THE USE of CAMPHOR in NATURAL PRODUCT SYNTHESIS by JOHN HOWARD HUTCHINSON B . S C , the U N I V E R S I T Y O F S T R a T H

THE USE OF CAMPHOR IN NATURAL PRODUCT SYNTHESIS

JOHN HOWARD HUTCHINSON

B.Sc, The University of Strathclyde, 1981

A THESIS SUBMITTED IN PARTIAL FULFILLMENT OF

THE REQUIREMENTS FOR THE DEGREE OF

DOCTOR OF PHILOSOPHY

THE FACULTY OF GRADUATE STUDIES

(Department of Chemistry)

We accept this thesis as conforming

to the required standard

THE UNIVERSITY OF BRITISH COLUMBIA

September 1985

© John Howard Hutchinson, 1985 In presenting this thesis in partial fulfilment of the requirements for an advanced degree at the University of British Columbia, I agree that the Library shall make it freely available for reference and study. I further agree that permission for extensive copying of this thesis for scholarly purposes may be granted by the head of my department or by his or her representatives. It is understood that copying or publication of this thesis for financial gain shall not be allowed without my written permission.

Department of (LA^^\SrTJ^~j

The University of British Columbia 1956 Main Mall Vancouver, Canada V6T 1Y3

Date 2a - S . ABSTRACT

(+)-9,10-Dibromocamphor 37, prepared in three steps from (+)-3-endo- bromocamphor 15a, was found to undergo facile ring cleavage to provide the cyclopentanoid ring systems 158, 159 and 161. The bromoacid 159 was readily lactonised to provide 160 in high yield.

The hydroxyacid 161 was converted into the hydrindenone 190 in three steps and a further six steps were required to complete the total enantiospecific synthesis of (-)-estrone ent41.

Studies directed toward the synthesis of vitamin (213) and metabolites have shown that diastereoselective alkylation of lactone 160 and ester 283 (derived from 161) can be accomplished in high yield and with almost complete stereoselectivity. As a result, diol 322, representing the structural sub-unit of ring D and side chain of vitamin D^, has been synthesised.

Ring cleavage of the bromoketone 350 (derived from 159) gave 352 which was transformed into the aldehyde 332 and the trienols 340a and 340b to complete a formal synthesis of 327a, one of the components of the California

Red Scale pheromone.

Methyl at ion of camphor J_0 yielded the 3-exo-methyI derivative 362b as the major product. The thermodynamica1ly most stable epimer was found to be

3-endo-methy1 camphor 362a. In contrast, 3-methylcamphor 362a.b undergoes preferential endo alkylation. The factors governing these results are discussed. (+)-3-endo-Bromocamphor 15a and (+)-3-endo-9-dibromocamphor 18a were found to rearrange to provide (-)-6-endo-bromocamphor 172 and (-)-6- endo-9-dibromocamphor 26. Deha1ogenation of 172 provided optically pure

(-)-camphor entlO while dehydrohalogenation gave (+)-5,6-dehydrocamphor 173.

i 1 18a X=Br Y=Br 159 X=Br Y=H 161 X=OH Y=H 283 X=OTBDMS Y=Me

•

362b exo Me TABLE OF CONTENTS

Page

Abstract i i

Table of Contents iv

List of Figures vii

List of Tables viii

Contents of Appendix 1 ix

Contents of Appendix 2 xi

List of Abbreviations and Terminology xii

Acknowledgements xv

General Introduction 1

Part 1: The Total Synthesis of Estrone 17

1.1.1 Introduction 18

1.1.2 Previous Syntheses of Estrone 19

1.1.3 Camphor and Steroidal Systems 41

Di scuss ion

1.2.1 Fragmentation Reactions of Camphor 44

1.2.2 Synthesis of the C/D Ring System of Estrone 55

1.2.3 The Transformation of (-)-Hydrindenone

190 into (-)-Estrone ent41 64

Part 2: An Approach to Steroids with Functionalised

Side-Chains: Vitamin D and Metabolites 81

2.1.1 Introduction 82

2.1.2 Vitamin 0 and Metabolites 83

2.1.3 Medical Aspects 86

2.1.4 Previous Syntheses of Vitamin D and Metabolites 88

i v (a) Partial Synthesis 89

(b) Total Synthesis 91

Discussion

2.2.1 Background Work and Basic Strategy 105

2.2.2 Construction of the Steroidal Side-Chain 109

2.2.3 Attempts to Construct Ring C and the

Formation of the C-14 Steroidal Chiral Centre 121

2.2.4 Conclusion 131

Part 3: A Formal Enantiospecific Synthesis of the

California Red Scale Pheromone 132

3.1.1 Introduction 133

3.1.2 Previous Syntheses of the Sex Pheromone

of the California Red Scale 134

3.2.1 Discussion 140

Part 4: Further Observations on the Reactions of

Camphor and Derivatives 152

4.1.1 Background 153

Di scussion

4.2.1 C-3 Methyl at ion of Camphor and Derivatives 162

4.2.2 Further Observations on the C-3

Reactivity of Camphor 174

4.2.3 Brominations and Rearrangements of

Camphor Derivatives 177

(i) The Attempted Preparation of

( + )-9,10-D i bromo-3-endo-methy1 camphor 177

(ii) Other Rearrangement Reactions of

v Camphor Derivatives: The Synthesis of

(-)-Camphor entlO and

(+)-5,6-Dehydrocamphor IT3 _ 182

Experimental ' 189

Bibliography 289

Appendix 1: *H NMR of Selected Compounds 301

Appendix 2: Stereoviews of Compounds Analysed

by X-Ray Crystallography 319

vi List of Figures

Page

Figure 1 400 MHz 'H NMR of the Cyano Hydroxyester j_55 46

Figure 2 Partial lH NMR (400 MHz) of Bromoester 158 49

Figure 3 400 MHz 'H NMR and NOE Difference Experiment

for Seco-Steroid 200a 72

l Figure 4a 400 MHz H NMR Spectra of (-)-Estrone and

(+)-Estrone 79

Figure 4b Low Resolution Mass Spectra of (-)-Estrone and

(+)-Estrone 80

Figure 5 The Structures of Vitamin D _ 84 2 5

Figure 6 Partial lH NMR Spectrum of Methyl lactone 279 106

Figure 7 Stereoviews of Methyl lactone 279 106

Figure 8 Alkylation of Ester 283 115

13 Figure 9 C NMR (100.6 MHz) Spectrum of the Alcohol 3J0 120

Figure 10 400 MHz lH NMR and NOE Difference Experiment

for Ether 319 124

Figure 11 *H NMR Spectra of the Aldehyde 332 147

Figure 12 Partial [H NMR Spectra (400 MHz) Showing the

C-3 Protons of the Diastereomeric Trienols

340a and 340b 148

Figure 13 *H NMR Spectrum and NOE Difference Experiment

of Ketones 377a and 377b 166

Figure 14 The Enolate of Ketone 379 172

Figure 15 The Enolate of Camphor 173

Figure 16 The Enolate of 3-Methylcamphor 174

vi i List of Tables

Page

Table 1: Ring Cleavage and Cyclisation of

Bromoketone 350 with NaOMe/HOMe 144

viii Contents of Appendix 1

Compound Spectrum Page

(+)-9,10-Dibromocamphor 37 'A 302

(+)-8,10-D i bromocamphor 38 •_B 302

(-)-Bromoacid 159 A 303

Bromoester 158 B 303

(-)-Hydroxyacid 161 A 304

(-)-Hydrindenone 190 B 304

(-)-Seco-Steroid 200a A 305

(+)-Seco-Steroid 200b B 305

{-)-Estrone-3-methy1 ether ent51 A 306

(+)-Estrone-3-methyl ether 51. B 306

(-)-Estrone ent41 A 307

(+)-Estrone 41 B 307

(-)-Lactone 160 A 308

(-)-Allyllactone 284 B 308

Ether 319 A 309

MTPA ester 289 B 309

(-)-Alcohol 305a A 310

Alcohol 305b B 310

Ester 309 A 311

(-)-Alcohol 310 B 311

(-)-Hydroxyalkene 313 A 312

Diol 322 B 312

(-)-Acyclic ester 352 A 313

(+)-Bicyclic ketone 353 B 313

(+)-Aldehyde 332 A 314 Aldehyde 332 (nmr supplied by

Dr. R.J. Anderson, Zoecon Corp., Palo Alto,

California) B 314

Trienols (+)- 340a and (-)- 340b A and B 315

(+)-3-endo-Methy1 camphor 362a A 316

(+)-3-exo-Methy1 camphor 362b B 316

(+)-9,10-Dibromo-3-endo-methylcamphor 150a A 317

Dibromoisofenchone 387 B 317

(-)-6-endo-Bromocamphor 172 A 318

( + )-Dehydrocamphor J_73 B 318

x Contents of Appendix 2

Appendix 2 contains stereoviews of the following compounds:

Compound Figure Page

(+)-9,10-Dibroniocamphor 37 A 320

(+)-9-Bromo-3-endo-methy1 camphor 376a B 320.

(-)-Bromoisofenchone 386 C 320

(-)-6-endo-9-D i bromocamphor 26 A 321

(-)-Dibromofenchone 394 B 321 para-Bromobenzoate 353b C 321

xi List of Abbreviations and Terminology

(a) Terminology

Since many of the compounds referred to in this thesis are optically active, in order to differentiate between enantiomers the term *ent' is used. 'Enf refers to the enantiomer of the compound given, eg. (+)-camphor

10 has the structure:

(+)-CAMPHOR 10

(-)-camphor is thus denoted as ent10.

(b) Abbreviations

The following abbreviations are used in this thesis:

Ac - Acetyl

A1BN - 2,2'-Azobisisobutyronitrile br - broad (ir and lH nmr)

Bu* - tertiary-Butyl

Bu - Butyl

C - concentration in g/100 mL of solvent

CD - circular Dichroism d - Doublet (*H nmr)

DIBAL - D1i sobuty1 a1 urn i num hydr i de

DMAP - 4-Dimethylaminopyridine

DMF - N,N-Dimethylformamide

DMS - Dimethyl sulphide

xii DMSO - Dimethylsulphoxide

E - Electrophile

Et - Ethyl glc - Gas-liquid Chromatography

HMPA - Hexamethylphosphoramide i r - 1nfrared

LDA - Lithium Diisopropylamide m - Multiplet ('H nmr) or Medium (ir)

Me - Methyl m/e - mass to charge ratio

MOM - Methoxymethyl mp - Melting point

Ms - Methanesulphony1

MTPA - a-Methoxy-a-(trifluoromethyl)phenylacetyl

NBS - N-Bromosuccinimide nmr - Nuclear Magnetic Resonance

NOE - Nuclear Overhauser Effect

PDC - Pyridinium Dichromate ph - Phenyl ppm - Parts per Million

_ py Pyr id i ne q - Quartet ('H nmr)

s - Singlet ('H nmr) or Strong (ir) t - Triplet (*H nmr)

TBAF - Tetrabutylammonium Fluoride

TBDMS - tert i ary-Buty1d i methy1s i1y1

THF - Tetrahydrofuran

xiii tic - Thin Layer Chromatography

TMS - Trimethyl silyl

triflate - Trif1uoromethanesu1phonate

UV - Ultra Violet

W - Weak (ir)

WM - Wagner Meerwein Rearrangement

[a] - Specific Rotation at 589 nm n

2,3 exo Me - 2,3-exo-Methyl shift

2,6 H - 2,6-Hydride shift

6 - Chemical shift in ppm from the tetramethy1 si lane signal

v - Wavenumbers (cm ')

xiv Acknow1edgement

I would like to thank the members of the nmr and the ms laboratories for their excellent technical assistance. Dr. Steve Rettig performed the X- ray crystallographic analyses, Mr. Peter Borda carried out the microanalyses and 1 am indebted to both of them.

I am very grateful to Mrs Anneke Rees, Chas Stone and Dr. Pat MacNeil for their valuable assistance in the preparation of this manuscript.

A special mention goes to Dr. Sue Piper for her expert help in the laboratory.

Finally, I would like to thank my research supervisor, Dr. Thomas

Money, for the unending help, support and enthusiasm which he has displayed over the past four years.

Thanks Tom - it's been a slice!

xv FOR MY PARENTS

xvi GENERAL INTRODUCTION

The Synthesis of Enantlomerteally Pure Natural Products

The isolation and structure elucidation of naturally occurring compounds has provided the organic chemist with a vast number of challenging structures to synthesise. Natural products generally occur enantiomerically pure and the synthesis of optically pure compounds whether for their biological properties, determination of configuration, or just for aesthetic reasons has become one of- the main thrusts of organic chemistry.

Before approximately 1950, the organic synthesis of natural products was a fairly haphazard affair with very little (or at least limited) control of regio and stereochemistry. Consequently this gave rise to tedious separation problems and low yields. An optical resolution was usually the only way to obtain a pure enantiomer. Building on this, syntheses began to appear which produced racemic products with a high degree of stereoselectivity. With separation problems kept to a minimum, commercial syntheses were now feasible, but still the natural enantiomer was often only available via a resolution step. Today, the state of the art of synthetic organic chemistry1 is such that virtually any target molecule can be constructed with excellent control of stereochemistry. Obtaining a single

2 enantiomer whether by resolution, asymmetric synthesis or the use of a chiral starting material3 is of prime importance.

The need for obtaining chiral molecules has been particularly evident in the pharmaceutical industry where a racemic drug may, at best, be a waste of 50% of the manufactured material or at worst it could give rise to devastasting side effects. The most widely cited example of a drug having to be withdrawn from the market because of the effect of the unwanted enantiomer is that of thalidomide 1. (R)-(+)-Thalidomide 1 is reported4 to

1 1_ have no teratogenic properties whatsoever when administered to rats and mice, even at high doses. Its enantiomer, (S)-(-)-thalidomide did produce deformities in the animals tested.

In order to obtain a pure enantiomer without resorting to a wasteful and often time consuming resolution step, the synthetic chemist must either devise an asymmetric synthesis or use an enantiomerica11y pure starting material. Consider the sequence shown in Scheme 1 below; starting with an

enantiomeric B (R)-AB + (S)-AB products

(R.R)-ABC + (S,S)-ABC enantiomeric and + + diastereomeric (R.S)-ABC + (S,R)-ABC products

SCHEME 1

achiral starting material, A, the first reaction which introduces an asymmetric centre will necessarily produce a racemate. Any further

2 reactions which result in chiral centres (AB >ABC) will afford diastereomers and enantiomers. The diastereomers can be separated but the enantiomers must be resolved. Thus it is obvious that for an asymmetric synthesis the first chiral centre created is the Important one for it is this step which will give rise to a racemic mixture. A method which will preferentially produce one enantiomer Is thus desirable (Scheme 2).

B* (R)-/r-,\ C +. (S)-~C enantiomeri«s c c7X chiral where (R)-C>(S)-C prochiral

SCHEME 2

This first step, the conversion of an achiral, but prochiral, starting material into an optically active product where the enantiomers (R)-C and

(S)-C are produced in unequal amounts requires a chiral reagent (B#) of some kind. Selecting one enantiomer over another Is possible due to the formation of diastereomeric transition states. The difference in free energy of activation (AAG*) between the diastereomeric transition states determines the relative amount of each enantiomer produced. For example, a difference In AG* of ~1.5 kcal/mol will give rise to a product ratio of

96:4. Hence one should strive to maximize AAG*.

The chiral reagent in this step may be required In a stoichiometric amount or, better still, catalytically.

Chirality may also be Introduced via the application of, for example, chiral solvents, enzymes and a physical force (circularly polarised light). Such methods will not be discussed here for the sake of brevity.

3 Examples of chlral auxiliaries used stiochiometrJcally are:

(i) Asymmetric Hydroboration

Brown has shown that (+)- and (-)-a-pinene will react with diborane to

produce optically active diisopinocampheylboranes which can be used in the

asymmetric synthesis of alcohols from alkenes. This reagent was used by

Partridge et §_[6 as the key step in their synthesis of (-)-loganin 2

(Scheme 3).

1 ' Me M

/\ M-R2BH H0 X V*

^ H202, NaOH \J R= ^^-^ 95% ee

O-p-D- glucose

(-)-LOGANIN, 2

SCHEME 3

In this case the chiral auxiliary is not recovered after the reaction.

(i i) Asymmetric Diels-Alder Reactions

An example of a chlral auxiliary which is recoverable after it has

fulfilled its purpose is the use of the (+)- or (-)-camphor derivative 3 in an asymmetric Diels-Alder reaction. Oppolzer and co-workers7 have shown

(Scheme 4) that the sultam 3 can be N-acylated and the resulting N-crotonoyl

sultarns (eg. 4) undergo Diels-Alder reactions in high yield with very high

4 O + 3

LAH

SCHEME 4

diastereomerIc Induction. Reduction with Uthfum aluminum hydride provides the chiral alcohol 5 and regenerates the chiral auxiliary.

The best chiral auxiliary Is one which can be used catalytically and if possible be recovered to be used again. Examples In this category are:

(i) Catalytic Hydrogenatlon

Rhodlum(I) complexes containing chiral bidentate phosphlnes, eg. (S,S)- 8 9 chiraphos and (S.S)-skewphos have been shown to be effective catalysts in the asymmetric hydrogenatlon of amino acid precursors. Using this

98% OP NHCOCH3

(R)-N-acylalanine, 6 methodology, (R)-N-acylalanine 6 was prepared in 98% optical yield. Unfortunately the catalyst Is not recovered In Its active state.

(11) Asymmetric AIdol Reactions

In 1971 two research groups'0,11 showed that the trIketone 7 could be eyeUsed using (S)-(-)-prolIne as a chiral catalyst. The chemical and optical yields for the formation of (+)-8 are very high (100% and 93%

5 respectively) and the catalyst can be easily recovered. This reaction and

its implications in steroid synthesis will be discussed more fully in Part

In all of the above cases, the chiral auxiliary invariably derives its chirality from nature but rarely is the chirality transfer tota1; some of the undesired enantiomer is usually formed. An alternative approach would be to start the synthesis with a chiral starting material and incorporate the chiral centre(s) directly into the target molecule.

For a chiral starting material to be of any widespread use it must be readily available at a reasonable cost. The compound must lend itself to chemical modifications which do not disturb the Innate chirality and it is an advantage if both enantiomers of the chiral starting material are available so that either enantiomer of the target molecule can be synthes i sed.

There are a large number of chlral starting materials3 available; some are synthetic but most are isolated from natural sources. The choice of a chlral starting material is left to the imagination of the chemist.

Initially, the target molecule and the starting material were from the same class of natural products with structural modifications being kept to a minimum. It is now often the case that the relationship between the intial and final product is not at al1 obvious at first glance. Of course it must

6 be said that a synthesis which utilises a chiral starting material and incorporates its chiralIty through a laborious series of steps may indeed be better carried out via a racemic synthesis and a resolution.

Although there are a wide variety of optically active starting materials available, additions to this "chiral pool" are always welcome.

Such additions include the introduction of new optically active compounds and modifications of existing ones.

Camphor as a Chiral Reagent

(+)-CAMPHOR, 10 (-)-BORNEOL, 11 (+)-GLUCOSE, 12

(+)-Camphor J_0 (shown), (-)-camphor and (±)-camphor all occur naturally. Both antipodes are readily available although (-)-camphor is 12 more conveniently obtained by the oxidation of (-)-borneol JJ_. Camphor is also prepared industrially from a-pinene13 but the product is racemic. With both enantiomers available, either enantiomer of the final product may be prepared, an advantage which most chiral starting materials do not share.

The history of camphor and Its chemistry is long and varied and it has been extensively reviewed by Money14 so only a brief outline of its reactivity and use In synthesis will be given.

7 (a) Camphor as a Chlral Auxiliary

Camphor derivatives have been successfully used to induce

diastereoselectivity In certain reactions and hence enantioselectivity when

the auxiliary is removed. The rigid nature of the molecule means it is

capable of presenting two very sterically different environments at a

reactive site.

The example of asymmetric Diels-Alder reactions has already been given

(p.4). A second example is the asymmetric alkylation of propionate

15 enolates. Helmchen has shown that the camphor derivative J_3 can be

deprotonated and alkylated to yield either diastereomer 14a or 14b depending on the geometry of the enolate. Alkylation occurs with a high level of

13 14b

diastereoface-differentlatlon of the enolate to give the ct-alkylpropionate,

14a or 14b, in *95% diastereoselectivity.

(b) Camphor as a Chiral Starting Material

On first examination camphor does not appear to be a very promising

starting point for any synthesis. Aside from the carbonyl and the adjacent methylene protons its reactivity seems to be very limited. This is quite a

contrast to carbohydrates such as D-(+)-glucose 12 where the abundance of

functional groups and chlral centres makes it a convenient starting material

1 for many syntheses ^. In fact the problem with D-(+)-glucose is often how

to successfully manipulate the chiral centres and functionality. Camphor on

8 the other hand sets the challenge of how to create functionality. Its chiral centres are fixed due to the nature of the b1cyclo[2.2.1] system and cannot be inverted without first fragmenting the carbon skeleton.

The versatility of camphor as a chiral starting material lies in its

"hidden' reactivity which allows it to be functionalIsed at remote sites.

The molecule can also be readily fragmented (C 1-2, C 2-3, and C 1-7 bonds) to yield cyclopentanold systems and finally, the carbon skeleton can be rearranged to provide, for example, the camphene skeleton. Examples of the various functionalised camphor derivatives, rearrangement products and fragmentation processes are shown In Schemes 5, 6 and 7.

A brief description of the methods used to functionalise camphor and the use of these derivatives in the enantiospecifIc synthesis of natural products is given below.

(1) C-9 Funct i ona1i sat i on

16 X= H, Y= SO H 10 X= H 17 X= Br,Y= SO^H 18a_ X= Br ,Y= Br 15a X= Br 19 X= H, Y= Br

ex -SANTALENE, 20

9 SCHEME 6 : Rearrangement Products From Camphor

10 (a) Cleavage of C-l - C-2 Bond

SCHEME 7 : Fragmentation Reactions of Camphor

11 Almost a century ago, in 1893, Kipping and Pope" described the preparation of sulphonic acid derivatives of camphor 10 and 3-bromocamphor

15. They found that treatment of camphor in fuming sulphuric acid or chlorosulphonic acid produced what was later proved to be camphor-9- sulphonic acid _16. Surprisingly, this compound was optically inactive due to the occurrence of racemisation. Fortunately the corresponding reaction with 3-bromocamphor J_5 proceeded with complete retention of optical activity

18,19 yielding 3-bromocamphor-9-su1 phonic acid 17. It was later found that with the presence of bromine in the reaction mixture 3,9-dibromocamphor |8 could be produced directly and in high yield. Selective debromination

i;7 (Zn/HBr) provides 9-bromocamphor 19 which was used by E. Corey et a}_ in their synthesis of a-santalene 20.

(i i) C-10 Funct1ona1i sat i on

12 Reychler in 1898 treated camphor with acetic anhydride and concentrated sulphuric acid and obtained a second camphor sulphonic acid derivative which unlike the previous case was optically active (!). This compound was shown to be camphor-10-sulphonic acid 2\_ (see equation 1).

Heating the corresponding sulphonyl bromide 22 at 130°C in xylene afforded

1O-bromocamphor 2321. (-)-Camphor-10-sulphonic acid was transformed into

(-)-khusimone 25 via (-)-a-campho1 enic acid 24^ (equation 2).

(iii) 6,9-Dibromocamphor 26

Nishikawa in 1952 found that treatment of 3-endo-9-dibromocamphor 18a

in cold fuming sulphuric acid produced 6-endo-9-dibromocamphor 26 with the opposite configuration. The same is true for 3,9-dichlorocamphor but 3- ch1orocamphor does not rearrange, giving 3-chlorocamphor-9-sulphonic acid

instead.

13 (1v) C-5 Substituted Camphor and Derivatives

33 (+)-Nojigiku alcohol

Ring opening of 3,5-cyc1ocamphor 27 with HBr (equation 3) gave 5-exo- bromocamphor 28 which has been converted into the corresponding 5-exo-

24 deuteriocamphor 29 . An alternative route to C-5 derivatives of camphor is through remote oxidation of bornylacetate 30 (equation 4). This can be done 2 either microbiologically or chemically ^ to provide predominantly 5-keto- bornylacetate 3_X with a small amount of the 6-keto isomer 32. Both of the and keto-acetates 3J_ I2 were used in the synthesis of (+)-nojigiku alcohol

33 by Darby et §126. In addition to the remote oxidations of camphor, our laboratory has devised simple practical routes to other functionalised camphors, thus extending the versatility of this compound as a chiral starting material.

14 (v) 8-Bromocamphor 34

— 35 X= H, Y= CH(CH3)2, "(+) -Sativene X= 36 CH(CH3)2, Y= H, (-)-Copacamphene

The first synthesis of a chiral 8-substituted camphor was reported by

Corey et al_27 in 1959. This multi-step route has now been circumvented by essentially a 2 step procedure28 from (+)-3-endo-bromocamphor 15a to yield

(+)-8-bromocamphor 34. This compound was subsequently converted into (-)-

29 sativene 35 and (-)-copacamphene 36 and several other natural products .

(vi) 9,10-Dibromocamphor 37_ and 8,10-Dibromocamphor 38

Recently it was found that prolonged treatment of (+)-3-endo-9- dibromocamphor 18a with bromine and chIorosulphonic acid (5 days) gave predominantly (+)-3-endo-9,10-tribromocamphor 39. Selective denomination

15 with zinc In glacial acetic acid provided (+)-9,10—dibromocamphor 37 as a colourless crystalline solid (equation 5).

Analogous treatment of (+)-3-endo-8-d1bromocamphor 40 yielded (after

30 debromination) (+)-8,10-dibromocamphor 38 (equation 6) .

The aim of this thesis is to illustrate the use and potential use of disubstituted camphor derivatives (8,10- and in particular 9,10- dibromocamphor) in the synthesis of natural products.

16 Part 1;

The Total Synthesis of (-)-Estrone

17 1.1.1 INTRODUCTION

(+)-Estrone 41_, the first steroidal hormone to be isolated and characterised in pure form31, was obtained in 1929 from the urine of pregnant women. It was shown to possess the tetracyclic steroidal ring system as shown which differs from the usual steroid skeleton In that there

(+)- estrone 41 (+)- estradiol 42.

is no side-chain functionality at C—17* and the angular methyl between rings

A and B is absent, ring A being aromatic. Several other related compounds have been Isolated. As a group the estrogens are responsible for the mature growth, development and maintenance of the female reproductive tract and the secondary sex organs. Initially it was thought that estrone 40 was the primary estrogen secreted by the ovary but it is now recognised that estradiol 42 is the main hormone.

The numbering system for steroids is as shown for cholesterol 43; each ring is designated either A, B, C or D and substltuents above the plane are designated '6', those below are 'a'.

18 The great interest in the estrogens initially because of their biological importance and later for their medical and industrial applications has prompted intensive research into these compounds.

Ironically, despite these compounds being amongst the least structurally complex steroids due to the presence of an aromatic ring and the lack of a side chain at C-17 they are difficult to obtain In large quantities. This is because the aromatic ring is not found in any plant sterol available in commercial quantities. The bulk of the world's supply of steroid precursors comes from just two species of plant: the Mexican yam which yields diosgenin

44 and the soyabean which gives stigmasterol 45. In both cases the side

HO" diosgenin 44 stigmasterol 45

chains must be removed by degradation and ring A aromatlsed which involves excision of the C-19 methyl group. The latter is not, as one would expect, •32 a very efficient process . As a consequence of this there has been a great drive to produce a viable synthetic route to these compounds and related systems possessing a wide variety of substituents.

1.1.2 Previous Syntheses of Estrone

To place our own approach to the synthesis of estrone in perspective It is necessary to consider briefly some of the successful research previously published in this area. Taub has published two reviews on the subject, the

19 J;5a first covers the literature prior to 1971 , and the second covers the time

33b period 1972 to 1982 . Syntheses prior to 1971, with several exceptions, will not be referred to here.

The synthesis of estrone poses the problem of how to construct the C

and D portion of the molecule; the 5 and 6 membered rings have the less

stable trans fusion with an angular methyl group (C-18) at the ring

junction. Rings B and C are trans fused which, for two 6 membered rings, Is the most thermodynamically stable arrangement and so this should not be too prob1emat i ca1.

A major development in the methods for constructing the estrone skeleton was the use of a pre-formed ring D containing the future C-18

34 methyl group. Smith and co-workers condensed enone 46 with 2-methyl-1,3- cyclopentadione 4J to produce the triketone 48 (Scheme 8). This was cyclised and dehydrated to give the unsaturated steroidal system 49 which

SCHEME 8

20 could be regloselectively hydrogenated to produce 50 with the trans fused

C/D ring junction. Lithium In ammonia reduction and subsequent oxidation afforded racemic estrone methyl ether 5_U

This route was modified slightly by a controlled cycllsation and chemoselective reduction of the non-conjugated ketone to provide the hydroxy-enone 52.

Catalytic reduction with hydrogen approaching from the side opposite to the angular methyl group and oxidation of the product gave the diketone 53.

The B ring was then completed via an acid premoted ring closure.

Hydrogenation gave (±)-estrone methyl ether. This second route, though longer, is superior in terms of the greater stereoselectivity (and hence overall yield) in the reactions involved.

At about the same time, Torgov and co-workers published their synthesis of (±)-estrone, the key step being the base premoted coupling of the bis-vinylcarbinol 54 with 47 to produce the seco-steroid 55 In

21 approximately 50% yield. Cyclisatton of 55 with para-toluene sulphontc acid in benzene gave the tetracyclic intermediate 49 which Smith had already converted to racemic estrone. The reaction of 54 and 47 was proven to be an acid catalysed process (not base catalysed as initially reported) by Kuo et al36. They found that stirring the two components at 120°C in acetic acid/xylene allowed the formation of 49 directly in 60% yield. Better yields are obtained if the bis-vlnylcarblnol 54 Is first converted Into the isothiuronium salt 56 and this then reacted with 2-methyl-1,3- cyclopentadione 47 to give 55 in 90% overall yield. ©

58 R= Ac

Seco-steroid 55_ is a meso compound and thus affords the possibility of being resolved so that both diastereomers can then be converted to estrone

41. Kuo treated seco-steroid 55 with lithium tri-tert-butoxy aluminum hydride and obtained a single compound, the ketol 57. This was resolved and the corresponding ketoacetate 58 converted into (+)-estrone in 5 more steps.

The 'unnatural' diastereomer from the resolution step was recycled back to

55. A similar approach was utilised by Terashlma and co-workers37 in 1978,

•3D although they did not improve on the method of Bucourt published a decade earlier. Bucourt found that when the diketone 55 was reacted with L- tartramie acid hydrazide the required diastereomer (60a) crystallised out of solution. Since the reaction was carried out under equilibrating conditions, a 75-80% yield of this compound could readily be obtained.

Cycl1 sation and hydrolysis provided (-)-estrapentaen-17-one 49 with the

22 correct configuration at C-13 for (+)-estrone 4}_.

Johnson-" used (S)-malic acid as a chiral starting material in his approach to (+)-19-hydroxyestrone, which was again based on the Torgov/Kuo

route. (S)-Malic acid was converted into the chiral ring D synthon40 60 and

reaction of this with the isothlouronium acetate 56 yielded the 8,14-seco-

steroids 61a and 61b (8:1). Separation and further elaboration eventually

resulted in the synthesis of (+)-18-hydroxyestrone. ©

61a 6-CO Me 61b a-CO^Me

Another early synthesis which is short enough to be commercially viable

Is that of Velluz41 (Scheme 9). Michael addition of 2-methyl-l,3-

cyc 1 opentad i one 47 with the enone-ester 62 results in the triketone 63 which

is cyclised under acidic conditions to provide the bicycllc system 64.

Fortunately this compound (64) can be resolved at this early stage in the

23 synthesis. Elaboration (including a hydrogenatlon step to fix the correct

stereochemistry about the C/D ring junction) in 3 steps gave a mixture of enol lactones 65a and 65b. The remaining carbon atoms were attached via a

Grignard reaction to produce 66 which was taken on to (+)-estradiol 42.

SCHEME 9

Both the syntheses of Smith and Velluz Involve construction of the C/D

portion of the molecule by an Intramolecular aIdol reaction from a prochiral

precursor. Intensive research has been conducted into this approach with

the hope of (1) improving the yields and (ii) introducing an asymmetric

cyclisation in the Intramolecular aldol reaction.

One of the first of these 'asymmetric C/D' approaches was published In

1973 by the workers at Hoffmann LaRoche42. They ammended the route of

Smith by incorporating a chlral centre (v\a a resolution) at the benzylIc

(C-6) position of the molecule in the hope that this would produce the

preferential formation of one diastereomer over the other. In the event,

24 68a 8 -Me 68b a -Me- compounds 68a and 68b were produced In an 8:1 ratio from 67. Separation was achieved by crystallisation of the corresponding para-bromobenzoate derivatives. This result was overshadowed by the discovery that optically active hydrindenones could be prepared in high chemical and optical yield using natural amino acids as chiral catalysts. This observation was made independently by two research groups. Hajos and Parrish10'43 found that cyclisations of the triketone 7 with a 3% molar equivalent of (S)-(-)- proline in dimethylformamide gave the bicyclic ketol, (+)- 8, in 100%

7 R= H 8 R= H 9 R= H

69 R= CH2CH2C6H4OMe-m 70 R= CH CH C,H OMe-m 2 2 6 4

isolated yield with an optical purity of 93%. Dehydration and purification gave the (+)-enone 9 in 84% yield (~95% optically pure). At the same time,

Eder et a]}1 found that a series of substituted triketones (eg. 69) could be cyclised again using natural amino acids. They also found that for the simple case, ie. compound 7, (S)-(-)-prolIne was the most effective catalyst. However, for 69 the best result was obtained by using (S)-(-)- phenylalanine; the hydr1ndendione 70 was obtained in 60% chemical and >90% optical yield.

25 A new problem arose, however, when it was discovered that enone 9 could

not be reduced to produce a trans fused C/D ring junction. This problem* was solved by introduction of a substituent at the C-4 position45 (Scheme

10); for example hydrogenation of keto acid 72, derived from enone J± by

carbonation with magnesium methyl carbonate46 gave compounds 73a and 73b in the ratio 95:5. In order to complete the synthesis of (+)-estrone methyl

ether 5147, keto acid 72 was transformed into the a-methylene ketone 74 via a dicarboxylative Mannich reaction48 (95% yield). 1,4-Addition of the meta- methoxybenzyImagnesium chloride in the presence of cuprous iodide afforded

in high yield the seco-steroid 75' Standard methodology provided the target

Stork44 has very recently (1983) devised a solution to this problem by using an iridium based hydrogenation catalyst.

26 molecule 5_1 in high optical purity. Other optically active 19-norsteroids were synthesised from the chiral a-methylene ketone 7448.

Eder et al_49, the other group investigating this area, devised a different solution to the problem of converting the hydrlndenone Jl_ into an estrogenic steroid (Scheme 11). Initial attempts at direct alkylation of 71 with ha 1 ides or tosylates of type 76 gave disappointing yields of 77 (about

15-30%) which is in keeping with previous experience in alkylations of this type34'49,50. An alternative way of introducing the future A and B rings

was found: reaction of the enone 7^ with meta-methoxyphenacylbromide 78 and sodium hydride furnished the diketone 79 in over 80% yield. Acid treatment converted it into the furanoid system 80 which was stereoselectively

27 hydrogenated to yield the alcohol 8^ with the trans fused C/D rings. This compound was then converted into (+)-estradiol 42.

Mander and Danishefsky both used similar asymmetric ring closures in their respective syntheses. Mander devised a highly convergent route to the prochiral triketone of Smith. "Reductive alkylation"53 of meta- methoxybenzoic acid with the bromide 82 followed by oxidative decarboxylation54 and deprotection provided the enone 46 which was reacted

46 48

(a la Smith) with 47 to yield the triketone 48 in about 80% overall yield.

The synthesis was completed via an asymmetric ring closure using (S)-(-)- phenylalanine as the chiral catalyst (cf. Eder).

Danishefsky's approach outlined In Scheme 12 Involved utilisation of a

2,6-lutidine derived precursor 83 and condensing ft with 47. An (S)-(-)-

86 85

SCHEME 12

28 phenylalanine promoted aldol of the trlketone 84 gave the tricyclic system

85 with an optical purity of 86%. Unfortunately catalytic reduction did not proceed in high yield (only 45%) to produce the trans ring junction. Ring A was unmasked by a Birch reduction of the pyridine moiety accompanied by cyclisat ion and deketalisat ion in the work-up affording the seco-steroid 86.

Intramolecular Di els-A1der Routes to Estrone

Early Diels-Alder routes to estrone involved eye 1oaddition to dienes of

86 : 14 ~~

SCHEME 13 type 87. Unfortunately any attempt to incorporate the C-18 methyl group in the dienophile (Scheme 13) resulted in the exclusive formation of the wrong stereoisomer (eg. 89). Valenta et a]_55 discovered that the regiochemistry of the Diels-Alder reaction could be dramatically reversed by the use of a

BFg catalyst. Thus compounds 90 and 89 were formed in a ratio of 86:14 with the major stereoisomer isolable in 69% yield. Brief treatment of the cis- fused adduct with sodium bicarbonate allowed the ring junction to be isomerised to the more stable trans geometry (91.). The remaining steps in the synthesis involve contraction of ring D to yield (±)-estrone.

29 An alternative approach by Jung and Halweg30 also involves a Diels-

Alder reaction to create the C/D portion of the molecule. In their case the reaction is intramolecular and they hoped that the correct relative stereochemistry would be set up in this step. This proved to be the case but the route was severely hampered by the great difficulty in generating the diene moiety. Eventually the diene system was produced j_n situ by dehydration of the allylic alcohol 92.

The tetracyclic products 93a and 93b were isolated in only 16% yield and found to be an epimerle mixture of trans to cis compounds in the ratio

2.5:1.

One of the most popular recent methods for the synthesis of estrone and some related compounds is by trapping ortho-quinodimethanes in an intramolecular Diels-Alder reaction. All the routes devised have the same basic strategy: an appropriately functionalised ring D portion is attached to a ring A moiety from which the ortho-qu1 nodimethane can be generated.

The product from the intramolecular [4+2] cycloaddition has the correct relative sterochemlstry and the correct absolute stereochemistry ff the ring

D precursor is optically active.

30 The first to employ this route was Kametani3' who initially made racemic D-homoestrone methyl ether 95 by thermolysis of the benzocyc1obutene

precursor 94. Subsequently the route was modified30 to produce (+)-estrone by synthesis of the ring D portion from the optically active hydrindanone 96 as shown in Scheme 14 below.

SCHEME 14

Formation of the keto thioketal 97 followed by treatment with alkali provided the eye 1opentano1d ring system 98 which was converted in 7 steps to

31 the Iodide 99. Alkylation of the anion generated from the nltrlle 100 with this Iodide followed by dlcyanatlon gave the required benzocyc1obutene

system 101. Thermolysis, deprotectlon, and oxidation gave (+)-estrone.

Similar methodology was applied In the synthesis of (+)-l1-ketoestrone

methyl ether59, (±)-14a-hydroxyestrone60a,b and (±)-18-hydroxyestrone61.

Grleco^2 also used the benzocyc1obutene approach In his synthesis of

(±)-estrone. The blcyc1o[2.2.1]heptane derivative 102 (Scheme 15) was

coupled with 2-(4-methoxybenzocyclobutenyl) ethyl Iodide _103 to give the

ester 104 as the sole product. Conversion of the ester to a methyl group

im> io5 SCHEME 15

and deketal1 sat Ion gave the ketoalkene 105. Baeyer-V1111ger oxidation and

rearrangement provided the hydroxy acid 106 with all the atoms In place for

estrone. The synthesis was completed In a further 8 steps. Since the

starting blcycllc compound 102 Is available In optically form (from a

resolution) this also constitutes a synthesis of (+)-estrone.

Cheleotroplc elimination of S02 from the benzo[c]thiophene dioxide 107a

also provides access to ortho-quInod1methanes. Both Oppolzer^3 and

Nlcolaou^4 used this process In their work although only Oppolzer carried

out the synthesis to Its conclusion, le. the synthesis of (+)-estradiol.

32 The problem of regioselectlvely deprotonating the thlophene dioxide was solved by using nltrile 107 (Scheme 16). The electron withdrawing nitrlle promotes deprotonation at the para-substituent allowing for efficient coupling (82% yield) with the optically active Iodide 108. This iodide was derived from 2-methyleyelopentenone 109 via the acid 110 which was resolved.

SCHEME 16

Thermolysis of the olefinic sulphone 111 generated the estrogen skeleton 112 in 80% yield and a further 3 steps provided (+)-estradiol.

65 66 Saegusa and Magnus both generated ortho-quinodimethane intermediates by making use of silicon chemistry. Saegusa used a fluoride ion promoted 1,4-elmi nation of a quaternary amine (equation 7) as their key step In the preparation of (±)-estrone. Similarly Magnus employed a 1,4- openlng of an epoxide (equation 8) en route to (±)-lla-hydroxyestrone methyl ether 113.

33 7

A photochemical route to (+)-estrone via ortho-quinodimethanes has been exploited by Quinkert and co-workers1,67. The ketone 114 photoenolises to produce the ortho-quinodimethanoid phototransient 115 which is then trapped in a [4+2] cycloaddition. Dehydration results in a mixture of 9,11- and

8,9-dehydroestrone methyl ethers (116 and 50).

In order to synthesise the enantiomerically pure compound, the ring D component was obtained optically pure by an asymmetric Induction step shown in Scheme 17.

34 SCHEME 17

The chlral diester 117 afforded the optically pure cyclopropane derivative 118 (67% isolated yield) which was then converted into the ring D synthon 120 (as shown above) by ring expansion to 119, hydrolysis and decarboxylation.

Yet another approach using ortho-quinodimethane methodology is that of 68

Funk and Vollhardt . Their method is based on a novel cobalt-mediated co• ol igomeri sat ion of bis(trimethylsilyl) acetylene 121 with a 1,5 hexadiyne

122 (Scheme 18). This provided a mixture of the benzocyc1obutene 123 and the tetracyclic product 124. 123 could be converted to 124 on heating for a total yield of 71%. Manipulation of the two trimethylsflyl groups gave in two further steps racemic estrone.

35 122 121

CpCo(CO)2

SCHEME 18

In a second synthesis, Vollhardt and Sternberg69 again used the cobalt mediated intramolecular cyclisation, this time with a diyne and an alkene.

Treatment of the enediyne 125 with CpCo(CO)„ followed by oxidative

demeta11at 1on (FeCl^) provided the steroidal nucleus. Acid catalysed deketalisation and double bond migration provided (±)-49, an intermediate tn

Smith's route to estrone.

36 Other Routes to Estrone

Danlewski70 In 1982 reported that the diazoketone 126 could be coupled with meta-methoxy styrene using copper tartrate as a chiral catalyst (Scheme

19). Reaction of the product with the anion of 2-methyl-l,3-cyclopentadione and isomerisation of the product to the more stable trans fused cyclopropane ring gave compound 127 in 30% overall yield and 46% e.e. Opening of the

cyclopropane ring with T1C14 and reduction of the crude product with zinc gave the known unsaturated diketone 70 with 22% e.e.

In an earlier synthesis by Daniewski' , the optically pure chlorodiazoketone 128 (obtained by resolution) was reacted with tris-(meta- methoxyphenethyl)borane to give the seco-steroid 129. A zinc dechlorination followed by an acid catalysed cycllsation gave (-)-49 which could be converted Into (+)-estrone 4}_ using the method of Smith et aJL The optical purity of 49 was found to be 100% indicating a remarkably high degree of asymmetric induction in the organoborane-dlazoketone condensation.

37 A hydroboration/carbonylation'^ reaction was employed by Bryson and

Reichel73 as the key step in their synthesis. The diene 130 was reacted with thexylborane and the cyclic borane Intermediate converted to the ketone

131 by a carbonyl insertion procedure. The product, isolated in 60% yield, had the C/D ring junction exclusively trans.

130 130a 131

As part of their general studies on polyolefin cyclisat ions, Johnson and his colleagues74 devised a route to (±)-estrone based on the Lewis acid

38 catalysed cycl i sat ion of diene 132. Thus treatment of 132 with SnCK a-t

TMSO

(+)-estrone 41

-100°C gave a 20:1 mixture of 133a and 133b from which the desired one,

133a, could be readily obtained by crystallisation. Epoxidation on the a-

face followed by a rearrangement using BF3 provided (±)-estrone.

In the first of his two synthetic routes, Ziegler75 employed a trimethylsilylcyanohydrin Cope rearrangement on triene 134 and a subsequent cyclisat ion of the diene-aldehyde to yield intermediate 135 previously reported by Valenta and co-workers (cf. p.29).

TMSO

The second synthesis/b contained a tandem Cope-Claisen reaction as its key step. Flash thermolysis of the triene 136 at 370°C provided a 60% yield of aldehydes 137a and 137b In the ratio 2:1.

39 OHC Me

MeO MeO 136 136b 137a 6-Me 137b a-Me

In a particularly short synthesis by Posner et al_77 the key step (shown below in Scheme 20) was a novel tandem Michael-Michael reaction terminating in an intramolecular Wittig reaction.

Michael

MeO MeO

Wittig

Me 0 MeO 138

SCHEME 20

The product (±)-9,1l-dehydro-8-epiestrone methyl ether was isolated in only 8% yield. Subsequent acid catalysed isomerisatlon of the double bond allowed the configuration at C-8 to be inverted and yielded (±)-9,ll- dehydroestrone methyl ether 116.

40 1.1.3 Camphor and Steroidal Systems

The use of camphor as a chiral starting material in steroid synthesis has also been investigated by the late Professor Stevens and his co- 78 workers . In their approach (Scheme 21) (-)-camphor was converted into the keto ester 139 in 5 steps. The corresponding oxime 140, on treatment with trifluoroacetic anhydride and trifluoroacetic acid, undergoes a Beckmann fragmentation (previously reported for the camphor oxime79) to yield the cyclopentene 141 as the sole product in 80% yield. When para- toluenesulphonyl chloride and pyridine are used, the product is a 3:2 mixture of endo (141) and exo (142) isomers. The exocyclic double bond can be readily isomerised under acid conditions to the endocyclic position.

Cyclisation using potassium tert-butoxide gave the C/D ring system 143 with an angular methyl group and a trans fused ring junction.

Attempts to annulate on the A and B rings were fraught with difficulties and eventually after much experimentation ring B was created.

41 Br I

entlO ent!9 ent!9b

Me02C\/^02Me

146 145

SCHEME 21

42 Conjugate addition to methyl vinyl ketone followed by selective ketalisation gave 144. The nitrile group was then removed from the B- cyanoketone using potassium dispersion on neutral alumina and the resulting product stirred in acetic acid to remove the protecting group and yield the diketone 145. An intramolecular a Idol reaction completed the steroidal

intermediate 146.

80 Using a very similar approach to Stevens', Narula and Sethi have recently transformed (-)-camphor into a steroidal C/D ring system using the

Beckmann fragmentation of 9-iodocamphor oxime 147 to produce the cyclopentene 148. Subsequent transformations as shown in Scheme 22 provided the hydrindenone 149 in a total of 15 steps.

I I

entl9b 147 148

CHO 148d 148c 148b

TMSO

148e 149

SCHEME 22

43 DISCUSSION

1.2.1 Fragmentation Reactions of Camphor Derivatives

In connection with an early synthetic route to steroid precursors from camphor 10, we required a tricyclic system eg. 151 which could presumably be cleaved open via its oxime to yield the hydrindene 152. This molecule would have the correct relative and absolute stereochemistry at C-13, C-17 and C-

20 (steroid numbering) for steroidal systems with functionalised side- chains. In addition the nitrile would allow various side-chains to be

introduced. We considered that a compound such as 151 could be prepared by converting 9,10-dibromo-3-endo-methy1 camphor 150 into the corresponding dinitrile followed by an appropriate cyclisat ion. Although 9,10-dibromo-3- endo-methylcamphor 150 was prepared (see Part 4), model studies on the des- methylcompound, 9,10-d1bromocamphor 37, showed that It could not be efficiently converted Into the dinitrile 154. Thus when the ethylene ketal of (+)-9,10-dibromocamphor 153 was treated with sodium cyanide in DMSO (or

HMPA, DMPU, DMF) the reaction was unexpectedly complicated by the formation

44 155 X= CN 156 X= Br of two products in approximately equal amounts. Isolation and

identification showed that one was indeed the desired ketal dinitrile 154 but the structure of the second compound was not Immediately obvious. The

ir spectrum of this product showed bands at 3500 (br), 2375 (w), 1730, 1660

-1 (w) and 900 (m) cm indicative that the molecule contained a hydroxy1, carbonyl (ester), nitrile and an exocyclic double bond! The mass spectrum showed that the molecule had a molecular weight of 237 and thus it did not contain a bromine atom. From the 400 MHz *H nmr spectrum (Figure 1) two triplets at 64.94 and 65.03 confirmed the presence of an exocyclic double bond. A broad singlet at 63.85 (two protons) which sharpened to a multiplet with and a multiplet at 64.24 indicated that the structure contained the

HOCHpQ^O-subunit. This evidence is consistent with the proposed cyclopentanoid structure 156. It was apparent that the ketal protecting group had been fragmented and this was accompanied by rupture of the C-l -

C-2 bond and expulsion of the bromine atom. The second bromine atom had simply been displaced by cyanide. A possible explanation for this remarkable transformation is shown in Scheme 23.

SCHEME 23

Presumably the oxygen of DMSO attacks the ketal which cleaves,

Initiating a Grob-type fragmentation. The intermediate sulphoxonium ion generated is hydrolysed in the work-up to provide the alcohol and at some stage of the process the other bromine atom is replaced by cyanide.

In order to check this hypothesis, the dibromoketal 153 was heated alone in dimethylsulphoxide under argon. Again fragmentation was observed and the product was shown to be the corresponding bromide 156. No reaction was observed when the dibromoketal 156 was heated In a non-polar solvent

like xylene. 9,10-Dibromocamphor remained unchanged when heated in DMSO

indicating that the reaction must Involve the intact ketal group and DMSO.

Assuming this to be correct, it was predicted that 9,10-dibromocamphor

37 should also be cleaved open with alkoxide (or hydroxide) since a similar

Intermediate, eg. 157, should be formed. This was indeed the case; 37 reacted with sodium methoxide In methanol to furnish the bromo methyl ester

158 in high yield (>95%). Similarly the bromoacid 159 could be obtained by treatment of 37 with potassium hydroxide in THF/water or more efficiently

(98% yield) in DMSO/water. It is possible to convert 9,10-d1bromocamphor 37

47 directly into the hydroxyacid 161 using potassium hydroxide, DMSO and water.

Heating the reaction at 60°C overnight causes the initially formed bromoacid to 1 actonise and this is immediately hydrolysed with the excess base. That

159 160 161

• 0

02H 162 this reaction proceeds via the lactone 160 was proved by running the experiment with insufficient base and monitoring the reaction by tic. Spots corresponding to starting material and the lactone 160 (an authentic sample

48 was prepared separately) were visible from an unacldlffed aliquot.

Acidification also showed the presence of the bromoacld 159 and hydroxyacid

161.

Confirmation that the double bond in the cleavage product 159 was In the thermodynamically less stable exocyclic position was demonstrated when ozonolysis of 159 gave the corresponding bromo keto acid 162 (vmax 1740 and

1705 cm"1).

An interesting feature in the 'rl nmr spectra of these cleavage products

(eg. 158, Figure 2) is the appearance of the vinyl protons as two distinct triplets (actually two sets of doublets of doublets). The gemina1 coupling constant is zero; each proton couples only with the two allylic protons with

J * 2-2.5 Hz.

J= 2.0Hz J= 2.5Hz

protons HAand Hfi

£o2Me

158

64.98 64.84

FIGURE 2 : Partial H NMR (400MHz) of Bromoester 158 The ring cleavage reactions of 9,10-dibromocamphor 37 described above are typical of blocked B-bromoketones (ie. a,a-disubstituted B- bromoketones); for example, Tarbell and Loveless81 treated 10-bromofenchone

163 with potassium hydroxide in ethanol and obtained y-fencholenlc acid j6>4

(26%) and the corresponding ethyl ester JhS5 (47%).

49 164 R= H 163 C02R 165 R= Et

fl?0 A recent report ^ indicates that dipolar aprotic solvents, such as hexamethylphosphoramide (HMPA), can cleave blocked B-bromoesters (eg. 166)

^Br HMPA \ .Ph jr^ ~7^C02Me 95% 166 167

to provide unsaturated products (eg. 167) in high yield.

The early literature describes the fragmentation of 10-bromocamphor

84 23 and 3,10-dibromocamphor 168 to give ct-campholenic acid ent24 or the corresponding bromo methyl ester 169 in which both compounds have an endocyclic double bond (equations 9 and 11 respectively). At the time this work was carried out (pre 1924) the correct structures of 23 and 168 were not known; in fact, based on these results, it was thought that the bromine was not at C-10 but at C-6 and the reaction proceeded as in equation 10

(Lipp and Lausberg In 1924 proposed the correct structure for 3,10- dibromocamphor). The fact that a C-10 substituted camphor gives rise to a product with an endocyclic double bond is inconsistent with our results.

For this reason 1O-bromocamphor £3 (equation 12) was heated at 60°C with hydroxide, DMSO and water. After 1 hour the reaction was complete and the product, isolated in 77% yield, was shown to be the exocyclic double bond

50 23 C02H ent24

10 Br entl72

Br 7% Br 11 Br 168 C02Me 169

Br 12

23 C02H !7 0

isomer 170 of ent24 We also prepared (-)-6-endo-bromocamphor 172

Since the term 'B-campholenic acid' has already been ascribed to compound 171 (obtained by acid treatment of a-campho1 enic acid ent24) we propose the name isocampholenic acid for 170.

r CO2H CO2H

170 171 51 (see Part 4) and subjected it to the same reaction conditions (equation 13).

This does indeed give a-carnpho1 enic acid 24 as well as (+)-dehydrocamphor

173. Similarly, (-)-6-endo-9-d1bromocamphor 26 (equation 14) yields the hydroxyacid J74 as well as 9-bromodehydrocamphor J7_5. The hydroxyacid J74

is presumably formed by 1 actonisation of the cleaved bromoacid 176 (to give

177) followed by hydrolysis.

Since isomerisation of the exocyclic double bond to the endo position does not seem to occur under basic conditions, it is difficult to explain the results of Burgess and Forster .

The ease and efficiency with which 9,10-dibromocamphor 37 can be converted into the bromo ester 158. bromoacid 159 and hydroxy acid 161

52 prompted us to examine the same reaction with 8,10-dibromocamphorJU 38

(Scheme 24). When 38 was stirred in methanol with ~2 equivalents of sodium methoxide it was smoothly transformed into the bromoester 178 in greater than 90% yield. Surprisingly, however, when the cleavage reaction was repeated using hydroxide in DMSO/water the reaction took a different course.

The major product (78%) was the bicyclo[3,2,0] system 179 with smaller amounts of the cis fused lactone 180 also isolated (formed via the bromoacid

181 which readily lactonises and hydrolyses to the hydroxy acid 182; this then relactonises on work-up). The proximity of the bromomethylene and the enolate in 38 is such that intramolecular cyclisation occurs very rapidly

53 and 10-bromo-3,8-cyclocamphor 183 is then cleaved open generating the bicyclo[3.2.0] heptane derivative 179. If ring cleavage occurs first, the

reaction takes the *normal' route to give the bromoacid 181. This compound

readily cyclises to the lactone 180.

The postulated intermediacy of 10-bromo-3,8-cyclocamphor 183 was

supported by subsequent studies which showed that treatment of 8- bromocamphor 34 with KOH/DMSO/water for 10 minutes afforded 3,8-

cyclocamphor 184 in 83% yield (98% pure by capillary glc). Corey and co-

27 workers also prepared this compound in 1959 by treating a mixture of 8- and 9-bromocamphor with potassium tert-butoxide in refluxing tert-butanol and distilling out the volatile 3,8-cyclocamphor 184.

The very fac i1e c1eavage of 10-bromocamphor der i vat Ives i s a new

fragmentation reaction which proceeds in high yield to provide a five membered ring with an exocyclic double bond. All other fragmentation

reactions of camphor which involve breaking of the C-l/C-2 bond give the

endocyclic double bond or a mixture of both exo and endo products. The

exclusive formation of an exocyclic double bond coupled with functionality at either C-8 or C-9 provides a new group of chiral synthons (Scheme 25).

54 37 159 R= H 161 160

SCHEME 25

1.2.2 Synthesis of the C/D Ring System of Estrone

Examination of the product formed by ring cleavage of 9,10- dibromocamphor (fe. the bromo ester 158, bromo acid 159, or hydroxyacid 161) clearly indicates that these compounds contain all the required structural elements for the ring D subunit of 17-keto steroids such as estrone.

(-)-estrone ent41

55 For example, the bromoester 158 obtained from (+)-9,10—dfbromocamphor

37 possesses an exocyclfc double bond which can be regarded as the progenitor of the 17-keto group. The bromomethylene group and the ester side chain are trans to each other and provide an opportunity to construct the trans C/D ring system. The absolute stereochemistry of this molecule is opposite to that found in natural steroids, ie. starting from (+)-camphor 10 one would produce (-)-estrone ent41 and vice versa. (+)-3-endo-Bromocamphor

15a is commercially available whereas (-)-3-endo-bromocamphor must be prepared from (-)-borneol JJ. in two steps. For this reason, (+)-3-endo- bromocamphor was taken as the starting point in our investigation of the proposed synthesis of estrone.

Our initial synthetic strategy (Scheme 26) was to prepare the hydrindenone .186 and then modify the route to Incorporate the future A and B rings of (-)-estrone. It was envisaged that the bromoester 158 could be converted to the bromo methyl ketone 185 and this in turn would cyclise, by

158b

SCHEME 26

56 Intramolecular alkylation, to yield 186. The bromoester 158 would also be an appropriate place to Introduce the A and 8 portion of the molecule by alkylation of the ester (it was assumed that the hindered nature of the neopentyl bromine atom would prevent it from interfering in any alkylation reaction).

(+)-3-endo-Bromocamphor 15a was converted to (+)-9,10-dibromocamphor 37 by modifications of the published procedures18,19,31'. It was found that the best way to prepare (+)-3-endo-9-dibromocamphor was to stir 15a in chlorosulphonic acid and bromine for 1 hour at room temperature. Work up gave a white crystalline solid (~95% recovery by weight) which was approximately 85% pure by glc. This material could be converted, without purification, to (+)-3-endo-9,10 tribromocamphor 39 and the crude product from that reaction immediately debrominated using zinc, acetic acid and ether at 0°C for 30 minutes. (+)-9,10-Dibromocamphor 37 was readily obtained as a white crystalline solid by trituration with petroleum ether or methanol. The overall yield of these three steps is usually ~25-30%.

Cleavage of 37 with sodium methoxide in methanol gave the bromo ester

158. Attempts to convert the ester directly to the methyl ketone 185 by the procedure of Demuth met with limited success. Demuth describes the conversion of methyl and ethyl esters into the corresponding methyl ketone by reaction with trimethyl silylmethyllithium in pentane (equation 15).

LiCH2TMS 0 LiO o 2R' ^TMS » R^ ^TMS 15 RC0 > p-^s S >

R'= Me or Et

Secondary and tertiary esters reacted in high yields but primary esters gave only about 40% of the methyl ketone. Repeated attempts to convert bromo

57 ester 158 to the methyl ketone 185 using this methodology failed to give reasonable yields and therefore this approach was abandoned.

At about this time, a report appeared In the literature concerning the conversion of carboxylic acids to methyl ketones in high yields by sequential treatment with methyl 1ithium and trimethyl silyl chloride

(Me^SiCl)87, Tne use or" trimethyl silyl chloride reduces the amount of tertiary alcohol formation which usually accompanies the reaction of carboxylic acids and alkyllithium reagents (equation 16). Addition of

159 185 trimethylsilyl chloride to the reaction mixture removes the excess methyl 1ithium and the methyl ketone can be isolated after an aqueous work• up.

Applying this method to the bromo acid 159 gave the corresponding bromo methyl ketone 185 in 70% yield after purification.

Intramolecular cyclisation was attempted by regiospecific deprotonation88 of the methyl ketone 185 by slow addition to a cold (-78°C)

solution of lithium diisopropylamide and HMPA and then warming the solution to ~60°C. Unfortunately the main product was the hydroxy methyl ketone 187 which was presumably formed by hydrolysis of the initially formed cyclic

enol ether (Scheme 27).

58 188

SCHEME 27

In order to promote intramolecular C-aIkylation, the reaction mixture required heating to approximately 60°C and the best result obtained was an equimolar mixture of 186 to 187. In some experiments, two other by-products were formed but they could not be separated from each other. The major component was identified as the bicyclo[2.1.0] hexene 183 based on its mass spectrum (obtained by gc-ms), ir and nmr. The 80 MHz JH nmr of the mixture showed singlets at 63.4 and 63.3, 1 proton each, assigned to the exocycllc double bond as well as a singlet at 62.1 (3H) corresponding to the methyl ketone and a singlet at 61.1 (3H) for the tertiary methyl group. The mass spectrum gave the molecular weight as 164 and no bromine isotope peaks were present. In the ir spectrum, bands at 1705 and 870 cm-1 were assigned to the ketone and exocyclic double bond respectively.

Metallation at allylic sites using n-butyl1ithium and N,N,N',N'-

59 tetramethylethylenediamine (TMEDA) is a well known procedure0'. Presumably a similar process is occurring in this case with HMPA complexing the lithium cation. The allylic anion generated can then cylise to produce the bicyclic system 188.

Examination of molecular models indicates that the difficulty in obtaining C-aIkylation in this reaction may be explained by strain involved

in obtaining the proper trajectory required for a 6-(enol endo)-exo-tet90 cyclisat ion. Should this be the case, the 6-exo-tet cyclisat ion (0- alkylation) becomes a viable alternative91,92. Nevertheless, a small amount of the volatile trans-hydrindanone derivative 186 was isolated and characterised. Rather than try to find ways of improving the yield of this

intramolecular C-alkylation product (eg. via the use of imine derivatives of

185) it appeared that it might be better to examine the possibility of using the hydroxy methyl ketone 187 as a synthetic precursor of suitably functionalised hydrindenones. Thus we envisaged that oxidation of 187 to the aldehyde 189 followed by an intramolecular aIdol reaction would give the hydrindenone 190 which could be alkylated regiospeclfically at the C-4 position.

In order to obtain a better yield of the hydroxymethyl ketone 187 the bromoketone 185 was deprotonated under thermodynamic conditions (potassium tert-butoxide In tert-butanol) to yield the more stable enolate. It was

60 hoped that this would be forced to undergo 0-aIkylation but unfortunately after work up, the hydroxy methyl ketone 187 was isolated in only ~30% yield.

It is conceivable that the enolate undergoes a fragmentation reaction in preference to 0-aIkylation. The structure of enol ether 191 was supported by its *H nmr spectrum (80 MHz) which showed three vinyl protons and a broad singlet at 61.7 for the allylic methyl protons. In addition, acid hydrolysis of enol ether 191 gave hydroxy methyl ketone 187.

After this setback, it was decided to prepare the hydroxy methyl ketone from the hydroxy acid 161 using the method described above (p.58).

Treatment of 161 with excess methyl 1ithium in tetrahydrofuran followed by trimethylsilyl chloride and work-up provided 187. The yield of this reaction (45-50%) was considerably lower than that for the conversion of bromo acid 181 to methyl ketone 185 (cf. p.58) and this is presumably due to the increased anionic character of the intermediate, making attack by methyl 1ithium much more unfavourable.

Oxidation of JJ$7 with pyridinium dichromate93 (PDC) gave the keto aldehyde J89 in 81% yield (Scheme 28). It was found that a better overall yield of Jj6J_ to ]89 could be obtained by oxidising the crude hydroxy

61 methyl ketone 187 and purifying at the aldehyde stage. In this way the yield over two steps was raised from ~35% to almost 50%.

The intramolecular aIdol reaction of 189 using potassium hydroxide in methanol and water provided the hydrindenone 190 in about 50-60% yield.

This reaction was complicated by the formation of two by-products, namely the keto ethers 192a and 192b. Although the aldol reaction is essentially instantaneous, the dehydration step is rather slow(as monitored by tic) and

SCHEME 28 as the hydrindenone 190 Is produced it undergoes a 1,4-Michael addition with

methoxide. Compounds 190, 192a and 192b all have similar Rf values so separation of the unwanted components is rather tedious. The keto ethers

192a and 192b were each isolated pure in a ratio of 2:1 and Identified on the basis of their 80 MHz *H nmr. The major one, 192a, has peaks at 63.38

(3H, 0CH3) and a doublet of doublets at 63.45 (IH, >CHOMe) with coupling constants of 11 Hz and 6 Hz. This is consistent with the proton being in an axial position; the axial-axial protons give rise to the 11 Hz coupling while the axial-equatorial protons give the 6 Hz value. Similarly, compound

192b has a singlet at 63.35 corresponding to the methoxy group and a triplet

62 at 63.68 (J = 3 Hz). The latter corresponds to a proton In an equatorial position coupling with two adjacent protons. The coupling constant for the. equatorial-equatorial and equatorial-axial protons are the same.

To avoid the formation of the by-products, it was decided to carry out the aIdol reaction in three steps. The crude aIdol product 190b

(KOH/MeOH/H 0°C. 5 min) was isolated as a crystalline solid whose proton 2o, nmr indicated that the hydroxy1 group Is predominantly in an equatorial position ie. the >CH0H proton at 63.98 appears as a doublet of doublets with

J = 10 Hz and J = 6 Hz. In practice however, the crude hydroxy ketol ga ae 190b was immediately treated with methanesulphony1 chloride and DMAP. Work• up provided the crude mesylate which was dissolved in dich1oromethane and reacted with DBU to afford hydrindenone 190 as a white crystalline solid in

84% yield.

190 189 187

(i)Br2/ClS03H,lhr (ii) BiyclSO^, 5 days (iii) Zn/HOAc/Et20

(iv)KOH/MeOH/H20,60'c,24hr (v)MeLi/TMSCl (vi)PDC/CH2C12 (vii)KOH/MeOH/H 0; MsCl/DMAP; DBU/CH Cl_

SCHEME 29

63 In summary, at this stage in our investigations the synthesis of the

C/D portion of (-)-estrone had been accomplished In seven steps (Scheme 29)

94 starting from (+)-3-endo-bromocamphor.

The synthesis of such trans angularly methylated hydrinane derivatives as intermediates in steroid synthesis has attracted a great deal of interest

95 in recent years and, for example, the very similar hydrindane derivatives

95c 95e 193a and 193b have been recently prepared.

1.2.3 The Transformation of (-)-Hydrindenone 190 Into (-)-Estrone ent41

In order to complete the synthesis of the tetracyclic estrone framework,, the remaining eight carbon atoms (equivalent to ring A and part of ring B) must be introduced at the C-4 position of the bicyclic dienone

< 0

190 ent41

190 or perhaps even earlier in the synthesis. The most direct method would

64 be to alkylate 190 at C-4 with 2-(meta-methoxyphenyl)ethyl iodide 76. Although other workers have attempted a Ikylations using this halide, the

34,50,51,96 results were not very promising. Despite this, we were encouraged to try this approach because of the recent report by Mikhail and

97 Demuth that the tricyclic ketone 194 could be alkylated with 76 in greater than 84X yield.

Alkylation of dienone 190 using their methodology failed to give the required product. Similar attempts to introduce this structural sub-unit earlier in the sequence eg. by alkylation of the bromo ester 158 or 9,10- dibromocamphor 37 also proved very unsatisfactory (Scheme 30).

SCHEME 30

65 Presumably this is due to the tendency of this halide to undergo elimination rather than substitution.

Other methods have been developed to attach the structural elements of rings A and B to hydridane derivatives. Velluz4* used a non-aromatic precursor (p.23) whereas Eder50 and France96 used meta-methoxyphenacy1 bromide. Cohen and colleagues48 converted their hydrindenone derivative 7J_ to the a-methylene ketone 74 (equation 17) and introduced the remaining atoms

by a copper(I) catalysed 1,4-addition of meta-methoxybenzyImagnesium chloride.

To attempt such an approach with our dienone 190 would require the

generation of the cross conjugated trienone 196 (equation 18) followed by

regioselective conjugate addition of the Grignard reagent to the exocyclic

enone. An analogy for this reaction is the reglospecifIc conjugate addition 98 of cyanide to the cross conjugated enone 197 .

66 The trienone 196 was prepared in two steps via the vinylogous amide 195

(Scheme 31) which was obtained by heating hydrindenone 190 with Bredereck's reagent99,100, tert-butoxybis(dimethy1amino)methane, according to the method of Trost'01. The product, 195, was obtained as a dark brown oil in near quantitative yield and was used without purification. From its *H nmr spectrum (270 MHz) the vinylogous amide 195 appeared to be essentially one geometric isomer which was assumed to have the E-configuration by analogy'01,102 to similar systems. DIBAL reduction103 of 195 gave the trienone 196 in 77% yield over two steps. This rather interesting molecule shows a carbonyl absorption at 1675 cm-1 and alkene absorptions at 1660 and

1630 cm"1.

All attempts to accomplish regiospecific conjugate addition of meta- methoxybenzylmagneisum chloride to trienone 196 failed to give reasonable

It should be noted that the preparation of the meta- methoxybenzylmagnesium chloride reagent was initially plagued by

formation of the dimer. Using the method of Helquist et al. , namely a 2-3 fold excess of freshly crushed magnesium turnings and rapid addition of the halide in ether, solved the problem. The use of tetrahydrofuran as solvent appeared to promote Wurtz coupling.

67 t + (i)CH(NMe9)OBu ,A (ii)DIBAL/H_0 (iii)Mg/m-Me0C^H„CHoCl Z i> O 4 Z

(iv)Li/NH3 (v)03/DMS (vi)HCl/HOAc (vii)Pd/C/H2 (viii)BBr3

SCHEME 31

68 yields of the required seco-steroid (Scheme 31). Ireland and co-workers added this Grignard reagent to 198 and obtained high yields of the 1,4-

adduct without the addition of copper salts. When this reaction was tried with intermediate 196 the alcohol 199 was the sole product isolated

11 (identified on the basis of its ir, nmr and ms). The use of Cu salts

(copper(II) acetate monohydrate) to promote conjugate addition of this

69 1 Grignard reagent (equation 19) was reported by Blschofberger and Bull .

Using this method, however, resulted in the conversion of trienone 196 to

199 and a mixture of 1,4-addition products (~30% yield). The method of

48 1 Cohen and co-workers using Cu (copper(I)Iodide) faired little better, and the major product (42% yield) was the alcohol 199.

The failure of this particular reaction led us to consider trying a conjugate addition of the Grignard reagent to the vinylogous amide 195

(equation 20). This type of reaction was first reported in 1931 by

107 Benary who found that Grignard reagents added in a conjugate fashion to vinylogous amides to provide a,B-unsaturated ketones after work up with

aqueous acid. Subsequently this reaction was exploited utilising I ino alkyllithium reagents Q2 . Ziegler and co-workers' ° also reported a similar addition of a Grignard reagent to a vinylogous carbamate.

Addition of meta-methoxybenzylmagnesium chloride in ether to a solution

of the vinylogous amide 195 followed by an acidic work up gave the seco-

steroids 200a and 200b in 73% yield after chromatography.

70 200a 200b

The minor isomer (7%) was identified as the cis enone 200a while the major one (66%) was shown to be the trans enone 200b. The assignments were I no based on the results of NOE difference experiments . Irradiation of the proton on the exocyclic enone system, H^, for compound 200a (Figure 3) produced a positive enhancement for the protons at C-6, C-14 and C-15

(steroid numbering) which is consistent with this proton being trans to the carbonyl group. Similar irradiation of Hg in 200b. showed no enhancement of protons on the D ring; only the C-6 (benzylic) protons gave a positive s i gna1.

The mechanism of the reaction of a Grignard (or an alkyl1ithium) with a vinylogous amide deserves some comment, in particular with respect to the 102 formation of trans enones as the major product. Abdul la and Fuhr found that treatment of trans-viny1ogous amides gave exclusively trans-enones when treated with alkyllithium reagents such as n-butyl1ithium (equation 21).

201

71 5 4 3 2 1

NOE Difference Experiment

72 Presumably the Intermediate formed after the initial attack of the alkyllithium is one such as 201a (Scheme 32) where the lithium cation chelates with the oxygen anion and the nitrogen lone pair of electrons. On

SCHEME 32 work-up the enolate becomes protonated at the oxygen and this Is followed by proton transfer to the nitrogen atom which then becomes a good leaving group. In order for the elimination of the protonated amine to occur, an antl-perlplanar transition state must be achieved where the C-N bond and the developing p-orbltals are co-planar. Two such transition states are possible, one in which the R group and the oxygen are In close proximity

(structure 202a) and the other where the bulky R group and the oxygen are furthest away from each other (structure 202b). The former obviously has a severe sterlc Interaction between the R group and the oxygen; thus the preferred transition state Is 202b and elimination In this case gives rise to the trans enone. This can be extrapolated to our system (see Scheme 33), where the Grignard reagent presumably attacks the vinylogous amide 195 predominantly from the least hindered top face of the molecule away from the

73 SCHEME 33

angular methyl group. The Intermediate formed can again be chelated this time by the magnesium cation. Protonation and proton transfer in the same

74 manner as before gives rise to two possible transition states from which the protonated amine can be eliminated. In transition state 203a there is a

steric interaction between the oxygen atom and the aromatic portion of the molecule. Bond rotation to transition state 203b removes this strain but

introduces a steric interaction between the bulky aromatic side chain and the protons at C-15 on ring D. Since ring D is twisted away slightly due to the trans fused nature of the C/D junction this interaction is reduced

somewhat and this is the preferred transition state from which the

elimination takes place. The trans enone 200b is therefore the major

product. That both transition states (203a and 203b) have some degree of

strain associated with them is reflected in the fact that the trans enone

200b is not formed exclusively; about 10% of the product is due to the cis

enone 200a.

With all the carbon atoms now in place, the next problem was how to achieve chemose1ect1ve reduction of the conjugated double bonds without

reducing the exocyclic double bond at C-17. This was accomplished using

lithium, liquid ammonia and ether (cf. Scheme 31). Thus, dissolving metal

reduction of 200b gave a mixture of starting material, the monoreduced

compound 204 and the desired compound 205. Column chromatography provided

pure 205 (~40% yield) and a mixture of 200b and 204 which were inseparable.

This mixture was subjected to the same reduction conditions and after

chromatography a further 17% yield (57% total) of 205 was obtained. The

proton nmr spectrum (400 MHz) of 205 showed only one compound and so,

presumably, the aromatic side-chain is in the equatorial position.

In a separate experiment no starting material remained after the

initial reduction and the monoreduced product 204a was obtained pure. No

11,12 sign of the isomeric enone 204b was found which indicates that the a

75 200b 204a 204b double bond is reduced first. Possibly the A7,8 enone is twisted slightly due to the steric interaction between C-6 and C-15, thus reducing the degree of conjugation with the carbonyl group. The reduced conjugation would make the reduction of this system more difficult.*

Ozonolysis of 205 in methanol followed by a dimethyl sulphide work-up gave the known diketone ent5334 in 76% yield. It was found that prolonged exposure of 205 to ozone gave dramatica11y reduced yields so the reaction was terminated at the first sign of a blue colour. Also, a large excess of dimethyl sulphide was required to reduce the intermediate hydroperoxide 206 formed in the reaction. On one occasion this hydroperoxide 206 was isolated as a white crystalline solid, mp 110—112°C, and then converted to the diketone ent53 with dimethyl sulphide in dichloromethane. The diketone ent53 exhibited spectral data consistent with the structure given; for

205 206 ent53

Reduction of the cis enone 200a was not a clean process since the tic of the crude reaction product showed at least four compounds.

76 1 example, the fr spectrum showed bands at 1740 and 1710 cm" due to carbonyls

in the 5 and 6 membered rings respectively. This compound represents a formal synthesis of (-)-estrone since Smith and co-workers have already converted racemic 53 into (±)-estrone. However, the remaining steps were carried out, with modifications, to obtain the final product, (-)-estrone.

96 France and colleagues found that cyclodehydration of the tricyclic diketone 207 was most efficiently accomplished by using concentrated

0 . 0

207 207a hydrochloric acid and acetic acid at room temperature for 24 hours. The more commonly used reagents for effecting this type of cyclodehydration (eg. po1yphosphoric acid, hydrofluoric acid, hydrochloric acid in ethanol and para-to1uenesu1phonic acid in benzene) gave lower yields. This method, when applied to the diketone ent53, gave a 68% yield of the tetracyclic products entl16 and ent50 (Scheme 31) in the ratio 3.7:1. However, by carrying out the reaction at 0°C for 2 hours the yield was raised to 85% and the ratio of entl16 to ent50. determined by capillary glc, was increased to 97:3.

Recrystal1isat ion of this product from methanol provided (-)-9,ll- dehydroestrone methyl ether 116b as a white crystalline solid, mp 143-

67 42 145.5°C (Lit. mp 143-144°C and 142.5-144°C ) and [Q] - 284° (C 0.208, d 67 CHC1 ) (Lit. [ -288.2° (C 0.5, dioxane) and; for the enantiomer: [Q]D 3 C]Q 67 42 +288.7° (C 0.479, dioxane) and [Q] +290.9° (C 0.5, CHCl,) ). d The other compound formed from the cyclodehydration step was identified as (-)-8,9-dehydroestrone methyl ether ent50b based on the characteristic position of the C-18 methyl group in the 400 MHz spectrum of a 3.7:1 mixture

77 of entl 16 and ent50. Rufer et aj_llu reported that the C-18 methyl group of

50 occurs as a singlet at 30.89 In the *H nmr, whereas the corresponding methyl group of 116 occurs at 60.9377. From the 400 MHz *H nmr spectrum of the above mixture, the C-18 methyls were found at 60.90 and 60.94 respectively (ratio 1:3.7).

Reduction of a mixture of entl16 to ent50 in the ratio of 93:7 was carried out according to the procedure of Smith and co-workers34 (Pd on charcoal catalyst) (Scheme 31). The product was found to contain two compounds, (-)-estrone methyl ether ent51 and an unknown isomer in the ratio

65:35. When the reduction was carried out on a 64:36 ratio of ent116 to ent50 the product was found to have approximately the same composition as before. Using PtOg as the catalyst also gave rise to the two isomers in roughly the same ratio. No further attempts were made to reduce the amount of the unwanted isomer produced. Nevertheless, (-)-estrone methyl ether ent51 was obtained as a white crystalline solid by recrystal1isation from

methanol, mp 167.5-170°C and [a]n -149.2° (C 0.126, dioxane). Authentic

(+)-estrone methyl ether 51a (prepared from (+)-estrone) had mp 170-173°C

0 and [a]n +154 (C 1.02, dioxane). The synthetic (-)-estrone methyl ether and the compound derived by methylation of (+)-estrone were identical in all respects (ir, nmr, ms, tic and glc).

Finally, demethylation of (-)-estrone methyl ether was accomplished by the method of Vikery, Pahler and Eisenbraun111. This involves the use of boron tribromide as the demethylating agent and the (-)-estrone obtained in this way112 was found to have the same tic, *H nmr (400 MHz) (Figure 4a), ir and ms (Figure 4b) characteristics as those of authentic (+)-estrone.

» —

rT "Ttif if

iff _

»f _)

11'i1; i i . rr -+4 -HT'TH-I I I'I'I'I'I'I I'I'I'I'I I I'I'I I'l'l I I•1• 1 •

l>f Kf IU Low Resolution Mass Spectrum of (-)-Estrone ent41

JJ_ 4W, i i "••..'•l.I'I'I'I'I'I'I'l.l I I I'I'I I'I i'i'i' -r-F- IM Low Resolution Mass Spectrum of (+)-Estrone 41

FIGURE 4b : Low Resolution Mass Spectra of (»)-Estrone and (+)-Estrone

80 Part 2 An Approach to Steroids with Functionalised

Side-Chains: Vitamin D and Metabolites

81 2.1.1 INTRODUCTION

Representative examples of steroids possessing functionalised side- chains are the plant growth hormone brassinolide 208, the insect moulting hormone ecdysone 209, the anti-tumour agent withaferin-A 210 and the calcium homeostatic hormone la,25-dihydroxycholecalciferol 211. The biological activity of steroids with functionalised side-chains has prompted

211 considerable research into their synthesis and, in particular, these efforts have focussed on the problem of creating the correct stereochemistry at C-17 and C-20 of the side-chain. The synthesis of steroidal systems falls into two categories (i) total synthesis and (ii) partial synthesis from readily available sterols. The latter has been by far the more popular approach since this avoids the need to construct the basic steroidal skeleton with the correct relative and absolute configuration. The introduction of side-

82 chains onto a steroid nucleus11-3'11 has been reviewed by Redpath and

I 1 K

Zeelan . Total synthesis of steroidal systems with functionalised side chains obviously presents a much more complex task. The majority of recent investigations in this area have concentrated on the construction of the C/D ring system of steroids which can serve as key intermediates in the synthesis of a particular steroid. Such an approach requires the formation of a trans-fused C/D ring junction (ie. the centres at C-13 and C-14) in addition to controlling the stereochemistry at C-17 and C-20.

2.1.2 Vitamin D and Metabolites116"120

Of all the steroidal systems known, vitamin D and its metabolites have probably attracted more current attention and research than any other due to their biological importance. It has been known for over 50 years that there is a connection between *vitamin D' and the disease rickets, but it is only recently that the true reason for the relationship has become apparent. It is now known that cholecalciferol 212 (or vitamin Dg or calciol) is involved with the regulation of calcium and phosphate ion concentration in the blood plasma and that the physiologically active compound is a metabolite of cholecalciferol, namely la,25-dihydroxycholecalciferol 211 (or

1a,25-dihydroxyvitamin D3 or calcitriol). The term 'vitamin D' is actually incorrect; vitamin D is in fact a hormone, not a vitamin, since with adequate exposure to sunlight no dietary supplements are needed. The

for the nomenclature of vitamin D and metabolites see reference 120.

83 subscripts for vitamin D are related to the order in which the compounds were initially discovered (vitamin Dj found to be a mixture of compounds was so that term has now been dropped) and the difference between them lies solely in the side-chain functionality (Figure 5). The natural 'vitamin

D' for man is vitamin D although vitamin D , ergocalciferol, obtained in 3 2 the diet, is almost as equally active.

FIGURE 5 : The Structures of Vitamin D

The production of la,25-dihydroxycholecalciferol 211 (Scheme 34) begins with the formation of the provitamin 7-dehydrocholesterol 216 from cholesterol 43. This provitamin 216 can then be converted into the previtamin precalciferol 217 by the action of sunlight on the skin and this electrocyclic reaction is followed by a thermal 1,7-sigmatropic shift of a hydrogen to give cho1eca1c1fero1 213 (vitamin hydroxylation occurs D3). A in the liver to introduce the C-25 hydroxyl group and this compound, 25- hydroxycholecalciferol 218, is then transported to the kidney where a second

hydroxylation occurs, this time at C-l, to provide the biologically active

compound la,25-dihydroxycholecalc1ferol 211.

84 SCHEME 34

85 The calcium homeostatic system is mainly controlled by the action of three hormones, viz.

(a) la,25-Dihydroxycholecalciferol - a steroid

(b) Parathyroid hormone (PTH) - a linear peptide containing 84 amino acids which is secreted by the parathyroid gland.

Both la,25-dihydroxycholecalciferol 211 and parathyroid hormone are

involved in maintaining the normal concentration of calcium ions in the blood. A decrease in the concentration of serum calcium ion stimulates the production of parathyroid hormone which then proceeds to two sites. The first site is the kidney where it triggers the production of 211 and the

second site is the bone where, in conjunction with 1Q,25- dihydroxycholecalciferol 211, it mobilises calcium ions from bone to blood.

la,25-Dihydroxycholecalciferol 211 is also transported in the blood to the

intestine where it helps to stimulate the intestinal absorption of calcium

ions. The third hormone, calcitonin, lowers the calcium ion concentration

by inhibiting their transfer from bone to blood.

Apart from la,25-dihydroxycholecalciferol 211, there are a number of other vitamin metabolites which have been isolated recently (Scheme 35)

but their exact biological roles are not well understood. It is thought

that when the calcium ion concentration reaches normal supersaturation

levels, the la,25-dihydroxycholeca1ciferol hormone is regulated by

conversion to la,24,25-tr1hydroxycholeca1ciferol 219. This trihydroxylated

compound is much less potent in Its ability to stimulate intestinal calcium

ion transportation. Another vitamin D metabolite Is 24,25-

86 SCHEME 35 dlhydroxycholecalcfferol 220 which Is claimed to be equally as potent as 211 but different In Its mode of action. Investigation into the biological function of these compounds continues to be an area of great Interest but it is inhibited by the small quantities of material available.

It is clear that patients with liver or kidney disorders which prevent the hydroxylation processes of cholecalclferol 213 will suffer imbalances in their blood serum calcium Ion concentration. For example. In patients with chronic renal osteodystropy the kidney fails to produce enough or any of the enzyme responsible for hydroxylation of 25-hydroxycholecalciferol 218 at

the C-l position. Conventional treatment with cholecalclferol, vitamin D3,

Is clinically ineffective but administration of la,25- dihydroxycholecalciferol 211 is successful in correcting the biochemical and bone abnormalities found. Other disease states have also been found to be

treatable by administration of vitamin D3 metabolites. Unfortunately it is difficult to obtain these compounds by isolation from blood serum since the quantities present are very small (eg. between 5 and 80 ng/mL for 25- hydroxycholecalciferol 218) and because of this the laboratory synthesis of these compounds becomes mandatory. There is also a growing interest in the

synthesis of more potent analogues of vitamin D3 metabolites for clinical use.

2.1.4 Previous Syntheses of Vitamin D and Metabolites

As stated previously, the synthesis of cholecalciferols can be divided into two groups, ie. partial synthesis and total synthesis. Both of these

-120 approaches have been extensively reviewed116 t the most recent overview of the subject being that of Pardo and Santelli120 in 1985, and therefore only a brief outline of the approaches used by other workers will be given.

88 (a) Partial Synthesis1**

The transformation of readily available naturally occurring sterols into vitamin D and derivatives has attracted a great amount of synthetic effort. The most commonly used sterols are cholesterol 43_, stigmasterol 45, pregnenolone 221, androstenolone 222 (available from diosgenin 44) and ergosterol 223.

Stigmasterol 45_ Pregnenolone 221

Androstenolone 222 Ergosterol 223

Two major problems associated with the partial synthesis approach are:

(a) the introduction of the required side-chain with the correct stereochemistry and (b) a procedure for cleavage of the C-9 and C-10 bond.

With stigmasterol 45 and ergosterol 223, the original side-chains must be removed by selective ozonolysis (for ergosterol this Involves protection of the diene moiety) and then a new side-chain may be grafted on. Pregnenolone

221 has C-17 fixed but a new side-chain must be introduced with

89 stereochemical control at C-20. This problem is enhanced with androstenolone 222 where both chiral centres at C-17 and C-20 must be created. Cholesterol 43 poses the problem of how to functionalise the unactivated side-chain without adversely affecting the rest of the molecule.

Fortunately it was found that irradiation of cholesterol 43 with excess peracetic acid in a quartz tube at 300 nm gives a reasonable yield (38%) of diol 224 produced by hydroxylation at the C-5 and C-25 positions.

Cholesterol 43 224

After elaboration of the side-chain, it is then necessary to cleave the

C-9 - C-10 bond. This is normally achieved by introduction of a second double bond between C-7 and C-8 in order to form the provitamin which can then be ring opened to the previtamin and subsequently isomerised to the

7,8 corresponding vitamin D. Introduction of the A double bond is usually done by allylic oxidation or bromination followed by a Bamford-Stevens reduction or dehydrobromination (Scheme 36).

90 RO provitamin D

Br hv

A RO previtamin D RO' vitamin D SCHEME 36 One of the major advantages of the partial synthesis approach Is the fact that many of the chiral centres are already present in the starting sterol. In addition, the rigid nature of the steroidal system allows other functional groups and new chiral centres to be Introduced with a high degree of stereoselectivity. A major disadvantage Is that all transformations must be done sequentially and they are dependent on the structural features already present in the starting material. A de novo synthesis offers the advantage of convergence where there Is greater flexibility in the construction of the molecule.

(b) Total Synthesis

As this chapter Is concerned with an enant1ospecIfIc approach to the

total synthesis of vitamin D3 and its derivatives from camphor it is appropriate at this juncture to briefly discuss those syntheses or synthetic approaches which have already been described In the literature.

91 92 Since the first reported synthesis of cholecalciferol by Inhoffen in

I960 , there has been intensive research carried out in this area, particularly during the past 10 years. Although total synthesis is not yet competitive with routes utilising natural steroids it is becoming more viable, especially with the structurally complex vitamin D metabolites and

in the synthesis of analogues of vitamin D.

Ten years after Inhoffen's synthesis of cholecalciferol, Lythgoe and co-workers published the total synthesis of precalciferol 217 in 1971 .

125 The Lythgoe group went on to synthesise vitamin D4 214 t la- hydroxycholecalciferol126 and la-hydroxyprecalciferol 225J27. Scheme 37 shows an abbreviated version of the synthesis of precalciferol 217.

A Claisen rearrangement between the optically active allylic alcohol

226 and the optically active orthoester 227 produced, after deprotection, the hydroxy ester 228. This then underwent a second Claisen rearrangement to provide the diester 229 which was elaborated into the C/D subunit 230.

The A ring of the molecule was derived from the optically active keto ester

231 which was transformed into the enyne 232. Coupling of 230 and 232 and elimination of the intermediate chlorohydrin gave the dienyne 233 which was partially hydrogenated to give precalciferol 217.

Subsequently, Lythgoe and co-workers prepared the C/D portion of the molecule by degradation of cholesterol 43128 to give the sulphone 234 which was then coupled to the ester 235 (again derived from the keto acid 231) as shown in Scheme 38. Subsequent elaboration yielded la-hydroxyprecalciferol

225.

93 Another of the major research groups involved in the total synthesis of vitamin D metabolites is the group at Hoffmann-LaRoche which has devised routes to la,25-dihydroxycholecal,ciferol 211 (1982)129, calcitriol lactone

236 (1983)130 and la,25(S)26-trihydroxycholecalciferol (1984)131. All three

94 SCHEME 39

95 syntheses were based on the same methodology which is outlined in Scheme 39 for la,25-dihydroxycholecalciferol 2]jL The optically pure ketoacid 72 (see

Part 1, p.25 for its preparation) was converted in 18 steps to the hydroxy ketone 238 and this was coupled via a Wittig-Horner reaction to the phosphine oxide 241. Phosphine oxide 241 was initially derived from the chiral starting material (+)-carvone 240 in 13 steps. This route allows the side-chain and ring A to be modified without too much alteration, to the basic synthetic route.

The Windaus-Grundmann ketone 239, obtained by ozonolysis of vitamin D^,

13? was used by Kametani et a]_ in their first synthesis of cholecalclferol

213 (Scheme 40). Deprotonation of the achiral cyclobutene derivative 242 was accompanied by ring opening and the formation of the intermediate ylid which was condensed JJJ situ with 239 to provide the triene 243. A further 5

SCHEME 40 steps were required in order to convert the ketal into an alcohol without affecting the labile triene system. In a second synthesis of cholecalclferol 213, Kamentani and co-workers devised another strategy

(equation 22) for the generation of the ring A structural subunit. In this

96 case the optically active bicyclic aldehyde 244 (obtained by a resolution step) was treated with the lithiated vinyl bromine 245 to yield 3,5- cyclocholecalciferol 246. Solvolysis and ring opening according to the

method of Sheves and Mazur then gave cholecalciferol 2j_3. In a similar approach Wilson et al_134 used the resolved bicyclic bromide 247 as the synthetic precursor of ring A. Unlike Kametani and co-workers, however, the

C/D portion was synthesised, as shown in Scheme 41, by an intramolecular 135

Diels-Alder reaction (cf. Parker and Iqbal ) of the tetraene 248. This provided the dienes 248a and 248b in ~90% isolated yield with the ratio of trans (249a) to cis. (249b) being 4:1. Deoxygenation and elaboration of the side-chains in 249a provided the aldehyde 250 which was treated with the anion of 247 to yield 3,5-cyclocholecalciferol 246. This was converted into cholecalciferol 213 as before. Since the tetraene 248 can be obtained in

249b BH(cis)

SCHEME 41

97 optically active form by resolution this route constitutes an asymmetric total synthesis of cholecalclferol (vitamin D^).

A novel strategy based on the thermal isomerisation of vinyl allenes has been developed and exploited by Okamura and his group in California in their synthesis of vitamin D analogues. The biologically active compound 3-

136 deoxy-la-hydroxycalciferol 254 was synthesised by this method , starting from the Windaus-Grundmann ketone 239 (Scheme 42). Deprotonation of the allene 251 and subsequent reaction with the enone 252 gave, after

253b aH. 254

SCHEME 42 isomerisation of the undesired vinyl allene 253b, the vinyl allene 253a.

The ketone was reduced and the molecule then underwent a thermally Induced

[1,5]-sigmatropic hydrogen shift to provide 3-deoxy-la- hydroxycholecalclferol 254. Several other analogues of vitamin D have 3 137 recently been synthesised using this vinyl allene approach .

98 There have been numerous publications dealing with the synthesis of steroidal C/D ring systems which have the potential to be further elaborated to steroids and vitamin D and metabolites. The final objective is to construct these hydrindane systems as enantiomerica11y pure intermediates with trans ring junctions and with the proper absolute stereochemistry at C-

17 and C-20.

Trost'38 and Grieco'39 simultaneously published virtually identical routes to a C/D ring system which controlled the stereochemistry at C-13, C-

14, C-17 and C-20. Both started from the bicyclo[2.2.l]heptanone 255 which

is available optically pure by resolution. Grieco and co-workers synthesised de-AB-cholestan-9-one 256 while Trost and his group made the

Inhoffen-Lythgoe diol 257.

The Inhoffen-Lythgoe diol 257 was also prepared by Johnson, Elliot and

Hanson140 using a Lewis acid catalysed cyclisation of the optically active acetal 258. Use of the chiral acetal group allowed the hydrindane

258 ' 259

99 derivative 259 to be synthesised in high chemical and optical yield (82% and

92% respectively). Unfortunately the chiral auxiliary is destroyed during its removal. Compound 259 was transformed into the Inhoffen-Lythgoe diol

257 in a further 7 steps.

14 Tsuji et a]. * used a double Michael reaction as the key step in their synthesis of the hydrindenones 263 and 264 (Scheme 43). Conjugate addition of the cuprate reagent derived from the optically active iodide 260 with 2- methylcyclopentenone followed by a second conjugate addition of the resulting enolate with the methyl vinyl ether 261 gave, after desilylation

263 264

SCHEME 43 and intramolecular aIdol reaction, the hydrindenone 262 (56% overall yield).

l41c Selective ozonolysis of this provided the diketone 263 in which the C-13 and C-17 centres have been created with the proper stereochemistry. Tsuji and co-workers also synthesised the hydrindenone 264 from 262 via a Claisen rearrangement and decarbonylation. This compound possesses the 'unnatural' configuration at C-20.

100 142 An alkoxy-Cope rearrangement was employed by Ziegler and Mencel as the key step in their synthesis of the steroid and vitamin D intermediate

267 (Scheme 44). 1,2-Addition of the anion of 2-(1-propenyl)-l,3-dithiane

SCHEME 44

(E/Z, 86/14) to 2-methyleyelopentenone followed by an HI situ alkoxy-Cope rearrangement of the intermediate and alkylation of the resulting enolate with allyl bromide provided 265 in 46% yield after chromatography.

Subsequent elaboration to the keto acid 266 followed by

cf ref 45 hydrogenation * * gave the C/D synthon 267 with the correct relative stereochemistry at the four chiral centres for steroidal and vitamin D^ systems. Unfortunately this synthesis provides a racemic product and incorporation of an asymmetric induction step or an early resolution may be difficult.

143a Desmaelle and colleagues constructed the eye 1opentanone 271 in 7 steps (not including the resolution steps) from 2-methyleyelopentenone and

101 the ynamine 268 (Scheme 45). The eyelobutenylamine 269 was hydrolysed under

thermodynamic conditions (HC02H, 5%) to provide the ketoacid 270 with the

correct configuration at C-17 and C-20. This ketoacid 270 was resolved with

(-)-ephedrine and then converted into the cyclopentanone 271. Several more

SCHEME 45 steps including a stereoselective hydrogenation to introduce the trans

C/D ring junction finally gave the sulphone 234 which was used by Lythgoe et 127 al in their synthesis of la-hydroxyprecalciferol 225 .

The cyclopentanone 271 was first made by Trost, Taber and A1 per144 in racemic form by a cuprate addition to the cyclopropane system 272 (equation

23). Recently two other syntheses of 271 have been reported145.

102 The bicyclic ketone ent9 (cf. p.25) has been used by Fukumoto,

146 Kametani and co-workers as a key intermediate for the construction of the

C-13, C-14, C-17 and C-20 chiral centres in cholecalclferol 213 (Scheme

46). Thus, conversion of ent9 to the a-methylene ketone by standard

46,49 procedures (see p.26) followed by 1,4-addition of the isoamyl group

provided the diketone 273 with the side-chain exclusively in the equatorial

position. The ketone in the 6-membered ring was selectively ketalised; the

remaining ketone was then transformed to the sulphone 274 and

stereoselectively reduced from the side opposite the angular methyl group.

Ozonolysis of the enol acetate 275 afforded the ring D synthon 276 with all

the required chiral centres in place. • P

276a 277

SCHEME 46

103 Further chemical transformations eventually afforded the sulphone 277.

The very similar sulphone 278 had previously been converted to vitamin 4 125 214 by Lythgoe and co-workers .

104 DISCUSSION

2.2.1 Background Work and Basic Strategy

The remarkable transformations of 3-endo-bromocamphor 15a in bromine and chlorosulphonic acid allow for the preparation of either (+) or (-)-3- endo-9,10-tribromocamphor 39. Selective debromination yields optically active 9,10-dibromocamphor 37 which can undergo extremely facile ring cleavage to provide cyclopentanoid systems such as the bromoacid 159 (Scheme 147 47) in over 90% yield. Work in our laboratory designed to explore and exploit the potential that systems of type 159 have in the enantiospecific synthesis of natural products has shown that the bromoacid 157 can be converted into the lactone 160. This lactone was alkylated with methyl iodide to provide a single crystalline product, 279, with the methyl group exclusively in the equatorial position. The 400 MHz 'H nmr of this compound showed that proton H. has a coupling constant of 13 Hz with the bridgehead

SCHEME 47

105 I I I 62.6 62.4 62.48

norma! spectrum decoupled spectrum

FIGURE 6 : Partial 1H NMR Spectrum of Methyllactonc 279 proton Hg (measured from the decoupled spectrum where the coupling of HA with the newly introduced methyl group had been removed by irradiation of the methyl doublet at 61.32, as shown in Figure 6. This observation is consistent with a 1,2-diaxial relationship between H^ and Hg in the methyl lactone 279. The structure and absolute configuration of this molecule was eventually proved unambiguously by an X-ray crystallographic 148 analysis (Figure 7).

FIGURE 7 : Stereoviews of Methyllactone 279

Equation 24 shows that the methylated lactone 279 can be ring opened using methanol and a trace of concentrated sulphuric acid to provide the hydroxy ester 280 which has many of the features of the ring D structural

106 0

subunlt of steroids with functionalIsed side-chains. The centres at C-2 and

C-3 (C-13 and C-17 steroid numbering) are derived from the rigid nature of the bicyclo[2.2.1]heptane system of camphor and the stereochemistry at C-9

(corresponding to C-20) can be controlled by alkylation of the lactone 160.

The hydroxyester 280 was then converted In a further 9 steps to the chiral enone 281a,a potentially useful intermediate for the proposed

synthesis of ent-he1ena11n 282 . The natural enantiomer, helenalin, is the best known member of a group of sesquiterpeneid lactones known as the helenanolides.

Based on these results, a scheme to syntheslse the ring D subunit of steroids and In particular vitamin D systems was devised (Scheme 48). Thus

107 SCHEME 48 alkylation of the lactone 160 with an appropriate alkyl halide followed by opening of the lactone and conversion of the ester to a methyl group would create 3 of the 4 chiral centres required for the ring D structural subunit. It was hoped that the remaining chiral centre could be introduced with a high degree of stereoselectivity via a hydroborat1on procedure to provide a trans junction between rings C and D. By starting the synthesis with (+)- camphor JO, the cyclopentanoid unit produced will have the correct absolute stereochemistry for naturally occurring vitamin D metabolites.

In a second approach to the problem of introducing the C-20 side-chain functionality, ft was hoped that the ester 283 could be alkylated to produce derivatives with the required stereochemistry about C-9.

283 283a

108 2.2.2 Construction of the Steroidal Side-chain

(+)-3-endo-Bromocamphor 15a was converted to (+)-9,10-dibromocamphor 37 as described in Part 1 and 37 was then treated with potassium hydroxide in

DMSO/water for 1 hour to provide the bromoacid 159 In over 95% yield. This molecule was found to undergo intramolecular 1 actonisat 1on in high yield using the method of Galli and colleagues . Thus stirring the bromoacid

159 with 1 equivalent of potassium hydroxide and silver(I) oxide in

DMSO/water (99:1) at 60°C gave the lactone .160 in excess of 90% yield.

With the lactone on hand, a choice of the alkylating agent had to be made.

It was decided to use allyl bromide in the first instance for several reasons: (i) the protons of the allyl unit would be clearly visible in the proton nmr; (ii) allyl bromide is a very good alkylating agent; (iii) it is readily available and (iv) the terminal double bond could be exploited later in the synthesis to introduce more complex side-chains. Deprotonation of the (-)-lactone 160 using lithium diisopropylamide in THF followed by addition of allyl bromide at -78°C gave, after work-up, an 85% yield of the allyllactone 284 (Scheme 49). The product 284 appeared to be a single compound from its 400 MHz *H nmr spectrum but unfortunately the stereochemistry of the allyl moiety could not be deduced from this spectrum.

The relevant protons (H and Hg) were both obscured by other protons in the A molecule. By analogy with the methylated lactone 279 this compound was assigned the structure shown with the allyl side-chain in the equatorial pos i t i on.

109 Ring opening of the allyllactone 284 with methanol and a catalytic amount of concentrated sulphuric acid provided the corresponding hydroxy ester 285 in quantitative yield. This compound (285) exhibited bands at

-1 3450 (br), 1720, 910 and 890 cm in the ir spectrum corresponding to an alcohol, ester, allyl double bond and the exocycllc double bond respectively. The hydroxy1 group of 285 was protected as its tert- butyldimethyl silyl ether (98% yield) to give 286, [a] -42.0° (C 0.59, Q

O^C^)- These mild conditions would not be expected to epimerise the chiral centre a to the ester and indeed the 270 MHz *H nmr spectrum of 286 showed no sign of a second component. Reduction of the ester functionality using lithium aluminum hydride (LAH) gave a 94% yield of the alcohol 286.

This yield was dependent on the nature of the LAH used. Some batches of LAH gave substantial amounts of the diol 293 as a by-product (up to 30%) due to

r- OH

293 the unwanted removal of the protecting group. Even the use of fresh batches of LAH gave this problem. Presumably the LAH had, in these cases, partially hydrolysed yielding lithium hydroxide which under the anhydrous conditions is able to cleave the TBDMS-ether. It was later found that the use of a fresh bottle of diisobutylaluminum hydride (DIBAL) gave more reliable results.

The hydroxy1 group in compound 287 was removed by conversion to the mesylate 288 followed by treatment with lithium triethy1borohydride

('superhydride'). Work-up and purification gave the diene 290 in a yield of

110 81% over two steps, Subsequent deprotection using fluoride ion in THF provided the alcohol 291.

291 R= H 290 288 R= Ms 292 R= MTPA 289 R= MTPA

SCHEME 49

In order to check the stereochemical purity of the chiral centre at C-

9, the alcohol 287 was converted to its (+)-a-methoxy-a-

(trifluoromethyl)phenyl acetate (( + )-MTPA) derivative 289 by reaction with 151

(+)-MTPA chloride. This reagent was introduced by Mosher et aj_ for the determination of the enantiomeric composition of amines and alcohols. The method works for both primary and secondary amines and alcohols and Is useful because the diastereomers produced usually have well separated signals in the proton and fluorine nmr spectra. The presence of a trifluoromethyl group makes the detection of a second enantiomer a relatively simple procedure since It should show up as a second singlet In the proton decoupled fluorine nmr spectrum. Thus the (+)-MTPA derivative

289 showed a singlet in the 19F nmr (254 MHz); the 400 MHz *H nmr also

indicated a single diastereomer. This does not necessarily prove that the

111 alcohol is diastereomerically pure since both diastereomers may give rise to isochronous fluorine signals. For this reason, the ester 286 was subjected to both refluxing sodium methoxide in methanol and LDA in THF in an attempt to equilibrate the chiral centre a to the ester group. Neither of these conditions produced any detectable change in the *H nmr (400 MHz) spectrum

19 or the F nmr of the corresponding (+)-MTPA ester. As final confirmation, the hydroxya1kene 291 was also converted to the corresponding (+)-MTPA ester

i q and again this showed a singlet in the F nmr. The evidence cited above confirms that the transformation of the lactone 160 to the alcohol 290

(scheme 49) has occurred without epimerisat ion of the chiral centre at C-9

(C-20 steroidal numbering).

Since we had proved that the allyl side-chain could be introduced with complete stereoselectivity by alkylation of the lactone 160, our attention then turned to the possibility of obtaining a similar result in the alkylation of the ester 283. Stereoselective alkylation of this ester would

C02Me

283 be advantageous since it would make the route two steps shorter and moreover the ester 283 is much less prone to hydrolysis than the lactone 160.

We had reason to expect some degree of stereoselectivity in this

152a?b reaction based on the results of Wicha and Bal and Partridge and co•

153a b 152b workers ' . Wicha and Bal studied the alkylation of the steroidal systems 294a and 294b using various electrophiles (equation 25) and in all

112 cases the product (295a-c) was a single compound with the 'R' configuration

at C-20. Similarly Partridge et aj_ prepared the steroidal systems 297a and

297b by alkylation of 296a and 296b with the iodide 298 (equation 26). In

THPO

296b X= OTHP 297b X=OTHP

both cases the product was formed in greater than 80% yield and little or none of the corresponding C-20 'S' alkylated product was detected.

54 Earlier work by Barton et §i* on the aldehydes 300a and 300b

(prepared by selective ozonolysis of the ergosterol derivative 299 as in equation 27) indicated that the more stable compound was aldehyde 300b. The initially formed aldehyde containing the C-20 'S' configuration (ie. 300a) was readily epimerised on alumina to give predominantly the C-20 'R'

113 I I

compound 300b. This suggests that the more thermodynamically stable product in steroidal systems of this type is one in which the C-20 chiral centre has the XR' configuration. The alkylation results cited above Indicate that this is also the kinetically favoured product.

The ester 283 was obtained from (+)-9,10-dibromocamphor 37 by cleavage to the hydroxy acid 161, ester ification (diazomethane, 100% yield) and

37 161 301 283

SCHEME 50 protection of the alcohol as its TBDMS-ether (98%) (Scheme 50). Reaction of the enolate of 283 with allyl bromide using the same conditions as before provided a 91% yield of the alkylated product. Examination of the 400 MHz

JH nmr spectrum of this material showed that it was a single compound and identical to the compound obtained via alkylation of the lactone 160.

Capillary glc analysis of this product gave a single peak and the optical

rotation ([a]Q -42.49° (C 0.426, CH2C12)) is virtually identical to the

value ([a]n -42.0° (C 0.59, CH2C12)) obtained for the compound prepared by the lactone route. Reduction of this product and conversion to the (+)-MPTA

114 derivative 289 again gave only one peak in the 254 MHz 'F nmr. The C nmr spectrum (100.6 MHz) of 289 also Indicated that there was only one compound present since no extraneous peaks were observed. It Is clear that the ester

283 behaves In exactly the same manner as the steroidal systems 294 and 296 and the stereoselectivity observed in these cases is probably not due to the presence of a rigid steroidal framework but due to the substituents present on the cyclopentane ring (ring D). At the time we were carrying out this research we became aware of a similar result obtained by Liu and Dieck-

Abularach155. They found that methylation of a-methylcampholenate 302

302 303 provided 303 as the only Isolable compound and all attempts to epimerise this compound failed. This result and our earlier Inability to eplmerlse the allyl ester 286 Is probably because both of these compounds have the thermodynamically more stable configuration which is in agreement with the 154 observations of Barton et aj. (cf. p. 113). An explanation for the stereoselectivity observed in the alkylation of the ester 283 may lie in the conformation of the intermediate anion 283a (Figure 8). In the more stable

8Me

-j-SiO ^-OSi+

283a FIGURE 8 Alkylation of Ester 283

115 conformation, the bulky lithium enolate moiety at C-9 lies between the small

(H.) and medium (C-4 methylene) substituents on C-3. The approach of the A alkyl halide then occurs from the less hindered side of the enolate away from the quaternary centre at C-2.

Further support for these proposals was obtained when the ester 283 was alkylated with methyl iodide to provide the methylated ester 304a. As

283 304a 305a

before, no other epimer could be detected (400 MHz H nmr and capillary glc) and the ester 304a was identical in all respects to the compound previously 147 obtained via methylat ion of the lactone 160. Reduction of 304a gave the

alcohol 305a which had an optical rotation ([a]D -45.2° (C 0.50, CH2C12))

almost Identical to that of the corresponding alcohol ([a]n -45.0° (C 0.22,

CH2C12)) obtained via alkylation of the lactone 160. The epimeric products

304a.b and 305a.b were synthesised for the purposes of comparison from 9,10- dibromo-3-methylcamphor (endo (150a) to exo (150b) ~6:1) (Scheme 51).

Cleavage of a mixture of 150a and 150b (for preparation see Part 4) followed by esterificat ion and protection of the alcohol gave the corresponding ester derivatives 304a and 304b, The *H nmr (400 MHz) spectrum of this mixture clearly showed the presence of two epimers and confirmed the validity of the nmr method for evaluating the stereoselectivity of the alkylation of the ester 283. Reduction of this mixture afforded the alcohols 305a and 305b (~

1:3.6) which were readily separated by column chromatography on silica gel.

116 305a 505b

SCHEME 51

The minor product (C-ll methyl, doublet, 60.96, J = 7 Hz) was found to be

identical to the alcohol 305a while the major product (C-ll methyl, doublet,

61.05, J = 7 Hz) was identified as its C-9 epimer 305b.

The stereoselective alkylation of the ester 283 to yield the product with the C-9 'R' configuration has potential application in the synthesis of natural products. For example, alkylation with methyl Iodide provides the methyl ester 304a which could be further elaborated to provide the side- chain found in halosterols ie. sterols possessing the 'unusual' C-20

114 stereochemistry. (ref.6) jhe methy] ester 304a has already been transformed In our laboratory Into the enone 281a147 and access to 304a by

direct methyl at ion of the ester 283 constitutes a simplification of this

route.

Alkylation of the ester 283 with the acetonyl equivalent 306156 157 (equation 28) followed by hydrolysis gave the ketoester 307- . Conversion

117 OMe

of the ester to a methyl group using similar methodology to the above should provide access to enone 281b which is a potential intermediate in the synthesis of ent-ambrosin. The naturally occurring enantiomer, ambrosin

308, is the best known member of a group of sesquiterpeneids known as the ambrosanolides. The ambrosanolides and the helenanolides (cf. p.107) are epimeric at C-10 and are sometimes collectively known as the pseudoguianolides.

Ambrosin 308

In order to prepare a ring D subunit with the vitamin D3 side-chain, the ester 283 was alkylated with l-iodo-4-methylpentane and the resulting

This compound was prepared by forming the Grignard reagent of 1-bromo- 3-methylbutane and reacting it with formaldehyde. The alcohol produced was heated in hydriodic acid (57%) to provide l-1odo-4-methylpentane.

(ii)CH20

118 compound 309 (Scheme 52) Isolated in 75% yield. Capillary glc analysis showed this to be contaminated with a small amount (<5%) of a second compound which is presumably the C-9 epimer. Reduction of the ester with

C02Me

512 R= TBDMS 510 R= H 313 R= H . 311 R= Ms

SCHEME 52

DIBAL provided the alcohol 310 in over 95% yield after column

13 chromatography. This compound was pure by nmr (400 MHz), C nmr (100.6

MHz) (Figure 9) and capillary glc; the other epimer could not be detected.

'Superhydride' displacement of the corresponding mesylate 311 gave the alkene 312 in 86% yield over two steps. Desilylation of 312 with tetrabutylammonium fluoride in THF gave the chlral hydroxya1kene 313 In quantitative yield. The latter compound represents the completion of the first aim of the project ie. the construction of a sterofdal side-chain with the correct configuration (relative and absolute) at C-17 and C-20 (steroid numbering) on the ring D subunlt. This has been achieved by a simple, efficient route In which many of the steps have yields in excess of 90%

(Scheme 52).

119

2.2.3 Attempts to Construct Ring C and the Format ton of the C-14 Steroidal

Chiral Centre

An initial approach to the problem of Introducing the remaining carbon atoms required for ring C involved the use of the model system bromide 315

(Scheme 53). It was hoped that displacement of the bromine by the dianion

I CO of methyl acetoacetate followed by ozonolysis, subsequent ring closure and hydrogenation would hopefully provide the C/D ring system with a trans ring junction and appropriate functionality to allow for the construction of the remaining part of vitamin D.

SCHEME 53

The bromide 315 was prepared from the bromoacid 157 by reduction followed by protection of the alcohol 314 as its methoxymethyl (MOM) ether . Unfortunately this bromide 315 remained inert to the dianion of methyl acetoacetate even after reflux with a large excess of the latter in

160 THF. Armstrong and Weiler reported a similar problem in the attempt to alkylate the dianion of methyl acetoacetate with electrophiles of type 316.

As a result of trying the reaction with various leaving groups, they

121 316 L= leaving group

eventually discovered that alkylation could be accomplished In low yield

(<30%) when the trif1uoromethane sulphonate (triflate) (316, L = 0S0pCF3) was employed. However, although it is possible that the replacement of a bromine in 3Jj> (Scheme 53) with a triflate group could lead to successful alkylation we confined our attention to an alternative way of constructing ring C.

In this route we hoped to Introduce the C-14 chiral centre (steroidal numbering) using a hydroboration reaction. Our initial plan was to utilise the hydroxy1 group in the hydroxya1kene 313 to direct the hydroborat1ng

313 317a X= OH 317b X= OH 318a X= I 318b X= I agent to attacking the exocyclic double bond from the bottom (a) face of the molecule. An oxidative work-up would then provide the diol 317a as the major product. If this approach were successful, then using a hydroboration/iodination procedure161 should give the hydroxyiodide 318a which could then be further elaborated.

Addition of BH^.THF complex to a solution of the hydroxya1kene 313 at

-78°C, allowing the solution to warm to ambient temperature overnight

122 followed by an oxidative work-up provided a 78% yield of the dlols 317a and

317b. The ratio of the two dfols was 1:2.24, the major product being the

cis diol 317b resulting from hydroboration from the less hindered face of

162 the molecule. The use of thexylborane as the hydroborat1ng agent did not

yield any significant Improvement in the ratio. In order to prove the

stereochemistry of the major diol formed in this reaction, it was converted to the cyclic ether 319 (equation 29) us.ing para-to 1 uenesu 1 phony 1 chloride

and DMAP in methylene chloride. The trans diol 317a would not be expected

to form a cyclic ether due to the inherent strain involved In the formation

of a trans-fused bicyclo[3.3.0]octane ring system. Indeed, reaction of the

minor diol 317a under the same conditions did not yield a cyclic ether.

Further confirmation of the structure of the major diol 317b was provided by

an NOE difference experiment carried out on the corresponding ether 319

(Figure 10). Irradiation of the bridgehead proton (H^) resulted in a

positive enhancement of the bridgehead methyl group which is consistent with

a cis relationship between the two substituents.

Since the stereoselectivity in this reaction was very poor, a modified

7? approach was proposed based on the work of Bryson and co-workers' . As

73a mentioned earlier (p.38), Bryson and Re1chel used a

hydroboration/carbonylation reaction as the key step in their synthesis of

estrone 41. Initial hydroboration of the more accessible monosubstituted

123 angular methyl group

NOE difference experiment

400MHz V nmr

0 ppm

FIGURE 10 : 400MHz H NMR and NOE Difference Experiment for Ether 319 double bond In dfene 130 with thexylborane followed by intramolecular hydroboration from the a face generated the cyclic trialkylborane 130a with a trans fused ring junction. Carbonylation using the method of Pelter and

72 co-workers (KCN; TFAA; H202/NaOH) gave the seco-steroid JJJ_ in 60% yield.

The use of cyclic trlalkylboranes for the synthesis of cyclic ketones was 163 first reported by Brown and Negishi . Their procedure involves the reaction of the cyclic trialkylborane intermediate (generated by addition of thexylborane to a diene) with carbon monoxide at high pressure and temperature. The Pelter procedure employs much less drastic conditions (KCN and TFAA followed by the usual oxidative work-up) and consequently appears to be the method of choice for this transformation.

We proposed to prepare de-AB-cholestan-9-one 256 by using this

313 320 R= 0 256

321 R= CH2

125 hydroboratlon/carbonylatIon procedure with diene 321 which was easily prepared in 71% overall yield from the hydroxya1kene 313. Oxidation of 313 to the aldehyde 320 (PDC In CH C1 ) followed by a Wittig reaction (Ph PCH , 2 2 3 2 THF) yielded the diene 321 as a colourless mobile oil. Hydroboration of 321 using thexylborane* at -78°C and allowing the reaction to warm to 0°C followed by sequential treatment of the intermediate with potassium cyanide, trifluoroacetic anhydride (TFAA), sodium hydroxide and hydrogen peroxide failed to yield any of the desired bicyclic ketone 256. Instead, the diols

322 and 323 were isolated in 24% and 36% yield respectively (Scheme 54).

The structure of diol 323 was deduced from its ir and 400 MHz 'H nmr spectra. The ir spectrum showed a strong, broad absorption centred at 3250

-1 cm showing the presence of at least one alcohol functional group. From the proton nmr spectrum a methyl doublet at 61.23 and a quartet at 64.00

(one proton) is consistent with the CH CH0H- subunit. A two proton 3 multiplet at 63.47 corresponds to the protons of the primary hydroxy1 group.

This compound must have arisen by Initial hydroboration of the double bond exocyclic to a 5-membered ring followed by Intramolecular hydroboration of the remaining double bond. The Intramolecular hydroboration would proceed to give the 5-membered ring boracycle 324 In preference to the 6-membered

16 165 ring analogue ^' and so yield the diol 323 on oxidation. Since the

The stereoselectivity of cyclic hydroborations is reported to be highly

dependent on the nature of the BH «THF complex used. Substantial 3 losses in stereoselectivity are observed if commercial samples of

164(ref 17) BH .THF are used approximately 7-10 days after being opened * . 3 A fresh bottle of BH .DMS was used in this reaction. 3

126 intermediate 324 contains two fused five membered rings, the rings must be cis fused and thus the final product 323 must have both primary alcohol groups cis to each other. The second diol isolated was assigned a structure

(322) in which the hydroxy1 substituents are trans to each other. Again the infra-red spectrum of this compound showed an intense absorption centred at

3250 cm-' while the mass spectrum gave a molecular weight of 270.2557 which corresponds to a molecular formula of Ci7H34°2* Peaks in the nmr spectrum between 63.50 and 63.80 integrate to four protons and correspond to two

CH^fjH subunits. This evidence is in good agreement with the proposed structure. The stereochemistry of the new chiral centre was assigned the

XR' configuration (ie. the hydroxy1 substituents are trans to each other) by analogy to the result of Bryson and Reichel; hydroboration of the monosubstituted olefin followed by an intramolecular hydroboration would be expected to yield the trans-fused boracycle 325. Oxidation of 325 would yield diol 322. Further support for the structural assignment of diol 322 can be found by comparing the chemical shifts of the angular methyl group in

127 325 compounds 317a, 317b, 322 and 323 (Scheme 55). The cis diol 317b has the

SCHEME 55 angular methyl group at significantly lower field than the trans diol 317a

(60.92 and 60.83 respectively). Similarly, the cis diol 323 has the angular methyl group at 61.00 (cf. 317b at 60.92) but the corresponding methyl group

In diol 322 occurs upfield at 60.78 which Is analogous to the value of 60.83 found In the trans diol 317a. Although the hydroxy1 groups In 322 are In a

1,5-relationshlp whereas all the other diols are 1,4 to each other, the chemical shift of the angular methyl group does appear to support the assignment given. Similar differences In the chemical shift of angular 165 95e 95h methyl groups in blcyclo[4.3.0]nonane systems have been reported ' *

128 The failure of the carbonylation procedure to work is disappointing but presumably with further work this reaction should prove successful. Lack of material and time prevented any further studies on this step in the synthesis. The poor stereoselectivity observed in this reaction is probably due to the fact that both alkenes in 321 are almost equally accessible even though one a Ikene is monosubstituted and the other is disubstituted. The disubstituted a 1kene is not as sterlcally crowded. This Is, of course, only

321a

a model system; the real system will contain a substituent on the exocyclic double bond making initial hydroboration of the monosubstituted olefin more likely and hence promote the format i on of a 6-membered r i ng trans-fused boracyclic intermediate (cf. Scheme 54) and provide more acceptable yields of the required trans fused product. Introduction of a substituent on the exocyclic double bond could be achieved by a variety of methods. For example an ene reaction similar to the reaction employed by Wovkulich and

Uskokovic167 (equation 30) could be used. Oxidation of the alcohol followed

96 : 4

129 by migration of the double bond would give the tr{substituted exocycllc double bond. Alternatively, the exocycllc double bond In 312 could be removed by ozonolysis and a trisubstituted double bond created by a suitable

cf 1Z9, 167 Wittig reaction * .

312 312a R 312b

Nevertheless, despite the disappointment of the last step, the preparation of diol does constitute a synthesis of the vitamin ring 322 D3 D subunit with the correct absolute configuration and all the chiral centres

(C-13, C-14, C-17 and C-20).

130 2.2.4 Conclusion

As can be seen from the results described, (+)-camphor JO is a useful

chiral starting material for the enantiospecific synthesis of intermediates of vitamin D and related metabolites. The approach described above and outlined in Scheme 56 is simple and highly convergent. The appropriate

side-chain may be prepared separately and incorporated into the ring D

structural subunit by a simple alkylation reaction. This proceeds in high

yield and with high asymmetric induction to give the product with the

correct absolute configuration at C-20. Ring A can also be synthesised

separately and then, presumably, joined to the C/D ring system.

Although ring C was not completed, it seems likely that it could be

constructed using the hydroboration/carbonylation procedures devised by

Brown and by Pelter. This route would also fix the chlral centre at C-14.

SCHEME 56

Other ways of constructing ring C can be devised and further research on this

aspect of the project will be pursued.

131 Part 3

A Formal Enantiospecific Synthesis of The California Red Scale Pheromone

132 3.1.1 INTRODUCTION

The California red scale, Aon i de i11 a auranti i (Maskell), is the most serious citrus pest in Australia, California and the Mediterranean countries. The control of this pest Is of great economic importance and a considerable amount of research has been directed towards this goal. Red scale females attract males by releasing sex pheromones and in 1977 Roelofs and co-workers reported the isolation and identification of 3-methyl-6-

isopropenyl-9-decen-l-yl acetate 326 and (Z)-3-methyl-6-isopropeny1-3,9- decadien-l-yl acetate 327a as the two principal components of the pheromone mixture.

326 327a

In order to isolate these compounds, approximately 400 million female- day-equivalents (ie. the amount of pheromone collected from one virgin female per day) of pheromone were accumulated from virgin female scales raised on potatoes. Separation and purification provided both 326 and 327a which were then identified on the basis of their spectral data and by partial degradation. Compound 326 has two chiral centres whereas compound

327a has one chiral centre and a trisubstituted double bond. Hydrogenation of both 326 and 327a yielded the same product. In order to prove the

stereochemistry and structure of 327a, all four possible stereoisomers were

synthesised (see p.134) and the natural pheromone was found to be the R,Z

i somer. 169

Snider and Rodini synthesised the other principal pheromone, 326,

(see p.138) and concluded that it probably has the 3-(S) configuration.

133 3.1.2 Previous Syntheses of the Sex Pheromone of the California Red Scale

Apart from proof of structure, the total synthesis of the California

Red Scale pheromone is important because the synthetic pheromone could replace the cumbersome and expensive virgin female traps in the field. The serious risk that a trap may become damaged, allowing mating and then infestation by these females would be alleviated by the use of a synthetic chemical substitute.

100 Roelofs and colleagues prepared the triene acetate 327a by synthesis from the optically active starting material carvone 240 as shown in Scheme

57. Epoxidation of (S)-(+)-carvone 240 followed by opening of the epoxide gave the corresponding keto diol 328 In 21% yield. This was then oxidised with lead tetraacetate in ethanol to yield the diastereomeric lactones 329

SCHEME 57

134 which were converted into the ester acetal 330 (92% yield). The ester 330 was transformed into the bromide 331 which on reaction with vinyl lithium and hydrolysis gave the aldehyde 332. A Wittig reaction followed by acetyl at ion provided a 52:48 ratio of the Z to E geometric isomers in 45% yield for two steps. Pure samples of the R,Z and R,E Isomers were isolated by preparative glc. Repetition of this 11 step sequence with (R)-(-)-carvone provided samples of the corresponding S,Z and S,E isomers. Greenhouse flight tests with the four stereoisomers showed that only the R,Z isomer 327 is active and the activity is not diminished by the presence of any of the other three stereoisomers.

In a similar synthesis, Caine and Crews170 also prepared the triene acetate 327a from (S)-(+)-carvone 240 (Scheme 58). Treatment of the epoxyenone 333 with thiophenol provided 334 which on reaction with the

Wittig reagent 335 (generated \n situ) gave, In 83% yield, an 85:15 mixture of the Z-alkenes 336a and 336b. The exclusive formation of the Z- trisubstituted alkene is in striking contrast to the 1:1 mixture of Z to E olefins (327a and 327b) prepared by Roelofs and co-workers who used the same

Wittig reagent 335. The mixture of 336a and 336b was used without separation. Acetyl at ion of the alcohol and oxidation of the sulphide to the sulphoxide gave the ketosulphoxide 337 in 85% yield. Thermal elimination of the sulphoxide, followed by reduction and acetylat ion provided the diacetate

338a which was freed from the by-product 338b by chromatography. The allylic acetate moiety was removed by chemose1ective hydrogenolysis to afford the pheromone 327a which unfortunately was contaminated by 11% of the double bond isomer 339.

135 338b R= H

SCHEME 58

Stfll and Mitra171 prepared racemic 327a In 6 steps from 6.B- d1methylaery1ic acid as shown in Scheme 59. The key step of the synthesis

327a 341 340a and 340b

SCHEME 59

136 was the generation of Z-trisubstituted double bond by a [2,3]-s1gmatrop1c

Wittig rearrangement. The dlastereomeric alcohols 340a and 340b were

deprotonated and alkylated with iodomethyltributyltin. The intermediate was

llthiated using n-butyl1ithium and a smooth [2»3]-sigmatroplc rearrangement

occurred to provide the homoallylic alcohol 341 which was then acetylated.

The final product was shown to consist of 95-96% of the Z isomer, 327a.

The formation of the Z isomer shows that the preferred transition state

for this reaction is one in which the side-chain is in a pseudoaxial

position (ie. transition state A). If the side-chain occupied a

TRANSITION STATE A TRANSITION STATE B

pseudoequatorial position (as in transition state B) it would experience a

severe steric interaction with the vinyl methyl group.

The charge-directed conjugate addition/alkylation reaction of the a,B- 172 unsaturated acylphosphorane 342 was employed by Cooke and Burman in their

synthesis of 327a. This route, outlined in Scheme 60, consists of 1,4-

addition of allyllithium followed by alkylation with the bromide 343 to give

344 In 87% yield. Decarboxylation, deprotection and removal of the

phosphorous ylid functionality was achieved in three steps in 63% overall

yield. The synthesis was completed by acetylat ion and a Wittig reaction to

provide racemic 327a (47% yield).

137 SCHEME 60

The other major component of the California Red Scale pheromone, the diene acetate 326, was synthesised by Snider and Rodini169. In their synthesis, (S)-(-)-citronellyl acetate 345 and methyl propiolate (Scheme 61)

SCHEME 61

138 undergo an aluminum chloride catalysed ene reaction to provide 346 in 851

yield as a mixture of diastereomers (~1:1). Selective reduction of the

conjugated double bond followed by treatment with

phenyl sulphonyl methyl 1ithium gave 347 in 64% yield. Subsequent elaboration

in a further 4 steps gave 326a and 326b as a 1:1 mixture of diastereomers.

This synthesis allows control of the chiral centre at C-3 by starting with

(+) or (-)-345 and bioassays indicate that the natural pheromone has the 3-

(S) configuration. The configuration of the isopropenyl side-chain in the

natural product was not determined but presumably it is the same as in its

co-metabolite, the triene acetate 327a.

139 3.2.1 DISCUSSION

We decided to attempt an enantiospeciffc synthesis of (Z)-3-methyl-6- isopropenyl-3,9-decadien-yl acetate 327a (one of the sex pheromones of the female California Red Scale) from (+)-camphor 10. The strategy for this synthesis was based on sequential Grob-type fragmentation reactions of blocked 6-bromoketones (see Part 1, p.49) to generate the remote chiral centre. It was expected that (+)-9,10-dibromocamphor 37 could be cleaved to

15a R= Br [

SCHEME 62 provide the bromoacid 159 (Scheme 62) which could then be transformed to the bromoketone 348 containing a second blocked B-bromoketone system. Cleavage of this compound in a similar manner as before would provide the acyclic ester containing the remote chiral centre with the correct absolute configuration for the natural pheromone. Subsequent elaboration should

140 yield the aldehyde 332 and the trlenols 340a and 340b, which are penultimate

168 171 intermediates in the synthetic routes of Roelofs and Still respectively.

In the first Grob-type cleavage reaction, (+)-9,10-dibromocamphor 37 was treated with potassium hydroxide in DMSO/water to provide the bromoacid

159 in 98% yield. This was reduced with LAH in THF to give the bromoalcohol

314 (Scheme 63) in 95% isolated yield. Ozonolysis of 314 followed by treatment of the crude bromoketol 349 with TBDMS-C1 and DMAP in dichloromethane afforded the eye 1opentanone derivative 350 (67% yield for two steps). The alternative approach to 350 from 314 by first protecting the alcohol and then ozonolysis of the double bond was not as satisfactory.

The protection step (equation 31) gave 351 In high yield (96%) but on

314 351 350 349 ozonolysis (ozone in methanol at -78°C) the silyl ether group was cleaved off and the major product isolated was the ketoalcohol 349 (75% yield); the required bromoketone 350 was formed in only 15% yield.

The bromoketone 350, like 9,10-dibromocamphor 37, Is an a,a- disubstituted B-bromoketone and therefore would be expected to undergo a

similar Grob-type fragmentation reaction. In the event, treatment of 350 with sodium methoxide In methanol at reflux for 1 hour led to the formation of two new products. The major component was found to be the desired acyclic ester 352 and exhibited spectral data consistent with the proposed

-1 structure. Bands at 1745 and 890 cm In the ir spectrum were assigned to the ester group and the dlsubstituted double bond. The *H nmr showed two

141 327a

0 )0 (i)KOH/DMSO/H2 (ii)LAH (iii 3/DMS (iv)TBDMSCl/DMAP/CH2Cl

(v)NaOMe/HOMe (vi)PDC/CH2Cl2 (vii)Ph3PCH2 (viii)TBAF/THF

(ix)Mg/CH2=CBrCH3

SCHEME 63

142 Br

» -f-SiO C02Me M-

. -f-SiO 350 352 A353a

broad singlets at 64.69 and 64.78 (attributed to the two vinyl protons) as well as a singlet at 63.65 and a broad singlet at 61.60, 3 protons each, assigned to the methyl ester and the vinyl methyl group respectively. The minor component showed a carbonyl stretch at 1795 cm-1 which is characteristic of a 4-membered ring ketone and is consistent with the bicyclic ketone 353a. Deprotonation of the bromoketone 350 followed by intramolecular cyclisation would give rise to 353a, the structure and absolute configuration of which was subsequently confirmed by an X-ray

14B crystallographic analysis of the corresponding para-bromobenzoate derivative 353b.

pBrBzO 353b

A similar result was obtained when the keto tosylate 358 was treated with potassium tert-butoxide; the major product was the tert-butyl 5-methyl-

5-hexanoate with approximately 10% of the bicyclo[2.1.1]hexanone also formed.

143 358

In order to maximise the yield of the acyclic ester 352, the reaction was repeated at lower temperatures since this should Inhibit the formation of the highly strained bicyclo[2.1.1] system 353. The results of these reactions are given in Table 1 and they confirm that lowering the reaction temperature does indeed increase the ratio of formation of 352 to 353.

Table 1: Ring Cleavage and Cyclisation of Bromoketone 350 with NaOMe/HOMea

Temp. Time Yield of 352 Yield of 353 Ratio 352:353 ref1ux 1 hr 53 22 2.4:1

60°C 3 hr 57 17 3.4:1

56°C 7 hr 55° 10 5.5:1 40°C no reaction - - RT no reaction - - a 0.06 M so1ut ion of 350 in methanol was treated with 10 equivalents of NaOMe. k The corresponding desilylated product 352b was isolated in ~10% yield.

The rate of the reaction is highly temperature dependent and below approximately 50°C almost no reaction is observed. At 56°C the amount of the unwanted by-product 353a was only 10%. Unfortunately though, the long reaction time required at this temperature allows the formation of a second

144 352b

by-product, the hydroxyester 352b, due to slow cleavage of the TBDhS-ether.

A compromise temperature of 60°C was found to give the best results.

The effect of a different nucleophile, hydroxide instead of methoxide, was also examined. This necessitated the use of a different protecting group for the keto alcohol 350 since the TBDMS-ether is not stable to prolonged exposure to aqueous base. The MOM-ether derivative 358 (equation 159 32) was prepared from 349 using the procedure of Fuji and co-workers

KS * MOMO'^v/ "-^C02H 32

359

(methylal and P2O5 in dichloromethane) to give 358 in 78% yield. Cleavage of the bromoketone 358 with KOH in either DMSO/water or THF/water to give the acyclic acid 359 did occur but the product was difficult to purify.

This route did not offer any improvement in terms of yield to that already

described so this approach was abandoned. Treatment of the bromoketone 358 with methoxide in methanol gave essentially the same result as with the

corresponding TBDMS-ether derivative.

145 Reduction of the acyclic ester 352 (Scheme 63) with LAH in THF gave the alcohol 354 which was oxidised to the aldehyde 355 (PDC in dich1oromethane,

70% overall yield from 352). Treatment of 355 with methylenetriphenylphosphorane gave the diene 356 in a yield of 71%. The key intermediate, the diene aldehyde 332, was then prepared in 62% yield from

356 by removal of the protecting group (Bu NF/THF) followed by oxidation of 4 the alcohol 357 with PDC in dichloromethane. The spectral data exhibited by the diene aldehyde 332 is in good agreement with the literature values

(Figure 11).

This unstable aldehyde 332 was converted to the natural pheromone by 168

Roelofs et §_L in a further two steps. Unfortunately the Wittig reaction they employed (see p.134) gave a mixture of double bond isomers (Z to E

~1:1) and this lack of stereoselectivity detracts somewhat from the synthesis. We therefore decided to convert 332 Into the diastereomeric

Authentic spectra (ir and H nmr (60 MHz)) were kindly supplied by Dr. R.J. Anderson of the Zoecon Corporation, Palo Alto, California.

146 H i

80MHz H nmr of 332 prepared from (+]-camphor

147 trfenols 340a and 340b both of which were transformed into the pheromone

327a by Still and Mitra171 (see p.138) with excellent control of the geometry of the trisubstituted double bond. Thus treatment of the diene aldehyde 332 with 2-propenylmagnesium bromide gave the trienols 340a and

340b (80% yield) which were easily separated by column chromatography on s i1i ca ge1.

It is Interesting to note that In the 400 MHz *H nmr spectra of these two compounds, the protons adjacent to the hydroxy1 group (the C-3 proton) are very different (Figure 12). The less polar diastereomer shows this proton as broad doublet of doublets centred at 64.00 with coupling constants

FIGURE 12 : Partial H NMR Spectra (400MHz) Showing the C^3 Protons of the Diastereomeric Trienols 340a and 340b of 9 Hz and 3 Hz respectively. The more polar diastereomer has a triplet at

64.08 (J = 6.5 Hz) for this proton. This difference and their behaviour on tic suggests that the two diastereomers (340a and 340b) are conformationally quite different in solution.

Both of the trienols 340a and 340b have been converted to the natural pheromone by a [2,3]-slgmatropic rearrangement. Thus the synthesis of the trienols 340a and 340b constitutes a formal enantiospectfic synthesis of the

California Red Scale sex pheromone and further Illustrates the use of

174 camphor as a chiral starting material In natural product synthesis

148 Alternative fragmentation reactions involving cleavage of the cyclopentanoid ring system to produce an acyclic system with a chiral

isopropenyl unit were also investigated. Reduction of the bromoketone 350

(equation 33) to give the diastereomeric bromoa1coho1s 360a and 360b (LAH or

DIBAL in THF) occurred in 85% yield. The bromoa1cohois 360a and 360b were treated with 1 equivalent of n-butyl1ithium in THF at -78°C and the reaction then warmed to 0°C. No reaction was observed (by tic) so the solution was heated to reflux. After 2 hrs all the starting material had been consumed but the tic of the reaction mixture showed several spots, none of which corresponded to the required aldehyde 355.

t 75

In another approach a boronate fragmentation reaction was attempted.

Marshall has shown that cyclic (and acylic) 1,4 unsaturated mesylates (cf. equation 34) on hydroboration and work-up with aqueous base yield 1,5-diene

149 systems through a solvolytic fragmentation of the Intermediate coronate.

Brown and Keblys176 in their study of the hydroboration of unsaturated chlorides found that the hydroboration of 4-chloro-l-butene (equation 35) followed by an alkaline work-up failed to produce any cyclobutane or ethene.

S G 35 -Cl B^/ \ci HOB'+ 2CH2=CH2+ CI

Moreover, this alkylborane appeared unchanged after the basic treatment indicating that the fragmentation pathway was not favourable in this case.

Despite this example of the failure of an unsaturated chloride to react, it was decided to attempt..a similar reaction on the bromoalkene 314 (equation

/OH

GOH Br . Cr V,

HO 314a 357 314 HO^

36) since this reaction, if successful, would save 7 steps in the synthetic route (cf. Scheme 63). Unfortunately, when this reaction was carried out according to the procedure of Marshall (excess dlborane in THF followed by treatment with aqueous sodium hydroxide at reflux) no sign of the hydroxydiene 357 could be detected. While the appropriate alkene-mesylate

361 may undergo fragmentation of this type to yield an acyclic system, it

150 was felt that the effort to synthesise compounds like 361. was not worthwh i1e.

151 Part 4

Further Observations on the Reactions of

Camphor and Derivatives

152 4.1.1 Background

As mentioned previously in Part 1, p.44, we initially set out to prepare a tricyclic camphor derivative (eg. 151) which could then, presumably, be cleaved open via the corresponding oxtme to provide a steroidal C/D ring system 152 with the correct stereochemistry at C-13, C-17 and C-20 (steroidal numbering). In order to obtain the correct configuration at C-20 in 152 the camphor system must have a C-3 endo-methyl

151" 151a 152

substituent incorporated into the molecule. We assumed that the most favourable orientation of the C-3 methyl group would indeed be endo since an exo substituent would experience steric interaction with the C-7 syn methyl group. This expectation was also based on analogous results obtained in similar bfcyclo[2.2.1]heptanone derivatives (see p.162). We considered that the tricyclic camphor derivative 151 could be prepared from 9,10-dibromo-3- endo-methy1 camphor 150a and two synthetic routes to the latter compound were considered. One approach involved the initial synthesis of 9,10- dibromocamphor 37 followed by methylation (route A, Scheme 64) and the other envisaged methylat ion of camphor JMO followed by sequential bromination

(route B, Scheme 64) of the C-9 and C-10 positions. The latter route Is two steps shorter and aesthetically more pleasing but it does assume that 3- endo-methy1 camphor 362a will behave like 3-endo-bromocamphor 15a and undergo

153 sequential bromination at the C-9 and C-10 positions.

150a

s s

ROUTE B

SCHEME 64

At this Juncture, it is necessary to consider the mechanisms involved

in the brominations of camphor and derivatives In order to understand the rationale of the synthesis of 150a by route B, Scheme 64. Camphor has long been known to undergo regiospeclfic bromination and sulphonatfon at the C-9 14 or C-10 methyl groups . For example, in strong acid, camphor is able to undergo a series of acid-catalysed rearrangements which, at some stage, converts the methyl groups to exo-methylene groups which can then react with

+ an available electrophile (H , SO^, Br2). 20

In the 10-sulphonation of camphor (Scheme 65) camphor is reacted with

fuming sulphuric acid (S03/H2S04). Here the carbonyl of camphor becomes protonated, thus promoting a Wagner-Meerwe1n rearrangement to generate the 154 intermediate cation 363. Loss of a proton yields an exocyclic double bond

which can then react with S03 to regenerate a cat ionic species 364. A retro

Wagner-Meerwein rearrangement and loss of a proton provides (+)-10-

camphorsulphonic acid with no loss of optical activity.

SCHEME 65

Changing the acid from fuming sulphuric acid to chlorosulphonic acid

changes the course of this reaction quite dramatically; the product is now 17 18 racemic camphor-9-su1 phonic acid (or (±)-9-bromocamphor if bromine and

chlorosulphonic acid are used). In order to explain the regiochemistry of

the sulphonation and bromination as well as the racemisation which occurrs

during C-9 functionalisat ion, a more complex mechanism has been

invoked23,177 Scheme 66). In this case, protonation, followed by a Wagner-

Meerwein rearrangement as before, could produce a cat ionic intermediate 363

which does not react with any electrophlles but Instead undergoes a 2,3 exo-

methyl shift to yield the cation 365. It must be emphasised that only the

155 exo methyl group migrates and this methyl (marked with an asterisk) is originally the C-8 carbon in camphor. Cation 365 can then do one of two things; it can lose a proton to create an exocyclic methylene derivative 366 or it can undergo a second Wagner-Meerwein reaction to yield 367. This intermediate is symmetrical and can readily undergo a 2,6-hydride transfer to provide the enantiomeric cation ent367. A Wagner-Meerwein rearrangement followed by loss of a proton then generates ent366. Both 366 and its enantiomer ent366 can react with an electrophile to yield the cationic intermediates 368 and ent368. A second exo-methyl shift and a Wagner-

Meerwein rearrangement regenerates the camphor skeleton with the 9-methyl group functionalised. Interestingly, the 8-methyl group (asterisked) in the starting material remains in the 8-position for the 9-substituted derivative with the same configuration. But in the enantiomeric compounds the 10- methyl group was initially the 8-methyl group in the starting material

Thus, in summary, the racemisation which occurs can be explained in terms of a symmetrical intermediate 367 and the exclusive formation of a 9- substituted camphor is a direct result of exclusive 2,3-exo-methyl shifts

(363 365 and 368 + 369).

endo-methy1 shifts are almost unprecedented in bicyclo[2.2.1]

1 7fi— 1 ftfl systems . An endo methyl shift has been postulated in the 28 synthesis of 8-bromocamphor 34 .

This Interconversion of the methyl groups has been confirmed by

labeling studies177.

156 X F© ent368 ent366 ent365

X= H, S03H, Br

SCHEME 66

157 SCHEME 67 When this series of reactions Is repeated with (+)-3-endo-bromocamphor

18 19

15a * , the product is (+)-3-endo-9-dibromocamphor 18a which is formed with complete retention of optica1 activity. The mechanism is similar to the mechanism for the bromination of camphor and is shown In Scheme 67.

Protonation of the carbonyl followed by Wagner-Meerwein rearrangement and a

2,3-exo-methyl shift leads to the cat ionic intermediate 370 and, as with

camphor, this intermediate can take two different routes. Pathway A results

in the formation of (+)-3-endo-9-dibromocamphor 18a whereas Pathway B would

eventually produce (-)-6-endo-9-d1bromocamphor 26. No symmetrical

intermediate is Involved in this process and therefore only one enantiomer of 3-endo-9-dibromocamphor 18a is produced.

Since (-)-6-endo-9-dibromocamphor 26 has not been detected as a product

of this reaction, it must be assumed that Pathway B (Scheme 67) is not

operative under these conditions. It is interesting to note however that

Nishikawa in 195223 found that treatment of (+)-3-endo-9-dibromocamphor 18a

370f 372b SCHEME 68

159 in fuming sulphuric acid or chlorosulphonic acid resulted in rearrangement to (-)-6-endo-9-d1bromocamphor 26 (see Scheme 68 for a mechanism). Thus, In summary, we have the interesting, though quite perplexing, observation that

(+)-3-endo-9-dibromocamphor \8a in ch1orosu1phonic acid and bromine does not rearrange to 26 but in chlorosulphonic acid alone this process is very facile. Why the presence of bromine In the reaction mixture should inhibit the isomerisation pathway is not immediately obvious.

Several years ago, work was started in our laboratory towards the synthesis of disubstituted camphor derivatives and In particular the preparation of (+)^-9,10-dibromocamphor. Some earlier Japanese work was re• examined and it was shown that treatment of (+)-3-endo-9-dibromocamphor 18a with bromine in chlorosulphonic acid for 5-6 days gave, as the major

30 product, 3-endo-9,10-tribromocamphor 39 . Starting with (+)-3-endo-10-

181 dibromocamphor or 1O-bromocamphor ZA did not give 9-brominated products.

SCHEME 69 160 To explain the formation of 39 it has been suggested that protonation of 3-endo-9-dibromocamphor 18a followed by a Wagner-Meerwein (Scheme 69) leads to intermediate 371. Loss of a proton and bromination eventually yields 3-endo-9,10-tribromocamphor 39. The intermediate 371 could, theoretically, undergo a 2,3-exo-methyl shift to provide 372 which is a postulated intermediate in the formation of (-)-6-endo-9-dibromocamphor 26

(cf. Scheme 68). Since 26 is not formed, this postulated 2,3-exo-methyl shift does not occur and this may be due to the fact that the bromomethyl group in 372 would destabilise the developing adjacent positive charge.

The above results indicate that in order to obtain a chiral 9,10- disubstituted camphor it is necessary to start with (+)-3-endo-bromocamphor

15a. The 3-endo-bromo substituent is essential for the production of optically active 3-endo-9-dibromocamphor 18a. A second bromination results in 3-endo-9,10-tribromocamphor 39. This reasoning can be extended to the synthesis of (+)-9,10-dibromo-3-endo-methy1 camphor 150a (Scheme 64, route

B). A 3-endo-methyl substituent should serve the same function as the 3- endo-bromo substituent above, namely to prevent the formation of any symmetrical intermediates in the bromination sequence. Bromination would

10 362a 376a 150a

SCHEME 64, ROUTE B (repeated) still be expected to occur initially at the C-9 methyl group and a second bromination would provide 150a by a bromination of the C-10 methyl group.

161 DISCUSSION

4.2.1 C-3 Methyl at ion of Camphor and Derivatives182

We expected that (+)-camphor could be stereoselectively methylated to provide 3-endo-methy1 camphor 362a as the major product. It was assumed that the 7-syn methyl group (C-8) would block the top face of the enolate thus forcing the methyl iodide to approach from the endo face. In support of this hypothesis, the very similar systems 373a-e138,139,183 (Scheme 70)

373a R=CH2OCH2Ph

ft ^ 373b R=CH(CH3)OTHP

/ 373c R=CH3

373d R=CH20THP

373e R=CH2CH2CH2OTHP

374a R=CH3 375

374b R=CH2CH2OCH2Ph

SCHEME 70

were methylated using LDA/THF and methyl iodide to give the endo-methyl compounds as the predominant or exclusive products In all cases. Compounds

373a-e all possess a 7-syn methyl group which is responsible for blocking the top face of the enolate towards electrophi1ic attack. In contrast, methylat ion of norbornanones (374 and 375) lacking the C-7-syn methyl substituent184,185 provided C-3-exo methyl derivatives as the sole product.

When camphor 10 was deprotonated using LDA (0.95 equivalent) In THF at

0°C followed by treatment with methyl iodide, the product (70-85% yield) was

162 362b 362a

found to be a mixture of 3-exo and 3-endo-methylcamphor in the ratio of

4:1 . These ratios were determined by capillary glc and Integration of the

400 MHz *H nmr. A sample of pure 3-exo-methylcamphor 362b (the major product) was obtained by flash chromatography of the mixture on silica gel to provide 3-exo-methylcamphor 362b as a crystalline solid (mp 50-54°C).

Equilibration of the kinetic product with refluxing sodium methoxide in methanol or glacial acetic acid/hydrochloric acid at 80°C provided 362b and

362a in the ratio of 1:9 (by capillary glc and 270 MHz lH nmr). Subsequent low temperature crystallisation from pentane provided 3-endo-methylcamphor

362a (mp 37-39°C; [a]n +25.4° (C 2.5, MeOH))** as a crystal 1ine sol id. The

Since some equilibration could have occurred during 'kinetic methylatI on' the true kinetic ratio may be greater than observed.

The earlier literature describes the preparation and isolation of 3-

186

methyl camphor but the stereochemistry of the product was not known. Q The compound Isolated, mp 38-39°C; [ ]d +27.3° (C10.0, EtOH), was

almost certainly 3-endo-methylcamphor 362a prepared under thermodynamic

conditions. 163 structural assignments of 362a and 362b were based on the splitting patterns of the C-3 protons in the 400 MHz *H nmr spectra of the two compounds. The

C-3 exo proton appears as a pentet (actually a partially overlapping quartet

of doublets) due to coupling with the C-3 endo methyl group and the C-4

bridgehead proton. In contrast, the C-3 endo proton does not couple with

the C-4 hydrogen (the dihedral angle between the two protons is 90°) and

appears as a quartet (J = 7.5 Hz). Substituents in the C-3-exo position

adjacent to the carbonyl group consistently appear further downfield than

substituents in the endo direction. For example, the C-3 methyl group

resonance in 3-exo-methy1 camphor 362b occurs as a doublet at 61.21 (J = 7.5

Hz) whereas in 3-endo-methylcamphor 362a it appears as a doublet at 61.06 (J

= 7.5 Hz).

The formation of 3-exo-methy1 camphor 362b as the kinetically favoured

product (~80% of the methylated product) was completely unexpected. Exo-

methylation was also found to dominate in two other camphor systems. Thus,

when 9-bromocamphor J_9 was methylated under similar conditions (Scheme 71),

the product was shown by 400 MHz *H nmr to consist of 9-bromo-3-exo-

methy 1 camphor 376b and 9-bromo-3-endo-methy1 camphor 376a in a ratio of

~1.7:1. Subsequent equilibration with HCl/HOAc provided the endo-methyl

isomer as the major component of the mixture (endo;exo ~10:1). Similarly,

9,10-dibromocamphor 37 can be methylated to provide 9,10-dibromo-3-exo-

methy1 camphor 150b and 9,10-dibromo-3-endo-methylcamphor 150a in a ratio of

~1.7:1. Equilibration with HCl/HOAc provided a 6:1 mixture of endo to exo

methyl epimers.

ln contrast to the kinetic exo-stereose1ectivity described above, C-3

methyl at ion of 3-methylcamphor 362 displays endo selectivity. Thus

sequential treatment of 3-methylcamphor 362 with LDA in THF at 0°C followed

164 362a,b 377a 377b

SCHEME 71 by addition of trideuteriomethyl iodide (CD D provided a product (~60% 3 l yield) which was shown by H nmr (400 MHz) to be a mixture of 3-exo-methyl-

3-endo-trideuteriomethy1 camphor 377a and its epimer 377b in the ratio ~4:1.

The structural assignments for 377a and 377b were made based on the fact that the chemical shift of an exo-methyl group appears between 0.1 and 0.15 ppm further downfield than the endo methyl substituent (Figure 13).

Confirmation of these assignments was provided by an NOE difference

165 CH3 CD,

CD3 CH,

377a 377b C-7 syn methyl group

C-4 proton irradiate C-3 cxo methyl group

NOE Difference Experiment

1 400MHz H nmr

^ >

uk \ i 0 DDB

FIGURE 13 : JH NMR Spectrum and NOE Difference Experiment of "~ Ketones 377a and 377b

166 experiment shown in Figure 13. Irradiation of the methyl singlet at 61.19 provided an enhancement of the methyl singlet at 60.91 (and thus assigned as the C-7 syn methyl group) and a multiplet at 61.82 (the C-4 proton). This

result is consistent with the singlet at 61.19 being due to the exo-methyl

substituent.

In order to provide an explanation for the kinetic exo-methylat ion of

camphor and derivatives it is first necessary to examine the results 184 obtained for other bicyclo[2.2.1]heptanone systems. Norcamphor 375 and l ft5 5,6-dehydronorcamphor derivatives 374 both undergo exclusive exo-

methyl at ion (Scheme 72) while the related 5,6-dehydroketones 373a-

138 139 183 e , which possess a 7-syn methyl group, give overwhelmingly the

endo methyl adduct as the major or exclusive product. In addition, it has

1R7 been reported that 5-ketobornyl methyl ether 378 ' can be converted

exclusively to the corresponding 3-exo-allyl derivative. Camphor, as has

already been described, provides the thermodynamically less stable exo-

methyl camphor as the major product. The difference between camphor and

compounds 373a-e is basically the absence of the C-5 and C-6 endo protons

and presumably it is the C-5 proton which is the main cause of the

difference. The bulky endo-methyl ether substituent in the epicamphor

derivative 378 provides exclusive exo alkylation which gives further

credence to the effect of a C-5 endo substituent. In order to test this

result on a system directly related to camphor, both 5,6-dehydrocamphor 173

and 9-bromo-5,6-dehydrocamphor J7j> were prepared (p.187) and methylated In

the same manner as before*. Both 173 and 175 yielded the endo-methyl

product as the major isomer (> 12:1 endo to exo) and in each case the These methyl ation experiments were performed by G. Antoniadis (UBC).

167 SCHEME 72 thermodynamic product is exclusively endo. Thus a C-5 endo substituent does play an Important role in the methyl at ion of bicyclo[2.2.l]heptanones.

The difference between compounds 373a-e and compound 374a.b is basically the presence or absence of a 7-syn-methyl group. Without it, the product is exclusively the exo-methyl derivative. Hence, the 7-syn methyl

group also plays an important role in determining the stereoselectivity of

168 C-3 alkylation of these ketones. The question arises then, why, in the

exo

374a absence of any steric effects (eg. as in compound 374a), is the product exclusively the one formed by exo-attack on the enolate?

Protonation/deuteration studies carried out on camphor and other

188a—f bicyclo[2.2.1]heptanones have shown that in all cases the enolate is protonated (deuterated) preferentially in the exo direction. Thus even with

steric factors in play (ie. a 7-svn methyl group and a C-5 endo hydrogen) exo-protonation results. These results indicate that there is an inherent preference for bicyclo[2.2.1]heptanone enolate systems to undergo exo attack.

189

Schleyer107 has proposed a steric argument based on torsional strain in the transition state to account for these results (Scheme 73) although the validity of this theory has been challenged1886. Attack on the enolate from the endo direction would cause the C-3 proton to move up and eclipse the C-4 proton. On the other hand, attack from the exo side would 169 D6?-D

u @ H 4 exo n4" 3 attack H

H © H H endo 0 attack

DO D

SCHEME 73

not give rise to any eclipsing between the C-3 and C-4 protons in the transition state. This theory does not apply to the result of treating the

enolate of 3-methylcamphor with C03i (equation 37). Here the major product is due to endo alkylation which should, according to von Schleyer's theory, be unfavoured due to the eclipsing of the C-3 methyl group and the C-4 proton in the transition state.

170 Perhaps another factor which could explain the observed results is one based on stereoelectronic control. There is some evidence to show that in norbornene and derivatives that the ir-system is distorted in favour of the

Norbornene

exo-direction * . These results have been cited as the reason for the exo-addition stereoselectivity (eg. in Diels-Alder reactions) observed for such derivatives. If these results can be extended from an a1kene to an enolate system this would explain the persistent exo-selectivity observed in the absence of other steric factors.

Again the fact that reaction of 3-methylcamphor 362 with CD^I gives rise to predominantly endo alkylation is difficult to explain. A similar 192 result has been observed by House and Umen in their study of the

SCHEME 74

171 stereochemistry in alkylations of substituted eye 1ohexanones (Scheme 74).

Methylat ion of 379 (R=H) yields approximately equal amounts of the axial and equatorial products, whereas for 379 (R=Me) axial alkylation predominates yielding 83% of the axial product and 13% of the equatorial product. House has proposed that these stereochemical results can all be explained in terms

193 of early reactant-1 ike transition states where the geometry of the

axial alkylation

alkylation

FIGURE 14 : The Enolate of Ketone 379 starting enolate determines the stereochemical outcome. More specifically, the enolate is not planar but skewed at an angle 6 in order to avoid eclipsing of the Cj-rj and C2-R substituents (Figure 14). The enolate is + deformed so that the C-l substituent (0~M ) does not eclipse the C-6 pseudoequator1a1 hydrogen. This deformation would result in a partial

3 rehybridisation of the p-orbital at C-2 towards an sp -orbital and this would favour axial attack. Equatorial attack would also be disfavoured

+ since it would cause eclipsing of the C-3 substituent R and 0~M in the transition state. The larger the C-3 substituent, R, the greater the distortion of the enolate and hence the increased tendency for axial attack.

The ideas expressed above can be used to explain the stereoselectivity of the alkylation of camphor j_0 and 3-methyl camphor 362 viz.:-

(a) Monoalkylatlon of camphor. The enolate of camphor (Figure 15) should not be particularly distorted since the C-3 substituent is a proton and

172 eclipsing interactions between it and the oxygen atom are minimal. The

FIGURE 15 : The Enolate of Camphor stereochemistry of methyl at ion would then be the result of a combination of the steric factors, ie the C-7 syn methyl group which promotes endo selectivity, the C-5 proton which promotes exo selectivity and the stereoelectronic factors which seem to favour exo attack. The sum of these effects, from our experiments, is that exo methylation is preferred although it is by no means exclusive. The formation of ~20% of the endo isomer indicates that the energy difference between the two transition states is very smal1.

(b) Dialkyl derivatives of camphor. The reversal of the approach of the electrophile in going from the camphor enolate (80% exo attack) to the 3- methylcamphor enolate (80% endo attack) indicates that perhaps another process is involved in this case. The enolate of 3-methylcamphor (Figure

16) should be skewed, according to the argument of House, to avoid the C-3 methyl substituent and the oxygen anion from being eclipsed. The direction of this distortion should be such that the oxygen atom has moved away from the C-10 methyl group to reduce the torsional strain between them. This would then cause the C-3 methyl substituent to move up and partially eclipse the C-4 proton. The net result of this distortion would be a partial rehybridisation of the C-3 p-orbital in the endo-dlrection thus favouring

173 FIGURE 16 : The Enolate of 3-Methylcamphor

endo attack. This alteration in the stereoelectronic factor coupled with the steric factors (a C-7 syn methyl group and a C-5 endo hydrogen) leads to endo attack. Presumably the combination of the C-7 syn methyl group and the

stereoelectronic factors now outweigh the effect of the C-5 endo proton.

Again the energy difference between exo and endo attack is small.

4.2.2 Further Observations on the C-3 Reactivity of Camphor

While investigating the stereoselectivity of the methylat ion of camphor and derivatives we also examined the stereoselectivity of the bromination of

camphor and derivatives.

This treatment of camphor enol trimethylsilyl ether 380 (Scheme 75) with bromine194 provided 3-exo-bromocamphor 15b and 3-endo-bromocamphor 15a

in high yield with the ratio of 15b to 15a being ~1:1. The same result was

obtained by treating camphor with pyridinium bromide perbromide in glacial

acetic acid at 100°C195. Epfmerisation of the epfmeric mixture provided 3-

endo-bromocamphor 15a as the major product, the ratio of endo (15a) to exo

174 SCHEME 75

(15b) being 91:9 (as determined by the integration of the C-3 protons in the

400 MHz *H nmr)*.

Similar treatment of 3-methylcamphor 362 and 9-bromo-3-methylcamphor

376 with pyridinium bromide perbromide provided the corresponding 3-endo- bromo to 3-exo-bromo compounds (381a and b and 382a and b, Scheme 76) in the ratio 4:1**. In contrast, the kinetic bromination of norcamphor 375 with

Compare this with the value of 92:8 for .15a to 15b obtained by Lowry 196 and co-workers by optical rotation measurements

This ratio was determined by capillary glc. The products were identified on the basis of the chemical shift of the 3-methyl substituents. Confirmation of these assignments was provided by an NOE difference experiment performed on 382a, see Experimental, p.278.

175 the same bromimating reagent provided a 95:5 mixture of 3-exo- bromonorcamphor 383a and 3-endo-bromonorcamphor 383b195. Equilibration with base (potassium tert-butoxide) provided an equimolar mixture of 383a and

383b. These results parallel the methylation experiments very closely and

Br 375 383a 383b

SCHEME 76

presumably they can be accounted for in a similar fashion even though the

electrophile in each case is quite different.

Camphor enol trimethylsilyl ether 380 on treatment with ozone (Scheme

75) yields a mixture "(1.3:1) of the 3-exo-trimethyl si 1yoxycamphor 384a and

its 3-endo epimer 384b197. Similarly, hydroboration of 380 yields (after an

oxidative work-up) the camphane-2,3-diols 385a (2-endo, 3-exo) and 385b (2-

exo. 3-endo) in a 2:3 ratio 19ft . Johnson and Fleming who published this

hydroboration work gave the opposite assignments to the products of the

176 reaction. They reasoned, erroneously, that hydroboration of camphor enol trimethylsilyl ether 380 would occur preferentially from "the less hindered endo face of the compound". From their result they proposed that the

1 99 assignment of the published nmr spectra of the trans camphane-2,3- diols*" should be reversed.

Earlier work in our laboratory on the chemical and microbiological oxidation of bornyl acetate 30 provided a small amount of 385a as a by-

30 385a

20? 1 product . The H nmr spectrum of 385a, the 2-endo, 3-exo-camphane diol, 201 199 was identical to that reported by Takeshita and Katajtma and Anet . This fact, coupled with our work on the C-3 stereoselectivity of camphor and derivatives, allowed us to conclude that the proposed correction 203 is in error . Further confirmation of this has recently been provided by 0 fl A

Angyal and co-workers by an X-ray crystallographic analysis on the dibenzoate of 385a.

4.2.3 Brominations and Rearrangements of Camphor Derivatives

(i) The Attempted Preparation of (+)-9,10-Dibromo-3-endo-methylcamphor 150a

In order to syntheslse 9,10-dibromo-3-endo-methy1 camphor 150a, we proposed to brominate 3-endo-methylcamphor 362a sequentially at the C-9 and

C-10 positions (cf. Scheme 64, route B). 3-endo-Methy1 camphor 362a was prepared by methyl ation of camphor, equilibrating the product, and crystallising the major isomer (362a). Treatment of 362a with bromine in

177 chlorosulphonic acid at room temperature for two days gave three new compounds (as monitored by glc). The major product (Scheme 77) was obtained

150a 387,

SCHEME 77

by column chromatography followed by crystallisation to provide (+)-9-bromo-

3-endo-methylcamphor 376a in 41% yield. Further elution of the column gave a second compound which was isomeric with 376a. The structure and absolute configuration of this by-product (and of the major product, 376a) was determined by an X-ray crysta11ographic analysis148 and this showed the compound to be the bromoisofenchone 386.

A proposed mechanism for the formation of the bromoisofenchone 386 is shown in Scheme 78. A Wagner-Meerwein rearrangement followed by a 2,3- methyl shift and bromination would yield the intermediate 389. This intermediate 389 could take path A (cf. Scheme 67) and give 9-bromo-3-endo- methy1 camphor 376a or it could rearrange via path B. Thus a Wagner-Meerwein rearrangement, a 2,6-hydride shift, another Wagner-Meerwein rearrangement and a 2,3-methyl shift would yield the cation 390. A cation of this type is

178 proposed as the penultimate step in the production of (-)-6-endo-9- dibromocamphor 26 (from (+)-3-endo-9-dibromocamphor 18a, Scheme 68) and of

(-)-camphor entlO (from (+)-camphor JfJ, cf. Scheme 66). Instead of producing (-)-9-bromo-6-endo-methy1 camphor 391, this cation 390 presumably undergoes a 2,6-hydride transfer and then a Wagner-Meerwein rearrangement to give the bromoisofenchone 386.

The reaction of 9-bromo-3-endo-methy1 camphor 376a with bromine in chlorosulphonic acid did not yield any of the desired 9,10-dibromo-3-endo- methy1 camphor 150a. The dibromoisofenchone 387 and the bromoisofenchone 386 were the only compounds isolated (Scheme 77). Presumably 376a rearranges under acidic conditions to 386 and then undergoes bromination to provide

387. This hypothesis is confirmed by the fact that in chlorosulphonic acid alone 9-bromo-3-endo-methylcamphor 376a does rearrange to the bromoisofenchone 386. Subsequent reaction of 386 with bromine in chlorosulphonic acid provides the dibromoisofenchone 387 as the exclusive product. The structure of this dibromo compound (387) was deduced in the following manner: the mass spectrum gave molecular ions at 326/324/322 in the ratio 1:2:1 indicating the presence of two bromine atoms. The 400 MHz

*H nmr showed a great deal of structural similarities to the

386 , 388

179 391 386

SCHEME 78

180 bromotsofenchone 386 and Indicated that the second bromine atom was situated at either C-3 or C-7. Bromination of 386 using pyridinium bromide perbromide provided the 3-exo-bromo derivative 388 which was different from the dibromo compound already isolated. Consequently this compound must have the bromine atom situated at the C-7 carbon atom. Examination of the 400

MHz 'H nmr spectrum showed the C-7 proton to be a triplet (J = 3 Hz) and this can only be explained by having the proton anti to the carbonyl group.

syn Br^H anti

387

In this configuration, the C-7 proton couples with the C-4 proton and the C-

3-endo proton by long range 'W coupling. Final confirmation of this structure was provided by an NOE difference experiment where irradiation of the bromomethylene protons resulted in an enhancement of the proton assigned as the C-7 anti hydrogen.

A mechanism to account for the formation of 387 is shown in Scheme 79.

Protonation of the carbonyl group followed by Wagner-Meerwein rearrangement yields the cationic Intermediate 392 which can lose-a proton to provide an endo-cyc1ic double bond 393. E1ectrophi1ic attack of this double bond exclusively from the exo direction and a retro Wagner-Meerwein would give rise to the dibromoisofenchone 387.

The formation of the isofenchone derivatives 386 and 387 during the bromination of 376a make this route to 3-endo-methy1-9,10-dibromocamphor

150a redundant. Compound 150a was prepared Instead by direct methylat ion of

181 9,10-djbromocamphor 37 (cf. route A, Scheme 64) as described earlier

(P.154).

SCHEME 79

(ii) Other Rearrangement Reactions of Camphor Derivatives: The Synthesis of

(-)-Camphor entlO and (+)-5,6-Dehydrocamphor 173

During the preparation of (+)-3-endo-9,10-tribromocamphor 39 from (+)-

3-endo-9-dibromocamphor 18a, a small amount of a by-product (approximately

8% of the crude product by glc) was isolated and characterised. This compound was found to be an isomer of 3-endo-9-d1bromocamphor and an X-ray analysis proved it to be the dibromofenchone 394. This compound could arise via a double Wagner-Meerwein rearrangement (Scheme 80). A small amount of the isomeric dibromofenchone 395 was also isolated from the analogous reaction performed on (+)-3,8-dibromocamphor 40147.

182 Br Br Br

SCHEME 80

These dibromofenchones (394 and 395) are interesting molecules from the point of view of their possible use as synthetic intermediates in organic synthesis. Because of this we decided to investigate this reaction further in the hope that the dibromofenchone 394 could be prepared in a sufficient yield to be synthetically useful. Since 394 was obtained by isomerisation of 3-endo-9-dibromocamphor 18a under bromination conditions which preferentially yield tribrominated products we decided to repeat the reaction in the absence of bromine. We were mindful of the fact that

Nishikawa had used these conditions in order to prepare (-)-6-endo-9- dibromocamphor 2623 (Scheme 68) but we thought it worthwhile to reinvestigate this reaction. Thus we were not surprised to find that (+)-3- endo-9-dibromocamphor 18a on treatment with chlorosulphonic acid at 55°C for

1 hour did indeed yield (-)-6-endo-9-dibromocamphor 26 (55% isolated yield) and a small amount of the dibromoisofenchone 394 (5% isolated yield). The structures and absolute configurations of both of these products were confirmed by X-ray analysis148. The rearrangement of (+)-3-endo- bromocamphor 15a to (-)-6-endo-bromocamphor 172 has, to our knowledge, not been reported although it is interesting to note that Nishikawa et a^ found

183 that 3-ch1orocamphor yielded only 3-chlorocamphor-9-sulphonic acid on reaction with fuming sulphuric acid. In contrast we found that treatment of

(+)-3-endo-bromocamphor 15a with chlorosulphonic acid at 50°C resulted in

15a 172 396

rearrangement to (-)-6-endo-bromocamphor 173. The reaction was complete in

14 minutes and 173 could be isolated in a yield of 36%. A minor by-product

(1% yield) is the bromofenchone 396.

Proof of structure and absolute configuration was provided by debromination of 396 with tri-n-butyltin hydride in benzene to give (-)-

camphor, entlO, [a]Q -44.75° (C 0.40, 95% EtOH). Authentic (+)-camphor

(Aldrich Chemical Co.) has an optical rotation of +44.8° (C 0.386, 95%

EtOH).

The mechanism for this reaction (cf. Scheme 68 p.159) predicts that the

C-8 and C-10 methyl groups should be interconverted. In order to confirm this, the reaction was repeated using (+)-3-endo-bromo-10-deuteriocamphor

398 which was prepared from (+)-10-bromocamphor 23 (Scheme 81) by

184 debromlnation with tri-n-butyltin deuteride* followed by bromination

at C-3 to yield 398. Rearrangement of the 10-deuterio-derivative 398

followed by hydrogenolysis (n-Bu3SnH) provided (-)-8-deuteriocamphor 400

which was identical (400 MHz 'H nmr, ms) to an authentic sample prepared 205

from 8-bromocamphor 34 . This reaction was carried out by T. Atlay (UBC). » 185 Thus the treatment of either (+)-3-endo-bromocamphor 15a or (+)-3-endo-

9-dibromocamphor 18 in chlorosulphonic acid at 50°C allows the preparation of (-)-6-endo-bromocamphor derivatives 172 and 26. Both of these compounds are potentially useful chiral synthons in organic chemistry*. For example, we required 5,6-dehydrocamphor 173 and 9-bromo-5,6-dehydrocamphor 175 in order to study the stereoselectivity of C-3 methyl at ion of the two compounds

(see p.168). The literature methods for the preparation of 5,6-

2f)6 2f)7 dehydrocamphor 173 ' are multistep procedures involving the remote oxidation of bornylacetate 30 (a reaction which is reported to occur in 40% yield) . The most recently published route (1982) has 9 steps and is, 206 according to the authors , the best method for the preparation of optically active 5,6-dehydrocamphor 173. It seemed to us that a dehydrobromination of (-)-6-endo-bromocamphor 172 would be a simple, more

I Br 172 R= H 173 R= H 26 R= Br 175 R= Br practical way of preparing this compound since dehydrobromination of 1(34 186 208 209 bicyclo[2.1.l]heptane systems is a well known procedure ' ''. For 208 example, Finch and colleagues treated the bromoketone 401 with DBU in refluxing xylene for 4 days and obtained the norbornenone 402 in high yield.

6-endo-bromocamphor 172 was prepared in 4 steps from a-pinene (no 206 yield given) by Hietaniemi and Malkonen as substrate analogues for studying the mechanism of cytochrome P-450 catalysed reactions. cam ' ,

186 When this reaction was attempted with (-)-6-endo-bromocamphor 172,

Br 401 402

dehydrocamphor 173 was not produced. The use of different solvents

(benzene, toluene, DMSO) or carrying out the reaction neat also proved fruitless. When potassium tert-butoxide was employed as the base (in either

tert-butanol or benzene) the major product isolated was a-campholenic acid

24 which is the result of attack by the tert-butoxide anion on the carbonyl followed by ring cleavage to yield the tert-butyl ester 403. Hydrolysis in the work-up provides 24. No dehydroha1ogenation was observed under these conditions. The use of potassium hydroxide in DMSO/water at 60°C, however, finally proved successful and 5,6-dehydrocamphor 173 was Isolated in 18% yield. Also formed in this reaction was a-campholenic acid 24 (see p.52 ).

Subsequent studies showed that raising the temperature of the reaction to

o * 70 C allowed the yield of 173 to be increased to a more acceptable 47% .

* The yields in this reaction were optimised by G. Antioniadis (UBC).

187 When (-)-6-endo-9-dIbromocamphor 26 was subjected to the same conditions, 9- bromo-5,6-dehydrocamphor 175 was Isolated in 22% yield with a small amount of the hydroxyacid 174 also obtained.

C02H 174

In summary, (+)-5,6-dehydrocamphor 173 can be prepared in just two

steps from (+)-3-endo-bromocamphor 15a, without purification of (-)-6-endo- bromocamphor , in 17% overall yield. Despite the fact that this yield is

rather low, the sheer simplicity of this route and the fact that it provides an optically pure product makes this the most convenient and efficient route

210 to JJ73 available . The UV, CD, and photochemical properties of (+)-5,6-

211 dehydrocamphor 173 have been investigated (eg. it has a remarkably high

specific rotation of +756° (C 0.5, CH and it has also been used as a 2ci2))

p_4 206,212 substrate for studying 50 epoxidation reactions - Other aspects cam of the chemistry of 173 and 175 are currently under investigation in our

213 laboratory • .

188 EXPERIMENTAL

General

Melting points (mp) were determined on a Kofler micro heating stage and

are uncorrected. Infrared (ir) spectra were recorded on a Perkin-Elmer

model 710 B spectrophotometer and were calibrated using the 1601 cm-1 band.

of polystyrene. Absorption positions (vmax) are given in cm Optical

rotations ([a]p) were measured on a Perkin-Elmer 141 polarimeter at ambient

temperature. The proton nuclear magnetic resonance ('H nmr) were taken in

deuterochloroform and recorded at 80 MHz on a Bruker WP-80 spectrometer, at

100 MHz on a Varian XL-100 spectrometer or at 270 MHz on a unit consisting

of an Oxford Instrument 63.4 KG superconducting magnet, a Nicolet 32K

, computer and Bruker TT-23 console. Signal positions are given in parts per

million downfield from tetramethylsi lane using the 6 scale. In the case of

compounds containing trialkylsilyl groups the chemical shifts were

determined relative to the chloroform signal (67.25). Signal multiplicity,

coupling constants and assignments of selected signals are indicated in

parentheses. nmr spectra were made in deuterochloroform and determined

on a Bruker WP-400 instrument at 100.6 MHz with signal positions given in

parts per million downfield from tetramethylsi lane (used as an external 19

standard). F nmr spectra were obtained in deuterochloroform using either

a Varian XL-100 instrument operating at 94.1 MHz or a Bruker HXS-270

spectrometer at 254 MHz. The signals are quoted in parts per million

downfield from trifluoroacetic acid (used as an external reference). Low

resolution mass spectra were obtained using a Varian MAT CH-4B spectrometer

and exact masses were obtained by high resolution mass spectroscopy on a

Kratos MS-50 mass spectrometer. All compounds characterised by high

resolution mass spectrometry exhibited 1 spot on tic. Low resolution gas

189 liquid chromatography/rnass spectra (gc/ms) were obtained on a Carlo Erba 41

60/Kratos MS80 RFA instrument using a 0.25 mm x 15 m column with helium as the carrier gas. Gas-liquid chromatography was performed on either a

Hewlett Packard model 5830A gas chromatograph with a. 6 ft x 1/8 in. column of 3% OV-17 or a Hewlett Packard model 5880A gas chromatograph using a 50 m or 12 m x 0.2 mm column of Carbowax 10 M or a 12 m x 0.2 mm column of 0V-

101. The carrier gas was nitrogen for the 5830A and helium for the 5880A.

In all cases a flame ionisation detector was used. X-Ray crystallographic analyses were carried out by Dr. S. Rettig and Microanalyses were performed by Mr. P. Borda, Microanalytical Laboratory, University of British Columbia,

Vancouver.

All reactions involving moisture sensitive reagents were performed under an atmosphere of dry argon using either oven or flame dried glassware.

All reaction products were dried by allowing the solutions to stand over anhydrous magnesium sulphate. The solvents and reagents used were purified as follows: tetrahydrofuran and dimethoxyethane were distilled from calcium hydride and then from lithium aluminum hydride (LAH). Diethyl ether was distilled from LAH and hexamethylphosphoramide (HMPA), benzene, methylene chloride, diisopropylamine, triethyl amine, dimethylsulphoxide (DMSO), and pyridine were distilled from calcium hydride. Methanol was obtained by distillation from magnesium methoxide. Petroleum ether (the hydrocarbon fraction of boiling range ~30-60°C) was distilled prior to use.

Flash chromatograpy was performed using Merck silica gel 60, 230-400 mesh and thin layer chromatography (tic) using Bakerflex silica gel 1B2-F sheets. All chemicals were supplied by Aldrich Chemical Company unless otherwise stated.

190 Preparation of (+)-9,10-Dibromocamphor 37 and Isolation of

(-)-Dibromofenchone 394

(i) (+)-3-endo-9-Dibromocamphor 18a

To (+)-3-endo-bromocamphor 15a (100 g, 0.433 mmol) in a 500 mL round bottom flask in an ice bath was added chlorosulphonic acid (80 mL) and bromine (35 mL, 0.683 mmol). The ice bath was then removed and the reaction stirred for 1 hr before being quenched on ice/sodium bisulphite (solid).

Extraction with ether (3 x 450 mL) followed by treatment of the ether layer with solid sodium bicarbonate then water (x 3) and removal of the dried solvent provided a white crystalline solid (133 g) which was 84% (+)-3,9- dibromocamphor 18 by glc (OV-17, 190°C). This material was used without further purification.

(ii) (+)-9,10-Dibromocamphor 37

To the crude 3-endo-9-dibromocamphor 18a (133 g) In a 1 L round bottom flask at 0°C was added chlorosulphonic acid (160 mL) and bromine (40 mL,

0.78 mmol). The ice bath was removed, the flask covered with aluminum foil and the reaction stirred for 6 days. Further portions of chlorosulphonic acid and bromine (20 mL and 15 mL respectively) were added after the second and third days. The mixture was worked up as before to yield the crude (+)-

3-endo-9,10-tribromocamphor 39 as a viscous dark orange oil (132 g). This

191 was immediately dissolved in ether (250 mL) and glacial acetic acid (100 mL) at 0°C in a 1 L erlenmeyer flask and treated with zinc (35 g, 0.54 mmol) in portions (care!) over 20 min. The reaction was stirred vigorously for 45 min. This was then poured onto water, extracted with ether (x 3) and the excess acetic acid removed ,with sodium bicarbonate. Two further water washes, drying (MgSO^) and evaporation provided a viscous oil (72 g). This oil is typically composed of 9,10-dibromocamphor 37 (557.), 9-bromocamphor 19

(30%) and dibromofenchone 394 (8%) as determined by glc (OV-17, 190°C).

(+)-9,10-Dibromocamphor 37 (30 g, 22% overall) was precipitated out by treatment of the crude oil with methanol/petroleum ether.

In a separate experiment, the by-products were isolated and identified.

Column chromatography (silica gel; petroleum ether/ether 24:1) provided the

(-)-dibromofenchone 394 as a white crystalline solid mp 70.5-72°C; [a]n

1 -225.3° (C 1.13, MeOH); vmax (CHC13). 1740 cm" ; * (CDC13, 270 MHz): 1.11

(3H, s), 1.23 (3H, s), 1.44 (IH, m), 1.87 (2H, m), 2.30 (IH, m), 2.53 (IH, d, J = 3.5 Hz), 3.36 (IH, d, J = 10.5 Hz), 3.48 (IH, d, J = 10.5 Hz), 4.19

(IH, br s); m/e (relative intensity): 312/310/308 (M+, 0.7/1.5/0.7), 231/229

(8/8), 203/201 (14/14), 121 (28), 107 (13), 93 (17), 81 (100), 79 (19);

Exact mass calcd. for C1()H140Br2: 311.9371/309.9391/307.9411; found:

311.9362/309.9394/307.9367; Anal. calcd. for C10H,4OBr2: C 38.74, H 4.55, Br

51.55; found: C 38.81, H 4.50, Br 51.36. The structure and absolute 148 configuration of this compound was confirmed by X-ray analysis

Further elution provided 9-bromocamphor ]9 as a white crystalline solid

1 19 identical (tic, glc, H nmr) to an authentic sample .

* 19 This is a modification of the method used by Corey et al_ . ** 30 This is a modification of the method used by Dadson et ai .

192 (+)-9,10-Dibromocamphor Ethylene Ketal 153

37 153

(+)-9,10-Dibromocamphor 37 (5.0 g, 16.1 mmol), ethylene glycol (15 mL,

0.27 mmol), para-toluenesulphonic acid (100 mg) and dry benzene (60 mL) were refluxed In a Dean-Stark trap containing 4A molecular selves for 1 week.

The seives were replaced every 24 hrs. The solution was poured onto brine and extracted with ether (3 times). The combined organic layers were washed twice with water, dried (MgS0 ) and filtered through a silica gel pad. 4 Removal of the solvent provided a crude oil (5.40 g). Column chromatography

(silica gel, petroleum ether/ether 50:1) gave starting material (1.0 g) and

(+)-9,10-dibromocamphor ethylene ketal 153 (3.66 g; 64% yield; 76% based on recovered starting material) as a white crystalline solid, mp 38-42°C; vmax

1 (CHC1 ): 2960, 2880, 1150, 1120 cm" ; 6 (CDClg, 400 MHz): 1.27 (3H, d, J = 1 3 Hz), 1.37 (IH, m), 1.50 (IH, d, J = 14 Hz), 1.80 (IH, m), 1.89 (IH, m), 2.02

(IH, m), 2.18 (2H, m), 3.43 (IH, d, J = 10 Hz), 3.51 (d) and 3.53 (d) (2H,

AB quartet, J = 12 Hz), 3.69 (IH, dd, J = 10 Hz, 1 Hz), 3.72-3.99 (4H, m,

+ ketal protons); m/e (relative intensity): 275/273 (M -Br, 98/100), 193 (47),

149 (18), 131 (24), 121 (26), 107 (79), 105 (26); Anal. calcd. for

C H Br : C 40 71 H 5 12, Br 45 13 12 18°2 2 ' ' * - ' found: C 40.96, H 5.17, Br 45.00.

193 Preparation of 9,10-Dicyanocamphor Ethylene Ketal 154 and Ring Cleaved

Product the Cyanoester 155

Br CN >Br tN

153

(+)-9,10-Dibromocamphor ethylene ketal 153 (2.1 g, 5.9 mmol), sodium cyanide (0.87 g, 17.8 mmol) and potassium iodide (50 mg) were stirred in dry dimethylsulphoxide (25 mL) at 110°C under argon for 6 days. The mixture was poured onto brine, extracted with ether three times and the combined organic layers washed twice with brine, dried and the solvent removed. The residue

(1.1 g) was shown to be 47% cyanoester 155 and 36% dicyano camphor ethylene ketal 154 by glc (OV-17, 210°C). A portion of this material was subjected to column chromatography (silica gel; petroleum ether/ether 1:1) to provide a sample of the dicyanocamphor ethylene ketal 154, which was recrystal1ised from ether/petroleum ether to yield colourless needles mp 73.5-74.5°C; vmax

1 (CHC1 ): 2250 cm" ;

~~(IH, d, J = 13.5 Hz; C-3 endo proton), 1.68 (IH, m), 1.81 (IH, m), 2.06 (IH, ddd, J = 13.5 Hz, 5 Hz and 3 Hz; C-3 exo proton), 2.18 (IH, dd, J = 4.5 Hz,~~

~~4.5 Hz; C-4 proton), 2.32 (IH, ddd, J = 13 Hz, 9 Hz, 4 Hz), 2.38 (d) and~~

~~2.46 (d) (2H, AB quartet, J = 18 Hz), 2.38 (d) and 2.54 (d) (2H, AB quartet,~~

~~J = 18 Hz), 3.75-4.0 (4H, m, ketal protons): m/e (relative intensity): 246~~

~~+ (M , 0.9), 231 (1.1), 206 (100), 120 (56), 87 (96); Exact mass calcd. for~~

~~C H N : 14 18°2 2 246-13685 found: 246.1376.~~

~~Further elution using pure ether provided the cyanoester 155 as a~~

~~1 colourless oil vmax (CHC1-): 3630, 3500 (br), 2375, 1730, 1660 and 900 cm" ;~~

~~194 6 (CDC13, 400 MHz): 1.06 (3Ht s), 1.42 (IH, m), 2.00 (2H, m, one proton~~

~~exchangeable with D20), 2.29 (IH, dd, J = 16 Hz, 8 Hz), 2.35-2.50 (3H, m),~~

~~2.50 (2H, s, CH2CN), 2.55 (IH, dd, J = 16 Hz, 4 Hz), 3.84 (2H, br s;~~

~~sharpens to a multiplet on addition of D20; CH2OH), 4.24 (2H, m; CH2CH2OH),~~

~~4.94 (IH, t, J = 2 Hz), 5.03 (IH, t, J = 2 Hz); m/e (relative intensity):~~

~~237 (M+, 4.5), 176 (46), 175 (25), 134 (96), 133 (29) 108 (100), 93 (46);~~

~~Exact mass calcd. for C^HjqOgN: 237.1365; found 237.1366.~~

~~Cleavage of 9,10-Dibromocamphor Ethylene Ketal 153 in Dimethy1su1phoxide~~

~~153~~

(+)-9,10-Dibromocamphor ethylene ketal 153 (180 mg) was dissolved in dry dimethylsulphoxide (10 mL) and heated to 110°C for 4 hr. The solution was cooled, acidified with 1 N hydrochloric acid and extracted three times with ether. The ethereal layers were washed with water (3 times), dried and evaporated to yield a colourless oil (94 mg). Purification by column chromatography (silica gel; petroleum ether/ether 2:1) gave starting material (34 mg) and the bromohydroxy ester 156 (36.4 mg) vmax (film): 3420

~~(br), 1740, 1660, 890 cm"1;~~

~~1.90 (IH, br s, exchangeable with D20), 1.97 (IH, m), 2.22 (IH, m), 2.30-~~

~~2.47 (2H, m), 2.53-2.64 (2H, m), 3.37 (IH, d, J = 10 Hz), 3.46 (IH, d, J =~~

~~10 Hz), 3.85 (2H, m), 4.24 (2H, m), 4.85 (IH, t, J = 2.5 Hz), 5.00 (IH, t, J~~

~~= 2.0 Hz); m/e (relative intensity): 292/290 (M+, 0.1/0.1), 275/273~~

~~(1.4/1.3), 197 (45), 107 (100).~~

~~195 Preparation of the Bromoester 158~~

~~V~Br~~

~~37 158~~

~~Sodium metal (0.41 g, 17.8 mmol) was added to dry methanol (50 ml) under argon at 0°C. When all the sodium had reacted, 9,10-dibromocamphor 37~~

(3.68 g, 11.9 mmol) was added and the solution warmed to aid the compound to dissolve. After 6 hr the reaction was terminated by pouring on to brine, acidifying with 1 N hydrochloric acid and then extracting three times with ether. The organic phase was washed once with brine, dried (MgSO^) and the solvent removed _in vacuo to yield the bromoester 158 (3.08 g, 99%). vmax

~~1 (CHC13): 1730, 1660, 1440, 900 cm" ; 6 (CDC13, 270 MHz): 1.05 (3H, s), 1.35~~

~~(IH, m), 1.93 (IH, m), 2.10 (IH, dd, J = 13.5 Hz, 11.5 Hz)', 2.25-2.41 (2H, m), 2.46-2.59 (2H, m), 3.36 (d) and 3.45 (d) (2H, AB quartet, J = 12 Hz),~~

~~3.67 (3H, s; 0CH3), 4.84 (IH, t, J = 2.5 Hz), 4.98 (IH, t, J = 2Hz); m/e~~

~~(relative intensity): 262/260 (M+, 0.1/0.1), 231/229 (1/1), 167 (57), 121~~

~~(15), 107 (100), 93 (22), 91 (24); Exact mass calcd. for CnH1702Br - OCH3:~~

~~231.0208/229.0228; found: 231.0211/229.0216.~~

~~(-)-Bromoacid 159~~

~~Nr^Br~~

~~196 METHOD A~~

To a solution of (+)-9,10-d1bromocamphor 37 (1.5 g, 4.8 mmol) in dimethylsulphoxide (51 mL) was added potassium hydroxide (1.35 g, 24 mmol) in water (10 mL). After 1 hr, the yellow solution was poured onto water and extracted once with ether. The ether layer was washed once with water and the combined aqueous layers were then carefully acidified with 6 N hydrochloric acid. This was extracted three times with ether and the combined ethereal layers washed with brine (twice), dried (MgS0 ) and 4 evaporated to yield the bromoacid 159 (1.17 g, 98%) as a white crystalline solid, one spot on tic. Recrystal1isation of a small amount of this material from petroleum ether afforded pure bromo acid 159, mp 62-64°C; [a] n

~~1 -45.8° (C 0.4, MeOH); vmax (CHClg): 2950 (br), 1705, 1640, 890 cm" ; 6~~

~~(CDC1 , 400 MHz): 1.08 (3H, s; angular methyl group), 1.39 (IH, m), 2.01 3~~

~~(IH, m), 2.18 (IH, dd, J = 16 Hz, 10 Hz), 2.32-2.48 (2H, m; allylic protons), 2.55 (IH, m; methine proton), 2.63 (IH, dd, J = 16 Hz, 4 Hz), 3.39~~

~~(d) and 3.47 (d) (2H, AB quartet, J = 10 Hz), 4.86 (IH, t, J = 2 Hz), 5.00~~

~~+ (IH, t, J = 2 Hz); m/_e (relative intensity): 248/246 (M , 0.4/0.4), 188/186~~

~~(4/4), 167 (7), 166 (17), 153 (100), 111 (32), 107 (98). Anal. calcd. for~~

~~C H 0 Br: C 48.58, H 6.12, Br 32.35; found: C 48.47, H 6.16, Br 32.20. in 1c o 10 15 C~~

~~METHOD B~~

(+)-9,10-Dibromocamphor 37, (1.0 g, 3.2 mmol), 0.5 N potassium hydroxide (80 mL, 40 mmol) and tetrahydrofuran (80 mL) were stirred at room temperature for 4.5 hr. Work-up as described above gave the bromoacid 159

~~(0.75 g, 94%) as a white solid.~~

~~197 Preparation of (-)-Hydroxyacid 161~~

~~METHOD A; From (+)-9,10-Dibromocamphor 37~~

A solution of (+)-9,10-dibromocamphor 37 (1.5 g, 4.8 mmol), potassium hydroxide (1.35 g, 24 mmol), dimethylsulphoxide (51 mL) and water (9 mL) was stirred at room temperature for 1.5 hr then 65°C for 20 hr. This was poured onto ice/brine and worked up as before to yield the hydroxyacid 161 (0.807 g, 917.) as a white crystalline solid. A pure sample of 161 was obtained by recrystal1isation of a portion from ethyl acetate/petroleum ether, mp 118-

~~1 119°C; [a] -21.4° (C 0.35, MeOH); vmax (CHC1 ): 2850 (br), 1705, 890 cm" ; D 3~~

~~(CDC1 , 400 MHz): 0.88 (3H, s), 1.39 (IH, m), 1.99 (IH, m), 2.22 (IH, dd, 6 3~~

~~J = 14 Hz, 9 Hz), 2.34 (IH, m), 2.40-2.56 (3H, m), 3.42 (d) and 3.53 (d)~~

~~(2H, AB quartet, J = 11 Hz), 4.82 (IH, t, J = 2.5 Hz), 5.02 (IH, t, J = 2.0~~

~~+ Hz); m/e (relative intensity): 184 (M , 2), 166 (8), 154 (32), 153 (34), 107~~

~~(97), 95 (85), 94 (100), 93 (65), 79 (52); Exact mass calcd. for C H, 0 : irj 6 3~~

~~184.1100; found: 184.1096; Anal. calcd. for C H 0 : C 65.19, H 8.75; irj 16 3 found: C 64.97, H 8.61.~~

~~METHOD B: From (-)-Lactone 160~~

~~160~~

~~198 (-)-Lactone j60 (49 mg, 0.3 mmol) was dissolved in tetrahydrofuran (5 mL) and treated with 0.5 N potassium hydroxide solution (5 mL, 2.5 mmol) for~~

~~30 min. The solution was partitioned between ether and 1 N hydrochloric~~

~~acid. After the usual work-up, the hydroxy acid 161 was obtained as a white~~

~~crystalline solid (54 mg, 1007.).~~

~~(-)-Lactone 160~~

~~A solution of the bromoacid 159 (1.67 g, 6.8 mmol), potassium hydroxide~~

~~in dimethylsulphoxide/water 9:1 (0.277 M, 24.55 mL, 6.8 mmol), silver(I)~~

~~oxide (0.35 g, 1.5 mmol) and dimethylsulphoxide (111 mL) was stirred at room~~

~~temperature for 1 hr and then at 70°C for 1 hr.~~

~~The solution was poured onto brine, extracted with ether (x 3) and the~~

~~ether extracts washed with brine and dried. Removal of the solvent provided~~

~~a yellow solid (1.23 g) which on trituration with cold petroleum ether gave~~

~~the lactone j60 (1.04 g, 92%; 96% pure by glc; 3% OV-17, 160°C) as a~~

~~crystalline solid. Subsequent recrystal1isat ion from petroleum ether~~

~~provided pure lactone J60; mp 96.5-98.5°C; [a]n -27.3° (C 0.42, CH2C12);~~

~~vrnax (CHClg): 1740, 1650, 890 cm"1; 6 (CDClg, 400 MHz): 1.05 (3H, s; angular~~

~~methyl group), i.45 (IH, nine line multiplet), 1.87 (IH, m), 2.01 (IH, seven~~

~~line multiplet; methine proton), 2.43 (IH, dd, J = 18 Hz, 13.5 Hz; HA), 2.43~~

~~(IH, m), 2.62 (IH, m), 2.78 (IH, dd, J = 18 Hz, 5.5 Hz; Hg), 4.23 (d) and~~

~~4.37 (d) (2H, AB quartet, J = 10 Hz), 4.63 (IH, t, J = 2.5 Hz), 4.83 (IH, t,~~

~~199 J = 2 Hz); m/e (relative intensity): 166 (M+, 15), 107 (23), 95 (18), 94~~

~~(100), 93 (24), 79 (70); Exact mass calcd. for C]()H]402: 166.0994; found:~~

~~: 166.0994; Anal. calcd. for ^lQ^l40z C 72.26, H 8.49, 0 19.25; found: C~~

~~72.12, H 8.68, 0 19.13.~~

~~Cleavage of (+)-10-Bromocamphor 23 to Provide (+)-Isocampholenic acid 170~~

~~(+)-10-Bromocamphor 23, (234 mg, 1.0 mmol) and potassium hydroxide~~

(284 mg, 5.0 mmol) were stirred in dimethylsulphoxide (11 mL) and water (1.5 mL) at 65°C for 1 hr. The solution was cooled, poured onto brine and extracted with ether. The aqueous phase was then acidified with 6 N hydrochloric acid and this then extracted with ethyl acetate (x 3). After

two washings with brine, the organic phase was dried (MgS04) and evaporated to yield a yellow of 1 (180 mg). Purification on silica gel (eluting with petroleum ether/ether 1:1) gave isocampho1 enic acid 170 as a colourless oil

~~(130.2 mg, 77%), [a]n +1.6° (C 0.5, CH2C12); vmax (film): 3000 (br), 1710,~~

~~1660, 885 cm"1;~~

~~J = 2 Hz); m/je (relative intensity): 168 (M+, 2), 153 (26), 108 (100), 93~~

~~(97), 91 (37), 79 (33); Exact mass calcd. for C10H16O2: 168.1150; found:~~

~~168.1152; Anal. calcd. for C10H16O2: C 71.39, H 9.59; found: C 71.13, H~~

~~9.59.~~

~~200 Cleavage of (-)-6-endo-Bromocamphor 172~~

~~(-)-6-endo-Bromocamphor 172 (300 mg, 1.3 mmol), potassium hydroxide~~

(364 mg, 6.5 mmol), dimethylsulphoxide (13 mL) and water (2 mL) were stirred together at 60°C for 36 hr. The solution was poured onto ice, extracted twice with ether and this washed once with brine, dried (MgSO.) and concentrated to yield a white solid (129.0 mg). Flash chromatography on silica gel (petroleum ether/ether 7:1) afforded a volatile white solid, (+)-

~~207 dehydrocamphor H3 (35 mg, 187.),* [a]n +756° (C 0.50, CH2C12) (lit [a]n~~

~~211b 1 -735° (C 1.0, EtOH), lit [a]n - 731° (EtOH)); vmax (CHClg): 1735 cm" ; 6~~

~~(CDC13, 400 MHz): 0.91 (3H, s), 1.01 (3H, s), 1.07 (3H, s), 1.93 (IH, d, J =~~

16.5 Hz; C-3 endo proton), 2.22 (IH, ddd, J = 16.5 Hz, 3.5 Hz, 1.0 Hz; C-3 exo proton), 2.68 (IH, br, s; C-4 proton), 5.58 (IH, br d, J = 5.5 Hz; C-6 proton), 6.71 (IH, dd, J = 5.5 Hz, 3 Hz; C-5 proton); m/e (relative

~~intensity): 150 (M+, 12), 93 (58), 85 (59), 71 (92), 69 (100); Exact mass calcd. for C.-H.,0: 150.1045; found: 150.1049. Further elution provided 10 14 starting material (65 mg).~~

~~The yields of this reaction have been improved to 47% for 5,6-~~

~~dehydrocamphor 173 and 42% for a-campholenic acid 24 by conducting the~~

~~. -,.or 210 reaction at 70 C.~~

~~201 The aqueous phases were combined and acidified with 1 N hydrochloric acid. It was then extracted with ether (x 3); washing with brine and~~

~~removal of the dried (MgS04) solvent gave (-)-a-campholenic acid 24 (86.5~~

~~mg, 40%; 50% based on recovered starting material), [a]n -8.2° (C 2.25,~~

~~22 1 CH2C12), (lit. [a]n -9.0° (C 1.1, CHClg)); vmax (film): 2950, 1710 cm" ? «5~~

~~(CDC13, 400 MHz): 0.80 (3H, s), 1.02 (3H, s), 1.62 (3H, br s), 1.94 (IH, m),~~

~~2.20-2.35 (2H, m), 2.40-2.52 (2H, m), 5.24 (IH, br s); m/_e (relative intensity): 168 (M+, 28), 153 (64), 135 (28), 108 (100), 107 (82), 93 (80),~~

~~91 (42).~~

~~Cleavage of (-)-6-endo-9-Dibromocamphor 26~~

~~(-)-6-endo-9-Dibromocamphor 26 (423 mg, 1.36 mmol), potassium hydroxide~~

(382 mg, 6.8 mmol), dimethylsulphoxide (13 mL) and water (2 mL) were stirred at 60°C for 24 hr. Work-up as before provided (before acidification of the aqueous phase) a crude oil (136 mg). Chromatography (silica gel; petroleum ether/ether 25:1) gave (+)-9-bromodehydrocamphor 175 (68.2 mg, 22%) as a

~~white crystalline solid, mp 46.5-48.5°C (sealed tube); [a]n + 377.2° (C 0.5,~~

~~1 CH2C12); vmax (CHClg): 1740 cm" ; <5 (CDC13, 400 MHz): 1.05 (3H, s), 1.08~~

~~(3H, d, J = 1 Hz; C-9 methyl), 2.01 (IH, d, J = 17 Hz; C-3 endo proton),~~

2.22 (IH, ddd, J = 17 Hz, 3.5 Hz, 1 Hz; C-3 exo proton), 3.00 (IH, br s; C-4 proton), 3.22 (IH, d, J = 10 Hz), 4.02 (IH, dd, J = 10 Hz, 1 Hz), 5.68 (IH, br d, J = 6 Hz; C-6 proton), 6.49 (IH, dd, J = 6 Hz, 3 Hz; C-5 proton), m/e

~~202 + relative intensity): 230/228 (M , 2/2), 188/186 (19/19), 107 (100), 91 (29),~~

~~79 (21); Exact mass calcd. for C^H^OBr: 230.0129/228.0150; found:~~

~~230.0135/228.0149; Anal. calcd. for C^H^OBr: C 52.42, H 4.72, Br 34.87; found: C 52.40, H 5.60, Br 34.77.~~

~~Further elution provided starting material (30.0 mg).~~

Acidification of the aqueous phase and work-up as before provided a crude solid (139 mg) which after chromatography (silica gel; petroleum ether/ether/acetic acid 150:50:1) gave the hydroxyacid 174 (59 mg) as a white crystalline solid, mp 102-103.5°C; [a] -19.52° (C 0.21, CH C1 ); n 2 2

~~1 vmax (CHC1 ): 3000 (br), 1705 cm" ; 6 (CDCl,, 400 MHz): 0.82 (3H, s), 1.65 3~~

~~(3H, br s), 1.97 (IH, m), 2.34 (IH, dd, J = 16 Hz, 9 Hz), 2.64 (IH, dd, J =~~

~~16 Hz, 5.5 Hz), 2.64 (IH, m), 2.70 (IH, m), 3.42 (IH, d, J = 11 Hz), 3.54~~

~~+ (IH, d, J = 11 Hz), 5.41 (IH, br s); m/e (relative intensity): 184 (M ,~~

~~0.01), 166 (17), 151 (32), 107 (59), 94 (100), 93 (80), 91 (63), 79 (95);~~

~~c H : 18 Exact mass calcd. for i6°3 4.1100; found: 184.1102; Anal. calcd. for 10~~

~~, 0 : C 65.19, H 8.75; found: C 65.01, H 8.70. C,nH c o 1U lb J~~

~~Cleavage of (+)-8•10-Dibromocamphor 38~~

~~(a) With Potassium Hydroxide~~

~~179 180~~

~~(+)-8,10-Dibromocamphor 38 (159 mg, 0.51 mmol), potassium hydroxide~~

~~(144 mg, 2.56 mmol), dimethylsulphoxide (6 mL) and water (0.75 mL) were~~

203 stirred for 1 hr at room temperature. The mixture was poured onto water and extracted with ether, the aqueous layer was then acidified (1 N hydrochloric acid) and extracted with ethyl acetate (x 3). After two washings with brine, the ethyl acetate layer was dried over MgS0 and then the solvent 4 removed under reduced pressure to provide a crude oil (118 mg). Flash chromatography (7 cm silica gel column; petroleum ether/ether 1:1) gave initially the alkene acid 179 (66.2 mg; 78%) as an oil which crystallised on standing, mp 45-48°C; [a] +167.9° (C 0.14, CH C1 ); vmax (film); 2950 (br), n 2 2 -1 1700, 1660, 890 cm ; 6 (CDCl,, 400 MHz): 1.33 (3H, s), 1.76 (2H, m; H and £ Hp), 1.99 (IH, ddd, J = 12 Hz, 9 Hz, 2 Hz; H^), 1.32 (IH, dd, J = 12 Hz, 9

~~Hz; Hg), 2.37 (IH, m; H or H^), 2.71 (IH, m; Hp), 2.77 (IH, m; H or H^), Q Q 3.38 (IH, ddd, J = 9 Hz, 9 Hz, 9 Hz; H ), 4.63 (br s) and 4.75 (br s) (IH c each; Hj and Hj); Irradiation at~~

~~+ Hz); m/e (relative intensity): 166 (M , 1), 151 (6), 121 (15), 105 (21), 94~~

~~for c (76), 93 (31), 91 (37), 79 (100), 77 (37); Exact mass calcd. H O : 10 14 2 H 0 : c 166.0994; found: 166.0992; Anal. calcd. for C i4 2 72.26, H 8.49; irj found: C 71.99, H 8.52.~~

Further elution provided the lactone 180 (17.5 mg, 20%) as a crystalline solid; mp 55-56.5°C; [a] +39.6° (C 0.23, CH C1 ); vmax (CHC1 ): D 2 2 3 -1 1740, 1660, 890 cm ; 6 (CDC1 , 400 MHz): 1.20 (3H, s), 1.40 (IH, 6 line 3 multlplet), 2.03 (IH, 6 line multiplet), 2.19 (IH, dddd, J = 7 Hz, 7 Hz, 7

~~Hz, 7 Hz; methine proton), 2.33 (IH, dd, J = 15 Hz, 7.5 Hz), 2.43 (2H, m; allylic protons), 2.64 (IH, dd, J = 15 Hz, 7 Hz), 3.96 (IH, d, J = 11.5 Hz;~~

~~204 CH_2-0), 4.07 (IH, d, J = 11.5 Hz; CH2-0), 4.82 (IH, t, J = 2 Hz), 5.02 (IH, t, J = 2 Hz); m/e (relative Intensity): 166 (M+, 1), 136 (21), 107 (25), 94~~

~~(100), 79 (82); Exact mass calcd. for C1DH1402: 166.0994; found: 166.0993;~~

~~H ^ o \40 C 72 26 H Anal . calcd. for l 2'' - « 8.49; found: C 72.10, H 8.50.~~

~~(+)-8,10-D1bromocamphor was kindly provided by Dr. S.E. Piper .~~

~~(b) With Sodium Methoxide~~

~~COsjMe~~

~~178~~

Sodium metal (17 mg, 0.74 mmol) was added to dry methanol (2.5 mL) and when all the metal had reacted (+)-8,10-dibromocamphor 38 (105 mg, 0.34 mmol) was added in one lot. The reaction was stirred at room temperature under an argon atmosphere for 20 hr before being quenched with a few drops of saturated ammonium chloride solution. The methanol was removed _in vacuo and the crude product partitioned between ether and brine. After two further extractions with ether, the combined ether extracts were washed

~~twice with brine, dried (MgS04) and the solvent removed to yield the bromo ester ±78 as a colourless oil (88 mg, 98% yield); vmax 1740, 1660, 890 cm-1;~~

~~6 (CDC13, 80 MHz): 1.23 (3H, s), 1.3-2.7 (7H, m), 3.32 (2H, s; CU2Br), 3.70~~

~~(3H, s; 0CH_3), 4.85 (IH, t, J = 2.5 Hz), 4.98 (IH, t, J = 2 Hz); m/e~~

~~(relative intensity): 262/260 (M+, 0.1/0.1), 231/229 (1/1), 167 (27), 107~~

~~(100).~~

~~205 Preparation of 3,8-Cyc1ocamphor 184~~

~~184 II~~

(+)-8-Bromocamphor 34 (447 mg, 1.94 mmol) and potassium hydroxide (542 mg, 9.68 mmol) were stirred in dimethylsulphoxide (22 mL) and water (3 mL) at room temperature. After 20 min, the dark orange solution was partitioned between water and ether. The aqueous layer was extracted 3 more times with ether, the ether layers combined and washed twice with water then dried

(MgSO^) and filtered through a pad of silica gel. Removal of the solvent under reduced pressure afforded (+)-3,8-cyclocamphor 184 (240 mg, 83%; 98% pure by capillary glc; OV-101, 120°C). Low temperature recrystal1isat ion o 27 from petroleum ether provided pure 184, mp 148-151 C (sealed tube), (lit

~~27 mp 151-152.5°C); [a]Q -194.2° (C 0.652, CHClg), (lit [cx]p -232°~~

~~1 (CHC13)**); vmax (CHCl,): 1745 cm' ; 6 (CDCl,, 400 MHz): 1.05 (3H, s), 1.06~~

~~(3H, s), 1.39 (IH, ddd, J = 14 Hz, 8 Hz, 8 Hz), 1.60 (IH, m; C-5 exo proton), 1.64 (IH, d, J = 8 Hz; C-8 proton), 1.80 (IH, ddd, J = 13 Hz, 9 Hz,~~

~~2.5 Hz), 1.90 (IH, m), 1.97 (IH, dd, J = 8 Hz, 3 Hz), 2.49 (IH, dd, J = 5~~

~~Hz, 2.5 Hz; C-4 proton), 2.86 (IH, dd, J = 3 Hz, 2.5 Hz; C-3 endo proton).~~

Decoupling of the proton at 61.97 causes the doublet at 61.64 to collapse to a singlet and the signal at 62.86 to a doublet (J = 2.5 Hz). Decoupling the signal at 62.49 causes the proton at 62.86 to appear as a doublet (J = 3 Hz) and the signal at 61.60 Is simplified, m/e (relative Intensity): 150 (M+,

~~11), 122 (22), 107 (61), 95 (100), 91 (54), 79 (93); Exact mass calcd. for~~

~~C,nH.A0: 150.1045; found: 150.1041. 10 14~~

~~206 28 This compound was kindly provided by Dr. S.E. Piper~~

~~Literature [a]n value is for the enantiomer of 184 although both~~

~~compounds are reported to have the same sign.~~

~~Ozonolysis of (-)-Bromoacid 159~~

~~159 162a 162b~~

(-)-Bromoacid 159 (1.08 g, 4.4 mmol) was dissolved in dry methanol (200 mL) at -78°C. Ozone in a stream of oxygen was bubbled through the solution until a deep blue colour formed and for 10 minutes after that. Excess ozone was purged with oxygen then dimethyl sulphide (1 mL) was added and the solution warmed to room temperature over 2 hr. The volatile components were removed under vacuum and the remaining crude dissolved in ether, dried

(MgSO^) and filtered through a pad of coarse grade silica gel. Removal of the solvent gave a viscous oil (1.11 g) which was subjected to column chromatography (silica gel, petroleum ether/ethyl acetate 3:1) provided the

~~keto acid 162a as a colourless oil (1.01 g, 87%), vmax (CHC13): 2950 (br),~~

~~1740, 1710 cm-1; 6 (CDClg, 400 MHz): 1.00 (3H, s), 1.56 (IH, m), 2.16-2.48~~

~~(4H, m), 2.64 (IH, dd, J = 16 Hz, 5 Hz), 2.97 (IH, m; methine proton), 3.34~~

~~(IH, d, J = 10 Hz), 3.61 (IH, d, J = 10 Hz); m/e (relative intensity):~~

~~250/248 (M+, 1/D, 169 (100), 151 (19), 123 (15), 109 (39), 105 (13), 95~~

~~(16).~~

~~A minor by-product from this reaction was found to be the corresponding~~

~~207 methyl ester 162b (50 mg), 6 (CDC1,, 80 MHz): 0.95 (3H, s), 3.27 (IH, d, J =~~

~~10 Hz), 3.60 (IH, d, = 10 Hz), 3.70 (3H, s; C0 CH ). J 2 3~~

~~(-)-Bromo Methyl ketone 185~~

~~Methyl 1ithium (2.43 mL, 3.0 mmol; 1.25 M solution in ether) was added~~

~~to a solution of the bromoacid 158 (250 mg, 1.0 mmol) in tetrahydrofuran (10~~

~~mL, 0°C). After 2 hr, freshly distilled trimethylsilyl chloride (2.54 mL,~~

~~20 mmol) was added in one lot and the solution warmed to room temperature~~

~~over 45 min. IN hydrochloric acid was added and the solution extracted 3~~

~~times with ether. The organic phase was washed twice with water, dried over~~

~~MgSO^ and the solvent removed to give a pale yellow liquid (241 mg).~~

~~Column chromatography on silica gel using distilled toluene as eluent~~

~~gave the methyl ketone 185 (173 mg, 70%), [a] -48.3° (C 0.4, MeOH); vmax Q~~

~~1 (CHC1 ): 3080, 1715, 1650, 890 cm" ; (CDClg, 400 MHz): 1.05 (3H, s); 1.24 3 6~~

~~(IH, m), 1.95 (IH, m), 2.18 (3H, s; C0CH. ), 2.26 (IH, dd, = 16 Hz, 10 Hz; 3 J~~

~~H ), 2.31-2.45 (2H, m), 2.54 (IH, m), 2.68 (IH, dd, = 16 Hz, 4 Hz; Hg), A J~~

~~3.39 (d) and 3.47 (d) (2H, AB quartet, J = 10 Hz), 4.84 (IH, br s), 4.99~~

~~+ (IH, br s); m/e (relative intensity): 246/244 (M , 0.1/0.1), 231/229~~

~~(0.6/0.6), 188/186 (26/27), 165 (10), 109 (23), 107 (100), 93 (26), 91 (23);~~

~~+ Exact mass calcd. for C-.H.-yO (M-Br) : 165.1279; found 165.1280.~~

~~208 Cyclisation of Bromoketone 185; Formation of Hydrindenone 186 and Bicyclic~~

~~Ketoalkene 188~~

~~185 186 188~~

To a cold (-60°C) solution of lithium diisopropylamide (3.28 mmol) in tetrahydrofuran (10 mL) containing a crystal of 1,10 phenanthroline as indicator (deep red-purple colour) was added the bromoketone 185 (200 mg,

~~0.82 mmol) in tetrahydrofuran (10 mL) dropwise over 30 min. The still red solution was then warmed to 0°C and hexamethylphosphoramide (2 mL) added.~~

~~This was heated to 70°C for 1.5 hr and then quenched by addition of water.~~

~~After three successive extractions with ether, the organic layers were washed with 1 N hydrochloric acid (x 2), sodium bicarbonate solution, water~~

(x 2) before being dried and concentrated. The crude product, 112 mg, was subjected to column chromatography (silica gel; petroleum ether/ether 24:1) which yielded a mixture of two compounds (43 mg) by glc (3% OV-17, 140°C).

~~The major component was assigned the [2.1.1] structure 188 based on the ir, nmr and ms spectra taken on the mixture: vmax (CHCl^): 1705, 875 cm 1; 6~~

~~(CDC13, 80 MHz): 1.1 (3H, s), 2.1 (3H, s), 4.28 (IH, s), 4.40 (IH, s); m/e~~

~~(relative intensity from gc-ms): 164 (M+, 4), 149 (10), 131 (11), 121 (88),~~

~~107 (80), 106 (100), 105 (59), 93 (84), 91 (97), 79 (91), 77 (80).~~

~~Further elution provided the hydrindenone 186 (22 mg, 16%); vmax~~

~~1 (CHC13): 1700, 1650, 890 cm" ; & (CDC13, 270 MHz): 1.02 (3H, s; angular methyl group), 1.45 (IH, m), 1.53-1.86 (3H, m), 1.99 (IH, m), 2.16 (IH, dd,~~

~~J = 18 Hz, 11 Hz), 2.22-2.44 (5H, m), 2.56 (IH, m), 4.67 (IH, br s), 4.72~~

~~209 + (1H, br s); m/e (relative intensity): 164 (M , 27), 146 (33), 122 (57), 119~~

~~(45), 107 (100), 106 (71), 94 (48), 93 (70), 91 (58), 79 (80); Exact mass~~

~~calcd. for C H 0: 164.1201; found: 164.1204. n 16~~

~~Preparation of the Enol Ether 191 and Hydrolysis to the Hydroxy Methyl ketone~~

~~187~~

~~x^O 191 187 185~~

~~The bromo methylketone 185 (130 mg, 0.53 mmol) was stirred in 5 mL of a~~

0.5 N solution of potassium tert-butoxide in tert-butanol under an argon atmosphere. The reaction was monitored by glc (3% OV-17, 140°C). After 1 hr at room temperature glc showed no change; 1 hr at 40°C, glc showed a trace of enol ether; 1 hr at 70°C and most of the starting material had reacted.

~~The solution was poured onto brine and extracted with petroleum ether~~

(3 times). After washing the organic phase with brine, it was dried with basic alumina and evaporated. The resulting oil was chromatographed on basic alumina (petroleum ether) to afford the almost pure enol ether 191.

1 vmax (film): 1660, 880, 830 cm" ; 6 (CDCI,, 80 MHz): 0.9 (3H, s), 1.7 (3H, dd, J = 2 Hz, 1 Hz; methyl on enol ether), 3.9 (d) and 4.1 (d) (2H, AB quartet, J = 10 Hz), 4.5 (2H, m), 4.7 (IH, t, J = 2 Hz).

~~Enol ether 191 (26 mg) was hydrolysed in 1 N hydrochloric acid/ether (1:1, 3 mL) for 45 min. Work up provided the hydroxy methylketone 187 (21 mg) Identical glc, Ir, nmr, with an authentic sample.~~

~~210 Hydroxy Methyl ketone 187 via Enol Ether 191~~

~~185~~

~~A solution of potassium tert-butoxide (914 mg, 8 mmol) in tetrahydrofuran (30 mL) was heated to 65°C under argon. The (-)-bromoketone~~

185 (500 mg, 2 mmol) in a further 10 mL of solvent was added and after 30 min the solution was poured onto 1 N hydrochloric acid to hydrolyse the enol ether 191. This was extracted with ether, washed with brine, dried and evaporated (j_n vacuo) to yield 344 mg of an orange oil which appeared to be very impure by tic.

~~Isolation of the hydroxyketone 187 was achieved by flash chromatography on silica gel (petroleum ether/ether 2:1) to yield 187 (99 mg, 27%), vmax~~

~~1 (film): 3420, 3080, 1705, 1650, 885 cm" ; 6 (CDClg, 400 MHz): 0.84 (3H, s),~~

~~1.28 (IH, m), 1.90 (IH, m), 2.09 (IH, br s, exchangeable with D 0), 2.17 2~~

~~(3H, s; C0CH ), 2.32 (IH, m), 2.32 (IH, dd, J = 16 Hz, 8.5 Hz), 2.45 (2H, 3 m), 2.60 (IH, dd, J = 16 Hz, 5 Hz), 3.36 (d) and 3.52 (d) (2H, AB quartet, J~~

~~= 11 Hz), 4.82 (IH, t, J = 2.5 Hz), 5.00 (IH, t, J = 2 Hz); m£e (relative~~

~~+ intensity): 182 (M , 0.4), 151 (11), 109 (35), 95 (15), 94 (100), 93 (30),~~

~~89 (34); Exact mass calcd. for C Hj 0 : 182.1307; found 182.1297. n 8 2~~

~~211 Hydroxy Ketone 187 and (-)-Keto Aldehyde 189~~

~~161 187 189~~

The hydroxyacid 161 (5.0 g, 27.2 mmol) in dry tetrahydrofuran (250 mL) at 0°C under argon was treated with methyl 1ithium (200 mL, 200 mmol; 1 M solution in ether) over 30 min. After 1 hr at 0°C, the reaction was warmed to room temperature and left to stir overnight. Trimethyl silyl chloride (52 mL, 408 mmol; freshly distilled) was added slowly (care!) quenching the yellow colour and forming a white precipitate. Ten mintues later, 1 N hydrochloric acid (100 mL) was added and after 30 min 2 N potassium hydroxide introduced until the solution was basic. The solution was extracted twice with ether; the ether layers washed with 2 N potassium

hydroxide (twice) then water, dried (MgS04) and the ether removed to yield the crude hydroxy methylketone 187 (3.60 g). It was found that the best overall yield of the ketoaldehyde 188 was obtained by oxidising this crude material without purification although the pure hydroxy methylketone 187 could be obtained by chromatography (silica gel; petroleum ether/ether

~~1.5:1). This material was identical to that obtained previously.~~

Acidification of the combined aqueous phases with 6 N hydrochloric acid and extraction with ether (x 3) then washing the ether layesr with water gave (after drying and evaporation) a white solid (1.16 g). Chromatography on Florisil eluting with ether afforded starting material 161 (754 mg).

~~Oxidation of the crude hydroxy methylketone 187 (3.4 g, ~18.7 mmol) was carried out with pyridinium dichromate (14 g, 37.4 mmol) in~~

~~212 dichloromethane (200 mL) at room temperature under argon for 24 hr. The~~

~~usual work-up provided a crude oil (3.16 g). Column chromatography (silica~~

~~gel; petroleum ether/ether 5:1) gave the keto aldehyde J89 (2.21 g, 48% over~~

~~2 steps), [a]n -22.2° (C 0.315, CH2C12); vmax (CHC13): 2725, 1720, 1650,~~

~~-1 6 900 cm ; (CDC13, 400 MHz): 1.03 (3H, s; tertiary methyl group), 1.42 (IH,~~

~~m), 2.0 (IH, m), 2.13 (3H, s; C0CH3), 2.34-2.57 (4H, m), 2.73 (IH, six line~~

~~multiplet; methine proton), 4.75 (IH, t, J = 2.5 Hz), 5.09 (IH, t, J = 2~~

~~Hz), 9.31 (IH, s; CHO); m/e (relative intensity): 151 (12), 109 (32), 95~~

~~(15), 94 (100), 93 (30), 79 (37); Exact mass calcd. for CJJHJ^ - CHO:~~

~~151.1123; found: 151.1131; Anal. calcd. for CnH1602: C 73.30, H 8.95;~~

~~found: C 73.05, H 9.00.~~

~~note: Oxidation of the pure hydroxy methyl ketone 187 (2.1 g) provided~~

~~the ketoaldehyde 189 (1.69 g) in 81% yield.~~

~~Preparation of (-)-Hydrindienone 190~~

~~189 190b 190~~

~~50 mL of 2 N sodium hydroxide was added to a cooled (0°C) solution of~~

~~the ketoaldehyde 189 (1.6 g, 8.9 mrnol) in methanol (50 mL). After 1 min,~~

~~tic indicated the reaction was complete so the mixture was poured onto brine~~

~~and carefully treated with 6 N hydrochloric acid until just neutral~~

~~(universal pH paper). After thoroughly extracting with ether, the combined~~

~~213 ether layers were washed with brine then dried and concentrated jjn vacuo.~~

~~The product, 1.75 g of a pale yellow solid, appeared to be one epimer, 190b, by 80 MHz nmr. vmax (film): 3450 (br), 1705, 1650, 890 cm"1; 6 (CDCl,, 80~~

~~MHz): 1.08 (3H, s), 4.00 (IH, dd, J = 20 Hz, 12 Hz), 4.82 (IH, m), 5.38 (IH, m); m/e (relative intensity): 180 (M+, 0.9), 120 (3), 91 (99), 79 (100).~~

~~The crude aIdol product was converted to the corresponding mesylate~~

(methanesulphony1 chloride, 1.8 mL; triethylamine, 4.4 mL; 4- dimethyl aminopyridine, 0.4 g; dichloromethane, 60 mL; argon; 24 hr) which was then treated with 1,8-diazabicyclo[5.4.0]undec-7-ene (1.3 g, 8.9 mmol) in dry dichloromethane (50 mL) for 45 min. The solution was diluted with dichloromethane washed successively with 1 N hydrochloric acid, then water

(twice), dried and evaporated to provide the enone 190 (1.21 g, 84%) as a white crystalline solid. The product was pure by tic and 'H nmr. A pure sample of 190 was obtained by low temperature recrystal1isation from pentane

~~mp 60.5-61.5°C (sealed tube); [a]D -13.5 ° (C 0.17, CH2C12); vmax (CHClg):~~

1 1670, 1665, 890 cm" ; 6 (CDC13, 400 MHz): 1.03 (3H, s; angular methyl group), 1.57 (IH, m), 1.81 (IH, m), 2.17 (IH, m; methlne proton), 2.41 (IH, dd, J = 17 Hz, 14 Hz), 2.41 (IH, m), 2.58 (IH, dd, J = 17 Hz, 4.5 Hz), 2.58

~~(IH, m), 4.87 (IH, t, J = 2 Hz), 4.92 (IH, t, J = 2.5 Hz), 5.90 (IH, d, J =~~

~~10 Hz), 7.30 (IH, d, J = 10 Hz); m/e (relative intensity): 162 (M+, 14), 147~~

~~(22), 120 (100), 105 (37), 91 (47), 77 (33); Exact mass calcd. for C..H..0: 11 14~~

~~162.1045; found: 162.1042; Anal. calcd. for CnHj40: C 81.44, H 8.70; found:~~

~~C 81.22, H 8.78.~~

~~214 Vinylogous Amide 195~~

~~0 NMe2 190 195~~

~~The enone 190 (280 mg, 1.73 mmol) and tert-~~

99 o butoxybis(dimethyl ami no)methane (870 mg) were stirred (neat) at 70 C for 6 hr. Water was added and the solution extracted with dichloromethane (3 times). The combined organic extracts were washed twice with water, dried and concentrated to provide the vinylogous amide 195 as a dark brown oil

~~(386 mg). This material was used without any further purification, vmax~~

~~-1 (film): 1640, 1610, 1560, 890, 820 cm ; 6 (CDC13, 270 MHz): 0.90 (3H, s; angular methyl group); 1.60 (IH, m), 1.81 (IH, m), 2.45 (IH, m) and 2.55~~

~~(IH, m), 3.05 (6H, s; N-CH3), 4.89 (IH, t, J = 2 Hz), 4.93 (IH, t, J = 2.5~~

~~Hz), 5.90 (IH, d, J = 9.5 Hz), 6.21 (IH, s), 6.98 (IH, d, J = 9.5 Hz); m/_e~~

~~(relative intensity): 217 (M+, 100), 202 (99), 200 (13), 85 (51), 84 (44),~~

~~83 (75), 73 (68), 72 (43); Exact mass calcd. for CuH190N: 217.1467; found:~~

~~217.1467.~~

~~DIBAL Reduction of Vinylogous Amide 195: Preparation of (+)-Trienone 196~~

~~H 'J H~~

~~HG NMe2~~

~~195 196~~

215 To a cold (-78°C) solution of the vinylogous amide 195 (377 mg, 1.69 mmol) in tetrahydrofuran (lo mL) under an argon atmosphere was added diisobutylaluminum hydride, DIBAL, (1.75 mL, 1.75 mmol; 1 M solution in hexane). The reaction was stirred for 3 hr (-78°C to room temperature) then

10 mL of ammonium chloride solution added and stirring continued for a further 10 hr. The mixture was parititioned between ether and 1 N hydrochloric acid. The aqueous layer was extracted twice more with ether and the ether layers shaken with water (x 3), dried and the solvent removed.

~~A pale yellow oil resulted which was subjected to chromatography on silica gel (petroleum ether/ether 24:1) to provide the trienone 196 (225 mg, 1.29~~

~~mmol, 76%), [a]D +123.2° (C 0.41, CH2C12); vmax (film): 1675, 1660, 1630,~~

~~885, 840 cm-1; 6 (CDCl,, 400 MHz): 0.94 (3H, s; angular methyl group), 1.80~~

~~(IH, nine line multiplet; Hc), 1.94 (IH, m; Hr); 2.52 (IH, m; Hu), 2.64 (IH, r Q H m; Hj), 2.82 (IH, dddd, J = 12 Hz, 6Hz, 2.5 Hz, 2.5 Hz; H^), 4.89 (IH, dd, J~~

~~= 2 Hz, 2Hz; H^), 4.94 (IH, dd, J = 2.5 Hz, 2.5 Hz; H^), 5.21 (IH, ddd, J =~~

~~2.5 Hz, 1.5 Hz, 0.75 Hz; HQ), 6.03 (IH, dd, J = 10 Hz, 0.75 Hz; Hg), 6.13~~

~~(IH, dd, J = 2.5 Hz, 1.5 Hz; Hc), 7.35 (IH, d, J = 10 Hz). Irradiation at~~

~~65.2 causes the following signals to collapse: 66.13 to a doublet (J = 2.5~~

~~Hz); 66.03 to a doublet (J = 10 Hz); 62.82 to a ddd (J = 12 Hz, 6Hz, 2.5~~

~~Hz). Irradiation at 62.52 causes both 64.89 and 64.94 to collapse to~~

~~doublets (J = 2 Hz and 2.5 Hz respectively). Similarly irradiation at 62.64 gives doublets at 64.89 and 64.94 (J = 2 Hz and 2.5 Hz respectively).~~

~~Irradiating 61.94 causes 62.82 to become a ddd (J = 12 Hz, 2.5 Hz, 2.5 Hz) and irradiation at 61.80 causes 62.82 to collapse to a broad singlet. NOE~~

~~difference experiments provided the following results:~~

~~irradiation at 61.80, enhancement at 62.64 and 65.21~~

~~irradiation at 62.82, enhancement at 61.94 and 62.52~~

~~216 irradiation at 67.53, enhancement at 64.94. m/e (relative intensity): 174 (M+, 100), 159 (50), 146 (19), 145 (21), 131~~

~~(42), 105 (18), 91 (36); Exact mass calcd. for CJ2H140: 174.1045; found~~

~~174.1049.~~

~~3-Methoxybenzyl Chloride~~

~~Using the method of Grice and Owen , 3-methoxybenzyl alcohol (10.0 g,~~

~~72.5 mmol), thionyl chloride (9.2 mL, 126 mmol), pyridine (0.2 mL) and dry~~

~~benzene (80 mL) were stirred at 100°C for 3 hr then cooled and poured onto~~

~~water. After three ether extractions, the organic layers were washed with 1~~

~~N hydrochloric acid, sodium bicarbonate solution, water then dried (MgSO.) 4 and evaporated. The crude product (11.0 g, 97%) was pure by tic, glc (3%~~

~~OV-17) and nmr. Distillation (high vacuum) gave 10 g (88%) of 3- methoxybenzyl chloride, vmax (film): 1600, 1590, 1490, 1270, 700 cm-1; 6~~

~~(CDC13, 100 MHz): 3.82 (3H, s), 4.58 (2H, s), 6.70-7.35 (4H, m); m/e~~

~~(relative intensity): 158/156 (M+, 15/49), 120 (100).~~

~~217 Grignard Addition to Vinylogous Amide 195~~

~~200a 200b~~

~~Preparation of the Grignard Reagent:~~

A 3-neck flask, dropping funnel, condenser and stir-bar were flame dried under a stream of argon. Magnesium turnings (534 mg, 22.2 mmol) were crushed using a mortar and pestle, introduced into the flask and meta- methoxybenzyl chloride (1.74 g, 11.1 mmol) in ether (20 mL) added immediately with heating to maintain a vigorous reflux. A further 20 mL of ether was added and the solution refluxed for 30 min then cooled to room temperature. A 1 mL aliquot was removed, added to water and the solution titrated with 0.05 N hydrochloric acid against phenolphthalein indicator.

~~The Grignard solution was found to be 0.425 M.~~

~~1,4-Addition Reaction:~~

~~To the vinylogous amide 195 (680 mg, 3.08 mmol, freshly prepared) in dry ether (20 mL at -78°C under argon was added the Grignard solution (9 mL,~~

3.8 mmol) in one lot. An immediate brown precipitate formed so a further 20 mL of ether was added to aid solubility. After 40 min the cold bath was removed and the reaction warmed at room temperature over 30 min. The solution was then transferred via a cannula needle to a rapidly stirred solution of ammonium chloride. This was then extracted with ether (3 times); the combined organic phases washed with 1 N hydrochloric acid then

~~218 twice with water and dried over MgS04. Stripping off the solvent provided~~

~~973 mg of a pale yellow oil.~~

~~Column chromatography (silica gel; petroleum ether/ether 12:1) gave initially a mixture of meta-methy1 aniso1e and 1,2-di-(3-methoxyphenyl)ethane~~

~~(144 mg). This was followed by the cis-enone 200a (61 mg, 7%) as a~~

~~colourless oil, [a]n -34.6° (C 0.24, MeOH); vmax (film): 1670, 1630, 1605,~~

~~-1 1590, 1495, 890 cm ; 6 (CDC13, 400 MHz): 0.95 (3H, s; angular methyl group), 1.67-1.86 (2H, m), 2.48 (IH, m; allylic proton), 2.60 (IH, m;~~

~~allylic proton), 2.82 (IH, m; methine proton), 3.80 (3H, s; 0CH3), 3.93-4.08~~

~~(2H, m; H^ and Hg), 4.89 (IH, t, J = 2 Hz), 4.94 (IH, t, J = 2.5 Hz), 5.85~~

~~(IH, ddd, J = 7.5 Hz, 7.5 Hz, 2.5 Hz; Hc), 6.00 (IH, d, J = 10 Hz), 6.73-~~

~~6.85 (3H, m), 7.21 (IH, t, J = 8 Hz), 7.24 (IH, d, J = 10 Hz). NOE difference experiment, irradiation at 65.85 gives a positive enhancement at~~

~~61.67-1.86 and 62.82; m/e (relative intensity): 294 (M+, 100), 279 (36), 173~~

~~(32), 135 (24), 121 (41), 91 (28); Exact mass calcd. for C20H2202: 294.1620; found: 294.1625.~~

~~Increasing the solvent polarity (petroleum ether/ether 2:1) provided~~

~~the trans-enone 200b (595 mg, 667.) as a colourless oil, [a]n +24.5° (C 0.2,~~

~~-1 MeOH); vmax (film): 1680, 1660, 1620, 1600, 1590, 1495, 890 cm ; 6 (C0C13,~~

400 MHz); 1.04 (3H, s; angular methyl group), 2.18 (IH, nine line multiplet), 2.29 (IH, m), 2.48 (IH, m; allylic proton), 2.66 (IH, m; allylic proton), 2.90 (IH, m; methine proton), 3.60 (IH, ddd, J = 16 Hz, 8 Hz, 2 Hz;

~~HA), 3.70 (IH, ddd, J = 16 Hz, 8 Hz, 1 Hz; Hg), 3.78 (3H, s; OCH3), 4.94~~

~~(IH, t, J = 2 Hz), 4.98 (IH, t, J = 2.5 Hz), 6.04 (IH, d, J = 10 Hz), 6.72-~~

~~6.81 (3H, m; aromatic protons), 6.94 (IH, ddd, J = 8 Hz, 8 hz, 2.5 hz; Hc),~~

~~7.22 (IH, t, J = 7.5 Hz; aromatic proton), 7.30 (IH, d, J = 10 Hz).~~

~~Decoupling the proton at 66.94 simplifies signals at 63.70, 63.60 and 62.90.~~

~~219 NOE difference experiment: Irradiation at 66.94 gave an enhanced signal at 6~~

~~6.72-6.81, no enhancement of protons on the cylcopentane ring was observed; m/e (relative intensity): 294 (M+, 100), 279 (53), 173 (99), 171 (34), 160~~

~~(38), 145 (40), 135 (38), 134 (31), 121 (69), 115 (35), 91 (70), 77 (43);~~

~~Exact mass calcd. for C_nH„„0_: 294.1620; found: 294.1625.~~

~~Lithium/Ammonia Reduction of the (+)-trans-Trienone 220b~~

~~2Q0b 204 205~~

~~To a solution of lithium (45 mg, 9.1 mmol) in ammonia (30 mL) under argon was added the trienone 200b (102 mg, 0.34 mmol) in ether (7 mL).~~

~~After 2 hr, the ammonia was boiled off and ammonium chloride (saturated~~

~~solution) added. The mixture was extracted with ether (x 3); the ether~~

~~layers shaken twice with water, dried and the solvent removed. A pale yellow oil (100 mg) resulted which showed two spots on tic.~~

Chromatography on silica gel using petroleum ether/ether 10:1 to elute afforded the methylenehydrindanone 205 (40.6 mg), followed by a mixture of starting material 200b and the mono reduced product 204 (32.2 mg). This mixture was subjected to the same reduction conditions (lithium, 20 mg; ammonia, 20 mL; ether, 5 mL; 30 min) and after chromatography provided the

~~desired methylenehydrindanone 205 (18.1 mg) (58.7 mg total, 57% combined~~

~~yield), [a]n -28.6° (C 0.405, MeOH); vmax (film): 1705, 1660, 1600, 1590,~~

~~1490, 880 cm"1; 6 (CDC1-, 400 MHz): 1.09 (3H, s; angular methyl group), 1.51~~

~~220 (1H, m), 1.61-1.76 (3H, m), 1.82 (1H, m), 1.93 (1H, m), 2.00 (IH, ddd, J =~~

~~13 Hz, 7 Hz, 2 Hz), 2.30-2.67 (6H, m), 2.73 (IH, eight line multiplet), 3.80~~

~~3H, s; OCH3), 4.68 (IH, t, J = 2.5 Hz), 4.73 (IH, t, J = 2 Hz), 6.70-6.81~~

~~(3H, m; aromatic protons), 7.19 (IH, t, J = 8 Hz; aromatic proton); m/e~~

~~(relative intenstiy): 298 (M+, 27), 164 (35), 134 (100), 122 (29), 121 (37),~~

~~94 (82), 91 (29); Exact mass calcd. for C2QH2602: 298.1933; found: 298.1928.~~

~~In a subsequent reaction the monoreduced product 204 was isolated in the same manner and found to be free of starting material. The data for 204~~

~~is vmax (film): 1695, 1660, 1600, 1490, 880 cm"1; 6 (CDCl,, 270 MHz): 0.94~~

~~3H, s), 1.74-2.11 (3H, m), 2.24-2.75 (6H, m), 3.46-3.72 (2H, m; Ar-CH2),~~

~~3.78 (3H, s; 0CH_3), 4.63 (IH, br s), 4.67 (IH, br s), 6.70-6.80 (4H, m),~~

~~7.20 (IH, t, J - 8 Hz); m/e (relative intensity): 296 (M+, 54), 175 (39),~~

~~147 (58), 135 (87), 122 (80), 121 (91), 91 (100), 77 (76).~~

~~Ozonolysis of Methylene Hydrindanone 205~~

~~205 206 ent53~~

~~Ozone in oxygen was bubbled through a cold (-78°C) solution of the methylene hydrindanone 205 (143.9 mg, 0.48 mmol) in dry methanol (25 mL).~~

~~At the first sign of a pale blue colour, the ozone was stopped and the~~

~~system purged with oxygen until colourless. Dimethyl sulphide (1 mL, large~~

~~excess) was added and the reaction allowed to warm to room temperature.~~

~~After 3 hr, the reaction appeared complete (tic) and the solvent was removed~~

~~221 In vacuo. The crude product (202.5 mg) was purified by flash chromatography~~

~~(petroleum ether/ether 2:1) to provide the pure diketone ent53 (110.6 mg,~~

~~76%) as a viscous oil [a]D -77.2° (C 0.47, MeOH); vmax (film): 1740, 1710,~~

~~1605, 780, 695 cm-1 (Lit.34 vmax (film): 1740, 1710, 1600, 780, 690 cm"1;~~

~~42 1 Lit vmax (film): 1740, 1715, 1600, 1585 cm" ); 6 (CDC13, 400 MHz): 1.13~~

~~(3H, s; angular methyl group), 1.62-1.80 (3H, m), 1.86 (IH, ddd, J = 13 hz,~~

~~12.5 hz, 5.5 hz), 1.94-2.09 (3H, m), 2.21 (IH, six line multlplet), 2.41-~~

~~2.62 (5H, m), 2.76 (IH, m), 3.80 (3H, s; 0CH3), 6.71-6.83 (3H, m), 7.19 (IH, t, J = 8 Hz); m/e (relative intensity): 300 (M+, 9), 135 (14), 134 (100),~~

~~122 (12); Exact mass calcd. for CjgH2403: 300.1726; found: 300.1730.~~

~~In another experiment, the intermediate hydroperoxide 206 was isolated~~

~~1 and characterised: mp 110-112°C; vmax (CHC13): 1705 cm" ;~~

~~MHz): 1.24 (3H, s), 3.32 (3H, s), 3.80 (3H, s), 7.58 (IH, s; 00H); m/e~~

~~(relative intensity): 348 (M+, 0.6), 330 (5), 300 (5), 196 (16), 134 (100).~~

~~This compound was converted to the diketone ent53 on treatment with dimethyl sulphide in dichloromethane.~~

~~Preparation of (-)-9,11-Dehydroestrone Methyl Ether entl16 and (-)-8,9-~~

~~Dehydroestrone Methyl Ether ent50~~

~~• 0~~

~~ent53~~

~~The (-)-diketone ent53 (57.4 mg, 0.19 mmol) was dissolved in ether (1 mL) and a mixture of glacial acetic acid/concentrated hydrochloric acid 10:1~~

222 (2 mL) at 0°C. After 2 hr, the reaction was poured onto brine and extracted with ether. The ether layers were washed with sodium bicarbonate solution, brine (twice), dried (MgSO^) and evaporated to yield 53.5 mg of a white crystalline solid. Column chromatography (silica gel; petroleum ether/ether

4:1) provided the tetracyclic products ent50 and entl16 (45.8 mg, 85%) in the ratio 97:3 (capillary glc, OV-101, 200°C). Recrystal1isat ion from methanol provided pure (-)-9,11-dehydroestrone methyl ether ent116, mp 143-

~~67 42 145.5°C (Lit. mp 143-144°C, Lit. mp 142.5-144°C); [a]n -284° (C 0.208,~~

~~67 67 CHC13), [Lit. [a]n -288.20 (C 0.5, dioxane) and for enantiomer, lit.~~

~~42 [a]n +288.7° (C 0.479, dioxane), lit. [a]n +290.0° (C 0.5, CHC13)]; vmax~~

~~1 (CHC13): 1735, 1610, 1500 cm" ; 6 (CDC13, 400 MHz): 0.95 (3H, s), 1.47 (IH, m), 1.68 (2H, m), 2.10-2.40 (6H, m), 2.54 (IH, m), 2.83-3.00 (2H, m), 3.80~~

~~(3H, s; 0CH3), 6.14 (IH, m; C-ll proton), 6.63 (IH, d, J = 3 Hz; C-4 proton), 6.73 (IH, dd, J = 8 Hz, 3 Hz; C-2 proton), 7.54 (IH, d, J = 8 Hz;~~

~~C-l proton); m/e (relative intensity): 282 (M+, 100), 267 (49), 249 (19),~~

~~225 (30), 224 (36), 211 (22); Exact mass calcd. for CjgHp^O;?: 282.1620; found: 282.1618; Anal. calcd. for ci<^2Z0Z: c 80.82, H 7.85; found: C 80.71,~~

~~H 7.88.~~

~~The infra-red and 'H nmr data is in good agreement with the published , 42,67 values~~

~~When the reaction was carried out at room temperature the ratio of (-)-~~

~~9,11 to (-)-8,9-dehydroestrone methyl ether ent116 and ent50 was found to be~~

3.7:1 by integration of the C-18-methyl resonances in the 400 MHz *H nmr spectrum. (-)-9,11-Dehydroestrone methyl ether ent116 has the C-l8-methyl at 60.9477 while the (-)-8,9-dehydroestrone methyl ether ent50 C-18-methyl resonance is at 60.90110.

~~223 (-)-Estrone Methyl Ether ent51~~

~~! P~~

~~MeO' Me~~

A -8,9 ent50 entSl A -9,11 ent!16 34 According to the method of Smith and co-workers , dehydroestrone methyl ether (38.4 mg; entl16:ent50 93:7), palladium on charcoal (10% catalyst, 13.1 mg) and methanol (8 mL) were stirred under an atmosphere of hydrogen for 2 hr. The solution was diluted with ether, filtered through a pad of Celite and the solvent removed to yield a white crystalline solid

(35.0 mg). Capillary glc analysis (OV101, 220°C) showed this to be two compounds; estrone methyl ether ent51 and an unidentified by product in the ratio 65:35. Recrystal1isation from methanol provided pure (-)-estrone

~~48 methyl ether ent51 (18.2 mg, 47%) mp 167.5-170°C (Lit. mp 164-167°C); [a]D~~

~~48 -149.2° (C 0.126, dioxane), (Lit. [a]n + 153.98° (C 1.0, dioxane)); vmax~~

~~1 (CHC13): 1735, 1620, 1500 cm" ; «5 (CDC13, 400 MHz): 0.91 (3H, s; CjQ-methyl)~~

~~1.35-1.70 (6H, m), 1.93-2.20 (4H, m), 2.26 (IH, m), 2.40 (IH, m), 2.50 (IH,~~

~~dd, J = 20 Hz, 8 Hz), 2,90 (2H, m), 3.78 (3H, s; 0CH3), 6.66 (IH, d, J = 3~~

~~Hz), 6.73 (IH, dd, J = 8 Hz, 3 Hz), 7.21 (IH, d, J = 8 Hz); m/e (relative intensity): 284 (M+, 100), 199 (56), 186 (24), 160 (32); Exact mass calcd.~~

~~for CigH2402: 284.1775; found: 284.1775. The synthetic material was found to be identical (tic, ir, *H nmr and ms) to an authentic sample of (+)- estrone methyl ether prepared from (+)-estrone.~~

Analysis of the crude product by glc-ms (DB-17 column, 220°C) showed the by-product to be isomeric with (-)-estrone methyl ether, m/e (relative intensity): 284 (M+, 100), 199 (38), 186 (15), 160 (24).

~~224 Preparation of (-)-Estrone ent41~~

~~ent51 ent41~~

~~Using the method of Vickery et aj_ , boron tribromide (11.5 yL, 0.12 mmol) was added to a cold (-78°C) solution of (-)-estrone methyl ether ent51~~

(31.3 mg, 0.11 mmol) in dichloromethane (2 mL) under argon. The cold bath was removed and the reaction allowed to warm over 30 min before being quenched on ice/brine. Three extractions with dichloromethane were followed by extraction with 2 N potassium hydroxide solution. The aqueous layer was acidified with 6 N hydrochloric acid and extracted with chloroform. Removal

~~of the dried (MgS04) solvent and trituration of the product with petroleum ether/ether afforded (-)-estrone ent41 (16 mg, 54%), vmax (CHClg): 3600~~

~~(sharp), 3350 (br), 1735, 1610 cm"1; 6 (CDClg, 400 MHz): 0.90 (3H, s), 1.38-~~

~~1.70 (6H, m), 1.93-2.28 (5H, m), 2.38 (IH, m), 2.50 (IH, dd, J = 19 Hz, 9~~

~~Hz), 2.86 (2H, m), 4.69 (IH, br s), 6.59 (IH, d, J = 3 Hz), 6.64 (IH, dd, J~~

~~= 8 Hz, 3 Hz), 7.15 (IH, d, J = 8 Hz); m/e (relative intensity): 270 (M+,~~

~~100), 185 (47), 172 (38), 146 (40). The synthetic (-)-estrone was found to be identical (tic, ir, *H nmr and ms) with authentic (+)-estrone (Sigma~~

~~Chemical Co.).~~

~~225 (+)-Estrone Methyl Ether 51~~

~~0 0~~

~~HO-~~

~~41 51~~

~~(+)-Estrone (108 mg, 0.4 mmol; Sigma Chemical Co.) potassium hydroxide~~

~~(100 mg, 1.79 mmol), methanol (6 mL), water (2 mL) and dimethyl sulphate~~

(0.6 mL, 6.3 mmol) were stirred for 24 hr. The mixture was then poured onto ammonium hydroxide solution, extracted with ether and the ether layers washed with 2 N potassium hydroxide solution followed by three washings with

~~water. The dried (MgS04) solution was evaporated to provide a white~~

~~crystalline solid (113 mg). Recrystal1isat ion from acetonitrile gave pure~~

~~48 ( + )-estrone methyl ether 5_1_ mp 170-173°C (lit. mp 164-167°C); [Q]D~~

~~48 +154.0° (C 1.02, dioxane) (lit. [a]n +153.98° (C 1.0, dioxane)).~~

~~226 Preparation of the Hydroxymethylester 301~~

~~161 301~~

~~215~~

Diazomethane in ether was added dropwise to a suspension of the hydroxyacid 161 (500 mg, 2.72 mmol) in ether (20 mL) until the solution became a permanent yellow colour. The excess diazomethane was destroyed with a few drops of 1 N hydrocholoric acid and the solution poured onto water. After three extractions with ether, the ether layers were washed once with brine then dried (MgSO^) and the solvent removed to yield the hydroxy ester 301 as a colourless oil (539 mg, 100%). vmax (film): 3460

1 (br), 1735, 1650, 890 cm" ; 6 (CDCl,, 400 MHz): 0.86 (3H, s), 1.37 (IH, m), 1.78 (IH, br s, exchangeable with D 0), 1.93 (IH, m), 2.20 (IH, dd, J = 13.5 2 Hz, 11 Hz), 2.34 (IH, m), 2.40-2.50 (2H, m), 3.39 (IH, d, J = 11.5 Hz), 3.52

~~(IH, d, J = 11.5 Hz), 3.69 (3H, s), 4.82 (IH, t, J = 2.5 Hz), 5.01 (IH, t, J~~

~~+ = 2 Hz); m/e (relative intensity): 180 (M - H 0, 8), 167 (22), 135 (10), 2 121 (16), 107 (100), 94 (51), 79 (48); Exact mass calcd. for C H 0 - H 0: n 18 3 2 180.1150; found 180.1145.~~

~~(-)-tert-Butyldimethyl silyloxy Ester 283~~

~~227 The hydroxyester 301 (493 mg, 2.5 mmol), 4-dimethyl aminopyridine (597 mg, 5.0 mmol) and freshly sublimed tert-butyldimethyl silyl chloride (750 mg,~~

~~5.0 mmol) were stirred in dichloromethane (30 mL) under argon for 48 hr.~~

~~After this time, tic indicated starting material was still present so more~~

4-dimethylaminopyridine (300 mg, 2.5 mmol) and tert-butyldimethyl silyl chloride (350 mg, 2.3 mmol) were added. After a further 24 hr, the mixture was diluted with dichloromethane and poured onto 1 N hydrochloric acid. Two further extractions with dichloromethane followed by washing successively

with 1 N hydrochloric acid then twice with water, drying (MgS04) and removal of the solvent resulted in a pale yellow oil (1.11 g). Column chromatography (silica gel; petroleum ether/ether 10:1) of this oil gave the pure tert-butyldimethylsilyl ether 283 as a colourless oil (762 mg, 98%).

~~1 [a]n -25.11° (C 0.94, CH2C12); vmax (film): 1740, 1650 cm" ; 6 (CDC13, 400 .3), MHz): 0.03 (3H, s; Si-CH_3), 0.04 (3H, s; Si-CH 0.89 (9H, s; 5i-C(CH3)3),~~

~~0.90 (3H, s), 1.28 (IH, m), 1.90 (IH, m), 2.10 (IH, dd, J = 15 Hz, 11 Hz),~~

~~2.25-2.45 (3H, m), 2.64 (IH, dd, J = 15 hz, 4 Hz), 3.42 (d) and 3.45 (d)~~

~~(2H, AB quartet, J = 9.5 Hz), 3.67 (3H, s), 4.75 (IH, br s), 4.89 (IH, br~~

~~mZe + s); (relative intensity): 297 (M - CH3, 4), 281 (5), 256 (38), 255~~

~~(100), 181 (75), 121 (44), 107 (97), 89 (99), 75 (87), 73 (95); Exact mass~~

~~calcd. for C17H32035i-CH3: 297.1886; found: 297.1900; Anal. calcd. for~~

~~C.,Ho_0oSi: C 65.33, H 10.32; found C 65.50, H 10.39.~~

228 To a cold (-24°C) solution of diisopropylamine (0.53 mL, 3.80 mmol), and 1,10-phenanthroline (1 crystal) in tetrahydrofuran (35 mL) under argon was added n-butyl1ithium (2.4 mL, 3.80 mmol; 1.6 M solution in hexane) and the lithium diisopropylamide allowed to form over 30 min. The solution was then cooled to -78°C and the lactone 160 (600 mg, 3.61 mmol) in tetrahydrofuran (15 mL) added. After 20 min allyl bromide (1.24 mL, 14.4 mmol) was added and the reaction stirred at -78°C for 1 hr then for a further hour at room temperature. The mixture was poured onto ammonium chloride solution, extracted with ether (3 times) and the ether layers washed with water times). Removal of the solvent from the dried (3 (MgS04) solution gave the alkylated lactone 284 (633 mg, 85%) as a single compound

~~(one spot on tic). Column chromatography (silica gel; petroleum ether/ether~~

~~of this product provided pure allyl lactone [a] (C 7:1) 284, n -9.56° 0.45,~~

~~1 Ch Cl ); vmax (film): cm" ; (CDCl,, MHz): 2 2 1730, 1660, 1640, 920, 890 6 400~~

~~s), m, H^) m; and m; and 1.08 (3H, 1.40 (IH, , 1.92 (2H, HQ Hj), 2.40 (2H, HR~~

~~Hj), m; and (IH, ddd, J Hz, 2.58 (2H, H^ H^), 2.75 = 14 Hz, 7.5 6 Hz; Hc),~~

~~4.21 (IH, d, J = 10 Hz), 4.52 (IH, d, J = 10 Hz), 4.60 (IH, t, J = 2.5 Hz),~~

~~4.82 (IH, t, J = 2.0 Hz), 5.07 (IH, br d, J = 10 Hz; H^), 5.11 (IH, br d, J~~

~~Hz; (IH, ddt, J Hz, Hz, H ). Irradiation at = 15 Hp), 5.76 = 15 10 7.5 Hz; n~~

~~65.76 sharpens the broad doublets at 65.07 and 6 5.11 to two broad singlets~~

~~(65.07 and 65.11) and the multiplet at 62.75 to a doublet of doublet (J = 14~~

~~+ Hz, 6 Hz), m/e (relative intensity): 206 (M , 19) 108 (100), 107 (34), 94~~

~~Exact mass calcd. for C H (33), 93 (90), 91 (44), 79 (78), 77 (31); 13 1802:~~

~~found: Anal, calcd. for C H C H 206.1307; 206.1307; ia lo0o: 75.69, 8.80; Id lo c found: C 76.00, H 8.88.~~

~~229 Preparation of Hydroxy Ester 285~~

~~C02Me~~

~~0 HO"~~

~~284 285~~

The allyllactone 284 (309 mg, 1.5 mmol) in dry methanol (20 mL) and cone, sulphuric acid (1 drop) were stirred at room temperature for 2 hr then poured onto water and the mixture extracted four times with ether. The ether layes were combined, washed with water, dried (MgSO^) and the solvent removed j_n vacuo to yield the hydroxyester 285 (360 mg, 100%) as a

~~-1 colourless oil; vmax (film): 3450 (br), 1720, 1630, 910, 890 cm ;~~

~~80 MHz): 0.9 (3H, s), 1.3 (IH, m), 1.6-2.1 (3H, m, one proton exchangeable~~

~~with D20), 2.1-2.6 (5H, m), 3.2 (IH, d, J = 12 Hz), 3.6 (IH, d, J = 12 Hz),~~

~~3.7 (3H, s), 4.85 (IH, t, J = 2 Hz), 4.9-5.2 (3H, m), 5.75 (IH, m); m/e~~

~~(relative intensity): 238 (M+, 0.1), 166 (27), 147 (29), 114 (41), 95 (100),~~

~~94 (22), 93 (28), 91 (24); Exact mass, calcd. for Cl4H2203 - OCH3: 207.1385; found: 207.1384.~~

~~Preparation of (-)-tert-Butyldimethyl siloxy Ester 286~~

~~CO2MQ C02Me~~

~~285 286~~

~~230 A solution of the hydroxy ester 285 (337 mg, 1.42 mmol), 4- dimethy1 aminopyridine (346 mg, 2.84 mmol), tert-butyldimethyl silyl chloride~~

~~(640 mg, 4.24 mmol) and dichloromethane (15 mL) was stirred under argon for~~

4 days. Work-up in the usual fashion provided a pale yellow oil (676 mg) which was purified on silica gel (petroleum ether/ether 10:1) to yield the tert-butyldimethyl silyloxy ester 286 (489 mg, 98%) as a colourless oil.

~~[ct]n -42.0° (C 0.59, CH2C12); vmax (film): 1740, 1660, 1640, 910, 890, 830,~~

~~1 770 cm" ; 6 (CDCl3, 270 MHz): -0.08 (3H, s), -0.07 (3H, s), 0.81 (9H, s),~~

~~0.85 (3H, s), 1.26 (IH, m), 1.81 (IH, m), 2.00-2.50 (6H, m), 3.19 (IH, d, J~~

~~= 10 Hz), 3.32 (IH, d, J = 10 Hz), 3.59 (3H, s), 4.73 (IH, br s), 4.85 (IH, br s), 4.95 (IH, br d, J = 9 Hz), 5.01 (IH, br d, J = 16 Hz), 5.69 (IH, ddt,~~

~~+ J = 16 Hz, 9 Hz, 8 Hz); m/e (relative intensity): 237 (M -CH3, 1), 195 (58),~~

~~189 (24), 147 (85), 107 (16), 89 (39), 73 (47), 40 (100); Exact mass calcd.~~

~~for C2QH3603Si-CH3: 337.2199; found: 337.2203; Anal. calcd. for C20H3603Si:~~

~~C 68.13, H 10.29; found: C 68.23, H 10.44.~~

~~Alkylation of Ester 283 with Allyl Bromide~~

~~C02Me~~

~~286~~

To tetrahydrofuran (8 mL) at -15°C under an argon atmosphere was added diisopropylamine (0.22 mL, 1.56 mmol), n-butyl1ithium (1 mL, 1.6 mmol; 1.6 M solution in hexane) and a crystal of 1,10-phenanthroline. The lithium diisopropylamide was allowed to form over 10 min then the solution was cooled to -78°C and the ester 283 (325 mg, 1.04 mmol) in tetrahydrofuran (7

~~231 mL) added. After 40 min, allyl bromide (1 mL, 11.7 mmol; purified by passing through a column of basic alumina) was added and the reaction mixture was stirred at -78°C for 15 min.~~

The solution was allowed to warm to room temperature over 1 hr and then after addition of 1 N hydrochloric acid, extracted three times with ether and the ether layers washed once with 1 N hydrochloric acid and twice with brine. Drying (MgSO^) and evaporation provided a yellow oil (376 mg) which

~~was subjected to column chromatography (silica gel; petroleum ether/ether~~

~~50:1) to provide the alkylated ester 286 as a colourless oil (333 mg, 91%).~~

[a] -42.49° (C 0.426, CH C1 ) (cf. the product from alkylation of the n 2 2 lactone [a] -42.0° (C 0.59, CH C1 )). Capillary glc analysis (OV-101, 160 Q 2 2 H Sl: C 68 13 H c 180°C) showed a single peak; Anal. calcd. for 2o 30°3 - « 10.29;

~~found: C 67.90, H 10.12. All other spectral data (ir, nmr, ms) were~~

~~identical to the compound previously prepared via alkylation of the lactone~~

~~160 with allyl bromide.~~

~~Reduction of the Ester 286~~

~~C02Me ^0H~~

~~286 287~~

~~A cooled (0°C) solution of the ester 286 (90.5 mg, 0.26 mmol) in dry~~

~~tetrahydrofuran (10 mL) under argon was treated with lithium aluminum~~

~~hydride (20 mg, 0.52 mmol) for one hour. The reaction was terminated by~~

~~pouring onto ice, the solution was carefully acidified with 1 N hydrochloric~~

232 acid and then extracted 3 times with ether. After drying (MgS04), the solvent was removed under reduced pressure to give a pale yellow oil (83.5 mg). Column chromatography on silica gel using petroleum ether/ether 1:1 as eluent provided the alcohol 287 (78.0 mg, 94%) as a colourless oil, vmax

~~(film): 3420 (br), 1640, 910, 880, 830 cm"1; 6 (CDClg, 270 MHz): -0.02 (3H, s), 0.00 (3H, s), 0.82 (9H, s), 0.84 (3H, s), 1.34 (IH, m), 1.58 (IH, m),~~

~~1.80 (IH, m), 1.92-2.26 (4H, m), 2.35 (IH, m), 3.49 (IH, d, J = 10 Hz), 3.52~~

~~(IH, dd, J = 11.5 Hz, 4 Hz), 3.59 (IH, d, J = 10 Hz), 3.71 (IH, dd, J = 11.5~~

~~Hz, 4 Hz), 4.70 (IH, br s), 4.86 (IH, br s), 5.02 (IH, br d, J = 10 Hz),~~

~~5.08 (IH, br d, J = 17 Hz), 5.83 (IH, ddt, J = 17 Hz, 7 Hz); rn/e (relative~~

~~intensity): 309 (M+, 0.1), 267 (14), 249 (5), 175 (16), 133 (25), 119 (38),~~

~~107 (57), 105 (51), 89 (57), 75 (100); Exact mass calcd. for Cj9H3602Si -~~

~~C4Hg: 267.1780; found: 267.1785.~~

~~Conversion of Alcohol 287 into its (+)-MTPA Ester Derivative 289~~

~~To the hydroxya1kene 287 (51.2 mg, 0.16 mmol) in dry pyridine (1.5 mL) 151 was added (+)-a-methoxy-a-trif1uoromethylphenylacetic acid chloride ((+)-~~

~~MTPA-chloride; 97 mg, 0.38 mmol) in pyridine (2 mL). After stirring for 2 hr at room temperature under argon, the solution was diluted with ether and~~

~~1 N hydrochloric acid. Two further ether extractions followed by washing the combined organic layers with 1 N hydrochloric acid then twice with~~

~~233 brine, drying (MgS04) and evaporation provided a yellow oil (188 mg).~~

~~Purification by chromatography (silica gel; petroleum ether/ether 4:1) yielded the pure (+)-MTPA ester 289 as a colourless oil (85.0 mg, 99%) vmax~~

~~-1 (film): 1755 cm ; 6 (CDC13, 400 MHz): 0.01 (3H, s), 0.02 (3H, s), 0.88 (9H, s), 0.96 (3H, s; tertiary methyl group), 1.35 (IH, m), 1.70 (IH, m), 1.91~~

~~(IH, m), 2.00 (2H, m), 2.19 (2H, m), 2.34 (IH, m), 3.33 (d) and 3.37 (d),~~

~~(2H, AB quartet, J = 10 Hz), 3.55 (3H, br s; 0CH3), 4.14 (IH, dd, J = 12 Hz,~~

~~4 Hz), 4.45 (IH, dd, J = 12 Hz, 4 Hz), 4.75 (IH, br s), 4.86 (IH, br s),~~

~~4.94 (IH, br s), 4.94 (IH, br d, J = 17 Hz), 5.00 (IH, br d, J = 10 Hz),~~

~~5.71 (IH, m), 7.39 (3H, m; aromatic protons), 7.51 (2H, m; aromatic~~

~~13 protons); C nmr (CDC13, 100.6 MHz): -1.77 and -1.62 (Si-CH3), 18.27 (Si-~~

~~C(CH3)3), 19.35 (C-8), 25.91 (Si-C(CH3)3), 25.79, 32.55 and 32.63 (C-4, C-5~~

~~and C—11), 36.90 and 49.24 (C-3 and C-9), 45.89 (0CH3), 55.36 (C-2), 68.85 and 71.15 (C-7 and C-10), 104.77 (C-6), 116.99 (C-13), 122.02 and 124.89~~

~~(CF3 and C-CF3), 127.42, 128.36, 129.53 and 132.51 (aromatic carbons),~~

~~19 135.87 (C-12), 158.76 (C-l), 166.69 (-C02CH2); F nmr (CDC13, 254 MHz) singlet at 64.190 in the resolution enhanced, proton decoupled spectrum; m/e~~

~~(relative intensity): 483 (0.6), 291 (26), 183 (34), 175 (74), 133 (40), 119~~

~~(53), 107 (76), 105 (44), 89 (100), 73 (81); Exact mass calcd. for~~

~~C H SiF C H : 483 2179; found: 29 43°4 4~ 4 9 * 483.2174; Anal. calcd. for C2gH4304S?F4:~~

~~C 64.42, H 8.02; found: C 64.62, H 8.02.~~

~~234 Hydrogenolysis of Alcohol 287~~

~~To the alcohol 287 (254 mg, 0.78 mmol) in dry dichloromethane (10 mL) at 0°C under argon was added triethyl amine (0.75 mL), a catalytic amount of~~

~~4-dimethyl aminopyridine and methanesulphony1 chloride (66 uL, 0.86 mmol).~~

~~Stirring at 0°C was maintained for 1 hr then the solution was added to 0.2 N hydrochloric acid and extracted three times with dichloromethane. The~~

~~bulked organic layers were washed twice with water, dried (MgS04) and the solvent removed under reduced pressure to provide the mesylate 288 as an oil~~

(310 mg), vmax (film): 1645, 1355, 830 cm"1; 6 (CDCl,, 80 MHz): 0.03 (6H, s), 0.88 (9H, s), 1.0 (3H, s), 3.0 (3H, s), 3.35 (d) and 3.45 (d) (2H, AB quartet, J = 10 Hz), 4.2 (2H, m), 4.78 (IH, t, J = 2 Hz), 4.9 (IH, t, J = 2

~~Hz), 4.95-5.25 (2H, m), 5.75 (IH, m).~~

The crude mesylate 288 (300 mg) was dissolved in dry tetrahydrofuran (5 mL) under an atmosphere of argon and was treated with lithium 216 triethylborohydride ('Superhydride'; 3.0 mL, 3.0 mmol; 1 M solution in tetrahydrofuran) for 24 hr. The mixture was added to ice and 1 N hydrochloric acid and then extracted with ether (x 3). After washing

(brine) and drying, the ether extracts were evaporated to give a pale yellow oil (235 mg) which was purified by column chromatography (silica gel; petroleum ether/ether 10:1) to provide the diene 290 (186 mg, 81% over 2

~~1 steps), [a]D -43.8° (C 0.5, CH2C12), vmax (film): 1640, 910, 880 cm" ; 6~~

~~(CDC13, 400 MHz): 0.00 (3H, s), 0.01 (3H, s), 0.89 (9H, s), 0.94 (6H, m;~~

~~235 doublet overlapping singlet), 1.33 (IH, m), 1.64 (IH, m), 1.80 (2H, m), 1.91~~

~~(IH, m), 2.23 (2H, m), 2.34 (3H, m), 3.38 (IH, d, J =9 Hz), 3.45 (IH, d, J~~

~~= 9 Hz), 4.74 (IH, br s), 4.84 (IH, br s), 4.95-5.04 (2H, m), 5.77 (IH, m);~~

~~+ m/e (relative intensity): 293 (M -CH3, 0.6), 266 (0.8), 251 (58), 107 (50),~~

~~89 (80), 75 (100), 73 (72); Anal. calcd. for CjgH36OSi: C 73.95, H 11.76; found: 74.22, H 11.96.~~

~~Preparation of the Dienealcohol 29_1_ and its (+)-MTPA Ester Derivative 292~~

~~290 291 292~~

~~Tetrabutylammonium fluoride (5.1 mL, 5.1 mmol; 1 M solution in tetrahydrofuran) was added to the tert-buty1dimethy1si1y1 ether 290 (158 mg,~~

0.51 mmol) and the solution stirred for 1 hr at room temperature (argon atmosphere). The reaction mixture was diluted with ether and the solution washed with water, dried and evaporated to give a yellow oil (173 mg).

~~Flash chromatography (silica gel; petroleum ether/ether 9:1) provided the~~

alcohol as a colourless oil (95 mg, 95%), [a]D -39.7° (C 0.37, CH2C12), vmax (film): 3400 (br), 1640, 905, 880 cm-1; 6 (CDClg, 270 MHz): 0.95 (3H, s), 0.98 (3H, d, J = 7 Hz), 1.38 (IH, m), 1.55-1.76 (2H, m), 1.76-1.96 (3H,

~~m), 2.28 (2H, m), 2.43 (IH, m), 3.51 (2H, s; 0CH2), 4.86 (IH, br s), 4.99-~~

~~5.11 (3H, m), 5.82 (IH, m); m/e (relative intensity): 194 (M+, 0.1), 163~~

~~(91), 125 (37), 121 (58), 107 (68), 95 (88), 93 (46), 81 (44), 79 (39), 75~~

~~(37), 69 (52), 55 (39), 43 (31), 41 (100); Exact mass calcd. for C,-,H„0:~~

~~236 c 194.1671; found: 194.1667; Anal. calcd. for C^H^O: 80.35, H 11.41; found: C 80.10, H 11.47.~~

19 The F nmr (CDCl,, 94.1 MHz) of the (+)-a-methoxy-a- trifluoromethylphenyl acetic ester 292 (prepared as before, p.xxx) of this alcohol showed essentially a singlet at 64.06 downfield from trifluoroacetic acid (external standard).

~~Alkylation of Ester 283 with Methyl Iodide~~

~~304a~~

n-Butyl1ithium (0.47 mL, 0.75 mmol; 1.6 M solution in hexane) was added to a cold (-15°C) solution of diisopropylamine (0.11 mL, 0.75 mmol) in tetrahydrofuran (4 mL) under an argon atmosphere. After 10 min the solution was cooled to -78°C and then the ester 283 (155 mg, 0.5 mmol) in tetrahydrofuran (4 mL) added. After 40 minutes methyl iodide (0.6 mL, 9.4 mmol) was added and the solution was stirred at -78°C for 1 hr then allowed to warm to room temperature. The reaction was terminated by addition to 1 N hydrochloric acid. Work-up in the usual way provided a yellow oil (118 mg) which was purified by column chromatography (silica gel; petroleum ether/ether 80:1) to provide the methylated ester 304a as a colourless oil

(70 mg, 43%), capillary glc (OV-101, 180°C) and 400 MHz lH nmr showed this to be a single compound. [a] -49.5°C (C 1.68, CH C1 ); vmax (film): 1740, n 2 2 -1 1660 cm ; 6 (CDCl,, 400 MHz): 0.00 (3H, s), 0.02 (3H, s), 0.88 (9H, s),

~~0.92 (3H, s; tertiary methyl group), 1.14 (3H, d, J = 7 Hz); 1.34 (IH, m),~~

237 1.84 (IH, m), 2.20-2.45 (3H, m), 2.53 (IH, dq, J = 7 Hz, 7 Hz; >CHC0 Me), 2 3.26 (IH, d, J = 10 Hz), 3.38 (IH, d, J = 10 Hz), 3.6S (3H, s), 4.77 (IH, br s), 4.87 (IH, br s), m/e (relative intensity): 311 (1.4), 295 (7), 269 (77),

~~181 (41), 135 (37), 107 (68), 89 (100), 75 (82), 73 (90); Exact mass calcd.~~

~~c for H 0 Si: -CH : 311.2043; found 311.2047. 18 34 3 3 Th i s compound i s i dent i ca1 (i r, nmr, ms, tic) to the compound obta i ned 147 via alkylation of the lactone 160 with methyl iodide.~~

~~Reduction of the Methylated Ester 304a~~

~~C02Me~~

~~-fso~~

~~304a 305a~~

~~The ester 304a (56.9 mg, 0.18 mmol) in tetrahydrofuran (5 mL) at 0°C under argon was treated with lithium aluminum hydride (17 mg, 0.44 mmol) for~~

~~1 hr. The reaction was worked up in the usual way to yield an oil (45 mg).~~

~~Column chromatography (silica gel; petroleum ether/ether 10:1) afforded the alcohol 305a as a colourless oil (33.4 mg, 64%). Capillary glc analysis~~

(OV-101, 180°C) and 400 MHz l nmr showed a single compound; [a] -45.2° (C H n 0.50, CH C1 ) [the corresponding alcohol derived via methyl at ion of lactone 2 2 147 -l 160 had [a] -45.0 (C 0.22, CH C1 )] vmax (film): 3150 (br), 1650 cm ; D 2 2 6 (CDC1 , 400 MHz): 0.04 (3H, s), 0.06 (3H, s), 0.90 (9H, s), 0.92 (3H, s; 3 tertiary methyl group), 0.97 (3H, d, J = 7 Hz), 1.39 (IH, m), 1.76 (2H, m),

~~2.10 (IH, six line multiplet), 2.19 (IH, br s), 2.25 (IH, m), 2.38 (IH, m),~~

~~3.47 (IH, dd, J = 11 Hz, 5 Hz), 3.48 (IH, d, J = 11 Hz), 3.58 (IH, d, J = 11~~

~~238 Hz), 3.65 (IH, dd, J = 11 Hz, 5 Hz), 4.73 (IH, br s), 4.88 (IH, br s); m/e~~

~~281 (M+ - OH, 0.2), 241 (14), 239 (12), 181 (5), 149 (50), 107 (72), 89~~

~~(55), 75 (100), 73 (76).~~

~~The alcohol 305a derived from alkylation of the ester 283 was identical~~

~~in all respects ([a]n, tic, capillary glc, ir, nmr, ms) to the alcohol 147 derived via methyl at ion of the lactone 160~~

~~Preparation of (9S) and (9R) Methylated Esters 304a and 304b~~

~~150a, 150b 304a, 304b~~

~~9,10-Dibromo-3-methylcamphor (1.21 g, 3.73 mmol; endo(150a)/exo(150b)~~

~~6:1) dissolved in dimethylsulphoxide (40 mL) was treated with potassium~~

~~hydroxide (1.05 g, 18.7 mmol) in water (7 mL) for 90 min at room temperature~~

~~then overnight at 60°C. The usual work-up provided the crude hydroxyacids as a viscous yellow oil (790 mg). Esterification of the crude product with~~

~~215~~

~~excess diazomethane in ether gave the crude esters 280a and 208b (847 mg)~~

~~which after column chromatography (silica gel; petroleum ether/ether 3:2)~~

~~yielded the epimeric hydroxy-a-methyl-methylesters 304a and 304b as a~~

~~colourless oil (473 mg), *H nmr analysis of this sample (CDC13> 80 MHz)~~

~~clearly showed the presence of two epimers, 280a: 60.95 (s; tertiary~~

~~methyl), 1.26 (d, J = 7 Hz; C-ll methyl group), 3.55 (s; CH20H), 3.68 (s;~~

~~C02CH3); 280b: 60.88 (s; tertiary methyl), 1.20 (d, J = 7 Hz; C-ll methyl~~

~~group), 3.20 (d) and 3.50 (d) (AB quartet, J = 12 Hz), 3.72 (s; C02CH3).~~

~~Protection of the alcohols 280a and 208b (473 mg, 2.23 mmol) was~~

239 accomplished by treatment with tert-butyldimethyl silyl chloride (750 mg, 5.0 mmol) and 4-dimethylaminopyridine (600 mg, 5.0 mmol) in dry dichloromethane for 3 days (argon atmosphere). After the usual work-up, the crude product was purified on silica gel (petroleum ether/ether 10:1) to provide the Q- methyl-methylesters 304a and 304b as a colourless oil (652 mg, 53% over 3

~~steps). The *H nmr (CDC13, 400 MHz) of this product clearly showed the presence of both epimers; 304a: 61.21 (d, J = 7 Hz; C-ll methyl group), 3.44~~

~~9d) and 3.50 (d) (AB quartet, J = 10 Hz; CHpOSi), 3.65 (s; C02CH3); 304b:~~

~~61.13 (d, J = 7 Hz; C-ll methyl group), 3.26 (d) and 3.38 (d) (AB quartet, J~~

~~= 9.5 Hz; CH_2OSi), 3.66 (s; C02CH3).~~

~~Reduction of Esters 304a and 304b: Preparation of (9S)-Alcohol 305b and~~

~~(9R)-Alcohol 305a~~

~~304a 304b 305a 305b~~

~~Lithium aluminum hydride (48 mg, 12.6 mmol) was added to a cooled (0°C) solution of the esters 304a and 304b (274 mg, 0.84 mmol) in tetrahydrofuran~~

(20 mL) under argon. After 2 hr the solution was poured onto ice and worked up as before to yield an oil (277 mg) which showed two spots on tic. Column chromatography (silica gel; petroleum ether/ether 4:1, recolumning the mixed fractions) gave the alcohol 305a as a colourless oil (34 mg, 14%) which was

~~identical (capillary glc, tic, nmr, ir) to the alcohol obtained via alkylation of either the ester 28J. or the lactone 16_fi_147. Further elution~~

~~240 provided the C-9 epimeric alcohol 305b (144 mg, 58%), vmax (film): 3350~~

~~-1 (br), 1650, 880 cm ; 6 (CDC13, 400 MHz): 0.00 (3H, s), 0.01 (3H, s), 0.01.~~

~~(3H, s), 0.87 (9H, s), 0.93 (3H, s; tertiary methyl group), 1.05 (3H, d, J =~~

~~7 Hz), 1.32 (IH, m), 1.38 (IH, br s, exchangeable with D20), 1.68-1.82 (2H, m), 1.98 (IH, six line multiplet), 2.23 (IH, m), 2.33 (IH, m), 3.42 (IH, dd,~~

~~J = 11 Hz, 7 Hz), 3.43 (d) and 3.49 (d) (2H, AB quartet, J = 10 Hz), 3.70~~

~~(IH, dd, J = 11 Hz, 4 Hz), 4.75 (IH, br s), 4.86 (IH, br s); m/e (relative intensity): 283 (0.2), 241 (21), 181 (18), 149 (55), 135 (36), 121 (34), 107~~

~~(94), 89 (72), 75 (100), 73 (71); Exact mass calcd. for Cj7H3402Si-CH3:~~

~~283.2093; found: 283.2085.~~

~~4-Methyl-l-Pentanol and l-Iodo-4-methylpentane~~

~~1 ^ Br > /^^N/OH > T~~

A 3-neck round bottom flask fitted with a condenser and dropping funnel was charged with freshly crushed magnesium turnings (2.41 g, 99.3 mmol) and one crystal of iodine. Ether (15 mL) was added and then l-bromo-3- methylpentane (12 g, 79.5 mmol) in ether (65 mL) was added at such a rate that a moderate reflux was maintained. After the addition was complete

(about 20 min) the solution was refluxed for 30 min. Paraformaldehyde (4.75 g, 159 mmol) was heated to 160°C (oil bath temperature) under a stream of argon and the argon stream bubbled through the grignard solution. After 1 hr, the mixture was cooled, poured onto water and extracted (x 4) with ether. The bulked organic phases were washed once with 1 N hydrochloric

~~241 acid then twice with water, dried (MgS04) and evaporated to yield a pale yellow mobile oil (8.2 g). Purification by chromatography on silica gel~~

~~(petroleum ether/ether 2:1) gave 4-methyl-l-pentanol (6.65 g, 82%) as a~~

~~colourless oil, vmax (film): 3350 (br); «S (CDC13, 80 MHz): 0.90 (6H, d, J =~~

~~6 Hz), 3.62 (2H, t, J = 6 Hz).~~

~~4-Methyl-l-pentanol (6.65 g, 65.2 mmol) in 57% hydriodic acid (85 mL) was heated at 115°C for 15 min then poured onto ice/sodium bisulphite.~~

After 3 ether extractions, the combined organic layers were washed with water (twice) and dried over MgSO^. Removal of the solvent gave the crude iodide (8.49 g). Column chromatography (silica gel; petroleum ether/ether

~~3:1) gave pure l-iodo-4-methylpentane (6.67 g), 6 (CDCl3f 80 MHz): 0.88 (6H, d, J = 6 Hz), 1.0-2.0 (5H, m), 3.18 (2H, t, J = 7 Hz); m/e (relative intensity): 212 (M+, 16), 85 (72), 43 (100).~~

~~Alkylation of Ester 283 with l-Iodo-4-methylpentane~~

~~Lithium diisopropylamide was generated from diisopropylamine (0.56 mL,~~

4.0 mmol) and n-buty11ithiurn (2.5 mL, 4.0 mmol; 1.6 M solution in hexane) in dry tetrahydrofuran (25 mL) at -15°C under an atmosphere of argon for 15 min. The solution was cooled to -78°C and the ester 283 (1.0 g, 3.2 mmol) in tetrahydrofuran (15 mL) was added. After 75 min l-iodo-4-methylpentane

~~(2.72 mg, 12.8 mmol) in tetrahydrofuran (15 mL) was introduced and the reaction stirred at -78°C for 1 hr, then at -15°C for 30 min and finally~~

242 room temperature for 1 hr. The mixture was poured onto ammonium chloride solution and extracted (x 3) with ether. The bulked organic phases were washed successively with 1 N hydrochloric acid, sodium bicarbonate solution then twice with brine and finally dried over MgSO.. Removal of the solvent 4 gave an oil (3.86 g) which was then purified by flash chromatography (silica gel; petroleum ether) to recover the unreacted iodide (1.3 g). Increasing the solvent polarity (petroleum ether/ether 50:1) provided the alkylated ester 309 as a colourless oil (949 mg, 75%). Capillary glc (OV-101, 200°C) showed this to be contaminated with 5% of the C-9 epimer. vmax (film):

~~1740, 1660 cm-1; 6 (CDClg, 400 MHz): -0.01 (3H, s), 0.01 (3H, s), 0.85 (6H,~~

~~overlapping doublets, J = 7 Hz and 7 Hz; CH(CH_3)2), 0.88 (9H, s; SiC(CH3)3),~~

~~0.92 (3H, s; tertiary methyl), 1.10-1.25 (4H, m), 1.32 (IH, m), 1.41-1.58~~

~~(3H, m), 1.85 (IH, m), 2.23 (IH, m), 2.30-2.45 (3H, m), 3.23 (IH, d, J = 9.5~~

~~Hz), 3.37 (IH, d, J = 9.5 Hz), 3.65 (3H, s; OCHg), 4.76 (IH, br s), 4.86~~

~~(IH, br s); m/_e (relative intensity): 339 (15), 181 (21), 107 (66), 89~~

~~(100), 75 (50), 73 (72); Exact mass calcd. for C23H4403Si - CH3: 381.2825;~~

~~found: 381.2837; Anal. calcd. for C23H4403Si: C 69.64, H 11.18; found: C~~

~~69.99, H 11.23.~~

~~Further elution provided starting material (98 mg).~~

~~Preparation of the (-)-Hydroxya1kene 310~~

~~243 To the ester 309 (900 mg, 2.27 mmol) in dry tetrahydrofuran (15 mL) at~~

0°C under argon was added diisobutylaluminum hydride (5.7 mL, 5.7 mmol); 1 M solution in toluene) via a syringe. The cold bath was removed and the reaction stirred for 2 hr before being quenched on ice. Ether and 1 N hydrochloric acid were added. After three ether extractions, the combined ether layers were washed twice with brine, dried (MgSO^) and filtered through a pad of silica gel. Concentration of the solution gave an oil

~~(1.01 g). Column chromatography (silica gel; petroleum ether/ether 5:1) afforded the pure hydroxya1kene 310 as a colourless oil (816 mg, 98%).~~

~~Capillary glc analysis (OV-101, 200°C) showed a single peak, [a]D -14.21°~~

~~1 (C 1.07, CH2C12); vmax (film): 3400 (br) cm" ; 6 (CDC13, 400 MHz): 0.04 (3H,~~

~~s), 0.06 (3H, s), 0.86 (6H, d, J = 6 Hz), 0.89 (12H, S; SiC(CH3)3 and tertiary methyl group), 1.10-1.60 (9H, m), 1.82 (IH, m), 2.15-2.27 (2H, m),~~

~~2.30-2.45 (2H, 1 proton exchangeable with D20), 3.52 (IH, dd, J = 11 Hz, 5~~

~~Hz), 3.54 (IH, d, J = 10 Hz), 3.63 (IH, d, J = 10 Hz), 3.76 (IH, dd, J = 11~~

~~13 Hz, 3.5 Hz), 4.73 (IH, br s), 4.89 (IH, br s); C nmr (CDC13> 100.6 MHz): -~~

~~5.39 (Si-CH3), -5.29 (Si-CH3), 18.40 (Si-C(CH3)3), 20.12 (C-8), 20.66 and~~

~~20.77 (C-15 and C-16), 25.98 (Si-C(CH3)3), 25.45, 26.68, 28.08, 29.80,~~

~~32.73, 39.57, 40.92, 44.15, 49.21 (C-2), 64.28 and 71.04 (C-7 and C-10),~~

~~104.18 (C-6), 159.92 (C-l); m/e (relative intensity): 353 (0.1), 311 (12),~~

~~219 (26), 135 (21), 121 (43), 107 (100), 95 (70), 89 (96), 75 (99), 73 (88);~~

~~C H S1 C H : 311 2406 Exact mass calcd. for 22 44°2 ~ 4 9 - ? found: 311.2407; Anal. calcd. for C„„H .0„Si: C 71.67, H 12.03; found: C 71.40, H 11.90.~~

~~244 Hydrogenolysis of Alcohol 310~~

~~To a solution of the alcohol 310 (515 mg, 1.4 mmol) in dichloromethane~~

(20 mL) and triethylamine (2 mL, 14.3 mmol) at 0°C under argon was added a catalytic amount of 4-dimethyl aminopyridine and then methanesulphony1 chloride (0.12 mL, 1.54 mmol). After 1 hr, the mixture was partitioned between ether and 1 N hydrochloric acid. The usual work-up gave the crude

~~1 6 mesylate 3_1_1_ (585 mg), vmax (film): 1650, 1355, 1180 cm" ; (CDC13> 80~~

~~MHz): 0.15 (6H, s), 0.95 (6H, d, J = 6 Hz), 1.00 (9H, s), 1.08 (3H, s), 3.05~~

~~(3H, s; S-CH3), 3.38 (d) and 3.50 (d) (2H, AB quartet, J = 10 Hz), 4.25 (2H, m), 4.78 (IH, br s), 4.90 (IH, br s). This material was used without further purification.~~

~~Lithium triethylborohydride (4.88 mL, 4.88 mmol; 1 M solution in tetrahydrofuran) was added to a cooled (0°C) solution of the mesylate 311~~

~~(543 mg. 1.2 mmol) in tetrahydrofuran (20 mL) under an atmosphere of argon.~~

The reaction was warmed to room temperature and after 24 hr it was partitioned between ether and 1 N hydrochloric acid. Three ether extractions followed by two water washes, drying (MgSO^) and evaporation of the solvent gave a colourless semi-solid (487.6 mg). Purification by chromatography (silica gel; petroleum ether/ether 24:1) provided the a 1kene

~~312 as a colourless oil (393 mg, 86% over 2 steps). Capillary glc (OV-101,~~

~~200°C) showed a single compound; [Q]d -20.59° (C 1.02, CH2C12); vmax~~

~~-1 (film): 1100 cm ; 6 (CDC13, 400 MHz): 0.01 (3H, s), 0.02 (3H, s), 0.87 (6H,~~

245 d, J = 7 Hz), 0.89 (9H, s), 0.92 (3H, s), 0.93 (3H, d, J = 8 Hz), 1.00 (IH, m), 1.05-1.60 (8H, m), 1.76 (IH, m), 1.88 (IH, m), 2.24 (IH, m), 2.33 (IH, rn), 3.38 (IH, d, J = 9.5 Hz), 3.43 (IH, d, J = 9.5 Hz), 4.73 (IH, br s),

~~4.84 (IH, br s); m/e (relative intensity): 337 (0.7), 295 (34), 107 (78), 89~~

~~(97), 75 (100), 73 (87); Exact mass calcd. for C H 0Si-CH : 337.2927; 22 44 3 found: 337.2922; Anal. calcd. for C H OSi: C 74.92, H 12.58; found: C 22 44 74.77, H 12.50.~~

~~Preparation of the (-)-Hydroxyalkene 313~~

~~312 313~~

The tert-buty 1 dimethy 1 si 1 y 1 ether 3JL2 (874 mg, 2.48 mmol), tetrabutylammonium fluoride (12.4 mL, 12.4 mmol; 1 M solution in tetrahydrofuran) and tetrahydrofuran (10 mL) were stirred together at room temperature for 3 hr. Work up in the usual way afforded a crude product

(1.08 g) which was chromatographed on silica gel (petroleum ether/ether 5:1) to give (after pumping under high vacuum to remove traces of tert- butyldimethylsilyl fluoride) the pure hydroxya1kene 313 (590 mg, 100%); [a] n -1 -1.85° (C 1.35, CH C1 ); vmax (film): 3400 (br), 1650, 880 cm ; 6 (CDC1 , 2 2 3

400 MHz): 0.87 (6H, d, J = 7 Hz), 0.94 (3H, s), 0.96 (3H, d, J = 7 Hz), 1.00-1.25 (4H, m), 1.28-1.45 (3H, m), 1.45-1.60 (3H, m, 1 proton exchangeable with D 0), 1.82 (2H, m), 2.25 (IH, m), 2.40 (IH, m), 3.47 (2H, 2 m; CH 0), 4.79 (IH, br s), 4.98 (IH, br s); m/e (relative intensity): 238

~~246 (M+, 1.5), 220 (0.4), 207 (23), 151 (11), 125 (31), 109 (18), 107 (19), 95~~

~~(100), 81 (35); Exact mass calcd. for C16H3Q0: 238.2297; found: 238.2290;~~

~~Anal. calcd. for C16H3Q0: C 80.61, H 12.68; found: C 80.35, H 12.59.~~

~~Preparation of Diastereomeric Diols 317a and 317b~~

~~The alcohol 213 (93 mg, 0.39 mmol) was dissolved in dry tetrahydrofuran~~

~~(7 mL) at -78°C under argon and borane-tetrahydrofuran complex (0.39 mL,~~

0.39 mmol; 1 M solution) added. The reaction was allowed to warm to room temperature over 20 hr. Water (0.5 mL) was added to destroy any excess hydride, this was followed by 3 N sodium hydroxide solution (3 mL) and hydrogen peroxide (3 mL; 30% solution). Four hours later, the solution was acidified with 6 N hydrochloric acid, extracted with ether (x 3) and the

ether layers washed twice with brine. After drying (MgS04) the solvent was removed under reduced pressure to afford a colourless oil (153 mg), which showed two spots on tic. Chromatography on silica gel (petroleum

~~ether/ether 3:2) gave the cis-dio1 317b (53.8 mg, 54%) as a clear oil, [a]n~~

~~1 +26.61° (C 0.59, CHC13); vmax (film): 3300 (br) cm" ;~~

~~0.87 (6H, two closely overlapping doublets each with J = 7 Hz; CH(CH3)2),~~

~~0.92 (3H, d, J = 7 Hz; C-l6 methyl group), 1.00 (3H, s; angular methyl group), 1.05-1.60 (10 H, m), 1.60-1.86 (4H, m), 3.35 (2H, br s, exchangeable~~

~~with D20), 3.54 (d) and 3.57 (d) (2H, AB quartet, J = 12 Hz), 3.64 (IH, dd,~~

~~J = 12 Hz, 3 Hz; CHCH20H) and 3.72 (IH, dd, J = 12 Hz, 8 Hz; CHCH20H); m/e~~

~~247 (relative intensity): 238 (0.6), 220 (2), 207 (4), 193 (25), 125 (23), 123~~

~~(22), 109 (31), 107 (35), 95 (100), 81 (60); Exact mass calcd. for Cj H 0 - 6 32 2 H 0: 238.2297; found: 238.2299; Anal. calcd. for Cj H 0 : C 74.94, H 12.58; 2 6 32 2 found: C 74.77, H 12.39.~~

~~Further elution provided the more polar trans-diol (317a) (24.0 mg,~~

~~-1 24%) vmax (film): 3250 br cm ; 6 (CDC1 , 400 MHz): 0.83 (3H, s; angular 3 methyl group), 0.87 (6H, two closely overlapping doublets each with J = 7~~

~~Hz; CH(CH ) ), 0.92 (3H, d, J = 7 Hz; C-16 methyl group), 1.00-1.20 (5H, m), 3 2 1.25-1.45 (5H, m), 1.52 (IH, m), 1.60-1.85 (2H, m), 1.94 (IH, ddd, J = 20~~

~~Hz, 10 Hz, 4 Hz), 3.26 (IH, d, J = 11 Hz), 3.46 (IH, dd, J = 10 Hz, 10 Hz),~~

3.53 (IH, dd, J = 10 Hz, 4 Hz), 3.81 (IH, d, J = 11 Hz), 4.00 (2H, br s, exchangeable with D 0); m/_e (relative intensity): 238 (1.6), 225 (12), 207 2 (46), 193 (17), 125 (37), 123 (40), 109 (46), 95 (100), 81 (65); Exact mass calcd. for C H 0 -H 0: 238.2297; found: 238.2293. 16 32 2 2

~~Cyclisation of the cis-diol 317b: Preparation of the Ether 319~~

~~I > / ^ ctT> c 319~~

~~A solution of the diol 317b (10 mg, 0.039 mmol), para-to1uenesu1 phony1~~

~~chloride (9 mg, 0.047 mmol) and 4-dimethylaminopyridine (47 mg, 0.39 mmol)~~

~~in dry dichloromethane (5 mL) was stirred at room temperature for 3 hr. The mixture was poured onto brine and extracted with ether (x 3). The combined~~

~~ether layers were washed twice with brine, dried and the solvent removed j_n~~

~~248 vacuo. Purification of the residue by column chromatography (silica gel; petroleum ether/ether 20:1) gave the ether 319 (3.3 mg, 35%) as a colourless~~

~~1 oil, vmax (film): 2970, 1465 cm" ; 6 (CDC13, 400 MHz): 0.86 (3H, d, J = 6~~

~~Hz; 0.87 (6H, two overlapping doublets each with J = 6.5 Hz; CH(CH3)2), 1.01~~

~~(3H, s; angular methyl group), 1.05-1.50 (IH, m), 1.92 (2H, m), 2.11 (IH, m; bridgehead proton), 3.28 (1H, d, J = 9 Hz), 3.52 (IH, dd, J = 9 Hz, 4 Hz),~~

~~3.73 (IH, dd, J = 9 Hz, 7 Hz), 3.79 (IH, d, J = 9 Hz), irradiation of the proton at 62.11 caused the signals at 63.52 and 63.73 to collapse to~~

doublets (both with J = 9 Hz); NOE difference experiment: irradiation of HA at 62.11 gave positive enhancement at 61.01 (the angular methyl group) and at 63.73 (Hg); m/e (relative intensity): 238 (M+, 15), 220 (13), 194 (20),

~~193 (91), 154 (34), 125 (64), 109 (46), 108 (21), 107 (53), 97 (45), 95~~

~~(100), 81 (89); Exact mass calcd. for C16H3[)0: 238.2297; found: 238.2299.~~

~~Preparation of (+)-Alkene Aldehyde 320~~

~~313 320~~

~~The alcohol 313 (275 mg, 1.15 mmol), pyridinium dichromate (1.59 g,~~

~~4.23 mmol) and dry dichloromethane (20 mL) were stirred under argon at room temperature for 24 hr. Work up in the usual fashion provided a yellow oil~~

~~(281 mg) which was purified by column chromatography (silica gel; petroleum ether/ether 19:1) to provide the a 1kene aldehyde 320 (193 mg, 71%) as a~~

~~colourless oil, [a]n +27.27° (C 0.66, CH?C17); vmax (film): 2825, 1725,~~

~~249 1650, 895 cm '; 6 (CDC13, 400 MHz): 0.73 (3H, d, J = 6.5 Hz; C=16 methyl group), 0.87 (3H, d, J = 6.5 Hz; C-14 methyl group), 0.88 (3H, d, J = 6.5~~

~~Hz; C-15 methyl group), 1.08 (3H, s; angular methyl group), 1.08-1.26 (4Hz, m), 1.30-1.56 (5H, m), 2.00-2.09 (2H, m), 2.35 (IH, m; allylic proton), 2.52~~

~~(IH, br dd, J = 17 Hz, 9 Hz; allylic proton), 4.64 (IH, t, J = 2.5 Hz), 5.02~~

~~(IH, t, J = 2 Hz), 9.28 (IH, s; CHO); m/e (relative intensity): 236 (M+,~~

~~0.3), 235 (0.3), 207 (31), 151 (21), 123 (64), 109 (32), 95 (100), 81 (39);~~

~~Exact mass calcd. for Cj6H280: 236.2140; found: 236.2135; Anal. calcd. for~~

~~C,^H,Q0: C 81.29, H 11.94; found: C 81.54, H 11.88. 16 «~~

~~Preparation of (+)-Diene 321~~

~~320 321~~

~~Methyl-triphenylphosphonium bromide (405 mg, 1.13 mmol) was suspended~~

in dry tetrahydrofuran (10 mL) at 0°C under argon and n-butyl1ithium (0.81 mL, 1.13 mmol; 1.4 M solution in hexane) added. The solution was stirred at room temperature for 1 hr then the aldehyde 320 (134.7 mg, 0.57 mmol) in tetrahydrofuran (8 mL) was added via a cannula needle. After 1 hr the solution was added to water and this extracted three times with ether. The combined ether layers were washed twice with brine, dried (MgSO^) and the solvent removed to yield a crude product which was chromatographed (silica

~~gel; petroleum ether) to give the pure diene 321 (134 mg, 100%); [a]D~~

~~-1 6 +48.42° (C 0.57, CH2C12); vmax (film): 905, 895 cm ; (CDC13, 400 MHz):~~

~~0.85 (3H, d, J = 6.5 Hz), 0.87 (6H, d, J = 6.5 Hz; CH(CH3)3), 1.02 (3H, s),~~

~~250 1.05-1.60 (10H, m), 1.90 (IH, m; C-3 proton), 2.30 (IH, m; allylic proton),~~

~~2.47 (IH, m; allylic proton), 4.68 (IH, br s), 4.78 (iH, br s), 4.99 (IH, dd, J = 10.5 Hz, 1 Hz; Hg), 5.01 (IH, dd, J = 18 Hz, 1 Hz; H^), 5.77 (IH,~~

~~+ (M , dd, J = 18 Hz, 10.5 Hz; Hc); m/e (relative intensity): 234 6), 219 (5),~~

~~163 (10), 149 (50), 121 (86), 107 (66), 93 (100); Exact mass calcd. for~~

~~Cj7H3(): 234.2348; found: 234.2355; Anal. calcd. for C^H^: C 87.10, H~~

~~12.90; found: C 87.20, H 12.88.~~

~~Attempted Hydroboration/Carbonylation Reaction of Diene 321: Isolation of diols 322 and 323~~

~~(a) Preparation of Thexylborane Solution :~~

Borane-dimethyl sulphide (1 mL, 10 mmol; 10 M solution) was added to tetrahydrofuran (10 mL) at 0°C under argon and 2,3-dimethyl-2-butene (1.19 mL, 10 mmol) in tetrahydrofuran (8 mL) was added dropwise over 15 min. The resulting solution was stirred for 2 hr to yield a 0.5 N solution of thexylborane.

~~(b) Hydroboration Reaction:~~

A cold (-78°C) solution of the diene 32J. (34.7 mg, 0.15 mmol) in tetrahydrofuran (3 mL) was treated with thexylborane (0.44 mL, 0.22 mmol) and the solution allowed to warm to 0°C. After 1.5 hr, potassium cyanide

~~(9.8 mg, 0.15 mmol) was added and after a further hour, the solution was~~

251 cooled to -78°C and trifluoroacetic anhydride (25 uL, 0.18 mmol) added. The reaction was warmed to room temperature over 1 hr then 3 M sodium hydroxide solution (1 mL) and 30% hydrogen peroxide solution (1 mL) added and the solution left to stir overnight. The mixture was poured onto brine, extracted three times with ether and the combined ether layers washed twice

with brine then dried over MgS04. Removal of the solvent gave a colourless oil (70 mg) which was subjected to column chromatography (silica gel; petroleum ether/ether 1:1) to yield the cis-diol 323 (9.6 mg, 24%) vmax

(film): 3250 (br), 1470, 1380; 6 (CDClg, 400 MHz): 0.87 (6H, two overlapping doublets each with J = 7 Hz), 0.91 (3H, s; angular methyl group), 0.92 (3H, d, J = 7 Hz), 1.23 (3H, d, J = 6.5 Hz; CH^CHOH), 2.23 (IH, m), 3.47 (2H, m;

~~CH20H), 4.00 (IH, q, J = 6.5 Hz; CHOH); m/_e (relative intensity): 255 (1 1 ),~~

~~225 (4), 193 (14), 169 (20), 123 (35), 109 (35), 107 (25), 97 (24), 96 (42),~~

~~95 (100).~~

~~Further elution provided the trans-diol 322 (14.4 mg, 36%) as a~~

~~colourless oil, vmax (film): 3250 (br); 6 (CDC13, 400 MHz): 0.78 (3H, s; angular methyl group), 0.86 (6H, overlapping doublets each with J = 7 Hz;~~

~~CH(CH3)2), 0.83 (3H, d, J = 7 Hz), 1.05-2.20 (18H, m), 3.55 (IH, dd, J = 10~~

~~Hz, 6 Hz), 3.70 (IH, dd, J = 10 Hz, 8 Hz), 3.78 (2H, m; CH2CH_2OH); m/_e~~

~~(relative intensity): 270 (M+, 2), 252 (5), 237 (6), 207 (29), 139 (54), 123~~

~~(36), 111 (51), 109 (58), 95 (100), 81 (68); Exact mass calcd. for Cj7H3402:~~

~~270.2559; found: 270.2557.~~

~~252 (-)-Bromoalcohol 314~~

~~Bromoacid 15_9_ (2.53 g, 10.2 mmol) was dissolved in tetrahydrofuran (80 mL) at 0°C under argon. To this was added lithium aluminum hydride (0.66 g,~~

~~17.4 mmol) in portions over 15 min. After a further 15 min at 0°C, the reaction was warmed to room temperature and quenched on ice 3 hr later.~~

Water and ether were then added and the aqueous phase carefully acidified with 1 N hydrochloric acid. Two further ether extractions followed by washing the combined organic layers wtih sodium bicarbonate solution then

water (twice), drying over MgS04 and concentration j_n vacuo yielded a pale yellow oil (2.30 g) which, by column chromatography (silica gel; petroleum ether/ether 3:2) gave the required bromoalcohol 314 (2.25 g, 95%) as a

~~colourless oil, [a]n -46.2° (C 1.0, MeOH); vmax (film): 3350 (br), 1650, 890~~

~~-1 cm ; 6 (CDC13, 400 MHz), 1.04 (3H, s; angular methyl group), 1.25-1.47 (2H,~~

~~m), 1.62 (IH, br s; exchangeable with D20), 1.80 (IH, m), 1.92 (IH, m), 2.16~~

~~(IH, m), 2.33 (IH, m; allylic proton), 2.42 (IH, m; allylic proton), 3.42~~

(d) and 3.49 (d) (2H, AB quartet, J = 10 Hz; CH^Br), 2.68 (IH, m), 2.75 (IH, m), 4.84 (IH, t, J = 2 Hz), 4.98 (IH, t, J = 2 Hz); m/e (relative intensity): 217/215 (26/27), 135 (43), 121 (39), 107 (66), 95 (100), 93

~~(89), 91 (71), 79 (74); Anal • calcd. for C^H^OBr: C 51.52, H 7.35, Br~~

~~34.27; found: C 51.81, H 7.27, Br 34.09.~~

~~253 Bromoketol 349 and (-)-Bromoketol-te£t-butyldimethyl si lyl Ether 350~~

~~Br Br Br~~

~~HO HO 314 349 350~~

~~A solution of the bromoa1coho1 314 (796 mg, 3.4 mmol) in dry methanol~~

~~(60 mL) was cooled to -78°C and subjected to a stream of ozone in oxygen.~~

Two mintues after the solution turned blue the solution was flushed with pure oxygen until colourless and then dimethyl sulphide (2 mL) added dropwise. After stirring the mixture at room temperature overnight, the methanol was removed under reduced pressure and the resulting oil redissolved in ether. After filtration through a plug of silica gel, the ether was removed to yield the crude bromoketol 349 (0.77 g), vmax (film):

~~-1 3400 (br), 1720 cm ; 6 (CDC13, 80 MHz): 1.00 (3H, s), 1.5-2.0 (4H, m, 1~~

~~proton exchangeable with D20), 2.0-2.9 (4H, m), 3.3 (d) and 3.7 (d) (2H, AB quartet, J = 10 Hz), 3.8 (2H, br t, J = 6 Hz); m/_e (relative intensity):~~

~~236/234 (M+, 0.5/0.6), 155 (22), 137 (9), 109 (10), 97 (100), 95 (20), 93~~

~~(19), 91 (19). Exact mass calcd. for CgHj502Br: 236.0235/234.0255; found:~~

~~236.0233/234.0245.~~

~~The crude bromoketol 349 (0.77 g), tert-buty1dimethy1si1y1 chloride~~

~~(0.98 g, 6.6 mmol, freshly sublimed), 4-dimethylaminopyridine (0.8 g, 6.6 mmol) were dissolved in dry dichloromethane (40 mL) under argon. After 24~~

~~hr at room temperature the reaction was partitioned between water and ether.~~

~~The ether extracts were washed with 1 N hydrochloric acid then twice with~~

~~water, dried (MgS04) and evaporated to give a pale yellow oil (1.41 g).~~

~~Purification by column chromatography (silica gel; petroleum ether/ether~~

~~254 9:1) provided the bromoketone 350 (0.789 g, 67% over 2 steps). [oOp -57.6°~~

~~(C 0.55, MeOH); vmax (film): 1740 cm-1; 6 (CDClg, 400-MHz): 0.07 (6H, s; Si-~~

~~CH3), 0.91 (9H, s; Si-C(CH3)3), 0.94 (3H, s; angular methyl group), 1.40-~~

~~1.54 (2H, m), 1.74 (IH, m), 2.07-2.25 (2H, m), 2.37 (IH, m), 2.62 (IH, m),~~

~~3.29 (IH, d, J = 10 Hz), 3.61 (IH, d, J = 10 Hz), 3.67-3.80 (2H, m; CH20); m/e (relative intensity): 293/291 (9/9), 211 (10), 169 (9), 167 (8), 137~~

~~(100), 119 (36), 109 (53), 95 (82), 93 (73); Anal. calcd. for Cj5H2902BrSi:~~

~~C51.57, H 8.37, Br 22.87; found: C 51.83, H 8.45, Br 22.77.~~

~~Protection of (-)-Bromoa1coho1 314 as the TBDMS-Ether~~

~~The bromoalcohol 314 (800 mg, 3.4 mmol), tert-butyldimethyl silyl~~

~~chloride (1.03 g, 6.8 mmol), DMAP (824 mg, 6.8 mmol) and dichloromethane (30~~

~~mL) were stirred at room temperature under argon for 2 days. The usual~~

~~work- up provided a pale yellow oil (1.65 g) which was purified by column~~

~~chromatography (silica gel; petroleum ether/ether 9:1) to yield the~~

~~bromoalkene 351 (1.14 g, 96% yield) as a colourless oil, vmax (film): 1660,~~

~~1 880 cm" ; 6 (CDC13, 80 MHz): 0.08 (6H, s; S1(CH3)2), 0.92 (9H, s;~~

~~SiC(CH3)3), 1.02 (3H, s; angular methyl group), 1.01-2.50 (7H, m), 3.42 (2H,~~

~~br s; CH2Br), 3.50-3.80 (2H, m; CH20), 4.82 (IH, t), 4.98 (IH, t); m/je~~

~~(relative intensity): 291/289 (1.5/1.5), 209 (13), 135 (92), 107 (59), 93~~

~~(100).~~

~~255 Protection of (-)-Bromoalcohol 314 as the MOM-Ether~~

~~Phosphorus pentoxide (1.5 g, 10.6 mmol) was added in portions to a solution of the bromoalcohol 314 (955 mg, 4.1 mmol) and methylal (25 mL,~~

0.28 mmol) in dichloromethane (20 mL). After 3 hr, the solution was added to sodium bicarbonate solution and this extracted (x 3) with ether. The combined ether layers were washed with sodium bicarbonate solution then

~~twice with brine, dried (MgS04) and the solvent removed. The crude product~~

~~(1.08 g) was subjected to column chromatography (silica gel; petroleum ether/ether 10:1) to yield the bromoalkene 315 as a colourless oil (561 mg,~~

~~49% yield), vmax (film): 1150, 1105, 1040 cm-1; 6 (CDClg, 400 MHz): 1.03~~

~~(3H, s; angular methyl group), 1.25-1.45 (2H, m), 1.77-1.94 (2H, m), 2.15~~

~~(IH, m), 2.30 (IH, m; allylic proton), 2.40 (IH, m; allylic proton), 2.37~~

~~(3H, s; 0CH3), 2.41 (d) and 2.47 (d) (2H, AB quartet, J = 10 Hz; CH2Br),~~

~~2.51-2.65 (2H, m; 0-CH2CH2), 4.62 (2H, s; 0-CH2-0), 4.83 (IH, t), 4.97 (IH, t); m/e (relative intensity): 247/245 (36/38), 246/244 (32/30), 233/231~~

~~(25/27), 202/200 (55/56), 183 (64), 93 (100).~~

~~256 Ring Cleavage of Bromoketone 350; Formation of (-)-Acyclic Ester 352 and~~

~~(+)-Bicyclic Ketone 353~~

Sodium metal (140 mg, 6.1 mmol) was added to dry methanol (5 mL) under argon using a water bath to cool the system. When all the sodium had reacted, the bromoketone 350 (215 mg, 0.61 mmol) in methanol (6 mL) was added via a cannula needle and the reaction heated to 60°C (oil bath temperature). After 3.5 hr the mixture was poured onto saturated ammonium chloride solution and then extracted (x 3) with ethyl acetate. The combined organic layers were washed with brine (twice), dried and the solvent removed. The residue (193 mg) was subjected to flash chromatography (silica gel; petroleum ether/ether 50:1) to give the ester 352 (105 mg, 57%; 61%

~~based on recovered starting material), [a]n -0.45° (C 0.66, MeOH); vmax~~

~~1 (film): 1745, 1650, 890 cm" ; 6 (CDC13, 400 MHz): 0.03 (6H, s; Si-CH3), 0.89~~

~~(9H, s; SiC(CH3)3), 1.53-1.77 (7H, m), 2.13-2.33 (3H, m), 3.46-3.60 (2H, m;~~

~~CH2-0), 3.65 (3H, s; C02CH3), 4.69 (IH, br s), 4.78 (IH, br s); m/e~~

~~(relative intensity): 285 (1.4), 269 (3), 243 (73), 211 (16), 171 (40), 157~~

~~C H 0 S, : c (40), 151 (100); Anal. calcd. for 16 32 3 ' 63.95, H 10.73; found: C~~

~~63.79, H 10.78.~~

~~Further elution provided the bicyclo[2.1.1] ketone 353 (28.4 mg, 17%;~~

~~19% based on recovered starting material), [a]n +54.1° (C 0.29, CH2C12);~~

~~1 vmax (film): 1790 cm" ; 6 (CDC13, 400 MHz): 0.04 (6H, s; Si-CH3), 0.89 (9H,~~

~~s; Si-C(CH3)3), 1.20 (3H, s; bridgehead methyl group), 1.46-1.62 (4H, m),~~

~~257 1.84 (IH, m), 2.00-2.08 (2H, m), 2.83 (IH, br s; bridgehead proton), 3.55-~~

~~+ 3.72 (2H, m; 0-CH2); m/_e (relative intensity): 268 (M , 2), 253 (4), 227~~

~~(36), 211 (71), 183 (41), 165 (33), 119 (34), 107 (32), 93 (32), 75 (100),~~

~~73 (49); Exact mass calcd. for Cj5H2g02Si: 268.1859; found: 268.1864; Anal.~~

~~calcd. for C15H2802Si: C 67.11, H 10.51; found: C 67.20, H 10.44.~~

~~The final fractions from the column yielded starting material 350 (11.5 mg).~~

~~Preparation of the para-Bromobenzoate Derivative 353b~~

~~To the bicyclic ketone 353a (83 mg, 0.31 mmol) was added tetrabutylammonium fluoride (3.1 mL, 3.1 mmol; 1 M solution in tetrahydrofuran) and the solution stirred under argon at room temperature~~

~~for 2 hr. The mixture was diluted with ether, poured onto brine and~~

~~extracted 3 times with ether. The ether extracts were washed with water (x~~

~~2), dried (MgSO^) and evaporated to provide a yellow oil (104 mg). Column~~

~~chromatography (silica gel; petroleum ether/ether 1:2) of this oil afforded~~

~~the ketoalcohol (32 mg, 67%); vmax (film): 3300 (br), 1790 cm-1; 6 (CDClg,~~

~~80 MHz): 1.18 (3H, s), 2.83 (IH, br s), 3.4-3.9 (2H, m); m/e (relative~~

~~intensity): 154 (M+, 1), 139 (3), 113 (44), 95 (41), 93 (87), 91 (29), 81~~

~~(100), 80 (58), 79 (68).~~

~~para-Bromobenzoy1 chloride (77 mg, 0.35 mmol) was added to a solution~~

~~258 of ketoalcohol (27.4 mg, 0.17 mmol) in dry pyridine (2 mL) and the mixture stirred under argon for 24 hr. After dilution with ether and addition of 1~~

N hydrochloric acid the ether layer was separated and washed twice with 2 N potassium hydroxide then with water (x 3). The crude product, after evaporation of the solvent, was chromatographed on silica gel (petroleum ether/ether 4:1) to give the para-bromobenzoate 353b (44 mg, 737.) as an oil which solidified on standing. Recrystal1isat ion from petroleum ether provided 353b as needles, mp 47.5-48.5°C; vmax (film): 1780, 1720, 1595 cm-1; 6 (CDC13, 80 MHz): 1.28 (3H, s; bridgehead methyl), 1.30-1.85 (4H, m), 1.85-

~~2.33 (3H, m), 2.90 (IH, br s; bridgehead proton), 4.38 (2H, t, J = 7 Hz),~~

~~7.50-8.00 (4H, m; aromatic protons); m/e (relative intensity): 338/336 (M+,~~

~~0.3/0.4), 297/295 (4/4), 185 (99), 183 (100), 108 (58), 93 (71).~~

~~The structure and absolute configuration of the para-bromobenzoate 148 derivative 353b has been proved by X-ray analysis~~

~~3-lsopropenyl-l,6-hexanediol-monosilyl Ether 354~~

~~-rSi0'^xx^C02Me 352~~

Lithium aluminum hydride (76 mg, 2.0 mmol) was added in 4 portions to a cooled (0°C) solution of the ester 352 (400 mg, 1.33 mmol) in tetrahydrofuran (30 mL) under argon. After 1 hr at 0°C and 1 hr at room temperature tic indicated no starting material remained and the solution was added to ice. The mixture was carefully acidified (1 N hydrochloric acid) and extracted with ether (x 3). Subsequent washing with water, drying

259 (MgSO^) and concentration jm vacuo afforded a pale yellow oil (380 mg) which was chromatographed on silica gel (petroleum ether/ether 1:2) to provide the required alcohol 354 (326 mg, 90%) as a colourless oil. vmax (film): 3350

~~-1 (br), 1640, 880 cm ; <5 (CDC13, 80 MHz): 0.08 (6H, s; Si-CH.3), 0.95 (9H, s;~~

~~Si-C(CH3)3), 1.25-1.75 (10H, m; 1 proton replaced with D20), 2.05-2.30 (IH,~~

~~m; C-3 proton), 3.40-3.80 (4H, m; CH2~0), 4.75 (2H, m; vinyl protons) m/e~~

~~(relative intensity): 257 (0.2), 215 (13), 123 (47), 105 (33), 81 (60), 75~~

~~c (100); Exact mass calcd. for i5H3jSi02-C4Hg: 215.1474; found: 215.1467.~~

~~(-)-4-1sopropeny1-6-tert-buty1d i methy1s ilyloxyhexana1 355~~

A solution of the hydroxya1kene 354 (170 mg, 0.63 mmol) and pyridinium dichromate (1.18 g, 3.13 mmol) in dry dichloromethane (20 mL) was stirred at room temperature under an argon atmosphere for 16 hr. The reaction mixture was then diluted with ether and filtered through a pad of silica gel. After washing the silica gel with more ether, the solvent was evaporated under reduced pressure and the crude product purified by flash chromatography

~~(petroleum ether/ether 10:1). This afforded the aldehyde 355 (128.9 mg,~~

~~76%) as a colourless oil, [a]n -3.58° (C 0.81, Ch2Cl2); vmax (film): 3100,~~

~~-1 2730, 1730, 1650, 895 cm ; 6 (CDClg, 80 MHz): 0.08 (6H, s; Si-CH3), 0.92~~

~~(9H, s; Si-C(CH3)3), 1.45-1.85 (7H, m), 2.05-2.52 (3H, m), 3.55 (2H, t, J =~~

~~6 Hz), 4.72 (IH, br s), 4.80 (IH, m), 9.68 (IH, t, J = 4 Hz; CHO); m/e~~

~~(relative intensity): 270 (M+, 0.1), 269 (0.4), 255 (0.5), 243 (9), 213~~

~~260 (27), 121 (58), 93 (59), 75 (100); Anal, calcd. for C15H30O2Si: C 66.60, H~~

~~11.18; found: C 66.70, H 11.25.~~

~~3-1sopropeny1-hept-6-en-1-o1-tert-buty1dimethy1s11y1 Ether 356~~

~~Methy1-triphenylphosphoniurn bromide (259 mg, 0.73 mmol) was suspended in dry tetrahydrofuran (5 mL) under an atmosphere of argon and cooled to~~

-78°C. n-Butyl1ithium (0.45 mL, 0.72 mmol; 1.6 M solution in hexane) was added in one lot. After 10 minutes at -78°C, the cold bath was removed and the reaction stirred for a further 40 min during which time all the solid disappeared and the solution became dark orange. The aldehyde 355 (97 mg,

~~0.36 mmol) in tetrahydrofuran (5 mL) was added and the reaction stirred for~~

~~1 hr.~~

After this time the mixture was diluted with hexanes (20 mL), the solution poured onto a prepacked column of Florisil and then eluted with hexanes. The fraction containing the product was evaporated and the material then rechromatographed on silica gel eluting with petroleum ether/ether 250:1. This yielded the diene 356 (68.3 mg, 71%), vmax (film):

~~1 3100, 1640, 910, 890 cm" ; 6 (CDClg, 400 MHz): 0.03 (6H, s; Si-CH3), 0.88~~

~~(9H, s; Si-C(CH3)3), 1.42 (2H, m), 1.56 (2H, m), 1.60 (3H, br s; vinyl~~

~~methyl group), 1.88-2.05 (2H, m), 2.20 (IH, m), 3.46-3.60 (2H, m; 0-CH2),~~

~~4.69 (IH, br s), 4.75 (IH, br s) 4.92 (IH, br d, JAX = 10 Hz; HAX), 4.99~~

~~(IH, br d; JnY = 17 Hz; HR), 5.80 (IH, overlapping dddd, J = 17 Hz, 10 Hz, 7~~

~~261 Hz, 7 Hz; Hx); m/e (relative intensity): 253 (0.1), 211 (20), 129 (26), 101~~

~~(39), 75 (100), 73 (27); Exact mass calcd. for Cj6H310Si-C4Hg: 211.1518; found: 211.1520.~~

~~(-t-)-3-Isopropenyl-6-heptenal 332~~

A solution of tetrabutylammonium fluoride (2.5 mL, 2.5 mmol; 1 M solution in tetrahydrofuran) was added to the diene 356 (67 mg, 0.48 mmol) under argon. After 2.5 hr the reaction was diluted with ether and water.

~~The aqueous layer was extracted twice more with ether and the ether layers were combined and washed twice with brine. After drying (MgSO.), the ether 4 was removed to yield a yellow oil (98.6 mg).~~

~~Purification by column chromatography (silica gel; petroleum ether/ether 6:1) provided the alcohol 35_2 (38 mg), vmax (film): 3320, 3080,~~

~~1 1640, 905, 890 cm" ; 6 (CDC13> 80 MHz): 1.72 (3H, dd, J = 1, 1 Hz), 3.65~~

~~(2H, t, J = 6 Hz), 4.70-5.18 (4H, m), 5.82 (IH, 10 line multiplet); m/e~~

~~(relative intensity): 154 (M+, 6), 41 (100).~~

Alcohol 357 (26 mg, 0.17 mmol) in dry dichloromethane (7 mL) was treated with pyridinium dichromate (315 mg, 0.85 mmol) and the reaction stirred under argon for 14 hr. The mixture was diluted with ether and filtered through a pad of silica gel. Removal of the solvent j_n vacuo at

~~0°C yielded 34.8 mg of crude product. Chromatography (silica gel; petroleum ether/ether 4:1) gave the aldehyde 332 (16 mg, 62X over 2 steps) as an~~

~~262 unstable volatile oil. [Q]D +6.1° (C 0.74, CH2C12); vmax (film): 3080,~~

~~1 2740, 1730, 1640, 890 cm" ; 6 (CDC13, 270 MHz): 1.52 (2H, m), 1.69 (3H, br s), 2.04 (2H, m), 2.46 (2H, m which simplified on irradiation at 69.66),~~

~~2.73 (IH, 5 line multiplet), 4.79 (IH, m), 4.83 (IH, m), 4.93-5.05 (2H, m),~~

~~5.80 (IH, ddt, J = 17 Hz, 11 Hz, 6 Hz), 9.66 (IH, t, J = 2 Hz; CHO); m/e~~

~~(relative intensity): 151 (M+-H, 0.9), 137 (3), 108 (17), 95 (29), 93 (29),~~

~~81 (33), 79 (29), 69 (100), 67 (53); Exact mass calcd. for C1()H160-H:~~

~~151.1123; found: 151.1129.~~

~~The ir and nmr of this compound were identical to spectra of the » authentic compound.~~

~~We are grateful to Dr. R.J. Anderson (Zoecon Corporation, Palo Alto, California) for providing comparative ir and nmr spectra for this compound.~~

~~(3R.5R)- and (3S,5R)-5-Isopropenyl-2-methyl-1,8-nonadien-3-ol 340a and 340b~~

A 3-neck flask fitted with a dry-ice condenser, and a pressure equalised dropping funnel was charged with 300 mg (12.5 mmol) of freshly crushed magnesium turnings. A crystal of iodine was added and then the 2- bromopropene (0.75 mL, 8.3 mmol) in tetrahydrofuran (20 mL) was added quickly dropwise. After the addition was complete, the mixture was refluxed for 30 min and then cooled to room temperature. Four mL of this solution

~~(approximately 1.6 mmol) was removed by syringe and added to a solution of~~

263 the aldehyde 332 (31 mg, 0.2 mmol) in tetrahydrofuran (4 mL) at -15°C. The reaction mixture was stirred at this temperature for 30 min then allowed to warm to ambient temperature over a further 30 min before being poured onto an ice/ammonium chloride solution. This was extracted with ether (x 3); the

~~ether washed twice with brine and dried over MgS04.~~

~~The crude product, 56 mg, was subjected to flash chromatography using petroleum ether/ether 12:1 as eluant. This gave both diastereomers as pure compounds with the following characteristics:~~

~~(a) The less polar diastereomer 340a or 340b, 15.5 mg; R^. 0.46 (petroleum~~

~~ether/ether 1:1); [a]n -15.47° (C 1.5, CH2C12); vmax (film): 3400 (br),~~

~~1 3100, 1645, 890 cm" ; 6 (CDC13, 400 MHz): 1.38-1.60 (5H, diffuse m, one~~

~~proton exchangeable with D20), 1.63 (3H, br s), 1.72 (3H, br s), 1.98 (2H, m), 2.39 (IH, seven line multiplet), 4.00 (IH, dd, J = 9 Hz, 3 Hz), 4.81~~

~~(2H, br s), 4.84 (IH, br s), 4.90-5.03 (3H, m), 5.83 (IH, dddd, J = 17 Hz,~~

~~10 Hz, 6.5 Hz, 6.5 Hz); m/e (relative intensity): 194 (M+, 0.4), 179 (7),~~

~~135 (30), 109 (35), 107 (34), 95 (34), 93 (45), 84 (47), 81 (65), 71 (86),~~

~~70 (57), 69 (100), 67 (73); Exact mass calcd. for Cj3H220: 194.1671; found:~~

~~194.1680.~~

~~R (b) More polar diastereomer 340a or 340b, 15.9 mg; f 0.32 (petroleum~~

~~ether/ether 1:1); [a]n +50.15° (C 1.34, CH2C12); vmax (film): 3380 (br),~~

~~1 3100, 1645, 890 cm" ; <5 (CDC13, 400 MHz): 1.45 (2H, m), 1.50-1.65 (3H, m,~~

~~one proton exchangeable with D20), 1.67 (3H, br s), 1.73 (3H, br s), 1.97~~

~~(2H, m), 2.14 (IH, seven line multiplet), 4.08 (IH, t, J = 6.5 Hz), 4.75~~

~~(IH, br s), 4.80 (IH, br s), 4.84 (IH, br s), 4.90-5.05 (3H, m), 5.80 (IH, dddd, J = 17 Hz, 10 Hz, 7 Hz, 7 Hz); m/e (relative intensity): 194 (0.6),~~

~~151 (5), 139 (5), 109 (20), 107 (26), 95 (24), 94 (35), 93 (24), 81 (49), 79~~

~~(35), 71 (100), 70 (32), 69 (82), 68 (78); Exact mass calcd. for C.,H 0-~~

~~264 H20: 176.1565; found: 176.1561.~~

~~Total yield of alcohols 340a and 340b: 31.4 mg (79%), Anal. (mixture of~~

~~C H 0: c H diastereomers) calcd. for 13 22 80.35, 11.41; found: C 80.30, H~~

~~11.47.~~

~~Bromoketol MOM-Ether 358~~

~~349~~

To a solution of the bromoketol 349 (309 mg, 1.3 mmol) and methylal (5 mL, 57.5 mmol, a large excess) in dry dichloromethane (9 mL) under an inert atmosphere (argon) was added phosphorus pentoxide (1.5 g) in three portions.

~~After 3 hr, tic indicated no starting material remained so the reaction was carefully quenched on ice cold sodium carbonate solution. Ether extraction~~

~~(3 times) followed by two water washes, drying (MgSO^) and concentration provided 297 mg of a yellow oil.~~

~~Chromatography on silica gel eluting with petroleum ether/ether 1.5:1, gave 358 (287.5 mg, 78%) as a colourless oil with the following~~

~~1 characteristics: vmax (film): 1740 cm" ; 6 (CDC13, 270 MHz): 0.94 (3H, s; angular methyl group), 1.50 (2H, m), 1.81 (IH, m), 2.17 (2H, m), 2.38 (IH,~~

~~m), 2.58 (IH, m), 3.28 (IH, d, J = 10 Hz; CH2Br), 3.37 (3H, s; CH30), 3.60~~

~~IH, d, J = 10 Hz; CH2Br), 3.64 (2H, m; OCH2CH2), 4.63 (2H, s; -OCH20-); m/e~~

~~(relative intensity): 280/278 (M+, 0.1/0.2), 199 (64), 167 (100), 149 (66),~~

~~137 (46), 111 (46), 107 (62), 97 (62), 95 (61), 67 (53); Exact mass calcd.~~

~~for CnHig03Br-Br: 199.1334; found: 199.1326.~~

~~265 \~~

~~Ring Cleavage of Bromoketol MOM-Ether 358~~

~~MOMO^ 358 -^2 MOMO 353c~~

Sodium metal (107 mg, 4.65 mmol) was added to dry methanol (5 mL, argon atmosphere) and after it had all reacted, the bromoketone 358 in a further 5 mL of methanol was added. The temperature was raised to 55°C (oil bath temperature) and 5 hr later the mixture was poured onto ammonium chloride

~~solution. Work-up as before yielded 109 mg of crude product. Column~~

~~chromatography (petroleum ether/ether 10:1) gave the acyclic ester 359b~~

~~1 (56.3 mg, 54%); vmax (film): 3080, 1740, 1640, 920, 890 cm" ;~~

~~MHz): 1.50-1.85 (5H, m), 2.00-2.40 (3H, m), 3.32 (3H, s; CH20CH3), 3.45 (2H,~~

~~t, J = 8 Hz; OCH2CH2-), 3.65 (3H, s; C02CH3), 4.58 (2H, s; 0CH20), 4.70 (IH,~~

~~br s), 4.80 (IH, br s) and a fraction (18.5 mg) containing a mixture of 359a~~

~~and the MOM-ether of bicyclic ketone 353c (the major component), vmax~~

~~1 (film): 1780 cm" ; 6 (CDC13> 80 MHz): 1.22 (3H, s; bridgehead methyl group),~~

~~2.85 (IH, br s; bridgehead proton), 3.35 (3H, s; 0CH3), 4.60 (2H, s; 0CH20).~~

~~Reduction of Bromoketone 350: Formation of Diasteromeric Alcohols 360a and~~

~~360b~~

~~! 0 ! OH~~

~~1 350 1 360~~

~~266 METHOD A:~~

~~To the bromoketone 350 (200 mg, 0.57 mmol) in dry tetrahydrofuran (20 mL) at 0°C under argon was added lithium aluminum hydride (22 mg, 0.57 mmol)~~

~~in one lot. After 1 hr at 0°C and 2 hr at room temperature the reaction was quenched on ice. The usual work up afforded 194 mg of crude product, two~~

~~spots on tic. Chromatography (petroleum ether/ether 10:1) gave~~

~~bromoalcohol, 360a (22.4 mg, 11%) Rf 0.3 (petroleum ether/ether 4:1); vmax~~

~~(film): 3450 (br); 6 (CDC13, 80 MHz): 0.10 (6H, s; Si-CH3), 0.95 (12H, s;~~

~~tertiary methyl group and Si-C(CH3)3 protons), 1.25-2.40 (8H, diffuse m),~~

~~3.30-3.78 (4H, m; CH_2Br and CH20), 3.92 (IH, br d, J = 5 Hz); m/e (relative~~

~~intensity): 295/293 (0.1/0.3), 277/275 (2/2), 213 (6), 121 (100), 95 (26),~~

~~93 (67), 79 (38), 75 (42).~~

~~Further elution of the column (petroleum ether/ether 2:1) gave the~~

~~bromoalcohol 360b (152.4 mg, 76%); R^. 0.16 (petroleum ether/ether 4:1); mp~~

~~-1 38-41°C; vmax (film): 3400 cm , 6 (CDC13, 400 MHz): 0.04 (6H, s; Si-CH3),~~

~~0.89 (12H, s; tertiary methyl group and Si-C(CH3)3), 1.25-1.65 (5H, m), 1.82~~

~~(2H, m), 2.02 (IH, m), 3.38 (IH, d, J = 10 Hz), 3.51 (IH, d, J = 10 Hz),~~

~~3.56 (IH, m; 0-CH_2), 3.65 (IH, m; 0CH2), 4.07 (IH, t, J = 8 Hz); NOE~~

~~experiment: irradiation at 64.07 OCHOH) resulted in a positive enhancement~~

~~of the signal at 63.38 (CH_2Br). No enhancement of the tertiary methyl group~~

~~at 60.89 was observed; m/e (relative intensity): 293 (0.2), 277/275~~

~~(1.2/0.9), 213 (4), 121 (100), 95 (41), 93 (83), 81 (25), 79 (52), 75 (64).~~

~~METHOD B:~~

~~The ketone 350 (95 mg, 0.27 mmol) in tetrahydrofuran (3 mL) was cooled~~

~~to -78°C under argon and diisobutylaluminum hydride (0.6 mL, 0.6 mmol), 1 M~~

~~solution in hexane from Aldrich Chemical Co.) added via a syringe. Stirring~~

~~was continued at -78°C for 1 hr then a further hour with the cold bath~~

~~267 removed. The mixture was poured onto ice/1 N hydrochloric acid and~~

extracted with ether (x 3). Two washes with brine then drying (MgS04) and evaporation yielded 105.3 mg of crude product. Purification (as before) gave bromoalcohol 360a (53.8 mg, 56%) and bromoalcohol 360b (28.5 mg, 30%).

~~Alkylation of (+)Camphor 10: Preparation of (+)-3-exo-Methylcamphor 362b~~

~~10 362a 362b~~

(+)-Camphor J_0 (4.0 g, 26 mmol) was added to a freshly prepared solution of lithium diisopropylamide (25 mmol) in dry tetrahydrofuran (30 mL) at 0°C under argon and the enolate allowed to form over 30 min. Methyl iodide (6.5 mL, 105 mmol) was then added and the reaction stirred for a further 30 min before being quenched with 1 N hydrochloric acid. The mixture was extracted with ether and the combined ether extracts washed with

water 3 times and dried over MgS04. Removal of the solvent yielded a pale oil (4.28 g) which partially crystallised on standing. Capillary glc analysis (Carbowax 20 M, 12 m column, 80°C) of the crude product indicated the ratio of 3-exo to 3-endo-methylcamphor (362b and 362a) to be in the range 3.4-3.8:1.

Purification by column chromatography (silica gel; petroleum ether/ether 50:1) afforded starting material (0.603 g) and a mixture of 3- exo and 3-endo-methylcamphor (3.16 g, 72%; 85% yield based on recovered starting material). *H nmr and capillary glc analysis showed the ratio of

~~3-exo to 3-endo-methylcamphor to be 3.4-3.8:1.~~

268 A sample of pure 3-exo-methylcamphor (362b) was obtained by re- chromatographing the above mixture using the same conditions. The fractions containing pure 3-exo-methylcamphor (monitored by capillary glc) were combined and sublimed to provide 362b as a white crystalline solid, mp 50-

~~1 54°C; [a]n +71.4° (C 0.57, MeOH); vmax (CHC13): 1740 cm" ;~~

~~MHz): 0.85 (3H, s), 0.90 (3H, s), 0.93 (3H, s), 1.21 (3H, d, J = 7.5 Hz),~~

~~1.36 (IH, ddd, J = 12 Hz, 9 Hz, 3 Hz), 1.48 (IH, m), 1.63 (IH, ddd, J = 14~~

~~Hz, 11 Hz, 3.5 Hz), 1.85 (IH, d, J = 4 Hz; C4 proton), 1.92-2.30 (2H, m underlying a quartet with J = 7.5 Hz); m/e (relative intensity): 166 (M+,~~

~~32), 123 (40), 108 (51), 95 (100), 83 (83); Exact mass calcd. forCjjHjgO:~~

~~166.1358; found: 166.1358; Anal. calcd. for CnH180: C 79.47, H 10.91; found: C 79.50, H 10.86.~~

~~Epimerisation of (+)-3-Methylcamphor 362a/362b: Preparation of (+)-3-endo-~~

~~Methylcamphor 362a~~

~~362a, 362b 362a~~

~~A mixture of 3-exo- and 3-endo-methylcamphor (362a and 362b; 239 mg,~~

1.4 mmol) in glacial acetic acid/concentrated hydrochloric acid (2 mL, 9:1) was heated at 80°C for 6 hr. The solution was diluted with water, extracted with ether (x 3) and the extracts washed with sodium bicarbonate solution and then with water. Removal of the dried (MgSO^) solvent yielded a white crystalline product (231 mg, 97%). Capillary glc (Carbowax 20 M, 12 m column, 80°C) and *H nmr (270 MHz) showed that the ratio of 3-exo- to 3-

~~269 endo-methy1 camphor was ~1:9.~~

~~Low temperature crystallisation (CC^/acetone bath) from pentane provided pure 3-endo-methy1 camphor (362a), mp 37-39°C" (Lit186 mp 38-39°C);~~

~~186 [Q]d +25.4° (C 2.5, MeOH) (Lit [a]n +27.3° (C 10.0 EtOH)); vmax (CHC13):~~

~~1735 cm-1; 6 (CDClg, 400 MHz): 0.87 (3H, s), 0.90 (3H, s), 1.00 (3H, s),~~

~~1.06 (3H, d, J = 7.5 Hz), 1.27 (IH, m), 1.55-1.80 (3H, m), 1.98 (IH, t, J =~~

~~4.5 Hz), 2.48 (IH, dq, J = 7.5 Hz, 4.5 Hz); m/e (relative intensity): 166~~

~~(M+, 37), 123 (37), 108 (63), 95 (100), 83 (70); Exact mass calcd. for~~

~~CnH180: 166.1358; found: 166.1362; Anal . calcd. for CjjHjgO: C 79.47, H~~

~~10.91; found: C 79.50, H 10.88.~~

~~Alkylation of (+)-9-Bromocamphor 19_: Preparation of (+)-9-Bromo-3-exo- methyl camphor 376b~~

~~CH3 H 376a 376b~~

(+)-9-Bromocamphor13 19 (2.0 g, 8.7 mmol) was added to a freshly prepared solution of lithium diisopropylamide (8.2 mmol) in dry tetrahydrofuran (9.8 mL) at 0°C under argon and the enolate allowed to form over 30 min. Methyl iodide (2.2 mL, 34.6 mmol) was then added and the reaction stirred for a further 30 min before being quenched with 1 N hydrochloric acid. After the normal work-up, removal of the solvent yielded a pale yellow solid (2.04 g).

~~Purification by column chromatography (silica gel; petroleum ether/ether 50:1) afforded starting material (0.471 g) and 9-bromo-3-~~

~~270 methyl camphor (1.49 g, 70%; 92% based on recovered starting material) as a mixture of epimers. The 400 MHz ^H nmr spectra of this product showed the~~

~~ratio of the 3-exo (376b) to 3-endo (376a) methyl epimers to be ~ 1.7:1.~~

~~Repeated recrystal1isation of the mixture of epimers from petroleum ether~~

~~provided pure (+)-9-bromo-3-exo-methylcamphor (376b), mp 115-116°C. [Q]Q~~

~~1 6 +158.4° (C 0.125, CH2C12); vmax (CHC13): 1745 cm" ; (CDC13, 270 MHz): 0.96~~

(3H, s), 1.02 (3H, s), 1.23 (3H, d, J = 8 Hz), 1.30-1.76 (4H, m), 1.99 (IH, m), 2.04 (IH, q, J = 8 Hz), 2.25 (IH, d, J = 4 Hz), 3.19 (IH, d, J = 10 Hz) and 3.57 (IH, d, J = 10 Hz); m/e (relative intensity): 246/244 (M+, 15),

~~188/186 (38/38), 165 (15), 137 (59), 123 (29), 107 (100), 95 (100); Exact mass calcd. for CjjHjyOBr: 246.0442/244.0462; found: 246.0449/244.0456.~~

~~Anal . calcd. for C{ jH^OBr: C 53.89, H 6.99, Br 32.59; found: C 53.87, H~~

~~6.98, Br 32.48.~~

~~Epimerisation of (+)-9-Bromo-3-methylcamphor (376a/376b): Isolation of (+)-~~

~~9-Bromo-3-endo-inethy 1 camphor 376a~~

~~376a, 376b CH3 576a~~

~~An epimeric mixture of (+)-9-bromo-3-methylcamphor (1.03 g) in glacial acetic acid (19 mL) and concentrated hydrochloric acid (1 mL) was heated at~~

~~80°C for 16 hr. Work-up in the usual way provided a white solid (1.02 g,~~

~~99%) which was shown by *H nmr (400 MHz) to be a mixture of 3-exo (376b) to~~

~~3-endo (376a) methyl epimers in the ratio ~1:9.5.~~

~~The major isomer, (+)-9-bromo-3-endo-methy1 camphor (376a) was identical~~

~~271 to an authentic sample prepared by bromination of 3-endo-methylcamphor~~

~~(362a).~~

~~Alkylation of (+)-9,10-Dibromocamphor 37: Isolation of (+)-9,lQ-Dibromo-3- exo-methyl camphor 150b~~

(+)-9,10-Dibromocamphor 37 (0.908 g, 2.9 mmol) was added to a freshly prepared solution of lithium diisopropylamide (2.78 mmol) in dry tetrahydrofuran (3.3 mL) at 0°C under argon. After 15 min methyl iodide

~~(0.72 mL, 11.6 mmol) was added and 30 min later the reaction terminated with~~

~~1 N hydrochloric acid. Work-up in the usual way yielded a pale yellow solid~~

~~(8.75 mg) which, on column chromatography (silica gel; petroleum ether/ether~~

50:1), gave starting material (512 mg) and an epimeric mixture of (+)-9,10- dibromo-3-methylcamphor (318 mg, 34%). Capillary glc (Carbowax 20 M, 12 m column, 180°C) and 400 MHz *H nmr showed the ratio of 3-exo to 3-endo methyl epimers to be "1.7:1. The major isomer, (+)-9,10-dibromo-3-exo-methy1 camphor 150b was obtained after repeated recrystal1isat ion from methanol, mp

~~-1 84-85.5°C. [a]n +102.0° (C 0.20, CHpC^); vmax (CHC13): 1735 cm ; 6~~

~~(CDC13, 400 MHz) 1.11 (3H, s), 1.24 (3H, d, J = 8 Hz), 1.56 (2H, m), 2.03~~

~~(IH, m), 2.09 (IH, q, J = 8 Hz), 2.23 (IH, m), 2.34 (IH, d, J = 4 Hz), 3.45~~

~~(IH, d, J = 12 Hz), 3.49 (IH, d, J = 10 Hz), 3.63 (IH, d, J = 10 Hz) and~~

~~3.67 (IH, d, J = 12 Hz); m/e (relative intensity): 245/243 (M+-Br, 40/40),~~

~~237/235 (23/23), 163 (17), 135 (100); Exact mass calcd. for CjjHjgOBr^~~

~~272 325.9527/323.9547/321.9567; found: 325.9540/323.9572/321.9566. Anal. calcd.~~

~~for CnH160Br2: C 40.77, H 4.98, Br 49.31; found: C 40.56, H 5.04, Br 49.20.~~

~~Epimerisation of (+)-9,10-Dibromo-3-methylcamphor 150a,b: Isolation of (+)-~~

~~9,10-D i bromo-3-endo-mVthy 1 camphor 150a~~

An epimeric mixture of (+)-9,10-dibromo-3-methylcamphor (1.49 g) in glacial acetic acid (27 mL) and concentrated hydrochloric acid (3 mL) was heated to 80°C for 16 hr. Work-up in the usual fashion afforded a crystalline product (1.3 g, 90%) which was shown by capillary glc (Carbowax

~~20 M, 12 m column, 180°C) and 400 MHz 'H nmr, to be a mixture of 3-exo~~

~~(150b) to 3-endo (150a) methyl epimers in the ratio of ~1:6.~~

~~Repeated crystallisation from methanol afforded pure (+)-9,10-dibromo-~~

~~3-endo-methylcamphor (150a). mp 62.5-63°C; [Q]d +46.7° (C 0.30, CH2C12);~~

~~1 vmax (CHC13): 1735 cm" ; 6 (CDClg, 400 MHz): 1.11 (3H, d, J = 8 Hz), 1.15~~

~~(3H, s), 1.33 (IH, m), 1.75 (IH, m), 1.84 (IH, m), 2.27 (IH, m), 2.43-2.54~~

~~(2H, m), 4.44 (d) and 4.66 (d) (2H, AB quartet, J = 12 Hz), 4.60 (d) and~~

~~4.74 (d) (2H, AB quartet, J = 10 Hz); m/_e (relative intensity): 326/324/322~~

~~(M+, 0.6/1.7/0.8), 245/243 (44/44), 217/215 (24/24), 163 (19), 135 (100);~~

~~c Exact mass calcd. for uHj6OBr2: 325.9527/323.9547/321.9567; found:~~

~~325.9512/323.9558/321.9562; Anal. calcd. for CuHj6OBr2: C 40.77, H 4.98, Br~~

~~49.31; found: C 40.65, H 4.92, Br 49.23.~~

~~273 3-Methyl-3-trideuteriomethylcamphor 377a and 377b~~

~~(+)-3-Methylcamphor (362a and 362b; 0.693 g, 4.17 mmol) dissolved in dry tetrahydrofuran (9 mL) was added to a freshly prepared solution of~~

lithium diisopropylamide (5.13 mmol) in tetrahydrofuran (9 mL) at 0°C under argon. After 45 min g^-methyl iodide (0.68 mL, 10.7 mmol) was added and the reaction quenched with 1 N hydrochloric acid 1 hr later. Work-up in the usual way afforded a yellow oil (0.737 g) which, on column chromatography

~~(silica gel; petroleum ether/ether 50:1), gave starting material (0.24 g) and 3-methyl-3-trideuteriomethylcamphor as a mixture of epimers (377a and~~

~~377b; 0.476 g, 627.; 95% based on recovered starting material). The 400 MHz~~

*H nmr spectrum showed the ratio of the 3-exo (377a) to 3-endo-methyl (377b)

~~1 epimers to be ~3.4:1. vmax (CHC13): 1740 cm" ; 6 (CDC13, 400 MHz): 0.87~~

~~(3H, s), 0.91 (3H, s), 1.00 (3H, s), 1.03 (0.7 H, s; C-3 endo-methyl), 1.19~~

~~(2.3H, s; C-3 exo-methyl); NOE difference experiment: irradiation of the methyl singlet at 61.19 produced positive enhancements at 60.91 (C-8 methyl~~

~~group) and at 61.81 (C-4 proton). Exact mass calcd. for Cj2Hj7D30:~~

~~183.1703; found: 183.1703.~~

~~274 Bromination of Camphor Enol Trimethyl silyl Ether 380~~

~~380 15b 15a~~

Camphor enol trimethylsilyl ether (380) (350 mg, 1.56 mmol) in dry tetrahydrofuran (5 mL) was stirred at 0°C under an argon atmosphere. To this was added bromine (0.15 mL, 3.0 mmol) in dichloromethane (0.85 mL), dioxane (1 mL) and pyridine (1 mL). After 5 min the reaction was quenched with sodium bisulphite solution and the mixture extracted 3 times with ether. The ether layers were washed with copper sulphate solution then water, dried (MgSO^) and the solvent removed to yield a pale yellow oil (368 mg). This oil was shown to be 94% pure (glc, 3% OV-17, 130°C) and to contain 3-exo-bromocamphor 15b and' 3-endo-bromocamphor 15a in the ratio 1:1

~~(integration of the C-3 proton in the 80 MHz lH nmr spectrum).~~

~~Bromination of Camphor I0cf' 195~~

~~12 15b 15a~~

~~Camphor J_0 (1.0 g, 6.6 mmol), pyridinium bromide perbromide (5.25 g,~~

~~~13.0 mmol) and glacial acetic acid (5 mL) were stirred on a steam bath for~~

~~1 hr before being poured onto sodium bisulphite solution. Work-up as before yielded a crude product (1.36 g) which contained 47% 3-bromocamphor (glc, 3%~~

~~275 OV-17, 130°C) with the ratio of epimers exo (15b): endo (15a) being 1:1~~

~~(integration of the C-3 proton in the 80 MHz lH nmr spectrum).~~

~~Epimerisation of (+)-3-endo-Bromocamphor 15a~~

~~Sodium metal (1.0 g, 43 mmol) was added to dry methanol (20 mL) under an argon atmosphere. When al1 the sodium had reacted 3-endo-bromocamphor~~

~~15a (1.0 g, 4.3 mmol) was added and the reaction heated at reflux for 24 hr.~~

~~The solution was cooled and poured onto 1 N hydrochloric acid. Three ether extractions followed by washing of the ether layers with water, drying~~

~~(MgSO^) and evaporation gave 3-bromocamphor (800 mg) with the exo (15b) to endo (J_5a) ratio being 9:9114 (determined from the 400 MHz lH nmr).~~

~~Bromi nation of (+)-3-flethyl camphor (362a and 362b)~~

~~Br CH3 362a. 362b 381a 381b~~

3-Methylcamphor 362a and 362b (1.27 g, 7.64 mmol), pyridinium bromide perbromide (2.93 g, ~9.17 mmol; ~80%) and glacial acetic acid (15 mL) were stirred at 80°C for 4 hr and then poured onto sodium bisulphite solution.

~~Extraction with ether followed by washing with sodium bicarbonate solution~~

~~276 then water, drying and evaporation gave a crystal 1ine product (1.78 g, 95%).~~

Capillary glc analysis (Carbowax 20 M, 12 m; 120°C) and the 400 MHz LH nmr spectrum showed the ratio of 3-exo-methy1 (381a) to 3-endo-methyl (381b) epimers to be 4:1. Recrystal1isat ion from petroleum ether provided a sample of pure 3-endo-bromo-3-exo-methy1 camphor (381a) as a white crystalline solid

~~1 mp 62-63.5°C; vmax (CHC13): 1750 cm" ; <$ (CDC13, 400 MHz): 0.92 (3H, s),~~

~~0.96 (3H, s), 1.10 (3H, s), 1.59 (2H, m), 2.03 (3H, s), 2.05 (IH, m), 2.22~~

~~(IH, d, J = 4 Hz; C-4 proton), 2.31 (IH, ddd, J = 13.5 Hz, 8.5 Hz, 3 Hz); m/e (relative intensity): 246/244 (M+, 6/7), 165 (13), 136 (50), 95 (16), 83~~

~~(100); Anal. calcd. for CNH170Br: C 53.89, H 7.00, Br 32.59; found: C~~

~~53.69, H 6.97, Br 32.57.~~

~~The minor epimer, 3-exo-bromo-3-endo-methy1 camphor (381b), had the following 'H nmr signals (taken from the spectrum of the epimeric mixture),~~

~~6 (CDC13, 400 MHz): 0.97 (3H, s), 1.04 (3H, s), 1.25 (3H, s), 1.83 (3H, s),~~

~~2.51 (IH, d, J = 4 Hz; C-4 proton).~~

~~Bromination of (+)-9-Bromo-3-inethylcamphor (376a and 376b)~~

To a solution of 9-bromo-3-methylcamphor (376a and 376b) (2.18 g, 8.92 mmol) in glacial acetic acid (20 mL) at 80°C was added pyridinium bromide perbromide (4.47 g, ~11.2 mmol; "80%) and the mixture stirred at this temperature for 4.5 hr and then at room temperature overnight. After pouring the solution on to aqueous sodium bisulphite it was extracted 3

~~277 times with ether and the ether layers combined and washed successively with~~

~~sodium bicarbonate solution and water. Drying (MgSO^) followed by removal of the solvent gave a yellow solid (2.84 g) which was shown to be a mixture~~

~~of the 3-endo-bromo (382a) to 3-exo-bromo (382b) compounds in the ratio~~

~~4.55:1, (capillary glc analysis: Carbowax 20 M, 12 m; 190°C). Purification~~

~~by column chromatography on silica gel (petroleum ether/ether 25:1) gave 3-~~

~~endo-9-dibromo-3-exo-methy1 camphor 382a (2.0 g, 72%) mp 45-46°C; vmax~~

~~1 (CHC13): 1750 cm" ; 6 (CDCl3t 400 MHz): 1.00 (3H, s), 1.09 (3H, s), 1.69~~

~~(1H, m), 1.81 (IH, m), 2.03 (3H, s; C-3 exo methyl group), 2.03 (IH, m; C-5~~

~~exo proton), 2.40 (IH, m), 2.59 (IH, d, J = 3.5 Hz; C-4 proton), 3.21 (IH,~~

~~d, J = 10 Hz), 3.65 (IH, d, J = 10 Hz). NOE difference experiment (80 MHz):~~

~~irradiation at 61.09 (7-syn methyl group) resulted in positive enhancement~~

~~at 62.03 (3-exo-methyl group), 62.59 (C-4 proton), 63.21 and 63.65. m/e~~

~~(relative intensity): 326/324/322 (M+, 18 /32/18), 298/296/294 (19/34/19),~~

~~245/243 (17/18), 217/215 (100/100), 163/161 (50/51); Anal. calcd. for~~

~~CnH160Br: C 40.77, H 4.98, Br 49.31; found: C 40.83, H 4.85, Br 49.10.~~

~~Further elution provided 3-exo-9-dibromo-3-endo-methy1 camphor (382b)~~

~~(370 mg, 13%) as a white crystalline solid mp 71-73.5°C; vmax (CHC13): 1760~~

~~1 cm" ; 6 (CDC13, 400 MHz): 1.02 (3H, s), 1.43 (3H, s), 1.48 (IH, m), 1.69~~

~~(IH, m), 1.86 (5H, m; C-3 endo methyl group overlying multiplet), 2.87 (IH,~~

~~br d, J = 3 Hz; C-4 proton), 3.16 (IH, d, J = 10 Hz), 3.61 (IH, d, J = 10~~

~~Hz); m/e (relative intensity): 326/324/322 (M+; 8/17/8), 296/294/292~~

~~(11/20/11), 245/243 (5/5), 217/215 (47/52), 163/161 (23/25), 135 (100);~~

~~Anal. calcd. for CnH160Br2: C 40.77, H 4.98, Br 49.31; found: C 40.94, H~~

~~4.80, Br 49.22~~

~~278 Bromination of (+)-3-endo-Methylcamphor 362a in Chlorosulphonic Acid~~

3-endS-Methylcamphor (362a) (2.0 g, 12.0 mmol) in bromine (1.5 mL, 29.3 mmol) and chlorosulphonic acid (3 mL) were stirred at room temperature for 2 days. The mixture was quenched on ice and solid sodium bisulphite and the resulting solution extracted with ether three times. The ether layers were treated with solid sodium bicarbonate then washed with water until neutral.

~~After drying over MgSO^, the solvent was removed and the crude product (2.91 g) purified by column chromatography (silica gel; petroleum ether/ether~~

50:1) to yield 1.90 g, 88% pure, of 9-bromo-3-endo-methy1 camphor (376a) contaminated with an unidentified by-product. Recrystal1isat ion from pentane provided the pure compound (1.2 g, 41%) as a white crystalline solid

~~1 mp 104-106°C; [Q]d +69.4° (C 0.386, MeOH); vmax (CHC13): 1740 cm" ; <5~~

~~(CDC13, 400 MHz): 0.93 (3H, s), 1.03 (3H, s), 1.08 (3H, d, J = 7 Hz), 1.35~~

~~(IH, m), 1.60-1.80 (3H, m), 2.37 (IH, t, J = 4 Hz), 2.45 (IH, dq, J = 4 Hz,~~

7 Hz), 3.23 (IH, d, J = 10 Hz), 3.65 (IH, d, J = 10 Hz); m/e (relative intensity): 246/244 (M+, 36/38), 188/186 (96/100), 165 (36); Exact mass calcd. for CjjHjyOBr: 246.0442/244.0462; found: 246.0444/244.0466; Anal.

~~calcd. for CnHj70Br: C 53.89, H 6.99, Br 32.59; found: C 53.66, H 7.12, Br~~

~~32.38.~~

~~Further elution provided the bromoisofenchone 386 (380 mg, 13%) as a~~

~~white crystalline solid mp 46-49°C; [a]Q = -87.7° (C 0.486, MeOH); vmax~~

~~1 (CHC13): 1740 cm" ; 6 (CDCI3, 400 MHz): 0.75 (3H, d, J = 8 Hz), 1.03 (3H,~~

~~279 s), 1.10 (3H, s), 1.58 (1H, d, J = 11 Hz; C-7 syn proton), 1.71 (IH, q, J =~~

~~8 Hz; C-6 exo proton), 1.90 (IH, ddd, J = 11 Hz, 4 Hz, 2 Hz; C-7 anti proton), 2.03 (IH, dd, J = 18 Hz; 4 Hz; C-3 exo proton), 2.28 (IH, dd, J =~~

~~18 Hz, 4 Hz; C-3 endo proton), 2.42 (IH, br s; C-4 proton), 3.49 (d) and~~

~~3.50 (d) (2H, AB quartet, J = 10 Hz). Decoupling the proton at 62.42 causes the proton at 62.03 to simplify to a doublet (J = 18 Hz) and the proton at~~

~~61.90 becomes a doublet of doublets (J = 11 Hz and 4 Hz). Decoupling at~~

~~62.28 causes the signal at 61.90 to collapse to a broad doublet (J = 11Hz), and the signal at 62.03 collapses to a broad singlet, m/e (relative~~

~~+ intensity): 246/244 (M , 22/23), 202/200 (57/60), 177/175 (11/9), 165 (45),~~

~~151 (61), 121 (61), 109 (47), 107 (31), 95 (100); Exact mass calcd. for~~

~~CnH170Br: 246.0442/244.0462; found: 246.0428/244.0461; Anal. calcd. for~~

~~CnH170Br: C 53.89, H 6.99, Br 32.59; found: C 53.65, H 7.17, Br 32.42.~~

~~The structures and absolute configurations of both 9-bromo-3-endo- methylcamphor 376a and the bromoisofenchone 386 were confirmed by X-ray analysis148~~

~~Preparation of (-)-Bromoisofenchone 386~~

~~376a 386~~

9-Bromo-3-endo-methylcamphor 376a (200 mg, 0.82 mmol) was stirred in chlorosulphonic acid (2.5 mL) at room temperature for 8 hr. The mixture was quenched on ice and the usual work-up afforded 160 mg of a crude product which by glc (3% OV-17, 140°C) was shown to contain starting material (42%),

280 bromoisofenchone 386 (48%) and an unidentified by-product (9%). Column chromatography (silica gel; petroleum ether/ether 50:1) provided pure bromoisofenchone 386 (65 mg, 33%), identical with an authentic sample, as well as starting material (37 mg after recrystal1isat ion from pentane).

~~Preparation of 7-syn-9-Dibromoisofenchone 387~~

~~METHOD A: Bromination of (-)-Bromoisofenchone 386~~

~~The bromoisofenchone 386 (447 mg, 1.8 mmol), bromine (1 mL, 19.5 mmol) and chlorosulphonic acid (2 mL) were stirred at room temperature for 4 days.~~

~~After the usual work-up a crude solid (290 mg) remained which was 92% a new~~

~~compound by glc (OV-17, 180°C). Isolation of the major compound by column~~

~~chromatography (silica gel; petroleum ether/ether 50:1) provided it as a~~

~~white crystalline solid (192 mg, 32%), mp 67-70°C; [a]n -46.8° (C 0.50,~~

~~MeOH). The compound was assigned as the dibromoisofenchone 387 based on its~~

~~1 spectral data; vmax (CHC13): 1750 cm" ; 6 (CDC13, 400 MHz): 0.81 (3H, d, J =~~

~~8 Hz), 1.11 (6H, s; coincident methyl groups), 1.79 (IH, q, J = 8 Hz; C-6~~

~~exo proton), 2.32 (IH, dd, J = 18.5 Hz, 3 Hz; C-3 endo proton), 2.65 (IH,~~

~~dd, J = 4.5 Hz, 2 Hz; C-4 proton), 2.73 (IH, dd, J = 18.5 Hz, 4.5 Hz; C-3~~

~~exo proton), 3.46 (d) and 3.48 (d) (2H, AB quartet, J = 9 Hz), 4.38 (IH, dd,~~

~~J = 3 Hz, 2 Hz; C-7 anti proton). Irradiation at 64.38 causes the resonance~~

~~at 62.32 to collapse to a doublet (J = 18.5 Hz) and 62.65 to collapse to a~~

~~doublet (J = 4.5 Hz). NOE difference experiment (80 MHz): irradiation at~~

281 63.49 (CH^Br protons), produced positive enhancements at 64.38 (C-7 anti proton), 62.65 (C-4 proton), 61.79 (C-6 exo proton) and 61.11; m/e (relative intensity): 326/324/322 (M+, 2/4/2), 245/243 (12/12); 203/201 (94/100);

~~Exact mass calcd. for CnHj60Br2: 325.9527/323.9548/321.9568; found:~~

~~325.9524/323.9536/321.9555; Anal. calcd. for CjjHjgOBr?: C 40.77, H 4.98, Br~~

~~49.31; found: C 40.94, H 5.14, Br 49.10.~~

~~METHOD B: Bromination of (+)-9-Bromo-3-endo-methy1 camphor 376a~~

~~376a 386 387~~

(+)-9-Bromo-3-endo-methy1 camphor (376a) (1.28 g, 5.22 mmol) bromine (3 mL, 58.5 mmol) and chlorosulphonic acid (6 mL) were stirred at room temperature for 4 days. The reaction was worked-up in the usual way to yield a crude brown oil (1.73 g). Column chromatography (silica gel; petroleum ether/ether 50:1) gave starting material (212 mg, 80% pure by glc) followed by the dibromoisofenchone 387 (422 mg, 25% yield) which was identical to the product obtained previously by direct bromination of the bromoisofenchone 386.

~~Further elution with petroleum ether/ether 9:1, gave the bromoisofenchone 386 (176 mg, 14%).~~

~~282 Preparation of (-)-3-exo-9-Dibromoisofenchone 388~~

A solution of the bromoisofenchone 386 (810 mg, 3.19 mmol) and pyridinium bromide perbromide (1.53 g, ~3.83 mmol; ~80%) in glacial acetic acid (15 mL) was stirred at 90°C for 4 hr then at room temperature overnight. The mixture was poured onto sodium bisulphite solution and extracted several times with ether. The bulked ether layers were washed with sodium bicarbonate solution, then twice with water and dried over

MgSO^. Removal of the solvent gave the dibromoisofenchone 388 as a white crystalline solid (1.06 g, 100%). Capillary glc analysis (Carbowax 20 M, 12 m, 160°C) showed the product to be 100% pure. Recrystal1isation from

~~methanol provided a pure sample of 388, mp 125-126.5°C; [a]n -145.9° (C 1.5,~~

~~1 CH2C12); vmax (CHC13): 1760 cm" ; 6 (CDClg, 400 MHz): 0.74 (3H, d, J = 7.5~~

~~Hz; C-6 endo methyl group), 1.08 (3H, s), 1.16 (3H, s), 1.74 (IH, q, J = 7.5~~

Hz; C-6 exo proton), 1.96 (IH, ddd, J = 11 Hz, 3.5 Hz, 2 Hz; C-7 anti proton), 2.25 (IH, d, J = 11 Hz; C-7 s*n proton), 2.57 (IH, br s, C-4 proton), 3.48 (d) and 3.52 (d) (2H, AB quartet, J = 10 Hz), 4.28 (IH, d, J =

~~3.5 Hz; C-3 endo proton). Irradiation at 64.28 simplifies the 61.96~~

~~resonance to a doublet of doublets (J = 11 Hz, 2 Hz). Irradiation at 61.96~~

~~causes both signals at 64.28 and 62.25 to collapse to singlets, m/e~~

~~(relative intensity): 326/324/322 (M+, 5/11/5), 298/296/294 (1/2/1), 245/243~~

~~(33/35), 177/175 (46/52), 135 (37), 41 (100); Exact mass calcd. for~~

~~CnH160Br2: 325.9527/323.9548/321.9568; found: 325.9556/323.9558/321.9573;~~

~~283 Anal. calcd. for CjjHjgOBr^ C 40.77, H 4.98, Br 49.31; found: C 40.60, H~~

~~4.90, Br 49.21.~~

~~Rearrangement of (+)-3-endo-9-Di bromocamphor 18a~~

~~18a 26_ 394~~

~~(+)-3-endo-9-Dibromocamphor 18a (2.13 g) was stirred in chlorosulphonic acid (7.5 mL) at 55°C for 45 min. The mixture was quenched on ice/sodium~~

~~chloride (care!), water added and the solution extracted with ether (x 3).~~

~~The combined ether layers were washed with aqueous potassium hydroxide/brine~~

~~(emulsion formed) then twice with brine before being dried over MgS04.~~

~~Removal of the solvent jn vacuo gave a waxy orange solid (1.73 g) which was~~

~~recrystal1ised from ether to yield (-)-6-endo-9-dibromocamphor 26 (1.01 g).~~

~~Chromatography (silica gel; petroleum ether/ether 13:1) of the mother~~

~~liquors provided additional product (144 mg, total yield of 54%) mp 153.5-~~

~~23 23 154°C (Lit. mp 152°C); [Q]d -98.3° (C 0.402, CH2C12) (Lit. [o.]n -81°~~

~~(EtOH)); 6 (CDC13, 270 MHz): 1.02 (3H, s), 1.07 (3H, s), 1.99 (IH, dd, J =~~

~~14 Hz, 3Hz; C-5 endo proton), 2.13 (IH, d, J = 19 Hz; C-3 endo proton), 2.46~~

~~(IH, ddd, J = 19 Hz, 5 Hz, 4 Hz; C-3 exo proton), 2.64 (IH, dd, J = 4 Hz, 4~~

~~Hz; C-4 proton), 2.83 (IH, m), 3.26 (IH, d, J = 10 Hz), 3.54 (IH, d, J = 10~~

~~Hz), 4.27 (IH, dd, J = 10 Hz, 3 Hz; C-6 exo proton); m/e (relative~~

~~intensity): 312/310/308 (M+, 2/5/2), 231/229 (67/67), 217/215 (24/24),~~

~~175/173 (24/25), 149 (34), 121 (26), 107 (100); Exact mass calcd. for~~

~~ClOH14°Br2: 311-9371/309-9391/307-9411; found: 311.9381/309.9393/307.9422;~~

~~284 Anal. calcd. for Cj0H14OBr2: C 38.74, H 4.55, Br 51.55; found: C 38.68, H~~

~~4.54, Br 51.49.~~

~~The structure and absolute configuration of this compound was confirmed 148 by X-ray analysis . Also isolated from the column was the dibromofenchone~~

~~395 (115 mg, 5%) identical to the compound obtained from bromination of 3- endo-9-d i bromocmaphor 18a.~~

~~Rearrangement of (+)-3-endo-Bromocamphor 15a~~

~~15a 172 396~~

(+)-3-endo-Bromocamphor 15a (7.5 g) in chlorosulphonic acid (30 mL) was stirred at 50°C for 14 min then poured onto ice. After extraction with ether (x 3), the ether layers were washed with sodium bicarbonate solution

~~then twice with water and finally dried over MgS04. Removal of the solvent under reduced pressure gave a light yellow crystalline solid (3.51 g).~~

~~Column chromatography (silica gel; petroleum ether/ether 9:1) gave the bromofenchone 396 (75 mg, 1%) as a crystalline solid, mp 49-50°C (sealed~~

~~1 tube); [a]n -133.15° (C 0.19, CH2C12); vmax (film): 1745 cm" ; 6 (CDC13, 400~~

~~MHz): 1.09 (3H, s), 1.13 (3H, s), 1.16 (3H, s), 1.38 (IH, m), 1.75-1.90 (2H, m), 2.22 (IH, m), 2.34 (IH, br d, J = 4 Hz; C-4 proton), 4.26 (IH, br s; C-7~~

~~syn proton); m/e (relative intensity): 232/230 (M+, 1/0.6), 151 (8), 123~~

~~(60), 81 (100); Exact mass calcd. for C1()H150Br: 232.0286/230.0306; found:~~

~~232.0291/230.0312. Further elution provided a mixture of unidentified~~

~~compounds (186 mg) which decomposed spontaneously and this was followed by~~

~~285 (-)-6-endo bromocamphor (172), (2.67 g, 36%) as a white crystalline solid,~~

~~-1 [a]n -51.77° (C 4.96, CH2C12); vmax (CHClg): 1745 cm ; 6 (CDC13, 400 MHz):~~

~~0.92 (3H, s), 0.97 (3H, s), 1.00 (3H, s) 1.90 (IH, dd, J = 15 Hz, 3.5 Hz; C-~~

~~5 endo proton), 2.05 (IH, d, J = 18 Hz; C-3 endo proton), 2.22 (IH, dd, J =~~

~~4 Hz, 4 Hz; C-4 proton), 2.44 (IH, ddd, J = 18 Hz, 4 Hz, 4Hz; C-3 exo proton), 2.85 (IH, dddd, J = 15 Hz, 10 Hz, 4 Hz, 4 Hz; C-5 exo proton), 4.22~~

~~(IH, dd, J = 10 Hz, 3.5 Hz; C-6 exo proton); m/e (relative intensity):~~

~~232/230 (M+, 1.2/1.8), 167 (11), 151 (39), 149 (30), 109 (100), 108 (34),~~

~~107 (43); Exact mass calcd. for C^H^OBr: 232.0286/230.0306; found:~~

~~232.0274/230.0303; Anal. calcd. for CjgHjgOBr: C 51.97, H 6.54, Br 34.57; found: C 51.93, H 6.45, Br 34.68.~~

~~(+)-3-endo-Bromo-10-Deuter i ocamphor 398~~

~~Br 397 398~~

~~(+)-3-endo-Bromo-10-deuteriocamphor (398) was prepared according to the 218 * procedure of Meyer et al from (+)-l0-deuteriocamphor (397) and had mp~~

~~74.5-76°C; 6 (CDClg, 400 MHz): 0.93 (3H, s), 0.96 (2H, t, J = 2 Hz), 1.08~~

~~(3H, s), 1.43 (IH, ddd, J = 14 Hz, 9 Hz, 5 Hz), 1.69 (IH, m), 1.88 (IH, m),~~

~~2.09 (IH, ddd, J = 13 Hz, 9 Hz, 4 Hz), 1.30 (IH, dd, J = 4.5 Hz, 4.5 Hz; C-4~~

~~proton), 4.62 (IH, br d, J = 4.5 Hz); Exact mass calcd. for Cj0H14DOBr:~~

~~233.0349/231.0369; found: 233.0348/231.0369.'~~

* This compound prepared by T. Atlay from 10-bromocamphor and tri-n-butyl tin deuteride.

~~286 (-)-6-endo-Bromo-8-Deuteriocamphor 399~~

~~(-)-6-endo-Bromo-8-deuteriocamphor (399) was prepared from ( + )-3-endo-~~

~~bromo-10-deuteriocamphor (398) as before and had mp 55-56°C; <5 (CDC13, 400~~

~~MHz): 0.90 (2H, b s), 0.97 (3H, s), 0.99 (3H, s), 1.90 (1H, dd, J = 14.5 Hz,~~

~~3 Hz), 2.05 (IH, d, J = 18.5 Hz), 2.21 (IH, dd, J = 4.5 Hz, 4.5 Hz), 2.44~~

~~(IH, ddd, J = 18.5 Hz, 5 Hz, 4.5 Hz), 2.85 (IH, m), 4.22 (IH, dd, J = 10 Hz,~~

~~3.5 Hz); Exact mass calcd. for C10Hj4DOBr 233.0349/231.0369; found:~~

~~233.0346/231.0374.~~

~~Preparation of (-)-Camphor ent10~~

~~172 ent10~~

To a solution of (-)-6-endo-bromocamphor (173) (107 mg, 0.46 mmol) and azobisisobutyronitrile (20 mg) in benzene (4 mL) was added tri-n-butyltin 219 hydride (0.2 mL, 0.74 mmol) and the mixture refluxed under argon for 16 hr. After cooling the solution, it was poured onto 10% aqueous potassium 220 fluoride and extracted twice with ether. The ether layers were washed twice with the potassium fluoride solution, dried (MgSO^) and evaporated to yield a colourless oil (377 mg). Column chromatography (silica gel;

~~287 petroleum ether/ether 20:1) gave (-)-camphor ent10 (33.4 mg, 47%), [a]n -~~

~~44.75° (C 0.40, 95% EtOH), authentic (-)-camphor (Aldrich Chemical Co.) had~~

~~[a]n -40.15° (C 0.396, 95% EtOH) and authentic (+)-camphor (Aldrich Chemical~~

~~Co.) had [a]n +44.80° (C 0.386, 95% EtOH). The synthetic (-)-camphor was identical (ir, lH nmr, tic, glc) to the authentic material.~~

~~(-)-8-Deuteriocamphor 400~~

~~D D~~

~~Br 399 400~~

~~(-)-8-Deuteriocamphor (400) was prepared via the method above in 60%~~

~~yield from (-)-6-endo-bromo-8-deuteriocamphor (399) and had vmax (CHC13):~~

~~1740 cm"1; 6 (CDClg, 400 MHz): 0.83 (2H, t, J = 3.5 Hz; C-8 methyl), 0.93~~

(IH, d; C-10 methyl), 0.97 (IH, s; C-9 methyl); 1.30-1.45 (2H, m), 1.68 (IH, m), 1.85 (IH, d, J = 18 Hz), 2.09 (IH, dd, J = 4.5 Hz, 4.5 Hz), 2.35 (IH, dd, J = 18 Hz, 5 Hz, 4.5 Hz); m/e (relative intensity): 153 (M+, 49), 109

~~(72), 96 (100), 84 (44), 81 (84); Exact mass calcd. for CinH15DO: 153.1264; found: 153.1264.~~

~~This compound was identical (400 MHz *H nmr) to an authentic sample 205 prepared from (+)-8-bromocamphor~~

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~~300 Append i x 1~~

~~H NMR Spectra of Selected Compounds~~

~~301~~

~~303 304 305 i 0 I II~~

~~306 307 308 309 310 311 312 313 332~~

~~I I I I I 1 I I I I I 1 I I 1 I I L «tr«S4»lt A 80MHz H nmr of 332 prepared from (+)-camphor~~

~~B 60MHz H nmr of 332 supplied by Dr R.J. Anderson of the Zoecon Corporation, Palo Alto, California.~~

~~314 315 316 317 318 Appendix 2~~

~~Stereoviews of Compounds Analysed by X-rav Crystallography~~

~~319 (+)-9-Bromo-3-endo-methylcamphor 376a~~

~~320 321~~