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A new annulation method and its application to terpenoid synthesis Tse, Hoi Lun Allan 1986

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A NEW ANNULATION METHOD AND ITS APPLICATION TO TERPENOID SYNTHESIS by HOI LUN ALLAN TSE B.Sc.(Hon.), University of Bradford, 1979 M.Sc, University of B r i t i s h Columbia, 1982 A THESIS SUBMITTED IN THE REQUIREMENTS DOCTOR OF PARTIAL FULFILLMENT OF FOR THE DEGREE OF PHILOSOPHY in THE FACULTY OF GRADUATE STUDIES (DEPARTMENT OF CHEMISTRY) We accept t h i s thesis as conforming to the required standard THE UNIVERSITY OF BRITISH COLUMBIA DECEMBER 1986 © Hoi Lun Allan Tse 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. The University of British Columl 1956 Main Mall Vancouver, Canada Department V6T 1Y3 DE-6(3/81) Abstract The major theme of the work described in this thesis i s concerned with the preparation of the 0-trimethylstannyl enoates 53, 54 and 55, and their u t i l i z a t i o n in annulation processes. Treatment of the enol t r i f l a t e s 88, 91 and 92 with the cuprate reagent 56 produces compounds 53, 54 and 55, respectively, in good y i e l d s . Base promoted a l k y l a t i o n of the enoates 53 and 54 with 3-iodo-1-chloropropane provides the products 111 and 119. Under similar reaction conditions, 55 was alkylated with 1,4-dibromobutane and 1,5-dibromopentane to give 132 and 136. By employing standard reactions, 111, 119, 132 and 136 were converted into 113, 123, 134 and 141, respectively. Treatment of 113, 123, 134 and 141 with methyllithium in THF, in the presence of HMPA, led to the formation of the substituted bicyclof4 .3.0]nonenes 114, 124 and 128, and the bicyclo[5.3.0]decene 142, respectively. The annulation method described above was applied successfully to the synthesis of the sesquiterpenoid (±)-chiloscyphone (151) and i t s isomer (±)-S-epi-chilos-cyphone (203). Thus, reaction of compounds 182 and 183, which were derived from 54 and the a l k y l a t i n g agent 178, with methyllithium in THF-HMPA provided the key b i c y c l i c intermediates 184 and 190, respectively. These two compounds were subsequently transformed into 151 and 203. i i The s e s q u i t e r p e n o i d e r e m o f u k i n o n e , whose s t r u c t u r e was p r o p o s e d a s 2 0 4 , was s y n t h e s i z e d by e x p l o i t i n g t h e a n n u l a t i o n m e t h o d d e s c r i b e d e a r l i e r . T r e a t m e n t o f compound 2 2 8 , w h i c h was p r o d u c e d f r o m 54 and t h e d i b r o m i d e 2 2 3 , w i t h m e t h y l l i t h i u m i n 1 , 2 - d i m e t h o x y e t h a n e a f f o r d e d t h e key i n t e r m e d i a t e 229 a l o n g w i t h t h e d i e n e 2 3 0 . S u i t a b l e c h e m i c a l m a n i p u l a t i o n s c o n v e r t e d 229 i n t o 204 . On c o m p a r i n g t h e 1H nmr s p e c t r a o f 204 a n d e r e m o f u k i n o n e , s u b s t a n t i a l d i f f e r e n c e s were n o t i c e d . S i n c e compound 204 was c o n s t r u c t e d by an u n a m b i g u o u s r o u t e , i t was c o n c l u d e d t h a t t h e o r i g i n a l s t r u c t u r a l p r o p o s a l f o r e r e m o f u k i n o n e i s i n e r r o r . R CI R1 53 (R M e 3 S n , n=2, R'=H) 111 (R=COOMe, R' =H) 54 (R M e 3 S n , n=2, R'=Me) 113(R=CH 2OTBDMS, R'=H) 55 (R M e 3 S n , n=1 , R'=H) 119(R=COOMe, R'=Me) 88 (R OTf, n=2, R'=H) 123(R=CH 2OTBDMS, R'=Me) 91 (R OTf, n=2, R'=Me) 92 (R OTf, n=1, R'=H) 56 i i i <H2Pn R* R SnMe: (CH2)n. Br 11A(n=2, m=1, R=CH2OTBDMS, R'=H) I24(n=2, m=1, R=CH2OTBDMS, R'=Me) 128(n=1, m=2, R=CH2OTBDMS, R'=H) 142(n=1, m=3, R=CH2OMe, R'=H) 132(n=l R=COOMe) 134(n=1, R=CH2OTBDMS) 136(n=2, R=COOMe) 141(n=2, R=CH2OMe) TBDM SiMe- TBDMSO / ^ ^SiMe^ 190 SnMe-j TBOMS1 Si Me: 182 iv V TABLE OF CONTENTS Page ABSTRACT i i TABLE OF CONTENTS v i LIST OF TABLES v i i i LIST OF FIGURES ix ABBREVIATIONS x ACKNOWLEDGEMENTS x i i INTRODUCTION 1 I. General 2 II . Previous Work 14 III . The Plan " 20 DISCUSSION 22 I. Preparation of Methyl 2-Trimethyl-stannyl-1-cyclohexene-1 -carboxylate, Methyl 6-Methyl-2-trimethylstannyl-1-cyclohexene-1-carboxylate and Methyl 2-Trimethyl-stannyl-1-cyclopentene-1 -carboxylate 23 A. Preparation of Methyl 2-Trimethyl-stannyl-1-cyclohexene-1-carboxylate 26 vi B. Preparation of Methyl 6-Methyl-2-trimethylstannyl-1-cyclohexene-1-carboxylate 35 C. Preparation of Methyl 2-Trimethyl-stannyl-1-cyclopentene-1 -carboxylate 37 II . Annulation Studies Involving the <3-Trimethylstannyl Enoates 53, 54 and 55 40 A. Five-membered Ring Annulation Studies 45 B. Six-membered Ring Annulation Studies 54 c. Seven-membered Ring Annulation Studies 60 I I I . Total Synthesis of the Sesquiterpenoid (t)-Chiloscyphone 64 A. Introduction 64 B. Total Synthesis of (t)-Chiloscyphone 69 IV. Total Synthesis of the Sesquiterpenoid (±)-"Eremofukinone" 102 A. Introduction 102 B. Total Synthesis of (±)-"Eremofukinone" 108 EXPERIMENTAL 136 REFERENCES \ 223 v i i LIST OF TABLES Table Page I. Spectral Data Derived from the Esters 213 and 214 125 II . Spectral Data Reported for the Esters 213 and 214 125 v i i i LIST OF FIGURES F i g u r e Page 1 The 270 'H nmr spectrum of 203 101 2 The 400 1H nmr spectrum of 151 101 3 The 400 1H nmr spectrum of 246 133 4 The 400 1H nmr spectrum of 247 133 5 The 60 'H nmr spectrum of (+)-eremofukinone .... 135 6 The 400 1H nmr spectrum of 204 135 i x ABBREVIATIONS The following abbreviations have been used throughout t h i s thesis: Ac acetyl Bu butyl d doublet DEG diethyleneglycol DIBAL-H = diisobutylaluminum hydride DMAP 4~dimethylaminopyridine DME 1,2-dimethoxyethane DMF dimethylformamide DMSO dimethylsulphoxide equiv equivalent(s) Et ethyl glc g a s - l i q u i d chromatography HMPA hexamethylphosphoramide i r = infrared LAH lithium aluminum hydride LDA lithium diisopropylamide m mult i p l e t Me methyl MEM methoxyethoxymethyl MOM methoxymethyl X m.p. = melting point Ms = methanesulphonyl nmr = nuclear magnetic resonance PCC = pyridinium chlorochromate Ph = phenyl Pr = propyl PPTS = pyridinium p-toluenesulphonate Py = pyridine rt = room temperature q = quartet s = sin g l e t t = t r i p l e t TBAF = tetra-/2-butylammonium fluoride TBDMS = t ert-butyIdimethy1sily1 Tf = trifluoromethanesulphony1 THF = tetrahydrofuran p-Ts = para-toluenesulphonyl t i c = thin layer chromatography TMS = t r i m e t h y l s i l y l xi ACKNOWLEDGEMENTS I wish to express my deep gratitude to my supervisor Professor Edward Piers for his guidance during the course of my studies. It has been a pleasure being an apprentice of a great sorcerer. I would l i k e to thank a l l the many members of Professor Piers' research group with whom I have the pleasure of associating for many helpful discussions and shared ideas, especially during the "problem-set time". Special thanks are due to Dr. Anderson Maxwell, and Messrs. Peter Marrs, Rick Friesen and Renato Skerlj for their c a r e f u l proofreading. Thanks are also extended to the technical s t a f f of the Department of Chemistry for their service. Financial support from the University of B r i t i s h Columbia in the form of a teaching assistantship i s gra t e f u l l y acknowledged. 1 INTRODUCTION 2 INTRODUCTION I. General The past two decades of organic chemistry may be characterized as a period of explosive development of new synthetic methods. This development is evident from the growing number of journals which are concerned with synthetic methods only. A great number of new synthetic reagents have evolved from these methods and many of them have been u t i l i z e d to synthesize highly complex molecules. Nevertheless, the search for more e f f i c i e n t and v e r s a t i l e synthetic reagents i s s t i l l largely unabated. It i s t h i s desire which lures synthetic organic chemists into new hor izons. An area which has experienced much input recently i s the design and preparation of bifunctional reagents. One d i s t i n c t advantage of these bi f u n c t i o n a l reagents relates to the e f f i c i e n c y they provide in the convergent construction of complex molecular structures. The chemical l i t e r a t u r e contains abundant examples of synthetic reagents that correspond to synthons* possessing * As defined by Corey, synthons are "structural units within a molecule which are related to possible synthetic operations" [E. J . Corey, Pure Appl. Chem. j_4 19(1967)]. For example, methylbenzyl ketone (A) can be prepared by combination of substances that are equivalent to the benzyl synthon B and the acetyl synthon C. (cont'd) 3 one donor** (d) or one acceptor** (a) s i t e . However, reagents possessing two or more reactive s i t e s are notably less common. Reagents with two reactive s i t e s have been referred to as "bifunctional conjunctive reagents". 1 The 2 term "conjunctive reagents" was f i r s t introduced by Trost to describe reagents which are incorporated in whole or in part into a substrate molecule and to d i f f e r e n t i a t e them from reagents that operate on, but are not incorporated into a substrate. Thus, d i e t h y l acetylenedicarboxylate would be a conjunctive reagent when i t undergoes a Diels-Alder reaction with a diene, while chromic acid would be a simple reagent when i t i s used to oxidize an alcohol to an aldehyde or a ketone. 3 Recently, Seebach and coworkers introduced the term "multiple coupling reagent" to describe reagents that are designed to unite two or more moieties together. The A B C ** Heteroatoms present in an organic molecule impose an alternating acceptor and donor r e a c t i v i t y pattern (as shown) upon the skeleton. C a r b o n s 1 ' 3 / 5 a r e c l a s s i f i e d as acceptors (attack by donors) while c a r b o n s 2 ' " ' 6 a r e c l a s s i f i e d as donors (attack by acceptors); by d e f i n i t i o n , X° is a donor center. [For a more detailed discussion, . X=N,0 d d d see D. Seebach, Angew. Chem. Int. Ed. Engl. J_8, 239(1979)] 4 important requirements for a multiple coupling reagent are 3 summarized as the following. 1. The reagent must provide the carbon skeleton and fu n c t i o n a l i t y pattern which are part of the target molecule. 2. It must allow for s e l e c t i v e , sequential i n t e r -molecular formation of two or more new bonds. 3. Heterotopic s i t e s present in the reagent must be well d i f f e r e n t i a t e d . 4. If the reactive s i t e s are diastereotopic, no mixtures of diastereoisomers should be formed from the reaction. Synthetic processes involving carbocyclic ring formation are of primary importance in organic synthesis. A large array of methods and reagents have been developed for 3 t h i s purpose. Over the years, a number of bifunctional reagents have been prepared s p e c i f i c a l l y for ef f e c t i n g ring angulations. These annulation reagents are designed to react with bifunctional substrates in a sequential manner. Thus, an intermolecular coupling step is followed by an intramol-3 ecular c y c l i z a t i o n reaction. Some examples of these reagents have been chosen from the l i t e r a t u r e and they are described in the following paragraphs. D i a l k y l malonates (1) are probably the most well-known reagents that have been used e f f e c t i v e l y as equivalents of the d,d synthon 2. Due to the fact that the protons alpha to 5 OOR OR d d :OOR :OOR 1 2 R = a l k y l t h e e s t e r g r o u p s a r e q u i t e a c i d i c , t h e y c a n be removed e a s i l y by b a s e a n d t h e a n i o n s t h u s f o r m e d r e a c t r e a d i l y w i t h a w i d e v a r i e t y o f e l e c t r o p h i l e s s u c h a s a l k y l h a l i d e s , 4 k e t o n e s and a l d e h y d e s . Compounds 1 h a v e p r o v e n t o be e x t r e m e l y u s e f u l i n t e r m e d i a t e s i n o r g a n i c s y n t h e s e s and have been u t i l i z e d i n numerous ways. One e x a m p l e i s t h e p r e p a r a t i o n o f t h e s y n t h e t i c a l l y v a l u a b l e c y c l o p r o p a n e -5 1 , 1 - d i c a r b o x y l i c a c i d ( 3 ) , w h i c h i s r e a d i l y p r o d u c e d by a l l o w i n g compound 1 (R=Et) t o r e a c t w i t h 1 , 2 - d i b r o m o e t h a n e u n d e r b a s i c c o n d i t i o n s i n t h e p r e s e n c e of a p h a s e t r a n s f e r r e a g e n t ^ ( e q u a t i o n 1 ) . S u l p h u r c o n t a i n i n g d e r i v a t i v e s o f f o r m a l d e h y d e , s u c h as t h e d i t h i o a c e t a l ( 1 , 3 - d i t h i a n e ) 4 a n d t h e s u l p h i d e -s u l p h o n e 5, a r e c l a s s i c e x a m p l e s o f r e a g e n t s t h a t a r e f o r m a l e q u i v a l e n t s o f t h e d,d s y n t h o n 6. I t has been shown t h a t 50% NaOH -j t r i e t h y l b e n z y l -Br ammonium c h l o r i d e ^ C O O H ^^COOH 3 ( D 7 0 A 6 5 6 when compound 5 (R=Me) i s a l l o w e d t o r e a c t w i t h a,w-dibro-moalkanes under the i n f l u e n c e of a base, c y c l i c p r o d u c t s a r e g o b t a i n e d i n good y i e l d ( e q u a t i o n 2 ) . Subsequent a c i d h y d r o l y s i s of these p r o d u c t s g i v e s the c o r r e s p o n d i n g k e t o n e s . These r e a c t i o n s c o n s t i t u t e a s i m p l e method f o r p r e p a r a t i o n of c y c l i c k e t o n e s . O r g a n o t r a n s i t i o n m e t a l complexes have become more and 9 more i m p o r t a n t i n s y n t h e t i c o r g a n i c c h e m i s t r y . Due t o t h e i r unique p r o p e r t i e s , s t r u c t u r a l t r a n s f o r m a t i o n s which cannot be a c h i e v e d d i r e c t l y v i a t r a d i t i o n a l pathways can be a c c o m p l i s h e d r e a d i l y . An example of a c y c l o p e n t a n e a n n u l a t i o n method, e x c e r p t e d from the r e c e n t l i t e r a t u r e , 1 ^ i n v o l v e s the ( T j 1 - a l l y l ) d i c a r b o n y l ( 7 j 5 - c y c l o p e n t a d i e n y l ) i r o n complex 7 (see e q u a t i o n 3 ) . Compound 7, which i s r e a d i l y p r e p a r e d from a l l y l c h l o r i d e and sodium Fp [Fp=Fe(CO) 2(cy-c l o p e n t a d i e n y l ) ] , r e a c t s w i t h a wide range of e l e c t r o n -d e f i c i e n t o l e f i n s such as 8, t o g i v e h i g h l y s u b s t i t u t e d c y c l o p e n t a n e s . T h i s unique b e h a v i o u r of 7, t h e r e f o r e , e s t a b l i s h e s t h i s s u b s t a n c e as b e i n g an e f f e c t i v e s y n t h e t i c H30* A (2) (n=3, 4, 5) (CH 2) n C=0 7 equivalent of the d,a synthon 9. d a COOEt 7 9 2-Bromo-3-(trimethylsilyl)propene 1 (10) was f i r s t 1 2 described by Trost as a synthetic equivalent of the valuable d 2,d 3 synthon 11. An example of u t i l i z a t i o n of 10 11 compound 10 for the construction of carbocycles i s i l l u s t r a t e d in equation 4. Generation of the Grignard reagent 12 from 10, followed by a copper(l) s a l t catalyzed Michael reaction with 3-methyl-2-cyclopenten-1-one, gave the adduct 13. Treatment of the l a t t e r substance with a Lewis acid provided compound 14. This sequence of reactions constitutes a f a c i l e entry into the bicyclo[2.2.1]heptane 8 skeleton, which i s a common structural component found in many natural products. The fact that the two reactive centers present in 10 can be deployed in reverse order further exemplifies the v e r s a t i l i t y of reagent 1 0 . Thus, under the influence of titanium tetrachloride, 10 undergoes smooth 1 , 4-addition to the enone 1 5 , producing the epimeric ketones 16 and 1 7 . Reaction of 17 with lithium metal containing a small amount of sodium e f f e c t s an intramolecular c y c l i z a t i o n and leads to the formation of the b i c y c l i c compound 18 (equation 5 ) . R e c e n t l y , an e l e g a n t s y n t h e s i s of g i b b e r e l l i n A5 was 1 3 r e p o r t e d by De C l e r q and c o w o r k e r s . The key s t e p i n 0 g i b b e r e l l i n A5 c o n s t r u c t i n g the D - r i n g i n v o l v e d the i n g e n i o u s u t i l i z a t i o n of 2,3-dibromopropane ( 1 9 ) , which, i n t h i s c a s e , behaved as a s y n t h e t i c e q u i v a l e n t of the d 2 , a 3 synthon 20. S t a r t i n g 19 20 from the d i e n e 21, c o n j u g a t e a d d i t i o n of the f u r a n moiety produced the i n t e r m e d i a t e e s t e r e n o l a t e a n i o n which, upon MeOOC (6) 23 10 reaction with 19, gave compound 22. Acid hydrolysis of the enol ether function in 22 gave the corresponding ketone. The donor center, which had been masked as the v i n y l bromide, was activated by treatment of the ketone with lithium di-n-butylcuprate to give the c y c l i z e d product 23 (equation 6). In the past decade, t r a n s i t i o n metals, p a r t i c u l a r l y palladium, have become extremely popular among synthetic 1 4 organic chemists. This popularity is evident from the large number of reports in the chemical l i t e r a t u r e that are concerned with various new applications of t r a n s i t i o n 1 5 metals. Trost has recently reported a novel methylene-cyclopentane annulation method in which palladium plays a key r o l e . Central to t h i s method i s the reagent 3-acetoxy-2-(trimethylsilyl)methylpropene (24) which, in the presence of tetrakis(triphenylphosphine)palladium [ ( * 3 P ) 4 P d ] , reacts as an equivalent of the trimethylenemethane d 3,d 3' synthon 25. Thus, under the influence of a c a t a l y t i c amount of (4>3P)„Pd, reagent 24 undergoes e f f i c i e n t cycloadditions with a wide variety of electron-deficient alkenes to y i e l d substituted methylenecyclopentanes [see, for example, equations (7) and (8)]. 1 6 Recently, Boger and coworkers have reported a novel procedure for construction of substituted cyclopentenones. This method involves the reaction of cyclopropenone ketals with electron-deficient o l e f i n s . A t y p i c a l example of t h i s process i s shown in equation 9. Thus, heating a solution of the alkene 26 and the cyclopropenone c y c l i c ketal 27 in 11 benzene afforded the protected cyclopentenone 28 in good y i e l d . The above reaction can be pictured as a formal 1,3-dipolar cycloaddition of 27 to the alkene 26. Therefore, compound 27 can be regarded as an e f f e c t i v e synthetic equivalent of the a 1,d 3 synthon 29. 3 12 The ene r e a c t i o n of c a r b o n y l compounds i s a powerful t o o l f o r carbon-carbon bond formation and has been e x p l o i t e d 1 7 f r e q u e n t l y i n organic s y n t h e s i s . To e f f e c t u n c a t a l y z e d ene r e a c t i o n s , e l e v a t e d temperatures are u s u a l l y r e q u i r e d . In some cases, these high temperatures cause decomposition of 1 8 the r e a c t a n t s and/or products. Snider and coworkers have r e p o r t e d an a n n u l a t i o n method that i s based on alkylaluminum h a l i d e mediated i n t r a m o l e c u l a r ene r e a c t i o n s of /3-keto e s t e r s . A d i s t i n c t f e a t u r e of t h i s method i s that a l l the r e a c t i o n s s t u d i e d thus f a r proceed e f f i c i e n t l y at room temperature. A s p e c i f i c example of t h i s procedure i s shown in equation 10. K O f - B u , H O f - B u , » 31, A, n h COOEt 30 M e 2 A l C l , MeN0 3, A . 1 d a 31 34 25°C,j 60h, (10) OH A l k y l a t i o n of the potassium s a l t of e t h y l 2-oxo-cyclo-hexanecarboxylate (30) with 4-iodo-2-methyl-1-butene (31) a f f o r d e d compound 32. Treatment of 32 with 1.0-1.2 e q u i v a l e n t ( s ) of dimethylaluminum c h l o r i d e at room 1 3 temperature produced the b i c y c l i c alcohol 33 in good y i e l d . The mild conditions employed for t h i s c y c l i z a t i o n are p a r t i c u l a r l y noteworthy. The reagent 31 which i s involved in the above annulation process serves as an e f f e c t i v e synthetic equivalent of the d 3\a a synthon 34. 1 4 I I . Previous Work In l i g h t of t h e i r f a c i l e t r a n s m e t a l l a t i o n with a l k y l l i t h i u m reagents to give the corresponding v i n y l l i t h i u m -. 19,20 compounds, v m y l t r l a l k y l s t a n n a n e s serve as a convenient source of v i n y l donor reagents. Owing to t h e i r r e l a t i v e l y h igh thermal s t a b i l i t y and low s u s c e p t i b i l i t i e s towards moisture and oxygen, v i n y l t r i a l k y l s t a n n a n e s are, i n g e n e r a l , q u i t e easy to handle. These p r o p e r t i e s render them a v a l u a b l e t o o l to s y n t h e t i c organic chemists. Over the past few years, a number of v i n y l t r i a l k y l -stannanes have been prepared i n our l a b o r a t o r y by r e a c t i o n of v a r i o u s t r i a l k y l s t a n n y l c o p p e r ( I ) reagents with a c e t y l e n i c 21 22 compounds. ' As was expected, these v i n y l s t a n n a n e s underwent t r a n s m e t a l l a t i o n r e a d i l y and the v i n y l l i t h i u m s p e c i e s thus formed reacted smoothly with a wide v a r i e t y of i * v • -i 1,21a e l e t r o p h i l e s . A s p e c i f i c example of t h i s type of chemistry i n v o l v e s the p r e p a r a t i o n and use of 4 - c h l o r o - 2 - t r i m e t h y l s t a n n y l - 1 -butene (36). T h i s substance, a p r e c u r s o r of a number of novel donor-acceptor c o n j u n c t i v e r e a g e n t s , 1 can be prepared 22 e f f i c i e n t l y from the commercially a v a i l a b l e 3-butyn-1-ol (35) (equation 11). Based on compound 36, an e f f i c i e n t 23 methylenecyclopentane a n n u l a t i o n method was developed. T h i s s y n t h e t i c a l l y u s e f u l process i s i l l u s t r a t e d i n equation 12. 15 OH Me 3SnCu'Me 2S MeOH, THF Y # 3P /CC1, E t 3 N , A * Me-jSn 35 36 36 1) MeLi, THF -78°C 2) Cu<i>S or CuCN 37a M=Li 37b M=cu (*s)Li 37c M=Cu(CN)Li KH, THF -CI (11) (12) T r a n s m e t a l l a t i o n of 36, followed by a d d i t i o n of 1.1 24 e q u i v a l e n t s of phenylthiocopper or c o p p e r ( l ) cyanide to the r e s u l t i n g s o l u t i o n of 4 - c h l o r o - 2 - l i t h i o - 1 - b u t e n e (37a), p r o v i d e s the cuprate reagent 37b or 37c. The l a t t e r s p e c i e s undergo smooth conjugate a d d i t i o n to a number of a,/3-unsa-t u r a t e d ketones. The a d d i t i o n products 38 can be induced to c y c l i z e by treatment with potassium h y d r i d e , to a f f o r d the b i c y c l i c products 39. T h i s a n n u l a t i o n process can be d e s c r i b e d s c h e m a t i c a l l y as the combination of a d 2 , a 3 16 substrate synthon (an a, /3-unsaturated ketone) with the 1-butene d 2,a" synthon 40, which i s masked as 36 (scheme 1). 4-scheme 1 This annulation method has been applied successfully to the t o t a l syntheses of two s t r u c t u r a l l y interesting triquinane 9(12) 25 sesquiterpenoids, namely (±)-A -capanellene and (±)-pentalenene. 26 t*\ A 9 ( 1 2 ) l±)-A -capanellene (±)-pentalenene Following a similar conceptual approach, a useful extension of the chemistry summarized above has been established. This extension involved the preparation and use 22 of the reagent 5-chloro-2-trimethylstannyl-1-pentene (41), i V ^ S n . 41 which i s a homologue of compound 36. Compound 41 can be prepared conveniently from 5-chloro-1-pentyne by reaction 17 with trimethylstannylcopper-dimethyl sulphide. It has been demonstrated that 41 serves as a convenient precursor of reagents that can be used to carry out . . 27 e f f i c i e n t methylenecyclohexane annulation reactions. The t o t a l syntheses of the sesquiterpenoids (±)-axamide-1 and (±)-axisonitrile-1 were achieved by a route in which t h i s 28 method played a key r o l e . The a b i l i t y of compound 41 to perform as an e f f e c t i v e synthetic equivalent of the 1-pentene d 2 , a 5 synthon 42 i s f u l l y demonstrated by these successful r e s u l t s . Another bifunctional conjunctive reagent that i s s t r u c t u r a l l y related to compounds 36 and 41 has been synthesized in our laboratory. This reagent, (Z)-5-chloro-3-trimethylstannyl-2-pentene (43) [a synthetic equivalent of the (E)-2-pentene d 3 , a 5 synthon 4 4 ] , was prepared from ethyl 29 (E)-3-trimethylstannyl-2-pentenoate (45) via the series of reactions depicted in equation 13. 18 Me^Srv A3 CI A3 EtOOC> 1) LDA, THF, -78°C Me3Sn 2) AcOH, E t 2 0 ^ ^ ^ S n M e 3 _ 9 8 o c A5 inverse addition :COEt 1) LAH, E t 2 0 2) * 3P, CC1,, A (13) A3 1) MeLi, THF-78°C BrMg-MgBr2, E t 2 0 f A7 A6 1) CuBr«Me 2S (0.3 equiv) CI 2) 47 BF 3 »Et 20 (14) A9 19 Compound 43 has been shown to be a v e r s a t i l e annulation reagent and i t played a key role in establishing a 30 (Z)-ethylidenecyclopentane annulation sequence. This sequence i s described in general terms in equation 14. Reaction of 43 with methyllithium, followed by addition of anhydrous magnesium bromide, afforded the Grignard reagent 46. In the presence of boron t r i f l u o r i d e etherate, 46 underwent a copper(I) salt catalyzed Michael addition to a number of a, /3-unsaturated c y c l i c ketones 47. Subsequent intramolecular a l k y l a t i o n of the resultant conjugate addition products 48 provided the b i c y c l i c o l e f i n i c ketones 49. The u t i l i t y of thi s annulation method was demonstrated by i t s use in the t o t a l syntheses of the sesquiterpenoids (±)-oplopanone^ and (±)-anhydro-oplopanone.^ (±))-oplopanone (±) - anhydro-oplopanone 20 I I I . The Plan As mentioned in the above s e c t i o n , three a n n u l a t i o n methods, based on b i f u n c t i o n a l reagents d e r i v e d from the v i n y l t r i a l k y l s t a n n a n e s 36, 41 and 43, r e s p e c t i v e l y , have been developed i n our l a b o r a t o r y . The three compounds 36, 41 and 43 share two common c h a r a c t e r i s t i c s i . e . they are a c y c l i c i n nature and each possesses one donor and one acceptor s i t e separated by a s a t u r a t e d hydrocarbon c h a i n . We e n v i s i o n e d that c y c l i c compounds p o s s e s s i n g two p o t e n t i a l donor s i t e s would complement these a c y c l i c molecules and would f u r t h e r enhance the u t i l i t y of v i n y l t r i a l k y l s t a n n a n e s in a n n u l a t i o n p r o c e s s e s . The p o t e n t i a l candidates which we thought might f u l f i l l our goal were the c y c l i c /3-tr i m e t h y l s t a n n y l a, / 3-unsaturated e s t e r s 50. I t i s w e l l e s t a b l i s h e d that e n o l a t e anions d e r i v e d from a, /3-unsaturated e s t e r s r e a c t predominantly at the alpha carbon when they undergo a l k y l a t i o n , d e c o n j u g a t i v e 1 22 29 p r o t o n a t i o n and a l d o l - t y p e condensation. ' ' T h e r e f o r e , the carbon alpha to the e s t e r group would serve as an e f f e c t i v e donor c e n t e r . Since the v i n y l carbon c o n t a i n i n g the t r i m e t h y l s t a n n y l group re p r e s e n t s another p o t e n t i a l donor c e n t e r , compounds 50 c o u l d perform as formal R=Me or Et 50 21 equivalents of the synthons 51, which contain two adjacent donor s i t e s . D i f f e r e n t i a t i n g the two reactive s i t e s should W=C02R or functional group derived therefrom pose no problem since they are activated by t o t a l l y d i f f e r e n t types of reactions. Interference i s , therefore, not expected. As depicted by scheme 2, the annulation method that was conceived involves the coupling of the d,d synthon 51 with an a,a synthon 52a. In practice, a,a>-dihaloalkanes serve as 0 w 51 52a scheme 2 convenient synthetic equivalents to 52a. The p o s s i b i l i t y of incorporating various functional groups into 51 and 52a renders this process p a r t i c u l a r l y a t t r a c t i v e . From the point of view of a synthetic organic chemist, the value of a synthetic method l i e s in i t s p r a c t i c a l application towards the synthesis of organic molecules. It was our intention that i f we were successful in r e a l i z i n g the annulation method proposed above, studies concerning i t s u t i l i z a t i o n in the t o t a l synthesis of natural products would be carried out. 22 DISCUSSION 23 DISCUSSION I. Preparation of Methyl 2-Trimethylstannyl-1-cyclohexene- 1-carboxylate (53) , Methyl 6-Methyl-2-trimethylstannyl-1- cyclohexene-1-carboxylate (54) , and Methyl 2- Trimethylstannyl-1-cyclopentene-1-carboxylate (55) The esters that we were especially interested in were 53, 54 and 55. Since f i v e - and six-membered carbocycles are ^ Y ^ S n M e 3 ^ ^ ^ C O O M e 53 SnMe: SnMe3 OOMe 55 common stru c t u r a l units found in many natural products, we f e l t that these compounds might be useful intermediates for the synthesis of naturally occurring substances. 32 Piers and Morton have reported a general method of preparing 0-tr imethylstannyl a,/3-unsaturated ketones, a novel class of organotin compounds. This method is based on the reaction of lithium (phenylthio)(trimethylstannyl)-cuprate (56) with (3-iodo a, ^ -unsaturated ketones*, which are * Another reagent that transfers the trimethylstannyl group, namely (trimethylstannyl)copper-dimethyl sulphide, has also been found to react favourably with 0-iodo a, ^ -unsaturated ketones in a conjugate sense (see reference 33). Recently, i t was shown that 3-trimethylstannyl 2-cyclopenten-1-one can be prepared e f f i c i e n t l y by the reaction of 3-iodo-2-cyclo-penten-1-one with either lithium (cyano)(trimethylstannyl)-cuprate or the higher order cuprate d i l i t h i u m 24 also valuable precursors of a variety of /3-alkyl a,j3-un-35 saturated ketones. A s p e c i f i c example of t h i s process is depicted in equation 15. Thus, treatment of a THF solution 58 of the cuprate reagent 56 with 3-iodo-2-cyclohexen-1-one afforded the B-trimethylstannyl enone 58 in good y i e l d (80%). This reaction can be pictured as occurring via an i n i t i a l conjugate addition of the trimethylstannyl moiety to the /3-iodo enone, followed by elimination of iodide from the intermediate enolate anion 57. It has also been demonstrated that reagent 56 e f f e c t s 1 , 4-addit ions e f f i c i e n t l y to various a,0-unsaturated 32 carbonyl compounds. For example, exposure of compounds 59, 60, 61 and 62 to 56 under appropriate conditions led to the formation of the <5-trimethylstannyl carbonyl compounds 63-66 respectively. From the above res u l t s , the a b i l i t y of 56 to act as an e f f i c i e n t trimethylstannyl-transfer reagent was *(cont'd) (cyano)(methyl)(trimethylstannyl)cuprate (see reference 34). 25 firmly established. 59 60 nMe-i 64 snMe-] MeO SnMe-] 62 66 As outlined in equation 16, we envisaged a simple ap-proach to the synthesis of the desired esters 68. Thus, i t was proposed that reaction of a /3-subst i tuted a,^-unsatu-rated ester of the general structure 67 with the cuprate reagent 56 would afford the corresponding B-trimethylstannyl enoate. The L group present in 67 would have to be a good leaving group, such as halide, acyloxy or a l k y l sulphonate. SnMe-j OOMe + Me3Sn(<j>S)CuLi 56 OOMe (16) (n=1,2) (R=H or Me) Although a,^-unsaturated esters generally undergo Michael 36 reactions less readily than their ketone counterparts, we believed that with the proper choice of the leaving group L, 26 the desired transformation could be achieved. Also, i t appeared to us that compounds 67 could be derived readily from the corresponding 0-keto esters 69, which are well-known substances. 69a n=2 69b n=1 A. Preparation of Methyl 2-Trimethylstannyl-1-cyclohexene- 1-carboxylate (53) 37 Casey and coworkers have demonstrated that a c y c l i c /3-keto esters can be stereoselectively converted into either the (E) or (Z) enol acetates. The l a t t e r substances were shown to undergo stereospecific reactions with a number of lithium dialkylcuprates (for examples, see equations 17a and 3 8 17b). However, in a later report by Sum and Weiler, i t was pointed out that enol acetates of several c y c l i c /3-keto esters, including 70, did not couple with lithium d i a l k y l -cuprates even under forcing conditions. Therefore, the p o s s i b i l i t y of using the enol acetate 70 as a reaction partner with lithium (phenylthio)(trimethylstannyl)cuprate (56) was not seriously considered. Another candidate which was considered was the chloro 39 derivative of 69a i . e . 71. In fact, Clark and Heathcock DAc fl ^ J ^ ^ C O O M e H* b) OOMe ^ v ^ - C O O M * (17a) ^ > \ ^ C O O M e a) AcO b) OOMe (17b) 'COOMe a) MeCOCl, Et 3N, HMPA; b) Et 2CuLi-P$ 3, -100°C. OAc OOMe 70 had reported that compound 71 can be converted into 72 by treatment with lithium dimethylcuprate. Unfortunately, they CI OOMe OOMe 71 72 did not report the procedure for the preparation of 71, although they did state that i t cannot be obtained by 39 reaction of 69a with oxalyl chloride. A number of other reagents, including phosphorus oxychloride, phosphorus t r i c h l o r i d e and thionyl chloride were also found to be 40 unsatisfactory for th i s conversion. Attempts to prepare other i3-halo enoates (71, Br or I in place of CI) from 69a under a variety of reaction conditions were unsuccess-28 r u l . ^ ' 4 1 In view of th e s e d i f f i c u l t i e s , a l t e r n a t i v e p r e c u r s o r s f o r the s y n t h e s i s of 53 were c o n s i d e r e d . 3 8 Sum and W e i l e r have r e p o r t e d a h i g h l y e f f i c i e n t method f o r the f o r m a t i o n of /3 - a l k y l a, /^-unsaturated e s t e r s from 0-keto e s t e r s . C e n t r a l t o t h i s method a r e the c o u p l i n g r e a c t i o n s of l i t h i u m d i a l k y l c u p r a t e s w i t h v a r i o u s e n o l phosphates, which a r e s y n t h e s i z e d from the c o r r e s p o n d i n g /3-keto e s t e r s . One p a r t i c u l a r example i n t h i s r e p o r t a t t r a c t e d our a t t e n t i o n ( e q u a t i o n 18). R e a c t i o n of the 1) NaH, OOMe E t 2 ° > 0°c * 2) ( E t O ) 2 P O C l P0(0Et)2 OOMe M e 2 C u L i 1 E t 2 0 :00Me (18) 69a 73 72 sodium s a l t of 69a w i t h d i e t h y l p h o s p h o r o c h l o r i d a t e gave the e n o l phosphate 73. Subsequent t r e a t m e n t of 73 w i t h l i t h i u m d i m e t h y l c u p r a t e p r o v i d e d the a, /3-unsaturated e s t e r s 72 i n e x c e l l e n t y i e l d (94% o v e r a l l ) . A c c o r d i n g t o t h i s f i n d i n g , i t appeared t h a t the e n o l phosphate 73 might se r v e as a u s e f u l s u b s t r a t e f o r s y n t h e s i z i n g 53. Towards t h i s end, a s o l u t i o n of l i t h i u m ( p h e n y l t h i o ) -( t r i m e t h y l s t a n n y l ) c u p r a t e (56) i n THF was a l l o w e d t o r e a c t w i t h 73 a t -20°C. As i n d i c a t e d by t i c a n a l y s i s , a l l the s t a r t i n g m a t e r i a l (73) was consumed a f t e r a r e a c t i o n time of 75 m i n u t e s . To our d i s a p p o i n t m e n t , a complex m i x t u r e of pr o d u c t s ( t i c a n a l y s i s ) , was o b t a i n e d a f t e r a normal workup p r o c e d u r e . Attempted p u r i f i c a t i o n of the r e a c t i o n m i x t u r e by 29 flash column chromatography did not afford any useful amount of 53. However, a compound was isolated in ca. 15% y i e l d . The 80 MHz 1H nmr spectrum of t h i s compound displayed broad multiplets centered at 5 1.60 (4H), 2.02 (2H) and 2.42 (2H). The presence of a methyl ester function was evident from the appearance of a sharp singlet at 6 3.80 (3H). Also observed in the spectrum was a complex multiplet in the region 6 7.28-7.60 (5H). The appearance of t h i s complex multiplet c l e a r l y indicated the presence of a phenyl ring in th i s molecule. Based on these data, t h i s compound was tenta t i v e l y assigned the structure 74. 74 Obviously, compound 74 resulted from transfer of the phenylthio moiety from the cuprate reagent 56 to the enol phosphate 73. We were quite puzzled by th i s observation, which seemed to suggest that delivery of the trimethyl-stannyl moiety from 56 to 73 was disfavoured for some unknown reason(s). Hoping to circumvent this obstacle, the reaction of 73 33 with lithium bis(trimethylstannyl)cuprate (75) in place of (Me3Sn)2CuLi 75 56 was investigated. However, no reaction was observed when 30 73 was treated with 75 at -48°C. At higher temperatures, decomposition of 75 occurred. Addition of HMPA to the reaction mixture at -48°C did not provide any improvement. When thi s reaction mixture was allowed to warm slowly to room temperature, a complex mixture of products was formed and none of the desired ester 53 could be detected. 35 . In an e a r l i e r report from our laboratory, i t was shown that when the /3-bromo enone 76 (X=Br) was treated with 24 42 lithium (phenylthio)(methyl)cuprate, ' the major product obtained was the phenylthio derivative 78. On the other hand, when the corresponding /3-iodo enone 76 (X=I) was allowed to react with the same cuprate reagent under similar conditions, the desired product 77 was isolated in excellent y i e l d (equation 19). These observations supported our Me(<I>S)CuLi > < 7r^ + THF 77 X=Br 15% 61% X=I 91% trace speculation that the beta substituent, i . e . the d i e t h y l -phosphate group, present in compound 73 was unsuitable for the coupling reaction with the cuprate reagent 56. Replace-ment of the phosphate group by another leaving group was, 31 therefore, deemed necessary. 33 Previous studies carried out in our laboratory had 43 demonstrated that the B-trialkylstannylacrylates 82 and 83 can be obtained readily by reaction of the tosyloxy ester 79 with (tri-n-butylstannyl)copper-dimethyl sulphide (80) and (trimethylstannyl)copper-dimethyl suphide (81), respectively (equation 20). Thus, treatment of 79 with 1.2 equivalents of 79 80 -> fl-Bu3SnCu.Me2S B u 3 ^ n TsQ COOEt OOEt 82 (20) Me3SnCu>Me2S M e 3 ^ n P°Et 81 83 80 in THF-HMPA (5:1) (-48°C, 2 h; -20°C, 1 h) gave 82 in 63% y i e l d . Similar treatment of 79 with 1.3 equivalents of 81 in THF (-48°C, 2 h; -20°C, 1 h; room temperature, 1 h) afforded 44 83 in 61% y i e l d . The requisite substrate 79 was synthe-sized by reaction of the sodium s a l t of ethyl formylacetate with /?-toluenesulphonyl chloride. Encouraged by these r e s u l t s , we embarked upon the preparation of the enol tosylate 84, which appeared to be a promising synthetic precursor for the B-trimethylstannyl enoate 53. Deprotonation of 69a with sodium hydride in THF generated the corresponding sodium s a l t . Much to our disappointment, reaction of t h i s s a l t with ^-toluene-sulphonyl chloride under a variety of conditions gave 32 OTs :OOMe 84 compound 84 in low y i e l d . The best y i e l d achieved after tedious chromatographic p u r i f i c a t i o n of the crude product was 36%. The enol tosylate 84 turned out to be a c r y s t a l l i n e white s o l i d (mp 53-54°C) whose mass spectrum exhibited a d i s t i n c t molecular ion peak at m/e 310. The 80 MHz 1H nmr spectrum of 84 displayed multiplets at 8 1.65 (4H) and 2.35 (4H), singlets at 5 2.47 (3H) and 3.60 (3H), and doublets at 6 7.36 (2H, 7=8.5 Hz) and 7.85 (2H, 7=8.5 Hz). The i r spectrum of t h i s compound showed the diagnostic absorption (1705 cm"1) due to the a, /3-unsaturated ester carbonyl group. It was g r a t i f y i n g to find that when 84 was allowed to react with 1.5 equivalents of the cuprate reagent 56 [-20°C, 2 h; HMPA (3 equiv), 0°C, 4 h], a single compound was produced in 76% y i e l d . The mass spectrum of th i s compound featured a very prominent peak at m/e 289 which corresponds to the M+-15 ion (based on 1 2 0 S n ) . The fact that trimethylstannyl compounds often do not exhibit molecular ions in their mass spectra, but do c h a r a c t e r i s t i c a l l y show 45 M+-15 peaks i s well known. The 80 MHz 1H nmr spectrum of the product displayed a singlet at 5 0.16 (9H, -SnMe3), with the c h a r a c t e r i s t i c s a t e l l i t e peaks due to the tin-proton coupling (7 S n_ H=54 Hz). Multiplets at 6 1.65 (4H) and 2.42 33 (4H), and a sharp singlet at 6 3.77 (3H, -COOMe) were also observed. A strong absorption at 1690 cm"1 was present in the i r spectrum. These spectral data showed c l e a r l y that the reaction product was, in fact, the desired 0-trimethyl-stannyl enoate 53. Compound 53 could also be produced, a l b e i t in lower y i e l d , by reaction of compound 84 with the 22 (trimethylstannyl)copper-dimethyl sulphide complex (81). Even though the enol tosylate 84 served well as a precursor of 53, the fact that the former substance could not be synthesized in sat i s f a c t o r y y i e l d prompted us to search for alternative substrates. It has been established that trifluoromethanesulphon-46 ates ( t r i f l a t e s ) derived from ketones undergo coupling reactions e f f i c i e n t l y with lithium dialkylcuprates reagents 47 to give substituted alkenes. The u t i l i t y of t h i s methodology was demonstrated in a t o t a l synthesis of the 48 complement i n h i b i t o r K-76 by Corey and Das. The required intermediate 87 was produced in good ov e r a l l y i e l d from the 0-keto ester 85, via the enol t r i f l a t e 86 (see equation 21). By employing reaction conditions i d e n t i c a l with those depicted in equation 21, the enol t r i f l a t e 88 was formed in 79% y i e l d from 69a. Reaction of 88 with the cuprate reagent 56 [-20°C, 1 h; HMPA (3 equiv), 0°C, 1 h] proceeded smoothly Me3Sn 81 53 34 OOMe 1) NaH, Et 2O , 0°C 2) T f 2 0 :OOMe )Tf 85 86 (21 ) Me,CuLi E t 2 0 87 t o a f f o r d the d e s i r e d p r o d u c t 53 (73%) ( e q u a t i o n 2 2 ) . I t was found t h a t the e n o l t r i f l a t e 88 i s r e l a t i v e l y u n s t a b l e . For .Q OOMe 1 ) NaH, E t 2 0 , 0 ° C > 2) T f 2 0 fv^Sn OOMe 56 THF :00Me (22) 6 9 a 88 53 example, when t h i s m a t e r i a l was s t o r e d a t room t e m p e r a t u r e , i t decomposed over a p e r i o d of t w e l v e h o u r s . T h e r e f o r e , compound 88 was always p r e p a r e d j u s t p r i o r t o use. 35 B. Preparation of Methyl 6-Methyl-2-trimethylstannyl-1- cyclohexene-1-carboxylate (54) After our success in synthesizing 53, we turned our attention to the next target, 54. Based on our strategy for the construction of 53, i t seemed that the /3-keto ester 89 would be a l o g i c a l precursor of 54. In addition, we f e l t that compound 89 could be accessed from the familiar ester 69a in a simple manner. The reaction sequence i l l u s t r a t e d in equation 23 has been employed for the synthesis of 89. (23) The unsaturated keto ester 90 was prepared according 50 to the procedure of Reich and coworkers. Thus, treatment of the sodium enolate of 69a with phenylselenenyl chloride at 0°C gave the intermediate selenide, which, on oxidation with hydrogen peroxide, produced compound 90. I n i t i a l l y , the transformation of 90 into 89 was ca r r i e d out using lithium dimethylcuprate. However, i t was discovered that the y i e l d of this conjugate addition reaction was not reproducible and 36 varied from 54 to 74%. To overcome th i s problem, i t was decided to investigate the use of a d i f f e r e n t type of cuprate reagent. 24 42 The reagent lithium (phenythio)(methyl)cuprate ' has been shown to transfer e f f i c i e n t l y a methyl group to the 35 beta carbon of a, j3-unsaturated carbonyl compounds. Therefore, i t was hoped that u t i l i z a t i o n of t h i s cuprate reagent would provide more f r u i t f u l r e s u l t s . Indeed, when 90 was allowed to react with lithium (phenylthio)(methyl)cup-rate in THF at -20°C, the desired product 89 was isolated in good y i e l d (82%). More importantly, the y i e l d of this conjugate addition reaction was highly reproducible, even in r e l a t i v e l y large scale preparations*. As depicted in equation 24, the enol t r i f l a t e 91 was obtained from 89 under the usual conditions in excellent y i e l d (91%). Subsequent reaction of 91 with lithium (phenylthio)(trimethylstannyl)cuprate (56) yielded the desired ester 54 (89%). The mass spectrum of 54 exhibited a Q COOMe 1) NaH, THF, 0°C 2) T f 2 0 89 1) 56,THF, OOMe "20°C 2) HMPA, 0°C 54 (24) 91 prominent peak at m/e 303, corresponding to the M"-15 ion (based on 1 2 0 S n ) . The 80 MHz 1H nmr spectrum of 54 displayed * This reaction has been performed with 1.39 and 31.9 mmols of 91. The yields of these reactions were 84 and 82%, respect i v e l y . 37 singlets at 5 0.16 (9H, -SnMe3, ^sn-H=54 H z> a n d 3 - 7 8 ( 3 H ' -COOMe), a doublet at 6 1.10 (3H, J=l Hz, secondary methyl), and multiplets at 6 1.62 (4H), 2.40 (2H), and 2.80 (1H). A strong absorption at 1690 cm"1 in the i r spectrum of 54 indicated the presence of an a, /3-unsaturated ester carbonyl group. C. Preparation of Methyl 2-Trimethylstannyl-1-cyclopentane- 1-carboxylate (55) Having accomplished the syntheses of compounds 53 and 54, attention was turned to the preparation of our last 51 target, compound 55. Based on the method developed for the construction of 53 from the /3-keto ester 69a, compound 55 was expected to be available by way of 69b. The ester 69b i s commercially available and i s r e l a t i v e l y inexpensive. The synthetic sequence that was u t i l i z e d for the construction of 55 was shown in equation 25. 69b 55 1) NaH, Et 20,0°C OTf 1) 56 ATHF, -20°C 69 b 2) T f 2 0 lOOMe 2) HMPA, 0°C 55 (25) 92 38 An unexpected problem was encountered during the preparation of the enol t r i f l a t e 92. Compound 92, obtained from reaction of the sodium s a l t of 69b with trifluorome-thanesulphonic anhydride, was found to be contaminated with the sta r t i n g material 69b. The presence of 69b in the product was indicated by the 1H nmr spectrum of the isolated material. The procedure used for the conversion of 79b into 92 was i d e n t i c a l with that employed for the transformations of 69a and 89 into 88 and 91, respectively. Therefore, i t seemed unlikely that the presence of the sta r t i n g material 69b in the product 92 was due to the chemical reactions involved. It appeared more l i k e l y that the product 92 had, during the aqueous workup procedure, p a r t i a l l y hydrolyzed back to the keto ester 69b. In order to investigate this p o s s i b i l t y , the reaction was repeated under i d e n t i c a l conditions. However, instead of treating the reaction mixture with water, the reaction mixture was diluted with ether and then was f i l t e r e d through a short column of F l o r i s i l . Removal of the solvent from the f i l t r a t e , followed by d i s t i l l a t i o n (reduced pressure) of the crude product, provided the desired material 92 (74%) uncontaminated with 69b, as revealed by 1H nmr spectroscopy. As anticipated, treatment of the enol t r i f l a t e 92 with the cuprate reagent 56 under the usual conditions produced the (3-trimethylstannyl enoate 55. Compound 55 was isolated in 78% y i e l d . The mass spectrum of 55 displayed a prominent 39 peak at m/e 275, corresponding to the M+-15 ion (based on 1 2 0 S n ) . A strong absorption at 1700 cm"1 in the i r spectrum of 55 indicated the presence of an a,0-unsaturated ester carbonyl group. The 80 MHz 1H nmr spectrum of 55 exhibited the c h a r a c t e r i s t i c singlet for the Me3Sn group (5 0.16, •^Sn-H=J>4 Hz). Also present in the spectrum are multiplets at 6 1.94 (2H) and 2.63 (4H), and a sharp singlet at 6 3.71 (3H, -COOMe). 40 11. A n n u l a t i o n S t u d i e s I n v o l v i n g the B-Tr i m e t h y l s t a n n y l  Enoates 53, 54 and 55 A n n u l a t i o n methods, i n v o l v i n g the c o n s t r u c t i o n of r i n g s onto c y c l i c or a c y c l i c s u b s t r a t e s , have been, and c o n t i n u e t o be, of g r e a t importance i n s y n t h e t i c o r g a n i c c h e m i s t r y . Indeed, i t i s d i f f i c u l t t o overemphasize the r o l e t h e s e a n n u l a t i o n s p l a y i n n a t u r a l p r o d u c t s y n t h e s i s . S i n c e the i n t r o d u c t i o n of the Robinson a n n u l a t i o n sequence h a l f a 53 c e n t u r y ago, many d i f f e r e n t six-membered r i n g a n n u l a t i o n 53 54 p r o c e s s e s have been d e s c r i b e d . ' More r e c e n t l y , a l a r g e number of five-membered r i n g a n n u l a t i o n methods have been de v e l o p e d f o r the s y n t h e s i s of n a t u r a l l y o c c u r r i n g s u b s t a n c e s c o n t a i n i n g f u n c t i o n a l i z e d c y c l o p e n t a n e r i n g 55 systems, such as p o l y q u m a n e s . As i n d i c a t e d e a r l i e r , the main o b j e c t i v e of the work d e s c r i b e d i n t h i s t h e s i s was t o d e v e l o p a g e n e r a l annu-l a t i o n p r o c e s s based on the B-trimethylstannyl enoates 53, 54 and 55. To pursue t h i s g o a l , a g e n e r a l i z e d r e a c t i o n scheme, as d e s c r i b e d below, was p l a n n e d (scheme 3 ) . D e p r o t o n a t i o n of a | 3 - t r i m e t h y l s t a n n y l enoate of g e n e r a l s t r u c t u r e 68 w i t h a s t r o n g base would produce a d i e n o l a t e a n i o n . A l k y l a t i o n of t h i s a n i o n w i t h an a r c o - d i h a l o a l k a n e 52b 3 1 would g i v e a B,7-unsaturated e s t e r 93. R e d u c t i o n of the m e t h y l e s t e r group p r e s e n t i n 93 by a s t a n d a r d p r o c e d u r e , f o l l o w e d by p r o t e c t i o n of the r e s u l t a n t a l c o h o l f u n c t i o n , would a f f o r d i n t e r m e d i a t e 94. T r a n s m e t a l l a t i o n of the 41 53 SnMe-j (H 2cy^ o o M e 4 R 68 ^'H2,m X 52b 54 'SnMe-COOMe ,SnMe-:OOMe <H2?n 'SnMe^ ( H 2 Q n R 96 94 . (n=1 , 2) (R=H or Me) 'P'=protecting group X=I, Br, CI scheme 3 trimethylstannyl group in 94 by treatment with methyllithium would generate the corresponding v i n y l l i t h i u m species 95, which would c y c l i z e to give a b i c y c l i c compound 96. It i s pertinent to point out that the transmetallation-cyclization step (94 •> 96) would play a pi v o t a l role in the success of the above reaction sequence. 42 Intramolecular alkylations of a r y l l i t h i u m intermediates have been studied extensively and have proven to be key 56 steps in e f f i c i e n t annulation methods. For example, the 57 s t r u c t u r a l l y interesting compound 98 was synthesized successfully by reaction of n-butyllithium with the t e t r a -bromide 97 (equation 26). On the other hand, intramolecular 97 1) rt-BuLi, -100°C Br Br 2) -100-25°C o 98 (26) a l k y l a t i o n of alkenylmetal species, leading to the formation of carbocycles, i s a p o t e n t i a l l y useful but largely unex-plored process. A few examples, excerpted from the limited number of reports in the recent chemical l i t e r a t u r e that address th i s p a r t i c u l a r aspect of synthetic organic chemistry, are described in the following paragraphs. 58 . In an interesting study by Negishi and coworkers, i t was shown that when the v i n y l iodides 99, 100 and 101 were allowed to react with 2 equivalents of t ert-butyllithium, the corresponding 1-trimethylsilyl-1-cycloalkenes 1 0 2 , 103 and 104 were obtained in good yie l d s (equations 27, 28 and 29). These interesting results led to the conclusion that the v i n y l l i t h i u m species, i n i t i a l l y derived from 99, 100 and 101 by iodine-lithium exchange, must have undergone geo-metric isomerization before c y c l i z a t i o n took place. In a 59 related report, Negishi and coworkers have further 43 99 SiMe- /-BuLi, E t 2 0 , -78-25°C SiMe-(27) 102 101 SiMe-(29) 104 demonstrated that c y c l i z a t i o n of v i n y l l i t h i u m derivatives i s an e f f i c i e n t method for the preparation of cycloalkenes. Thus, treatment of the (Z) -w-bromo- 1 - iodo-1 -alkenes 105, 106 and 107 with n- or tert-butyllithium produced cyclopentene, cyclohexene and 1-n-butyl-5-methyl-1-cyclohexene in yie l d s of 85%, 76% and 75%, respectively. /=\ Br(CH 2) 3 I Br(CH 2) 4 I Br(CH 2) 2CHCH 2 Me A n r j 107 60 105 106 Recently, Oshima and coworkers"" have reported a novel c y c l i z a t i o n process. This process involved s i l y l m e t a l l a t i o n of functionalized terminal acetylenes with (methyl)(di-44 methylphenylsilyl)magnesium using copper(I) iodide as a cat a l y s t . A number of (dimethylphenylsilylmethylene)cyclo-alkanes have been synthesized by t h i s method. Thus, when the terminal acetylenes 108 were allowed to react with 3 equivalents of (methyl)(dimethylphenylsilyl)magnesium (0°C, 0.5 h; 25°C, 1 h) in the presence of a c a t a l y t i c amount of copper(I) iodide, the products 110 were formed in yields of 28% (n=l), 91% (n=2) and 60% (n=3) (equation 30). (CH9) 2'n /// 108 PhMe2SiMgMe, Cul, THF, 0-25°C (CH,), Y MgMe SiMe 2Ph_ 109 (30) n=1, 2; Y=OTs n=3, Y=OMs SiMe 2Ph Presumably, the f i r s t step of t h i s process involves regioselective addition of the silyl-magnesium reagent to the t r i p l e bond of 108 to generate the alkenylmagnesium derivatives 1 0 9 . Subsequent c y c l i z a t i o n of the l a t t e r intermediate would result in the formation of the observed products 1 1 0 . In fact, the intermediate alkenylmetal species 109 (n=3, Y=OMs) has been trapped by treatment of the reaction mixture with D 20 at 0°C. In thi s manner, the mesylate of (E)-6-deuterio-7-dimethylphenylsilyl-6-hepten-1-ol was obtained qu a n t i t a t i v e l y . 45 A. F i v e - m e m b e r e d R i n g A n n u l a t i o n S t u d i e s T r e a t m e n t o f a THF s o l u t i o n o f t h e e s t e r 53 w i t h LDA (1. 5 e q u i v ) a n d HMPA (3 e q u i v ) a t -48°C f o r 40 m i n u t e s , f o l l o w e d by t h e a d d i t i o n o f 3 - i o d o - 1 - c h l o r o p r o p a n e (-48°C, 40 min) ga v e t h e e x p e c t e d a l k y l a t i o n p r o d u c t 111 ( 7 8 % ) (scheme 4 ) . The mass s p e c t r u m o f t h s m a t e r i a l showed t h e :00Me 53 ^ \ z S n M e 3 OTBDMS 113 a ) b) d) SnMe-c ) •SnMe-: a) LDA-HMPA, THF, -48°C; b) I ( C H 2 ) 3 C 1 ; c ) DIBAL-H, E t 2 0 , -20°C; d) TBDMS-C1, i m i d a z o l e , DMF. scheme 4 c h a r a c t e r i s t i c M +-15 ( 1 2 0 S n , 3 5 C 1 ) peak a t m/e 365. E x p o s u r e o f an e t h e r e a l s o l u t i o n o f 111 t o d i i s o b u t y l a l u m i n u m h y d r i d e ( 2 . 5 e q u i v ; -20°C, 1 h) p r o d u c e d t h e a l c o h o l 112 ( 9 0 % ) , t h e i r s p e c t r u m o f w h i c h d i s p l a y e d t h e r e q u i r e d -OH a b s o r p t i o n a t 3350 cm" 1. P r o t e c t i o n o f t h e a l c o h o l f u n c t i o n i n 112 a s 46 the t ert-butyldimethylsilyl ether^ 1 113 was accomplished by reaction of 112 with 2 equivalents of t ert -butyldimethyl-s i l y l chloride in dimethylformamide in the presence of 4 equivalents of imidazole (94%). With compound 113 a v a i l a b l e , the stage was set for an investigation of the transmetallation-cyclization operation. As indicated by t i c and c a p i l l a r y glc analyses of reaction mixture aliquots, no reaction took, place when a cold (-78°C) THF solution of 113 was exposed to 1.3 equivalents of methyllithium for 3 hours. Introduction of an additional 3 equivalents of methyllithium to the above solution and prolonging the reaction time by 1.5 hours did not provide any improvements. Again, only compound 113 was detected in the reaction mixture ( c a p i l l a r y glc and t i c analyses). In the hope that higher reaction temperatures might result in successful transmetallation, an experiment was performed at -20°C. A large excess (>20 equiv) of methyl-lithium and a prolonged reaction time (>7 h) were employed. Analysis ( c a p i l l a r y glc) of the material obtained upon workup showed that i t consisted of the s t a r t i n g material 113 and a new compound in a r a t i o of ca. 3 :1, respectively. The new compound, isolated by f l a s h column chromatography of the crude product mixture on s i l i c a gel, was shown to be the desired b i c y l i c alkene 114 by i t s spectral c h a r a c t e r i s t i c s . The 80 MHz 1H nmr spectrum of 114 exhibited singlets at 6 0.05 (6H, -SiMe 2t-Bu) and 0.93 (9H, -SiMe 2J-Bu) and broad multiplets at 6 0.70-1.30 (2H), 1.43-1.88 (4H), and 47 ^-OTBDMS 114 1.88-2.45 (6H). An unresolved multiplet at 6 5.45 (1H, o l e f i n i c proton), and a pair of doublets centered at 5 3.25 and 3.44 (1H each, 7=10 Hz, -CH20-) were also observed in the spectrum. The mass spectrum of 114 showed the molecular ion (M+) peak at m/e 266, and a high intensity peak at m/e 209 (M+-57) resulting from the loss of a tert-butyl fragment from the molecular ion. The sluggishness of the reaction of methyllithium with the vinylstannane 113 was surprising. It has been estab-lished that transmetallation of t r i a l k y l s t a n n y l compounds 62 with a l k y l l i t h i u m reagents is an equilibrium process. Accordingly, one might think i n i t i a l l y that transmetallation of the trimethylstannyl group in 113 with methyllithium i s thermodynamically unfavourable. However, i t has been shown that a large number of vinyltrialkylstannanes, for example 1 63 34 33 36 , 115 , 116 and 117 , undergo smooth reaction with «-butyl- or to produce, methyllithium under similar reaction conditions e f f i c i e n t l y , the corresponding v i n y l l i t h i u m 48 d e r i v a t i v e s . Therefore, the observed reluctance of compound 113 to react with methyllithium i s probably due to unfavour-able kinetic factors c o n t r o l l i n g the process. It has been pointed out that the rate of these t i n - l i t h i u m exchange reactions i s strongly dependent upon 64 the reaction solvent employed. In general, transmetal-l a t i o n occurs more readily in polar media (e.g. THF) than in less polar media (e.g. ether, pentane). Furthermore, smooth exchange (often) occurs when the reaction i s c a r r i e d out in less polar solvents but in the presence of strong lithium chelating agents,^ 5 such as HMPA or TMEDA. Another factor which plays an important part in these transmetallation processes i s the s t e r i c environment about 64 the t i n atom. For example, McGarvey and coworkers have reported that in the reaction of compounds 118 with a l k y l -lithium reagents, the rate of transmetallation follows the order Me3Sn >> «-Bu 3Sn >> (c-C 6H,,) 3Sn. These results r e f l e c t the general trend that the more s t e r i c a l l y shielded the t i n atom i s , the slower the transmetallation rate. Taking into account a l l of the above factors, i t seems reasonable to propose that the extremely sluggish nature of the reaction of 113 with methyllithium i s the result of the s t e r i c a l l y hindered nature of the trimethylstannyl group. OR1 118 49 The presence of two substituents on the sp 3 carbon adjacent to the trimethylstannyl function was, presumably, the cause of t h i s s t e r i c hindrance. To overcome th i s problem, i t was decided that trans-metallation of 113 should be conducted in the presence of a chelating reagent e.g., HMPA. Thus, a cold ( - 2 0 ° C ) THF solution of 113 was treated with 1.5 equivalents of methyllithium in the presence of 3 equivalents of HMPA (equation 31) . Analysis of an aliquot of the reaction mixture by c a p i l l a r y glc after a period of 30 minutes indicated that a l l the star t i n g material (113) had been consumed and that only the desired product 114 was present. Normal workup, followed by d i s t i l l a t i o n of the crude product under reduced pressure, afforded compound 114 in excellent y i e l d (92%). To demonstrate further the v i a b i l i t y of thi s f i v e -membered ring annulation method, the enoate 54 was u t i l i z e d in place of 53 and the whole reaction sequence was repeated. Deprotonation of the ester 54 with LDA (1.5 equiv) and HMPA (3 equiv) at - 4 8 ° C for 40 minutes was followed by addition of 3 -iodo-1-chloropropane. The reaction mixture was treated with saturated ammonium chloride solution after a SnMe- MeLi, HMPA, 113 114 50 period of 40 minutes at -48°C (equation 32). As shown by 'SnMe3 w J ^ D A - H M P A , ^SnMe -COOMe 1) LDA- P  THF, -48°C 2) I(CH 2),C1 (32) COOMe 54 119 both t i c and c a p i l l a r y glc analyses, a single compound was formed from the reaction. This material was assigned the structure 1 1 9 . The i r spectrum of 119 displayed a strong ester carbonyl absorption at 1710 cm"1. In the mass spectrum of 1 1 9 , an intense peak at m/e 379, which corresponded to the M+-15 ( 1 2 0Sn) ion, was present. The 270 MHz 1H nmr spectrum of 119 exhibited a t r i p l e t at 6 6.03 (1H, /=4 Hz, o l e f i n i c proton), a singlet at 6 3.69 (3H, -COOMe), multiplets at 6 3.53 (2H, -CH 2C1), 2.30-1.87 (4H) and 1.85-1.59 (5H), a doublet at 6 0.92 (3H, J=l Hz, secondary methyl group), and a singlet at 6 0.15 (9H, ^sn-H = 5^ H z ' -SnMe 3). The clean nature of the *H nmr spectrum also suggested that a single product had been produced from the reaction. It was g r a t i f y i n g that the a l k y l a t i o n of the enoate 54 was highly stereoselective. To r a t i o n a l i z e t h i s high s e l e c t i v i t y , one has to consider the possible t r a n s i t i o n states involved in the reaction. Generally, i t i s assumed that, for stereoelectronic reasons, the a l k y l a t i n g agent must attack the enolate anion perpendicular to the plane of the l a t t e r species. Based on t h i s assumption, four t r a n s i t -51 ion states 1 2 0 c , 1 2 0 d , 120e and 120 f should be considered. These t r a n s i t i o n states are derived from the energetically d i f f e r e n t half-chair conformations 120a and 120b of the dienolate anion generated from 5 4 . It should be noted that conformation 120b i s destab-. 66 l i z e d by A1'3 s t r a i n between the pseudo-equatorial secondary methyl group and either the OLi moiety or the methoxy group. If one assumes that the two t r a n s i t i o n states 120e and 1 2 0 f , derived from the dienolate anion conformation 1 2 0 b , are, at least to some extent, reactant l i k e in shape, then these t r a n s i t i o n states would also be destablized by A 1 , 3 s t r a i n . Furthermore, 120e and 120f would be destablized by a 52 gauche- type i n t e r a c t o n between the incoming a l k y l a t i n g agent and the secondary methyl g r o u p . In 1 2 0 d , A 1 - 3 s t r a i n i s a b s e n t , but t h i s t r a n s i t i o n s t a t e i s d e s t a b l i z e d by a ( n e a r l y e c l i p s e d ) i n t e r a c t i o n between the a l k y l a t i n g agent and the secondary methyl g r o u p . In t r a n s i t i o n s t a t e 1 2 0 c , A 1 , 3 s t r a i n i s absent and the a l k y l a t i n g agent i s approach ing the e n o l a t e an ion from the s i d e o p p o s i t e the secondary methyl g r o u p . T h e r e f o r e , o v e r a l l , one would p r e d i c t 120c to be the t r a n s i t i o n s t a t e of lowest energy , l e a d i n g to the observed product 1 1 9 . 67 F i n a l l y , i t has been r e p o r t e d that when the extended •enolate an ion d e r i v e d from the e s t e r 121 was a l l o w e d to r e a c t w i th e t h y l 3-bromopropanoate and e t h y l 4-bromobutan-o a t e , a s i n g l e compound ( d i a s t e r e o i s o m e r ) was o b t a i n e d in each c a s e . The s t e r e o c h e m i s t r y a s s i g n e d to these p r o d u c t s was as shown in e q u a t i o n 33. Thus , we were c o n f i d e n t that the s t e r e o c h e m i c a l s t r u c t u r e (119) a s s i g n e d to our a l k y l -a t i o n p r o d u c t i s c o r r e c t . 1 ) LDA COOEt 2 > B ^ ( C H 2 ) n - C 0 0 E t (33) ( C H2W00Et COOEt 121 (n=1, 2) To complete the a n n u l a t i o n sequence, the s e r i e s of r e a c t i o n s d e p i c t e d in scheme 5 was e x e c u t e d . R e a c t i o n of the e s t e r 119 w i t h 3 e q u i v a l e n t s of d i i s o b u t y l a l u m i n u m h y d r i d e ( 0 ° C , 2 h) f u r n i s h e d the a l c o h o l 122 (86%). P r o t e c t i o n of 53 124 123 a) DIBAL-H, Et 2 0 , 0°C; b) TBDMS-C1, imidazole, DMF; c) MeLi, HMPA, THF, -20°C. scheme 5 the alcohol group as the t ert-butyldimethylsilyl ether was achieved by the exposure of a dimethylformamide solution of compound 122 to t ert-butyldimethylsilyl chloride (2 equiv) and imidazole (4 equiv) at room temperature for 17 hours (94%). Transmetallation-cyclization of the resultant product 123 proceeded smoothly when this material was treated with 1.5 equivalents of methyllithium (-20°C, 0.5 h) in the presence of 3 equivalents of HMPA. The substituted b i c y c l i c alkene 124 was obtained in 94% y i e l d . The mass spectrum of compound 124 exhibited an intense peak at m/e 223 which was due to the M+-57 ion (cleavage of the tert-butyl group from the molecular ion). The 400 MHz 1H nmr spectrum of 124 showed singlets at 6 0.00 (6H, -SiMe 2?-Bu) and 0.87 (9H, -SiMe 2*-Bu), doublets at 6 0.99 54 (3H, J=l Hz, secondary methyl), 3.31 and 3.47 (1H each, /=10 Hz, -CH 20-), and a multiplet at 6 5.40 (1H, o l e f i n i c proton). B. Six-membered Ring Annulation Studies It was g r a t i f y i n g to discover that five-membered rings can be prepared in a highly e f f i c i e n t fashion by our proposed annulation method (scheme 3). In order to determine the scope and li m i t a t i o n s of thi s method, investigations directed at the construction of six-membered carbocycles were undertaken. Having demonstrated the a b i l i t y of the 0- trimethylstannyl a,^-unsaturated esters 53 and 54 to perform e f f e c t i v e l y as substrates in the five-membered ring annulations, i t was decided to employ a d i f f e r e n t enoate, namely compound 55, as the substrate for t h i s study. Treatment of compound 55 with LDA (1 .5 equiv) and HMPA (3 equiv) at -48°C for 40 minutes, followed by addition of 1- bromo-4-chlorobutane gave the expected a l k y l a t i o n product 125 (84%) (scheme 6). Reduction of 125 with d i i s o b u t y l a l u -minum hydride (2 .5 equiv; -20°C, 1 h) produced the alcohol 126 (96%), the i r spectrum of which showed the required -OH stretching absorption at 3400 cm"1. S i l y l a t i o n of 126 with tert-butyldimethylsilyl chloride (2 equiv) and imidazole (4 equiv) in dimethylformamide furnished the s i l y l ether 127 (94%). Compound 127 was then allowed to react with methyl-lithium (1 . 5 equiv) in the presence of HMPA (3 equiv) at 55 a) LDA-HMPA, THF, - 4 8 ° C ; b) B r ( C H 2 ) , C l ; c) D I B A L - H , E t 2 0 , - 2 0 ° C ; d) TBDMS-C1, i m i d a z o l e , DMF. scheme 6 - 2 0 ° C . S u p r i s i n g l y , a mixture of t h r e e compounds was o b t a i n e d . These s u b s t a n c e s , produced in a r a t i o of 12:10:75 ( c a p i l l a r y g l c a n a l y s i s ) , were i d e n t i f i e d as 128, 129, and 130, r e s p e c t i v e l y (see equat ion 34 ) . ^OTBDMS 129 56 The mass spectrum of the desired product 128 showed an intense peak at m/e 209 (M +-57), resulting from the loss of a t ert-butyl fragment from the molecular ion. The 80 MHz *H nmr spectrum of 128 displayed a broad unresolved multiplet at 5 5.30 (1H, o l e f i n i c proton), a pair of doublets at 6 3.60 and 3.35 (1H each, 7=10 Hz, -CH 20-), and sharp singlets at 6 0.92 (9H, -SiMe 2r-Bu) and 0.05 (6H, -SiMe 2f-Bu). The structural differences between 129 and 130 were c l e a r l y v i s i b l e in their mass, i r and 1H nmr spectra. For example, both 129 and 130 exhibited a prominent peak at m/e 245 (M*-57)( 3 5C1) in their mass spectrum. However, the appearance of a d i s t i n c t peak due to the M+-31 ion (m/e 277) in the spectrum of 130 but not in that of 129 c l e a r l y indicated the presence of a -CH2OH group in the former compound. The i r spectrum of 130 showed a strong -OH stretching absorption at 3360 cm"1, while such an absorption was absent in the spectrum of 1 2 9 . Furthermore, the 270 MHz 1H nmr spectrum of 130 exhibited an unresolved multiplet at 5 6.29 (1H, o l e f i n i c proton) whereas two multiplets were present at 6 5.48 and 5.70 (1H each, o l e f i n i c protons) in the spectrum of 1 2 9 . Presumably, the vinylsilan'e 130 was formed by migration of the t ert-butyldimethylsilyl group from oxygen to carbon in the v i n y l l i t h i u m intermediate 1 3 1 , which was generated by transmetallation of the corresponding vinyltrimethylstan-nane. The o l e f i n 129 was, obviously, produced by protonation 57 131 of the v i n y l anion 131. Interestingly, the competition between ring closure (6-centered t r a n s i t i o n state, chloride as leaving group) and t ert-butyldimethylsilyl group transfer (5-centered t r a n s i t i o n state) favoured the l a t t e r process to the extent of about 6:1. This disappointing result c l e a r l y demonstrated that, not unexpectedly, the "size" of the c y c l i c t r a n s i t i o n state has a dramatic effect on the rate of the ring-closure process. It was evident that the use of t h i s annulation method for the construction of six-membered carbocycles, with chloride ion as the leaving group, i s not f e a s i b l e . A possible solution to t h i s problem would be replace-ment of the chlorine on the side chain by a better leaving group, such as bromide. Hopefully, a more e f f i c i e n t leaving group would enhance the rate of c y c l i z a t i o n so that the competing side reactions would be suppressed or eliminated. To prepare the bromide 134 necessary for the projected annulation process, the following series of reactions was performed (scheme 7). Base promoted a l k y l a t i o n of 55 with 1,4-dibromobutane under the usual conditions gave compound 132 (77%) which was reduced to the alcohol 133 (98%). A strong hydroxyl group absorption at 3400 cm"1 was observed in the i r spectrum of 133. Unexpectedly, attempted 58 SnMe 3 a) Br OOMe b) COOMe 132 c) d) ^ S n M e 3 B r ^ O T B D M S 134 133 a) LDA-HMPA, THF, -48°C; b) Br(CH 2)„Br; c) DIBAL-H, E t 2 0 , -20°C; d) TBDMS-OTf, 2 , 6-lutidine, CH 2C1 2. protection of the alcohol group in 133 by treatment of t h i s material with tert-butyldimethylsilyl chloride and imidazole in dimethylformamide afforded a mixture of the desired bromide 134 and the chloride 127, in a r a t i o of 41:52, respectively ( c a p i l l a r y g l c ) . It i s safe to assume that the chloride 127 arose from nucleophilic displacement of the bromide ion from compound 134 by the chloride ion, which i s produced in the s i l y l a t i o n process. This problem was overcome by employing the reagent t ert-butyldimethylsilyl 68 69 trifluoromethanesulphonate ' instead of the s i l y l chloride. Thus, by exposure of a dichloromethane solution of 69 133 to t h i s reagent (2 equiv) and 2,6-lutidine (2.7 equiv), the s i l y l ether 134 was obtained in 92% y i e l d . scheme 7 59 Reaction of 134 with m e t h y l l i t h i u m (1.5 equiv) i n the presence of HMPA (3 equiv) f o r 0.5 hour at -20°C l e d to the pro d u c t i o n of a 6:1 mixture ( c a p i l l a r y g l c ) of the an n u l a t i o n product 128 and the diene 135 (equation 35). None of the corresponding s i l y l group t r a n s f e r product was MeLi, HMPA, 134 » THF, -20°C + (35) OTBDMS ^OTBDMS 128 135 d e t e c t e d . Compounds 128 and 135 were i s o l a t e d i n 61 and 7% y i e l d , r e s p e c t i v e l y , by column chromatography of the product mixture on s i l v e r n i t r a t e impregnated s i l i c a g e l . The 80 MHz 1H nmr spectrum of the diene 135 e x h i b i t e d m u l t i p l e t s at 6 5.70 (2H, o l e f i n i c p r o t o n s ) , 5.50 (1H, o l e f i n i c p r o t o n ) , and 5.15-4.80 (2H, t e r m i n a l o l e f i n i c protons) and s i n g l e t s at 5 3.38 (2H, -CH 20-), 0.87 (9H, -SiMe 2*-Bu), and 0.00 (6H, -SiMe 2 J-Bu). The mass spectrum of 135 d i s p l a y e d prominent peaks at m/e 251 (M*-15) and 209 (M +-57), these ions corresponded to the l o s s of a methyl and a tert-butyl fragment, r e s p e c t i v e l y , from the molecular i o n . Probably, the diene 135 was d e r i v e d from an i n t r a -molecular e l i m i n a t i o n process (6-centered t r a n s i t i o n s t a t e ) i n v o l v i n g the v i n y l anion (as shown) produced by tr a n s m e t a l -l a t i o n of compound 134. 60 C. Seven-membered R i n g A n n u l a t i o n S t u d i e s H aving succeeded i n the c o n s t r u c t i o n of f i v e - and six-membered c a r b o c y c l e s v i a our a n n u l a t i o n method, a t t e n -t i o n was t u r n e d t o our l a s t o b j e c t i v e i . e . p r e p a r a t i o n of seven-membered r i n g s . D e p r o t o n a t i o n of compound 55 ( i n THF) under the u s u a l c o n d i t i o n s , f o l l o w e d by the a d d i t i o n of 1,5-dibromopentane, p r o v i d e d the ex p e c t e d a l k y l a t i o n p r o d u c t 136 (72%) (scheme 8). The mass spectrum of t h i s p r o d u c t d i s p l a y e d a prominent peak a t m/e 423 (M +-15) ( 1 2 0 S n , 7 9 B r ) , as e x p e c t e d . R e d u c t i o n of the e s t e r group w i t h d i i s o b u t y l a l u m i n u m h y d r i d e f u r n i s h e d the a l c o h o l 137 ( 9 4 % ) . A d i a g n o s t i c s t r o n g -OH s t r e t c h i n g a b s o r p t i o n a t 3400 cm" 1 was obser v e d i n the i r spectrum of 137. S i l y l a t i o n of the a l c o h o l f u n c t i o n was a c c o m p l i s h e d (90%) by t r e a t m e n t of 137 w i t h t ert-butyldi-m e t h y l s i l y l t r i f l u o r o m e t h a n e s u l p h o n a t e (2 e q u i v ; 25°C, 0.5 h) and 2 , 6 - l u t i d i n e (2.7 e q u i v ) i n d i c h l o r o m e t h a n e . R e a c t i o n of compound 138 w i t h m e t h y l l i t h i u m (1.5 e q u i v ) i n the presence of HMPA (3 e q u i v ) a f f o r d e d the d e s i r e d p r o d u c t 139 (35%) which was accompanied by the v i n y l s i l a n e 140 (17%) ( e q u a t i o n 36). A s i g n i f i c a n t amount of i n t r a c t a b l e m a t e r i a l 61 o r ^ s n M e 3 ^ ' ^ C O O M e 55 -SnMe a) 'SnMe b) a) LDA-HMPA, THF, -48°C; b) Br(CH 2) 5Br; c) DIBAL-H, Et 20, -20°C; d) TBDMS-OTf, 2,6-lutidine, CH 2C1 2. scheme 8 MeLi, HMPA, 138 > THF, -20°C + OTBDMS 139 140 was also produced from the reaction. In th i s case, even though the leaving group on the 5-carbon side chain was bromide, the rate of ring closure was only about twice that of tert-butyldimethylsilyl group migration. In the mass spectrum of 1 3 9 , a prominent peak at m/e 223 (M +-57), resulting from the loss of a r-Bu group from the molecular ion, was observed. The 80 MHz 1H nmr spectrum of 139 displayed an unresolved multiplet at 6 5.40 (1H, 62 o l e f i n i c proton) and singlets at 6 3.38 (2H, -CH 20-), 0.91 (9H, -SiMe 2?-Bu) and 0.02 (6H, -SiMe 2r-Bu). The mass spectrum of 140 showed two prominent peaks at m/e 313 (M+-57, 7 9 B r ) and 315 (M+-57, 8 1 B r ) . In addition, two weak but d i s t i n c t peaks at m/e 329 (M+-31, 7 9 B r ) and 331 (M+-31, 8 ' B r ) , which resulted from the loss of a -CH2OH fragment from the molecular ion were also present. A strong absorption at 3370 cm"1 (-OH strecthing vibration) was observed in the i r spectrum of 1 4 0 . The 80 MHz 1H nmr spectrum of 140 exhibited a t r i p l e t at 6 6.28 (1H, 7=4 Hz, o l e f i n i c proton), a multiplet at 6 3.60-3.25 (4H, -CH20- and -CH 2Br), and singlets at 6 0.93 (9H, -SiMe 2i-Bu) and 0.13 (6H, -SiMe 2t-Bu). To eliminate the annoying problem of s i l y l group migration, the alcohol function in 137 was protected as a methyl ether. By refluxing a mixture of the alcohol 1 3 7 , potassium hydride (2.5 equiv) and dimethyl sulphate (5 equiv) in THF for 7.5 hours, the methyl ether 141 was obtained in 84% y i e l d (equation 37). Treatment of 141 with methyllithium under normal conditions gave the substituted bicyclo[5.3.0]dec-7-ene 142 (54%) (equation 38), which was accompanied by a number of minor, unidentified side products. A substantial amount of intractable material was also formed from the reaction. Attempts to improve the y i e l d of 142 by conducting the transmetallaton-cyclization experiment at -78°C and -35°C were not successful. At these 6 3 ^ O M e ^ O M e 141 142 temperatures, the amount of the d e s i r e d alkene 142 produced from the r e a c t i o n d i m i n i s h e d while that of the s i d e products i n c r e a s e d . The mass spectrum of 142 d i s p l a y e d a molecular ion peak at m/e 180 and a base peak at m/e 135 (M +-45), which r e s u l t e d from the l o s s of a CH2OMe fragment from the molecular i o n . The 80 MHz 1H nmr spectrum showed an unresolved m u l t i p l e t at 6 5.43 (1H, o l e f i n i c p r o t o n ) , sharp s i n g l e t s at 8 3.30 (3H, -OMe) and 3.15 (2H, -CH 20-), and a broad d i f f u s e m u l t i p l e t at 6 2.51-1.00 (14H). 64 I I I . Total Synthesis of the Sesquiterpenoid  (±)-Chiloscyphone (151) A. Introduct ion Chiloscyphone, a sesquiterpenoid f i r s t i solated by 79 Hayashi et al. , i s a major component of the essential o i l obtained from the plant Chi I os cyphus polyanthus (L.) Corda, Hepaticae. On the basis of the spectral data derived from chiloscyphone and i t s hydrogenation products, t h i s material was i n i t i a l l y assigned the structure 143. A t o t a l synthesis of 143 was reported by Gras ten years after this structure had been proposed for chiloscyphone. This elegant synthesis was centered about an intramolecular Diels-Alder reaction which enabled the three c h i r a l centers present in 143 to be assembled with the correct r e l a t i v e stereochemistry in a single step. The synthetic route employed to prepare compound 143 i s summarized in scheme 9. Copper(I) iodide catalyzed addition of the Grignard reagent 144 to isoprene oxide (145) occurred regioselec-65 a) 10% Cul, THF, -25°C; b) PCC, CH 2C1 2, 15°C; c) Ph3P=CH2, THF, 0°C; d) 10% HC1-THF; e) /-Bu(TMS) 2COHf / i-BuLi , (CH3)2CHCHO, THF; f) p-TsOH, Benzene, 42°C; g) PhNH2Me•CF3COO-, (CH 20) n, THF, A . scheme 9 66 t i v e l y to give the a l l y l i c alcohol 146. Oxidation of th i s material with pyridinium chlorochromate, followed by a Wittig reaction on the resultant product, afforded the diene 147. Acid catalyzed removal of the ketal group generated a keto diene which was subjected to a s i t e - s e l e c t i v e aldol condensation with 2-methylpropanal to produce compound 148. Dehydration of 148 with />-toluenesulphonic acid in benzene led to the intermediate 149 which underwent c y c l i z a t i o n under the reaction conditions to provide the b i c y c l i c ketone 150. F i n a l l y , treatment of compound 150 with N-methylani-linium t r i f l u o r o a c e t a t e and paraformaldehyde yielded the target 143. The spectral data derived from t h i s synthetic material were in complete accord with the structure 143. However, these data were found to be d i s t i n c t i v e l y d i f f e r e n t from those reported for the natural product. Furthermore, the ketone 143 did not react with 2,4-dinitrophenylhydrazine to give the corresponding hydrazone while the natural product did. Therefore, i t was concluded that the structure 143 o r i g i n a l l y assigned to chiloscyphone was incorrect. 72 In 1982, Connolly et al. proposed a revised structure (151) for chiloscyphone. Their proposal was based on a 151 67 detailed 1H nmr spectroscopic study. The carbon skeleton of 151 is novel and may be regarded as s t r u c t u r a l l y related by ring contraction to eremophilane-type sesquiterpenoids. 73 Recently, Wolf and Gerling reported a t o t a l synthesis of (±)-chiloscyphone (151). Central to thi s synthesis, which is summarized in scheme 10, was a diastereoselective 74 cationic 71—cyclization involving the enone 152. Thus, in one step, the three c h i r a l centers present in 153 were constructed with the desired r e l a t i v e stereochemistry. Saponification of the b i c y c l i c enol acetate 153 gave two ketones (154), which are epimeric at the ring junction (C-10). Reduction of 154 produced a mixture of alcohols 155, 156a (C-1 a-OH) and 156b (C-1 0-OH), which, upon ozonolysis, afforded the corresponding keto alcohols 157, 158a (C-1 a-OH), and 158b (C-1 0-OH), respectively. Dehydration of 157 and 158a led to the formation of the desired alkene 159 whereas a similar operation on 158b gave a double bond isomer of 159. Based promoted methylation of compound 159 yielded the ethyl ketone 160. Incorporation of the methylene unit was achieved by treatment of 160 with N-methylanilinium t r i f l u o r o a c e t a t e and paraformaldehyde. The f i n a l product obtained displayed spectral properties i d e n t i c a l to those reported for chiloscyphone. Thus, the structure of chiloscyphone (151) was confirmed. 68 160 a) A c 2 0 , HC10, ( c a t . ) , C H 2 C 1 2 , 0°C; b) KOH, MeOH, -10°C; c) LAH, E t 2 0 , 0°C; d) 0 3 ; e) P O C l 3 , p y r i d i n e , 20°C; f) LDA, Mel; g) PhNH 2Me•CF 3COO~, ( C H 2 0 ) n , THF, A . scheme 10 69 B. T o t a l S y n t h e s i s of (±)-Chiloscyphone (151) Upon examination of the s t r u c t u r e of chiloscyphone (151), i t appeared that the s u b s t i t u t e d b i c y c l i c s k e l e t o n c o u l d be c o n s t r u c t e d i n a s t r a i g h t f o r w a r d manner by the a n n u l a t i o n method d e s c r i b e d e a r l i e r i n t h i s t h e s i s . Based on t h i s assumption, the s y n t h e s i s of 151 would be mainly concerned with i n c o r p o r a t i o n of the m e t h a c r o l y l s i d e c h a i n onto the five-membered r i n g with c o r r e c t r e l a t i v e s t e r e o c h e m i s t r y . With t h i s n o t i o n , a r e t r o s y n t h e t i c plan f o r chiloscyphone was proposed (scheme 11). I t was evident that the success of t h i s plan hinged on the a c q u i s i t i o n of the b i c y c l i c ketone 162. The s t r a t e g i c placement of a ketone f u n c t i o n at the C-6 p o s i t i o n of t h i s i n t e r mediate (162) would p r o v i d e a handle f o r the attachment of the r e q u i r e d s i d e c h a i n . It was envisaged that ketone 162 c o u l d be prepared r e a d i l y from the corresponding a l c o h o l 163 (P=H) which i n t u r n c o u l d be obtained, i n p r i n c i p l e , by combination of the d \ d 2 synthon 164 and the a 1 , a 3 synthon 165. I t appeared that the B-trimethylstannyl enoate 54 and 3-chloropropanal 166 would be s u i t a b l e s y n t h e t i c e q u i v a l e n t s f o r synthons 164 and 165. 151 70 scheme 1 1 71 To r e a l i z e this plan, the f i r s t task at hand was to prepare the required aldehyde 166. The procedure reported by 75 Kirrmann et al. , which involves reaction of dry hydrogen chloride gas with acrolein at low temperature (-10°C), was employed. However, attempted p u r i f i c a t i o n of compound 166 by d i s t i l l a t i o n of th i s material under reduced pressure provided polymeric materials only. After several unsuccessful t r i a l s , i t was decided that alternative routes to t h i s aldehyde should be sought. Unfortunately, low temperature reduction of 3-chloropropionyl chloride or ethyl 3-chloropropionate with 1 equivalent of diisobutylaluminum hydride led only to complex mixtures. Oxidation of 1-chloro-3-hydroxypropane with pyridinium chlorochromate produced similar results and no useful products could be isolated from the reaction. In view of these d i f f i c u l t i e s , replacement of this elusive compound (166) with another synthetic equivalent of 165 seemed unavoidable. A candidate which was considered an appropriate 7 6 substitute was 1,3-dichloro-1-methoxypropane (167). It has OMe Cl 167 been shown that compound 167 couples e f f i c i e n t l y with a number of Grignard reagents derived from primary a l k y l halides to give the corresponding 1-chloro-3-methoxy alkanes. Therefore, i t was anticipated that 167 would serve as an a l k y l a t i n g agent for the enoate 54. An added advantage 72 of using 167 was that the alcohol function required for introduction of the ketone [163 (P=H) •» 162] during the later stage of the synthesis was already protected as a methyl ether. Compound 167 was prepared by the procedure developed by 7 6 Wartski. Thus, when dry hydrogen chloride (2 equiv) was passed into a solution of methanol (1 equiv) and acrolein (1 equiv) at -10°C, the desired product 167 was obtained in 60% y i e l d . With the alk y l a t i n g agent 167 available, the stage was set for an investigation of i t s reaction with the dienolate anion derived from the enoate 54. Treatment of 54 with LDA (1.5 equiv) and HMPA (3 equiv) in THF at -48°C for 40 minutes generated the dienolate anion which was allowed to react with 167 (2 equiv) at -78°C for 40 minutes (equation (39) 39). C a p i l l a r y glc analysis of the material obtained upon 73 workup indicated that i t consisted of a mixture of two products (2:1 r a t i o , presumably compounds 168 and 169) along with a number of minor unidentified side products. The major product, isolated by subjection of the crude product mixture to fla s h column chromatography, was obtained in 32% y i e l d . For reasons given l a t e r , t h i s compound was tent a t i v e l y assigned structure 168. Unfortunately, we were unable to obtain the minor product, assumed to be 169, free of unwanted substances. Attempts to improve the y i e l d of this a l k y l a t i o n process by performing the reaction under various experimental conditions were unsuccessful. The 270 MHz 'H nmr spectrum of compound 168 displayed singlets at 6 0.12 (9H, ^sn-H = 5 2 H z » ~SnMe3), 3.47 (3H, -OMe), and 3.72 (3H,-COOMe), a doublet at 6 0.89 (3H, 7=7 Hz, secondary methyl), and a t r i p l e t at 6 6.03 (1H, 7=4 Hz, o l e f i n i c proton). Reduction of the ester 168 with diisobutylaluminum hydride (6 equiv) at 25°C afforded the alcohol 170 (96%) (scheme 12). The i r spectrum of t h i s compound showed a strong hydroxyl group absorption at 3400 cm"1. Reaction of th i s alcohol with / e r t - b u t y l d i m e t h y l s i l y l t r i f l u o r o -methanesulphonate (1.5 equiv) and 2,6-lutidine (2 equiv) in dichloromethane at 25°C provided the s i l y l ether 171 (87%). Transmetallation-cyclization proceeded smoothly when a solution of t h i s substance in THF was treated with methyllithium (1.5 equiv) in the presence of HMPA (3 equiv). The mass spectrum of 172 displayed a molecular ion peak at 175 a) DIBAL-H, Et 2 0 ; b) TBDMS-OTf, CH 2C1 2, 2,6-lutidine c) MeLi, HMPA, THF, -20°C; d) TBAF, THF; e) PCC, CH2 f) N 2H a.H 20, KOH, DEG, 210°C. scheme 12 75 m/e 310. Subsequent cleavage of the s i l y l ether group by treatment of a THF solution of compound 172 with t e t r a -/7-butylammonium fluoride (1.8 equiv) at 25°C gave the expected alcohol 173 (91%). The i r spectrum of compound 173 exhibited a strong absorption at 3400 cm"1 (-OH stretching vibrat ion). According to the synthetic plan, deoxygenation of the primary alcohol function of compound 173 was c a l l e d for at thi s stage. This operation would generate the requisite angular methyl substituent. The widely used Wolff-Kishner 77 reducton method was adopted for this transformation. The aldehyde 174, which was required as the substrate for the deoxygenation process, was obtained in 87% y i e l d by oxidation of the alcohol 173 with pyridinium chlorochromate (2 equiv) at 25°C. The aldehyde 174 showed, in i t s i r spectrum, a strong carbonyl group absorption at 1710 cm"1. In addition, the 270 MHz 1H nmr spectrum of 174 displayed the expected signal (singlet at 6 9.63) for the aldehydic proton. Reaction of 174 with excess hydrazine hydrate (30 equiv) and potassium hydroxide (30 equiv) in diethylene-glycol (100°C, 1 h; 210°C, 3 h) provided the desired product 175 in 75% y i e l d . ^Hc ' H a .Hb 175 76 The mass spectrum of compound 175 showed a molecular ion peak at m/e "180. The 400 MHz 1H nmr spectrum of this material exhibited a singlet at 8 0.80 (3H) for the angular methyl group, a doublet at 6 0.89 (3H, secondary methyl), a singlet at 6 3.29 (3H, -OMe) and an unresolved multiplet at 8 5.42 (1H, o l e f i n i c proton). A one proton singlet at 8 3.38 ^w1/2~6 H z ) w a s assigned the proton (Ha) on the carbon bearing the methoxy group. Examination of a molecular model of 175 revealed that, in what appears to be the favoured conformation of 1 7 5 , the dihedral angles between Ha and Hb and between Ha and Hc are approximately 40° and 80°, respectively. Therefore, on the 7 8 basis of the Karplus equation, the magnitudes of and J a f C would be expected to be quite small. On the other hand, i f Ha had been trans to the angular methyl group, the dihe-dral angles between Ha and Hb and between Ha and Hc would have been about 160° and 40°, respectively. Consequently, one would have anticipated a r e l a t i v e l y large coupling constant between Ha and Hb. The fact that Ha appeared as a broad singlet provided good evidence for the conclusion that compound 175 possessed the r e l a t i v e stereochemistry in which the angular methyl and the methoxy function have a trans relationship. To secure the advanced intermediate 1 6 2 , the alcohol 176 was required. The l a t t e r substance was to be acquired by demethylation of the methyl ether 175. A large number of reagents and combinations of reagents have been developed 77 OH 162 176 79 s p e c i f i c a l l y f o r the cleavage of e t h e r s . Among these 8 0 reagents, t r i m e t h y l s i l y l i o d i d e i s g e n e r a l l y c o n s i d e r e d to be the reagent of c h o i c e . The r e a c t i o n c o n d i t i o n s r e q u i r e d for ether cleavage are q u i t e m i l d and the r e a c t i o n s are 8 1 g e n e r a l l y e f f i c i e n t . A l s o , i t has been reported that t h i s reagent i s p a r t i c u l a r l y e f f e c t i v e f o r demethylation of a l k y l methyl e t h e r s . Encouraged by these f i n d i n g s , i t was decided that t r i m e t h y l s i l y l i o d i d e would be u t i l i z e d f o r demethyla-t i o n of compound 175. Towards t h i s end, a carbon t e t r a c h l o r i d e s o l u t i o n of 175 was t r e a t e d (25°C, 3 h) with t r i m e t h y l s i l y l i o d i d e (2 e q u i v ) , which was prepared a c c o r d i n g to a l i t e r a t u r e 8 2 procedure. C a p i l l a r y g l c a n a l y s i s of an a l i q u o t of the r e a c t i o n mixture i n d i c a t e d that a s u b s t a n t i a l amount of s t a r t i n g m a t e r i a l was present. A f t e r a t o t a l r e a c t i o n time of 5 hours, another 2 e q u i v a l e n t s of t r i m e t h y l s i l y l i o d i d e was added and the r e a c t i o n mixture was s t i r r e d f o r an a d d i t i o n a l 2 hours. A n a l y s i s ( c a p i l l a r y g l c ) of the m a t e r i a l obtained upon workup showed that a l l of the s t a r t i n g m a t e r i a l had been consumed and a major product, together with a small amount of u n i d e n t i f i e d s i d e products, had been formed. T h i s major product was i s o l a t e d from the crude product mixture by column chromatography. N e v e r t h e l e s s , the 78 1H nmr spectral data derived from t h i s substance c l e a r l y indicated that i t was not the desired alcohol 176. S p e c i f i c a l l y , although the signal due to the methoxy group was not observed in the 'H nmr spectrum, signals corresponding to the angular methyl group and the o l e f i n i c proton were also absent. Furthermore, the i r spectrum of th i s material did not display a hydroxyl group absorption. An attempt to convert the methyl ether 175 into the acetate 177 by the method reported by Sharma and coworkers was unsuccessful. No reaction was observed when 175 was treated with excess t r i m e t h y l s i l y l chloride in acetic anhydride for a prolonged period of time. F u j i t a ' s method of 84 demethylation also f a i l e d to produce useful r e s u l t s . Thus, treatment of compound 175 with ethanethiol in the presence of boron t r i f l u o r i d e etherate led to decomposition of the substrate and a complex mixture was obtained. After these unsuccessful attempts to convert compound 175 into the alcohol 176, i t was decided to replace the methyl ether function with a p o t e n t i a l l y more l a b i l e protecting group. This replacement required substitution of compound 167 with another a l k y l a t i n g agent. The alternative reagent that was considered a suitable substitute was the dichloride 178. 79 It has been demonstrated that the 2 - ( t r i m e t h y l s i l y l ) -ethoxymethyl moiety i s a useful alcohol protecting group. Thus, reaction of 2-(trimethylsilyl)ethoxymethyl chloride with alcohols provides the corresponding ethers in good y i e l d . Treatment of the l a t t e r substances with tetra-n-but-ylammonium fluoride regenerates the parent alcohols with 8 5 great f a c i l i t y (equation 40). On t h i s basis, i t was F" Me 3Si(CH 2) 20CH 20R » ROH + HCHO + C 2H„ + Me 3SiF (40) expected that the 2 - ( t r i m e t h y l s i l y l ) e t h y l group could be removed from an oxygen atom under similar conditions. Compound 1 7 8 was synthesized by a method e s s e n t i a l l y i d e n t i c a l with that employed for the preparation of 1 6 7 . Thus, when dry hydrogen chloride (2 equiv) was passed into a mixture of acrolein (1 equiv) and 2-(trimethylsilyl)ethanol (1 equiv) at -10°C, the d i c h l o r i d e 1 7 8 was obtained in 78% y i e l d . The 80 MHz 'H nmr spectrum of 1 7 8 exhibited a singlet at 5 0.06 (9H, -SiMe 3), multiplets at 5 1.00 (2H, -CH 2SiMe 3), 2.45 (2H, -CH 2CH 2C1), and 3.50-4.10 (4H, -CH20-and -CH2C1), and a t r i p l e t at 5 5.80 (1H, J=5 Hz, -CHC10-). Base promoted a l k y l a t i o n of the enoate 54 with compound 1 7 8 (2 equiv) under the usual conditions produced a mixture 80 of products. Tic analysis of this mixture indicated the presence of two major substances (presumably 179 and 180, see equation 41) and a number of minor, unidentified side products. Interestingly, we were unable to separate 179 and 180 by c a p i l l a r y g lc. The compound with lower mobility on s i l i c a gel turned out to be the major product of the reaction and was isolated in 41% y i e l d from the crude product mixture by flash column chromatography. For reasons given l a t e r , this major product was assigned structure 179. The mass spectum of 179 showed a prominent peak at m/e 495 which corresponded to the M+-15 ( 1 2 0 S n , 3 5C1) ion. Unfortunately, we were unable to obtain the minor product, presumably 180, free from contaminants even after repeated column chromatography of the mixture on s i l i c a g el. Hence, compound 180 was used in the next step as a mixture. Reduction of the ester 179 with diisobutylaluminum hydride (6 equiv) at 25°C for 3 hours gave the alcohol 181 81 (81%), the i r spectrum of which displayed a strong absorption at 3400 cm"1 (-OH stretching vibration) (equation 42). Subsequent treatment of 181 with tert-butyldimethyl-DIBAL-H, E t 2 0 179 TBDMS1 (42) TBDMS-OTf, 2,6-lutidine CH 2C1 2, 182 s i l y l trifluoromethanesulphonate (1.8 equiv) and 2,6-lutidine (2.4 equiv) at 25°C for 0.5 hour gave the s i l y l ether 182 (85%). The y i e l d of compound 1 8 2 , based on the enoate 54, was 28% over these three steps. The 400 MHz 1H nmr spectrum of 182 showed singlets at <5 0.02 (9H, -SiMe 3), 0.04 and 0.06 (3H each, -SiMe 2?-Bu), 0.16 (9H, 7 S n_ H=52 H z ' -SnMe3) and 0.89 (9H, -SiMe 2*-Bu), a doublet at 6 1.04 (3H, 7=7 Hz, secondary methyl), a pair of doublets at 6 3.39 and 4.03 (1H each, 7=9.5 Hz, -CH20-) and a t r i p l e t at 6 5.92 (1H, 7=4 Hz, o l e f i n i c proton). Subjection of the mixture containing compound 180 to a sequence of reactions similar to that depicted in equation 42 led to the production of the s i l y l ether 183 (equation 43). At thi s stage, compound 183 could be isolated in pure 82 •SnMe 1 )DIBAL-H, Et 20 (43) 180 2)TBDMS-OTf, 2,6-lut idine CH 2C1 2, TBDMS1 form by fl a s h column chromatography of the product mixture derived from the reactions summarized in equation 43. Based on the enoate 54, the s i l y l ether 183 was obtained in 9% over a l l y i e l d . The 400 MHz 'H nmr spectrum of 183 displayed singlets at 6 0.02 (9H, -SiMe 3), 0.05 (9H, ^ sn-H = 5 2 H z> "SnMe3), 0.06 and 0.08 (3H each, -SiMe 2/-Bu), 0.91 (9H, -SiMe 2r-Bu), and 3.58 (2H, -CH 2OSiMe 2f-Bu), a doublet at 6 1.02 (3H, J=l Hz, secondary methyl), and a t r i p l e t at 6 6.04 (1H, J=4 Hz, o l e f i n i c proton). Reaction of compound 182 with methyllithium (1.5 equiv) in the presence of HMPA (3 equiv) proceeded smoothly, leading to the desired b i c y c l i c product 184 (86%) (scheme 13). The mass spectrum of 184 showed a M+-57 peak at m/e 339, which resulted from the loss of a ten -butyl fragment from the molecular ion. Selective removal of the t ert -butyl-d i m e t h y l s i l y l group in the presence of the 2-(trimethyl-s i l y D e t h y l ether f u n c t i o n was accomplished by treatment of -61 compound 184 with tetra-n-butylammonium fluoride (1.5 equiv) in THF for 18 hours. The primary alcohol 185 was produced in 96% y i e l d . The i r spectrum of t h i s material displayed the expected hydroxyl group absorption at 3400 83 a) MeLi, HMPA, THF, -20°C; b) TBAF, THF; c) PCC, CH 2C1 2; d) N2H, , MeOH, A; e) NaOMe, DEG, 210°C. scheme 13 cm - 1. The aldehyde 186, required for the deoxygenation operation, was provided by oxidation of 185 with pyridinium chlorochromate (2.5 equiv) at 25°C (88%). A strong carbonyl group absorption at 1710 cm"1 was observed in the i r spectrum of compound 186. The previously employed one-pot procedure for the Wolff-Kishner reduction of 174, which involved heating a mixture of aldehyde and hydrazine in the presence of a large 8 4 e x c e s s of p o t a s s i u m h y d r o x i d e a t e l e v a t e d t e m p e r a t u r e s , was u t i l i z e d f o r the d e o x y g e n a t i o n of 1 8 6 . Under t h e s e c o n d i t i o n s , the d e s i r e d p r o duct 187 was produced i n an u n s a t i s f a c t o r y 60% y i e l d . R e p l a c i n g p o t a s s i u m h y d r o x i d e w i t h a m i l d e r base, namely p o t a s s i u m c a r b o n a t e , d i d not p r o v i d e any improvement. A f t e r some e x p e r i m e n t a t i o n , a s a t i s f a c t o r y p r o c e d u r e f o r t h i s r e d u c t i o n p r o c e s s was found. The hydrazone of the aldehyde 186 was p r e p a r e d by r e f l u x i n g a methanol s o l u t i o n of 186 and h y d r a z i n e (20 e q u i v ) f o r 1 hour. Removal of the s o l v e n t and e x c e s s h y d r a z i n e under reduced p r e s s u r e a f f o r d e d the r e q u i r e d hydrazone, w h i c h , upon r e a c t i o n w i t h sodium methoxide (3 e q u i v ) i n d i e t h y l e n e g l y c o l a t 210°C f o r 1.8 h o u r s , gave the d e s i r e d d e o x y g e n a t i o n p r o d u c t 187 i n 84% y i e l d . The 400 MHz 'H nmr spectrum of compound 187 d i s p l a y e d s i n g l e t s a t 6" -0.01 (9H, - S i M e 3 ) and 0.78 (3H, a n g u l a r m e t h y l ) , a d o u b l e t a t 6 0.87 (3H, J=l Hz, secondary m e t h y l ) , m u l t i p l e t s a t 6 3.35 and 3.60 (1H each, -OCH 2-), and an u n r e s o l v e d m u l t i p l e t a t 6 5.38 (1H, o l e f i n i c p r o t o n ) . A d o u b l e t a t 6 3.47 (1H, /=4 Hz) was a s s i g n e d t o the p r o t o n (Ha) on the carbon b e a r i n g the 2 - ( t r i m e t h y l s i l y l ) e t h o x y s i d e c h a i n . 187 85 Inspection of a molecular model of compound 187 revealed that,in what appears to be the most stable conformation of 187, the dihedral angle between Ha and Hc is close to 90°. Therefore, on the basis of the Karplus 7 8 equation, one would expect the coupling constant / 3 f C to be very small or even zero. On the other hand, i f Ha had been trans to the angular methyl group, the dihedral angles between Ha and Hb and between Ha and Hc would have been approximately 150° and 30°, respectively. Consequently, Ha would have appeared as a doublet of doublets or a t r i p l e t . The l a t t e r pattern was, in fact, observed in the spectrum of compound 193 (vide infra), the epimer of 187 with the 2-(trimethylsilyl)ethoxy group ci s to the angular methyl group. The fact that Ha appeared as a doublet (^ a,b = 4 H z ^ * n the 1H nmr spectrum of 187 was in agreement with the stereochemistry assigned to thi s substance. With compound 187 available, the stage was set for the c r i t i c a l operation of deprotecting the alcohol function which had been masked as the 2 - ( t r i m e t h y l s i l y l ) e t h y l ether. No reaction was observed when a dimethylsulphoxide solution of 187 and tetra-n-butylammonium fluoride was heated at 90°C for 20 hours. S i m l i a r l y , when a HMPA solution of 187 was treated with 5 equivalents of cesium fluoride (25°C, 5 h; 90°C, 12 h), the starting material 187 was recovered unchanged. However, when compound 187 was allowed to react with excess tetra-n-butylammonium fluoride (10 equiv) in HMPA (25°C, 5 h), a clean reaction took place and a new 86 compound was formed. Curiously, the i r spectrum of thi s material did not display the expected hydroxyl group absorption. The 80 MHz 1H nmr spectrum of thi s substance showed a three-proton multiplet in the region 8 3.20-3.75 (-CHOCH2-) and a three-proton t r i p l e t at 5 1.15 (/=7 Hz, -CH2Me), but the h i g h - f i e l d singlet due to the t r i m e t h y l s i l y l group was absent. Furthermore, the mass spectrum of this compound exhibited a prominent molecular ion peak at m/e 194. On the basis of these spectral data, i t was concluded that the product obtained was the ethyl ether 1 8 8 . Apparently, treatment of a solution of compound 1 8 7 in HMPA with tetra-rt-butylammonium fluoride effected a protio-86 d e s i l y l a t i o n process and led to the formation of the observed product 1 8 8 . After these unsuccessful attempts to remove the protecting group, a di f f e r e n t approach was considered. Instead of using fluoride ion to induce cleavage of the 2 - ( t r i m e t h y l s i l y l ) e t h y l ether moiety, i t was f e l t that u t i l i z a t i o n of a Lewis acid which can interact strongly with the oxygen atom of the ether linkage, might provide a more f r u i t f u l r e s u l t . Toward this end, a dichloromethane solution of 1 8 7 was treated with diethylaluminum chloride ( 2 equiv). 87 9P ^SiMe^ 187 J After the resultant solution had been s t i r r e d for 8 hours at 25°C, a complex mixture containing a s i g n i f i c a n t amount of the sta r t i n g material 187 was formed. Attempted reaction of 187 with tin(IV) chloride (3.5 equiv) in dichloromethane (25°C, 1 h) again produced a mixture. The major component of thi s mixture was isolated in low y i e l d by column chromatography and was found to be the desired alcohol 176. I OH 176 The i r spectrum of 176 showed the expected hydroxyl group absorption at 3350 cm"1. The mass spectrum of th i s compound displayed an intense molecular ion peak at m/e 166. The 400 MHz 1H nmr spectrum of 176 exhibited a singlet at 6 0.80 (3H, angular methyl), doublets at 6 0.93 (3H, 7=7 Hz, secondary methyl), 3.92 (1H, J= 4H, -CHOH) and an unresolved multiplet at 5 5.49 (1H, o l e f i n i c proton). Although removal of the 2 - ( t r i m e t h y l s i l y l ) e t h y l group from 187 could be achieved by using tin(IV) chloride, the unsatisfactory y i e l d of the desired product prompted us to search for a more e f f i c i e n t a l t e r n a t i v e . 88 At th i s time, The reagent lithium tetrafluoroborate was suggested to us* for accomplishing t h i s transformation. This inorganic reagent has been used e f f e c t i v e l y for the cleavage 8 7 of t ert-butyldimethylsilyl ethers and for the conversion of 2 - ( t r i m e t h y l s i l y l ) e t h y l glycosides into the corresponding 8 8 parent carbohydrates. G r a t i f y i n g l y , treatment of 187 with a 1:1 mixture of boron t r i f l u o r i d e etherate and lithium 8 8 fluoride in a c e t o n i t r i l e at 25°C afforded the alcohol 176 in excellent y i e l d (87%). Oxidation of compound 176 with pyridinium chlorochromate (2 equiv) at 25°C proceeded uneventfully to give the ketone 162 in 83% y i e l d . 162 The 270 MHz 'H nmr spectrum of 162 exhibited a singlet at 6 1.02 (3H, angular methyl), a doublet at 6 1.14 (3H, J=l Hz, secondary methyl), and a multiplet at 6 5.55 (1H, o l e f i n i c proton). The i r spectrum of this ketone displayed a strong absorption at 1730 cm"1 due to the carbonyl group. The mass spectrum of compound 162 showed an intense molecular ion peak at m/e 164. The sequence of reactions employed for the conversion of compound 182 into the ketone 162 was repeated with compound 183. Treatment of 183 with methyllithium (1.5 equiv) and HMPA (3 equiv) at -20°C gave the expected product * We are grateful to Professor B. H. Lipshutz for suggesting th i s reagent to us. 182 183 190 (78%), which, upon reaction with tetra-/i-butylammonium fluoride (3 equiv) at 25°C, produced the alcohol 191 (86%) (scheme 14). The i r spectrum of 191 exhibited the expected hydroxyl group absorption at 3450 cm"1. Oxidation of compound 191 with pyridinium chlorochromate (2.5 equiv) afforded the aldehyde 192 (83%). By employing the procedure u t i l i z e d for the deoxygenation of compound 1 8 6 , the aldehyde 192 was transformed into 193 in 78% y i e l d . The 270 MHz 1H nmr spectrum of 193 showed a t r i p l e t at 6 3.25 (1H, J=9 Hz) which was assigned to the proton on the carbon bearing the 2-(trimethylsilyl)ethoxy side chain. The coupling pattern of thi s p a r t i c u l a r proton supported the stereochemistry assigned to 1 9 3 . iMe 193 Examination of a molecular model revealed that in what appears to be the most stable conformation of 1 9 3 , the dihedral angles between Ha and Hb and between Ha and He are approximately 150° and 30°, respectively. On the basis of 7 8 the Karplus equation, the magnitudes of / 3 f b a n c ^ ^a,c 90 a) MeLi, HMPA, THF, -20°C; b) TBAF, THF; c) PCC, CH 2C1 2; d) N 2H 4, MeOH, A; e) NaOMe, DEG, 210°C; f) BF 3•OEt 2-LiF, CH3CN; g) PCC, CH 2C1 2. scheme 14 91 would be expected to be quite s i m i l a r . Consequently, Ha would appear as a doublet of doublets or a t r i p l e t . The fact that Ha appeared as a t r i p l e t (/=9 Hz) in the 1H nmr spectrum of 193 agreed well with the stereochemical assignment of th i s material. Reaction of compound 193 with boron t r i f l u o r i d e etherate and lithium fluoride (1:1) in a c e t o n i t r i l e provided the expected alcohol 194 (93%) which was oxidized with pyridinium chlorochromate (2 equiv) to afford the ketone 162 in 80% y i e l d . According to the synthetic plan, homologation of the ketone 162 to the aldehyde 161 was c a l l e d for at t h i s juncture. A procedure that seemed highly appropriate for thi s operation was a Wittig reaction involving the reagent (methoxymethylene)triphenylphosphorane. However, treatment (25°C, 4 h) of the ketone 162 with an excess of the phosphorane derived from (methoxymethyl)triphenylphosphonium chloride and n-butyllithium in THF, f a i l e d to provide any product. The starting material 162 was recovered unchanged. In attempts to overcome this problem, compound 162 was treated (70°C, 11 h) with the same phosphorane generated 8 9 from the phosphonium chloride and dimsyl sodium in dimethylsulphoxide. Again, no product was formed and the 162 161 92 ketone 162 was r e c o v e r e d . I t seemed l i k e l y t h a t t h e s e d i s a p p o i n t i n g r e s u l t s were caused by the h i n d e r e d n a t u r e of the ketone f u n c t i o n . 90 T h e r e f o r e , the use of the reagent 1 9 5 , which has been shown t o be h i g h l y e f f e c t i v e f o r h o m o l o g a t i o n of s t e r i c a l l y h i n d e r e d k e t o n e s , was i n v e s t i g a t e d . D i s a p p o i n t i n g l y , t r e a t m e n t of compound 162 w i t h an ex c e s s of t h i s reagent i n THF l e d t o a m i x t u r e c o n t a i n i n g m a i n l y the s t a r t i n g ketone 162 and a number of u n i d e n t i f i e d p r o d u c t s . 91 Magnus and coworkers have demonstrated t h a t the c a r b a n i o n d e r i v e d from the r e a c t i o n of ( c h l o r o m e t h y l ) t r i -m e t h y l s i l a n e w i t h an a l k y l l i t h i u m reagent r e a c t s e f f i c i e n t l y w i t h ketones and a l d e h y d e s t o g i v e a , 0 - e p o x y s i l a n e s . These e p o x y s i l a n e s can be c o n v e r t e d i n h i g h y i e l d i n t o the c o r r e s p o n d i n g a l d e h y d e s by a c i d h y d r o l y s i s . For example, cyclohexanone has been t r a n s f o r m e d e f f i c i e n t l y i n t o c y c l o h e x a n e c a r b o x a l d e h y d e by t h i s method ( e q u a t i o n 44 ) . 195 (44) N e v e r t h e l e s s , when the ketone 162 was t r e a t e d w i t h the r e q u i r e d reagent under s i m i l a r c o n d i t i o n s , no p r o d u c t was 93 f o r m e d . A g a i n , t h e s t a r t i n g m a t e r i a l 162 was r e c o v e r e d . F u r t h e r m o r e , u s e o f t h e more r e a c t i v e [ m e t h o x y ( t r i m e t h y l -92 s i l y l ) m e t h y l ] l i t h i u m , w h i c h h a s been r e p o r t e d t o be a 93 s u p e r i o r r e a g e n t f o r t h i s t y p e o f h o m o l o g a t i o n p r o c e s s , a l s o f a i l e d t o p r o d u c e t h e d e s i r e d p r o d u c t . J u d g i n g f r o m t h e a b o v e o b s e r v a t i o n s , t h e f a i l u r e o f t h e k e t o n e 162 t o u n d e r g o t h e d e s i r e d c o u p l i n g r e a c t i o n w i t h t h e s e r e a g e n t s was p r o b a b l y c a u s e d by e n o l i z a t i o n o f t h e k e t o n e f u n c t i o n u n d e r t h e r e a c t i o n c o n d i t i o n s . K l u g e a n d 94 C l o u d s d a l e have r e p o r t e d t h a t t h e r e a g e n t 1 9 7 , p r e p a r e d by l i t h i a t i o n o f t h e p h o s p h o n a t e e s t e r 1 9 6 , r e a c t s w e l l w i t h r e a d i l y e n o l i z a b l e k e t o n e s a t low t e m p e r a t u r e . The r e s u l t a n t a d d u c t s a r e c o n v e r t e d i n t o e n o l e t h e r s , w h i c h u n d e r g o f a c i l e a c i d h y d r o l y s i s t o a f f o r d t h e c o r r e s p o n d i n g a l d e h y d e s ( e q u a t i o n 4 5 ) . I n d e e d , r e a c t i o n o f t h e r e a g e n t 197 (5 e q u i v ) ( E t O ) 2 P O C H 2 0 ( C H 2 ) 2 O M e LDA, ( E t O ) 2 P O C H O ( C H 2 ) 2 O M e Li 197 THF 196 (45) R,R 2CO R,R 2C=CHO(CH 2) 2OMe ( E t O ) 2 P O C H O ( C H 2 ) 2 O M e R,R 2COH H 30* R,R 2CHCHC w i t h t h e k e t o n e 162 i n THF a t -98°C d i d p r o v i d e t h e e x p e c t e d a d d u c t , b u t i n low y i e l d (=*30%). N ot u n e x p e c t e d l y , a b o u t 40% of t h e s t a r t i n g m a t e r i a l 162 was a l s o r e c o v e r e d . Due t o t h e 94 unsatisfactory y i e l d associated with this reaction, other homologation methods were sought. Up to t h i s point, a l l the unsuccessful attempts to homologate compound 162 involved the use of nucleophilic reagents that, invariably, possessed an appreciable degree of b a s i c i t y . Presumably, i t was t h i s inherent property which causes enolization of the ketone function in 162 and therefore, prevented i t from undergoing the desired reaction. Consequently, a l o g i c a l solution to t h i s problem would be the u t i l i z a t i o n of a very weakly basic reagent. The above consideration led to an investigation of the 95 use of dimethylsulphonium methylide, a highly nucleophilic yet weakly basic reagent. Based on this reagent, a d i f f e r e n t approach to the preparation of compound 161 was planned. It was expected that reaction of dimethylsulphonium methylide 95 with ketone 162 would produce an epoxide which, upon treatment with a Lewis acid, would rearrange to the desired 96 aldehyde. G r a t i f y i n g l y , treatment of compound 162 with dimethylsulphonium methylide in dimethylsulphoxide at 0°C provided a single epoxide ( c a p i l l a r y glc and t i c ) 198 in 77% y i e l d . 198 The 300 MHz 'H nmr spectrum of 198 displayed a doublet at 6 0.75 (3H,y=7 Hz, secondary methyl), a singlet at 5 1.02 95 (3H, a n g u l a r methyl ) and a m u l t i p l e t at 6 5.40 (1H, o l e f i n i c p r o t o n ) . The two p r o t o n s a s s o c i a t e d wi th the epox ide moiety appeared as a p a i r of d o u b l e t s at 6 2.62 and 3.04 (1H each , 7=5 Hz , - C H 2 0 - ) . The assignment of s t e r e o c h e m i s t r y at the s p i r o c e n t e r was based on the assumption that the m e t h y l i d e reagent would p r e f e r to a t t a c k the ketone f u n c t i o n of 162 from the s t e r i c a l l y more a c c e s s i b l e bottom s i d e . The r e l a t i v e l y l o w - f i e l d p o s i t i o n (<5 1.02) of the 1 H nmr s i g n a l due to the angu lar methyl group suppor ted t h i s a s s u m p t i o n . Presumably , the methyl pro tons are d e s h i e l d e d by the epoxide oxygen which i s ci s to the angu lar methyl g r o u p . When the epoxide 198 was a l l o w e d to r e a c t w i t h boron t r i f l u o r i d e e t h e r a t e at 0 ° C , a complex mix ture of compounds was formed and no u s e f u l product c o u l d be i s o l a t e d . No r e a c t i o n was observed when a benzene s o l u t i o n of 198 was 97 t r e a t e d wi th l i t h i u m bromide-hexamethylphosphoramide (1:1) ( 8 0 ° C , 4.5 h ) , a c o m b i n a t i o n which had been shown to be h i g h l y e f f e c t i v e for the rearangement of epox ides to the c o r r e s p o n d i n g c a r b o n y l compounds. The use of anhydrous magnesium bromide, a m i l d Lewis a c i d which had been u t i l i z e d 98 f r e q u e n t l y for t h i s type of rearrangement , a l s o f a i l e d to produce a u s e f u l r e s u l t . I n t e r e s t i n g l y , r e a c t i o n of the epoxide 198 wi th magnesium bromide a f f o r d e d a compound that e x h i b i t e d , in i t s i r spectrum, an i n t e n s e h y d r o x y l group a b s o r p t i o n at 3400 c m ' 1 . Presumably , t h i s compound was a bromohydrin that r e s u l t e d from r i n g opening of the epoxide 98b y bromide i o n . 96 99 A report by Conia and Limasset described a method which i s p a r t i c u l a r l y useful for the o l e f i n a t i o n of hindered ketones. This method involves the reaction (at high temp-eratures) of ketones with (methylene)triphenylphosphorane generated by treatment of methyltriphenylphosphonium bromide with sodium t ert-amylate. Under such conditions, camphor was 99 converted into the o l e f i n 199 in 72% y i e l d . This result 199 appeared very promising since the ketone function in camphor is not only hindered but also undergoes f a c i l e e nolization. A brief l i t e r a t u r e survey revealed that this method had been applied successfully for constructing the side chains of 1 00 steroids, s t a r t i n g from pregnenolone. It has also been employed in a synthesis of (±)-modhephene. 1^ It was g r a t i f y i n g to find that treatment (benzene, 25°C) of the ketone 162 with the phosphorane generated by reaction of (methoxymethyl)triphenylphosphonium chloride with sodium t ert-amylate provided the desired enol ethers as a mixture of geometric isomers. Hydrolysis of t h i s mixture with hydrochloric acid (1M) in THF gave a mixture of the aldehydes 161 and 200 in a r a t i o of 1:4, respectively ( c a p i l l a r y g l c ) . The o v e r a l l y i e l d of this mixture from the ketone 162 was 43%. 97 Examination of molecular models of these aldehydes indicated that 161 would be the isomer of lowest energy. In aldehyde 2 0 0 , the aldehyde group experiences a gauche-type interaction with the angular methyl group. In addition, a s t e r i c interaction between the secondary methyl group and the aldehyde function is also present. For aldehyde 1 6 1 , the main s t e r i c repulsion seems to be a s yn-axial type i n t e r -action between the aldehyde group and the proton on the carbon bearing the secondary methyl group. Consequently, one would predict that subjection of both aldehydes to e q u i l i -brating conditions would lead to a mixture predominated by 1 6 1 . Disappointingly, for reasons unknown, sodium methoxide catalyzed e q u i l i b r a t i o n (25°C, 1 h) of a mixture of the two aldehydes led to a the formation of a 1:1 mixture of 161 and 200 ( c a p i l l a r y g l c ) . Further treatment of t h i s mixture with sodium methoxide and prolonging the reaction period did not change the r a t i o between 161 and 2 0 0 . Much to our disappointment, we were unable to separate these two aldehydes by column chromatography on s i l i c a gel using various solvent systems. Therefore, the mixture of 161 and 200 was used for the next step of the synthetic sequence. 98 Reaction of a 1:1 mixture of aldehydes 161 and 200 with isopropenylmagnesium bromide produced the a l l y l i c alcohols 201 and 202 in a 1:1 r a t i o ( c a p i l l a r y g l c ) . Compounds 201 and 202 were isolated by subjection of the mixture to column chromatography on s i l i c a gel. The yields.of 201 and 202 were 33 and 42%, respectively. The i r spectrum of each of the alcohols showed an intense absorption at 3450 cm"1 due to the hydroxyl group. Pyridinium chlorochromate (2 equiv) oxidation of the alcohol 202 afforded 6-epi-chiloscyphone (203) in a d i s -appointing 34% y i e l d . Substantial amounts of side products 203 were also formed from th i s reaction. Curiously, Swern 1 02 oxidation of compound 202 resulted in a complex mixture which contained only a small amount of 203. Oxidation of 201 with pyridinium chlorochromate (2 equiv) provided compound 151 in 59% y i e l d . For comparison purposes, the spectral data derived from natural 99 151 ( - ) - c h i l o s c y p h o n e , s y n t h e t i c (±)-chiloscyphone (151), a n d s y n t h e t i c (±)-6-epi-chiloscyphone (203) a r e s u m m a r i z e d i n t h e f o l l o w i n g p a r a g r a p h s . ( - ) - C h i l o s c y p h o n e . I r ( f i l m ) : 1670, 1629 cm" 1; 1H nmr (360 MHz, CDC1 3) 6 : 0.84 ( d , 3H, 7=6.2 Hz, s e c o n d a r y m e t h y l ) , 0.96 ( s , 3H, a n g u l a r m e t h y l ) , 1.83 ( b r o a d s, 3H, v i n y l m e t h y l ) , 3.56 (d o f d, 1H, 7=7.5 and 1.4 H z , -CHC=0), 5.40 ( u n r e s o l v e d m, 1H, o l e f i n i c r i n g p r o t o n ) , 5.72 and 5.92 ( s , s, 1H e a c h , t e r m i n a l o l e f i n i c p r o t o n s ) . E x a c t Mass c a l c d . f o r C 1 5 H 2 2 0 : 21 8 . 1 6 7 0 ; f o u n d 2 18.1676. (±)-Chiloscyphone (151). I r ( f i l m ) : 1670, 1630 cm" 1; 1H nmr (400 MHz, CDC1 3) 5 : 0.85 ( d , 3H, 7=6.0 Hz, s e c o n d a r y m e t h y l ) , 0.97 ( s , 3H, a n g u l a r m e t h y l ) , 1.85 ( b r o a d s, 3H, v i n y l m e t h y l ) , 3.58 (d o f d, 1H, 7=8.0 and 1.3 Hz, -CHC=0), 5.41 ( u n r e s o l v e d m, 1H, o l e f i n i c r i n g p r o t o n ) , 5.73 and 5.94 ( s , s, 1H e a c h , t e r m i n a l o l e f i n i c p r o t o n s ) . E x a c t Mass c a l c d . f o r C 1 5 H 2 2 0 : 21 8 . 1 6 7 0 ; f o u n d 2 1 8 . 1 6 7 1 . (±)-6-epi-Chiloscyphone (203). I r ( f i l m ) : 1670, 1630 cm" 1; 'H nmr (270 MHz, CDC1 3) 6 : 0.72 ( d , 3H, 7=6.0 Hz, s e c o n d a r y m e t h y l ) , 0.90 ( s , 3H, a n g u l a r m e t h y l ) , 1.91 ( s i n g l e t , 3H, v i n y l m e t h y l ) , 3.18 ( d o f d, 1H, 7=12.0 and 8.0 Hz, -CHC=0), 5.30 ( u n r e s o l v e d m, 1H, o l e f i n i c r i n g 100 proton), 5.72 and 5.97 (s, s, 1H each, terminal o l e f i n i c protons). Exact Mass caicd. for C 1 5H 2 20 : 218.1670; found 218.1670. By comparing the spectral c h a r a c t e r i s t i c s of natural 70 72 (-)-chiloscyphone ' and that of the synthetic material, there was no doubt that 151 i s (±)-chiloscyphone. Not unexpectedly, the i r and mass spectral c h a r a c t e r i s t i c s of compound 203 were very similar to those of 1 5 1 . However, the structural differences between these two substances were c l e a r l y v i s i b l e in the 1H nmr spectra (see figure 1 and figure 2). Most notably, for compound 2 0 3 , the proton alpha to the ketone function gave r i s e to a doublet of doublets at 5 3 . 1 8 with coupling constants of 12.0 and 8.0 Hz. In the 'H nmr spectrum of compound 1 5 1 , the same proton appeared at 8 3.58 as a doublet of doublets with coupling constants of 8.0 and 1.3 Hz. 101 4 3 2 1 0 6* Figure 2: The 400 MHz 1H nmr spectrum of 151 102 IV. Total Synthesis of the Sesquiterpenoid  (±)-"Eremofukinone" (204) A. Introduct ion Eremofukinone (204) was isolated from the rhizomes of the wild plant Pet asi tes Japonicus Maxim, and i t s 1 03 subspecies, subsp. gigantus Kitam. The. str u c t u r a l elucidation of t h i s sesquiterpenoid was carr i e d out by a combination of spectroscopic methods and a chemical correlation study with the known natural product eremo-1 03 philene (205). The cor r e l a t i o n study is i l l u s t r a t e d in scheme 15. Selective hydrogenation of the disubstituted double bond of eremophilene (205) afforded the dihydro derivative 206. Hydroboration of th i s derivative, followed by Jones' oxidation of the resultant alcohol, furnished the ketone 207. This ketone was found to be i d e n t i c a l with that obtained from eremofukinone by hydrogenation of the disubstituted double bond. Consequently, the structure of eremofukinone was proposed to be as shown in structural formula 204. On the basis of i t s c h a r a c t e r i s t i c structural 103 204 207 a) Ra-Ni; b) BH 3; c) Cr0 3, rl2SOk; d) Pd-H2. scheme 15 framework, this natural product is a member of the erempohilane family of sesquiterpenoids. In designing a synthetic plan for eremofukinone, i t was recognized from the outset that the hydroboration-oxidation reaction sequence employed in the chemical c o r r e l a t i o n study would be a convenient means of i n s t a l l i n g the ketone function at C-1. In connection with t h i s idea, the 1 04 sesquiterpenoid eremoligenol (208) was considered an 208 1 04 appropriate synthetic precursor-of 2 0 4 . The t e r t i a r y hydroxyl group present in 208 would serve as a handle for introducing the disubstituted double bond present in 204 . Based on the reasonable assumption that eremofukinone (204) could be prepared by way of eremoligenol ( 2 0 8 ) , a synthesis of the former would translate into an exercise of constructing the l a t t e r . 1 05 Some time ago, Coates and Shaw reported syntheses of eremoligenol (208) and v a l e r i a n o l 1 ^ ( 2 0 9 ) , which is also a naturally occurring sesquiterpenoid. The synthetic sequence employed for the synthesis of these two compounds i s shown in scheme 16. Robinson annulation of 2-methylcyclohexane-1,3-dione with t ra«5-3-penten -2-one, followed by a selective deoxy-genation of the carbonyl group at C-2 of the resultant condensation product, provided the key intermediate 210 in low y i e l d . Reaction of the ketone 210 with sodium hydride and diethylcarbonate afforded the 0-keto ester 2 1 1 . Depro-tonation of the l a t t e r compound with sodium hydride in HMPA, followed by addition of chloromethyl methyl ether to the resultant enolate gave the enol ether 2 1 2 . Reduction of 212 with lithium in l i q u i d ammonia produced, stereoselectively the ester 2 1 3 , which was treated with methyllithium to furnish eremoligenol ( 2 0 8 ) . Sodium ethoxide catalyzed epimerization of the ester function in 213 led to the more stable isomer 2 1 4 , which, on reaction with methyllithium, provided v a l e r i a n o l ( 2 0 9 ) . 1 05 OH 209 a) (EtO) 2CO, NaH; b) NaH, HMPA; c) MeOCH2Cl; d) L i , NH3; e) MeLi, E t 2 0 ; f) NaOEt, EtOH; scheme 16 106 1 07 Naf and coworkers have developed a t o t a l l y d i f f e r e n t approach to the synthesis of the ester 2 1 3 , which was subsequently transformed into 208 and 209 by Coates' procedure. This approach involved a stereoselective intramolecular Diels-Alder reaction which, in a single step, assembled the b i c y c l i c skeleton with a l l the substituents possessing the desired r e l a t i v e stereochemistry. The synthetic sequence u t i l i z e d for the construction of 213 is shown in scheme 17. Reaction of 5,6-dimethyl-6-hepten-2-one with sodium hydride and diethylcarbonate produced the /3-keto ester 2 1 5 , which, upon hydrolysis, gave the acid 2 1 6 . Mixing t h i s acid with ethyl (£)-4~oxo-2-butenoate at 25°C gave the corresponding al d o l product, which, upon treatment with dimethylformamide dimethyl acetal, underwent concomitant dehydration and decarboxylation to afford the triene keto ester 2 1 7 . An intramolecular Diels-Alder c y c l i z a t i o n proceeded smoothly when a toluene solution of 217 in a sealed tube was heated at 250°C. A 1:1 mixture of compounds 218 and 219 was produced. These two substances were transformed into the enone 220 by an acid catalyzed double bond isomerization. Reduction of the tosylhydrazone derivative of compound 220 with catecholborane in chloroform furnished the desired ester 2 1 3 . F i n a l l y , t h i s ester was converted into eremoligenol and valerianol according to Coates' procedure. 215 218 219 220 213 a) NaH, (EtO) 2CO, A ; b) KOH, H20; c) H*; d) (£)-HCOCH=CHCOOEt e) Me2NCH(OMe)2; f) toluene, 250°C; g) p-TsOU, toluene, A ; h) />-TsNHNH2 , i) catecholborane, CHC13, 0°C. scheme 17 108 B. Total Synthesis of (±")-"Eremofukinone" (204) The synthetic planning for the t o t a l synthesis of eremofukinone was s i m p l i f i e d somewhat by the fact that eremoligenol (208), the planned precursor for 204, can be prepared in a straightforward manner from the ester 105,107 213. It appeared that one could secure this ester from the b i c y c l i c diene 221 which, in turn, should be obtained by the combination of substances that serve as synthetic equivalents to the synthons 164 and 222 (scheme 18). An obvious choice for a synthetic equivalent of the a,a synthon 222 was the dihalide 4-bromo-2-(bromomethyl)-1 -butene (223). In l i g h t of our previous success with the /3-trimethylstannyl enoate 54, th i s compound was selected again as a synthetic equivalent of the d,d synthon 164. A search of the l i t e r a t u r e revealed that the dibromide 1 0 8 223 had been prepared by Evans and Mitch from cyclo-propane- 1,1-dicarboxylic acid^ (3) (see equation 46). — O H BH 3•THF, THF -OH 224 (46; ZnBr 2, benzene, A PBr 3, HBr, CH 2C1j Br 223 225 Reduction of the di a c i d 3 with borane-tetrahydrofuran 109 scheme 18 1 10 1 09 afforded the d i o l 224, which, upon reaction with phosphorus t r i b r o m i d e 1 1 ^ and 48% hydrobromic acid in dichloromethane (25°C, 96 h) furnished the dibromide 225 1 1 1 (75%). The desired material 223 was produced in 80% y i e l d via zinc bromide catalyzed cyclopropylcarbinyl rearrange-1 1 2 ment of 225, car r i e d out in benzene (80°C, 36 h). This sequence of reactions constituted an e f f i c i e n t preparation of compound 223 and was adopted, with some modifications, for our preparation of this material. Reduction of the d i a c i d 3, obtained according to the procedure of Danishefsky and Singh,^ with borane-dimethyl-sulphide (2.6 equiv) in THF (25°C, 5.5 h) furnished the d i o l 224 (49%). For the conversion of compound 224 into 225, i t 1 1 3 was found that triphenylphosphine dibromide was a more e f f i c i e n t reagent than phosphorus tribromide. Thus, treatment of 224 with triphenylphosphine dibromide (2.1 equiv) in dichloromethane at 0°C for 1 hour produced the desired product 225 in good y i e l d (85%). To obtain the dibromide 223, an ethereal solution of compound 225 was treated with freshly sublimed zinc bromide (1.4 equiv) at 25°C. After the mixture had been s t i r r e d for 47 h, an additional 1 equivalent of zinc bromide was introduced and s t i r r i n g was then continued for another 9 h. This further addition of Lewis acid was necessary to complete the conversion of 225 into 223. D i s t i l l a t i o n (reduced pressure) of the crude product obtained upon workup provided 223 in 84% y i e l d . 111 The 270 MHz 1H nmr spectrum of 223 displayed t r i p l e t s at 6 2.80 (2H, /=8 Hz, -CH 2CH 2Br) and 6 3.53 (2H, 7=8 Hz, -CH 2CH 2Br), and singlets at 6 3.99 (2H,=CCH2Br), 5.06, and 5.32 (1H each, o l e f i n i c protons). The mass spectrum of 223 showed two equally intense peaks at m/e 149 ( 8 1Br) and 147 ( 7 9Br) which resulted from the loss of a bromine atom from the molecular ion. With ample quantities of the dibromide 223 in hand, the study towards the synthesis of eremofukinone was begun. Reaction of the dienolate anion, generated from compound 54 under the usual conditions, with 223 (2 equiv) in THF (-78°C, 1 h) produced the coupling product 226 in 88% y i e l d (scheme 19). The 270 MHz 1H nmr spectrum of 226 exhibited a singlet at 5 0.06 (9H, /sn-H = 5 4 H z> _SnMe 3), a t r i p l e t at 6 5.95 (1H, 7=4 Hz, o l e f i n i c ring proton), and broad singlets at 6 4.88 and 4.92 (1H each, terminal o l e f i n i c protons). Exposure of an ethereal solution of 226 to d i i s o -butylaluminum hydride (3 equiv; 0°C, 2 h) afforded the alcohol 227,the i r spectrum of which showed a strong hydroxyl group absorption at 3450 cm"1. Treatment of this alcohol in dichloromethane with t ert -butyldimethylsilyl trifluoromethanesulphonate (2 equiv) and 2,6-lutidine (2.7 equiv) at 25°C for 0.5 h provided the s i l y l ether 228 (95%). Reaction of 228 in THF with methyllithium (1.5 equiv) in the presence of HMPA (3 equiv) at -20°C for 0.5 h led to a mixture of the desired b i c y c l i c product 229 and the triene 1 12 229 230 a) LDA-HMPA, THF, -48°C; b) 223, -78°C; c) DIBAL-H, Et 20, 0°C; d) TBDMS-OTf, 2,6-lutidine, CH 2C1 2; e) MeLi. scheme 19 230 in a r a t i o of 42:54 ( c a p i l l a r y g l c ) . Most probably, compound 230 arose from an intramolecular dehydrobromination process involving the v i n y l l i t h i u m species 231 generated from 228 by transmetallation (vide infra). This result was reminiscent of that observed during the study of the 1 1 3 TBDMSO 231 c y c l i z a t i o n of compound 134. In that case, compound 128 and 135 were formed in a r a t i o of 6:1 (equation 35). In the X)TBDMS 135 present case, the amount of elimination product produced, r e l a t i v e to that resulting from annulation, had increased sub s t a n t i a l l y . This observation could be related to the increase of a c i d i t y of the proton involved in the elimination process due to the presence of an adjacent double bond. The 300 MHz 1H nmr spectrum of 229 displayed a pair of doublets at 6 3.44 and 3.55 (1H each, 7=10 Hz, -CH 20-), broad singlets at 5 4.59 and 4.67 (1H each, terminal o l e f i n i c protons), and an unresolved multiplet at 6 5.55 1 14 (1H, o l e f i n i c ring proton). The 300 MHz 1H nmr spectrum of 2 3 0 exhibited a singlet at 6 3.41 (2H, -CH 20-), a doublet of t r i p l e t s at 6 5.66 (1H, 7=10 and 4 Hz, o l e f i n i c proton), a doublet of doublets at 6 6.36 (1H, 7=17 and 10 Hz, -CH=CH2), multiplets in the region 6 5.14-5.36 (3H, o l e f i n i c protons), and a multiplet at 8 5.00 (2H, o l e f i n i c protons). In the hope of improving the y i e l d of the desired annulation product, the transmetallation-cyclization reaction was conducted at a lower temperature. However, treatment of compound 2 2 8 in THF with methyllithium (1.5 equiv) and HMPA (3 equiv) at -78°C led to a mixture of 2 2 9 and 2 3 0 in a r a t i o of 27:67, respectively ( c a p i l l a r y g l c ) . A more favourable r a t i o of 64:30, respectively ( c a p i l l a r y g l c ) , of these two compounds was obtained when the experiment was performed at 0°C. Apparently, a higher reaction temperature favoured the formation of the annulation product. However, t i c analysis of the crude product mixture indicated the presence of a substantial amount of baseline material. Reaction of compound 2 2 8 with methyllithium (1.5 equiv) in 1., 2-dimethoxyethane at 0°C led to the formation of 2 2 9 and 2 3 0 in a r a t i o of 55:45, respectively ( c a p i l l a r y g l c ) . When thi s experiment was repeated at 25°C, the two products were produced in an improved 70:30 r a t i o ( c a p i l l a r y g l c ) . Nevertheless, as shown by t i c analysis of the crude product obtained from t h i s reaction, a s i g n i f i c a n t amount of baseline material and side products were also formed. 1 1 5 Interestingly, when N,N,N',N'-tetramethylethylene-diamine was employed as solvent, the product isolated from the reaction of 228 with methyllithium at 0°C was the triene 232 (70%). Evidently, under these conditions, a d i r e c t , methyllith.ium-promoted elimination reaction was much faster than transmetallation. The mass spectrum of 232 showed a d i s t i n c t M+-15 ion at m/e 455 ( 1 2 0 S n ) . Also, in the 1H nmr spectrum of 232, the expected signals for the trimethylstan-nyl group and for the six o l e f i n i c protons were observed. To support our e a r l i e r proposition that the triene 230 was generated by an intramolecular elimination process, the following experiment was performed. Treatment of 228 with 0.9 equivalent of methyllithium in 1,2-dimethoxyethane at 0°C furnished a mixture containing 228, 229 and 230 in a r a t i o of 9.5:45:38.5 ( c a p i l l a r y g l c ) . Since approximately 90% of the amount of 228 employed for the reaction had undergone transmetallation, methyllithium was d e f i n i t e l y not d i r e c t l y involved in the formation of 230. Thus, i t is reasonable to conclude that the formation of compound 230 was due to an intramolecular elimination process. Since the "optimum" results for the conversion 228 • 229 were obtained when the transmetallation-cycli-1 16 zation operation was carried out in 1,2-dimethoxyethane at 0°C, these reaction conditions were u t i l i z e d for a l l subsequent preparations of compound 229. Thus, by exposing a 1,2-dimethoxyethane solution of 228 to methyllithium (1.5 equiv) at 0°C for 1 h, a mixture containing 229 and 230 in a 229 230 r a t i o of 54:43, respectively ( c a p i l l a r y glc) was obtained in 84% y i e l d . The unwanted triene 230 was removed e f f i c i e n t l y from t h i s mixture by a chemical operation.* Treatment of a solution of the above mixture in THF with the highly 1 1 4 reactive dienophile tetracyanoethylene at 25°C for 45 minutes, followed by appropriate workup and p u r i f i c a t i o n procedures, provided the desired product 229 (44%) in a pure form. The s i l y l ether group in compound 229 was cleaved by reaction of t h i s substance with tetra-n-butylammonium fluoride (2 equiv) in THF. The corresponding alcohol 233, a c r y s t a l l i n e white s o l i d (m.p. 71-72°C), was produced in 90% y i e l d (scheme 20). Oxidation of 233 with pyridinium chlorochromate (2.5 equiv) in dichloromethane gave the expected aldehyde 234 in 83% y i e l d . The i r spectrum of this * We were unable to achieve clean separation of these two compounds by column chromatography on s i l i c a g el. The approximate Rf values (pentane) of 229 and 230 on s i l i c a gel t i c plates were 0.57 and 0.50, respectively. 1 1 7 221 234 a) TBAF, THF; b) PCC, CH 2C1 2; c) N 2H«, MeOH, A; d) NaOKe, DEG, 210°C; e) KOf-Bu, DMSO, 70°C scheme 20 aldehyde showed a strong carbonyl absorption at 1715 cm"1. To generate the required methyl substituent, the hydrazone of compound 2 3 4 was allowed to react with sodium methoxide ( 3 equiv) in diethyleneglycol (210°C, 1 h). It had been anticipated that the resultant hydrocarbon 2 2 1 would be highly v o l a t i l e and caution was exercised during the i s o l a -tion of th i s compound. However, compound 2 2 1 was obtained in 1 1 5 low y i e l d (19%). Therefore, a milder procedure for the Wolff-Kishner reduction was u t i l i z e d . Thus, the hydrazone derived from 2 3 4 was treated with potassium t ert-butoxide (1.5 equiv) in dimethylsulphoxide at 70°C for 2 h. A 1 18 c a r e f u l l y executed workup and i s o l a t i o n procedure p r o v i d e d compound 2 2 1 , but a g a i n in an u n s a t i s f a c t o r y y i e l d (41%). I t seemed l i k e l y t h a t , due to i t s h i g h v o l a t i l i t y , a s i g n i f i c a n t amount of 221 was l o s t d u r i n g the i s o l a t i o n and p u r i f i c a t i o n p r o c e d u r e . In order to c i rcumvent t h i s o b s t a c l e , a change i n the s y n t h e t i c route was deemed n e c e s s a r y . O r i g i n a l l y , i t had been p lanned tha t the angu lar methyl s u b s t i t u e n t would be i n s t a l l e d be fore the e x o c y c l i c bond was f u n c t i o n a l i z e d ( i . e . 229 •» 221 -* 2 1 3 ) . N e v e r t h e l e s s , the order of these t r a n s f o r m a t i o n s c o u l d be e a s i l y r e v e r s e d , p r o v i d e d that the f u n c t i o n a l group i n t o which the e x o c y c l i c double bond was t r a n s f o r m e d would s u r v i v e the r e a c t i o n c o n d i t i o n s i n v o l v e d in the subsequent W o l f f - K i s h n e r r e d u c t i o n . I t was expected t h a t w i th the presence of such a f u n c t i o n a l group , the p r o d u c t o b t a i n e d upon deoxygenat ion would be l e s s v o l a t i l e . The e x o c y c l i c double bond p r e s e n t in 229 was s e l e c t i v e l y h y d r o b o r a t e d by r e a c t i o n of 229 wi th d i s i a m y l -b o r a n e 1 1 6 (2 .5 equ iv ) in THF at 0 - 2 5 ° C . Treatment of the r e s u l t a n t r e a c t i o n mixture wi th a l k a l i n e hydrogen p e r o x i d e a f f o r d e d the a l c o h o l 235 as a white s o l i d (m.p. 8 3 - 8 4 ° C a f t e r sumbl imat ion) i n 85% y i e l d (scheme 21) . The f o r m a t i o n of compound 235 as the s o l e p r o d u c t can be r a t i o n a l i z e d on the b a s i s of s t e r i c arguments . T h u s , in order to a v o i d s t e r i c i n t e r a c t i o n wi th the s u b s t i t u e n t at the a n g u l a r p o s i t i o n in the t r a n s i t i o n s t a t e of the h y d r o b o r a t i o n r e a c t i o n , the s t e r i c a l l y demanding h y d r o b o r a t i n g reagent 1 19 238 239 a) S i a 2 B H , THF, 0-25°C; b) H 2 0 2 , NaOH; c). MEMC1, C H 2 C 1 2 , ( M e 2 C H ) 2 N E t ; d) TBAF, THF; e) PCC, C H 2 C 1 2 ; f ) N 2 H „ , MeOH, A; g) K O r - B u , DMSO, 70°C. scheme 21 w o u l d p r e f e r t o a t t a c k t h e d o u b l e bond f r o m t h e s i d e o p p o s i t e t h i s s u b s t i t u e n t ( s e e A ) . As a r e s u l t , one w o u l d e x p e c t t h a t t h e h y d r o b o r a t i o n r e a c t i o n w o u l d p r o d u c e a l c o h o l 235 a s t h e s o l e p r o d u c t o r p r e d o m i n a n t p r o d u c t . 1 20 A The i r spectrum of compound 235 showed a strong hydroxyl group absorption at 3270 cm-1. The 270 MHz 1H nmr spectrum of 235 displayed singlets at 6 0.22 and 0.37 (3H each, -SiMe 2r-Bu), 0.90 (9H, -SiMe 2?-Bu), and a doublet at 8 0.96 (3H, 7=7 Hz, secondary methyl), and multiplets at 5 3.36-3.63 (4H, -CH2OH and -CH 2OSi) and 8 5.47 (1H, o l e f i n i c proton). The alcohol group in 235 was protected as the 1 1 7 2-methoxyethoxymethyl ether by reaction of 235 with 2-methoxyethoxymethyl chloride (2 equiv) in the presence of ethyldiisopropylamine (2 equiv) at 25°C. Under these conditions, compound 236 was acquired in 84% y i e l d . This p a r t i c u l a r protecting group was chosen with two reasons in 1 1 7 mind; (1) i t can survive strongly basic conditions such as those encountered in the Wolff-Kishner reduction, (2) i t has been shown that t h i s p a r t i c u l a r protecting group can be cleaved e f f i c i e n t l y by treament with a mild Lewis acid, namely zinc bromide. 1 1"^ Upon reaction with tetra-n-butylammonium fl u o r i d e (3 equiv) at 25°C, compound 236 was converted into the expected alcohol 237 (95%), the i r spectrum of which displayed a hydroxyl group absorption at 3450 cm"1. This alcohol was 121 oxidized with pyridinium chlorochromate (2.5 equiv) to afford the aldehyde 238 in 89% y i e l d . G r a t i f y i n g l y , treatment of the hydrazone of 238 with potassium t e r t -butoxide (2.6 equiv) in dimethylsulphoxide (70°C, 1 h) led to the desired product 239 in excellent y i e l d (90%). The 270 MHz 1H nmr spectrum of 239 exhibited singlets at 6 0.91 (3H, angular methyl) and 3.41 (3H, -OMe), a doublet at 6 0.86 (3H, J=7 Hz, secondary methyl), and an unresolved multiplet at 6 5.33 (1H, o l e f i n i c proton). In order to cleave the 2-methoxyethoxymethyl ether group, compound 239 was allowed to react with 7 equivalents of zinc bromide (freshly sublimed) in dichloromethane (25°C, 12 h). Tic and c a p i l l a r y glc analyses of an aliquot of the reaction mixture indicated that a somewhat complex mixture containing a major component was produced. The major product was subsequently i d e n t i f i e d as the desired alcohol 240. Unfortunately, attempts to obtain 240 free of contaminants by column chromatography were unsuccessful. 240 An attempt to cleave the 2-methoxyethoxymethyl ether . . . . 118 group in 239 by u t i l i z i n g dimethylboron bromide was not successful. Treatment of 239 with 5 equivalents of th i s boron reagent (-78°C, 2 h) led to a complex mixture and no 1 22 useful product could be isolated. A similar f r u s t r a t i n g result was obtained when 239 was treated with t r i m e t h y l s i l y l 1 1 9 chloride-sodium iodide in a c e t o n i t r i l e . F i n a l l y , the conversion of 239 into 240 was accom-1 20 plished by the method developed by Monti et al. Thus, when a solution of 239 in l e r t - b u t y l alcohol containing pyridinium p-toluenesulphonate (9 equiv) was refluxed for 7 h, the desired alcohol 240 was produced in 82% y i e l d . The i r spectrum of th i s alcohol exhibited a strong absorption at 3350 cm"1 (-OH stretching v i b r a t i o n ) . The 400 MHz 1H nmr spectrum of 240 showed a doublet at 5 0.83 (3H, J=l Hz, secondary methyl), and a singlet at 6 0.91 (3H, angular methyl), and multiplets at 6 3.56 and 3.67 (1H each, -CH2OH), and an unresolved multiplet at 5 5.34 (1H, o l e f i n i c proton). According to plan, oxidation of compound 240 to the corresponding carboxylic acid 2 4 1 , required for the 241 213 preparation of the ester 213 , was c a l l e d for at th i s stage. 1 2 1 Attempted oxidation of 240 with pyridinium dichromate (4 equiv) (25°C, 19 h) led to a complex mixture and no useful amount of 241 could be isolated. Treatment of 240 with 1 22 Jones' reagent (2 equiv) at -10°C provided a mixture from 123 which the desired acid 2 4 1 , a c r y s t a l l i n e white s o l i d , was isolated in about 50% y i e l d . The melting point of a recrys-t a l l i z e d sample (hexane) of 241 was 133.5-134.5°C. Attempts to optimize the y i e l d of 241 by conducting the Jones oxidation under various conditions were unsuccessful. Owing to the unsatisfactory y i e l d associated with t h i s p a r t i c u l a r oxidation reaction, a l t e r n a t i v e methods for converting 240 to 241 were sought. 1 23 Lindgren and Nilsson have reported an exceptionally mild method for transforming an aldehyde into the corres-ponding acid by employing sodium c h l o r i t e as the oxidizing agent. In general, the oxidation i s carried out in water or tert-butyl alcohol in the presence of a buffer solution (pH 3.5-4.5) and a chlorine scavenger, such as resorcinol or 2-methyl-2-butene. This method has been applied successfully to the conversion of a number of sensitive a, /3-unsaturated 1 24 aldehydes into the corresponding acids and to the preparation of an intermediate required in a synthesis of 1 25 the natural product verrucarol. Therefore, i t appeared that t h i s oxidation procedure would be useful for the preparation of compound 2 4 1 . 1 02 Swern oxidation of the alcohol 240 afforded the aldehyde 242 , which, without p u r i f i c a t i o n , was immediately oxidized with sodium c h l o r i t e (3 equiv) in tert-butyl alcohol in the presence of a buffer solution (pH 4.5) and 2-methyl-2-butene. Under these conditions, the desired acid 241 was produced in 83% y i e l d , based on 240 (equation 47). 124 Treatment of the acid 241 with ethanol (4 equiv), 126 4-dimethylaminopyridine (0.15 equiv) and N-(3-dimethyl-1 27 aminopropyl)-N-ethylcarbodiimide hydrochloride (2 equiv) in dichloromethane gave the expected ethyl ester 213 in 90% y i e l d . Treatment of compound 213 with sodium ethoxide in refluxing ethanol afforded the epimeric ester 2 1 4 . 213 214 For comparison purposes, the spectral data derived from the esters 213 and 214 and those reported 1^ 7* 5 for these two substances are compiled in tables I and II, respectively. It is obvious that the spectral c h a r a c t e r i s t i c s of 213 and 214 are in good accord with those reported. As a res u l t , the stereochemical structure of compound 213 was established unequivocally. Since the ester 213 had been converted into 125 Table I. Spectral Data Derived from the Esters 213 and 214 213 2 U Ir ( f i l m ) : 1731, 1459, 1377, 1201 cm"1; 1H nmr (CDC13) 6: 0.85 (s, 3H, angular methyl), 0.89 (d, 3H, 7=6 Hz, -CHMe), 1.30 (t, 3H, 7=7 Hz, -OCH2Me), 4.17 (q, 2H, 7=7 Hz, -OCH2Me), 5.34 (m, 1H, o l e f i n i c proton); Ms (m/e): 236 (M*), 162, 147, 1 20. Ir ( f i l m ) : 1734, 1458, 1375, 1306 cm*1; 'H nmr (CDC13) 6: 0.89 (d, 3H, 7=6 Hz, -CHMe), 0.95 (s, 3H, angular methyl), 1.26 (t, 3H, 7=7 Hz, -OCH2Me), 2.59 (t of t, 1H, 7=13 and 3.5 Hz, -CHCOOEt), 4.13 (q, 2H, 7=7 Hz, -OCH2Me), 5.36 (m, 1H, o l e f i n i c proton); Ms (m/e): 236 (M*), 221, 190, 163, 162, 147. Table I I . Spectral Data Reported for the Esters 213 and 214 213 2 U Ir ( f i l m ) : 1730, 1460, 1 3.76, 1370 cm"1; 1H nmr (CDC13) 6: 0.83 (s, 3H, angular methyl), 0.88 (d, 3H, 7=6 Hz, -CHMe), 1 .28 (t, 3H, 7=7 Hz, -OCH2Me), 4.16 (q, 2H, 7=7 Hz, -OCH2Me), 5.33 (m, 1H, o l e f i n i c proton); Ms (m/e): 236 (MM, 162, 147, 1 20. Ir ( f i l m ) : 1730, 1457 cm"1; 'H nmr (CDC13) 6: 0.88 (d, 3H, 7=6 Hz, -CHMe), 0.93 (s, 3H, angular methyl), 1.25 (t, 3H, 7=7 Hz, -OCH2Me), 2.58 (t of t, 1H, 7=13 and 3.25 Hz, -CHCOOEt), 4.12 (q, 2H, 7=7 Hz, -OCH2Me), 5.33 (m, 1H, olef i n i c proton); Ms (m/e): 236 (M +), 197, 163, 162. 126 (±)-valerianol, (±)-valencene and (±)-eremophilene, our synthesis of 213 constituted a formal t o t a l synthesis of each'of these natural products. (±)-Eremoligenol (208) was prepared from 213 by the OH 208 1 05 procedure of Coates and Shaw. Thus, exposure of an ethereal solution of 213 to methyllithium (3 equiv) at 0°C produced (±)-208 in excellent y i e l d (93%). The spectral data 1 04 reported by I s h i i et al . for (-)-eremoligenol and those derived from (±)-208 are summarized in the following paragraphs. (-)-Eremoliqenol. Ir ( f i l m ) : 3400, 1672, 1382, 1372 cm"1; 1H nmr (CDC13) 5: 0.87 (d, 3H, J=6 Hz, secondary methyl), 0.91 (s, 3H, angular methyl), 1.12 (s, 6H, -CMe2OH), 5.31 (m, 1H, o l e f i n i c proton). (±)-Eremoliqenol (208). Ir ( f i l m ) : 3392, 1673, 1381, 1370 cm"1; 1H nmr (CDC13) 6: 0.87 (d, 3H, J=l Hz, secondary methyl), 0.91 (s, 3H, angular methyl), 1.122 and 1.137 (s, s, 3H each, -CMe2OH), 5.31 (m, 1H, o l e f i n i c proton); ms (m/e) : 222(M +), 204 (M +-H 20). As can be seen, spectral data derived from (±)-208 are in excellent agreement with those reported for (-)-eremoli-genol. Consequently, there i s no doubt that our synthetic 127 m a t e r i a l (208) i s (±)-eremoligenol. I t should be p o i n t e d out that the h y d r o b o r a t i o n - o x i d -a t i o n r e a c t i o n sequence planned f o r the p r e p a r a t i o n of (±)-eremofukinone (204) from (±)-eremoligenol (208) had been 1 04 performed by I s h i i et al. on (-)-eremoligenol. In order to complete our s y n t h e s i s of (±)-eremofukinone, i t was decided to f o l l o w the procedures r e p o r t e d by these workers. Hydroboration of (±)-208 with b o r a n e - t e t r a h y d r o f u r a n (3 equiv) i n THF (25°C, 2 h), f o l l o w e d by treatment of the r e a c t i o n mixture with a l k a l i n e hydrogen peroxide, p r o v i d e d a s i n g l e product (89%) which was a s s i g n e d s t r u c t u r e 243 (vide infra). The m e l t i n g p o i n t of a r e c r y s t a l l i z e d sample HO 243 (ether-hexane) of (±)-243 was 141.5-143°C. The m e l t i n g p o i n t of the d i o l obtained by I s h i i et al. from (-)-eremoligenol 104 was 149-151°C. The s p e c t r a l c h a r a c t e r i s t i c s d e r i v e d from the s y n t h e t i c m a t e r i a l (±)-243 and those r e p o r t e d f o r the 1 04 ( + ) - d i o l prepared from (-)-eremoligenol are summarized below. ( + ) - D i o l . Ir (CHC1 3): 3610, 3450 cm" 1; 1H nmr (CDCl 3) 6: 0.78 (d, 3H, J=6 Hz, secondary methyl), 1.05 (s, 3H, angular methyl), 1.15 (s, 6H, -CMe 2OH), 3.77 (m, 1H, -CHOH). 1 28 (±)-Diol (243). I r ( K B r ) : 3360, 1450, 1000 cm' 1; 1H nmr (CDC1 3) 6: 0.79 ( d , 3H, /=7Hz, secondary m e t h y l ) , 1.06 ( s , 3H, a n g u l a r m e t h y l ) , 1.165 and 1.175 ( s , s, 3H each, -CMe 2OH), 3.79 ( u n r e s o l v e d m, 1H, -CHOH). C l e a r l y , the s p e c t r a l d a t a d e r i v e d from (±)-243 agreed w e l l w i t h those r e p o r t e d f o r the ( + ) - d i o l p r e p a r e d from ( - ) - e r e m o l i g e n o l . In p r i n c i p l e , the h y d r o b o r a t i o n of compound 208 c o u l d l e a d t o one or both of two p r o d u c t s , 243 and 244. For each of these s u b s t a n c e s , the c h a i r c o n f o r m a t i o n s of the c y c l o -hexane r i n g c o n t a i n i n g the secondary h y d r o x y l group are shown i n 243a and 244a. The r e l a t i v e l y d e s h i e l d e d n a t u r e of the s i g n a l due t o the a n g u l a r methyl group (6 1.06) i n the 1H nmr spectrum of the h y d r o b o r a t i o n p r o d u c t suggested t h a t t h e r e was a 1 , 3 - d i a x i a l r e l a t i o n s h i p between the secondary 1 29 hydroxyl group and t h i s methyl s u b s t i t u e n t . T h i s r e l a t i o n -s h i p i s p o s s i b l e only i n the c/s-fused b i c y c l i c d i o l 243 (see 243a) . Furthermore, as shown i n 243a, Hx i n 243 i s i n an e q u a t o r i a l o r i e n t a t i o n and, on the b a s i s of the Karplus 78 equation, one would expect that the c o u p l i n g c o n s t a n t s between Hx and the three adjacent protons would be r e l a t i v e l y s m a l l . In 244a, Hx i s i n an a x i a l o r i e n t a t o n and, t h e r e f o r e , r e l a t i v e l y l a r g e c o u p l i n g c o n s t a n t s between Hx and the adjacent a x i a l protons would be expected. The f a c t t h a t the proton (Hx) on the carbon bearing the secondary hydroxyl group appeared as an unresolved m u l t i p l e t (w 1/2-7.5Hz) i n the 1H nmr spectrum of the hyd r o b o r a t i o n product p r o v i d e d a d d i t i o n a l s t r o n g evidence i n favour of the s t r u c t u r a l assignment (243) . To account f o r the s t e r e o s e l e c t i v i t y observed i n the hydro b o r a t i o n of (±)-eremoligenol (208), the f o l l o w i n g r a t i o n a l e i s proposed. Examination of a molecular model of 208 r e v e a l s that when the cyclohexane r i n g i s i n a c h a i r conformation, a severe i n t e r a c t i o n e x i s t s between the -CMe2OH moiety and the angular methyl group, s i n c e they are in a 1 , 3 - d i a x i a l r e l a t i o n s h i p . To minimize t h i s i n t e r a c t i o n , the six-membered r i n g c o n t a i n i n g the -CMe2OH group c o u l d adopt a t w i s t boat conformation (as shown below) i n which the proton Hb i s i n c l o s e p r o x i m i t y to the s p 2 carbon on the r i n g j u n c t i o n . T h e r e f o r e , i t i s proposed that hydroboration takes p l a c e v i a a t r a n s i t i o n s t a t e d e r i v e d from a t t a c k on the double bond of t h i s conformation from the more a c c e s s i -130 HO ble top face of the molecule. This process would lead to the observed product, 243. Oxidation of the d i o l 243 with 2 equivalents of Jones' reagent (0°C, 10 min) proceeded smoothly and the keto alcohol 245, a c r y s t a l l i n e white s o l i d , was obtained in OH 245 excellent y i e l d (94%). The melting point of a r e c r y s t a l l i z e d sample (hexane) of (±)-245 was 104-105.5°C whereas the melting point of the (-)-keto alcohol, generated from 1 04 (-)-eremoligenol by way of the (+)-diol, was reported to be 97°C. The spectral data from (±)-245 and those reported for (-)-245 1 <^ are summarized below. Racemic 245. Ir (KBr): 3462, 1694 cm"1; 'H nmr (CDCl 3) 6: 0.78 (s, 3H, angular methyl), 0.85 (d, 3H, 7=7 Hz, secondary methyl), 1.158 and 1.163 (s, s, 3H each, -CMe2OH); ms (m/e): 238 (M +), 220 (M +-H 20). 131 (-)-Enantiomer of 245. Ir (CHC1 3): 3625, 3470, 1695 cm"1; 1H nmr (CDC13) 8: 0.79 (s, 3H, angular methyl), 0.88 (d, 3H, 7=6.5 Hz, secondary methyl), 1.17 (s, 6H, -CMe20H). Clearly, the two sets of spectral data summarized above are in good agreement. Dehydration of the keto alcohol 245 was achieved by treatment of this compound with thionyl chloride (5 equiv) in pyridine (0°C, 20 min). Under these conditions, a mixture of three products, which were i d e n t i f i e d as compounds 204, 246 and 247, was obtained. Apparently, compound 246 had 204 246 247 undergone p a r t i a l epimerization under the reaction conditions to produce i t s epimer 247. Compound 246, a c r y s t a l l i n e white s o l i d , was isolated in 13% y i e l d by column chromatography of the product mixture. The melting point of a r e c r y s t a l l i z e d sample (hexane) of 246 was 83.5-84°C. Chromatographic separation ( s i l i c a gel) of compounds 204 and 247 was d i f f i c u l t [the approximate Rf values (1:4 ether-petroleum ether) of 204 and 247 were 0.31 and 0.38, respectively] and we were unable to completely separate these two substances. The combined y i e l d of 204 and 247, as a 2.2:1 mixture ( c a p i l l a r y g l c ) , was 71%. Nevertheless, by careful column chromatography (3:17 ether-petroleum ether) 1 32 of the m i x t u r e , pure samples of 204 and 247 were o b t a i n e d and these substances were f u l l y c h a r a c t e r i z e d . The s t r u c t u r a l d i f f e r e n c e between 246 and 247 was c l e a r l y v i s i b l e in t h e i r 1 H nmr s p e c t r a . For example, i n the 400 MHz 1 H nmr spectrum of 246 ( f i g u r e 3 ) , the i s o p r o p y l i -dene methyl groups appeared as. two sharp s i n g l e t s at 5 1.55 and 1.58 whereas a broad s i n g l e t (w 1 /2~6 Hz) at 6 1.69 was observed i n the 400 MHz spectrum of 247 ( f i g u r e 4) for the c o r r e s p o n d i n g methyl g r o u p s . A l t h o u g h compound 247 (one enant iomer) had been o b t a i n e d d u r i n g the course of d e t e r m i n i n g the s t r u c t u r e of v a l e r i a n o l , 1 ^ C the s p e c t r a l c h a r a c t e r i s t i c s of t h i s substance were, u n f o r t u n a t e l y , not r e p o r t e d . A survey of the c h e m i c a l l i t e r a t u r e r e v e a l e d „ „ . „ 1 2 8 ^ 106c t h a t , i n the 'H nmr s p e c t r a of compounds 248 and 249, the s t r u c t u r e s of which are q u i t e s i m i l a r to 247, the i s o p r o p y l i d e n e methyl groups appeared as s i n g l e t s at <5 1.69 (6H) and 6 1.70 (6H), r e s p e c t i v e l y . Based on the s i m i l a r i t y of the c h e m i c a l s h i f t s of the i s o p r o p y l i d e n e methyl groups in 247, 248 and 249, the r r a n s - f u s e d b i c y c l i c s t r u c t u r e was a s s i g n e d to compound 247. S u r p r i s i n g l y , the 1 H nmr s p e c t r a of eremofukinone* * We are g r a t e f u l to D r . K. Naya f o r sending us a copy of the 1 H nmr spectrum of eremofukinone . 1 33 3 2 1 OS F i g u r e 3: The 400 MHz 'H nmr spectrum of 246 H 20 3 2 1 0 S F i g u r e 4: The 400 MHz 'H nmr spectrum of 247 134 ( f i g u r e 5) and compound 204 ( f i g u r e 6) are q u i t e d i f f e r e n t . For example, i n the spectrum of the s y n t h e t i c m a t e r i a l 204, the a n g u l a r methyl group appeared a t h i g h e r f i e l d (6 0.77) than the secondary m e t h y l group (6 6.87, J=l H z ) . However, i n the spectrum of eremofukinone, the secondary methyl d o u b l e t appeared a t h i g h e r f i e l d (6 0.77, J=6 Hz) than the a n g u l a r methyl s i n g l e t (6 1.03). As e x p e c t e d , the mass spectrum of compound 204 e x h i b i t e d a d i s t i n c t m o l e c u l a r i o n peak a t m/e 220. F u r t h e r m o r e , the i r spectrum of 204 showed c h a r a c t e r i s t i c a b s o r p t i o n s a t 1704 cm - 1 (C=0 s t r e t c h i n g v i b r a t i o n ) , and at 3083, 1645 and 887 cm" 1 ( i s o p r o p e n y l g r o u p ) . These s p e c t r a l d a t a were i n complete a c c o r d w i t h the s t r u c t u r e of compound 204. S i n c e compound 204 was s y n t h e s i z e d by an unambiguous r o u t e and s i n c e the s p e c t r a l c h a r a c t e r i s t i c s of a number of i n t e r m e d i a t e s i n v o l v e d (213, 208, 243, and 245) were i n e x c e l l e n t agreement w i t h those p r e v i o u s l y r e p o r t e d f o r these s u b s t a n c e s , t h e r e appeared t o be l i t t l e doubt about i t s s t r u c t u r a l i d e n t i t y . As a r e s u l t , i t was c o n c l u d e d t h a t the o r i g i n a l s t r u c t u r a l p r o p o s a l f o r eremofukinone i s i n e r r o r . 1 35 3 2 1 OS F i g u r e 6: The 400 MHz 1H nmr s p e c t r u m o f 2 0 4 136 Experimental 1 37 Experimental General Melting points were determined using a Fisher-Johns melting point apparatus and are uncorrected. Infrared ( i r ) spectra were obtained on l i q u i d films or KBr p e l l e t s , employing a Perkin-Elmer model 1710 spectrophotometer (internal c a l i b r a t i o n ) or a Perkin-Elmer model 710B spectrophotometer c a l i b r a t e d using the 1601 cm"1 band of a polystyrene f i l m . Proton nuclear magnetic resonance ( 1H nmr) spectra were recorded on deuterochloroform solutions using Bruker models WP-80, HXS-270 or WH-400 spectrometers or Varian models T-60 or XL-300 instruments. Signal positions are given in 5 units and were measured r e l a t i v e to the tetramethylsilane (TMS) signal as the internal standard or 1 29 to the chloroform signal (6 7.25). The m u l t i p l i c i t y , number of protons, coupling constants, and assignments (where possible) are indicated in parentheses. The tin-proton coupling constants (^sn-H^ a r e given as an average of the 1 1 7 S n and 1 1 9 S n values. Low and high resolution mass spectra were recorded with Varian/MAT CH4B and Kratos/AE1 MS 50 mass spectrometers, respectively. In cases of compounds with a trimethylstannyl group, the molecular weight determinations (high resolution mass spectrometry) were based on 1 2 0 S n and were on the (M+-Me) 138 Gas-liquid chromatography (glc) analyses were performed on Hewlett-Packard models 5880 or 5890 gas chromatographs using 25 m x 0.21 mm fused s i l i c a c a p i l l a r y columns coated with cross-linked SE-54 and flame ionization detectors. Thin layer chromatography ( t i c ) analyses were ca r r i e d out on commercial aluminum-backed s i l i c a gel plates (E. Merck, Type 5554). V i s u a l i z a t i o n was accomplished with u l t r a v i o l e t l i g h t , iodine, and/or by spraying with 5% ammonium molybdate-10% aqueous sulphuric acid. Conventional column chromatography was done on 70-230 mesh s i l i c a gel (E. 1 30 Merck, S i l i c a Gel 60) while flas h column chromatography was done on 230-400 mesh s i l i c a gel (E. Merck, S i l i c a Gel 60) . A l l compounds that were subjected to mass spectrometric determinaton were homogenous by t i c and glc analyses. Unless otherwise stated, a l l reactions were carr i e d out under an atmosphere of dry argon using thoroughly flame-dried glassware. Cold temperatures were maintained by the use of the following baths: ice-acetone (-10°C), 27 g CaCl 2/lOO mL H 20/dry ice (-20°C), 1 3 1 46 g CaCl 2/l00 mL H 20/dry ice (-48°C), 1 3 1 acetone/dry ice (-78°C) and methanol/N 2 (-98°C). 1 39 S o l v e n t s and Reagents S o l v e n t s and r e a g e n t s were p u r i f i e d and d r i e d u s i n g 1 32 e s t a b l i s h e d p r o c e d u r e s . E t h e r and THF were d i s t i l l e d from sodium benzophenone k e t y l . T r i e t h y l a m i n e , d i i s o p r o p y l a m i n e , 2 , 6 - l u t i d i n e , d i i s o p r o p y l e t h y l a m i n e , HMPA, d i m e t h y l -s u l p h o x i d e and dimethylformamide were d i s t i l l e d from c a l c i u m h y d r i d e . D i c h l o r o m e t h a n e and t e t r a c h l o r o m e t h a n e were d i s t i l l e d from phosphorus p e n t o x i d e . P e t r o l e u m e t h e r r e f e r s t o the f r a c t i o n w i t h a b o i l i n g range of ca. 30-60°C. H e x a m e t h y l d i t i n was o b t a i n e d from O r g a n o m e t a l l i c s , I n c . and was used w i t h o u t f u r t h e r p u r i f i c a t i o n . S o l u t i o n s of m e t h y l l i t h i u m (low h a l i d e ) i n e t h e r and n - b u t y l l i t h i u m i n hexane were p u r c h a s e d from A l d r i c h C h e m i c a l Co., I n c . and were s t a n d a r d i z e d u s i n g the pr o c e d u r e 1 33 of K o f r o n and B a c l a w s k i . P h e n y l t h i o c o p p e r was p r e p a r e d by the method of 2 4 Posner. L i t h i u m d i i s o p r o p y l a m i d e (LDA) was pr e p a r e d by a d d i t i o n of a s o l u t i o n of n - b u t y l l i t h i u m i n hexane t o a s o l u t i o n of d i i s o p r o p y l a m i n e (1 e q u i v ) i n d r y THF a t -78°C. The r e s u l t i n g s l i g h t l y y e l l o w s o l u t i o n was s t i r r e d a t 0°C f o r 10 minutes b e f o r e b e i n g used. A s t o c k s o l u t i o n of sodium t ert -amylate i n benzene was 99 p r e p a r e d a c c o r d i n g t o the proce d u r e of Coma and L i m a s s e t . The c o n c e n t r a t i o n of the s o l u t i o n was determined by a d d i t i o n of an a l i q u o t of the s o l u t i o n t o a m i x t u r e of H 20-THF (1:4) 140 followed by t i t r a t i o n of the resultant THF solution with standard 0.1M hydrochloric acid. In between use, t h i s solution was stored under argon at room temperature. 1 34 Preparation of Trimethylstannyllithium To a cold (-20°C), s t i r r e d solution of hexamethylditin in dry THF was added a solution of methyllithium in ether (1 equiv). The resulting yellow solution was s t i r r e d at -20°C for 15 minutes to afforded a solution of trimethylstannyl-lithium. Preparation of Lithium (Phenylthio)(trimethylstannyl)-32 cuprate (56) To a cold (-20°C), s t i r r e d solution of trimethylstan-nyllithium in dry THF was added s o l i d phenylthiocopper (1 equiv). The res u l t i n g slurry was s t i r r e d at -20°C for 20 minutes to produce a dark red solution of lithium (phenyl-thio) (trimethylstannyl)cuprate (56). 141 . 50 Preparation of 2-Carbomethoxy-2-cyclohexen-1-one (90) O O M e To a cold (0°C), s t i r r e d suspension of sodium hydride (231 mg, 9.63 mmol) in 15 mL of dry THF was added, dropwise, 1 35 a solution of the 0-keto ester 69a (1.00 g, 6.41 mmol) in 2 mL of dry THF. The resultant mixture was s t i r r e d for 10 minutes at 0°C. A solution of phenylselenenyl chloride (1.73 g, 8.97 mmol) in 3 mL of dry THF was introduced rapidly and the reaction mixture was kept at 0°C for 5 minutes. This solution was then added to a s t i r r e d mixture of 30 mL of ether-petroleum ether (1:1), 15 mL of saturated aqueous sodium bicarbonate, and some ice. The layers were separated and the aqueous layer was extracted with 20 mL of ether-petroleum ether (1:1). The combined organic extract was washed with brine and then dried (MgSOa). After removal of the solvent under reduced pressure, the crude selenide was redissolved in 20 mL of dichloro-methane. To the resultant solution was added, with s t i r r i n g , a solution of hydrogen peroxide (1.8 mL of 30% aqueous hydrogen peroxide) in 7 mL of water in three equal portions at intervals of 10 minutes. The reaction mixture was cooled occassionally in an ice-water bath in order to keep the temperature at about 25°C. After the mixture had been 142 s t i r r e d for an additional 10 minutes at 25°C, the aqueous layer was separated and extracted with 30 mL of dichloro-methane. The combined organic solution was washed with saturated aqueous sodium bicarbonate and brine, and then dried (MgSOa). Removal of the solvent under reduced pressure, followed by d i s t i l l a t i o n (air-bath temperature 70-80°C/0.1 Torr) of the remaining material afforded 830 mg (83%) of 90 as a colourless o i l ; i r ( f i l m ) : 1700 cm"1; 1H nmr (80 MHz, CDC13) 6: 1.70-2.10 (m, 2H, -CH 2CH 2CH 2-), 2.15-2.51 (m, 4H, 0=CCH2- and =CHCH2-), 3.60 (s, 3H, -COOMe), 7.55 (t, 1H, 7=4 Hz, o l e f i n i c proton). Exact Mass calcd. for C BH 1 00 3 : 154.0630; found: 154.0638. Preparation of Methyl 6-Methy1-2-oxocyclohexanecarboxylate To a cold (-20°C), s t i r r e d suspension of phenylthio-copper (7.7 g, 44.7 mmol) in 140 mL of dry THF was added slowly a soluton of methyllithium (31.9 mL, 44.7 mmol) in ether. The resultant pale yellow solution was s t i r r e d at -20°C for 5 minutes. A solution of 90 (4.92 g, 31.9 mmol) in 10 mL of dry THF was added and the reaction mixture was (89) •COOMe 143 s t i r r e d at -20°C for 1 hour. Saturated aqueous ammonium chloride (30 mL) and petroleum ether (200 mL) were added and the mixture was allowed to warm to 25°C. S t i r r i n g of the mixture was continued u n t i l a clear colourless organic layer was formed and the p r e c i p i t a t i o n of phenylthiocopper was complete. The pre c i p i t a t e was removed by suction f i l t r a t i o n and the f i l t r a t e was washed with water, brine and dried (MgSO„). Removal of the solvent under reduced pressure, followed by d i s t i l l a t i o n (air-bath temperature 80-90°C/0.1 Torr) of the residual o i l provided a mixture of the /3-keto ester 89 and i t s enol tautomer in a r a t i o of approximately 2:1, respectively (4.47 g, 82%). This mixture exhibited i r (f i l m ) : 3450, 1735, 1700 cm"1; 'H nmr (80 MHz, CDC13) 6: 1.03 and 1.07 (d, d, 3H t o t a l , J=6 Hz in each case, -CHMe), 1.25-2.90 (broad di f f u s e m, 7H), 3.05 (d, 0.7H, J=11 Hz, -CHCOOMe), 3.75 (s, 3H, -COOMe), 12.26 (s, 0.3H, enolic proton). Exact Mass calcd. for C 9H 1 t l0 3 : 170.0942; found: 170.0942. 144 P r e p a r a t i o n of the Enol T r i f l a t e 88 :00Me. To a c o l d (0°C), s t i r r e d suspension of sodium hydride (92.2 mg, 3.85 mmol) i n 12 mL of dry ether was added slowly a s o l u t i o n of the /3-keto e s t e r 69a (0.50 g, 3.21 mmol) i n 3 mL of dry e t h e r . A f t e r the mixture had been s t i r r e d f o r 10 minutes at 0°C, t r i f l u o r o m e t h a n e s u l p h o n i c anhydride (403 mg, 3.85 mmol) was int r o d u c e d and s t i r r i n g was continued at 0°C fo r 1 hour. Saturated aqueous ammonium c h l o r i d e (=2 mL) and ether (15 mL) were added and the r e s u l t a n t mixture was s t i r r e d f o r 5 minutes at 25°C. The aqueous l a y e r was removed and the organic l a y e r was washed (water, b r i n e ) and d r i e d (MgSO«). Removal of the sol v e n t under reduced pressure, f o l l o w e d by d i s t i l l a t i o n ( a i r - b a t h temperature 80-90°C/0.1 Torr) of the r e s i d u a l o i l provided compound 88 (732 mg, 79%). T h i s m a t e r i a l d i s p l a y e d i r ( f i l m ) : 1710, 1650, 1420, 1210 cm" 1; 'H nmr (80 MHz, CDC1 3) 6: 1.50-1.95 (m, 4H, n o n - a l l y l i c r i n g p r o t o n s ) , 2.15-2.60 (m, 4H, a l l y l i c p r o t o n s ) , 3.76 (s, 3H, -COOMe), Exact Mass c a l c d . f o r C 9 H n 0 5 S F 3 : 288.0279; found: 288.0281. 1 45 Preparation of the Enol T r i f l a t e 91 To a cold (0°C), s t i r r e d suspension of sodium hydride (292 mg, 12.2 mmol) in 40 mL of dry ether was added slowly a solution of the (3-keto ester 89 ( 1 .59 g, 9.34 mmol) in 5 mL of dry ether. After the mixture had been s t i r r e d for 10 minutes at 0°C, trifluoromethanesulphonic anhydride (1.13 g, 11.2 mmol) was introduced and s t i r r i n g was continued at 0°C for 1 hour. Saturated aqueous ammonium chloride (=5 mL) and ether (30 mL) were added and the resultant mixture was s t i r r e d for 5 minutes at 25°C. The aqueous layer was removed and the organic layer was washed (water, brine) and dried (MgSO„). Removal of the solvent under reduced pressure, followed by d i s t i l l a t i o n (air-bath temperature 90-1000C/0.1 Torr) of the remaining material gave compound 91 (2.58 g, 91%). This material exhibited i r ( f i l m ) : 1710, 1420, 1210 cm'1; 1H nmr (80 MHz, CDC13) 8: 1.01 (d, 3H, 7=7 Hz, secondary methyl), 1.40-2.00 (m, 4H, n o n - a l l y l i c ring protons), 2.25-2.50 (m, 2H, -CH2C=C), 2.90 (m, 1H, -CHMe), 3.80 (s, 3H, -COOMe). Exact Mass calcd. for C 1 0 H 1 3 0 5 S F 3 : 302.0437; found: 302.0437. 146 P r e p a r a t i o n of the Enol T r i f l a t e 92 art :00Me To a c o l d (0°C), s t i r r e d suspension of sodium hydride (101 mg, 4.22 mmol) i n 10 mL of dry ether was added slowly a s o l u t i o n of methyl 2-oxocyclopentanecarboxylate (69b) (0.50 g, 3.52 mmol) in 3 mL of dry e t h e r . A f t e r the mixture had been s t i r r e d f o r 10 minutes at 0°C, t r i f l u o r o m e t h a n e -sulphonic anhydride (389 mg, 3.87 mmol) was i n t r o d u c e d and s t i r r i n g was continued at 0°C f o r 1 hour. The r e a c t i o n mixture was d i l u t e d with ether (10 mL) and f i l t e r e d through a short column of F l o r i s i l ( e l u t i o n with e t h e r ) . The combined e l u a t e was c o n c e n t r a t e d under reduced p r e s s u r e . D i s t i l l a t i o n ( a i r - b a t h temperature 70-80°C/0.1 T o r r ) of the crude product thus obtained p r o v i d e d the d e s i r e d m a t e r i a l 92 (714 mg, 74%). Compound 92 d i s p l a y e d i r ( f i l m ) : 1720, 1660, 1420, 1210 cm" 1; 1H nmr (80 MHz, CDC1 3) 6: 1.90-2.25 (m, 2H, n o n - a l l y l i c r i n g p r o t o n s ) , 2.55-2.90 (m, 4H, a l l y l i c p r o t o n s ) , 3.80 (s, 3H, -COOMe). Exact Mass c a l c d . f o r C 8 H 9 0 5 S F 3 : 274.0123; found: 274.0119. 147 G e n e r a l P r o c e d u r e 1: P r e p a r a t i o n of the ff-Trimethylstannyl  Enoates 53, 54 and 55 To a c o l d (-20°C), s t i r r e d s o l u t i o n of l i t h i u m ( p h e n y l t h i o ) ( t r i m e t h y l s t a n n y l ) c u p r a t e (56) (1.0 e q u i v , p r e p a r e d as p r e v i o u s l y d e s c r i b e d ) i n dry THF was added a s o l u t i o n of the a p p r o p r i a t e e n o l t r i f l a t e (0.67 e q u i v ) i n dr y THF. The r e s u l t a n t m i x t u r e was s t i r r e d f o r 1 hour a t -20°C. Hexamethylphosphoramide (2 e q u i v ) was i n t r o d u c e d and the r e a c t i o n m i x t u r e was a l l o w e d t o warm t o 0°C and then was s t i r r e d f o r a f u r t h e r 1 hour. S a t u r a t e d aqueous ammonium c h l o r i d e and e t h e r - p e t r o l e u m e t h e r (3:7) were added and the m i x t u r e was s t i r r e d u n t i l the o r g a n i c l a y e r was c o l o u r l e s s and the p r e c i p i t a t i o n of p h e n y l t h i o c o p p e r was complete. The p r e c i p i t a t e was removed by s u c t i o n f i l t r a t i o n and the f i l t r a t e was washed s u c c e s s i v e l y w i t h s a t u r a t e d aqueous copper s u l p h a t e , water, and b r i n e . The o r g a n i c l a y e r was d r i e d over anhydrous magnesium s u l p h a t e and the s o l v e n t was removed under reduced p r e s s u r e . The r e s u l t a n t o i l was s u b j e c t e d t o f l a s h column chromatography and the m a t e r i a l t h u s o b t a i n e d was d i s t i l l e d t o g i v e the d e s i r e d p r o d u c t . 1 4 8 Preparation of the j3-Trimethylstannyl Enoate 53 ^ . S n M e 3 -COOMe Following general procedure 1, a solution of lithium (phenylthio)(trimethylstannyl)cuprate (56) (1.38 mmol) in 5 mL of dry THF was treated with a solution of the enol t r i f l a t e 88 in 2 mL of dry THF. After the mixture had been s t i r r e d at -20°C for 1 hour, HMPA (2.76 mmol) was added. Upon completion of the reaction, 10 mL of saturated aqueous ammonium chloride and 50 mL of ether-petroleum ether (3:7) were added to the reaction mixture. Normal workup, followed by f l a s h column chromatography of the crude product (elution with 1:4 benzene-petroleum ether) and d i s t i l l a t i o n (air-bath temperature 85-95°C/0.1 Torr) of the o i l thus obtained, yielded 210 mg (75%) of 53 as a colourless o i l ; i r ( f i l m ) : 1690, 1250, 770 cm'1; 1H nmr (270 MHz, CDC13) 6: 0.16 (s, 9H, /sn-H=54 Hz, -SnMe3), 1.65 (m, 4H, n o n - a l l y l i c protons), 2.42 (m, 4H, a l l y l i c protons), 3.77 (s, 3H, -COOMe). E x a c t Mass calcd. for C 1 0H 1 70 2Sn (M+-Me): 289.0250; found: 289.0250. 1 49 Preparation of the /3-Trimethylstannyl Enoate 54 ^ T ^ C O O M e Following general procedure 1, a solution of lithium (phenylthio)(trimethylstannyl)cuprate (56) (12.8 mmol) in 40 mL of dry THF was treated with a solution of the enol t r i f l a t e 91 (2.58 g, 8.55 mmol) in 5 mL of dry THF. After the mixture had been s t i r r e d at -20°C for 1 hour, HMPA (25.7 mmol) was added. Upon completion of the reaction, 25 mL of saturated aqueous ammonium chloride and 200 mL of ether-petroleum ether (3:7) were added to the reaction mixture. Normal workup, followed by fl a s h column chromatography of the crude product (elution with 3:17 benzene-petroleum ether) and d i s t i l l a t i o n (air-bath temperature 90-1000C/0.1 Torr) of the o i l thus obtained, yielded 2.43 g (89%) of 54 as a colourless o i l ; i r ( f i l m ) : 1690, 1250, 770 cm"1; 1H nmr (80 MHz, CDC13) 6: 0.16 (s, 9H, /Sn-H = 5 4 H z » -SnMe3), 1.10 (d, 3H, /=7 Hz, secondary methyl), 1.62 (m, 4H, n o n - a l l y l i c ring protons), 2.40 (m, 2H, a l l y l i c methylene protons), 2.80 (m, 1H, a l l y l i c methine proton), 3.78 (s, 3H, -COOMe). Exact Mass calcd. for C n H 1 9 O j S n (M+ -Me): 303.0407; found: 303.0406. 150 Preparation of the ft-Trimethylstannyl Enoate 55 Following general procedure 1, a solution of lithium (phenylthio)(trimethylstannyl)cuprate (56) (13.7 mmol) in 40 mL of dry THF was treated with a solution of the enol t r i f l a t e 91 (2.50 g, 9.12 mmol) in 5 mL of dry THF. After the mixture had been s t i r r e d at -20°C for 1 hour, HMPA (27.4 mmol) was added. Upon completion of the reaction, 25 mL of saturated aqueous ammonium chloride and 200 mL of ether-petroleum ether (3:7) were added to the reaction mixture. Normal workup, followed by flash column chromatography of the crude product (elution with 3:7 benzene-petroleum ether) and d i s t i l l a t i o n (air-bath temperature 70-80°C/0.1 Torr) of the o i l thus obtained, yielded 2.05 g (78%) of 55 as a colourless o i l ; i r ( f i l m ) : 1700, 1260, 770 cm"1; 1H nmr (80 MHz, CDC13) 6: 0.16 (s, 9H, /Sn-H = 5 4 H z ' ~SnMe 3), 1.94 (m, 2H, n o n - a l l y l i c ring protons), 2.63 (m, 4H, a l l y l i c protons), 3.71 (s, 3H, -COOMe). E x a c t Mass calcd. for C 9H 1 50 2Sn (M+-Me): 275.0094; found: 275.0092. 151 General Procedure 2: Alkylation of Enoates 53 and 54 with  1-Chloro-3-iodopropane To a cold (0°C), s t i r r e d solution of LDA (1 equiv, prepared as described previously) in dry THF was added HMPA (2 equiv) and the resultant yellow solution was cooled to -48°C. A solution of the appropriate enoate (0.67 equiv) in dry THF was introduced and s t i r r i n g was then continued for 40 minutes at -48°C. 1-Chloro-3-iodopropane (1.33 equiv) was added and the reaction mixture was s t i r r e d for a further 40 minutes at -48°C. Saturated aqueous ammonium chloride (=1 mL) was added and the mixture was allowed to warm to 25°C. Ether was added and the resultant mixture was washed successively with saturated aqueous copper sulphate, water, and brine. The organic layer was dried over anhydrous magnesium sulphate and the solvent was evaporated under reduced pressure. The crude product was subjected to flash column chromatography and the material thus obtained was d i s t i l l e d to give the desired product. Preparation of Compound 111 Cl COOMe 1 52 Following general procedure 2, a solution of LDA (3.71 mmol) and HMPA (7.43 mmol) in 7 mL of dry THF was treated with a solution of the enoate 53 (746 mg, 2.48 mmol) in 3 mL. of dry THF. The mixture was s t i r r e d for 40 minutes at -48°C. To the resultant yellow solution was added, with s t i r r i n g , 1-chloro-3-iodopropane (1.01 g, 4.94 mmol) and s t i r r i n g was continued for 40 minutes at -48°C. Normal workup, followed by flas h column chromatography of the crude product (elution with 6:94 ether-petroleum ether) and d i s t i l l a t i o n (air-bath temperature 125-135°C/0.1 Torr) of the material thus obtained afforded 111 (728 mg, 78%) as a colourless o i l ; i r ( f i l m ) : 1710, 1440, 770 cm"1; 1H nmr (80 MHz, CDC13) 6: 0.15 (s, 9H, / S n_ H=52 Hz, -SnMe3), 1.50-1.90 (m, 6H), 1.95-2.25 (m, 4H), 3.50 (m, 2H, -CH2C1), 3.68 (s, 3H, -COOMe), 5.98 (t, 1H, /=4 Hz, o l e f i n i c proton). Exact Mass calcd. for C , 3 H 2 2 0 2 3 5 C l S n (M*-Me): 365.0331; found: 365.0321. Preparation of Compound 119 Following general procedure 2, a solution of LDA (2.37 mmol) and HMPA (4.74 mmol) in 10 mL of dry THF was treated with a solution of the enoate 54 (500 mg, 1.58 mmol) in 2 mL 1 53 of dry THF. The mixture was s t i r r e d for 40 minutes at -48°C. To the resultant yellow solution was added, with s t i r r i n g , 1-chloro-3-iodopropane (646 mg, 3.16 mmol) and s t i r r i n g was continued for 40 minutes at -48°C. Normal workup, followed by flas h column chromatography of the crude product (elution with 2:3 benzene-petroleum ether) and d i s t i l l a t i o n (air-bath temperature 135-145°C/0.1 Torr) of the material thus obtained, afforded 119 (551 mg, 89%) as a colourless o i l ; i r ( f i l m ) : 1710, 1210, 770 cm"1; 1H nmr (270 MHz, CDC13) 6: 0.15 (s, 9H, 7 S n_ H=52 Hz, -SnMe3), 0.92 (d, 3H, 7=6 Hz, secondary methyl), 1.59-1.85 (m, 5H), 1.87-2.30 (m, 4H), 3.53 (m, 2H, -CH2C1), 3.69 (s, 3H, -COOMe), 6.03 (t, 1H, 7=4 Hz, o l e f i n i c proton). Exact Mass calcd. for C,„H 2«0 2 3 5ClSn (M+-Me): 379.0486; found: 379.0485. General Procedure 3: Alkylation of the Enoate 55 with  g,cj-Dibromoalkanes To a cold (0°C), s t i r r e d solution of LDA (1 equiv, prepared as described previously) in dry THF was added HMPA (2 equiv) and the resultant yellow solution was cooled to -48°C. A solution of the enoate 55 (0.67 equiv) in dry THF was introduced and s t i r r i n g was continued for 40 minutes at -48°C. The resultant solution was cooled to -78°C and the appropriate a l k y l a t i n g agent (10 equiv) was added. After the reaction mixture had been s t i r r e d for 10 minutes at -78°C, 1 54 i t was allowed to warm to -48°C and then was s t i r r e d for a further 40 minutes. Saturated aqueous ammonium chloride (^ 1 mL) was added and the resultant mixture was warmed to 25°C. Ether was added and the mixture was washed successively with saturated aqueous copper sulphate, water, and brine. The organic layer was dried over anhydrous magnesium sulphate and the solvent was evaporated under reduced pressure (aspirator). The excess a l k y l a t i n g agent was removed by d i s t i l l a t i o n under reduced pressure. The crude product was subjected to flash column chromatography and the material thus obtained was d i s t i l l e d to give the desired product. Preparation of Compound 132 Following general procedure 3, a solution of LDA (3.63 mmol) and HMPA (7.26 mmol) in 20 mL of dry THF was treated with a solution of the enoate 55 (700 mg, 2.42 mmol) in 3 mL of dry THF. The mixture was s t i r r e d for 40 minutes at -48°C. The solution was cooled to -78°C and 1,4-dibromobutane (7.85 g, 36.3 mmol) was introduced. The mixture was s t i r r e d for 10 minutes at -78°C and for 40 minutes at -48°C. Normal workup, followed by removal of excess 1,4-dibromobutane by COOMe 1 55 d i s t i l l a t i o n (air-bath temperature 125-1350C/30 Torr), provided the crude product. Subjection of thi s material to flash column chromatography (elution with 7:93 ether-petroleum ether) and d i s t i l l a t i o n (air-bath temperature 120-130°C/0.1 Torr) of the substance thus obtained gave 792 mg (77%) of the desired product 132; i r ( f i l m ) : 1710, 1160, 770 cm-1; 1H nmr (80 MHz, CDC13) 6: 0.13 (s, 9H, ^sn-H = 5 4 Hz, -SnMe3), 1.10-1.53 (m, 3H), 1.60-2.05 (m, 4H), 3.40 (t, 2H, 7=7 Hz, -CH 2Br), 3.68 (s, 3H, -COOMe), 6.00 (t, 1H, 7=4 Hz, o l e f i n i c proton). Exact Mass calcd. for C, 3H 2 20 2 7 9BrSn (M+-Me): 408.9787; found 408.9796. Preparation of Compound 136 Following general procedure 3, a solution of LDA (1.56 mmol) and HMPA (3.12 mmol) in 10 mL of dry THF was treated with a solution of the enoate 55 (300 mg, 1.04 mmol) in 2 mL of dry THF. The mixture was s t i r r e d for 40 minutes at -48°C. The solution was cooled to -78°C and 1,5-dibromopentane (3.59 g, 15.6 mmol) was introduced. The resultant mixture was s t i r r e d for 10 minutes at -78°C and for 40 minutes at -48°C. Normal workup, followed by removal of excess COOMe 156 1 ,5-dibrornopentane by d i s t i l l a t i o n (air-bath temperature 55-65°C/0. 1 "Torr) provided the crude product. Subjection of t h i s substance to flas h column chromatography (elution with 7:93 ether-petroleum ether) and d i s t i l l a t i o n (air-bath temperature 150-160°C/0.1 Torr) of the material thus obtained afforded 136 (330 mg, 72%) as a colourless o i l ; i r ( f i l m ) : 1710, 1220, 770 cm"1; 1H nmr (80 MHz, CDC13) 6: 0.14 (s, 9H, J S n_ H=54 Hz, -SnMe3), 1 .00-1 .65 (m, 5H) , 1.66-2.15 (m, 4H), 2.17-2.70 (m, 3H), 3.40 (t, 2H, J=l Hz, -CH 2Br), 3.65 (s, 3H, -COOMe), 5.98 (t, 1H, /=4 Hz, o l e f i n i c proton). Exact Mass calcd. for C,«H 2„0 2 7 9BrSn (M*-Me): 422.9982; found: 422.9980. General Procedure 4: Reduction of the Esters 111, 132 and 136 To a cold (-20°C), s t i r r e d solution of the ester (1 equiv) in dry ether was slowly added a solution of diisobutylaluminum hydride (2.5 equiv) in hexanes. The resultant mixture was s t i r r e d for 1 hour at -20°C. Saturated aqueous ammonium chloride (1-2 mL) and petroleum ether were added and the mixture was allowed to warm to 25°C. The resultant mixture was s t i r r e d u n t i l the organic layer was clear and the p r e c i p i t a t i o n of the aluminum s a l t s was complete. The p r e c i p i t a t e was removed by f i l t r a t i o n of the mixture through a short column of F l o r i s i l (elution with 157 e t h e r ) . The f i l t r a t e was c o n c e n t r a t e d under reduced p r e s s u r e and the crude p r o d u c t thus o b t a i n e d was d i s t i l l e d t o g i v e the d e s i r e d a l c o h o l . P r e p a r a t i o n of the A l c o h o l 112 F o l l o w i n g g e n e r a l procedure 4, a s o l u t i o n of the e s t e r 111 (500 mg, 1.32 mmol) i n 10 mL of dry e t h e r was t r e a t e d w i t h a s o l u t i o n of d i i s o b u t y l a l u m i n u m h y d r i d e (3.30 mL, 3.30 mmol) i n hexanes. Normal workup, f o l l o w e d by d i s t i l l a t i o n ( a i r - b a t h temperature 125-135°C/0.1 T o r r ) of the crude p r o d u c t , a f f o r d e d 419 mg (90%) of 112 as a c o l o u r l e s s o i l ; i r ( f i l m ) : 3350, 1030, 770 cm" 1; 'H nmr (80 MHz, CDC1 3) 6: 0.17 ( s , 9H, / S n_ H=52 Hz, -SnMe 3), 1.30 (m, 1H, exchanged w i t h D 20, -OH), 1.45-1.75 (m, 8 H ) , 1.80-2.20 (m, 2H), 3.30-3.62 (m, 4H, -CH2OH, and -CH 2C1), 6.08 ( t , 1H, 7=4 Hz, o l e f i n i c p r o t o n ) . E x a c t Mass c a l c d . f o r C , 2 H 2 2 0 3 5 C l S n (M +-Me): 337.0382; found: 337.0382. •SnMe-158 Preparation of the Alcohol 133 Following general procedure 4, a solution of the ester 132 (792 mg, 1.87 mmol) in 20 mL of dry ether was treated with a solution of diisobutylaluminum hydride (4.67 mL, 4.67 mmol) in hexanes. Normal workup, followed by d i s t i l l a t i o n (air-bath temperature 125-135°C/0.1 Torr) of the crude product, gave 729 mg (98%) of 133 as a colourless o i l ; i r ( f i l m ) : 3400, 1020, 770 cm"1; 1H nmr (80 MHz, CDC13) 6: 0.17 (s, 9H, / S n_ H=54 Hz, -SnMe3), 1.13-1.50 (m, 5H), 1.60-2.05 (m, 4H), 2.30-2.55 (m, 2H, a l l y l i c protons), 3.30-3.55 (m, 4H, -CH2OH, and -CH 2Br), 6.03 (t, 1H, 7=4 Hz, o l e f i n i c proton). Exact Mass calcd. for C, 2H 2 20 B 1BrSn (M*-Me): 382.9857; found: 382.9851. 159 Preparation of the Alcohol 137 Following general procedure 4, a solution of the ester 136 (313 mg, 0.17 mmol) in 10 mL of dry ether was treated with a solution of diisobutylaluminum hydride (1.78 mL, 1.78 mmol) in hexanes. Normal workup, followed by d i s t i l l a t i o n (air-bath temperature 150-160°C/0.1 Torr) of the crude product, gave 137 (277 mg, 94%) as a colourless o i l ; i r ( f i l m ) : 3400, 1020, 770 c u r 1 ; 1H nmr (80 MHz, CDC13) 6: 0.13 (s, 9H, 7 S n_ H=54 Hz, -SnMe3), 1.03-1.60 (m, 7H), 1.61-2.08 (m, 4H), 2.23-2.63 (m, 2H, a l l y l i c protons), 3.25-3.55 (m, 4H, -CH2OH, and -CH 2Br), 6.00 (t, 1H, y=4 Hz, o l e f i n i c proton). Exact Mass calcd. for C, 3H 2„0 7 9BrSn (M*-Me): 395.0007; found: 395.0004. 160 Preparation of the Alcohol 122 ^ < \ ^ S n M e 3 To a cold (0°C), s t i r r e d solution of the ester 119 (95 mg, 0.24 mmol) in 3 mL of dry ether was added a solution of diisobutylaluminum hydride (0.72 mL, 0.72 mmol) in hexanes. The resultant mixture was s t i r r e d for 2 hours at 0°C. Saturated aqueous ammonium chloride (^ 1 mL) and petroleum ether (15 mL) were added and the mixture was s t i r r e d at 25°C u n t i l the organic layer was clear and p r e c i p i t a t i o n of the aluminum s a l t s was complete. The inorganic s a l t s were removed by f i l t r a t i o n of the mixture through a short column of F l o r i s i l (elution with ether). The f i l t r a t e was concentrated under reduced pressure and the crude product was d i s t i l l e d (air-bath temperature 125-135°C/0.1 Torr) to provide 122 (76 mg, 86%) as a colourless o i l . This compound displayed i r ( f i l m ) : 3400, 1030, 770 cm"1; 'H nmr (80 MHz, C D C 1 3) 6: 0 . 1 9 (s, 9H, / S n_ H=52 Hz, -SnMe3), 1.00 (d, 3H, J=6 Hz, secondary methyl), 1.25 (m, 2H), 1.40-1.88 (m, 6H), 1.92-2.25 (m, 2H), 3.15-3.78 (m, 4H, -CH2OH, and -CH 2 C 1 ) , 6.18 (t, 1H, y=4 Hz, o l e f i n i c proton). Exact Mass calcd. for C, 3H 2„0 3 5ClSn (M+-Me): 351.0538; found: 351.0538. 1 6 1 Preparation of Compound 113 To a solution of the alcohol 112 (419 mg, 1.19 mmol) in 2 mL of dry dimethylformamide at 25°C was added imidazole (325 mg, 4.76 mmol) and tert-butyldimethylsilyl chloride (360 mg, 2.38 mmol). The resultant mixture was s t i r r e d for 17 hours at 25°C. Ether (35 mL) was added and the mixture was washed thoroughly with water, and brine. The organic layer was dried over anhydrous magnesium sulphate and concentrated under reduced pressure. D i s t i l l a t i o n (air-bath temperature 135-145°C/0.1 Torr) of the crude product gave 520 mg (94%) of the desired product 113 as a colourless o i l ; i r ( f i l m ) : 1460, 1260, 1080, 850, 770 cm"1; 'H nmr (80 MHz, CDCl 3) 5: 0.06 (s, 6H, -SiMe 2f-Bu), 0.15 (s, 9H, / S n_ H=52 Hz, -SnMe3), 0.92 (s, 9H, -SiMe 2f-Bu), 1.35-1.75 (m, 8H), 1.90-2.23 (m, 2H), 3.30-3.63 (m, 4H, -CH20-, and -CH2C1), 5.96 (t, 1H, /=4 Hz, o l e f i n i c proton). Exact Mass calcd. for C , B H 3 6 0 3 S C l S i S n (M*-Me): 451.1246; found: 451.1247. 162 Preparation of Compound 123 / ^ / S n M e 3 OTBDMS To a solution of the alcohol 122 (400 mg, 1.09 mmol) in 1 mL of dry dimethylformamide at 25°C was added tert-butyl-d i m e t h y l s i l y l chloride (330 mg, 2.18 mmol) and imidazole (302 mg, 4.36 mmol). The resultant mixture was s t i r r e d for 17 hours at 25°C. Ether (35 mL) was added and the mixture was washed thoroughly with water, and brine. The organic layer was dried over anhydrous magnesium sulphate and was concentrated under reduced pressure. D i s t i l l a t i o n (air-bath temperature 135-145°C/0.1 Torr) of the crude product afforded 123 (495 mg, 94%) as a colourless o i l ; i r ( f i l m ) : 1460, 1260, 1090, 850, 770 cm"1; 'H nmr (400 MHz, CDC13) 6: 0.03 and 0.04 (s, s, 3H each, -SiMe 2i-Bu), 0.14 (s, 9H, / S n- H=52 Hz, -SnMe3), 0.90 (s, 9H, -SiMe 2f-Bu), 0.96 (d, 3H, J=6 Hz, secondary methyl), 1.25 (m, 1H), 1.54 (m, 1H), 1.65 (m, 2H), 1.71-1.83 (m, 3H), 2.07 (m, 2H), 3.44 (s, 2H, -CH 20-), 3.50 (m, 2H, -CH 2C1), 5.94 (t, 1H, /=4 Hz, o l e f i n i c proton). Exact Mass calcd. for C , 9 H 3 B 0 3 5 C l S i S n (M+-Me): 465.1402; found: 465.1404. 1 63 Preparation of Compound 134 ^OTBDMS To a solution of the alcohol 133 (150 mg, 0.38 mmol) in 1 mL of dry dichloromethane at 25°C was added 2,6-lutidine (130 mg, 1.03 mmol) and t eri-butyldimethylsilyl t r i f l u o r o -methanesulphonate (152 mg, 0.76 mmol). The resultant mixture was s t i r r e d for 30 minutes at 25°C. Water (1 mL) and dichloromethane (25 mL) were added and the mixture was s t i r r e d for 5 minutes at 25°C. This mixture was washed with water, and brine, and dried over anhydrous magnesium sulphate. Removal of the solvent under reduced pressure provided the crude product which was passed through a short column of s i l i c a gel (elution with dichloromethane). The combined eluate was concentrated under reduced pressure and the material thus obtained was d i s t i l l e d (air-bath temperature 125-135°C/0.1 Torr) to give 178 mg (92%) of the desired product 134 as a colourless o i l . This compound displayed i r ( f i l m ) : 1460, 1260, 850, 770 cm"1; 1H nmr (80 MHz, CDC13) 6: 0.03 (s, 6H, -SiMe 2f-Bu), 0.13 (s, 9H, J S n_ H=54 Hz, -SnMe3), 0.88 (s, 9H, -SiMe 2/-Bu), 1.15-2.03 (broad diffuse m, 8H), 2.20-2.53 (m, 2H, a l l y l i c protons), 3.25-3.55 (m, 4H, -CH20- and -CH 2Br), 5.88 (t, 1H, /=4 Hz, o l e f i n i c proton). Exact Mass calcd. for C , B H 3 6 7 9 B r S i S n 164 (M+-Me): 4 9 5 . 0 7 4 0 ; found: 4 9 5 . 0 7 5 1 . Preparation of Compound 138 To a solution of the alcohol 137 ( 7 0 mg, 0.17 mmol) in 1 mL of dry dichloromethane at 25°C was added 2 , 6 - l u t i d i n e ( 5 0 mg, 0.46 mmol) and t ert-butyldimethylsilyl t r i f l u o r o -methanesulphonate ( 9 0 mg, 0.34 mmol). The resultant mixture was s t i r r e d for 30 minutes at 25°C. Water (1 mL) and dichloromethane ( 1 5 mL) were added and the mixture was s t i r r e d for 5 minutes at 25°C. This mixture was washed with water, and brine, and dried over anhydrous magnesium sulphate. Removal of the solvent under reduced pressure provided the crude product, which was passed through a short column of s i l i c a gel (elution with dichloromethane). The combined eluate was concentrated under reduced pressure and the material thus obtained was d i s t i l l e d (air-bath temperature 125-135°C/0.1 Torr) to afford 81 mg ( 9 0 % ) of the desired product 138 as a colourless o i l . This compound showed i r ( f i l m ) : 1 4 6 0 , 1 2 6 0 , 8 5 0 , 770 cm"1; 1H nmr ( 8 0 MHz, CDC13) 6: 0.05 (s, 6H , -SiMe 2*-Bu), 0.15 (s, 9H, / Sn-H = 5 4 Hz, -SnMe3), 0.91 (s, 9H, -SiMe 2t-Bu), 1.05-2.13 165 (broad diffuse m, 10H), 2.18-2.55 (m, 2H, a l l y l i c protons), 3.30-3.58 (m, 4H, -CH20- and -CH 2Br), 5.90 (t, 1H, /=4 Hz, o l e f i n i c proton). Exact Mass calcd. for C t 9 H 3 B 7 9 B r S i S n (M+-Me): 509.0897; found: 509.0911. Preparation of Compound 1 4 1 To a s t i r r e d suspension of potassium hydride (80 mg, 2.00 mmol) in 1 mL of dry THF was added a solution of the alcohol 1 3 7 (328 mg, 0.80 mmol) in 2 mL of dry THF. Dimethyl sulphate (544 mg, 4.00 mmol) was added. After the mixture had been s t i r r e d under reflux for 7.5 hours, i t was transferred slowly into 10 mL of 1M aqueous ammonium hydroxide. The resultant mixture was extracted with ether (2x10 mL). The combined organic extract was washed with water, and brine, and dried over anhydrous magnesium sulphate. Removal of the solvent under reduced pressure provided the crude product which was subjected to fl a s h column chromatography (elution with 1:4 dichloromethane-petroleum ether). D i s t i l l a t i o n (air-bath temperature 125-135°C/0.1 Torr) of the material thus obtained afforded 1 4 1 (283 mg, 84%) as a colourless o i l ; i r ( f i l m ) : 1450, ^ O M e 1 66 1100, 770 cm"1; 'H nmr (80 MHz, CDC13) 6: 0.10 (s, 9H, y S n_ H=54 Hz, -SnMe3), 1.13-2.05 (broad diffuse m, 10H), 2.23-2.50 (m, 2H, a l l y l i c protons), 3.00-3.50 (m, 4H, -CH20-and -CH 2Br), 3.18 (s, 3H, -OMe), 5.88 (t, 1H, 7=4 Hz, o l e f i n i c proton). Exact Mass calcd. for C,„H 2 60 7 9BrSn (M+-Me): 409.0162; found: 409.0157. General Procedure 5: Transmetallation-Cyclization of the  Vinylstannanes 113 , 1 2 3 , 134, 138 and 141 To a cold (-20°C), s t i r r e d solution of the vinylstannane (1 eguiv) in dry THF was added HMPA (3 equiv) and a solution of methyllithium (1.5 equiv) in ether. The resultant mixture was s t i r r e d for 30 minutes at -20°C. Saturated aqueous ammonium chloride (=1 mL) was added and the mixture was allowed to warm to 25°C with s t i r r i n g . Ether was added and the mixture was washed successively with water, saturated aqueous copper sulphate, and water. The organic layer was dried over anhydrous magnesium sulphate and concentrated under reduced pressure. The crude product was subjected to chromatographic p u r i f i c a t i o n ( i f necessary) and the material thus obtained was d i s t i l l e d to give the desired product. 167 Preparation of Compound 114 Op Following general procedure 5, a solution of 113 (50 mg, 0.11 mmol) in 1 mL of dry THF was treated with a solution of methyllithium (0.11 mL, 0.16 mmol) in ether. Normal workup, followed by d i s t i l l a t i o n (air-bath temperature 85-95°C/0.1 Torr) of the crude product, provided 114 (26.5 mg, 92%) as a colourless o i l ; i r ( f i l m ) : 1460, 1250, 1090, 1070, 850 cm'1; 1H nmr (80 MHz, CDC13) 6: 0.05 (s, 6H, -SiMe 2?-Bu), 0.93 (s, 9H, -SiMe 2f-Bu), 0.70-1.30 (m, 2H), 1.43-1.88 (m, 4H), 1.88-2.45 (m, 6H), 3.25 and 3.44 (d, d, 1H each, 7=10 Hz, -CH 20~), 5.45 (unresolved m, 1H, o l e f i n i c proton). Exact Mass calcd. for C 1 2 H 2 1 O S i [M +-(*-Bu)]: 209.1362; found: 209.1360. 168 Preparation of Compound 124 Following general procedure 5, a solution of 123 (50 mg, 0.10 mmol) in 1 mL of dry THF was treated with HMPA (56 mg, 0.30 mmol) and a solution of methyllithium (0.11 mL, 0.16 mmol) in ether. Normal workup, followed by d i s t i l l a t i o n (air-bath temperature 85-95oC/0.1 Torr) of the crude product, afforded 124 (28.0 mg, 94%) as a colourless o i l ; i r (f i l m ) : 1460, 1250, 1090, 840 cm"1; 1H nmr (400 MHz, CDC13) 6: 0.00 (s, 6H, -SiMe 2f-Bu), 0.87 (s, 9H, -SiMe 2f-Bu), 0.99 (d, 3H, J=S Hz, secondary methyl), 1.13 (m, 1H), 1.31 (m, 1H), 1.45 (m, 1H), 1.55-1.70 (m, 3H), 1.98-2.13 (m, 3H), 2.20 (m, 1H), 2.39 (m, 1H), 3.31 and 3.47 (d, d, 1H each, 7=10 Hz, -CH 20-), 5.40 (unresolved m, 1H, o l e f i n i c proton). Exact Mass calcd. for C 1 3H 2 3OSi [M +-(f-Bu)]: 223.1513; found: 223.1522. 169 Preparation of Compounds 128 and 135 Following general procedure 5, a solution of 134 (195 mg, 0.38 mmol) in 3 mL of dry THF was treated with HMPA (211 mg, 1.14 mmol) and a solution of methyllithium (0.59 mL, 0.57 mmol) in ether. Normal workup provided the crude product which was subjected to column chromatography on s i l v e r n i t r a t e impregnated s i l i c a gel [1:4 (by weight) s i l v e r n i t r a t e - s i l i c a gel, elution with 1:19 ether-petroleum ether]. The fractions containing the less polar product 128 were combined. Removal of the solvent under reduced pressure, followed by d i s t i l l a t i o n (air-bath temperature 90-100°C/0.1' Torr) of the material thus obtained, gave 128 (64.4 mg, 61%) as a colourless o i l ; i r ( f i l m ) : 1460, 1260, 1100, 850 cm"1; 1H nmr (80 MHz, CDC13) 6: 0.05 (s, 6H, -SiMe 2*-Bu), 0.92 (s, 9H, -SiMe 2t-Bu), 1.00-1.68 (m, 6H) , 1.95-2.45 (m, 6H), 3.35 and 3.60 (d, d, 1H each, 7=10 Hz, -CH 20-), 5.30 (unresolved m, 1H, o l e f i n i c proton). Exact Mass calcd. for C 1 2 H 2 1 O S i [M +-(r-Bu)]: 209.1362; found: 209.1360. Concentration of the fractions containing the more polar product 135 , followed by d i s t i l l a t i o n (air-bath 170 temperature 90-1000C/0.1 Torr) of the residual material afforded 135 (7.7 mg, 7%) as a colourless o i l ; i r ( f i l m ) : 1630, 1250, 1100, 840 cm"1; 1H nmr (80 MHz, CDC13) 6: 0.00 (s, 6H, -SiMe 2r-Bu), 0.87 (s, 9H, -SiMe 2f-Bu), 1.36-1.68 (m, 4H), 1.80-2.50 (broad diffuse m, 4H), 3.38 (s, 2H, -CH 20~), 4.80-5.15 (m, 2H, terminal o l e f i n i c protons), 5.38-5.60 (m, 1H, o l e f i n i c proton), 5.60-5.90 (m, 2H, o l e f i n i c protons). Exact Mass calcd. for C 1 2 H 2 1 O S i [M +-(?-Bu)]: 209.1362; found: 209.1361. Preparation of Compound 142 ^ O M e Following general procedure 5, a solution of 141 (61 mg, 0.14 mmol) in 2 mL of dry THF was treated with HMPA (79 mg, 0.43 mmol) and a solution of methyllithium (0.15 mL, 0.22 mmol) in ether. Normal workup provided the crude product which was subjected to fl a s h column chromatography (elution with 1:6 dichloromethane-petroleum ether). The material thus obtained was d i s t i l l e d (air-bath temperature 105-115°C/0.1 Torr) to give 142 (14 mg, 54%) as a colourless o i l ; i r ( f i l m ) : 1440, 1110 cm"1; 1H nmr (80 MHz, CDC13) 6: 1.00-2.51 (broad di f f u s e m, 14H), 3.15 (broad s, 2H, 171 -CH2C~), 3.30 (s, 3H, -OMe), 5.43 (unresolved m, 1H, o l e f i n i c proton). Exact Mass calcd. for C i 2 H 2 0 0 : 180.1514; found: 180.1517. Preparation of Compounds 139 and 140 Following general procedure 5, a solution of 138 (76 mg, 0.15 mmol) in 2 mL of dry THF was treated with HMPA (78.0 mg, 0.45 mmol) and a solution of methyllithium (0.15 mL, 0.23 mmol) in ether. Normal workup provided the crude product which was subjected to column chromatography (elution with heptane). D i s t i l l a t i o n (air-bath temperature 95-105oC/0.1 Torr) of the material thus obtained gave 139 (14.2 mg, 35%) as a colourless o i l . To obtain 1 4 0 , the column was eluted with ether and the eluate was concentrated under reduced pressure. The residual material was subjected to column chromatography (elution with 3:7 ether-petroleum ether) and the substance thus obtained was d i s t i l l e d (air-bath temperature 110-120°C/0.1 Torr) to give the alcohol 140 (9 mg, 17%) as a colourless o i l . Compound 139 displayed i r ( f i l m ) : 1450, 1250, 1100, 850 cm"1; 1H nmr (80 MHz, CDC13) 5: 0.02 (s, 6H, -SiMe 2f-Bu), 139 HO 172 0.91 (s, 9H, -SiMe 2«-Bu),- 1.00-2.60 (broad di f f u s e m, 14H), 3.38 (broad s, 2H, -CH 20-), 5.40 (unresolved m, 1H, o l e f i n i c proton). Exact Mass calcd. for C, 3H 2 3OSi [M +-(«-Bu)]: 223.1518; found: 223.1524. Compound 140 exhibited i r ( f i l m ) : 3370, 1460, 1260, 1020, 840 cm-1; 1H nmr (80 MHz, CDC13) 8: 0.13 (s, 6H, -SiMe 2r-Bu), 0.93 (s, 9H, -SiMe 2?-Bu), 1.10-2.10 (broad dif f u s e m, 11H), 2.20-2.60 (m, 2H, a l l y l i c protons), 3.25-3.60 (4H, -CH20- and -CH 2Br), 6.28 (t, 1H, 7=4 Hz, o l e f i n i c proton). Exact Mass calcd. for C, 3H 2„0 7 9BrSi [M +-(r-Bu)]: 303.0780; found: 303.0783. 1 73 Preparation of the Alkylating Agent 178 0 / - ~ \ ^ S i M e 3 To a cold (-10°C), s t i r r e d solution of 2-(trimethyl-s i l y l ) e t h a n o l (9.30 g, 78.8 mmol) was added acro l e i n (4.41 g, 78.8 mmol). Dry hydrogen chloride was passed into the above solution at -10°C u n t i l the required amount (5.80 g, 158 mmol) of hydrogen chloride had been added. The resultant mixture was dil u t e d with dichloromethane (^35 mL) and then was dried over anhydrous magnesium sulphate. Removal of the solvent under reduced pressure, followed by d i s t i l l a t i o n (air-bath temperature 90-1000C/0.1 Torr) of the o i l thus obtained, gave 178 (14.1 g, 78%) as a colourless o i l . This substance displayed i r ( f i l m ) : 1250, 1120, 840 cm"1; 1H nmr (80 MHz, CDC13) 6: 0.06 (s, 9H, -SiMe 3), 1.00 (m, 2H, -CH 2SiMe 3), 2.45 (m, 2H, -CH 2CH 2C1), 3.50-4.10 (m, 4H, -CH20- and -CH 2C1), 5.80 (t, 1H, /=5 Hz, -OCHC1-). E x a c t Mass calcd. for C 6H,„0 3 5ClSi (M +-CH 2CH 2 3 5C1): 165.0502; found: 165.0504. 174 P r e p a r a t i o n Compounds 1 7 9 and 1 8 3 To a c o l d (0°C), s t i r r e d s o l u t i o n o f LDA (1.04 mmol) i n 11 mL o f d r y THF was a d d e d HMPA (2.08 mmol) a n d t h e r e s u l t a n t y e l l o w s o l u t i o n was c o o l e d t o -48°C. A s o l u t i o n o f t h e e n o a t e 5 4 (220 mg, 0.69 mmol) i n 2 mL o f d r y THF was i n t r o d u c e d i n t o t h e ab o v e s o l u t i o n a n d s t i r r i n g was c o n t i n u e d f o r 40 m i n u t e s a t -48°C. The r e s u l t a n t m i x t u r e was c o o l e d t o -78°C a n d t h e a l k y l a t i n g a g e n t 1 7 8 (318 mg, 1.39 mmol) was a d d e d . A f t e r t h e r e a c t i o n m i x t u r e h a d been s t i r r e d f o r 40 m i n u t e s a t -78°C, s a t u r a t e d a q u e o u s ammonium c h l o r i d e (=2 mL) was a d d e d a n d t h e m i x t u r e was a l l o w e d t o warm t o 25°C. The r e s u l t a n t y e l l o w s o l u t i o n was d i l u t e d w i t h w a t e r (=35 mL) and t h e n was e x t r a c t e d w i t h e t h e r ( 3 x 3 5 mL). The c o m b i n e d o r g a n i c e x t r a c t was washed s u c c e s s i v e l y w i t h s a t u r a t e d a q u e o u s c o p p e r s u l p h a t e , w a t e r , a n d b r i n e , and t h e n was d r i e d (MgSOi,). R emoval o f t h e s o l v e n t u n d e r r e d u c e d p r e s s u r e p r o v i d e d t h e c r u d e p r o d u c t . T i c a n a l y s i s o f t h e c r u d e p r o d u c t i n d i c a t e d t h e p r e s e n c e o f two m a j o r c o m p o n e n t s a nd a number o f m i n o r s i d e p r o d u c t s . The c r u d e p r o d u c t m i x t u r e was s u b j e c t e d t o f l a s h c o l u m n c h r o m a t o g r a p h y ( e l u t i o n w i t h 1:19 e t h e r - p e t r o l e u m 175 ether). The fractions containing one of the major products (179), which had the lower mobility on s i l i c a gel, were combined. Removal of the solvent under reduced pressure, followed by d i s t i l l a t i o n (air-bath temperature 150-160°C/0.1 Torr) of the material thus obtained, afforded 179 (145 mg, 41%) as a colourless o i l . Compound 179 exhibited i r ( f i l m ) : 1725, 1250, 1070, 840, 770 cm'1; 1H nmr (400 MHz, CDC13) 6: 0.00 (s, 9H, -SiMe 3), 0.12 (s, 9H, J S n_ H=54 Hz, -SnMe3), 0.90 (d of d, J=9.5 and 8 Hz, -CH 2SiMe 3), 0.96 (d, 3H, J=l Hz, secondary methyl), 1.60 (m, 1H), 1.72 (m, 1H), 1.90-2.16 (m, 5H), 3.48 (m, 1H), 3.56-3.76 (m, 3H), 3.66 (s, 3H, -COOMe), 3.86 (d of d, 1H, 7=10 and 3 Hz), 5.97 (t, 1H, /=4 Hz, o l e f i n i c proton). Exact Mass calcd. for C , 9 H 3 6 0 3 3 5 C l S i S n (M*-Me): 495.1144; found: 495.1138. Fractions containing the other major product (presumably 180), which had the higher mobility on s i l i c a gel, were found to be contaminated with unwanted side products. These fractions were combined and the solvent was evaporated under reduced pressure. D i s t i l l a t i o n (air-bath temperature 150-160°C/0.1 Torr) of the resultant material provided a mixture (54 mg) containing mainly 180, as a colourless o i l . A solution of t h i s mixture (54 mg) in 2 mL of dry ether was treated with a solution of d i i s o b u t y l -aluminum hydride (0.63 mL, 0.63 mmol) in hexanes and the solution was s t i r r e d for 3 hours at 25°C. Saturated aqueous ammonium chloride (=0.5 mL) and petroleum ether (7 mL) were added and the mixture was s t i r r e d u n t i l p r e c i p i t a t i o n of the 176 aluminum s a l t s was complete. The inorganic s a l t s were removed by f i l t r a t i o n of the mixture through a plug of sand. The f i l t r a t e was dried (MgSO„) and concentrated under reduced pressure. The material thus, obtained was d i s t i l l e d (air-bath temperature 150-160°C/0.1 Torr) to give a colourless o i l (36.5 mg). To a s t i r r e d solution of t h i s colourless o i l (36.5 mg) in 1 mL of dry dichloromethane at 25°C was added 2,6-lutidine (24 mg, 0.22 mmol) and iert-butyldimethylsilyl trifluoromethanesulphonate (37 mg, 0.14 mmol). After the resultant mixture had been s t i r r e d for 30 minutes at 25°C, saturated aqueous sodium bicarbonate (0.5 mL) and ether (12 mL) were added. The mixture was washed with water and brine, and then was dried (MgSOa). Removal of the solvent under reduced pressure provided the crude product. Subjection of the crude product to flas h column chromatography (elution with petroleum ether) and d i s t i l l a t i o n (air-bath temperature 160-170°C/0.1 Torr) of the material thus obtained gave compound 183 (39.2 mg, 9% o v e r a l l y i e l d from 54) as a colourless o i l . Compound 183 displayed i r ( f i l m ) : 1470, 1260, 1080, 850, 770 cm'1; 1H nmr (400 MHz, CDC13) 6: 0.02 (s, 9H, -SiMe 3), 0.05 (s, 9H, ^sn-H = 5 2 H z ' _SnMe 3), 0.06 and 0.08 (s, s, 3H each, -SiMe2<-Bu), 0.91 (s, 9H, -SiMe 2r-Bu), 1.02 (d, 3H, J=l Hz, secondary methyl), 0.96-1.09 (m, 2H), 1.48 (m, 1H), 1.56-1.70 (m, 2H), 1.72-1.81 (m, 1H), 1.92-2.01 (m, 1H), ,2.11 (m, 2H), 3.55 (m, 1H), 3.58 (s, 2H, -CH 2OSiMe 2«-Bu), 3.67 (m, 2H), 3.75-3.85 (m, 1H), 4.01 (d of 177 d, 1H, 7=9.5 and 3.5 Hz, -CHOCH2-), 6.04 (t, 1H, /=4 Hz, o l e f i n i c proton). Exact Mass calcd. for C 2 5 H 5 3 0 2 3 5 C l S i 2 S n (M*-Me): 581.2060; found: 581.2065. Preparation of the Alcohol 181 To a s t i r r e d solution of 181 (145 mg, 0.285 mmol) in 3 mL of dry ether at 25°C was added a solution of d i i s o b u t y l -aluminum hydride (1.71 mL, 1.71 mmol) in hexanes. After the reaction mixture had been s t i r r e d for 3 hours at 25°C, saturated aqueous ammonium chloride (=*1 mL) and petroleum ether (10 mL) were introduced and s t i r r i n g was then continued u n t i l p r e c i p i t a t i o n of the aluminum s a l t s was complete. The inorganic s a l t s were removed by f i l t e r i n g the mixture through a plug of sand. The f i l t r a t e was dried over anhydrous magnesium sulphate. Removal of the solvent under reduced pressure, followed by d i s t i l l a t i o n (air-bath temperature 150-160°C/0.1 Torr) of the substance thus obtained, provided the alcohol 181 (109 mg, 81%) as a colourless o i l ; i r ( f i l m ) : 3380, 1260, 1180, 1060, 840, 770 cm"1; 1H nmr (400 MHz, CDC13) 6: 0.03 (s, 9H, -SiMe 3), 0.18 (s, 9H, / S n_ H=52 Hz, -SnMe3), 0.98 (t, 2H, J=9 Hz, 178 -CH 2SiMe 3), 1.09 (d, 3H, 7=7 Hz, secondary methyl), 1.52 (m, 2H, one of these protons exchanged with D 20), 1.66 (m, 1H), 1.82-2.06 (m, 3H), 2.11 (m, 2H), 3.55 [d of d, 7=10.5 and 8 Hz, collapsed to a doublet (7=10.5 Hz) on addition of D 20, -CHOH], 3.59-3.75 (m, 5H), 3.85 [d of d, 7=10.5 and 8 Hz, collapsed to a doublet (7=10.5 Hz) on addition of D 20, -CHOH], 6.17 (t, 1H, 7=4 Hz, o l e f i n i c proton). Exact Mass calcd. for C , B H 3 6 0 2 3 5 C 1 2 S i S n (M*-Me): 467.1195; found: 467.1195. Preparation of the S i l y l Ether 182 To a s t i r r e d solution of the alcohol 181 (109 mg, 0.23 mmol) in 1.5 mL of dry dichloromethane at 25°C was added 2,6-lutidine (69 mg, 0.54 mmol) and tert-butyldimethylsilyl trifluoromethanesulphonate (108 mg, 0.41 mmol). After the reaction mixture had been s t i r r e d for 30 minutes at 25°C, saturated aqueous sodium bicarbonate (=0.5 mL) and ether (12 mL) were added. The resultant mixture was washed with water and brine, and then was dried (MgSO,,). Removal of the solvent under reduced pressure provided the crude product which was subjected to fl a s h column chromatography (elution 179 with 1:19 dichloromethane-petroleum ether). D i s t i l l a t i o n (air-bath temperature 160-170°C/0.1 Torr) of the resultant o i l afforded the s i l y l ether 182 (115 mg, 85%) as a colourless o i l ; i r ( f i l m ) : 1250, 1070, 840, 770 cm"1; nmr (400 MHz, CDCl 3) 8: 0.02 (s, 9H, -SiMe 3), 0.04 and 0.06 (s, s, 3H each, -SiMe 2f-Bu), 0.16 (s, 9H, 7 S n_ H=52 Hz, -SnMe3), 0.89 (s, 9H, -SiMe 2«-Bu), 0.90-1.00 (m, 2H), 1.04 (d, 3H, 7=7 Hz, secondary methyl), 1.60 (m, 2H), 1.92 (m, 1H), 1.99 (m, 2H), 2.06 (m, 2H), 3.39 (d, 1H, 7=9.5 Hz, -CHOSiMe2f-Bu), 3.43-3.64 (m, 4H), 3.68 (m, 1H), 4.03 (d, 1H, 7=9.5 Hz, -CHOSiMe2f-Bu), 5.92 (t, 1H, 7=4 Hz, o l e f i n i c proton). Exact Mass calcd. for C 2 5 H 5 3 0 2 3 5 C l S i 2 S n (M+-Me): 581.2060; found: 581.2075. Preparation of Compound 184 Following general procedure 5, a solution of 113 (3.14 g, 5.73 mmol) in 20 mL of dry THF was treated with HMPA (3.09 g, 17.2 mmol) and a solution of methyllithium (6.52 mL, 8.60 mmol) in ether. Normal workup provided the crude product which was subjected to flas h column chromatography (elution with 1:9 dichloromethane-petroleum ether). The 180 material thus obtained was d i s t i l l e d (air-bath temperature 130-140°C/0.1 Torr) to give 1 8 4 (1.94 g, 86%) as a colourless o i l ; i r ( f i l m ) : 1460, 1250, 1090, 850 cm"1; 1H nmr (400 MHz, CDC13) 8: -0.01 (s, 9H, -SiMe 3), 0.01 and 0.02 (s, s, 3H each, -SiMe 2t-Bu), 0.89 (s, 9H, -SiMe 2f-Bu), 0.88-0.95 (m, 2H), 0.98 (d, 3H, J=l Hz, secondary methyl) 1.52 (m, 1H), 1.79 (m, 2H), 1.92-2.13 (m, 4H), 2.36 (m, 2H), 3.20 and 3.57 (d, d, 1H each, /=10 Hz, -CH 2OSiMe 21-Bu) , 3.37 and 3.61 (mr m, 1H each, -OCH2CH2-), 3.94 (d, 1H, /=4 Hz, -CHOCH2-), 5.47 (unresolved m, 1H, o l e f i n i c proton). Exact Mass calcd. for C 1 8 H 3 5 0 2 S i 2 [M +-(t-Bu)]: 339.2176; found: 339.2169. Preparation of Compound 190 Following general procedure 5, a solution of 183 (1.20 g, 2.02 mmol) in 10 mL of dry THF was treated with HMPA (1.06 g, 6.06 mmol) and a solution of methyllithium (2.30 mL, 3.03 mmol) in ether. Normal workup provided the crude product, which was subjected to flash column chromatography (elution with petroleum ether). The material thus obtained was d i s t i l l e d (air-bath temperature 130-140°C/0.1 Torr) to provide compound 190 (623 mg, 78%) as a colourless o i l ; i r 181 ( f i l m ) : 1460, 1250, 1100,-860, 780 cm'1; 1H nmr (400 MHz, CDC13) 6: -0.01 and 0.01 (s, s, 3H each, -SiMe 2f-Bu), 0.02 (s, 9H, -SiMe 3), 0.86 (s, 9H, -SiMe 2/-Bu), 0.90 (m, 2H), 1.07 (d, 3H, 7=7 Hz, secondary methyl) 1.38 (m, 2H), 1.56-1.67 (m, 1H), 1.78-1.91 (m, 1H), 2.02 (m, 3H), 2.06-2.17 (m, 1H), 2.45-2.56 (m, 1H), 3.31-3.45 (m, 2H), 3.57 (m, 1H), 3.73 and 3.75 (d, d, 1H each, 7=10.5 Hz, -CH 2OSiMe 2f-Bu), 5.47 (unresolved m, 1H, o l e f i n i c proton). Exact Mass calcd. for C 1 B H 3 5 0 2 S i 2 [M +-(?-Bu)]: 339.2176; found: 339.2188. Preparation of the Alcohol 185 To a s t i r r e d solution of tetra-n-butylammonium fluoride (1.93 g, 7.37 mmol) in 3 mL of dry THF at 25°C was added a solution of 184 (1.95 g, 4.91 mmol) in 8 mL of dry THF. The resultant mixture was s t i r r e d for 18 hours at 25°C. After d i l u t i o n with ether (50 mL), the mixture was washed with water and brine, and then was dried (MgSO«). The organic layer was concentrated on a rotary evaporator and the v o l a t i l e silicon-containing by-product was removed from the crude product under reduced pressure (0.1 Torr) at 25°C. The 182 material thus obtained was d i s t i l l e d (air-bath temperature 105-115°C/0.1 Torr) to give compound 185 (1.34 g, 96%) as a colourless o i l ; i r ( f i l m ) : 3400, 1250, 1100, 850 cm"1; 1H nmr (400 MHz, C D C 1 3 ) 6: 0.00 (s, 9H, -SiMe 3), 0.90 (m, 2H, -CH 2SiMe 3), 1.00 (d, 3H, 7=7 Hz, secondary methyl), 1.17 (d of d, 1H, J=8 and 4 Hz, exchanged with D 20, -OH), 1.55 (m, 1H), 1.65 (m, 1H), 1.76-1.96 (m, 2H), 1.98-2.17 (m, 3H), 2.40 (m, 2H), 3.38 (m, 2H, s i m p l i f i e d on addition of D 20, -CHOH and -OCHCH2-), 3.50 [d of d, 1H, /=12 and 8 Hz, collapsed to a doublet (7=12 Hz) on addition of D 20, -CHOH], 3.62 (m, 1H, -OCHCH2-), 3.67 (d, 1H, /=4 Hz, -CHOCH2CH2-), 5.68 (unresolved m, 1H, o l e f i n i c proton). Exact Mass calcd. for C, 6H 2 8OSi (M +-H 20): 264.1910; found: 264.1910. Preparation of the Alcohol 191 Following the procedure employed for the preparation of compound 1 8 5 , a solution of 190 (623 mg, 1.57 mmol) in 3 mL of dry THF was treated with a solution of tetra-/?-butyl-ammonium fluoride (1.23 g, 4.71 mmol) in 2 mL of dry THF for 18 hours at 25°C. Similar workup and p u r i f i c a t i o n procedures gave the crude product which was d i s t i l l e d (air-bath 183 temperature 105-115°C/0.1 Torr) to afford the alcohol 191 (381 mg, 86%) as a colourless o i l . This material displayed i r ( f i l m ) : 3450, 1250, 840 cm'1; 1H nmr (400 MHz, CDC13) 6: 0.03 (s, 9H, -SiMe 3), 0.97 (m, 2H, -CH 2SiMe 3), 1.25 (d, 3H, 7 = 7 Hz, secondary methyl), 1.41-1.57 (m, 2H), 1.63 (m, 1H), 1.79 (m, 1H), 2.01-2.21 (m, 4H) , 2.44-2.58 (m, 1H), 3.25 (d of d, 1H, 7=8 and 4 Hz, exchanged with D 20, -OH), 3.45 (m, 1H), 3.65 (m, 2H), 3.72 [d of d, 1H, 7=12 and 8 Hz, collapsed to a doublet (7=12 Hz) on addition of D 20, -CHOH], 3.79 [d of d, 1H, 7=12 and 4 Hz, collapsed to a doublet (7=12 Hz) on addition of D 20, -CHOH], 5.45 (unresolved m, 1H, o l e f i n i c proton). Exact Mass calcd. for C 1 6 H 2 8 O S i (M +-H 20): 264.1910; found: 264.1920. Preparation of the Aldehyde 186 To a s t i r r e d solution of the alcohol 185 (300 mg, 1.06 mmol) in 18 mL of dry dichloromethane was added s o l i d pyridinium chlorochromate (573 mg, 2.66 mmol). The resultant solution-suspension was s t i r r e d for 1 hour at 25°C. Dry ether (70 mL) was added and the mixture was s t i r r e d for a further 15 minutes. The resultant mixture was f i l t e r e d 184 through a short column of neutral alumina (elution with ether). The combined f i l t r a t e was concentrated under reduced pressure and the crude product was passed through a short column of s i l i c a gel (elution with 1:1 dichloromethane-petroleum ether). Concentration of the combined eluate under reduced pressure and d i s t i l l a t i o n (air-bath temperature 95-105oC/0.1 Torr) of the material thus obtained provided the aldehyde 186 (263 mg, 88%) as a colourless o i l ; i r (f i l m ) : 1710, 1250, 840 cm"1; 1H nmr (300 MHz, CDC13) 6: 0.00 (s, 9H, -SiMe 3), 0.91 (m, 2H, -CH 2SiMe 3), 0.99 (d, 3H, J=l Hz, secondary methyl), 1.62-1.86 (m, 4H), 2.10-2.30 (m, 4H), 2.30-2.45 (m, 1H), 3.40 and 3.64 (m, m, 1H each, -OCH2CH2-), 4.18 (d, 1H, 7=4.5 Hz, ~CHOCH2-), 5.72 (unresolved m, 1H, o l e f i n i c proton). 9.76 (s, 1H, aldehydic proton). Preparation of the Aldehyde 192 Following the procedure employed for the preparation of compound 186, a solution of 191 (200 mg, 0.71 mmol) in 12 mL of dry dichloromethane was treated with pyridinium chlorochromate (382 mg, 1.77 mmol). The resultant mixture 185 was s t i r r e d for 2 hours at 25°C. Similar workup and p u r i f i c a t i o n procedures provided the aldehyde 192 (166 mg, 83%) as a colourless o i l ; i r ( f i l m ) : 1710, 1250, 860 cm"1; 1H nmr (270 MHz, CDC13) 8: 0.00 (s, 9H, -SiMe 3), 0.93 (m, 2H, -CH 2SiMe 3), 1.31 (d, 3H, 7=7 Hz, secondary methyl), 1.38-1.68 (m, 4H), 1.95-2.24 (m, 4H), 2.36-2.54 (m, 1H), 3.49 (m, 1H), 3.57-3.72 (m, 2H), 5.59 (unresolved m, 1H, o l e f i n i c proton). 9.92 (s, 1H, aldehydic proton). Preparation of Compound 187 To a s t i r r e d solution of the aldehyde 186 (260 mg, 0.93 mmol) in 3 mL of methanol was added anhydrous hydrazine (600 mg, 18.6 mmol). The resultant solution was s t i r r e d under reflux for 1 hour. This solution was concentrated under reduced pressure. The residual material was di l u t e d with benzene (3 mL). The benzene was d i s t i l l e d under reduced pressure. This procedure was repeated. The residual solvent was removed under reduced pressure (0.1 Torr) at 25°C and a viscous o i l was obtained. To a s t i r r e d solution of this o i l in 2 mL of diethyleneglycol was added sodium methoxide (150 mg, 2.78 mmol). The resultant mixture was heated at 210°C 186 for 1.8 hours. A f t e r the mixture had been c o o l e d to 25°C, water (25 mL) was i n t r o d u c e d and the r e s u l t a n t mixture was e x t r a c t e d with ether (3x20 mL). The combined e x t r a c t was washed with water and b r i n e , and then was d r i e d (MgSO„). The s o l v e n t was removed under reduced pressure and the crude product was s u b j e c t e d to f l a s h column chromatography ( e l u t i o n with 1:4 dichloromethane-petroleum e t h e r ) . The m a t e r i a l thus obtained was d i s t i l l e d ( a i r - b a t h temperature 90-100 0C/0.1 Torr) to give 187 (210 mg, 84%) as a c o l o u r l e s s o i l ; i r ( f i l m ) : 1250, 1100, 840 cm" 1; 1H nmr (400 MHz, CDC1 3) 6: -0.01 (s, 9H, - S i M e 3 ) , 0.78 (s, 3H, angular methyl), 0.87 (d, 3H, 7=7 Hz, secondary methyl), 0.90 (m, 2H, -CH 2SiMe 3), 1.35-1.50 (m, 2H), 1.71-1.91 (m, 2H), 1.93-2.15 (m, 3H), 2.25-2.50 (m, 2H), 3.35 and 3.60 (m, m, 1H each, -OCH 2CH 2-), 3.47 (d, 1H, 7=4 Hz, -CHOCH 2CH 2-), 5.38 (unresolved m, 1H, o l e f i n i c p r o t o n ) . Exact Mass c a l c d . f o r C i 6 H 3 0 O S i : 266.2066; found: 266.2062. P r e p a r a t i o n of Compound 193 To a s t i r r e d s o l u t i o n of the aldehyde 192 (159 mg, 0.57 mmol) in 1.5 mL of methanol was added anhydrous hydrazine 187 (455 mg, 14.2 mmol). The resultant solution was s t i r r e d under reflux for 1 hour. This solution was concentrated under reduced pressure. The residual material was di l u t e d with benzene (2 mL). The benzene was d i s t i l l e d under reduced pressure. This procedure was repeated. The residual solvent was removed under reduced pressure (0.1 Torr) at 25°C and a viscous o i l was obtained. To a s t i r r e d solution of this o i l in 1 mL of diethyleneglycol was added sodium methoxide (92 mg, 1.70 mmol). The resultant mixture was heated at 210°C for 1.5 hours. After the mixture had been cooled to 25°C, water (20 mL) was introduced and the resultant mixture was extracted with ether (3x15 mL). The combined extract was washed with water and brine, and then was dried (MgSO,,). Removal of the solvent under reduced pressure provided the crude product which was subjected to flash column chromatography (elution with 1:9 dichloromethane-petroleum ether). The material thus obtained was d i s t i l l e d (air-bath temperature 105-115°C/ 0.1 Torr) to give 193 (118 mg, 78%) as a colourless o i l ; i r ( f i l m ) : 1250, 1110, 840 cm - 1; 1H nmr (270 MHz, CDC13) 6: 0.00 (s, 9H, -SiMe 3), 0.82 (s, 3H, angular methyl), 0.90 (m, 2H, -CH 2SiMe 3), 0.99 (d, 3H, 7=7 Hz, secondary methyl), 1.37 (m, 3H), 1.43-1.60 (m, 1H), 1.90-2.13 (m, 4H), 2.35-2.52 (m, 1H), 3.25 (t, 1H, 7=9 Hz, -CHOCH2CH2-), 3.42 and 3.57 (m, m, 1H each, -OCH2CH2-), 5.28 (unresolved m, 1H, o l e f i n i c proton). Exact Mass calcd. for C 1 6 H 3 0 O S i : 266.2066; found: 266.2068. 188 Preparation of the Alcohol 176 To a s t i r r e d suspension of lithium f l u o r i d e (360 mg, 13.8 mmol) in 7 mL of dry a c e t o n i t r i l e was added boron t r i f l u o r i d e etherate (1.96 g, 13.8 mmol). The resultant l i g h t suspension was s t i r r e d for 5 minutes at 25°C. A solution of compound 187 (368 mg, 1.38 mmol) in 2 mL of dry dichloromethane was added to the above suspension and s t i r r i n g was continued for 2.5 hours at 25°C. Saturated aqueous sodium bicarbonate (2 mL) and water (25 mL) were added and the resultant mixture was extracted with ether (3x35 mL). The combined extract was washed with water and brine, and then was dried (MgSO„). Removal of the solvent under reduced pressure, followed by d i s t i l l a t i o n (air-bath temperature 85-95°C/0.1 Torr) of the o i l thus acquired, afforded the desired alcohol 176 (200 mg, 87%) as a colourless o i l . This material exhibited i r ( f i l m ) : 3350, 1460, 1070, 970 cm'1; 1H nmr (400 MHz, CDC13) 6: 0.80 (s, 3H, angular methyl), 0.93 (d, 3H, 7=7 Hz, secondary methyl), 1.26 (m, 1H), 1.40-1.56 (m, 2H), 1.64 (m, 1H), 1.85 (m, 1H), 1.95-2.16 (m, 3H), 2.31-2.53 (m, 2H), 3.92 (d, 1H, 7=4 Hz, -CHOH), 5.49 (unresolved m, o l e f i n i c proton). Exact Mass calcd. for C n H 1 B 0 : 166.1357; found: 166. 1 356. 189 Preparation of the Alcohol 194 To a s t i r r e d suspension of lithium f l u o r i d e (170 mg, 6.54 mmol) in 2 mL of dry a c e t o n i t r i l e was added boron t r i f l u o r i d e etherate (929 mg, 6.54 mmol). The resultant l i g h t suspension was s t i r r e d for 5 minutes at 25°C. A solution of compound 193 (116 mg, 0.44 mmol) in 0.6 mL of dry dichloromethane was introduced to the above suspension and s t i r r i n g was continued for 2.5 hours at 25°C. Saturated aqueous sodium bicarbonate (1 mL) and water (20 mL) were added and the resultant mixture was extracted with ether (4x10 mL). The combined extract was washed with water and brine, and then was dried (MgSO„). Removal of the solvent under reduced pressure gave the crude product which was subjected to flash column chromatography (elution with 3:7 ether-petroleum). The material thus obtained was d i s t i l l e d (air-bath temperature 95-105 oC/0.1 Torr) to afford the alcohol 194 (68 mg, 93%) as a colourless o i l ; i r ( f i l m ) : 3350, 1460, 1430, 1080 cm"1; 1H nmr (270 MHz, CDC13) 6 : 0.86 (s, 3H, angular methyl), 1.02 (d, 3H, J=l Hz, secondary methyl), 1.33-1.50 (m, 4H), 1.55 (m, 1H), 1.95-2.20 (m, 4H), 2.36-2.52 (m, 1H), 3.73 (t, 1H, J=9 Hz, -CHOH), 5.33 (unresolved m, 1H, o l e f i n i c proton). Exact Mass calcd. for 190 C,,H,,0: 166.1357; found: 166.1361. Preparation of the Ketone 162 from Compound 176 To a solution of the alcohol 176 (125 mg, 0.75 mmol) in 7 mL of dry dichloromethane was added s o l i d pyridinium chlorochromate (325 mg, 1.51 mmol). The resultant solution-suspension was s t i r r e d for 1 hour at 25°C. Dry ether (25 mL) was added to the mixture and s t i r r i n g was continued for a further 15 minutes. The mixture was f i l t e r e d through a plug of neutral alumina (elution with ether). The combined f i l t r a t e was concentrated under reduced pressure and the crude product was subjected to flash column chromatography (elution with 1:2 dichloromethane-petroleum ether). D i s t i l l a t i o n (air-bath temperature 85-95°C/0.1 Torr) of the material thus acquired gave the desired ketone 162 (102 mg, 83%) as a colourless o i l ; i r ( f i l m ) : 1735, 1460, 1030 cm'1; 1H nmr (270 MHz, CDC13) 6: 1.02 (s, 3H, angular methyl), 1.14 (d, 3H, J=7 Hz, secondary methyl), 1.35-1.64 (m, 3H), 2.05 (m, 2H), 2.10-2.25 (m, 1H), 2.40-2.52 (m, 2H), 2.56-2.71 (m, 1H), 5.55 (unresolved m, 1H, o l e f i n i c proton). Exact Mass calcd. for C H ^ O : 164. 1200; found: 164.1200. 191 Preparation of the Ketone 162 from Compound 194 To a s t i r r e d solution of the alcohol 194 (64 mg, 0.39 mmol) in 4 mL of dry dichloromethane was added s o l i d pyridinium chlorochromate (166 mg, 0.77 mmol). The resultant solution-suspension was s t i r r e d for 1.25 hours at 25°C. Dry ether (20 mL) was added to the above mixture and s t i r r i n g was continued for a further 15 minutes. The resultant mixture was f i l t e r e d through a plug of neutral alumina (elution with ether). The combined f i l t r a t e was concentrated under reduced pressure and the crude product was subjected to flash column chromatography (elution with 1:2 dichloro-methane-petroleum ether). D i s t i l l a t i o n (air-bath temperature 85-95°C/0.1 Torr) of the material thus acquired afforded the desired ketone 162 (51 mg, 80%) as a colourless o i l . This material was found to be i d e n t i c a l in every respect with the oxidation product derived from compound 176. 1 92 Preparation of (±)-Chiloscyphone (151) and {±)-6-epi-Chiloscyphone (203) 151 203 To a s t i r r e d solution of (methoxymethyl)triphenylphos-phonium chloride (732 mg, 2.14 mmol) in 4 mL of dry benzene was added a solution of sodium t ert -amylate (1.78 mL, 2.14 mmol) in benzene. The dark red solution was s t i r r e d for 10 minutes at 25°C. A solution of the ketone 162 (50 mg, 0.31 mmol) in 1 mL of dry benzene was introduced and the reaction mixture was s t i r r e d for 1.5 hours at 25°C. Dropwise addition of water (0.5 mL) to the reaction mixture led to the formation of a yellow suspension which was f i l t e r e d through a plug of s i l i c a gel (elution with ether). The f i l t r a t e was concentrated under reduced pressure and the crude product was dissolved in 2.5 mL of THF. To thi s solution was added 1 mL of 1M hydrochloric acid and the resultant solution was s t i r r e d for 34 hours at 25°C. Ether (25 mL) was added and the mixture was washed successively with saturated aqueous sodium bicarbonate, water and brine. The organic layer was dried over anhydrous magnesium sulphate. The solvent was evaporated under reduced pressure and the crude product was 193 subjected to flash column, chromatography (elution with 1:2 dichloromethane-petroleum ether) to give a mixture (23.5 mg, 43%) of the aldehydes 161 and 200 in a r a t i o of 1:4, respectively ( c a p i l l a r y g l c ) . 1 6 1 2 0 0 To a s t i r r e d solution of the above mixture (161 and 200) in 1 mL of dry methanol was added sodium methoxide (21 mg, 0.39 mmol). After t h i s solution had been s t i r r e d for 50 minutes at 25°C, c a p i l l a r y glc analysis of an aliquot indicated that the aldehydes 161 and 200 were present in a ra t i o of 1:1. Further treatment of this mixture with sodium methoxide and prolonging the reaction period did not change thi s r a t i o . Saturated aqueous ammonium chloride (10 mL) was added and the resultant mixture was extracted with ether (3x8 mL). The combined extract was washed with water and brine, and then was dried (MgSOi,). Removal of the solvent under reduced pressure provided the crude product mixture which was f i l t e r e d through a short column of s i l i c a gel (elution with 1:2 dichloromethane-petroleum ether) to afford the aldehydes 161 and 200 (21.4 mg, 40% y i e l d based on 162) as a 1:1 mixture ( c a p i l l a r y g l c ) . This mixture displayed i r (f i l m ) : 2710, 1720, 1460, 1380 cm"1. Exact Mass calcd. for C 1 2H l 80: 178.1358; found: 178.1361. 194 To a s t i r r e d solution of a 1:1 mixture of the aldehydes 161 and 200 (21.4 mg, 0.12 mmol) in 1 mL of dry THF at 25°C was added, dropwise, a solution of isopropenylmagnesium bromide (0.33 mL, 0.48 mmol) in dry THF. After the reaction mixture had been s t i r r e d for 1 hour at 25°C, saturated aqueous ammonium chloride (1.5 mL) was slowly introduced. The resultant mixture was dil u t e d with water (10 mL) and then was extracted with ether (3x10 mL). The combined extract was washed with water and brine, and then was dried (MgSOa). Removal of the solvent under reduced pressure provided the crude product which was shown ( c a p i l l a r y glc) to be a 1:1 mixture of two products (presumably 201 and 2 0 2 ) . Subjection of the crude product mixture to column chromatography (elution with 1:9 ether-petroleum ether) gave 8.7 mg (33%) of the less polar component (201) and 11.1 mg (42%) of the more polar component ( 2 0 2 ) . The i r spectrum of each of these compounds showed absorptions at 3450, 1640 and 900 cm"1. To a solution of the less polar alcohol (201) (8.5 mg, 0.039 mmol) in 1 mL of dry dichloromethane was added s o l i d pyridinium chlorochromate (17 mg, 0.077 mmol). The resultant 2 0 1 2 0 2 195 s o l u t i o n - s u s p e n s i o n was s t i r r e d f o r 2.25 hours a t 25°C. Dry e t h e r (7 mL) was added and the r e s u l t a n t m i x t u r e was s t i r r e d f o r a f u r t h e r 15 m i n u t e s . The m i x t u r e was f i l t e r e d t h r o u g h a p l u g of n e u t r a l a l u m i n a ( e l u t i o n w i t h e t h e r ) and the f i l t r a t e was c o n c e n t r a t e d under reduced p r e s s u r e . The crude p r o d u c t o b t a i n e d was s u b j e c t e d t o column chromatography ( e l u t i o n w i t h 1:4 d i c h l o r o m e t h a n e - p e t r o l e u m e t h e r ) . D i s t i l l a t i o n ( a i r - b a t h temperature 85-95°C/0.1 T o r r ) of the m a t e r i a l thus a c q u i r e d p r o v i d e d (±)-chiloscyphone (151) (5 mg, 59%) as a c o l o u r l e s s o i l . (±)-Chiloscyphone d i s p l a y e d i r ( f i l m ) : 1670, 1630, 1450, 1370, 1080 cm' 1; 1H nmr (400 MHz, CDC131 6: 0.85 (d, 3H, 7=6 Hz, secondary m e t h y l ) , 0.97 ( s , 3H, a n g u l a r m e t h y l ) , 1.33-1.46 (m, 3H), 1.64-1.76 (m, 1H), 1.85 (broad s, 3H, v i n y l m e t h y l ) , 1.90-2.02 (m, 2H), 2.02-2.15 (m, 1H), 2.53 (m, 2H), 3.58 (d of d, 7=8 and 1.3 Hz, -CHC=0), 5.41 (m, 1H, o l e f i n i c r i n g p r o t o n ) , 5.73 and 5.94 ( s , s, 1H each, t e r m i n a l o l e f i n i c p r o t o n s ) . Exact Mass c a l c d . f o r C 1 5 H 2 2 0 : 218.1670; found: .218.1671. To a s t i r r e d s o l u t i o n of the more p o l a r a l c o h o l (202) (6.0 mg, 0.027 mmol) i n 1.5 mL of d r y d i c h l o r o m e t h a n e was added s o l i d p y r i d i n i u m c h l o r o c h r o m a t e (12 mg, 0.054 mmol). The r e s u l t a n t s o l u t i o n - s u s p e n s i o n was s t i r r e d f o r 2 hours a t 25°C. Dry e t h e r (7 mL) was i n t r o d u c e d and the r e s u l t a n t m i x t u r e was s t i r r e d f o r a f u r t h e r 15 m i n u t e s . The m i x t u r e was f i l t e r e d t h r ough a p l u g of n e u t r a l a l u m i n a ( e l u t i o n w i t h e t h e r ) and the f i l t r a t e was c o n c e n t r a t e d under reduced p r e s s u r e . The crude p r o d u c t o b t a i n e d was s u b j e c t e d t o column 196 chromatography ( e l u t i o n w i t h 1:19 e t h e r - p e t r o l e u m e t h e r ) . D i s t i l l a t i o n ( a i r - b a t h temperature 80-90°C/0.1 T o r r ) of the m a t e r i a l thus o b t a i n e d p r o v i d e d (±)-6-epi-chiloscyphone (203) (2 mg, 34%) as a c o l o u r l e s s o i l . T h i s compound e x h i b i t e d i r ( f i l m ) : 1670, 1630, 1460, 1390, 1090 cm" 1; 1H nmr (270 MHz, CDC1 3) 6: 0.72 ( d , 3H, 7=6 Hz, secondary m e t h y l ) , 0.90 ( s , 3H, a n g u l a r m e t h y l ) , 1.43 (m, 3H), 1.70-1.85 (m, 1H), 1.91 (broad s, 3H, v i n y l m e t h y l ) , 1.95-2.08 (m, 3H), 2.12-2.32 (m, 1H), 2.48-2.65 (m, 1H), 3.18 (d of d, 1H, 7=12 and 8 Hz, -CHOO) , 5.30 (m, 1H, o l e f i n i c r i n g p r o t o n ) , 5.72 and 5.97 ( s , s, 1H each, t e r m i n a l o l e f i n i c p r o t o n s ) . E x a c t Mass c a l c d . f o r C 1 5 H 2 2 0 : 218.1670; found: 218.1670. 197 Preparation of the Dibromide 223 To a cold (0°C), s t i r r e d solution of cyclopropane-1,1-dicarboxylic acid^ (3) (7.27 g, 55.9 mmol) in 90 mL of dry THF was added, slowly, borane-dimethylsulphide complex (14.5 mL, 145 mmol). The resultant mixture was allowed to warm to 25°C and was s t i r r e d for 5.5 hours. After the mixture had been cooled to 0°C, water (2 mL) was introduced slowly to quench the excess hydride. Aqueous 1OM sodium hydroxide (6 mL) was added dropwise to the vigorously s t i r r e d mixture. A small amount of water was also added so that proper s t i r r i n g could be maintained. The resultant mixture was then s t i r r e d overnight. The aqueous phase was separated and saturated with potassium carbonate, and then was extracted with THF (3x60 mL). The combined organic phase was dried over anhydrous potassium carbonate. The solvent was removed under reduced pressure to give the crude product which was subjected to flash column chromatography (elution with 3:7 acetone-ether). The material thus obtained was d i s t i l l e d (air-bath temperature 90-1000C/0.1 Torr) to provide the d i o l 224 (2.81 g, 49%) as a colourless l i q u i d ; 1 09 1H nmr (60 MHz, CDC13) 6: 0.53 (s, 4H, cyclopropyl ring protons), 3.08 (s, 2H, hydroxyl protons), 3.60 (s, 4H, 198 methylene protons). To a cold (0°C), s t i r r e d solution of triphenylphosphine (27.0 g, 103 mmol) in 150 mL of dry dichloromethane was added, slowly, bromine (5.28 mL, 103 mmol). After the mixture had been s t i r r e d for 10 minutes at 0°C, a solution of the d i o l 224 (5.00 g, 49.0 mmol) in 38 mL of dry dichloromethane was introduced over a period of 10 minutes. The reaction mixture was s t i r r e d for 1 hour at 0°C. Saturated aqueous sodium carbonate (100 mL) was added and the mixture was s t i r r e d for 30 minutes at 25°C. The organic layer was separated and washed with 50 mL of saturated aqueous sodium carbonate, and then was dried (MgSO„). Upon removal of the solvent under reduced pressure, a large amount of white pre c i p i t a t e was formed. Petroleum ether (150 mL) was added to the residual material and the pr e c i p i t a t e was removed by suction f i l t r a t i o n . When the f i l t r a t e was concentrated under reduced pressure, more white p r e c i p i t a t e was obtained. Petroleum ether (100 mL) was added to the residual material and the pr e c i p i t a t e was removed by suction f i l t r a t i o n . The f i l t r a t e was concentrated under reduced pressure and the crude product was passed through a short column of s i l i c a gel (elution with petroleum ether). 199 C o n c e n t r a t i o n of the combined e l u a t e , followed by d i s t i l l a t i o n " (105-115°C/25 T o r r ) of the m a t e r i a l thus obtained, gave the dibromide 225 (9.50 g, 85%) as a c o l o u r l e s s o i l ; 1H n m r 1 1 1 b (60 MHz, CDC1 3) 6: 0.98 (s, 4H, c y c l o p r o p y l r i n g p r o t o n s ) , 3.51 (s, 4H, methylene p r o t o n s ) . To a c o l d (0°C), s t i r r e d s o l u t i o n - s u s p e n s i o n of anhydrous z i n c bromide (12.7 g, 56.4 mmol) i n 25 mL of dry ether was added a s o l u t i o n of the dibromide 225 (9.00 g, 39.5 mmol) i n 17 mL of dry et h e r . A f t e r the mixture had been s t i r r e d f o r 47 hours at 25°C, an a d d i t i o n a l 8.89 g (39.5 mmol) of anhydrous z i n c bromide was introduced and s t i r r i n g was continued f o r another 9 hours. Ether (50 mL) and pentane (50 mL) were added and the mixture was washed with water and s a t u r a t e d aqueous sodium b i c a r b o n a t e , and then was d r i e d (MgSO„). The organic l a y e r was conc e n t r a t e d slowly under reduced pressure and the crude product was passed through a short column of s i l i c a g e l ( e l u t i o n with pentane). Removal of the s o l v e n t , f o l l o w e d by d i s t i l l a t i o n ( a i r - b a t h temperature 105-1l5°C/25 Torr) of the m a t e r i a l thus obtained gave the d e s i r e d product 223 (7.53 g, 84%) as a c o l o u r l e s s o i l ; i r ( f i l m ) : 1640, 1430, 1260, 1210, 920 cm" 1; 1H nmr (270 MHz, CDC1 3) 5: 2.80 ( t , 2H, 7=8 Hz, -CH 2CH 2Br), 3.53 200 ( t , 2H, 7=8 Hz, -CH 2CH 2Br), 3.99 (s, 2H, =CCH 2Br), 5.06 and 5.32 (s, s, 1H each, o l e f i n i c p r o t o n s ) . Exact Mass c a l c d . f o r C 5 H 8 7 9 B r ( M + - 7 9 B r ) : 146.9809; found: 146.9815. P r e p a r a t i o n of Compound 226 F o l l o w i n g general procedure 2, a s o l u t i o n of LDA (2.46 mmol) and HMPA (4.91 mmol) in 20 mL of dry THF was t r e a t e d with a s o l u t i o n of the enoate 54 (600 mg, 1.89 mmol) i n 6 mL of dry THF. The mixture was s t i r r e d f o r 45 minutes at -48°C. The r e s u l t a n t s o l u t i o n was c o o l e d to -78°C and a s o l u t i o n of the a l k y l a t i n g agent 223 i n 4 mL of dry THF was in t r o d u c e d . A f t e r the mixture had been s t i r r e d f o r 1 hour at -78°C, s a t u r a t e d aqueous ammonium c h l o r i d e (=1 mL) was added. Normal workup, fo l l o w e d by f l a s h column chromatography ( e l u t i o n with 1:4 benzene-petroleum ether) of the crude product and d i s t i l l a t i o n ( a i r - b a t h temperature 145-155°C/0.1 T o r r ) of the m a t e r i a l thus obtained, gave 226 (774 mg, 88%) as a c o l o u r l e s s o i l ; i r ( f i l m ) : 1715, 1640, 1430, 1200, 770 cm" 1; 1H nmr (270 MHz, CDC1 3) 6: 0.06 (s, 9H, 7 S n_ H=54 Hz, -SnMe 3), 0.82 (d, 3H, 7=7 Hz, secondary methyl), 1.57 ( q u i n t e t , 1H, 7=7 Hz), 1.80 (m, 1H), 2.09 (m, 3H), 2.42-2.60 201 (m, 4H), 3.40 ( t , 2H, 7=8 Hz, -CH 2Br), 3.66 (s, 3H, -COOMe), 4.82 and 4.92 (broad s, broad s, 1H each, t e r m i n a l o l e f i n i c p r o t o n s ) , 5.95 ( t , 1H, 7=4 Hz, o l e f i n i c p r o t o n ) . Exact Mass c a l c d . f o r C , 6 H 2 6 0 2 7 9 B r S n (M*-Me): 449.0139; found: 449.0130. P r e p a r a t i o n of the A l c o h o l 227 To a c o l d (0°C), s t i r r e d s o l u t i o n of 226 (774 mg, 1.67 mmol) i n 15 mL of dry ether was added a s o l u t i o n of diis o b u t y l a l u m i n u m hydride (5 mL, 5.00 mmol) in hexanes. The r e s u l t a n t mixture was s t i r r e d f o r 2 hours at 0°C. Saturated aqueous ammonium c h l o r i d e (-1 mL) and petroleum ether (20 mL) were added and the mixture was s t i r r e d at 25°C u n t i l p r e c i p i t a t i o n of the aluminum s a l t s was complete. The i n o r g a n i c s a l t s were removed by s u c t i o n f i l t r a t i o n . The f i l t r a t e was concentrated under reduced pressure and the crude product was sub j e c t e d to f l a s h column chromatography ( e l u t i o n with 1:9 ether-petroleum e t h e r ) . The m a t e r i a l thus obtained was d i s t i l l e d ( a i r - b a t h temperature 150-160°C/0.1 To r r ) to provide the a l c o h o l 227 (682 mg, 94%) as a c o l o u r l e s s o i l ; i r ( f i l m ) : 3450, 1640, 1040, 770 cm" 1; 'H 202 nmr' (270 MHz, CDC13) 8: 0.14 (s, 9H, ^sn-H=54 H z ' ~SnMe3), 0.92 (d, 3H, 7=7 Hz, secondary methyl), 1.26 (d of d, 1H, 7=8 and 3 Hz, exchanged with D 20, -OH), 1.62 (m, 2H), 1.86-1.98 (m, 1H), 2.00-2.22 (m, 4H), 2.46-2.62 (m, 2H), 3.30 [d of d, 1H, 7=10 and 3 Hz, collapsed to doublet (7=10 Hz) on addition of D 20, -CHOH], 3.43 (t, 2H, 7=8 Hz, -CH 2Br), 3.57 [d of d, 1H, 7=10 and 8 Hz, collapsed to doublet (7=10 Hz) on addition of D 20, -CHOH], 4.90 and 4.97 (broad s, broad s, 1H each, terminal o l e f i n i c protons), 6.08 (t, 1H, 7=4 Hz, o l e f i n i c proton). Exact Mass calcd. for C , 5H 2 6 0 7 9BrSn (M+-Me): 421.0164; found: 421.0172. Preparation of the S i l y l Ether 228 To a s t i r r e d solution of the alcohol 227 (69 mg, 0.16 mmol) in 2 mL of dry dichloromethane was added 2,6-lutidine (46 mg, 0.43 mmol) and / e r t - b u t y l d i m e t h y l s i l y l t r i f l u o r o -methanesulphonate (84 mg, 0.32 mmol). After the reaction mixture had been s t i r r e d for 30 minutes at 25°C, saturated aqueous sodium carbonate (=1 mL) and ether (25 mL) were added. The mixture was washed with water and brine, and the organic phase was dried (MgSO„). Removal of the solvent TBDMSO ' 203 under reduced pressure provided the crude product, which was f i l t e r e d through a short column of s i l i c a gel (elution with 7:93 ether-petroleum ether). The f i l t r a t e was concentrated under reduced pressure and the material thus obtained was d i s t i l l e d (air-bath temperature 155-165°C/0.1 Torr) to afford 228 (82 mg, 95%) as a colourless o i l ; i r ( f i l m ) : 1640, 1470, 1260, 1100, 770 cm'1; 'H nmr (270 MHz, CDC13) 6: 0.22 and 0.37 (s, s, 3H each, -SiMe 2*-Bu), 0.13 (s, 9H, / S n_ H=54 Hz, -SnMe3), 0.89 (s, 9H, -SiMe 2f-Bu), 0.90 (d, 3H, J=l Hz, secondary methyl), 1.57 (m, 2H), 1.90 (m, 1H), 2.00-2.15 (m, 3H), 2.28 (d, 1H, /=15 Hz), 2.52 (d, 1H, J=8 Hz), 2.78 (d, 1H, 7=8 Hz), 3.34-3.45 (m, 4H, -CH20- and -CH 2Br), 4.84 and 4.94 (broad s, broad s, 1H each, terminal o l e f i n i c protons), 5.90 (t, 1H, /=4 Hz, o l e f i n i c proton). Exact Mass calcd. for C 2 ^ i , 0 0 7 9BrSiSn (M + -Me) : 535.1028; found: 535.1028. Preparation of Compound 229 (and 230) To a cold (0°C), s t i r r e d solution of the s i l y l ether 228 (351 mg, 0.64 mmol) in 4 mL of dry 1,2-dimethoxyethane was added a solution of methyllithium (0.85 mL, 0.96 mmol) 204 in ether. After the reaction mixture had been s t i r r e d for 1 hour at 0°C, saturated aqueous ammonium chloride (=3 mL) and water (=8 mL) were added. The mixture was extracted with ether (3x15 mL). The combined extract was washed with brine and then was dried (MgSO„). Removal of the solvent under reduced pressure gave the crude product, which was shown (c a p i l l a r y glc) to be a mixture of 229 and 230 in a r a t i o of 54:42. The crude product mixture (164 mg, 84%) was dissolved in 2 mL of THF and tetracyanoethylene (103 mg, 0.80 mmol) was added. The resultant yellow solution was s t i r r e d for 45 minutes at 25°C. The solvent was removed under reduced pressure and the crude product was f i l t e r e d through a short column of s i l i c a gel (elution with petroleum ether). The f i l t r a t e was concentrated under reduced pressure and the residual material thus obtained was d i s t i l l e d (air-bath temperature 100-110°C/0.1 Torr) to afford the desired product 229 (86 mg, 44%) as a colourless o i l ; i r ( f i l m ) : 1645, 1460, 1250, 1100, 850 cm'1; *H nmr (300 MHz, CDC13) 6: -0.04 and -0.02 (s, s, 3H each, -SiMe 2f-Bu), 0.83 (s, 9H, -SiMe 2«-Bu), 0.97 (d, 3H, 7=7 Hz, secondary methyl), 1.32-1.50 (m, 2H), 1.66 (d, 1H, 7=13 Hz), 1.76-1.86 (m, 1H), 1.90-2.06 (m, 3H), 2.08-2.23 (m, 2H), 2.25-2.35 (m, 1H), 2.52 (d, 1H, 7=13 Hz), 3.44 and 3.55 (d, d, 1H each, 7=10 Hz, -CH 20-), 4.59 and 4.67 (broad s, broad s, 1H each, terminal o l e f i n i c protons), 5.55 (unresolved m, 1H, o l e f i n i c proton). Exact Mass calcd. for C 1 5 H 2 5 S i O [M +-(t-Bu)l: 249.1674; found: 249.1684. 205 The crude product mixture, obtained from a separate transmetallation experiment, was subjected to careful column chromatography (elution with pentane) to afford a pure sample of 230. This triene displayed i r ( f i l m ) : 1590, 1250, 1100, 850 cm'1; 1H nmr (300 MHz, CDC13) 6: 0.03 (s, 6H, -SiMe 2?-Bu), 0.90 (s, 9H, -SiMe 2f-Bu), 0.94 (d, 3H, J=7 Hz, secondary methyl), 1.20-1.35 (m, 1H), 1.45-1.70 (m, 2H), 1.75 (m, 1H), 1.96 (m, 1H), 2.35 (d, 1H, /=13 Hz, a c y c l i c a l l y l i c proton), 2.47 (d, 1H, /=13 Hz, ac y c l i c a l l y l i c proton), 3.41 (s, 2H, -CH 2C~), 5.00 (m, 2H, o l e f i n i c protons), 5.14-5.36 (m, 3H, o l e f i n i c protons), 5.66 (d of t, 1H, /=10 and 4 Hz, o l e f i n i c proton), 6.36 (d of d, 1H, 7=17 and 10 Hz, o l e f i n i c proton). Exact Mass calcd. for C 1 5 H 2 5 S i O [M +-(r-Bu)]: 249.1674; found: 249.1680. Preparation of the Alcohol 235 To a solution of disiamylborane (3.68 mmol) in 8.6 mL of dry THF at 0°C was added a solution of 229 (450 mg, 1.47 mmol) in 8 mL of dry THF. The reaction mixture was s t i r r e d for 6 hours (0 to 25°C). After the mixture had been cooled to 0°C, water (=1 mL) was introduced slowly, followed by the addition of 3M aqueous sodium hydroxide (1.23 mL). The TBDMSO' 206 resultant mixture was s t i r r e d vigorously at 0°C and 30% hydrogen peroxide (1.23 mL) was added slowly. After the mixture had been s t i r r e d for 3 hours at 25°C, i t was dil u t e d with water (40 mL) and then was extracted with a 1:1 mixture of ether-petroleum ether (3x70 mL). The combined extract was washed with water and brine, and then was dried (MgSOn). The solvent was evaporated under reduced pressure and the crude product was subjected to flash column chromatography (elution with 1:2 ether-petroleum ether) to give the alcohol 235 (407 mg, 85%) as a white s o l i d (m.p. 83-84°C after sublimation at 150°C/0.1 Torr). This compound exhibited i r (KBr): 3270, 1460, 1260, 1080 cm'1; 'H nmr (270 MHz, CDC13) 5: 0.22 and 0.37 (s, s, 3H each, -SiMe 2«-Bu), 0.90 (s, 9H, -SiMe 2'-Bu), 0.96 (d, 3H, J=7 Hz, secondary methyl), 1.17-1.34 (m, 2H), 1.35-1.55 (m, 3H), 1.56-1.71 (m, 2H), 1.72-2.05 (broad diffuse m, 5H, one of these protons exchanged with D 20), 2.15-2.35 (unresolved m, 1H), 3.36-3.63 (m, 4H, si m p l i f i e d on addition of D 20, -CH2OH and -CH 2OSi), 5.47 (unresolved m, o l e f i n i c proton). Exact Mass calcd. for C 1 5H 2 7 0 2 S i [M'-d--Bu) ]: 267.1781; found: 267.1784. 207 Preparation of Compound 236 OMEM To a s t i r r e d solution of the alcohol 235 (290 mg, 0.90 mmol) in 4 mL of dry dichloromethane at 25°C was added ethyldiisopropylamine (231 mg, 1.79 mmol) and 2-methoxy-ethoxymethyl chloride (233 mg, 1.79 mmol). The mixture was s t i r r e d for 10 hours at 25°C. Ether (30 mL) was added and the resultant mixture was washed successively with water, 1M hydrochloric acid and saturated sodium carbonate. The organic layer was dried over anhydrous magnesium sulphate. The solvent was removed under reduced pressure and the crude product was subjected to flash column chromatography (elution with 1:3 ether-petroleum ether). The material obtained was d i s t i l l e d (air-bath temperature 160-170°C/0.1 Torr) to give 236 (308 mg, 84%) as a colourless o i l ; i r (f i l m ) : 1460, 1260, 1100, 850 cm"1; 1H nmr (270 MHz, CDC13) 8: -0.07 and 0.07 (s, s, 3H each, (-SiMe 2f-Bu), 0.87 (s, 9H, -SiMe 2t-Bu), 0.95 (d, 3H, J=l Hz, secondary methyl), 1.32-1.48 (m, 4H), 1.50-1.68 (m, 2H), 1.70-1.84 (m, 2H), 1.86-2.12 (m, 3H), 2.20-2.33 (m, 1H), 3.37 (s, 3H, -OMe), 3.35-3.47 (m, 3H), 3.49-3.57 (m, 3H), 3.63-3.70 (m, 2H), 5.68 (s, 2H, -OCH20-), 5.47 (unresolved m, 1H, o l e f i n i c proton). Exact Mass calcd. for C 1 9H 3 50i,Si [M +-(t-Bu)]: 208 355.2304; found: 355.2299. Preparation of Compound 237 To a s t i r r e d solution of 236 (2.51 g, 6.09 mmol) in 40 mL of dry THF at 25°C was added tetra-n-butylammonium fluoride (4.77 g, 18.3 mmol). The mixture was s t i r r e d for 10.5 hours at 25°C. Ether (130 mL) was added and the mixture was washed with water and brine, and then was dried (MgSOft). Removal of the solvent under reduced pressure provided the crude product which was subjected to flash column chromatography (elution with 3:2 ether-petroleum ether). The material thus obtained was d i s t i l l e d (air-bath temperature 165-175°/0.1 Torr) to give the alcohol 237 (1.73 g, 96%) as a colourless o i l ; i r ( f i l m ) : 3450, 1460, 1100, 1050 cm'1; 1H nmr (270 MHz, CDC13) 6: 1.01 (d, 3H, J=l Hz, secondary methyl), 1.35-1.58 (m, 5H), 1.60-1.78 (m, 3H, one of these protons exchanged with D 20), 1.80-1.92 (m, 1H), 1.95-2.08 (m, 3H), 2.17-2.34 (m, 1H), 3.40 (s, 3H, -OMe), 3.48 (d, 2H, 7=8 Hz), 3.53-3.58 (m, 4H, si m p l i f i e d on addition of D 20), 3.67-3.74 (m, 2H, si m p l i f i e d on addition of D 20), 4.72 (s, 2H, -OCH20-), 5.64 (unresolved m, 1H, o l e f i n i c proton). 209 Exact Mass calcd. for C 1 7 H 2 B 0 3 (M*-H20): 280.2038; found: 280.2040. Preparation of the Aldehyde 238 To a s t i r r e d solution of the alcohol 237 (1.73 g, 5.82 mmol) in 110 mL of dry dichloromethane was added pyridinium chlorochromate (3.14 g, 14.5 mmol). The resultant solution-suspension was s t i r r e d for 1 hour at 25°C. Dry ether (400 mL) was added and the mixture was s t i r r e d for a further 15 minutes. The mixture was f i l t e r e d through a short column of neutral alumina (elution with ether). The combined eluate was concentrated under reduced pressure and the crude product was subjected to flash column chromatography (elution with 1:1 ether-petroleum ether). The material thus obtained was d i s t i l l e d (air-bath temperature 150-160°C/0.1 Torr) to provide the aldehyde 238 (1.54 g, 89%); i r ( f i l m ) : 1715, 1460, 1120, 1060 cm'1; 'H nmr (270 MHz, CDC13) 5: 1.00 (d, 3H, J=l Hz, secondary methyl), 1.45 (d of d, 1H, /= 1 4 and 5 Hz), 1.48-1.59 (m, 5H), 1.61-1.73 (m, 1H), 1.90-2.07 (m, 2H), 2.08-2.17 (m, 2H), 2.50 (d of d, 1H, 7=14 and 5 Hz), 3.40 (s, 3H,-OMe), 3.38-3.47 (m, 2H), 3.53-3.60 (m, 2H), 3.66-3.74 (m, 2H), 4.71 (s, 2H, -OCH20-), 5.77 OMEM 210 (unresolved m, 1H, o l e f i n i c proton), 9.66 (s, 1H, aldehydic proton). Exact Mass calcd. for C 1 7 H 2 e O „ : 296.1987; found: 296.1991. Preparation of Compound 239 To a s t i r r e d solution of the aldehyde 238 (1.54 g, 5.20 mmol) in 5 mL of methanol was added anhydrous hydrazine (832 mg, 26.0 mmol). The resultant solution was s t i r r e d under reflux for 45 minutes and then was concentrated under reduced pressure. The residual material was diluted with dry benzene (4 mL). The benzene was d i s t i l l e d under reduced pressure. This procedure was repeated twice. The residual solvent was removed under reduced pressure (0.1 Torr) at 25°C and a viscous o i l was obtained. To a s t i r r e d solution of t h i s o i l in 7 mL of dry dimethylsulphoxide was introduced potassium i ert-butoxide (1.50 g, 13.5 mmol). The resultant mixture was heated for 1 hour at 70°C. After the mixture had been cooled to 25°C, water (40 mL) was introduced and the resultant mixture was extracted with a 1:1 mixture of ether-petroleum ether (4x30 mL). The combined extract was washed with water and brine, and then was dried (MgSO«). 21 1 Removal of the solvent under reduced pressure, followed by d i s t i l l a t i o n (air-bath temperature 130-140°C/0.1 Torr) of the material thus acquired, afforded 239 (1.32 g, 90%) as a colourless o i l ; i r ( f i l m ) : 1460, 1120, 1060 cm"1; *H nmr (270 MHz, CDC13) 6: 0.86 (d, 3H, 7=7 Hz, secondary methyl), 0.91 (s, 3H, angular methyl), 1.35-1.64 (m, 7H), 1.80-2.06 (m, 4H), 2.18-2.40 (m, 1H), 3.41 (s, 3H, -OMe), 3.47 (d of d, 1H, 7=9 and 6 Hz), 3.52-3.63 (m, 3H), 3.65-3.75 (m, 2H), 4.73 (s, 2H, -OCH 2 0- ) , 5.33 (unresolved m, 1H, o l e f i n i c proton). Exact Mass calcd. for C 1 7 H 3 o 0 3 : 282.2195; found: 282.2197. Preparation of the Alcohol 240 To a s t i r r e d solution of compound 239 (1.32 g, 4.68 mmol) in 50 mL of dry t ert-butyl alcohol was added pyridinium p-toluenesulphonate (10.8 g, 42.9 mmol). The resultant solution was s t i r r e d under reflux for 7 hours. After the solution had been cooled to 25°C, ether (100ml) was introduced and the mixture was washed with water (40 mL). The aqueous washing was re-extracted with ether (35 mL). The combined organic phase was washed with brine and 212 then was dried (MgSO„). On removal of the solvent under reduced pressure, a white s o l i d was formed. The residual material was diluted with ether (30 mL) and then was f i l t e r e d . The f i l t r a t e was concentrated (reduced pressure) and the crude product was subjected to flash column chromatography (elution with 2:3 ether-petroleum ether). The material thus obtained was d i s t i l l e d (air-bath temperature 95-105o/0.1 Torr) to afford the alcohol 240 (745 mg, 82%) as a colourless o i l ; i r ( f i l m ) : 3350, 1460, 1030 cm"1; 1H nmr (400 MHz, CDC13) 6: 0.83 (d, 3H, J=l Hz, secondary methyl), 0.91 (s, 3H, angular methyl), 1.35 (broad d, 1H, J=6 Hz, exchanged with D 20, -OH), 1.38-1.47 (m, 2H), 1.48-1.53 (m, 3H), 1.54-1.64 (m, 2H), 1.71-1.84 (m, 1H), 1.88-2.10 (m, 3H), 2.23-2.35 (m, 1H), 3.51-3.61 [m, 1H, collapsed to a d of d (/=11 and 8 Hz) on addition of D20, -CHOH], 3.63-3.72 [m, 1H, collapsed to a d of d (/=11 and 6 Hz) on addition of D 20, -CHOH], 5.34 (unresolved m, 1H, o l e f i n i c proton). Exact Mass calcd. for C 1 3H 2 20: 194.1671; found: 194.1671. Preparation of the Acid 241 COOH 213 To a c o l d (-78°C), s t i r r e d s o l u t i o n of o x a l y l c h l o r i d e (61 mg, 0.47 mmol) i n 1 mL of dry dichloromethane was added di m e t h y l s u l p h o x i d e (65.7 mg, 0.91 mmol). The mixture was s t i r r e d f o r 5 minutes at -78 °C. To t h i s mixture at -78°C was added a s o l u t i o n of the a l c o h o l 240 (70 mg, 0.37 mmol) in 1 mL of dry dichloromethane. A f t e r the mixture had been s t i r r e d f o r 15 minutes at -78°C, t r i e t h y l a m i n e (203 mg, 2 mmol) was int r o d u c e d and s t i r r i n g was continued f o r 5 minutes at -78°C. The r e a c t i o n mixture was allowed to warm to 25°C and water (=1 mL) was added. The mixture was d i l u t e d with water (12 mL) and then was e x t r a c t e d with ether (2x13 mL). The combined e x t r a c t was washed with a s o l u t i o n of pH 4.5 sodium dihydrogen phosphate b u f f e r and b r i n e , and then was d r i e d (MgSO«). The so l v e n t was removed under reduced p r e s s u r e . The crude product was d i s s o l v e d i n 1.75 mL of t e r f - b u t y l a l c o h o l . To t h i s s o l u t i o n at 25°C was added 2-methyl-2-butene (384 mg, 5.47 mmol) and a s o l u t i o n of sodium c h l o r i t e (96 mg, 1.06 mmol) i n 0.96 mL of aqueous sodium dihydrogen phosphate b u f f e r (pH 4.5). A f t e r the r e a c t i o n mixture had been s t i r r e d f o r 35 minutes at 25°C, water (10 mL) was int r o d u c e d and the mixture was e x t r a c t e d with ether (2x14 mL). The combined e x t r a c t was washed with water and b r i n e , and then was d r i e d (MgSO„). Removal of the so l v e n t under reduced pressure gave the crude product, which was s u b j e c t e d to f l a s h column chromatography ( e l u t i o n with 3:7 ether-petroleum) to a f f o r d the a c i d 241 (62 mg, 83%) as a c r y s t a l l i n e white s o l i d . The m e l t i n g p o i n t of a 214 r e c r y s t a l l i z e d (hexane) sample of 241 was 133.5-134.5°C. This compound displayed i r (KBr): 3400-2600, 1700, 1260 cm"1; 1H nmr (400 MHz, CDC1 3) 8: 0.89 (d, 3H, J=l Hz, secondary methyl), 0.91 (s, 3H, angular methyl), 1.35-1.55 (m, 6H, one of these proton exchanged with D 20), 1.87-2.09 (m, 3H), 2.13-2.24 (m, 1H), 2.34-2.44 (m, 1H), 2.46-2.59 (m, 1H), 2.64-2.73 (m, 1H), 5.35 (unresolved m, 1H, o l e f i n i c proton). Exact Mass calcd. for C 1 3 H 2 0 0 2 : 208.1464; found: 208.1473. Preparation of the Ester 213 To a s t i r r e d solution of the acid 241 (60 mg, 0.29 mmol) in 1.5 mL of dry dichloromethane was added 4-dimethyl-aminopyridine (5.3 mg, 0.04 mmol), dry ethanol (53 mg, 1.15 mmol) and N-(3-dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride (102 mg, 0.58 mmol). The resulting pale yellow solution was s t i r r e d for 2 hours at 25°C. Water (7 mL) was added and the mixture was extracted with ether (3x7 mL). The combined extract was washed with brine and then was dried (MgSO„). The solvent was removed under reduced pressure and the crude product was subjected to flash column 215 chromatography (elution with 8:92 ether-petroleum ether). The material thus obtained was d i s t i l l e d (air-bath temperature 100-110°C/0.1 Torr) to provide the ester 213 (61 mg, 90%) as a colourless o i l ; i r ( f i l m ) : 1731, 1459, 1377, 1201 cm"1; 'H nmr (270 MHz, CDC13) 6: 0.85 (s, 3H, angular methyl), 0.89 (d, 3H, /=6 Hz, secondary methyl), 1.30 (t, 3H, J=7 Hz, -OCH2Me), 1.37-1.52 (m, 5H), 1.84-2.08 (m, 3H), 2.12-2.25 (m, 1H), 2.28-2.40 (m, 1H), 2.42-2.63 (m, 2H), 4.17 (q, 2H, J=l Hz, -OCH2Me), 5.34 (unresolved m, 1H, o l e f i n i c proton). Exact Mass calcd. for C 1 5H 2 l (0 2 : 236.1777; found: 236.1777. Preparation of the Ester 214 To a s t i r r e d solution of sodium ethoxide (0.26 mmol) in 0.5 mL of dry ethanol was added a solution of the ester 213 (22 mg, 0.09 mmol) in 1 mL of dry ethanol. After the mixture had been s t i r r e d under reflux for 2.5 hours, i t was cooled to 25°C. Saturated aqueous ammonium chloride (l mL) and water (4 mL) were added and the mixture was extracted with ether (3x5 mL). The combined extract was washed with brine and then was dried (MgSO,,). Removal of the solvent under COOEt 216 reduced pressure gave the crude product, which was f i l t e r e d through a short column of s i l i c a gel (elution with 1:19 ether-petroleum ether). The f i l t r a t e was concentrated under reduced pressure and the material thus obtained was d i s t i l l e d (air-bath temperature 105-115°C/0.1 Torr) to afford the ester 214 (8.6 mg, 39%) as a colourless o i l ; i r (f i l m ) : 1734, 1458, 1375, 1306 cm"1; 1H nmr (300 MHz, CDC13) 6: 0.89 (d, 3H, 7=6 Hz, secondary methyl), 0.95 (s, 3H, angular methyl), 1.26 (t, 3H, 7=7 Hz, -OCH2Me), 1.36-1.53 (m, 4H), 1.87-2.15 (m, 6H), 2.21-2.38 (m, 1H), 2.59 (t of t, 7=13 and 3.5 Hz, -CHCOO-), 4.13 (q, 2H, 7=7 Hz, -OCH2Me), 5.36 (unresolved m, 1H, o l e f i n i c proton). Exact Mass calcd. for C 1 5H 2 l l0 2: 236.1777; found: 236.1772. Preparation of (±)-Eremoligenol (208) To a cold (0°C), s t i r r e d solution of the ester 213 (71 mg, 0.30 mmol) in 2 mL of dry ether was added a solution of methyllithium (0.56 mL, 0.90 mmol) in ether. The mixture was s t i r r e d for 1 hour at 0°C. Saturated ammonium chloride (0.1 mL) and ether (5 mL) were added and the mixture was then s t i r r e d for 5 minutes at 25°C. The resultant mixture was OH 217 dried over anhydrous magnesium sulphate. Removal of the solvent under reduced pressure gave the crude product which was subjected to flas h column chromatography (elution with 2:3 ether-petroleum ether). The material thus obtained was d i s t i l l e d (air-bath temperature 105-115°C/0.1 Torr) to provide (±)-eremoligenol (208) (62 mg, 93%) as a colourless o i l ; i r ( f i l m ) : 3392, 1673, 1381, 1370 cm"1; 1H nmr (300 MHz, CDC13) 8: 0.87 (d, 3H, 7=7 Hz, secondary methyl), 0.91 (s, 3H, angular methyl), 1.122 and 1.137 (s, s, 3H each, -CMe2OH), 0.95-1.24 (m, 1H), 1.25-1.80 (broad diffuse m, 8H, one of these protons exchanged with D 20), 1.84-2.13 (m, 3H), 2.15-2.33 (m, 1H), 5.31 (unresolved m, 1H, o l e f i n i c proton). Exact Mass calcd. for C 1 S H 2 6 0 2 : 222.1984; found: 222.1985. Preparation of the Diol 243 To a cold (0°C), s t i r r e d solution of (±)-eremoligenol (208) (136 mg, 0.58 mmol) in 2 mL of dry THF was added a solution of borane-tetrahydrofuran complex (1.08 mL, 1.73 mmol) in THF. The reaction mixture was allowed to warm to 25°C and then was s t i r r e d for 2 hours. After the mixture had been cooled to 0°C, water (0.12 mL) and aqueous 3M sodium 218 h y d r o x i d e (0.67 mL) was added. Hydrogen p e r o x i d e (30%, 0.67 mL) was then i n t r o d u c e d s l o w l y t o the above m i x t u r e . A f t e r the r e s u l t a n t m i x t u r e had been s t i r r e d f o r 2 hours a t 25°C, b r i n e (6 mL) and water (6 mL) were added. The m i x t u r e was e x t r a c t e d w i t h e t h e r (3x12 mL) and the combined e x t r a c t was d r i e d (MgSO„). The s o l v e n t was removed under reduced p r e s s u r e t o p r o v i d e the crude p r o d u c t , which was s u b j e c t e d t o f l a s h column chromatography ( e l u t i o n w i t h 7:3 e t h e r -p e t r o l e u m e t h e r ) t o a f f o r d the d i o l 243 (109 mg, 90%) as a c r y s t a l l i n e s o l i d . The m e l t i n g p o i n t of a r e c r y s t a l l i z e d ( e t h e r - h e x a n e ) sample of 243 was 141.5-143°C. T h i s compound e x h i b i t e d i r ( K B r ) : 3360, 1450, 1000 cm' 1; !H nmr (400 MHz, CDC1 3) 6: 0.75 ( t , 1H, 7=13 H z ) , 0.79 ( d , 3H, 7=7 Hz, secondary m e t h y l ) , 0.96-1.05 (m, 1H), 1.06 ( s , 3H, a n g u l a r m e t h y l ) , 1.165 and 1.175 ( s , s, 3H each, -CMe 2OH), 1.24-1.35 (m, 2H, one of th e s e p r o t o n s exchanged w i t h D 2 0 ) , 1.36-1.53 (m, 4H), 1.55 ( s , 1H, exchanged w i t h D 20, -OH), 1.58-1.95 (broad d i f f u s e m, 6H), 3.79 ( u n r e s o l v e d m, 1H, -CHOH). E x a c t Mass c a l c d . f o r C 1 5 H 2 8 0 2 : 240.2089; found: 240.2085. E l e m e n t a l a n a l y s i s c a l c d . f o r C 1 5 H 2 8 0 2 : C 74.95, H 11.74; found: C 74.70, H 11.63. 219 P r e p a r a t i o n of the Keto A l c o h o l 2 4 5 OH To a c o l d (0°C), s t i r r e d s o l u t i o n of the d i o l 243 (109 mg, 0.45 mmol) i n 3.5 mL of acetone was added Jones' reagent [0.23 mL, 0.61 mmol of C r ( V I ) ] . A f t e r the r e a c t i o n mixture had been s t i r r e d f o r 10 minutes at 0°C, 2-propanol (=0.5 mL) was added and s t i r r i n g was c o n t i n u e d u n t i l a c o l o u r l e s s s o l u t i o n was o b t a i n e d . The s o l v e n t was removed under reduced pressure and the r e s i d u a l m a t e r i a l was d i l u t e d with water (12 mL). The r e s u l t i n g mixture was e x t r a c t e d with ether (3x12 mL). The combined e x t r a c t was washed with water and b r i n e , and then was d r i e d (MgSO f t). Removal of the s o l v e n t (reduced pressure) gave the crude product which was s u b j e c t e d to f l a s h column chromatography ( e l u t i o n with 3:1 ether-petroleum ether) to a f f o r d 245 (101.5 mg, 94%) as a c r y s t a l l i n e white s o l i d . The m e l t i n g p o i n t of 245 a f t e r r e c r y s t a l l i z a t i o n (hexane) was 104-105.5°C. T h i s compound showed i r (KBr): 3462, 1694 cm" 1; 'H nmr (400 MHz, CDC1 3) 6: 0.71 ( t , 1H, 7=13 Hz), 0.78 (s, 3H, angular methyl), 0.85 (d, 3H, 7=7 Hz, secondary methyl), 1.00 (q of d, 1H, 7=13 and 4 Hz), 1.158 and 1.163 (s, s, 3H each, -CMe 20H), 1.53 (s, 1H, exchanged with D 20, -OH), 1.54-1.73 (m, 3H), 1.74-2.03 (m, 5H), 2.15-2.24 (m, 1H), 2.25-2.38 (m, 1H), 220 2.54 (d of d of d, 1H, 7=15.5, 14 and 7.5 H z ) . E x a c t Mass c a l c d . f o r C 1 5 H 2 6 0 2 : 238.1933; found: 238.1935. E l e m e n t a l a n a l y s i s c a l c d . f o r C 1 5 H 2 6 0 2 : C 75.58, H 10.99; found: C 75.80, H 11 .00. P r e p a r a t i o n of Compounds 204, 246 and 247 2 0 4 2 4 6 2 4 7 To a c o l d (0°C), s t i r r e d s o l u t i o n of compound 245 (59.5 mg, 0.25 mmol) i n 1 mL of dry p y r i d i n e was added, d r o p w i s e , t h i o n y l c h l o r i d e (150 mg, 1.26 mmol). A f t e r the r e a c t i o n m i x t u r e had been s t i r r e d f o r 20 minutes a t 0°C, c o l d (0°C) water was added and the m i x t u r e was e x t r a c t e d w i t h e t h e r (3x12 mL). The combined e x t r a c t was washed s u c c e s s i v e l y w i t h h a l f - s a t u r a t e d aqueous copper s u l p h a t e , water, and b r i n e , and then was d r i e d (MgSO f l). The s o l v e n t was removed under reduced p r e s s u r e t o a f f o r d the crude p r o d u c t . S u b j e c t i o n of the crude product t o column chromatography ( e l u t i o n w i t h 3:17 e t h e r - p e t r o l e u m e t h e r ) p r o v i d e d 246 (7.4 mg, 13%) as a w h i t e s o l i d . The m e l t i n g p o i n t of 246 a f t e r r e c r y s t a l l i -z a t i o n (hexane) was 83.5-84°C. S e p a r a t i o n of 204 and 247 was d i f f i c u l t and we were unable t o c o m p l e t e l y s e p a r a t e t h e s e two s u b s t a n c e s a l t h o u g h pure samples of each compound were 221 obtained. The combined y i e l d of 204 and 247, as a 2.2:1 mixture ( c a p i l l a r y g l c ) , was 71% (39.1 mg) after d i s t i l l a t i o n (air-bath temperature 100-110°C/0.1 Torr). Compound 204 displayed i r ( f i l m ) : 3083, 1704, 1645, 887 cm"1; 1H nmr (400 MHz, CDC13) 8: 0.77 (s, 3H, angular methyl), 0.78-0.90 (m, 1H), 0.87 (d, 3H, 7=7 Hz, secondary methyl), 1.15 (q of d, 1H, 7=13 and 4 Hz), 1.55-1.75 (m, 2H), 1.77 (broad s, 3H, v i n y l methyl), 1.77-1.91 (m, 4H), 1.94-2.04 (m, 1H), 2.09-2.15 (m, 2H), 2.28-2.41 (m, 1H), 2.53 (d of d of d, 1H, 7=15.5, 13.5 and 7.5 Hz), 4.70 (broad d, 2H, 7=8 Hz, terminal o l e f i n i c protons). Exact Mass calcd. for C 1 5H 2,0: 220.1827; found: 220.1822. Compound 246 exhibited i r (KBr): 1698, 1473, 1455, 1372 cm"1; 1H nmr (400 MHz, CDC13) 5: 0.81 (s, 3H, angular methyl), 0.89 (d, 3H, 7=7 Hz, secondary methyl), 1.11 (q of d, 1H, 7=13 and 4 Hz), 1.550 and 1.575 (s, s, 3H each, v i n y l methyls), 1.64 (d of d, 1H, 7=13 and 5 Hz), 1.67-1.78 (m, 1H), 1.79-1.93 (m, 3H), 1.96-2.13 (m, 3H), 2.22 (d of d, 1H, 7=15 and 5 Hz), 2.26-2.38 (m, 1H), 2.53 (d of d of d, 1H, 7=15.5, 13.5 and 7.5 Hz), Exact Mass calcd. for C 1 5H 2 f tO: 220.1827; found: 220.1833. Compound 247 showed i r ( f i l m ) : 1708, 1456, 1374 cm" 1; 1H nmr (400 MHz, CDC13) 8: 0.80 (s, 3H, angular methyl), 0.89 (d, 3H, 7=7 Hz, secondary methyl), 1.44-1.66 (m, 3H), 1.69 (broad s, 6H, v i n y l methyls), 1.67-1.89 (m, 3H), 1.94-2.06 (m, 1H), 2.09-2.21 (m, 2H), 2.48 (d of d of d, 1H, 7=15, 12.5 and 7 Hz), 2.58-2.68 (m, 2H). Exact Mass calcd. for C 1 5H 2,0: 220.1827; found: 220.1826. 223 REFERENCES REFERENCES E. P i e r s a n d V. K a r u n a r a t n e , /. Org. Chem. 48, 1774 ( 1 9 8 3 ) . B. M. T r o s t , Acc. Chem. Res. 1 1 , 453 ( 1 9 7 8 ) . D. S e e b a c h , Helv. Chim. Acta. 6 7 , 261 ( 1 9 7 8 ) . (a) A. C. Cope, H. L. Holmes a n d H. 0. H o u s e , Organic Reactions 9 , 107 ( 1 9 5 7 ) . (b) F. F r e e m a n , Chem. Rev. 6 9 , 591 ( 1 9 6 9 ) . ( a ) P. I . A b e l l a n d R. T i e n , /. Org. Chem. 3 0 , 4212 (19 6 5 ) . (b) S. D a n i s h e f s k y a n d R. K. S i n g h , /. Amer. Chem. Soc. 9 7 , 3239 ( 1 9 7 5 ) . S. D a n i s h e f s k y a n d R. K. S i n g h , /. Org. Chem. 40, 2969 ( 1 9 7 5 ) . ( a ) E. J . C o r e y and D. S e e b a c h , Angew. Chem. Int. Ed. Engl. 4, 1075 ( 1 9 6 5 ) . (b) D. S e e b a c h , N. R. J o n e s and E. J . C o r e y , /. Org. Chem. 3 3 , 300 ( 1 9 6 8 ) . ( c ) D. S e e b a c h , Synthesis 17 ( 1 9 6 9 ) . (d) D. S e e b a c h , a n d A. K. B e c k , Organic Synthesis 5 1 , 76 ( 1 9 7 1 ) . ( a ) K. O g u r a , M. Y a m a s h i t a , S. K u r u k a w a , M. S u z u k i a nd G. T s u c h i h a s h i , Tetrahedron Lett. 2767 ( 1 9 7 5 ) . (b) K. O g u r a , M. S u z u k i a n d G. T s u c h i h a s h i , Bull. 225 Chem. Soc. Jph. 53, 1414 (1980). (c) K. Ogura, M. S u z u k i , J . Watanabe, M. Yama s h i t a , H. I i d a and G. T s u c h i h a s h i , Chem. Lett. 813 (1982). (a) J . P. Collman and L. S. Hegedus, " P r i n c i p l e s and A p p l i c a t i o n s of O r g a n o t r a n s i t i o n M e t a l C h e m i s t r y " , U n i v e r s i t y S c i e n c e Books, 1980. (b) S. G. D a v i e s , " O r g a n o t r a n s i t i o n M e t a l C h e m i s t r y : A p p l i c a t i o n s t o Or g a n i c S y n t h e s i s " , Pergamon P r e s s , 1983. (c) M. Semmelhack, Tet r ahedr on 4 1 , 5741 (1985). T. S. Abram, R. Baker, C. M. Exon and B. Rao, J. Chem. Soc. Perkin Tran. II 285 (1982). H. N i s h i g a w a , S. N a r i m a t s u i and K. I t o h , Tetrahedron Lett. 23, 1267 (1982). B. M. T r o s t and B. P. Coppo l a , J. Amer. Chem. Soc. 1 0 4 , 6879 (1982). W. M. G r o o t a e r t and P. J . De C l e r q , Tetrahedron Lett. 27, 1731 (1986). (a) H. M. Colquhoun, J . H o l t o n , D. J . Thompson and M. V. Twigg, "New Pathways f o r O r g a n i c S y n t h e s i s . P r a c t i c a l A p p l i c a t i o n s of T r a n s i t i o n M e t a l s " , Plenum P r e s s , 1984. (b) J . T s u j i , "Organic S y n t h e s i s w i t h P a l l a d i u m Compounds", S p r i n g e r - V e r l a g , B e r l i n H e i d e l b e r g New York, 1980. (c) J . T s u j i , "Organic S y n t h e s i s by means of 226 Transition Metal Complexes", Springer-Verlag Berlin Heidelberg New York, 1975. 15. (a) B. M. Trost and D. M. T. Chan, /. Amer. Chem. Soc. 1 0 1 , 6429 (1979). (b) B. M. Trost and D. M. T. Chan, J. Amer. Chem. Soc. 1 0 5 , 2315 (1983). 16. D. L. Boger and C. E. Brotherton, /. Amer. Chem. Soc. 1 0 6 , 805 (1984). 17. (a) B. B. Snider, Acc. Chem. Res. 1 3 , 426 (1980). (b) W. Oppolzer and V. Snieckus, Angew. Chem. Int. Ed. Engl. 1 7 , 476 (1978). (c) H. M. R. Hoffmann, Angew. Chem. Int. Ed. Engl. 8, 556 (1969). 18. A. C. Jackson, B. E. Goldman and B. B. Snider, J. Org. Chem. 4 9 , 3988 (1984). 19. D. Seyferth and M. A. Weiner, Chem. Ind. (London), 402 (1959). 20. M. Gielen, "Recent Developments in the Syntheses, Properties and Uses of Tetraorganotin Compounds" in Reviews on S i l i c o n , Germanium, Tin and Lead  Compounds, v o l . V, number 2, Freund Publishing House LTD., Tel-Aviv, 1981, p. 5. 21. (a) E. Piers and H. E. Morton, /. Org. Chem. 45, 4263 (1980). (b) E. Piers , J. M. Chong and H. E. Morton, Tetrahedron Lett . 22, 4905 (1981). 22. E. Piers and J. M. Chong, /. Chem. Soc. Chem. 227 Commun. 934 (1983). 23. E. Piers and V. Karunaratne, /. Chem. Soc. Chem. Commun. 935 (1983). 24. G. H. Posner, D. J. Brunelle and L. Sinoway, Synthesis 662 (1974). 25. E. Piers and V. Karunaratne, Can. J. Chem. 6 2 , 629 (1984). 26. E. Piers and V. Karunaratne, J. Chem. Soc. Chem. Commun. 959 (1984). 27. E. Piers and B. W. A. Yeung, /. Org. Chem. 49, 4567 (1984). 28. E. Piers and B. W. A. Yeung, in press. 29. E. Piers and A. V. Gavai, /. Chem. Soc. Chem. Commun. 1241 (1985). 30. E. Piers and A. V. Gavai, Tel r ahedr on Lett. 27, 313 (1986). 31. (a) W. M. Rathke and D. Sul l i v a n , Tetrahedron Lett. 4249 (1972). (b) A. S. Kende and B. H. Toder, J. Org. Chem. 47, 163 (1982). 32. E. Piers and H. E. Morton, /. Chem. Soc. Chem. Commun. 1033 (1978). 33. H. E. Morton, Ph.D. Thesis, The University of B r i t i s h Columbia, 1980. 34. S. Nadarajah, M.Sc. Thesis, The University of B r i t i s h Columbia, 1986. 35. E. Piers, K. F. Cheng and I. Nagakura, Can. J. Chem. 228 6 0 , 1256 (1982). 36. (a) G. H. Posner, Organic Reactions 1 9 , 1 (1972). (b) B. H. Lipshutz, Tet r ahedr on Lett. 24, 127 (1983). (c) Y. Yamamoto, S. Yamamoto, H. Yatagai, Y. Ishihara and K. Maruyama, /. Org. Chem. 47, 119 (1982). 37. (a) C. P. Casey and D. F. Marten, Syn. Commun. 3, 321 (1973). (b) C. P. Casey , D. F. Marten and R. A. Boggs, Tetrahedron Lett. 2071 (1973). (c) C. P. Casey and D. F. Marten, Tetrahedron Lett. 925 (1974). 38. F. W. Sum and L. Weiler, Can. J. Chem. 57, 1431 (1979). 39. R. D. Clark and C. H. Heathcock, J. Org. Chem. 41, 636 (1976). 40. K. E. Harding and C. Y. Tseng, /. Org. Chem. 43, 3974 (1978). 41. E. Piers, unpublished r e s u l t s . 42. G. H. Posner, C. E. Whitten and J . J. St e r l i n g , J. Amer. Chem. Soc. 9 5 , 7788 (1973). 43. D. E. Seitz and S. H. Lee, Tetrahedron Lett. 22, 4909 (1981). 44. (a) S. Ramaswamy, Ph.D. Thesis, The University of B r i t i s h Columbia, 1982. (b) S. Danishefsky, T. Harayama and R. K. Singh, J. 229 Amer. Chem. Soc. 1 0 1 , 7008 (1979). 45. J. L. Occolowitz, Tetrahedron Lett. 5291 (1966). 46. (a) P. J. Stang and W. Treptow, Synthesis 283 (1980). (b) J. E. McMurry and W. J . Scott, Tetrahedron Lett. 2 4 , 979 (1983). 47. J . E. McMurry and W. J. Scott, Tet r ahedr on Lett. 2 1 , 4313 (1980). 48. E. J. Corey and J. Das, J. Amer. Chem. Soc. 1 0 4 , 5551 (1982). 49. D. L i o t t a , C. Barmun, R. Puleo, G. Zima, C. Bayer and H. S. Kezar I I I , /. Org. Chem. 4 6 , 2920 (1981). 50. H. J. Reich, J. M. Renga and I. L. Reich, /. Amer. Chem. Soc. 97, 5434 (1975) . 51. E. Piers and R. T. S k e r l j , J. Chem. Soc. Chem. Commun. 626 (1986). 52. H. 0. House, "Modern Synthetic Reactions", The Benjamin/Cummings Publishing Company, 1972, p. 492-509. 53. R. E. Gawley, Synthesis 111 (1976). 54. M. E. Jung, Tet rahedron 3 2 , 3 (1976). 55. (a) L. A. Paquette, "Topics in Current Chemistry" v o l . 119, Springer-Verlag, Berlin Heidelberg New York, 1984. (b) M. Ramaiah, Synthesis 529 (1985). (c) B. M. Trost, Angew. Chem. Int. Ed. Engl. 2 5 , 1 (1986). 230 (d) L. A. Paquette,- "Topics in Current Chemistry" v o l . 79, Springer-Verlag, B e r l i n Heidelberg New York, 1979, p. 41-165. (e) M. Demuth and K. Schaffner, Angew. Chem. Int. Ed. Engl. 2 1 , 820 (1982). (f) B. M. Trost, Acc. Chem. Res 1 3 , 385 (1980). (g) R. Noyori, Acc. Chem. Res 1 2 , 61 (1979). 56. W. E. Parham and C. K. Bradsher, Acc. Chem. Res. 1 5 , 300 (1982). 57. C. K. Bradsher and D. A. Hunt, J. Org. Chem. 4 6 , 4600 (1981). 58. E.-I. Negishi, L. D. Boardman, J. M. Tour, H. Sawada and C. L. Rand, J. Amer. Chem. Soc. 1 0 5 , 6344 (1983). 59. E.-I. Negishi, L. D. Boardman, V. Bagheri and H. Sawada, J. Amer. Chem. Soc. 1 0 6 , 6105 (1984). 60. Y. Okuda, Y. Morizawa, K. Oshima and H. Nozaki, Tet r ahedr on Lett. 2 5 , 2483 (1984). 61. E. J . Corey and A. Venkateswarlu, J. Amer. Chem. Soc. 94 , 6190 (1972). 62. D. Seyferth and M. W. Weiner, J. Amer. Chem. Soc. 84 , 361 (1962). 63. W. C. S t i l l , G. Revial and K. Yoshihara, /. Amer. Chem. Soc. 1 0 5 , 625 (1983). 64. J. S. Sawyer, T. S. Macdonald and G. J. McGarvey, /. Amer. Chem. Soc. 1 0 6 , 3376 (1984). 65. H. J . Reich and N. H. P h i l i p s , /. Amer. Chem. Soc. 231 108, 2102 (1986).-66. (a) F. Johnson, Chem. Rev. 68, 375 (1968). (b) H. C. Brown, J. H. Brewster and H. Shechter, /. Amer. Chem. Soc. 76, 467 (1954). 67. T. Ibuka, K. Hayashi, H. Minakata and Y. Inubushi, Tetrahedron Lett. 159 (1979). 68. R. F. Stewart and L. L. M i l l e r , /. Amer. Chem. Soc. 102, 4999 (1980). 69. E. J. Corey, H. Cho, C. Rucker and D. H. Hua, Tetrahedron Lett. 22, 3455 (1981). 70. (a) S. Hayashi, A. Matsu and T. Matsura, T el r ahedr on Lett. 1599 (1969). (b) S. Hayashi and A. Matsu, Tel rahedron Lett. 1289 (1970). (c) A. Matsu, Tel r ahedr on 28, 1203 ( 1972). 71. J.-L. Gras, J. Org. Chem. 46, 3738 (1981). 72. J. D. Connolly, L. J. Harrison and D. S. Rycroft, J. Chem. Soc. Chem. Commun. 1236 (1982). 73. K.-G. Gerling and H. Wolf, Tetrahedron Lett. 26, 1293 (1985). 74. (a) F.-H. Koster and H. Wolf, Tet r ahedr on Lett. 3937 (1981). (b) A. Franke, H. Wolf and V. Wray, Tet r ahedr on 40, 3491 (1984). 75. A. Kirrmann, M. Goudard and M. Chahidzadeh, Bull. Soc. Chim. 21 47 (1935). 76. L. Wartski, Bull. Soc. Chim. 3066 (1965). 232 77. H. 0. House, "Modern Synthetic Reactions", W. A. Benjamin, Inc., 1972, p. 229-239. 78. (a) M. Karplus, J. Chem. Physics 3 0 , 11 (1959). (b) M. Karplus, /. Amer. Chem. Soc. 85, 2870 (1963). (c) A. A. Bothner-By, Advan. Magn. Res onance 1, 195 (1965). 79. M. V. Bhatt and S. U. Kulkarni, Synthesis 249 (1983). 80. (a) G. A. Olah, S. C. Narang, G. B. Gupta and R. Malhotra, J. Org. Chem. 44, 1247 (1979). (b) M. E. Jung and T. A. Blumenkopt, Tetrahedron 3657 (1978). (c) M. E. Jung, M. A. Mazurek and R. M. Lim, Synthesis 588 (1978). (d) T.-L. Ho and G. A. Olah, Synthesis 417 (1977). 81. M. E. Jung, and M. A. Lyster, J. Org. Chem. 42, 3761 ( 1 977) . 82. D. E. Seitz and L. F e r r e i r a , Syn. Commun. 9, 931 (1979). 83. N. C. Barua, R. P. Sharma and J. N. Baruh, Tetrahedron L e t t . 24, 1189 (1983). 84. M. Node, H. Hori and E. F u j i t a , /. Chem. Soc. Perkin I 2237 (1976) . 85. B. H. Lipshutz, Tet r ahedr on L e t t . 21, 3343 ( 1980). 86. (a) T. H. Chan, P. W. K. Lau and M. P. L i , Tetrahedron L e t t . 2667 (1976). (b) H. Tomika, T. Suzuki, K. Oshima and H. Nozaki, 233 Tet r ahedr on Lett. 2 3 , 3387 ( 1 9 8 2 ) . 87. B. W. Metcalf, J . P. Burkhart and J. Jund, Tet rahedron Lett. 2 1 , 35 ( 1 9 8 0 ) . 88. B. H. Lipshutz, J. J. Pegram and M. C. Morey, Tet r ahedr on Lett. 22 , 4603 ( 1 9 8 1 ) . 89. S. Danishefsky, K. Nagaswa and N. Wong, /. Org. Chem. 40, 1989 ( 1 9 7 5 ) . 90. E. J. Corey and M. A. Tius, Tel r ahedr on Lett. 2 1 , 3535 ( 1 9 8 0 ) . 9V. C. Burford, F. Cooke, E. Ehlinger and P. Magnus, /. Amer. Chem. Soc. 99, 4536 ( 1 9 7 7 ) . 92. (a) P. Magnus and G. Roy, Organomet alI i cs 1, 533 (1 9 8 2 ) . (b) P. Magnus and G. Roy, J. Chem. Soc. Chem. Commun. 822 ( 1 9 7 9 ) . 93. A. S. Kende and T. J. Blacklock, Tetrahedron Lett. 2 1 , 3119 ( 1 9 8 0 ) . 94. A. F. Kluge and I. S. Cloudsdale, J. Org. Chem. 44, 4847 ( 1 9 7 9 ) . 95. E. J. Corey and M. Chaykovsky, J. Amer. Chem. Soc. 87, 1353 ( 1 9 6 5 ) . 96. (a) J. G. Smith, Synthesis 637 ( 1 9 8 4 ) . (b) A. Roswosky, "Heterocyclic Compounds" v o l . 19, part I, A. Weissberger Ed., Interscience, 1964, p. 231-261. 97. B. Rickborn and R. M. Gerkin, J. Amer. Chem. Soc. 93, 1693 ( 1 9 7 1 ) . 234 98. (a) M. Rosenberger, W. Jackson and G. Saucy, Helv. Chim. Acta. 63, 1665 (1980). (b) S. M. Nagvi, J . P. Horowitz and R. F u l l e r , J. Amer. Chem. Soc. 79, 6283 (1957). 99. J.-M. Conia and J.-C. Limasset, Bull. Soc. Chim. 1936 (1967). 100. S. R. Schow and T. C. McMorris, J. Org. Chem. 44, 3760 (1979). 101. A. B. Smith and P. J. J e r r i s , /. Org. Chem. 47, 1849 (1982). 102. (a) K. Omura and D. Swern, Tet rahedron 34, 1651 (1978). (b) A. J. Mancuso, S.-L Huang and D. Swern, J. Org. Chem. 43, 2480 (1978). 103. K. Naya, M. Kawai, M. Naito and T. Kasai, Chem. Lett. 241 (1972). 104. H. I s h i i , T. Tozyo and H. Minato, /. Chem. Soc. (c) 1545 (1966). 105. (a) R. M. Coates and J. E. Shaw, Tet rahedron Lett. 5405 (1968). (b) R. M. Coates and J. E. Shaw, J. Org. Chem. 35, 2597 (1970). 106. (a) G. Jommi, J. Krepinsky, V. Herout and F. Sorm, Tetrahedron Lett. 611 (1967). (b) H. Hikino, N. Suzuki and T. Takemoto, Chem. Pharm. Bull. 16, 832 (1968). (c) G. Jommi, J. Krepinsky, V. Herout and F. Sorm, 235 Collection of Czechosl av. Chem. Commun. 34, 593 (1969). 107. (a) F. Naf, R. Decorzant and W. Thommsen, Helv. Chim. Acta. 62, 114 (1979). (b) F. Naf, R. Decorzant and W. Thommsen, Helv. Chim. Acta. 65, 2212 (1982). 108. D. A. Evans anf C. H. Mitch, Tet r ahedr on Lett. 23, 285 (1982). 109. 0. Itoh, Y. Kohmura, Y. Ichikawa, M. Umezu, T. Okita and K. Ichikawa, Bull. Chem. Soc. Jpn. 53, 146 (1980). 110. R. O. Hutchins, D. Masilamani and C. A. Maryanoff, /. Org. Chem. 41, 1071 (1976). 111. (a) N. Zelinsky, Chem. Ber. 46, 165 (1913). (b) M. R. R i f i , Organic Synthesis 52, 22 (1972). 112. (a) D. E. Applequist and J. D. Roberts, /. Amer. Chem. Soc. 78, 874 (1956). (b) D. E. Applequist, G. F. Fanta and B. W. Henrikson, J. Org. Chem. 23, 1715 (1958). (c) S. F. Brady, M. A. Ilton and W. S. Johnson, /. Amer. Chem. Soc. 90, 2882 (1968). 113. L. F. Fieser and M. Fieser, "Reagents for Organic Synthesis", John Wiely and Sons Inc., 1967, p. 1247-1249. 114. J. Sauer, H. Wiest and A. Mielert, Chem. Ber. 97, 3183 (1964). 115. (a) D. J. Cram, M. R. V. Sahyun and G. R. Knox, 236 J. Amer. Chem. Soc. 84, 1734 (1962). (b) H. H. Szmant and M. N. Roman, /. Amer. Chem. Soc. 88, 4034 (1966). 116. H. C. Brown and G. Zweifel, /. Amer. Chem. Soc. 83, 1241 (1961). 117. E. J. Corey, J.-L. Gras and P. U l r i c h , Tetrahedron Lett. 809 (1976). 118. (a) Y. Guidon, H. E. Morton and C. Yoakim, Tet rahedr on Lett. 24, 3969 ( 1 983). (b) Y. Guidon, H. E. Morton and C. Yoakim, /. Org. Chem. 49, 3912 (1984). 119. J. H. Rigby and J. Z. Wilson, Tetrahedron Lett. 25, 1429 (1984). 120. H. Monti, G. Leandri, M. Klos-Ringuet and C. C o r r i o l , Syn. Commun. 1 3 , 1021 (1983). 121. E. J. Corey and G. Schmidt, Tet r ahedr on Lett. 399 ( 1979) . 122. (a) A. Bowers, T. G. H a l s a l l , E. R. H. Jones and A. J. Lenin, J. Chem. Soc. 2548 (1953). (b) G. C a i n e l l i and G. C a r d i l l o , "Chromium Oxidation in Organic Chemistry", Springer-Verlag, B e r l i n Heidelberg New York, 1984, p. 133. 123. B. 0. Lindgren and T. Nilsson, Acta. Chem. Scand. 27, 888 (1973). 124. B. S. Bal, W. E. Childers J r . and H. W. Pinnick, Tetrahedron 37, 2091 (1981). 125. G. A. Kraus and B. Roth, /. Org. Chem. 45, 4825 237 (1980). 126. (a) B. Neises and W. Steglich, Angew. Chem. Int. Ed. Engl. 1 7 , 522 (1978). (b) A. Hassner and V. Alexanian, Tetrahedron Lett. 4475 (1978). 127. (a) J. C. Sheehan, P. A. Cruickshank and G. L. Boshart, J. Org. Chem. 26 , 2525 (1961). (b) K. D. Kopple and D. E. Nit e c k i , J. Amer. Chem. Soc. 8 4 , 4457 (1962). 128. H. Hikino, N. Suzuki and T. Takemoto, Chem. Pharm. Bull. 16 , 832 (1968). 129. D. H. Williams and I. Fleming, "Spectroscopic Methods in Organic Chemistry", McGraw-Hill, London, 1973, p. 145. 130. W. C. S t i l l , M. Kahn and A. Mitra, /. Org. Chem. 4 3 , 2923 (1978). 131. Y. P. Bryan and R. H. Byrne, J. Chem. Ed. 4 7 , 1361 (1970) . 132. D. D. Perrin, W. L. F. Armarego and D. R. Perrin, " P u r i f i c a t i o n of Laboratory Chemicals", Pergamon Press, Oxford, 1980. 133. W. G. Kofron and L. M. Baclawski, /. Org. Chem. 4 1 , 1879 (1976). 134. W. C. S t i l l , J. Amer. Chem. Soc. 99, 4836 (1977). 135. L. Ruest, G. Blouin and P. Deslongchamps, Syn. Commun. 6, 169 (1976). 

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