oil.

ïLC (30% EtOAcIhexanes): Rr = 0.47.

IR (CHC13): 1448.287 1,2946.30 18,3626 cm".

'H NMR (CDCI3): 6 -0.08 (1H. t. I = 4.0 Hz H-9), 0.28 (1H. m. H-9). 1.08 (3H. s, C-8-

C h ) , 1 .O9 (IH. m. H-IO), 1.35-1.46 (4H, m), 1.56-1.60 (IH. m. H-J), 1.61 (IH. 4 J = 4.0

Hz. H-7). 1.72-1.77 (2H, m). 2.07 (IH, s, H-11),2.29 (lH, t, J = 8.0 Hz, H-2),2.32 (lH, rn,

H-11), 2.58 (lH, q, J=8.0Hz, Ha), 3.11-3.54 (SH, AB, J = 12.OHz, AvAB = 148.0 Ht.

CHIOH). -

I3c NMR (CDCl3): 6 16.9 ( C - & a ) , 17.6 (C-9), 26.2 (C-4),26.4 (C-IO), 28.2 (C-3),29.1

(C-8), 32.1 (C-5), 36.5 (Cd), 42.0 (C-11), 44.9 (C-2), 48.2 (C-1), 52.2 (C-7), 66.3

(CH20H).

MS ndz (rel intens): 192 (3), 175 (5 1 ), 124 (71), 95 (76), 93 (100), 81 (78).

HRMS calcd for C13H200 192.1518, found 192.15 14.

To dry CH2CI~ ( 5 mL) at RT was added in the following order, triphenylphosphe

(0.227 g, 0.867 mmol. 3 eq). imidazole (0.0688 g, 1.01 mmol. 3.5 eq). and il (0.220 g.

0.867 mmol, 3 eq). The solution was allowed to stir under argon for 5 min îhen a solution

of dcohol 177 (0,0555 g, 0.289 mmol) in dry CH2C12 (0.2 rnL) was added dlpwise by

Pasteur pipette. The reaction was wrapped in foi1 and left to stir overnigtit (-18 h). under

argon at RT. A 0.1 M solution of NazS103 (5 mi.) was added and the mixture became a

pale yellow colour. The solution was allowed to stir for 5 min and then the two layers were

separateci. The aqueous layer was extractecl with CH2Clz (3 x 15 mi,). The orgaaic layers

were combined. washed with b ~ e (1 x 2mL) and dned over MgSOs. The solvent was

rernoved in v m o and residue was purified by FC (100% hexane) to give 176 (0.0699 g,

80%) as a light yellow oil.

TLC (100% EtOAchexanes): Rr= 0.65

IR (CHC13): 1 178,1447,2864,2950,2995,3055 cm".

'H NMR(CDC13): 64.15 (IH, t, J=4.0 Hz, H-9), 0.35-0.38 (IH, q, J=4.0 HZ, H-9), 1.06

(3H. s, C-8-CH3), 1.08-1.10 (IH, m, H-IO), 1.37-1.43 (2H, m), 1.49-1.55 (2H. m), 1.72

(lH, d, H-7), 1.74 (lH, m, H-4), 1.89 (IH, q, J = 4.0 Hz, H-3), 2.00-2.08 (2H, m, H-Il),

2.21(1H,~J=8.0HzH-2),2.53(1H,q,J=8.0Hz,Hd),2.89-3.13(2H.AB,J=8.0Hz,

A v ~ = 80.0 HZ Cl-&[).

"C NMR (CDCl,): 6 17.3 (C-8-CH3), 18.1 (C-9). 18.7 (Chi), 25.7 (C-10). 26.1 (C-4).

27.4 (C-31, 30.7 (C-8), 3 1.6 (C-5), 35.4 (C-6), 46.2 (C-1 l), 46.88 (C-1). 46.85 (C-2), 55.0

K-7).

MS d z (rel intens): 175 ([M-11'. 100), 133 (43), 107 (99). 93 (91 ), 91 (62). 8 1 (67).

HRMS calcd for C 13Hd - 1 175.1494, found 175.1487.

A 0.1 M solution of Sudz (5.76mL, 0.576 mmol, 3 eq) was added dropwise. by syringe,

at RT to a solution of iodide 178 (0.0579 g, 0.192 rnmol) in anhydrous THF (2 mL) and dry

HMPA (0.805 mi., 3.41 mmol, 6 eq rel. to Sud2). Addition continued until a purple colour

persistai, then the reaction was lefi to stir at room temperature for 30 min. The excess

SmIr was quenched by the addition of an aqueous saturated solution of sodium bicarbonate

(NaHC03) (2 d). The solution was then extracted with peutane (3 x 15 mL) and the

organic layers were washed with H20 (1 x 2 mL) foiiowed by brine (1 x 1 mL). The

organic layers were combined and dried over MgS04, then the solvent was removed in

vumo. The remaining residue was purified by FC (100% hexanes) to afXord 179 (0.0226 g,

67 %) as a colouless oil.

TLC (100% hexanes): Rr = 0.62.

IR (CHC13): 890,1457,1635,2870,2930,2954 cm".

'H NMR (CDC13): 61.03 (3H, d, J = 4.7 Hz, Cd-CH3), 1.23-1.54 (2H, m), 1.62 (3H. S. C-

3-CH3), 1.72-1.94 (3H. m). 1.97 (2H, AB, J = 10.4 Hz, AvAB = 3.2 Hz, H-S), 2.34 (lH, m,

H-5), 2.59 (2H, m), 2.78 (lH, m, H-1), 4.67 (lH, s, =Ci&), 4.68 (1H. s.=C&). 5.12 (1H. 6

J = 4.0 HZ. H-2).

I3c NMR (CDC13): 617.2 (Cd-CH3), 19.6 (C-3-CH3), 24.1 (C-9), 29.1 (C-8), 33.5 (C-IO),

33.8 (C-4), 40.1 (C-l), 42.8 (C-5), 45.4 (C-7), 108.3 (=CH2), 127.1 (C-2): 137.9 (C-3).

149.5 (C-6).

MS m/7 (rel intens): 176 (M+, 19), 133 (43), 1 19 (40). 105 (45),49 (97), 4 1 (1 00).

HRMS calcd for CI3HZO 176.1557, found 176.1565.

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