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Total synthesis of (±)-palauolide, (±)-isolinaridiol and (±)-isolinaridiol diacetate Wai, John Sui Man 1988

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TOTAL SYNTHESIS OF (±)-PALAUOLIDE, (±)-ISOLINARIDIOL AND (±)-ISOLINARIDIOL DIACETATE By JOHN SUI MAN WAI B.Sc, U n i v e r s i t y of Hong Kong, 1982 M.Phil., U n i v e r s i t y of Hong Kong, 1984 A THESIS SUBMITTED IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY i n 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 February 1988 © J o h n Sui Man WAI, 1988 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 Columbia 1956 Main Mall Vancouver, Canada Department V6T 1Y3 Date 2 ( n DE-6(3/81) i i ABSTRACT This thesis describes the t o t a l syntheses of the sesterterpenoid (±)-palauolide (55) and the diterpenoids (±)-isolinaridiol (64) and (±)-isolinaridiol diacetate (61). In the t o t a l synthesis of (±)-palauolide, the d e c a l i n substructure was constructed by a copper(I) bromide-dimethyl s u l f i d e catalyzed a d d i t i o n of the Grignard reagent 40 to 3,6-dimethyl-2-cyclohexen-1-one (115), followed by intramolecular a l k y l a t i o n of the r e s u l t a n t chloro ketone 121. The r e s u l t a n t annulation product 114 was converted into the n i t r i l e 112, which was s t e r e o s e l e c t i v e l y a l k y l a t e d with ICH2CH2CH2OCH2OCH3 to provide the n i t r i l e 173. The l a t t e r substance was transformed v i a a s e r i e s of reactions into compound 175 which was con-verted into the a.^-unsaturated aldehyde 107. J u l i a o l e f i n a t i o n of 107 with the l i t h i u m s a l t of the sulfone 223 provided s t e r e o s e l e c t i v e l y the t r i e n e 216, which was photooxygenated to provide (±)-palauolide (55). In the t o t a l syntheses of (±)-isolinaridiol (64) and (±)-isoli-n a r i d i o l diacetate (61), the b i c y c l i c substance 276 was prepared by following the chemistry developed i n the synthesis of (±)-palauolide (55). Conversion of 276 into the aldehyde 234, followed by treatment of t h i s material, under c a r e f u l l y defined conditions, with the anion of the 7-lactone phosphonate 261, provided the Z lactone 279 as the major product. Diisobutylaluminum hydride reduction of 279 y i e l d e d (±)-iso-l i n a r i d i o l (64). B i s - a c e t y l a t i o n of the l a t t e r material provided (±) -i s o l i n a r i d i o l diacetate (61). i i i i v TABLE OF CONTENTS Page ABSTRACT i i TABLE OF CONTENTS i v LIST OF TABLES v i i LIST OF FIGURES v i i i ABBREVIATIONS ix ACKNOWLEDGEMENTS x i i INTRODUCTION 1 I. General 1 II . Previous Work 9 I I I . I s o l a t i o n and S t r u c t u r a l E l u c i d a t i o n of Palauolide (55) 13 IV. I s o l a t i o n and St r u c t u r a l E l u c i d a t i o n of I s o l i n a r i d i o l (64) and I s o l i n a r i d i o l diacetate (61) . . . . 15 V. Previous Syntheses of Clerodane-type Diterpenoids . . . . 17 DISCUSSION 29 I. T o t a l Synthesis of (±)-Palauolide 29 A. Retrosynthetic Analysis 29 B. Synthesis of the n i t r i l e 112 31 V C. Synthesis of the homoallylic iodide 113 41 D. A l k y l a t i o n of the n i t r i l e 112 with the iodide 113. Attempts to prepare compound 145 48 E. A l k y l a t i o n of the n i t r i l e 112 with the iodide 172. Preparation of the a,^-unsaturated aldehyde 107 67 F. Synthesis of the phosphonium s a l t 188 80 G. Conversion of 7-methoxybutenolides into 7-hydroxybutenolides 88 H. Reaction of a.^-unsaturated aldehydes with phosphoranes and phosphonate anions derived from 4-(halomethyl)-butenolides 91 I. Reaction of aunsaturated aldehydes with phosophoranes derived from 4-(halomethyl)-2-t r i m e t h y l s i l y l f u r a n s 96 J . Reaction of geranial (211) with the sulfone 223. Photosensitized oxidation of the resultant triene 221 to the corresponding butenolide 99 K. Reaction of the aldehyde 107 with the sulfone 223. Photosensitized oxidation of the r e s u l t a n t t r i e n e 216 to (±)-palauolide (55) 104 I I . T o t a l synthesis of (±)-Isolinaridiol (64) and (±)-Isolinaridiol diacetate (61) 110 A. Retrosynthetic analysis 110 B. Z s e l e c t i v e Horner-Wittig o l e f i n a t i o n s 112 1. O l e f i n a t i o n s with a c y c l i c b i s ( t r i f l u o r o -ethyl)phosphonates 112 2. O l e f i n a t i o n s with 7-lactone a-phosphonates . . . . 118 C. Synthesis of the aldehyde 234 126 D. Synthesis of (±)-isolinaridiol (64) and i t s geometric isomer 278 132 E. Synthesis of (±)-isolinaridiol diacetate (61) . . . . 139 v i F. Attempt to oxidize (±)-isolinaridiol (64) to (±)-isolinaridial (60) 144 I I I . Miscellaneous l/+7 EXPERIMENTAL 152 REFERENCES 240 v i i LIST OF TABLES Table Page 1 nmr s p e c t r a l data of natural palauolide and synthetic (±)-palauolide (55) 106 2 Reaction of 3-methylbutanal with the 7-lactone phosphonate 261 121 3 Reaction of aldehydes with the 7-lactone phosphonate 261 123 4 P a r t i a l nmr and i n f r a r e d data f o r o l e f i n a t i o n products derived from reactions of aldehydes with the 7-lactone phosphonate 261 127 5 nmr s p e c t r a l data of i s o l i n a r i d i o l (64) 137 6 nmr s p e c t r a l data reported f o r natural i s o l i n a r i d i o l diacetate, and those derived from our synthetic (±)-isolinaridiol diacetate (61) and the diacetate 281 143 v i i i LIST OF FIGURES Figure Page 1 The 400 MHz XH nmr spectrum of 111 50 2 The 400 MHz  lH nmr spectrum of 175 75 3 The 270 MHz ^H nmr spectrum of 107 81 4 The XH nmr spectrum of natural palauolide 107 5 The 400 MHz XH nmr spectrum of (±)-palauolide (55) 108 7 The 400 MHz XH nmr spectrum of natural i s o l i n a r i d i o l 135 8 The 400 MHz XH nmr spectrum of (±)-isolinaridiol (64) 136 9 The 300 MHz % nmr spectrum of 278 138 10 The 300 MHz XH nmr spectrum of (±)-isolinaridiol diacetate (61) 140 11 The 300 MHz XH nmr spectra of 281 142 i x LIST OF ABBREVIATIONS Ac - a c e t y l AIBN - 2,2' - a z o b i s i s o b u t y r o n i t r i l e br - broad Bu - b u t y l Bn - benzyl Bz - benzoyl d - doublet DBU - l,8-diazobicyclo[5.4.0]undec-7-ene DEG - diethylene g l y c o l DIBAL-H - diisobutylaluminum hydride DMAP - 4-N,N-dimethylaminopyridine DME - 1,2-dimethoxyethane DMF - N,N-dimethylformamide DMSO - dimethylsulfoxide equiv - equivalent(s) Et - ethyl g l c - g a s - l i q u i d chromatography h - hour(s) HMPA - hexamethylphosphoramide i r - i n f r a r e d LAH - li t h i u m aluminum hydride LDA - l i t h i u m diisopropylamide m - mu l t i p l e t X Me - m e t h y l m i n - m i n u t e ( s ) mp - m e l t i n g p o i n t Ms - m e t h a n e s u l f o n a t e NBS - N - b r o m o s u c c i n i m i d e nmr - n u c l e a r m a g n e t i c r e s o n a n c e nOe - n u c l e a r O v e r h a u s e r enhancement PCC - p y r i d i n i u m c h l o r o c h r o m a t e Ph - p h e n y l PPTS - p y r i d i n i u m p . - t o l u e n e s u l f o n a t e P r - p r o p y l Py - p y r i d i n e q - q u a r t e t r t - room t e m p e r a t u r e s - s i n g l e t t - t r i p l e t t e r t - t e r t i a r y TBAF - te t r a - n - b u t y l a m m o n i u m f l u o r i d e TBDMS - t e r t - b u t y l d i m e t h y l s i l y l THF - t e t r a h y d r o f u r a n THP - t e t r a h y d r o p y r a n y l t i c - t h i n l a y e r chromatography TMEDA - N,N , N ' , N ' - t e t r a m e t h y l e n e d i a m i n e TMS - t r i m e t h y l s i l y l TosMIC - ( p . - t o l u e n e s u l f o n y l ) m e t h y l i s o c y a n i d e TPP - t e t r a p h e n y l p h o r p h i n x i p.-TsOH - p a r a - t o l u e n e s u l f o n i c a c i d Ts - p a r a - t o l u e n e s u l f o n v l v - v e r y A - h e a t x i i ACKNOWLEDGEMENTS T h i s t h e s i s i s b a s e d on t h e r e s e a r c h work c a r r i e d o u t i n t h e Department o f C h e m i s t r y , U n i v e r s i t y o f B r i t i s h C o l u m b i a f r o m J a n u a r y , 1985 t o November, 1987, under t h e s u p e r v i s i o n o f P r o f e s s o r Edward P i e r s . I w o u l d l i k e t o e x p r e s s my d e e p e s t g r a t i t u d e t o P r o f e s s o r P i e r s f o r h i s i n v a l u a b l e g u i d a n c e , encouragement and d i s c u s s i o n t h r o u g h o u t t h e c o u r s e o f t h e r e s e a r c h work, and f o r h i s immense e f f o r t i n s e t t i n g up our p r o b l e m s e t s t o f u r t h e r e d u c a t e us i n t h e s c i e n c e o f o r g a n i c chemis-t r y . H i s a d v i c e on w r i t i n g t h i s t h e s i s i s g r e a t l y a p p r e c i a t e d . I w o u l d l i k e t o than k a l l t h e members o f P r o f e s s o r P i e r s ' r e s e a r c h group w i t h whom I have s h a r e d t h e p l e a s u r e o f d i s c u s s i o n , t h e f r u s t r a -t i o n o f f a i l u r e , and t h e j o y o f success., S p e c i a l t h a n k s a r e due t o Dr. Montse L l i n a s - B r u n e t , Mr. F r a s e r F l e m i n g , and M i s s B e t t y - A n n e S t o r y f o r t h e i r c a r e f u l p r o o f r e a d i n g , and t o P r o f e s s o r J.R. S c h e f f e r f o r showing me how t o do MM2 c a l c u l a t i o n s . Thanks a r e a l s o e x t e n d e d t o t h e t e c h n i c a l s t a f f s o f the n u c l e a r m a g n e t i c r e s o n a n c e and mass s p e c t r o s c o p y s e r v i c e s f o r t h e i r r e l i a b l e and u s u a l l y e f f i c i e n t s e r v i c e , and t o Mrs. R a n i T h e e p a r a j a h f o r t y p i n g t h e t h e s i s . The g e n e r o s i t y o f t h e S w i r e Company (HK) f o r p r o v i d i n g a " f r e e r i d e " t o Vanc o u v e r i s acknowledged w i t h t h a n k s . x i i i TO MY WIFE JENNY - 1 -INTRODUCTION I . G e n e r a l The a c h i e v e m e n t o f t h e c h e m i c a l s y n t h e s i s o f a complex o r g a n i c m o l e c u l e i n v o l v e s t h e development and e x p e r i m e n t a l e x e c u t i o n o f a s y n t h e t i c p l a n . When th e c h e m i c a l b e h a v i o u r o f t h e compounds i n the s y n t h e t i c sequence i s d i f f e r e n t from what was e x p e c t e d , t h e p l a n i s m o d i f i e d , r e p e a t e d l y i f n e c e s s a r y , u n t i l s u c c e s s i s a c c o m p l i s h e d . I n p l a n n i n g a s y n t h e s i s , t h e complex t a r g e t m o l e c u l e i s t h e o r e t i c a l l y b r o k e n i n t o p i e c e s i n s u c h a way t h a t t h e y m i g h t be r e j o i n e d e xperimen-t a l l y t o c o n s t r u c t t h e t a r g e t m o l e c u l e . Thus, t h e p l a n n i n g o f a s y n t h e s i s i s g r e a t l y f a c i l i t a t e d by r e c o g n i z i n g , w i t h i n t h e t a r g e t m o l e c u l e , c e r t a i n f r a g m e n t s w h i c h ca n be s y n t h e s i z e d and j o i n e d by known or c o n c e i v a b l e s y n t h e t i c o p e r a t i o n s . Such f r a g m e n t s a r e r e f e r r e d t o as s y n t h o n s . 1 The r e a c t i o n s most f r e q u e n t l y u s e d i n o r g a n i c s y n t h e s i s a r e p o l a r i n n a t u r e . They u s u a l l y i n v o l v e n u c l e o p h i l i c s i t e s i n t e r a c t i n g w i t h e l e c t r o p h i l i c s i t e s t o form bonds. Thus, most o f t h e c h e m i c a l r e a g e n t s u s e d t o c a r r y o u t s y n t h e t i c o p e r a t i o n s have e i t h e r a n u c l e o p h i l i c s i t e o r an e l e c t r o p h i l i c c e n t e r . However, some c h e m i c a l r e a g e n t s p o s s e s s two r e a c t i v e s i t e s , e.g. two n u c l e o p h i l i c s i t e s , two e l e c t r o p h i l i c s i t e s o r one n u c l e o p h i l i c and one e l e c t r o p h i l i c s i t e . These s p e c i e s , i f t h e y a r e i n c o r p o r a t e d i n whole o r i n p a r t i n t o a s u b s t r a t e m o l e c u l e t o g i v e a more complex system, a r e commonly r e f e r r e d t o as " b i f u n c t i o n a l c o n j u n c -- 2 -t i v e reagents". Examples of some simple b i f u n c t i o n a l reagents are given below. D i a l k y l malonates and dithianes are well-known, simple examples of conjunctive reagents. They have been used e f f e c t i v e l y as synthetic equivalents of donor-donor (d,d) synthons. For example, d i e t h y l malonate (1) has been used i n the preparation of the s y n t h e t i c a l l y valuable cyclopropane-1,1-dicarboxylic a c i d (2)^ (equation 1), while 1,3-dithiane (3) had been employed i n the preparation of d i t h i o k e t a l s 4. Hydrolysis of the l a t t e r materials provides access to c y c l i c ketones 5 of d i f f e r e n t r i n g s i z e s ^ (equation 2). In these reactions, reagents 1 and 3 serve as synthetic equivalents of the d,d synthons 6 and 7, re s p e c t i v e l y . In organic synthesis, annulation reactions are frequently involved i n the construction of a target molecule. Many b i f u n c t i o n a l conjunctive reagents have been used to e f f e c t annulation reactions. On such occasions, the b i f u n c t i o n a l reagents react with a s u i t a b l e substrate v i a an intermolecular coupling step, followed by an intramolecular c y c l i z a -Heteroatoms i n an organic molecule impose an a l t e r n a t i n g acceptor and donor r e a c t i v i t y pattern (as shown) upon the carbon skeleton. Thus, carbons 1•^ are acceptors (attack by donors) and carbons 2 are donors (attack by acceptors); the heteroatom X° i s a donor center. X = 0,N [For a d e t a i l e d discussion, see D. Seebach, Angew. Chem. Int. Ed  Engl., 18, 239 (1979)] . - 3 -/c°2Et • r B r _ f ! i ^ > tx~ 2u \ T r i e t h y l b e n z y l - ^ ^ U ^ H LLot* ^^Br ammonium c h l o r i d e 1 2 r sy H ^  > r sY H -^ -> rs)GH^ N - S A H 2 . c i ( c H 2 ) n c i \-sAcH2)nCI S <CH2)nCt 3 n=2-7 4 HgCl 2,H 20 > o=GH)n (2) x C 0 2 E t t i o n s t e p . S e l e c t e d examples o f such r e a g e n t s a r e g i v e n below. C o n d e n s a t i o n o f t h e d i a n i o n 8 w i t h e t h y l 4-bromobutanoate i n THF-HMPA a t -60° t o -80°C gave t h e d i e s t e r 9 i n 60% y i e l d . 5 D e c a r b o x y l a t i o n and s a p o n i f i c a t i o n o f t h e l a t t e r m a t e r i a l p r o v i d e d the v a l u a b l e o c t a l o n e 10 ( e q u a t i o n 3 ) . I n t h i s c a s e 8 a c t s as a s y n t h e t i c e q u i v a l e n t o f t h e d,d s y n t h o n 11 . The k e t o n e 10 has been u s e d as an i n t e r m e d i a t e i n s e s q u i t e r p e n e syntheses.** - 4 -fi 11 The a r y l l i t h i u m r e a g e n t 12 i s a s y n t h e t i c e q u i v a l e n t o f t h e d,a s y n t h o n 13. The r e a g e n t has been shown t o add t o v i n y l s u l f o n e s and the r e s u l t i n g a - l i t h i o s u l f o n e s undergo spontaneous i n t r a m o l e c u l a r a l k y l a t i o n . ? F o r example, r e a c t i o n o f t h e a r y l l i t h i u m 12 w i t h t h e s u l f o n e 14 i n d i e t h y l e t h e r (-78°C t o room t e m p e r a t u r e ) a f f o r d e d t h e a n n u l a t i o n p r o d u c t 15 i n 78% y i e l d ( e q u a t i o n 4). T h i s t e t r a h y d r o n a p t h a -l e n e a n n u l a t i o n sequence c o u l d have c o n s i d e r a b l e a p p l i c a t i o n i n t h e s y n t h e s i s o f s t e r o i d s and o t h e r p o l y c y c l i c s y s t e m s . Compounds s u c h as 16 (X = l e a v i n g group; M = S I o r Sn) were f i r s t d e s c r i b e d by T r o s t ^ a as e q u i v a l e n t s o f s y n t h e t i c a l l y v a l u a b l e d,a s y n t h o n s o f t h e g e n e r a l s t r u c t u r e 17. The f o r m e r s u b s t a n c e s have been d e m o n s t r a t e d t o be v e r y e f f e c t i v e f o r t h e s y n t h e s e s o f five-membered r i n g s . F o r example, t r e a t m e n t o f t h e a c e t o x y a l l y l s i l a n e 18 w i t h 2 - c y c l o p e n t e n - l - o n e (19) i n t h e p r e s e n c e o f c a t a l y t i c amount o f t e t r a -- 5 -k i s ( t r i p h e n y l p h o s p h i n e ) p a l l a d i u m and b i s ( d i p h e n y l p h o s p h i n o ) e t h a n e [dppe] i n r e f l u x i n g THF f o r 20 h gave t h e k e t o n e 20 i n 56% y i e l d ( e q u a t i o n 5 ) . O D T h i s r e a c t i o n was one o f t h e key s t e p s i n an e l e g a n t s y n t h e s i s o f h i r s u t e n e (21). 8 c - 6 -M e c h a n i s t i c a l l y , t h e above r e a c t i o n i n v o l v e s f i r s t l y t h e i n t e r a c t i o n o f t h e a c e t o x y a l l y s i l a n e 18 w i t h p a l l a d i u m ( O ) complexes t o g i v e a 7 r - a l l y l p a l l a d i u m i n t e r m e d i a t e 22 and a c e t a t e i o n . A t t a c k o f t h e l a t t e r s p e c i e s on t h e s i l y l group r e s u l t s i n t h e f o r m a t i o n o f t h e p a l l a d i u m complex 23, w h i c h a t t a c k s t h e e l e c t r o n d e f i c i e n t c a r b o n - c a r b o n d o u b l e bond o f t h e a,ji-unsaturated k e t o n e 19 t o a f f o r d t h e m e t h y l e n e c y c l o p r o -pane a n n u l a t i o n p r o d u c t 20 (Scheme l ) . 8 c * , e Scheme 1 - 7 -An a l t e r n a t i v e approach which inverts the e l e c t r o n i c sense of the reagents of general structure 16 has also been reported. In these cases, the reagents 16 s t i l l function as equivalents to the d,a synthon 17. For example, r e a c t i o n of the potassium enolate of the ketone 24 with 3-iodo-2-(trimethylsilylmethyl)-1-propene (25) gave the a l k y l a t i o n product 26. Fluoride ion induced c y c l i z a t i o n of the l a t t e r material afforded the alcohol 27 (equation 6 ) . ^ c SPh 24 25 SiMe3 KH DME SPh 26 (6) 26 OH SPh n-Bu.NF — 4 THF, lh >-OH SPh 27 17 (6) Recently, Danheiser has described the use of ( t r i m e t h y l s i l y l ) -allenes 28 as synthetic equivalents of the d,a synthon 29.^ For example, r e a c t i o n of 2-cyclohexen-1 -one (30) with the ( t r i m e t h y l s i l y l ) -allene 31 i n the presence of titanium t e t r a c h l o r i d e i n dichloromethane at -78°C f o r 1 h gave r e g i o s e l e c t i v e l y the ( t r i m e t h y l s i l y l ) c y c l o p e n t e n e annulation product 34 i n 85% y i e l d (equation 7 ) . - 8 -The r e a c t i o n i s thought to involve f i r s t l y complexation of titanium t e t r a c h l o r i d e with the enone to generate the alkoxy a l l y l i c carbocation 32, which i s r e g i o s e l e c t i v e l y attacked by the ( t r i m e t h y l s i l y l ) a l l e n e 31 to a f f o r d the v i n y l c a t i o n 33. Such a c a t i o n i s s t a b i l i z e d by i n t e r -a c t i o n with the adjacent c a r b o n - s i l i c o n bond. A 1,2-shift of the t r i m e t h y l s i l y l group, followed by i n t e r c e p t i o n of the isomeric v i n y l c a t i o n by the titanium enolate, produces the annulated product 34 (Scheme 2). - 9 -TiCl \ - S i M e 3 4-34 SiMe3 32 31 SiMe3 33 Scheme 2 I I . Previous Work Previous work i n our laboratories had shown that the (trimethyl-stannyl) copper reagent 35 adds r e g i o s e l e c t i v e l y to u>-substituted 1-alkynes 36 (X = leaving group or p o t e n t i a l leaving group). Thus, treatment of 36 with 35 i n THF at - 7 8 ° C f o r 6 h provided e f f i c i e n t l y the corresponding 2-(trimethylstannyl)-1-alkenes 37 (equation 8 ) . ^ The vinylstannanes 37 have been shown to serve as e f f e c t i v e precursors of a number of b i f u n c t i o n a l conjunctive reagents that are synthetic equivalents to the donor-acceptor synthons 3 8 . i X ' i 2 Thus, - 10 -Me.SnCu.Me.S (35, 2equiv.) /SnMe3 HC=C(CH2)nX ^ 2 : — 1> = < (8) MeOH (60equiv.), THF \CH2)nX 3 6 -63°C, 12h 37 _ d /SnMB3 ^ C H 2 ) n - l C H 2 XCH2)3Cl 38 3 9 transmetalation of 5-chloro-2-(trimethylstannyl)-1-pentene (39) with methyllithium i n THF at -78°C, followed by add i t i o n of anhydrous magnesium bromide-etherate, provided the corresponding Grignard reagent 40. In the presence of copper(I) bromide-dimethyl s u l f i d e complex, t h i s reagent underwent conjugate ad d i t i o n to enones 41. In some cases, a d d i t i o n of boron t r i f l u o r i d e - e t h e r a t e s i g n i f i c a n t l y improved the y i e l d s of the reactions (equation 9).12 11 The conjugate a d d i t i o n products 42 were r e a d i l y c y c l i z e d by tre a t -ment with potassium hydride i n THF (equation 10). As e x p e c t e d , 1 2 a under such conditions, the " k i n e t i c " products possessed a c i s r i n g j u n c t i o n and i n each case i n which subsequent e q u i l i b r a t i o n was not possi b l e , a s i n g l e , c i s - f u s e d annulated product was obtained. For example the adduct 45 c y c l i z e d to give only the cis-decalone 46 i n 78% y i e l d (equation 11). me ^ KH, THF ^ ' Cl^O r t , 2h (11) In other cases, varying degrees of e q u i l i b r a t i o n occurred under the conditions of c y c l i z a t i o n and f o r the decalones, further e q u i l i b r a t i o n gave the trans -decalones as the major products. For example the conjugate a d d i t i o n product 47 c y c l i z e d to give a 3.5:1 mixture of the decalones 48 and 49, r e s p e c t i v e l y on treatment with potassium hydride i n THF. A f t e r further e q u i l i b r a t i o n with sodium methoxide i n b o i l i n g methanol, a 1:2.8 mixture of the ketones 48 and 49, r e s p e c t i v e l y was obtained (equation 12). 47 A8 49 before further equilibration 3.5 : 1 after further equilibration 1 : 2.8 12 -I t can be seen that, i n the above reactions, 5-chloro-2-(trimethyl-stannyl)-1-pentene (39) serves as a synthetic equivalent of the 1-pentene d2,a-* synthon (50). Use of the former substance as shown i n the above examples provided a valuable methylenecyclohexane annulation sequence. The methylenecyclohexane moiety i s a f a i r l y common s t r u c t u r a l feature i n the terpenoid family of natural products. 53 R=-NHCH0. 54 R = -N=C Scheme 3 - 13 -The u t i l i t y of t h i s methylenecyclohexane annulation process was demonstrated by i t s a p p l i c a t i o n to the synthesis of (±)-axamide-1 (53) and (±)-axisonitrile-1 ( 5 4 ) . 1 3 Thus, CuBr.Me2S-BF3.Et2O catalyzed a d d i t i o n of the Grignard reagent (40) to 2-methyl-2-cyclopenten-l-one (51), followed by treatment with potassium hydride i n THF, afforded the annulation product 52 i n 85% y i e l d . A f t e r incorporation of the side chain and appropriate f u n c t i o n a l group manipulations, (±)-axamide-1 (53) and (±)-axisonitrile (54) were obtained (Scheme 3). I I I . I s o l a t i o n and S t r u c t u r a l E l u c i d a t i o n o f P a l a u o l i d e (55) In 1982 S u l l i v a n and Faulkner x^ i s o l a t e d a new sesterterpenoid from the methanolic extract of a mixture of at l e a s t three d i f f e r e n t species of sponges c o l l e c t e d from Palau, Western Caroline Islands. This new compound, which i n h i b i t e d the growth of B a c i l l u s s u b t i l i s and Straphvlococcus aureus at 10 /ig/disc, was named palauolide. I t had the molecular formula C25H36O3. Infrared bands at 3500 and 1740 cm"-'-indi c a t e d the presence of a 7-hydroxybutenolide moiety and an u l t r a v i o -l e t absorption at 322 nm (e 17,000) indicated that the butenolide was further conjugated to two carbon-carbon double bonds. Signals at S 5.95 (d, 1H, J = 11 Hz), 7.16 (dd, 1H, J - 15.5, 11 Hz), 6.28 (d, 1H, J = 15.5 Hz), 5.83 (s, 1 H ) , and 6.26 (s, 1H) i n the % nmr spectrum of palauolide and a resonance at S 15.18 (q) i n the ^ 3C nmr spectrum in d i c a t e d the stereochemistry and the s u b s t i t u t i o n pattern of t h i s t r i e n e u n i t . - 14 -C o m p a r i s o n o f t h e r e m a i n i n g s i g n a l s i n t h e ^ C and nmr s p e c t r a o f p a l a u o l i d e (55) w i t h t h o s e o f i l l i m a q u i n o n e (56) i n d i c a t e d t h a t b o t h s u b s t a n c e s have t h e same b i c y c l i c r i n g system. T h i s was f u r t h e r s u p p o r t e d by t h e f a c t t h a t c h e m i c a l d e g r a d a t i o n s o f b o t h s u b s t a n c e s l e d t o t h e same d i k e t o n e 57. Thus, t h e s t r u c t u r e o f p a l a u o l i d e (55) was e s t a b l i s h e d . A l t h o u g h t h e c a r b o n s k e l e t o n t h a t c o m p r i s e s t h e b i c y c l i c p o r t i o n o f p a l a u o l i d e i s r e l a t i v e l y common among sponge m e t a b o l i t e s , t h e e n t i r e c a r b o n framework o f p a l a u o l i d e (55) had n o t been r e p o r t e d p r e v i o u s l y i n t h e l i t e r a t u r e . 15 -IV. I s o l a t i o n and S t r u c t u r a l E l u c i d a t i o n of I s o l i n a r i d i a l (60) and I s o l i n a r i d i o l diacetate (61) In 1982, San F e l i c i a n o e t _ _ a l . 1 ^ reported the i s o l a t i o n of a new ent-clerodane type diterpenoid from the hexane extract of the a e r i a l part of L i n a r i a s a x a t i l i s ( L .). a plant which grows i n the northern and c e n t r a l part of Spain and i n Portugal. The chemical composition of L i n a r i a s a x a t i l i s (L.) had not been studied previously. The new compound showed two strong i n f r a r e d bands at 1725 and 1675 cm"1 i n d i c a t i n g the presence of saturated and a, (3-unsaturated carbonyl moieties. The signals at 6 9.93 (s, 1H), 9.45 (br s, 1H), 6.41 (br s, 1H, sharpened on i r r a d i a t i o n at 6 9.93-9.45 and 6.41), 2.57 (m, 2H) i n CHO I the -41 nmr spectrum indicated the presence of a (Z)-RCH2CH=CCH2CHO moiety i n the molecule. The remaining signals i n the ^H nmr spectrum and the i r spectrum of the new compound indic a t e d the presence of clerodane-type b i c y c l i c substructure. This new substance was chemically transformed into solidagolactone (62) (see Scheme 4), an ent-clerodane. the structure and absolute stereochemistry of which had already been esta b l i s h e d by Okazaki et a l . 1 ^ Thus, structure 60 was proposed for the According to Rowe's nomenclature, D structures 5 8 and 5 9 with absolute stereochemistry indicated are r e f e r r e d to as clerodane and ent-clerodane. r e s p e c t i v e l y . For d e t a i l e d discussion, see F. P i o z z i , Heterocvcle. 15, 1489 (1981). 58 59 - 16 -Scheme 4 new compound and i t was named i s o l i n a r i d i a l , since i t i s s t r u c t u r a l l y c l o s e l y r e l a t e d to the diterpenoid l i n a r i d i a l (63), which was i s o l a t e d e a r l i e r by Kitagawa et a l . 1 8 from L i n a r i a japonica (Scheme 4). In 1985, the same Spanish group reported the i s o l a t i o n from L i n a r i a - 17 -s a x a t l l i s (L.) of another ent-clerodane- type diterpenoid having a carbon skeleton i d e n t i c a l with that of i s o l i n a r i d i a l ( 6 0 ) . x ^ This new compound showed i r absorptions due to acetoxy groups at 1745, 1240, 1030 cm"x. In the XH nmr spectrum, signals at S 1.97, 1.91 (s,s, 3H each) also i n d i c a t e d the presence of two acetate groups. S a p o n i f i c a t i o n of t h i s new diterpene and l i t h i u m aluminum hydride reduction of i s o l i n a r i d i a l (60) l e d to the same d i o l 64 (Scheme 5), which was named i s o l i n e r i d i o l . Thus structure 61 was proposed f o r the new diterpenoid and was named i s o l i n a r i d i o l diacetate. V . Previous Syntheses of Clerodane-type Diterpenoids The terpenoids, palauolide (55), i s o l i n a r i d i o l (64) and i s o l i n a r i -d i o l diacetate (61) had not been synthesized p r i o r to the work described i n t h i s t h e s i s . However, the syntheses of a number of trans-fused clerodane type diterpenoids had been reported. Thus, the t o t a l syn-theses of (±)-annonene ( 6 5 ) , 2 ^ (±)-ajugarin-IV ( 6 6 ) , 2 x (±)-ajugarin-I ( 6 7 ) , 2 2 (±)-4-epi-ajugarin, 2 3 c (±)-maingayic a c i d ( 6 8 ) , 2 4 a and (-)-methyl kolavenate ( 6 9 ) 2 4 d had been c a r r i e d out. - 18 -In the following discussion, which reviews b r i e f l y the above syntheses, the st r a t e g i e s employed for the construction of the d e c a l i n substructure of the clerodane diterpenoids w i l l be emphasized. Kende et a l . . 2 ^ and de Groot et a l . . 2 3 employed b a s i c a l l y the same approach f o r the construction of the d e c a l i n moiety. S t a r t i n g with a s u i t a b l e d e r i v a t i v e of the Wieland-Miescher ketone (70), reductive a l k y l a t i o n provided a t r a n s - r i n g j u n c t i o n and produced the desired stereochemistry at C-9. A su i t a b l e sequence of reactions then i n t r o -duced the required secondary methyl group at C-8. For example, i n the t o t a l synthesis of (±)-ajugarin-IV, 2^ reductive a l k y l a t i o n of the enone 71 with a l l y l bromide afforded the ketone 72. The l a t t e r material was converted into the conjugated ketone 73 i n f i v e steps. Lithium-ammonia reduction of 73 i n the absence of an alcohol provided ketone 74, which was converted into (±)-ajugarin-IV (66) (Scheme 6). - 19 -Scheme 6 on K a k i s a w a e t a l . u a l s o employed t h e W i e l a n d - M i e s c h e r k e t o n e (70) as a s t a r t i n g m a t e r i a l f o r t h e s y n t h e s e s o f ( i ) - a n n o n e n e ( 6 5 ) . F u r t h e r -more, t h e y a l s o u s e d an a l k a l i metal-ammonia r e d u c t i o n t o p r o v i d e t h e t r a n s - f u s e d r i n g j u n c t i o n (Scheme 7 ) . However, t h e y employed a C l a i s e n r e a r r a n g e m e n t p r o c e s s t o i n t r o d u c e t h e r e q u i r e d s i d e c h a i n a t C-9. T h i s r e a c t i o n was f o u n d t o be l e s s s t e r e o s e l e c t i v e t h a n t h e r e d u c t i v e a l k y l a t i o n m e n t i o n e d above and p r o v i d e d an 85:15 m i x t u r e o f the a l d e -hydes 75 and 76, r e s p e c t i v e l y . Subsequent c a t a l y t i c h y d r o g e n a t i o n o f t h e c a r b o n - c a r b o n d o u b l e bond i n 75 p r o v i d e d t h e a l d e h y d e 77, w h i c h was c o n v e r t e d i n t o (±)-annonene (65) (Scheme 7 ) . - 20 -/ C l a i s e n Scheme 7 Ley e t _ a l . 2 2 employed a very d i f f e r e n t approach and b u i l t up the required d e c a l i n system from the keto d i t h i o a c e t a l 78. In t h i s case, the necessary C-8 and C-9 substituents were already present i n compound 78 and an annulation sequence was employed to construct the carbon skeleton of r i n g A. Thus, compound 78 was treated with (CH2= CHCH2CH2)2CuMgBr to provide the o l e f i n 79, which was treated success-- 21 -i v e l y with borane-dimethyl s u l f i d e complex and hydrogen peroxide-sodium hydroxide to give the alcohol 80. The l a t t e r material was oxidized to the aldehyde 81 which underwent an a l d o l condensation to provide the enone 82 (Scheme 8). The remaining appendages were added stereoselec-t i v e l y to the annulated product 82 to give 83, which was converted into (±)-ajugarin-I (67) (Scheme 8). Scheme 8 - 22 -A s l i g h t l y d i f f e r e n t approach was employed by Tokoroyama et a l . 2 4 a i n the t o t a l synthesis of (±)-maingayic a c i d (68). Reaction of 3,4-di-methyl-2-cyclohexen-l-one (84) with CH2=CHMgBr.(n-Bu^PCuI)^ complex, followed by trapping of the r e s u l t i n g enolate anion with formaldehyde provided the alcohol 85. Mesylation of the l a t t e r material gave compound 86 which was treated successively with [RCH2COCH~CC>2CH3]Na+ and methanolic hydrogen chloride, to a f f o r d the decalone 87 (Scheme 9). The C-5 substituent was then introduced. By a proper choice of conjugate a d d i t i o n reagent, e i t h e r the trans-fused or c i s - f u s e d b i c y c l i c product could be obtained s e l e c t i v e l y . For example, treatment of the enone 87a successively with Me 2CuLi, formaldehyde, methanesulfonyl c h l o r i d e , and l,8-diazabicyclo[5.4.0]undec-7-ene provided the c i s - f u s e d decalone 88 (equation 13). On the other hand, treatment of 87b with diethylaluminum 87b R=Me Scheme 9 - 23 -cyanide provided the trans-fused decalone 89 s t e r e o s e l e c t i v e l y (Scheme 10). Thus, t h i s approach provided access to both the trans- and c i s -clerodane systems. The n i t r i l e 89 was converted into (±)-maingayic a c i d (68) (Scheme 10). Scheme 10 Recently, the Japanese group employed the same method to construct the b i c y c l i c substructure of (-)-methyl kolavenate (69). 2^k The s t a r t i n g material was the enantiomerically pure (R)-3,4-dimethyl-2-cyclo-hexen-l-one (90), which was converted into the o p t i c a l l y a c t i v e decalone 91 . Hydrocyanation of the l a t t e r material provided the n i t r i l e 92, which was converted into (-)-methyl kolavenate (69) (Scheme 11). In a d d i t i o n to the syntheses of clerodane-type diterpenoids summa-r i z e d above, Goldsmith et a l . 2 5 and Kato et a l . 2 ^ have reported p r e l i m i -- 24 -n a r y s t u d i e s on t h e p o t e n t i a l a p p l i c a t i o n o f a D i e l s - A l d e r r e a c t i o n i n t h e c o n s t r u c t i o n o f t h e c l e r o d a n e d e c a l i n s u b s t r u c t u r e . B o t h groups chose t h e s u b s t i t u t e d q u inone 93 as t h e s t a r t i n g m a t e r i a l and con-s t r u c t e d t h e d e c a l i n s k e l e t o n i n t h e f i r s t s t e p . F o r example, a D i e l s - A l d e r r e a c t i o n o f t h e d i e n e 94 w i t h t h e q u i n o n e 9 3 , 2 6 f o l l o w e d by s u i t a b l e r e d u c t i o n s and e q u i l i b r a t i o n , p r o v i d e d t h e k e t o n e 95. Subse-qu e n t s u c c e s s f u l t r a n s f o r m a t i o n o f 95 i n t o t h e k e t o n e 96 and t h e n i t r i l e 97 opened up a new p o t e n t i a l r o u t e t o t h e t o t a l s y n t h e s i s o f c l e r o d a n e s (Scheme 1 2 ) . A d i s t i n c t l y d i f f e r e n t s y n t h e t i c a p p r o a c h t o t h e s y n t h e s i s o f c l e r o d a n e s has been r e p o r t e d by ApSimon e t _ a l . 2 ^ I n s t e a d o f i n t r o d u c i n g t h e s i d e c h a i n i n t o t h e d e c a l i n by a l k y l a t i o n , t h e y made use o f t h e - 25 -Scheme 12 cleavage of the c y c l i c hemiacetal 98 to prepare 99. The key i n t e r -mediate 98 was prepared i n f i v e steps, which included the condensation of 2-methyl-l,3-cyclohexadione (100) with the hydroxy a,^-unsaturated ketone 101, the c a t a l y t i c hydrogenation of the condensation product 102, the a d d i t i o n of methyl magnesium bromide to the hydrogenation product 103, dehydration of the resultant alcohol 104, and the hydration of the enol ether function i n 105 (see Scheme 13). Provided that the necessary v i c i n a l methyl groups at C-8 and C-9 can be introduced stereoselec-t i v e l y , compound 98 would be a valuable intermediate f o r the t o t a l synthesis of clerodanes. - 26 -Scheme 13 - 27 V I . Aim As m e n t i o n e d p r e v i o u s l y , a new m e t h y l e n e c y c l o h e x a n e a n n u l a t i o n sequence h a d been d e v e l o p e d i n o u r l a b o r a t o r y . F u r t h e r m o r e , as a l s o n o t e d e a r l i e r , t h e r e a r e a f a i r number o f known n a t u r a l l y o c c u r r i n g t e r p e n o i d s t h a t p o s s e s s a m e t h y l e n e c y c l o h e x a n e m o i e t y as p a r t o f t h e i r c a r b o n s k e l e t o n . I n t h e a n n u l a t i o n r e a c t i o n between 3 - m e t h y l - 2 - c y c l o -h e x e n - l - o n e (106) and t h e G r i g n a r d r e a g e n t 40, t h e d e c a l o n e 49 i s o b t a i n e d as t h e major p r o d u c t (Scheme 1 4 ) . 1 2 The l a t t e r m a t e r i a l Scheme 14 p o s s e s s e s t h e same r e l a t i v e s t e r e o c h e m i s t r y a t t h e r i n g j u n c t i o n and t h e same m e t h y l e n e c y c l o h e x a n e m o i e t y as t h e n a t u r a l p r o d u c t s p a l a u o l i d e (55), i s o l i n a r i d i o l (64) and i s o l i n a r i d i o l d i a c e t a t e (61). Thus, i t was d e c i d e d t o a t t e m p t t h e t o t a l s y n t h e s e s o f t h e s e n a t u r a l p r o d u c t s v i a r e a c t i o n sequences i n w h i c h t h e m e t h y l e n e c y c l o h e x a n e a n n u l a t i o n p r o c e s s w o u l d p l a y a k e y r o l e . - 28 -61 - 29 -DISCUSSION I . T o t a l S y n t h e s i s o f (±)-Palauolide (55) A. R e t r o s y n t h e t i c A n a l y s i s Our r e t r o s y n t h e t i c a n a l y s i s o f (±)-palauolide (55) was b a s e d on t h e p r e m i s e t h a t t h e d e c a l i n s u b s t r u c t u r e o f t h i s s u b s t a n c e w o u l d be p r e p a r e d r e a d i l y by use o f t h e m e t h y l e n e c y c l o h e x a n e a n n u l a t i o n method d i s c u s s e d i n t h e I n t r o d u c t i o n s e c t i o n o f t h i s t h e s i s . D i s c o n n e c t i o n o f t h e c a r b o n - c a r b o n d o u b l e bond a t o t h e b u t e n o l i d e m o i e t y , a l o n g w i t h s u i t a b l e f u n c t i o n a l i z a t i o n o f t h e r e s u l t a n t f r a g -ments, w o u l d p r o v i d e t h e o,/3-unsaturated a l d e h y d e 107 and t h e s t a b i l i z e d p hosphorane 108. I t was e x p e c t e d t h a t t he phosphorane 108 w o u l d c o u p l e w i t h t h e a l d e h y d e 107 t o g i v e p r i m a r i l y t h e d e s i r e d E o l e f i n . The phosphorane 108 was a n t i c i p a t e d t o be a v a i l a b l e f r o m t h e c h l o r i d e 109, w h i c h , i n t u r n , s h o u l d be p r e p a r a b l e from t h e 2 - t r i m e t h y l s i l y l f u r a n 110. R e c e n t l y , 2 - t r i m e t h y l s i l y l f u r a n d e r i v a t i v e s have been s u c c e s s f u l l y p h o t o - o x y g e n a t e d t o a f f o r d 7 - h y d r o x y b u t e n o l i d e s . 2 8 S u i t a b l e r e t r o s y n t h e t i c f u n c t i o n a l group i n t e r c o n v e r s i o n s o f t h e a l d e h y d e 107 w o u l d p r o v i d e t h e n i t r i l e 111. D i s c o n n e c t i o n a t t h e c a r b o n - c a r b o n bond j o i n i n g t h e s i d e c h a i n and t h e b i c y c l i c s y stem, a l o n g w i t h s u i t a b l e f u n c t i o n a l i z a t i o n o f t h e r e s u l t a n t f r a g m e n t s , w o u l d p r o v i d e t h e n i t r i l e 112 and t h e h o m o a l l y l i c i o d i d e 113. A l k y l a t i o n o f the n i t r i l e 112 w i t h t h e l a t t e r s u b s t a n c e w o u l d , f o r s t e r i c r e a s o n s , be - 31 -expected to take place with the desired stereochemistry to form the required n i t r i l e 111. Disconnection of the n i t r i l e group of 112, along with i n t r o d u c t i o n of a s u i t a b l e f u n c t i o n a l group, would provide the ketone 114. The l a t t e r material was a n t i c i p a t e d to be the thermodyna-m i c a l l y most stable product derived from a methylenecyclohexane annula-t i o n r e a c t i o n i n v o l v i n g the vinylstannane 39 and the enone 115. Thus, the c o r r e c t r e l a t i v e stereochemistry of three of the c h i r a l centers i n the b i c y c l i c r i n g system was expected to be i n s t a l l e d at the annulation stage of the synthesis. A r e t r o s y n t h e t i c disconnection, along with s u i t a b l e f u n c t i o n a l group interconversions i n v o l v i n g the homoallylic iodide 113, would provide the Z chloro pentenoate 116. This ester was expected to be a v a i l a b l e from the chloro pentynoate 117. Previous work i n our l a b o r a t o r i e s had shown that the elements of trimethylstannane can be added regioselec-t i v e l y to a,y9-acetylenic esters and that the stereochemistry of such additions may be c o n t r o l l e d by a j u d i c i o u s choice of reagents and r e a c t i o n c o n d i t i o n s . 2 ^ B. Synthesis of the n i t r i l e 112 3-Methyl-2-cyclohexen-1-one (106) was k i n e t i c a l l y deprotonated by treatment with l i t h i u m diisopropylamide i n THF at -78°C. The resultant enolate anion was allowed to react with iodomethane to a f f o r d , on the basis of a g l c analysis and ^H nmr spectroscopy, e x c l u s i v e l y the desired 3,6-dimethyl-2-cyclohexen-l-one (115) i n 93% y i e l d (equation 1 4 ) . 3 0 The - 32 -i r spectrum of 115 exhibited an absorption at 1672 cm"!, i n d i c a t i n g the presence of an a,^-unsaturated six-membered r i n g ketone. The nmr spectrum of 115 exhibited a broad s i n g l e t at 6 1.96 due to the v i n y l methyl group and a doublet at 8 1.13 (J - 7 Hz) due to the secondary methyl group. Reaction of the (trimethylstannyl)copper(I) reagent 3 5 i U with 5-chloro-l-pentyne (118)* i n THF at -78°C for 6 h afforded, on the basis of a glc a n a l y s i s , a mixture of the desired chloro vinylstannane 39 and i t s isomer 119 3^ i n a r a t i o of 85:15, r e s p e c t i v e l y (equation 15). Fortunately, when t h i s mixture was subjected to (slow) column chromato-graphy on s i l i c a g e l , only the desired vinylstannane 39 was recovered (62% y i e l d ) . ^ However, when the mixture was subjected to f l a s h column chromatography, both isomers could be recovered, but were not cleanly separated. A f t e r a s o l u t i o n of a mixture of these two isomeric materi-a l s i n aqueous a c e t i c acid-THF had been s t i r r e d at room temperature for 12 h, only the vinylstannane 39 was recovered (30%). Glc analysis i n d i c a t e d t o t a l disappearance of the other isomer. These experiments i n d i c a t e d that while both isomers are susceptible to acid-catalyzed destannylation, the minor isomer 119 i s more l a b i l e . * This material i s commercially a v a i l a b l e from A l d r i c h Chemical Company. - 33 -The nmr spectrum of 39 showed signals due to two o l e f i n i c protons ( H A and Hg) as a p a i r of doublet of t r i p l e t s at 6 5.71 (J = 2.5, 1.2 H z> ^Sn-H = 1 5 0 H z> a n d 5 - 2 3 <i = 2.5, 0.8 Hz, J S n . H = 70 H z ) , 3 2 r e s p e c t i v e l y . HC=C(CH2)3Cl 118 1. Me 3SnCu.Me 2S (35) THF, -78°C, 6h 2. HOAc, aq NHjCl / ^ C H 2 ) 3 C I 39 Me3Sn + HcH2,3C, , , K 85:15 119 The vinylstannane 39 was transmetalated by a d d i t i o n of an ethereal s o l u t i o n of methyllithium to a THF s o l u t i o n of 39 at -78°C. 1 2 The r e s u l t a n t v i n y l l i t h i u m reagent 120 was converted into the corresponding Grignard reagent 40 by a d d i t i o n of s o l i d magnesium bromide-etherate. Successive a d d i t i o n of copper(I) bromide-dimethyl s u l f i d e complex, boron t r i f l u o r i d e - e t h e r a t e and the enone 115 gave a b r i g h t yellow s l u r r y which was s t i r r e d at -78°C f o r 3 h. A f t e r appropriate workup, a mixture of two epimeric chloro ketones 121 was obtained i n 77% y i e l d (equation 16). 'SnMe3 MeLi.THF -78°C 120 MgBr 2.Et 20 -78°C 1. CuBr.Me 2S B F 3 . E t 2 0 ketone 115 -MgBr 2- a l N H 4 C 1 40 (16) The i r spectrum of 121 exhibited absorptions at 1705 and 905 cm"1, i n d i c a t i n g the presence of a saturated six-membered c y c l i c ketone and a terminal double bond, re s p e c t i v e l y . Upon exposure to potassium tert-butoxide i n t e r t - b u t y l alcohol at - 34 -30°C f o r 12 h, the chloro ketones 121 underwent intramolecular a l k y l a -t i o n and the i n i t i a l l y formed annulation product(s) was (were) e q u i l i -brated to produce a 94:6 mixture of the ketones 114 and 122, r e s p e c t i v e l y i n 89% y i e l d (equation 17). A pure sample of each isomer was obtained by subjecting a portion of the crude product to column chromatography on s i l i c a gel impregnated with 25% s i l v e r n i t r a t e . The iH nmr spectrum of the major product 114 showed signals due to the o l e f i n i c protons (5 4.70, broad s i n g l e t ) , the secondary methyl group (5 0.99, doublet, J = 6 Hz) and the angular methyl group (5 0.87, s i n g l e t ) . By c o r r e l a t i o n of the l a t t e r value with the chemical s h i f t s of the angular methyl groups i n trans- and cis-1-decalones (6 0.75-0.9 and 1.05-1.20, r e s p e c t i v e l y ) , as reported by Boeckman et a l . . 3 3 114 was t e n t a t i v e l y assigned a trans-fused r i n g junction. The ^H nmr spectrum of 122 exhibited two o l e f i n i c s i g n a l s at S 4.74 and 4.63. The signals due to the angular and the secondary methyl groups appeared at S 1.31 and 0.98 (J = 6 Hz), r e s p e c t i v e l y . By c o r r e l a t i o n of the former value with Boeckman's data, 122 was tenta-t i v e l y assigned a c i s - f u s e d r i n g j u n c t i o n . Since there are two epimerizable c h i r a l centres i n the annulation product(s), four isomeric products, possessing structures 114, 123, 122, and 124, could have been produced. Based on conformational analysis, - 35 -s t r u c t u r e s 114 and 122 (see c o n f o r m a t i o n s 114a and 122a) w o u l d be e x p e c t e d t o be more s t a b l e t h a n s t r u c t u r e s 123 and 124 ( c o n f o r m a t i o n s 123a and 124a). M o l e c u l a r mechanics c a l c u l a t i o n s ( M M 2 ) 3 4 p r e d i c t e d t h a t s t r u c t u r e 114 w o u l d be more s t a b l e t h a n s t r u c t u r e 122 by -0.7 k c a l m o l ' l . A l t h o u g h t h i s e n e r g y d i f f e r e n c e i s n o t l a r g e enough t o r e s u l t i n an e q u i l i b r i u m r a t i o o f 94:6, t h e c a l c u l a t i o n d i d i n d i c a t e t h a t t h e m a j o r a n n u l a t i o n p r o d u c t s h o u l d be t h e t r a n s i s o m e r 114. 114 123 122 124 1Ka 123a 122a 1 2 4 a L i t h i u m aluminum h y d r i d e r e d u c t i o n o f t h e k e t o n e 114 ( d i e t h y l e t h e r s o l u t i o n , room t e m p e r a t u r e , 3 h) a f f o r d e d e x c l u s i v e l y t h e a x i a l a l c o h o l 125 i n 84% y i e l d ( e q u a t i o n 18). The s t e r e o s e l e c t i v i t y o f t h i s r e d u c t i o n i s p r i m a r i l y due t o t h e f a c t t h a t a p p r o a c h o f t h e h y d r i d e r e a g e n t t o t h e a - f a c e o f t h e k e t o n e i s h i n d e r e d by t h e a n g u l a r m e t h y l group, whereas /3 a t t a c k i s r e l a t i v e l y u n h i n d e r e d . On t h e o t h e r hand, d i s s o l v i n g m e t a l r e d u c t i o n ( c a l c i u m , l i q u i d ammonia) o f t h e k e t o n e 114 a t -33°C f o r 10 m i n a f f o r d e d s t e r e o s e l e c t i v e l y t h e t h e r m o d y n a m i c a l l y more s t a b l e e q u a t o r i a l a l c o h o l 126 i n 75% y i e l d ( e q u a t i o n 19). 36 -The i r spectrum of 125 showed a broad absorption at 3490 cm" , i n d i c a t i n g the presence of an alcohol group. The ^ H nmr spectrum of 125 exhibited a broad s i n g l e t at S 3.56 for the >CH0H proton. The f a c t that t h i s proton was only weakly coupled with i t s v i c i n a l neighboring protons i n d i c a t e d that i t was e q u a t o r i a l l y o r i e n t e d . 3 4 a The alcohol 126 exhib-i t e d a broad i r absorption at 3300 cm"1. The ^H nmr spectrum showed a t r i p l e t at J 3.04 (J = 9 Hz) for the >CH0H proton. Thus, i n t h i s case, 3 4 a i t was c l e a r that the ca r b i n o l proton was i n an a x i a l o r i e n t a t i o n . Treatment of the alcohol 126 with j > -toluenesulfonyl ch l o r i d e i n the presence of 4-N,N-dimethylaminopyridine i n dichloromethane at room temperature f o r 12 h afforded the p.-toluenesulfonate 127 i n 83% y i e l d (equation 20). Reaction of the l a t t e r material 127 with sodium cyanide i n HMPA at 80°C for 3 h provided the a x i a l n i t r i l e 112a i n 44% y i e l d (equation 21). 37 -127 112a The i r s p e c t r u m o f 112a e x h i b i t e d a n i t r i l e a b s o r p t i o n a t 2225 cm'^. I n t h e nmr s p e c t r u m o f 112a t h e >CH-CN p r o t o n a p p e a r e d as a t r i p l e t o f d o u b l e t s a t 5 2.60 ( J = 4.5, 1.3 H z * ) , i n d i c a t i n g t h a t t h i s p r o t o n i s e q u a t o r i a l l y o r i e n t a t e d . The s i g n a l due t o t h e a n g u l a r m e t h y l group was s t r o n g l y d e s h i e l d e d b y t h e n i t r i l e group (1,3 d i a x i a l r e l a t i o n s h i p ) and ap p e a r e d a t 5 1.24. T h i s c h e m i c a l s h i f t may be compared w i t h t h a t o f th e a n g u l a r m e t h y l group o f 126 (6 0.98). These o b s e r v a t i o n s f u r t h e r s u p p o r t e d t h e a s s i g n m e n t o f a t r a n s - f u s e d r i n g j u n c t i o n t o k e t o n e 114, s i n c e s u c c e s s i v e metal-ammonia r e d u c t i o n , t o s y l a t i o n , and n i t r i l e f o r m a t i o n on t h e c i s - f u s e d 1-decalone 122 w o u l d n o t g i v e a n i t r i l e i n w h i c h t h e a n g u l a r m e t h y l group c o u l d be d e s h i e l d e d b y t h e n i t r i l e group (Scheme 15). The p r e p a r a t i o n o f t h e d e s i r e d n i t r i l e 112 f r o m t h e k e t o n e 114 v i a The o r i g i n o f t h e s m a l l c o u p l i n g ( J - 1.3 Hz) i s n o t known. - 38 -122 Scheme 15 th e r o u t e d e s c r i b e d above was b o t h t e d i o u s and low y i e l d i n g . T h e r e f o r e , a more d i r e c t r o u t e was i n v e s t i g a t e d . T r e a t m e n t o f a 94:6 m i x t u r e o f th e k e t o n e s 114 and 122, r e s p e c t i v e l y , w i t h p . - t o l u e n e s u l f o n y l m e t h y l i s o c y a n i d e 3 5 and p o t a s s i u m t e r t - b u t o x i d e i n HMPA a t 45°C f o r 88 h gave, b a s e d on a g l c a n a l y s i s , a 15:85 m i x t u r e o f n i t r i l e s 112a and 112b, r e s p e c t i v e l y , i n 68% y i e l d ( e q u a t i o n 22). CN C H 3 - Q - S O 2 C H 2 N S C tert-BuOK, HMPA 114 122 112a 112b 15:85 Column chromatography o f a p o r t i o n o f t h i s m i x t u r e on s i l i c a g e l i m p r e g n a t e d w i t h 25% s i l v e r n i t r a t e a f f o r d e d a p u r e sample o f each compound. The m i n o r i s o m e r e x h i b i t e d s p e c t r a i d e n t i c a l w i t h t h o s e o f th e a x i a l n i t r i l e 112a o b t a i n e d from t h e r o u t e d e s c r i b e d e a r l i e r . The majo r i s o m e r e x h i b i t e d a n i t r i l e a b s o r p t i o n a t 2225 cm" 1 i n t h e i r - 39 -sp e c t r u m . The i H nmr s p e c t r u m showed a t r i p l e t a t 6 2.08 ( J = 11.5 Hz) f o r t h e >CH-CN p r o t o n , i n d i c a t i n g t h a t t h i s p r o t o n was a x i a l l y o r i e n -t a t e d , and a s i n g l e t a t 5 0.96 f o r t h e a n g u l a r m e t h y l group, i n d i c a t i n g t h a t t h e m e t h y l group was n o t 1,3 d i a x i a l t o t h e n i t r i l e group ( c f . t he a n g u l a r m e t h y l o f 112a ap p e a r e d a t 5 1.24). S i n c e t h e r e s t o f t h e ^ H nmr s p e c t r u m was v e r y s i m i l a r t o t h a t o f t h e min o r i s o m e r , t h e major i s o m e r was a s s i g n e d s t r u c t u r e 112b. The e x c l u s i v e f o r m a t i o n o f t h e t r a n s - f u s e d n i t r i l e s 112a and 112b i s i n a c c o r d w i t h r e p o r t s t h a t t r a n s - 1 - d e c a l o n e s u s u a l l y r e a c t f a s t e r w i t h n u c l e o p h i l e s t h a n t h e c o r r e s p o n d i n g c i s - l - d e c a l o n e s . T h e r e f o r e , under r e a c t i o n c o n d i t i o n s i n w h i c h t h e two k e t o n e s a r e i n e q u i l i b r i u m , t h e p r o d u c t s a r e e x p e c t e d t o be d e r i v e d m a i n l y o r even s o l e l y from the t r a n s - 1 - d e c a l o n e . 3 ^ F o r example, M a r s h a l l e t a l . ^ r e p o r t e d t h a t t r e a t m e n t o f a 2:1 m i x t u r e o f t h e 1-dec a l o n e s 128 and 129, r e s p e c t i v e l y , w i t h m e t h y l e n e - t r i p h e n y l p h o s p h o r a n e i n d i m e t h y l s u l f o x i d e a f f o r d e d an 87:13 m i x t u r e o f t h e t r a n s - and c i s - f u s e d a l k e n e s 130 and 131, r e s p e c t i v e l y ( e q u a t i o n 23). K a t o e t _ _ a l . , 2 6 b r e p o r t e d t h a t t r e a t m e n t o f the k e t o n e 96 w i t h p _ - t o l u e n e s u l f o n y l m e t h y l i s o c y a n i d e and p o t a s s i u m t e r t - b u t o x i d e p r o d u c e d o n l y t h e t r a n s - f u s e d n i t r i l e 97 ( e q u a t i o n 24). (23) 128 129 130 131 87:13 - 40 -96 97 When a 15:85 m i x t u r e o f t h e n i t r i l e s 112a and 112b, r e s p e c t i v e l y , was d e p r o t o n a t e d w i t h l i t h i u m d i i s o p r o p y l a m i d e i n HMPA -THF a t 0°C and th e r e s u l t a n t a n i o n was a l k y l a t e d w i t h n - b u t y l i o d i d e , o n l y t h e n i t r i l e 132 was o b t a i n e d i n 92% y i e l d ( e q u a t i o n 25). T h i s r e s u l t f u r t h e r s u p p o r t e d t h e e a r l i e r c o n c l u s i o n t h a t t h e n i t r i l e s 112a and 112b a r e e p i m e r i c o n l y a t t h e c a r b o n b e a r i n g t h e n i t r i l e group. The h i g h s t e r e o s e l e c t i v i t y o f t h e a l k y l a t i o n i s p r o b a b l y due t o t h e f a c t t h a t a l k y l a t i o n o f t h e n i t r i l e a n i o n f r o m t h e a f a c e o f t h e m o l e c u l e i s s t e r i c a l l y h i n d e r e d by t h e a n g u l a r m e t h y l group whereas t h e p f a c e i s r e l a t i v e l y u n h i n d e r e d . Thus, p r e d o m i n a n t o r e x c l u s i v e f o r m a t i o n o f t h e n i t r i l e 132 w o u l d be e x p e c t e d . 1120. 112b 15:85 T r e a t m e n t o f a THF s o l u t i o n o f 15:85 m i x t u r e o f t h e a x i a l and e q u a t o r i a l n i t r i l e s 112a and 112b, r e s p e c t i v e l y , w i t h l i t h i u m d i i s o -p r o p y l a m i d e i n t h e absence o f HMPA, f o l l o w e d by a d d i t i o n o f i o d o -methane, p r o v i d e d a 15:85 m i x t u r e o f t h e a l k y l a t e d p r o d u c t and t h e o r i g i n a l e q u a t o r i a l n i t r i l e 112b, r e s p e c t i v e l y . Thus, under t h e s e c o n d i t i o n s , o n l y t h e a x i a l n i t r i l e 112a underwent d e p r o t o n a t i o n . - 41 -The nmr spectrum of 132 exhibited a s i n g l e t at 6 1.26 due to the angular methyl group, which i s deshielded by the a x i a l n i t r i l e (1,3 d i a x i a l r e l a t i o n s h i p ) . I t may be r e c a l l e d that the angular methyl groups of the a x i a l and equatorial n i t r i l e s 112a and 112b appeared at S 1.24 and 0.96, r e s p e c t i v e l y . The exclusive formation of 132 demon-st r a t e d that a high stereochemical c o n t r o l of the desired r e l a t i v e stereochemistry of the newly formed c h i r a l centre i s poss i b l e . C. Synthesis of the homoallylic iodide 113 Reaction of 3-butyn-l-ol (133) with phosphorus t r i c h l o r i d e - d i m e t h y l -formamide 3 8 at room temperature f or 40 min afforded, a f t e r two c a r e f u l f r a c t i o n a l d i s t i l l a t i o n s of the crude product, the v o l a t i l e chloro alkyne 1 3 4 ^ i n 42% y i e l d (equation 26). I t was necessary that the reagents and solvent be c a r e f u l l y p u r i f i e d before use, otherwise no desired material was obtained. The i r spectrum of 134 exhibited absorptions at 3000 and 2120 cm"-1-, i n d i c a t i n g the presence of a terminal alkyne function. The -^H nmr spectrum of 134 showed a t r i p l e t at 6 3.63 (J = 7 Hz) for the -CH2CI This alcohol i s commercially a v a i l a b l e from A l d r i c h Chemical Company. - 42 -protons, a doublet of t r i p l e t s at 8 2.68 (J = 2.5, 7 Hz) for the -CH2CH2C1 protons and a t r i p l e t at 5 2.11 (J = 2.5 Hz) for the a c e t y l e n i c proton. A s o l u t i o n of the chloro alkyne 134 i n THF was treated with an ethereal s o l u t i o n of methyllithium at -78°C. The r e s u l t a n t acetylenic anion was allowed to react with ethyl chloroformate at -20°C f o r 1 h and then at room temperature for 1 h. A f t e r appropriate workup and column chromatography of the crude product on s i l i c a g e l , the required a c e t y l e n i c ester 117 was obtained i n 63% y i e l d (equation 27). The i r spectrum of 117 showed the acetylene and carbonyl absorptions at 2235 and 1710 cnT^, r e s p e c t i v e l y . ^ C 0 2 E t ( 2 ? ) 117 Reaction of l i t h i u m (trimethylstannyl)(phenylthio)cuprate 1 3 5 w i t h the a c e t y l e n i c ester 117 i n THF at -48°C f o r 4 h 2 9 afforded a 4:1 mixture of the desired ester 116 and the b i s ( t r i m e t h y l s t a n n y l ) compound 136, r e s p e c t i v e l y (equation 28). When t h i s mixture was subjected to c a r e f u l f r a c t i o n a l d i s t i l l a t i o n and column chromatography, a pure sample of each compound was obtained. The i r spectrum of 116 showed an absorption at 1704 cnT^, i n d i c a t i n g the presence of an a,/9-unsaturated ester group. The ^H nmr spectrum of 116 exhibited a broad t r i p l e t at 8 3.56 due to the C lC^-protons and a t r i p l e t at 8 6.43 (J = 1.1 Hz, J_sn_H — 114 Hz) due to the o l e f i n i c proton. The coupling constant J _ s n _ H of 114 Hz i n d i c a t e d that t h i s product possessed the Z geometry. 3 2 1. MeLi, T H F 2. ClC0 2Et ci--C02Et 117 - 43 1. [ M e 3SnCuSPh]Li (135) THE, -48°C, 4h 2. aq. NH4C1 CI M e j S n nMe3 C02Et 116 A +-1 nMe3 ^ /C0 2 Et 136 (28) The i r spectrum of 136 exhibited a carbonyl absorption at 1702 cm"1 while the nmr spectrum showed two signals (5 0.22, 0.12) due to the trimethylstannyl groups. Furthermore, a m u l t i p l e t at 5 0.83 due to the Me3SnCH.2CH2- protons indicated that the chlorine had been replaced by a trimethylstannyl group. This conclusion was supported by the high r e s o l u t i o n mass spectrum of 136 which indicated that the M+-CH3 peak had a mass corresponding to Cj2H2502^^n 2 • This n u c l e o p h i l i c s u b s t i t u t i o n of a chloride by a trimethylstannyl group had not been observed previously i n our la b o r a t o r i e s when s i m i l a r reactions had been c a r r i e d out on higher homologues of the acetylenic ester 117.^ u j n order to eliminate the undesired s u b s t i t u t i o n reaction, the synthetic route f or preparing the homoallylic iodide 113 was modified by repl a c i n g the chlorine atom by a t e r t - b u t y l d i m e t h y l s i l y l o x y group (Scheme 16). O ^ C K CO^t nMe; ^ C 0 2 E t Scheme 16 139 - 44 -Reaction of 3-butyn-l-ol (133) with t e r t - b u t y l d i m e t h y l s i l y l c h l o r i d e i n the presence of imidazole i n dimethylformamide at room temperature fo r 12 h afforded the alkyne 137 i n 98% y i e l d (equation 2 9 ) . 4 1 The i r spectrum of 137 showed absorptions at 3300 and 2100 cm"1, i n d i c a t i n g the presence of a terminal alkyne. A s o l u t i o n of the l a t t e r material 137 i n THF was treated with methyllithium at -78°C. The r e s u l t a n t anion was allowed to react with ethyl chloroformate at -20°C f o r 1 h and then at room temperature f o r 1 h. The required pentynoate 138 was obtained i n 90% y i e l d (equation 30). The i r spectrum of 138 showed absorptions at 2230 and 1705 cm"1, i n d i c a t i n g the presence of an alkyne and a conjugated ester carbonyl group, r e s p e c t i v e l y . 133 TBDMSCl, imidazole DMF (29) 1. MeLi, THF 2. ClC0 2Et C02Et (30) Treatment of the pentynoate 138 with l i t h i u m (trimethylstan-nyl) (phenylthio)cuprate 135 3 9 i n THF at -40°C f o r 9 h afforded, a f t e r workup, the Z ester 139 i n 91% y i e l d (equation 31). The 1H nmr spectrum of 139 exhibited a s i n g l e t at 6 0.18 (J.sn-H = 52/54 Hz), i n d i c a t i n g the presence of a trimethylstannyl group. The o l e f i n i c proton appeared at - 45 C02Et [Me SnCuSPhjLi \ 2. aq. NH CI nMe3 139 8 6.40 as a t r i p l e t (J = 1 Hz, Js n-H = 1 2 0 H z ) • T n e value of l^n-W confirmed the Z geometry of the e s t e r . 3 2 The ^H nmr spectrum also showed s i n g l e t s at 5 0.90 and 0.04 due to the methyl protons of the t e r t - b u t y l s i l y l o x y group, confirming that the ether linkage was i n t a c t . Diisobutylaluminum hydride reduction of the ester 139 i n THF at -78°C f o r 1 h and then at 0°C for 1 h provided the a l l y l i c alcohol 140 i n 96% y i e l d (equation 32). The i r spectrum of 140 showed a broad absorption at 3350 cm"-'-, i n d i c a t i n g the presence of a hydroxy group. The ^H nmr spectrum of 140 showed a t r i p l e t at 8 4.08 (J = 6 Hz, collapsed to a doublet on D2O exchange), i n d i c a t i n g the presence of an a l l y l i c alcohol group. Reaction of the alcohol 140 with chloromethyl nMe3 . DIBAL-H, THF . ^ i 0 / ^ ^ C 0 2 E t > > 4 i 0 ^ > ^ 0 H <32> / / 139 methyl ether i n the presence of diisopropylethylamine i n dichloromethane at room temperature for 12 h afforded the ether 141 i n 90% y i e l d (equation 33). The ^H nmr spectrum of 141 showed a s i n g l e t at 8 4.63 for the ac e t a l protons and a s i n g l e t at 5 3.38 for the methoxy protons, i n d i c a t i n g that the methoxymethoxy group had been i n s t a l l e d . - 46 -SnMe CH30CH2C1 i,-Pr 2NEt, CH 2 C1 2 " / -> >-SiO (33) 141 The vinylstannane 141 was transmetalated with methyllithium i n THF at -78°C. The r e s u l t a n t v i n y l l i t h i u m reagent was treated with iodomethane to give the E o l e f i n 142 i n 90% y i e l d (equation 34) . The ^H nmr spectrum of 142 exhibited a broad s i n g l e t at S 1.69 due to the v i n y l methyl group. The s i l y l ether linkage i n compound 142 was cleaved by treatment of t h i s material with tetra-n-butylammonium f l u o r i d e i n THF at room temperature f o r 40 min. The alcohol 143 was produced i n 98% y i e l d (Scheme 17). The i r spectrum of 143 exhibited a broad absorption at 3400 cm"1 due to the hydroxy group. Reaction of the alcohol 143 with p_-toluenesulfonyl c h l o r i d e i n the presence of 4-N .N-dimethylamino-pyr i d i n e i n dichloromethane at room temperature for 12 h gave, a f t e r appropriate workup and column chromatography of the crude product, the p.- toluenesulf onate 144 i n 75% y i e l d (Scheme 17). This material decomposed on heating under vacuum and slowly turned brown on storage - 47 Scheme 17 under argon i n a freezer. The -"-H nmr spectrum of 144 showed two doublets at 6 7.83 (J = 8 Hz) and 7.37 (J - 8 Hz) and a s i n g l e t at 5 2.48 due to the p_-toluenesulf onate group. The p.-toluenesulf onate 144 was r e a d i l y converted into the iodide 113 by treatment with sodium iodide i n dimethylformamide at room temperature i n the dark f o r 4 days (91% y i e l d , Scheme 17). The o v e r a l l y i e l d f o r the synthesis of the homoallylic iodide 113, based on the s t a r t i n g 3-butyn-l-ol (133), was 42%. The high r e s o l u t i o n mass spectrum of 113 showed a molecular i on at m/e 270.0111, consistent with a formula of C3HJ5O2I. An attempt to by-pass the p.-toluenesulfonation step by conversion of the alcohol 143 d i r e c t l y into the iodide 113 using triphenylphosphine d i i o d i d e gave the desired material 113 i n only 21% y i e l d (equation 35). - 48 -D. A l k y l a t i o n of the n i t r i l e 112 with the iodide 113. Attempts to  prepare compound 145 Treatment of a 15:85 mixture of the n i t r i l e s 112a and 112b, r e s p e c t i v e l y (1 mmol), i n THF at 0°C with l i t h i u m diisopropylamide (1.2 mmol) i n the presence of HMPA for 15 min, was followed by a d d i t i o n of the homoallylic iodide 113 (1.3 mmol). The re s u l t a n t s o l u t i o n was gradually warmed to room temperature. Workup gave a mixture of the s t a r t i n g material, 112a and 112b (0.23 mmol), the desired a l k y l a t e d n i t r i l e 111 (0.69 mmol; 94% y i e l d based on recovery of s t a r t i n g m a t e r i a l ) , and the diene 146 (equation 36). 146 - 49 -The p r e s e n c e o f t h e d i e n e 146 i n d i c a t e d t h a t an e l i m i n a t i o n r e a c t i o n was i n c o m p e t i t i o n w i t h t h e d e s i r e d a l k y l a t i o n p r o c e s s . Thus, t h e n i t r i l e a n i o n f u n c t i o n e d n o t o n l y as a n u c l e o p h i l e ( d i s p l a c e m e n t o f i o d i d e ) , b u t a l s o as a base t h a t e f f e c t e d d e h y d r o h a l o g e n a t i o n o f t h e h o m o a l l y l i c i o d i d e 113. The nmr s p e c t r u m o f t h e a l k y l a t e d m a t e r i a l 111 showed t h a t i t c o n s i s t e d o f o n l y one compound ( F i g . 1 ) . The s i g n a l s due t o t h e a n g u l a r m e t h y l group a p p e a r e d a t 6 1.27, i n d i c a t i n g t h a t t h e m e t h y l was 1,3 d i a x i a l t o t h e n i t r i l e group and t h a t t h e p r o d u c t w i t h t h e e x p e c t e d r e l a t i v e s t e r e o c h e m i s t r y had been o b t a i n e d . The s i n g l e t s a t 6 4.62, 3.38 and 1.68 were due t o t h e a c e t a l p r o t o n s , methoxy p r o t o n s and v i n y l m e t h y l p r o t o n s , r e s p e c t i v e l y , on t h e s i d e c h a i n . The i r s p e c t r u m o f 111 showed a b s o r p t i o n s a t 1671 and 1638 cm*-'-, i n d i c a t i n g t h e p r e s e n c e o f t h e t r i s u b s t i t u t e d d o u b l e bond and t h e e x o c y c l i c d o u b l e bond, r e s p e c t i v e l y . The ^H nmr s p e c t r u m o f 146 showed t h r e e s i n g l e t s a t S 4.65, 3.40 and 1.80 due t o t h e a c e t a l , methoxy and v i n y l m e t h y l p r o t o n s , r e s p e c t i v e l y , and a d o u b l e t a t 5 4.22 ( J = 7 Hz) due t o t h e -CH20M0M p r o t o n s . The r e m a i n i n g s i g n a l s a t 5 6.43 (dd, 1H, J = 11, 17 Hz, H A ) , 5.63 ( b r t , 1H, J = 7 Hz, Hg), 5.23 ( d , 1H, J = 17 Hz, H c ) , 5.05 ( d , 1H, J = 11 Hz, Hp) i n d i c a t e d t h e p r e s e n c e o f a d i e n e u n i t w i t h t h e s t e r e o c h e m i s t r y shown. I t i s e v i d e n t t h a t t h e s y n t h e t i c sequence d i s c u s s e d above had p r o d u c e d a p r o d u c t 111 i n w h i c h the r e l a t i v e s t e r e o c h e m i s t r y o f the f o u r c h i r a l c e n t r e s on the d e c a l i n s u b s t r u c t u r e o f p a l a u o l i d e (55) had been c o r r e c t l y e s t a b l i s h e d . The n e x t r e q u i r e d t r a n s f o r m a t i o n was the c o n v e r s i o n o f t h e n i t r i l e group i n t o a m e t h y l group. - 51 -When the n i t r i l e 111 was treated with diisobutylaluminum hydride at room temperature i n benzene, ether, THF or dimethoxyethane, no reduction occurred and the n i t r i l e 111 was recovered i n t a c t . On the other hand, when the reduction was c a r r i e d out i n benzene at 80°C f o r 8 h, a l l the s t a r t i n g material was consumed. A f t e r aqueous workup and aqueous a c i d h y d r o l y s i s of the crude product, there was obtained, on the basis of -^H nmr spectroscopy, a 4:1 mixture of two aldehydes. The ^H nmr spectrum of t h i s mixture showed two aldehyde proton signals at S 9.98 and 9.93. The former s i g n a l was due to the major component which was l a t e r found to be the desired aldehyde 147. No further work was c a r r i e d out to determine the structure of the minor component. Fortunately, reduction of the n i t r i l e i n dimethoxyethane at 60°C for 6 h gave, a f t e r workup and aqueous a c i d h y d r o l y s i s of the crude product, only the desired aldehyde 147 i n 87% y i e l d (equation 37). The intermediate imine 148 was rather i n s e n s i t i v e to the aqueous a c i d workup, and the aldehyde 147 was obtained only a f t e r the imine had been s t i r r e d i n an aqueous THF-acetic a c i d s o l u t i o n at room temperature f o r 12 h. The i r spectrum of the imine 148 showed a broad absorption at 3254 cm"1 due to the N-H group. The i r spectrum of the aldehyde 147 exhibited a strong absorption at 1713 cm"1 due to the carbonyl. In the ^ nmr spectrum of 147, the - 52 -1. DIBAL-H, DME, 60°C 111 148 (37) a l d e h y d e p r o t o n a p p e a r e d a t 5 9.98 as a s i n g l e t and t h e a n g u l a r m e t h y l group gave r i s e t o a s i n g l e t a t S 0.96. To g e n e r a t e t h e r e q u i r e d m e t h y l s u b s t i t u e n t , t h e a l d e h y d e 147 was t r e a t e d w i t h an e x c e s s o f anhydrous h y d r a z i n e (10 e q u i v ) i n m e t h a n o l under r e f l u x f o r 24 h. The r e s u l t a n t h y d r a z o n e 149, w h i c h e x h i b i t e d a b r o a d a b s o r p t i o n a t 3250 cm'^, was a l l o w e d t o r e a c t w i t h p o t a s s i u m h y d r o x i d e 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 3 h. The r e a c t i o n m i x t u r e g r a d u a l l y t u r n e d from c o l o r l e s s t o d a r k brown. Workup and column chro m a t o g r a p h y o f t h e c r u d e p r o d u c t p r o v i d e d two d i f f e r e n t o i l s (equa-t i o n 38) . The more p o l a r component was i s o l a t e d i n 10% y i e l d and i t s s p e c t r a were c o n s i s t e n t w i t h t h o s e e x p e c t e d f o r t h e d e s i r e d d e o x y g e n a t e d m a t e r i a l 145. Thus, t h e nmr s p e c t r u m o f t h i s m a t e r i a l showed s i n g l e t s a t 6 4.63, 3.37 and 1.66 due t o t h e a c e t a l , methoxy and v i n y l m e t h y l p r o t o n s , r e s p e c t i v e l y , on t h e s i d e c h a i n . I t a l s o e x h i b i t e d a b r o a d s i n g l e t a t S 4.51 due t o the e x o c y c l i c o l e f i n i c p r o t o n s and m e t h y l s i g n a l s a t 6 1.05 ( s i n g l e t ) , 0.82 ( d o u b l e t , J = 6 Hz), and 0.74 53 ( s i n g l e t ) . The c h e m i c a l s h i f t s o f t h e s e s i g n a l s a s s o c i a t e d w i t h the d e c a l i n s u b s t r u c t u r e o f 145 were a l m o s t e x a c t l y t h e same as t h o s e r e p o r t e d f o r p a l a u o l i d e ( 5 5 ) 1 4 [ c f . S 4.51 ( s , 2H) , 1.05 ( s , 3H), 0.82 ( d , 3H, J = 7 H z ) , and 0.74 ( s , 3 H ) ] . The l e s s p o l a r p r o d u c t . f r o m t h e W o l f f - K i s h n e r r e d u c t i o n was i s o l a t e d i n 45% y i e l d . I t e x h i b i t e d an i r band a t 1594 cm" 1, i n d i c a t i n g the p r e s e n c e o f a d i e n e m o i e t y . 4 ^ T h i s c o n c l u s i o n was s u p p o r t e d by s i g n a l s a t S 6.45 (dd, 1H, J = 10, 16 Hz, H A ) , 5.20 ( d , 1H, J = 16 Hz, H B ) , 5.04 ( d , 1H, J - 10 Hz, H c ) , 4.97 ( b r t , 1H, J - 6 Hz, H D ) , 1.70 ( b r s, 3H, v i n y l m e t h y l ) i n t h e ^H nmr s p e c t r u m o f t h i s m a t e r i a l and the - 54 -d i s a p p e a r a n c e o f t h e s i g n a l s due t o the methoxymethoxy group. The t h r e e m e t h y l groups o f t h e d e c a l i n s u b s t r u c t u r e a p p e a r e d a t 5 1.06 ( s i n g l e t ) , 0.82 ( d o u b l e t , J = 6 Hz) and 0.78 ( s i n g l e t ) . These c h e m i c a l s h i f t s were s i m i l a r t o t h o s e o f t h e c o r r e s p o n d i n g s i g n a l s i n t h e ^H nmr s p e c t r u m o f 145. Thus, s t r u c t u r e 150 was a s s i g n e d t o t h i s l e s s p o l a r m a t e r i a l . The W o l f f - K i s h n e r r e d u c t i o n o f 147 was c a r r i e d o u t i n d i e t h y l e n e g l y c o l i n t h e p r e s e n c e o f anhydrous p o t a s s i u m c a r b o n a t e , a m i l d e r b a s e , and t h e r e a c t i o n t e m p e r a t u r e was s l o w l y r a i s e d from 110° t o 180°C. T i c a n a l y s i s o f a l i q u o t s o f t h e r e a c t i o n m i x t u r e i n d i c a t e d t h a t t h e r e was no r e a c t i o n u n t i l t h e r e a c t i o n t e m p e r a t u r e r e a c h e d 160°C. F u r t h e r m o r e , b o t h p r o d u c t s 145 and 150 appe a r e d s i m u l t a n e o u s l y . The 3 - p r o t o n v i n y l m e t h y l group s i g n a l a t 5 1.70 i n t h e ^H nmr s p e c t r u m o f t h e d i e n e 150 i n d i c a t e d t h a t t h e e l i m i n a t i o n r e a c t i o n l e a d i n g t o t h i s s u b s t a n c e was h i g h l y r e g i o s e l e c t i v e . T h i s s e l e c t i v i t y c a n be a c c o u n t e d f o r by p o s t u l a t i n g an i n t r a m o l e c u l a r r e a c t i o n mechanism i n w h i c h t h e i n c i p i e n t c a r b a n i o n r e s u l t i n g f r o m d e c o m p o s i t i o n o f the h y d r a z o n e group a b s t r a c t s an a l l y l i c p r o t o n from t h e s i d e c h a i n v i a a five-membered c y c l i c t r a n s i t i o n s t a t e ( s e e Scheme 1 8 ) . I f t h i s p o s t -u l a t e i s c o r r e c t , i t i s a p p a r e n t t h a t t h e e l i m i n a t i o n r e a c t i o n v i a the c y c l i c t r a n s i t i o n s t a t e competes r e l a t i v e l y w e l l w i t h t h e d e s i r e d - 55 -150 145 Scheme 18 intermolecular protonation of the carbanion by the solvent, diethylene g l y c o l (Scheme 18). When the hydrazone 149 was treated with potassium tert-butoxide i n dimethylsulfoxide at room temperature, 4 3 only the diene 150 was i s o l a t e d , i n 36% y i e l d (equation 39). In an attempt to slow down the eli m i n a t i o n process, i t was decided to convert the methoxymethoxy group on the hydrazone 149 to a hydroxy - 56 -group. Thus, the aldehyde 147 was treated with dimethylboron bromide 4 4 i n dichloromethane (-78°C, 1 h) to a f f o r d the alcohol 151 i n 72% y i e l d (equation 40). The i r spectrum of 151 showed absorptions at 3366 and 1714 cm"1 due to the hydroxy group and the carbonyl group, r e s p e c t i v e l y . The -41 nmr spectrum of 151 exhibited a s i n g l e t at 5 9.98 due to the aldehyde proton and a doublet at J 4.14 (J - 8 Hz) due to the ^CCH^OH protons. The aldehyde 151 was allowed to react with anhydrous hydrazine i n r e f l u x i n g methanol f o r 24 h. However, treatment of the re s u l t a n t hydrazone with potassium hydroxide or potassium carbonate i n diethylene g l y c o l at 170°C for 3 h afforded the diene 150 as the only i s o l a b l e product (equation 41). Since a l l these attempts to convert the aldehyde 147 into the - 57 -b i c y c l i c diene 145 using the Wolf-Kishner reduction, f a i l e d to give the desired product i n s y n t h e t i c a l l y u s e f u l y i e l d s , other deoxygenation methods were investigated. Thus, the aldehyde 147 was reduced with l i t h i u m aluminum hydride (ether s o l u t i o n , room temperature) to the alcohol 152 (93%, equation 42). The i r spectrum of 152 showed a broad absorption at 3469 cm"1 due to the hydroxy group. The 1H nmr spectrum of 152 exhibited a p a i r of doublet of doublets at S 3.80 and 3.70 (J = 6, 12 Hz) due to the -CH2OH protons, and each of them collapsed to a doublet (J = 12 Hz) on D2O exchange. These signals also showed a p o s i t i v e enhancement i n a nuclear Overhauser enhancement differ e n c e experiment i n which the si g n a l (5 1.06) due to the angular methyl group was i r r a d i a t e d . This experiment confirmed the expectation that the -CH2OH and angular methyl groups are i n 1,3 d i a x i a l r e l a t i o n s h i p i n the alcohol 152. The alcohol 152 was converted into the corresponding xanthate 153 and the l a t t e r substance was subjected to Barton's deoxygenation conditions. Thus, successive treatment of a s o l u t i o n of the alcohol 152 i n dimethylformamide with 1,8-diazabicyclo[5.4.0]undec-7-ene, carbon d i s u l f i d e , and iodomethane afforded, a f t e r column chromatography of the crude product on s i l i c a gel, the xanthate 153 (100%, equation 4 3 ) . 4 5 - 58 -The -"-H nmr spectrum of 153 showed a s i n g l e t at 8 2.57 due to the -SCH3 protons. The high r e s o l u t i o n mass spectrum of 153 showed a molecular ion at m/e 440.2410, consistent with a formula of £24^40^2^3• Following the conditions normally employed for Barton deoxygena-t i o n , 4 ^ a toluene s o l u t i o n of the xanthate 153 and t r i - n - b u t y l t i n hydride i n the presence of 2 , 2 ' - a z o b i s i s o b u t y r o n i t r i l e (AIBN) was re f l u x e d f o r 4 h. However, no deoxygenation occurred and the xanthate 153 was recovered i n t a c t . I t i s pertinent to note that both Barton 4-' and F r a s e r - R e i d 4 ^ have reported that xanthates of some primary alcohols f a i l e d to undergo the desired deoxygenation. Recently, Barton et a l . 4 - * have reported that s t e r i c a l l y hindered primary alcohols can be deoxygenated e f f i c i e n t l y when a p.-cymene s o l u t i o n of t r i - n - b u t y l t i n hydride i s added slowly to a Q-cymene s o l u t i o n of the corresponding xanthates at 150°C. Under these conditions, the s o l u t i o n contains a very low concentration of t i n hydride and i n the case of our xanthate 153, i t i s c e r t a i n l y possible that the neopentyl r a d i c a l 154 formed would c y c l i z e onto the double bond of the side chain before i t would abstract a hydrogen atom from the t i n hydride. Nevertheless, the reaction was c a r r i e d out and a mixture of compounds was obtained. On the basis of ^H nmr spectroscopy, the - 59 -154 m i x t u r e c o n s i s t e d o f a t l e a s t f o u r compounds w h i c h were n o t s e p a r a b l e by column chromatography on s i l i c a g e l . No f u r t h e r work was c a r r i e d o u t t o d e t e r m i n e t h e s t r u c t u r e o f t h e s e compounds. More r e c e n t l y , R o b i n s e t a l . 4 * * r e p o r t e d t h a t p h e n y l t h i o n o c a r b o n a t e e s t e r s o f a l c o h o l s undergo d e o x y g e n a t i o n more r e a d i l y t h a n t h e c o r r e s -p o n d i n g x a n t h a t e s . F u r t h e r m o r e , t h e d e o x y g e n a t i o n r e a c t i o n c o u l d be c a r r i e d o u t i n t h e p r e s e n c e o f an e x c e s s o f t i n h y d r i d e . Thus, i t was f e l t t h a t , u n d e r . t h e s e c o n d i t i o n s , t h e n e o p e n t y l r a d i c a l 154, i f i t was formed, m i g h t a b s t r a c t a h y d r o g e n f r o m n - B^SnH r a t h e r t h a n c y c l i z e . T r e a t m e n t o f t h e a l c o h o l 152 w i t h p h e n o x y t h i o c a r b o n y l c h l o r i d e i n a c e t o n i t r i l e i n t h e p r e s e n c e o f 4 - N > N - d i m e t h y l a m i n o p y r i d i n e p r o v i d e d t h e t h i o n o c a r b o n a t e 155 (40%, e q u a t i o n 44). The i r s p e c t r u m o f 155 e x h i b i t e d an a b s o r p t i o n a t 1729 cm" 1. The nmr s p e c t r u m o f 155 showed - 60 -a 2-proton t r i p l e t at 8 7.40 (J = 8 Hz), a 1-proton t r i p l e t at 8 7.27 (J = 8 Hz), and a 2-proton doublet at 8 7.40 (J = 8 Hz) due to the phenyl group, i n d i c a t i n g that the phenylthionocarbonate f u n c t i o n a l group had been i n s t a l l e d . Reaction of the thionocarbonate 155 with t r i - n - b u t y l t i n hydride (10 equiv., 0.41 M s o l u t i o n i n toluene) i n the presence of AIBN ( r a d i c a l i n i t i a t o r ) at 70°C for 3 h afforded cleanly, but rather s u r p r i s i n g l y , the methyl ether 156 (75%, equation 45). The -"-H nmr spectrum of 156 showed a p a i r of doublets at 8 3.39 (J = 10 Hz) and 3.21 (J = 10 Hz) due to the MeOCH2C< protons and two 3-proton s i n g l e t s at 8 3.38 and 3.74 due to the two methoxy groups. The mass spectrum of 156 showed a molecular ion consistent with a formula of C23 H40°3-The formation of 156 can be r a t i o n a l i z e d on the basis of the postulated r e a c t i o n mechanism of Barton deoxygenation of alcohols. Recently, Beckwith et a l . 4 9 have gathered evidence that suggests that the deoxygenation proceeds v i a the following pathway: Reaction of an O-alkyl-S-methyl dithiocarbonate(xanthate) 157 with a t r i a l k y l t i n r a d i c a l affords an alkoxythiocarbonyl r a d i c a l 158 (see Scheme 19). The l a t t e r species, which has been detected by e l e c t r o n spin resonance - 61 -s R>sn (1) ROCSMe — — • ROC=S + R 3SnSMe 157 158 slow ^ - f i s s i o n (2) R0C=S • R- + COS 158 159 160 R"3SnH (3) R- • RH +• R 3Sn-159 161 Scheme 19 s p e c t r o s c o p y undergoes s l o w / 3 - f i s s i o n t o g i v e an a l k y l r a d i c a l 159 and c a r b o n o x y s u l f i d e 160. The a l k y l r a d i c a l 159 r e a c t s w i t h t r i a l k y l t i n h y d r i d e t o g i v e t h e a l k a n e 161 (Scheme 19). I f t h i s mechanism o p e r a t e s i n t h e r e a c t i o n o f o u r t h i o n o c a r b o n a t e 155 w i t h n - B ^SnH, th e s u b s t r a t e 155 w o u l d be c o n v e r t e d i n i t i a l l y i n t o t h e a l k o x y t h i o c a r b o n y l r a d i c a l 162 (see Scheme 2 0 ) . S i n c e t h e r e a c t i o n was c a r r i e d o u t i n t h e p r e s e n c e o f a r e l a t i v e l y h i g h c o n c e n t r a t i o n o f n - B ^ S n H (0.4 M), t h e r a d i c a l 162 c o u l d a b s t r a c t a h y d r o g e n atom from n - B ^ S n H ( t o g i v e 163) r a t h e r t h a n undergo ( s l o w ) ^ - f i s s i o n t o t h e c o r r e s p o n d i n g a l k y l r a d i c a l 164. F u r t h e r r e d u c t i o n o f 163 v i a t h e t h i o a c e t a l r a d i c a l 165, t h e t h i o a c e t a l 166, and t h e a l k o x y a l k y l r a d i c a l 167 w o u l d a f f o r d t h e m e t h y l e t h e r 156 (Scheme 2 0 ) . P e t e e t a l . -*Q have r e p o r t e d t h a t i r r a d i a t i o n o f a c e t a t e s o f p r i m a r y , s e c o n d a r y , t e r t i a r y and some h i g h l y h i n d e r e d a l c o h o l s i n a 5% aqueous hex a m e t h y l p h o s p h o r a m i d e s o l u t i o n w i t h u l t r a v i o l e t l i g h t (254 nm) a t room - 62 -Scheme 20 - 63 -temperature gives good to excel l e n t y i e l d s of the desired deoxygenated products. The r a d i c a l mechanism they propose f o r t h i s process i s s i m i l a r to that of Barton deoxygenation. Treatment of the alcohol 152 with a c e t i c anhydride i n pyridine i n the presence of 4-N,N-dimethylamino-pyri d i n e ( c a t a l y s t ) afforded the acetate 168 (95%, equation 46). The i r spectrum of 168 exhibited a strong absorption at 1741 cm"1 due to the carbonyl group. The nmr spectrum of 168 showed a 3-proton s i n g l e t at 8 2.06 due to the a c e t y l protons, i n d i c a t i n g that the acetate had been formed. However, when the acetate 168 was subjected to the p h o t o l y t i c deoxygenation conditions described above f or 3 h, no r e a c t i o n occurred ( t i c a n a l y s i s ) . Since a l l of the above-described attempts to deoxygenate the alcohol 152 f a i l e d to give u s e f u l y i e l d s of the desired material 145, i t was decided to investigate the Ireland deoxygenation. Following Ireland's procedure,-' 2 the alcohol 152 was treated with n-but y l l i t h i u m and bis(dimethylamino)phosphorochloridate i n a 4:1 mixture of dimethoxy-ethane and N,N,N',N'-tetramethylethylenediamine (TMEDA) at room tempera-ture f o r 12 h. However, no rea c t i o n took place and the s t a r t i n g material was recovered. L i u et a l . - * 3 have reported the use of - 64 -dimethylaminophosphorodichloridate to prepare phosphorodiamidates of h i g h l y hindered alcohols. Thus, a s o l u t i o n of the alcohol 152 i n a 4:1 mixture of dimethoxyethane and TMEDA was treated successively with n- b u t y l l i t h i u m f o r 30 min and dimethylaminophosphorodichloridate for 12 h at room temperature, and then with anhydrous dimethylamine at 0°C for 2 h. Column chromatography of the crude product on s i l i c a gel provided the phosphorodiamidate 169 (71%, equation 47). The iH nmr spectrum of 169 exhibited two broad 6-proton s i n g l e t s at 0 5 2.69 and 2.66 due to the -P(NMe2)2 protons, i n d i c a t i n g that the phosphorodiamidate group had been i n s t a l l e d . Reaction of 169 with a s o l u t i o n of l i t h i u m i n anhydrous ethylamine i n the presence of t e r t - b u t y l alcohol at 0°C f o r 30 min afforded the over-reduction product 170 i n 75% y i e l d (equation 48). The nmr spectrum of 170 showed a quartet at S 5.16 (J = 7 Hz) due to the o l e f i n i c proton 1.58 4.50 - 65 i n the side chain, a broad doublet at 6 1.55 (J = 7 Hz) and a broad s i n g l e t at 6 1.58 due to the v i n y l methyl groups. These s i g n a l s , along with the f a c t that resonances due to the methoxymethoxy group were not present, i n d i c a t e d that the a l l y l i c ether linkage had been cleaved. However, the chemical s h i f t s of the signals due to the o l e f i n i c protons and the methyl groups on the d e c a l i n p o r t i o n of 170 [6 4.50 (s, 2H), 1.05 (s, 3H), 0.82 (d, 3H, J = 6 Hz), 0.74 (s, 3H)] were almost exactly the same as those reported f o r palauolide (55) [S 4.51 (s, 2H), 1.05 (s, 3H), 0.82 (d, 3H, J - 7 Hz), 0.74 (s, 3 H ) ] . 1 4 These data ind i c a t e d that the r e l a t i v e stereochemistry of the d e c a l i n substructure of 170 was the same as that of palauolide (55). 4.51 In an attempt to avoid the reductive cleavage of the methoxymethoxy group, the r e a c t i o n of the phosphorodiamidate 169 with a s o l u t i o n of l i t h i u m i n ethylamine i n the presence of t e r t - b u t y l alcohol was c a r r i e d out at -48°C and was quenched prematurely a f t e r 15 minutes. A mixture of the s t a r t i n g material 161 and a new compound was obtained. The ^H nmr spectrum of the l a t t e r material showed that the phosphorodiamidate group was i n t a c t while the methoxymethoxy group had been cleaved. This suggested that reductive cleavage of the methoxymethoxy group was occurring p r e f e r e n t i a l l y to the reductive removal of the phosphoro-- 66 -diamidate group. In an attempt to avoid the loss of the a l l y l i c oxygen function on the side chain, the a c e t a l linkage on 169 was cleaved to the correspon-ding alcohol 171. I t was hoped that, during the reduction process, the alcohol function would e x i s t l a r g e l y as an alkoxide and, therefore, would be l e s s susceptible to reductive cleavage than the methoxymethoxy group. Thus, the phosphorodiamidate 169 was treated with dimethylboron bromide 4 4 i n dichloromethane at -78°C f o r 1 h to a f f o r d the a l l y l i c a l c o h o l 171 (65%, equation 49). The i r spectrum of 171 exhibited a broad absorption at 3350 cm"1. The nmr spectrum of 171 showed a t r i p l e t at 6 5.40 (J •= 7 Hz) due to the o l e f i n i c proton i n the side chain, a doublet at S 4.13 (J = 7 Hz) due to the "CCH^OH protons, and two 6-proton doublets at 6 2.66 (J = 4 Hz) and 2.64 (J = 4 Hz) due to the -P0(NMe2)2 protons. Treatment of 171 with a s o l u t i o n of l i t h i u m i n ethylamine i n the presence of t e r t - b u t y l alcohol at 0°C also l e d to an over-reduction product, the i r and ^H nmr spectra of which were i d e n t i c a l with that of 170 (equation 50). - 67 -E. A l k y l a t i o n o f the n i t r i l e 112 w i t h the i o d i d e 172. P r e p a r a t i o n o f  t h e a.ft-unsaturated a l d e h y d e 107 Of t h e v a r i o u s d e o x y g e n a t i o n methods t r i e d (see p r e v i o u s s e c t i o n ) , i t a p p e a r e d t h a t o n l y t h e I r e l a n d d e o x y g e n a t i o n was c a p a b l e o f r e d u c i n g t h e -CH2OH group t o a m e t h y l group i n a c l e a n and s y n t h e t i c a l l y u s e f u l y i e l d . However, t h i s method a l s o r e s u l t e d i n r e d u c t i v e c l e a v a g e o f t h e a l l y l i c a l k o x y group on t h e s i d e c h a i n a t t a c h e d t o t h e d e c a l i n sub-s t r u c t u r e . C l e a r l y t h i s u n d e s i r e d s i d e r e a c t i o n c o u l d be a v o i d e d i f t h e d o u b l e bond was i n s t a l l e d a f t e r t h e d e o x y g e n a t i o n . Thus, t h e s y n t h e t i c p l a n t o c o n s t r u c t t h e a,0-unsaturated a l d e h y d e 107 from t h e n i t r i l e 112 was m o d i f i e d a c c o r d i n g t o t h e f o l l o w i n g p l a n (see Scheme 2 1 ) . I t was e x p e c t e d t h a t a l k y l a t i o n o f t h e n i t r i l e 112 w i t h t h e a l k y l i o d i d e 172 w o u l d be s t e r e o s e l e c t i v e . C o n v e r s i o n o f t h e r e s u l t a n t p r o d u c t 173 i n t o t h e p h o s p h o r o d i a m i d a t e 174, f o l l o w e d by r e d u c t i o n o f t h e l a t t e r s u b s t a n c e w o u l d be e x p e c t e d t o a f f o r d c l e a n l y t h e e t h e r 175. A - 68 -Scheme 21 - 69 -straightforward sequence of reactions would e f f e c t the conversion of 175 into the methyl ketone 176. Reaction of the l a t t e r material with the anion of a t r i a l k y l phosphonoacetate was expected to give the E a,/S-unsaturated ester 177 as the major product. F i n a l l y , reduction of the ester 177 would give the desired aldehyde 107. Indeed, t h i s plan worked very well and i t s execution i s described i n the following paragraphs. Reaction of 3-chloro-1-propanol (178) with chloromethyl methyl ether i n the presence of diisopropylethylamine i n dichloromethane gave 3-chloro-l-methoxymethoxypropane 179 (80%). Treatment of the l a t t e r m aterial with sodium iodide i n acetone at 60°C i n the dark f o r 30 h gave 3-iodo-l-methoxymethoxypropane (172) i n 70% y i e l d (equation 5 1 ) . 5 4 Vigorous r e f l u x of the reac t i o n mixture l e d to a low y i e l d of the iodide 172 and the formation of side products. CH 30CH 2C1 U i - P r 2 N E t , CH 2C1 2 178 179 Nal, 60°C 179 • l^s^O^O' (51) acetone 172 The •LH nmr spectrum of 172 exhibited two s i n g l e t s at 5 4.63 and 5 3.40 due to the ace t a l and methoxy protons, r e s p e c t i v e l y . The t r i p l e t s at S 3.60 (J = 6 Hz) and 3.30 (J = 6 Hz) were due to the -CH2CH20- and -CH 2I protons, re s p e c t i v e l y , and the quintet at 5 2.05 (J = 6 Hz) was - 70 -due to the -CH2CH2CH2- protons. A 15:85 mixture of the n i t r i l e s 112a and 112b, r e s p e c t i v e l y , was treated with l i t h i u m diisopropylamide i n THF at 0°C i n the presence of hexamethylphosphoramide. Addition of the iodide 172, followed by s t i r r i n g of the re s u l t a n t s o l u t i o n at 0°C f o r 30 min and at room temperature f o r 1 h, gave the a l k y l a t e d n i t r i l e 173 i n 99% y i e l d (equation 52). Glc analysis and ^H nmr spectroscopy showed that only one a l k y l a t i o n product had been formed. 112a 112b 173 15:85 The i r spectrum of 173 showed absorptions at 2228 and 1638 cm"1 due to the n i t r i l e group and the exocyclic o l e f i n , r e s p e c t i v e l y . The ^H nmr spectrum of 173 exhibited a s i n g l e t at S 1.27 due to the angular methyl group, i n d i c a t i n g that t h i s group was i n a 1,3 d i a x i a l r e l a t i o n s h i p to the n i t r i l e function. (Note that the angular methyl protons of 112a and 112b appeared at 5 1.24 and 0.96, r e s p e c t i v e l y ) . The signals due to the a c e t a l protons and one of the o l e f i n i c protons overlapped and appeared at S 4.59. Following the procedures developed e a r l i e r f o r the transformation of the n i t r i l e 111 into the phosphorodiamidate 169, the n i t r i l e 173 was converted into the corresponding phosphorodiamidate. 71 -Thus, diisobutylaluminum hydride reduction of the n i t r i l e 173 i n dimethoxyethane at 60°C for 6 h, followed by a c i d catalyzed h y d r o l y s i s of the r e s u l t a n t product, provided the aldehyde 180 i n 85% y i e l d (equation 53).* The i r spectrum of 180 exhibited a strong absorption at 1713 cm"1 due to the carbonyl group. The nmr spectrum 180 showed a s i n g l e t at 8 9.53 due to the aldehyde proton, a doublet at 6 1.02 (J = 6 Hz) due to the secondary methyl protons, and a s i n g l e t at 5 0.98 due to the angular methyl protons. The aldehyde 180 was treated with an ethereal solution-suspension of l i t h i u m aluminum hydride at room temperature. A f t e r workup, the An attempt to deoxygenate the aldehyde 180 using the Wolff-Kishner reduct ion f a i l e d . No desired product was i s o l a t e d . - 72 -alcohol 181 was obtained i n 91% y i e l d (equation 54). The i r spectrum of 181 exhibited a broad absorption at 3462 cm"1 due to the hydroxyl group. The nmr spectrum of 181 showed a p a i r of doublets at 5 3.78 (J «= 12 Hz) and S 3.70 (J = 12 Hz) due to the -CH20H protons. A s o l u t i o n of the alcohol 181 i n a 4:1 mixture of dimethoxyethane and N,N,N',N'-tetramethylethylenediamine, r e s p e c t i v e l y , at room temperature, was treated successively with n-butyllithium and dimethyl-aminophosphorodichloridate. 5 3 The resultant s o l u t i o n was treated with anhydrous dimethylamine at 0°C for 2 h. A f t e r workup and column chromatography of the crude product on s i l i c a g e l , the phosphorodiami-date 174 was obtained i n 88% y i e l d (equation 55). 0 The •LH nmr spectrum of 174 showed a p a i r of doublet of doublets at 6 4.00 (J - 4, 12 Hz) and 6 3.95 (J = 4, 12 Hz) due to the -CH20P0-protons. I t also showed a p a i r of doublets at 5 2.66 (J = 4 Hz) and - 73 -2.64 (J = 4 Hz) due to the -PO(NMe2)2 protons, i n d i c a t i n g the presence of the phosphorodiamidate group. The phosphorodiamidate 174 was subjected to Ireland deoxygenation. Reaction of 174 with an anhydrous ethylamine s o l u t i o n of l i t h i u m i n the presence of t e r t - b u t y l alcohol at 0°C for 10 min-*2 gave a 1:1 mixture of the desired deoxygenated material 175 and an over-reduced product 182 i n which the carbon-carbon double bond on the b i c y c l i c substructure had also been reduced (equation 56). The r a t i o of products was improved to 2:1, i n favour of 175, when the rea c t i o n was c a r r i e d out at -10°C f o r 5 min. This experiment suggested that the phosphorodiamidate group could be reduced s e l e c t i v e l y under su i t a b l e conditions. When a more d i l u t e ethylamine s o l u t i o n of l i t h i u m was employed f o r the reaction, the s e l e c t i v i t y improved to 25:1 i n favour of the desired material 175. However, when t h i s r e a c t i o n was c a r r i e d out on a la r g e r scale, the s e l e c t i v i t y dropped. Fortunately, when the reduction was c a r r i e d out i n (56) 182 174 - 74 -anhydrous methylamine i n the absence of t e r t - b u t y l alcohol at -20°C f or 10 min, the phosphorodiamidate group was reduced s e l e c t i v e l y and 175 was obtained i n 81% y i e l d (equation 5 7 ) . The i r spectrum of 175 showed absorptions at 1636 and 891 cm"1 due to the exo c y c l i c double bond. The nmr spectrum of 175 (Fig. 2) exhibited two s i n g l e t s at 8 1.04 and 0.73, and a doublet at 8 0.80 (J = 6 Hz) due to the methyl substituents on the b i c y c l i c moiety. That the C-5 angular methyl protons appeared at lower f i e l d (8 1.04) than the C-9 methyl protons (8 0.73) was probably due to the f a c t that the former experienced a deshielding anisotropic e f f e c t from the adjacent exocyclic o l e f i n . The ^H nmr spectrum of 175 also showed three d i s t i n c t signals at 6 2.28 (br dt, 1H, J = 5, 13.5 Hz), 2.09 (br d, 1H, J = 13.5 Hz), and 1.87 (br d, 1H, J = 12 Hz). These signals d i d not overlap with one another and were well separated from the remaining s i g n a l s . In a decoupling experiment, i r r a d i a t i o n at 8 4.49 ( o l e f i n i c protons) caused the s i g n a l at 8 2.28 to sharpen. This r e s u l t suggested that the l a t t e r s i g n a l was due to an a l l y l i c proton, and based on i t s appearance (br dt, J = 5 , 13.5 Hz), i t was assigned to proton A. On i r r a d i a t i o n of proton H A at 8 2.28, the broad doublet at 8 2.09 became a broad s i n g l e t and was therefore assigned to proton B. I r r a d i a t i o n of proton H A also caused the broad doublet at 8 1.87 to sharpen and, thus, t h i s resonance was assigned to HQ. The ^H nmr spectra of other compounds i n t h i s s e r i e s exhibited s i m i l a r signals i n the region 8 2.3-1.8 and these signals were assigned on the basis of the decoupling experiments c a r r i e d out on compound 175, as described above. - 76 -A pure sample of the over-reduction product 182 was obtained by treatment of the phosphorodiamidate 174 with an anhydrous ethylamine s o l u t i o n of l i t h i u m i n the presence of t e r t - b u t y l alcohol at 0°C f o r 20 min (equation 58). The i r spectrum of the overreduction product 182 d i d not show the c h a r a c t e r i s t i c absorptions at -1635 and -890 cm"-*- due to the exocyclic o l e f i n . The nmr spectrum of 182 exhibited two doublets at 8 0.78 and 5 0.73 due to the secondary methyl protons, and two s i n g l e t s at 5 0.77 and 8 0.70 due to the t e r t i a r y methyl protons. The C-4 methyl group was assumed to be i n an equatorial o r i e n t a t i o n since d i s s o l v i n g metal reduction u s u a l l y lead to the thermodynamically more stable product. The high r e s o l u t i o n mass spectrum of 182 showed a peak at m/e 296.2707, corresponding to the molecular ion with a formula of C19H36O2. Treatment of 175 with pyridinium p.-toluenesulf onate i n t e r t - b u t y l a l c o h o l 3 3 at 70°C f o r 12 h gave the alcohol 183 (91%, equation 59). Vigorous r e f l u x of the reaction s o l u t i o n l e d to a s i g n i f i c a n t amount of a side product i n which the o l e f i n i c double bond had isomerized into the r i n g . The i r spectrum of 183 showed a broad absorption at 3319 cm~^ due to the hydroxyl group and absorptions at 1635 and 891 cm'^ due to the e x o c y c l i c o l e f i n . The alcohol 183, upon oxidation with pyridinium chlorochromate i n the presence of anhydrous sodium acetate i n dichloromethane (room temperature, 1 h), afforded the aldehyde 184 (99%, equation 60). The i r spectrum of 184 showed a strong absorption at 1728 cm'^ due to the carbonyl group. The nmr spectrum of 184 exhibited a t r i p l e t at S 9.74 (J = 2 Hz) due to the aldehyde proton. Reaction of the aldehyde 184 with methyllithium i n ether at 0°C gave a mixture of epimeric alcohols 185 (see equation 61). The i r spectrum - 78 -of the l a t t e r material showed a broad sbsorption at 3349 cm"1 due to the hydroxy group. The high r e s o l u t i o n mass spectrum of 185 showed a peak at m/e 264.2455, corresponding to a molecular ion with a formula of C^8^32<-)- Subsequent oxidation of the mixture of epimeric alcohols 185 with pyridinium chlorochromate i n the presence of sodium acetate i n dichloromethane provided the methyl ketone 176 i n an o v e r a l l y i e l d of 97% (from the aldehyde 184) (equation 61). The i r spectrum of 176 exhibited a strong absorption at 1718 cm"1 due to the carbonyl group. The 1H nmr spectrum of 176 exhibited a s i n g l e t at 5 2.13 due to the -COCH3 protons, i n d i c a t i n g the presence of a methyl ketone. I t should be noted that the ketone 176 has been prepared by Sharma et al.-*6 v i a a route very d i f f e r e n t from that described above. The 1H nmr and i r spectroscopic data r e p o r t e d 5 ^ f o r t h i s material were i d e n t i c a l with those derived from our material. I t i s w e l l - known that under su i t a b l e conditions, treatment of an unsymmetrical ketone with the s a l t of a phosphonoacetate gives the trans ester as the major product.^7 Indeed, re a c t i o n of the ketone 176 (65 Atmol) with [Et0 2CCHPO(OEt) 2]K + (0.7 mmol) i n THF (3 mL) at room temperature f o r 15 h provided, i n nearly quantitative y i e l d , a 10:1 mixture of 177 and i t s geometric isomer 186. These two products were - 79 -2.14 1.85 r e a d i l y s e p a r a b l e by column chromatography on s i l i c a g e l ( e q u a t i o n 6 2 ) . B o t h t h e i r s p e c t r a o f 177 and 186 e x h i b i t e d an a b s o r p t i o n a t 1718 cm"l due t o t h e c a r b o n y l group o f t h e e s t e r . I n t h e nmr s p e c t r u m o f 177, t h e v i n y l m e t h y l p r o t o n s and t h e -CH.2(CH3)C= p r o t o n s a p p e a r e d a t S 2.14 ( d , J = 1.5 Hz) and 6 2.02-1.78 (m), r e s p e c t i v e l y . On t h e o t h e r hand, t h e ^H nmr s p e c t r u m o f 186 showed a d o u b l e t a t 5 1.85 ( J = 1.3 Hz) due t o t h e v i n y l m e t h y l p r o t o n s and a p a i r o f b r o a d d o u b l e t s o f t r i p l e t s a t 5 2.32 ( J - 5, 12 Hz) and 5 2.24 ( J = 5, 12 Hz) due t o t h e -CFJ2(CH3)C= p r o t o n s . S i n c e the a l l y l i c p r o t o n s on t h e same s i d e o f t h e d o u b l e bond as t h e e s t e r group i n an a,/3-unsaturated e s t e r w o u l d e x p e r i e n c e an a n i s o t r o p i c m a g n e t i c d e s h i e l d i n g e f f e c t f r o m t h e c a r b o n y l g roup, compound 177 was a s s i g n e d t h e E s t e r e o c h e m i s t r y , w h i l e 186 was a s s i g n e d t h e Z s t e r e o c h e m i s t r y . The a , / ? - u n s a t u r a t e d e s t e r 177, upon t r e a t m e n t w i t h d i i s o b u t y l a l u m i -num h y d r i d e i n THF a t -78°C f o r 1 h and 0°C f o r 2 h, a f f o r d e d t h e a l l y l i c a l c o h o l 187 i n 98% y i e l d ( e q u a t i o n 6 3 ) . The i r s p e c t r u m o f 187 showed a b r o a d a b s o r p t i o n a t 3327 cm'^ i n d i c a t i n g t h e p r e s e n c e o f the h y d r o x y l group. The ^H nmr s p e c t r u m o f 187 e x h i b i t e d a d o u b l e t a t 6 4.12 ( J = 8 Hz) due t o t h e =CCH 20H p r o t o n s . - 80 -Manganese(IV) oxide oxidation of the alcohol 187 i n hexane provided the key intermediate, the a.^-unsaturated aldehyde 107, i n 88% y i e l d (equation 64). The i r spectrum of 107 exhibited an absorption at 1676 cm"1 due to the conjugated carbonyl group. The nmr spectrum of 107 showed a doublet at 8 9.97 (J - 8 Hz) due to the aldehyde proton and a broad doublet at 5 5.86 (J = 8 Hz) due to the o l e f i n i c proton on the side chain ( F i g . 3). F. Synthesis of the phosphonium s a l t 188 Recently, Katsumura et a l . ° reported a very e f f i c i e n t synthesis of 7-hydroxybutenolides by photosensitized oxygenation of substituted - 82 -2 - t r i m e t h y l s i l y l f u r a n s . For example the s i l y l f u r a n 189a could be transformed r e a d i l y into the butenolide 190a i n 91% y i e l d (equation 65). It was expected that the phosphonium s a l t 188 could be synthesized from the chloro butenolide 109, and that the l a t t e r material could be prepared from 4-chloromethyl-2-trimethylsilylfuran (110) (Scheme 22). . X ^ O S i — 0 , iodo-halogen lamp t=\ \ ^ M e j S l ^ ^ s o ^ tetraphenylphorphin O v / r i 189a _ 7 8 ° c ' C H 2 C 1 2 ' 5 m i n 190a Following the chemistry reported by Goldsmith et a l . 3 8 and Tanis et a l . 5 9 , the furan 110 was prepared from 3-furanmethanol (189) i n s i x steps i n an o v e r a l l y i e l d of 45% (equations 66 to 71). 3-Furanmethanol (189) (6 mmol) was treated with n-bu t y l l i t h i u m (13 mmol) i n THF at 0°C. The r e s u l t a n t dianion was treated with d i p h e n y l d i s u l f i d e at 0°C f o r 12 h to give r e g i o s e l e c t i v e l y the furan alcohol 190 (81%, equation 66). The ^H nmr spectrum of 190 exhibited two doublets at 6 7.59 (J = 2 Hz) and - 83 -8 6.65 (J — 2 Hz) due to the furan protons, a 5-proton m u l t i p l e t at 8 7.25-7.15 due to the phenylthio group, and a t r i p l e t at 5 1.62 (J - 5 Hz) due to the hydroxyl proton. The l a t t e r s i g n a l underwent D 20 exchange. -OH 1. n-BuLi[2 equiv.), THF 2. PhSSPh, 0°C, 12h 189 190 (66) The alcohol 190 was treated with t e r t - b u t y l d i m e t h y l s i l y l c h l o r i d e i n the presence of imidazole i n dimethylformamide at room temperature to give the furan 191 (95%, equation 67). The ^H nmr spectrum of 191 exhi b i t e d a 9-proton s i n g l e t and a 6-proton s i n g l e t at 8 0.91 and 5 0.07, r e s p e c t i v e l y , due to the s i l y l p r otecting group, i n d i c a t i n g that the l a t t e r had been i n s t a l l e d . N y ^ s P h TBDMSCl, imidazole DMF, r t (67) 190 191 An ethereal s o l u t i o n of the furan 191 (4.7 mmol) was treated with n - b u t y l l i t h i u m (5.2 mmol). The resultant mixture was treated with t r i m e t h y l s i l y l c h l o r i d e at 0°C for 48 h to give the s i l y l f u r a n 192 (83%, equation 68). The -41 nmr spectrum of 192 exhibited a broad s i n g l e t at 5 84 -6.85 due to the furan proton and 9-proton s i n g l e t at 8 0.38 due to the t r i m e t h y l s i l y l group. S P h 1. n-BuLi, Et 0 ± 2. TMSCl, 0°C, 48h M e s S i 191 192 An ethanolic s o l u t i o n of the phenylthiofuran 192 (2.6 mmol) was refl u x e d i n the presence of Raney n i c k e l (7 g) for 3 h to provide the furan d e r i v a t i v e 193 i n 90% y i e l d (equation 69). An excess of Raney n i c k e l l e d to an over-reduced tetrahydrofuran d e r i v a t i v e . The nmr spectrum 193 showed two broad s i n g l e t s at 6 7.56 and 8 6.60 due to the furan protons. . — X ^ O S i - ^ : Ra-Ni, EtOH _ / ^ 0 5 i - ^ jrA \ > c.jr\ \ (69) M e 3 S i - ^ c r ^ S P h r e f l u x , 3h M e 3 S i - ^ s 0 X 192 193 Treatment of compound 193 with a 3:1:1 mixture of a c e t i c acid, water and THF, r e s p e c t i v e l y , ^ ^ at room temperature f o r 12 h provided the Raney n i c k e l i s commercially a v a i l a b l e as a 50% s l u r r y i n water, pH 10, from A l d r i c h Chemical Co. The reagent was washed three times with d i s t i l l e d water and s i x times with d i s t i l l e d absolute ethanol before use. The required quantity (-2.7 g per mmol of the phenyl-thiof u r a n 192) of Raney-nickel was obtained by weighing together with a minimum amount of ethanol under an atmosphere of argon. - 85 -alcohol 194 (99%, equation 70). The i r spectrum of 194 showed a broad absorption at 3326 cm'^ due to the hydroxy group. The nmr spectrum of 194 showed two broad s i n g l e t s at 5 7.60 and 6.66 due to the furan protons, and a s i n g l e t at 6 0.30 due to the trimethyl s i l y l group. Me3Si 0Si-< H0Ac-H20-THF r t , 12h / --OH Me 3Si""\ lr 170) 193 194 The alcohol 194 was treated with a mixture of l i t h i u m c h l o r i d e , s - c o l l i d i n e and methanesulfonyl chloride i n dimethylformamide at 0°C for 2 h to give the ch l o r i d e 110 i n 79% y i e l d (equation 71). The nmr spectrum of 110 exhibited a s i n g l e t at S 4.45 due to the -CH2CI protons. JTS 194 L i C l , MeS0 2Cl, 0 C s - c o l l i d i n e , DMF 110 (71) With the a c q u i s i t i o n of 4-chloromethyl-2-trimethylsilylfuran (110), the stage was set for the c r i t i c a l photosensitized oxygenation. Following the conditions reported by Katsumura et a l . . ^ 8 a c o l d (-78°C) dichloromethane s o l u t i o n of 110 (10 mmol), containing a c a t a l y t i c amount of tetraphenylporphin, was i r r a d i a t e d with a halogen-tungsten lamp (325W) while oxygen was bubbled through the s o l u t i o n . A f t e r a r e a c t i o n - 86 -time of 27 min, the s o l u t i o n was concentrated and the residue was diss o l v e d i n methanol. The resultant s o l u t i o n was s t i r r e d f o r 12 h at room temperature. A f t e r workup and column chromatography of the crude product on s i l i c a g e l , the (chloromethyl)butenolide 109 was obtained i n 78% y i e l d (equation 72). The i r spectrum of 109 showed a broad absorption at 3357 cm"! due to the hydroxy group and an absorption at 1736 cm"l due to the carbonyl group. The nmr spectrum of 109 showed a 2-proton broad s i n g l e t at 6 6.21 due to the v i n y l and >CH0H protons, whose signals overlapped with one another. The signals due to the hydroxy and -CH2CI protons appeared at 6 4.80 and S 4.37, r e s p e c t i v e l y . 1. 0 2, l i g h t tetraphenylphorphin /^*CI o — > ~ J r \ . (72) CH 2C1 2, -78°C O ^ Q / ^ O H 2. MeOH, r t -jQg Recently, Faulkner et a l . ^ ^ reported that photosensitized oxygena-t i o n of 3-substituted furans 195 i n the presence of d i i s o p r o p y l e t h y l -amine at 0°C provides r e g i o s e l e c t i v e l y the corresponding -y-hydroxy butenolides 196 (equation 73). This approach makes the presence of the - 87 -t r i m e t h y l s i l y l group on the furan r i n g unnecessary and thus shortens s u b s t a n t i a l l y the route to 7-hydroxybutenolides. The 7-hydroxybutenolide 109, upon treatment with a methanolic s o l u t i o n of p_-toluenesulfonic a c i d at room temperature f o r 12 h, was r e a d i l y transformed into the methoxybutenolide 197 i n 92% y i e l d (equation 74). The i r spectrum of 197 exhibited absorptions at 1800 and 1768 cm"1 due to the carbonyl group. I t i s known that the carbonyl absorption of a 6-butenolide i s s p l i t i n the presence of an a v i n y l p r o t o n . ^ The nmr spectrum of 197 showed a m u l t i p l e t at 8 6.20 and a broad s i n g l e t at 8 5.80 due to the v i n y l proton and the >CH0Me proton, r e s p e c t i v e l y . The spectrum also showed a s i n g l e t at 6 3.61 due to the methoxy group. Treatment of the chlo r i d e 197 with triphenylphosphine i n r e f l u x i n g benzene provided the phosphonium s a l t 188 i n 70% y i e l d (equation 75). 4-/—CI Ph„P, benzene PPh 3 CI O ^ Q ^ O M e r e f l u x O ^ ^ ^ i O M e 197 188 - 88 -The nmr spectrum of 188 exhibited a broad m u l t i p l e t at S 6.00 due to + the -CH.2PPh3 protons. With the phosphonium s a l t 188 now a v a i l a b l e , i t was possible to inves t i g a t e the re a c t i o n of the corresponding phosphorane with some a,^-unsaturated aldehydes. G. Conversion of -Y-methoxybutenolides into -y-hvdroxvbutenolides P r i o r to the i n v e s t i g a t i o n of the o l e f i n a t i o n of a,0-unsaturated aldehydes with butenolide phosphoranes and phosphonate anions, the conversion of 7-methoxybutenolides into 7-hydroxybutenolides was studied. This type of reaction was to be employed i n the generation of (±)-palauolide (55) from the product 198 of the re a c t i o n between the aldehyde 107 and the phosphorane 108 (Scheme 23). Scheme 23 - 89 -Recently, Wernuth et al.^3 reported the preparation of the 7-ethoxybutenolide 199. Their procedure was modified for the preparation of the 7-methoxybutenolide 200, which was employed as a model f o r studying the transformation of 7-methoxybutenolides into 7-hydroxybutenolides. Thus, re a c t i o n of g l y o x y l i c a c i d 201 with propanal i n the presence of morpholine hydrogen chloride i n aqueous dioxane at room temperature f o r 1 h and at r e f l u x temperature f o r 24 h provided the 7-hydroxybutenolide 2 0 2 ^ i n 63% y i e l d (see equation 76). Treatment of the l a t t e r material with methanolic hydrogen ch l o r i d e (-7 g anhydrous hydrogen c h l o r i d e gas i n 150 mL of dry methanol) under r e f l u x f o r 16 h provided the 7-methoxybutenolide 200 i n 47% y i e l d (equation 76). 199 R=Et 200 R = Me The i r spectrum of 200 exhibited absorptions at 1797 and 1769 cm"1 due to the carbonyl group. The nmr spectrum of 200 showed two broad s i n g l e t s at 8 5.89 and 5.60 due to the o l e f i n i c and >CH0CH3 protons r e s p e c t i v e l y , a s i n g l e t at 8 3.58 due to the methoxy protons and a doublet at 5 2.06 (J = 2 Hz) due to the v i n y l methyl group. - 90 -Wermuth et al.^3 reported that treatment of 199 with r e f l u x i n g concentrated hydrochloric a c i d (2 ml per gram of 199) f o r 15 min regenerated the 7-hydroxybutenolide 202 (equation 77). However, i t was thought that under such d r a s t i c conditions, the o l e f i n i c double bonds present i n the palauolide skeleton would undergo rearrangement reac-t i o n s . Therefore, milder r e a c t i o n conditions would have to be developed f o r our synthesis. A c i d h y d r o l y s i s of the 7-methoxybutenolide 200 under a v a r i e t y of conditions f a i l e d to provide useful y i e l d s of the 7-hydroxybutenolide 202. However, recently, Larcheveque et a l . ^ 4 reported that the 7-methoxybutenolide 203 may be converted into the 7-hydroxybutenolide 204 by treatment with hydroxide ion (equation 78). Unfortunately, no information on the experimental conditions was reported. 203 204 A f t e r some experimentation, i t was found that treatment of the 7-methoxybutenolide 200 with sodium hydroxide i n aqueous a c e t o n i t r i l e at - 91 -room temperature for 30 min produced the a c i d aldehyde 205 (see equation 79). When d i l u t e hydrochloric a c i d was added to the above product s o l u t i o n , the 7-hydroxybutenolide 202 could be obtained d i r e c t l y (70%) without i s o l a t i o n of the intermediate a c i d aldehyde 205 (equation 79). The i r and nmr s p e c t r a l data of the l a t t e r material were i d e n t i c a l with those of the 7-hydroxybutenolide 202 prepared as described e a r l i e r i n t h i s s ection of the thesis (see equation 76, p. 89). The i r spectrum of the a c i d aldehyde 205 showed absorptions at 3034 and 1698 cm"1 due to the hydroxy group and the carbonyl groups, r e s p e c t i v e l y . The nmr spectrum of 205 showed a s i n g l e t at 8 9.60 due to the aldehyde proton and two broad s i n g l e t s at 8 6.53 and 8 2.21 due to the o l e f i n i c and the v i n y l methyl protons, re s p e c t i v e l y . Thus, a method for the conversion of 7-methoxybutenolides into 7-hydroxybutenolides under mild r e a c t i o n conditions had been developed. H. Reaction of a.B-unsaturated aldehydes with phosphoranes and  phosphonate anions derived from 4-("halomethvDbutenolides Recently, T h a l l e r et a l . 3 reported the i s o l a t i o n and t o t a l synthesis of a new monoterpene, scobinolide ( 2 0 6 ) . In t h e i r synthesis, - 92 -the phosphonium s a l t 207 was treated with an aqueous methanolic s o l u t i o n of sodium hydroxide and the resultant stable phosphorane 208 was i s o l a t e d as a yellow s o l i d (see equation 80). The phosphorane 208 was then allowed to react with the aldehyde 209 i n r e f l u x i n g dichloromethane fo r 3 h. Preparative t h i n layer chromatography of the crude product mixture gave scobinolide (206) and the corresponding Z-isomer 210 i n y i e l d s of 47% and 11%, r e s p e c t i v e l y (equation 80). Following the chemistry reported by Boeckman et a l . b b and T h a l l e r et al., * ' 3 ' the phosphorane 208 was prepared and i s o l a t e d . When we repeated the above o l e f i n a t i o n r e a c t i o n exactly according to the conditions reported, ^  most of the phosphorane 208 was recovered and the o l e f i n a t i o n product mixture was i s o l a t e d i n only 10% y i e l d . However, when the r e a c t i o n mixture was refluxed f o r 24 h, scobinolide (206) was i s o l a t e d i n 48% y i e l d . Treatment of geranial (211) with the phosphorane 208 i n r e f l u x i n g - 93 -dichloromethane (bp 40°C) for 24 h did not give much of the o l e f i n a t i o n products. However, when the r e a c t i o n was c a r r i e d out i n b o i l i n g 1,2-dichloroethane (bp 80°C) f o r 16 h, compound 212 was i s o l a t e d i n 46% y i e l d (equation 81). These r e s u l t s suggest that the phosphorane 208 i s not very r e a c t i v e and that the o l e f i n a t i o n i s s e n s i t i v e to s t r u c t u r a l changes i n the a,unsaturated aldehyde. 211 The i r spectrum of 212 showed absorptions at 1778 and 1747 cm"l due to the carbonyl group. In the ^H nmr spectrum of 212, the o l e f i n i c protons appeared at 6 6.75 (dd, 1H, J - 12, 16 Hz, H A), 6.35 (d, 1H, J = 16 Hz, Hg), 5.97 (d, 1H, J = 12 Hz, H c), 5.84 (br s, 1H, H D), and 5.07 (br s, 1H, H E) and the methyl groups at S 1.85 (br s ) , 1.69 (br s) and 1.63 (br s ) . In order to by-pass the i s o l a t i o n of the phosphorane, the butenolide phosphonium s a l t 207 was treated with dimsyl potassium i n a minimum amount of dimethyl sulfoxide. The resultant s o l u t i o n was treated with a 1,2-dichloroethane s o l u t i o n of geranial (211) and the mixture was refl u x e d f o r 17 h. Workup and column chromatography of the crude product on s i l i c a gel provided compound 212 i n 47% y i e l d . This r e s u l t showed that the o l e f i n a t i o n could be c a r r i e d out s u c c e s s f u l l y without - 94 -i s o l a t i o n of the phosphorane 208. However, when the rea c t i o n of geranial (211) with the 7-methoxybute-nolide phosphonium s a l t 188 was attempted under conditions i d e n t i c a l with those j u s t described, geranial (211) was recovered i n t a c t and no o l e f i n a t i o n product could be detected by glc and t i c analysis (equation 82) . In view of t h i s f a i l u r e , a t t e n t i o n was turned to the use of the butenolide phosphonate 213, the anion of which was expected to be more rea c t i v e than the corresponding phosphorane. The phosphonate 213 was prepared i n 78% y i e l d by heating a mixture of the /3-(chloromethyl) -butenolide 197 and p u r i f i e d t riethylphosphite at 150°C f o r 18 h (equation 83). The ^H nmr spectrum of 213 exhibited a broad quintet at 6 4.15 (J = 7 Hz) due to the -P(0CH 2CH3) 2 protons, a s i n g l e t at S 3.60 due to the methoxy protons, and a p a i r of doublet of doublets at 5 3.01 (J - 16, 21 Hz) and 6 2.89 (J = 16, 21 Hz) due to the -CH 2P0(0Et) 2 no reaction (82) protons. (83) 197 213 95 -The phosphonate 214 was prepared according to the procedure reported by Boeckman et a l . . ^ and was employed as a model for studying the ol e f i n a t i o n of an a,B-unsaturated aldehyde. Under a variety of conditions, as reported by Boeckman et a l . . ^ b Corey et a l . . ^ and fi ft Masamune et a l . . 0 0 for coupling of 7-phosphonates of a,yS-unsaturated esters with a.^-unsaturated aldehydes, no o l e f i n a t i o n product could be isol a t e d from the reaction of geranial (211) with the anion of the phosphonate 214 (equation 8 4 ) . Nevertheless, the reactions were repeated with the 7-methoxybutenolide phosphonate 213, and not surp r i s i n g l y , no o l e f i n a t i o n product could be isolated (equation 8 5 ) . 213 Without any success i n o l e f i n a t i o n of a,^-unsaturated aldehydes using the 7-methoxybutenolide phosphonium s a l t 188 or the phosphonate 213, other means of o l e f i n a t i o n were investigated. - 96 -I. Reaction of a.fl-unsaturated aldehydes with phosphoranes derived from  4- (halomethyl') - 2 - t r i m e t h y l s i l v l f u r a n s Our a t t e n t i o n was turned to the use of the phosphonium s a l t s derived from 4-(halomethyl)-2-trimethylsilylfurans. Deprotonation of such phosphonium s a l t s would provide the s t a b i l i z e d phosphorane 215 (see Scheme 24). The l a t t e r material was expected to react with the a,/9-unsaturated aldehyde 107 to give the E o l e f i n 216 as the major product. Se l e c t i v e photosensitized oxygenation of the s i l y l f u r a n moiety of 216 would provide (±)-palauolide (55) (Scheme 24). The desired chemoselective photosensitized oxygenation was expected since oxygena-t i o n of s i l y l f u r a n s proceeds at a rate f a s t e r than the a l l y l i c oxygena-28 t i o n of alkenes. Furthermore, the diene moiety i n the side chain of 216 i s not l i k e l y to undergo a [2+4] cy c l o a d d i t i o n with generated s i n g l e t oxygen, since t h i s r e a c t i o n would require the diene moiety to adopt a s t e r i c a l l y congested c i s o i d conformation. Scheme 24 - 97 -In an attempt to prepare the required phosphonium s a l t , 4-chloro-m e t h y l - 2 - t r i m e t h y l s i l y l f u r a n (110) was treated with triphenylphosphine i n r e f l u x i n g benzene f o r 24 h. However, no product was obtained and the s t a r t i n g materials were recovered i n t a c t . Treatment of the furan 110 with a mixture of calcium bromide monohydrate and tetra-n-butylammonium bromide (catalyst)*^ 9 i n hexane at 50°C f o r 2 h provided the corresponding bromo d e r i v a t i v e 217 (equation 86). The ^H nmr spectrum of 217 exhibited two s i n g l e t s at S 7.65 and 6 6.64 due to the furan protons, a s i n g l e t at 6 4.37 due to the -C^Br protons and a s i n g l e t at 6 0.28 due to the t r i m e t h y l s i l y l protons. •CI Me3S'r n-Bu^NBr, CaBr.H 20 hexane, 50°C 110 M e 3 S i - - ^ c r 217 (86) Reaction of the bromide 217 with triphenylphosphine i n e t h e r / u under r e f l u x f o r 24 h provided the phosphonium s a l t 218 as a white, amorphous s o l i d (77% from the furan 110, equation 87). The -^H spectrum of 218 + exhibited a 2-proton m u l t i p l e t at S 5.30 due to the -CH^PPl^ protons. - 98 -S i m i l a r l y the phosphonium iodide 219 was prepared as follows. Treatment of the chl o r i d e 110 with sodium iodide i n acetone at 60°C gave the iodide 220. Reaction of the l a t t e r substance with triphenylphos-phine i n ether afforded the phosphonium s a l t 219 (equation 88). With both phosphonium s a l t s 218 and 219 a v a i l a b l e , t h e i r use i n the o l e f i n a t i o n of geranial (211) was studied. To a s o l u t i o n of the phosphonium bromide 218 i n ether was added, successively, an ethereal s o l u t i o n of ph e n y l l i t h i u m ^ 1 and a dichloromethane s o l u t i o n of ge r a n i a l . The re s u l t a n t mixture was s t i r r e d at room temperature f o r 1 h. Workup provided, on the basis of nmr spectroscopy and a glc ana l y s i s , a 3:2 mixture of the o l e f i n a t i o n products 221 and 222, r e s p e c t i v e l y (equation 89). When the phosphonium iodide 219 was subjected to the same rea c t i o n conditions, the s t e r e o s e l e c t i v i t y of the o l e f i n a t i o n improved s l i g h t l y to 2:1 i n favour of 221 (equation 90). - 99 -+ M e 3 S i - ^ PPh3l 1 . P h L i , ether 221 2 Me 3Si + 2. OHC^i 219 Me3Si 222 1 The o l e f i n a t i o n products 221 and 222 were unstable and decomposed on s i l i c a gel during chromatography. Attempts to separate them on deacti-vated neutral alumina were not successful. However, the major product was l a t e r confirmed to be the E o l e f i n (see p. 102). I t was expected that r e f l u x i n g a s o l u t i o n of the mixture of 221 and 222 i n n-hexane i n the presence of iodine would convert the Z o l e f i n to the E o l e f i n . However, l i t t l e stereomutation was detected and the mixture underwent slow decomposition. Since the o l e f i n a t i o n s with the phosphorane 215 were not very s t e r e o s e l e c t i v e , another method that might eventually be used for the (±)-palauolide synthesis was investigated. J . Reaction of geranial (211) with the sulfone 223. Photosensitized  oxidation of the resultant triene 221 to the corresponding  butenolide Our a t t e n t i o n turned to the p o s s i b i l i t y of employing the J u l i a o l e f i n a t i o n . In general, the synthesis of 1,2-disubstituted alkenes - 100 -using t h i s method provide e x c l u s i v e l y the E olefins.72 p o r example, successive treatment of the sulfone 224 with n-butyllithium, benzaldehyde and a c e t i c anhydride provided the a-acetoxy sulfone 225. The l a t t e r material underwent smooth reductive e l i m i n a t i o n with sodium amalgam to give s t e r e o s e l e c t i v e l y the diene 226 i n 93% y i e l d (equation 91).72 xhe stereochemistry of the r e a c t i o n can be r a t i o n a l i z e d by 3. Ac 0 224 225 226 proposing that the reductive cleavage of the phenylsulfonyl group generates an anion which assumes the lowest energy conformation (see structure 225a) from which the E-alkene i s formed. 225a Recently, i n connection with work di r e c t e d toward the t o t a l synthe-s i s of i n d a n o m y c i n , L e y employed the J u l i a o l e f i n a t i o n to couple the s t r u c t u r a l l y complex a,@-unsaturated aldehyde 227 with the highly f u n c t i o n a l i z e d sulfone 228. The o l e f i n a t i o n was t o t a l l y s t e r e o s e l e c t i v e and produced only the E,E-l,3-diene 229 (equation 92). - 101 -227 C0 2M C " ^ V ^ C H 0 PhS0 2 228 1. a. n-BuLi, THF, -78°C b. benzoyl c h l o r i d e SEM=CH2OCH2CH2SiMe3 2. Na(Hg), MeOH-THF V (92) 229 The sulfone 223 required f o r our work was prepared by heating a mixture of 4-(chloromethyl)-2-trimethylsilylfuran (110) and sodium benzenesulfinate i n dimethylformamide at 80-90°C f o r 2.5 h (72%, equation 93). The nmr spectrum of 223 showed a s i n g l e t at S 4.15 due to the -CH2S02Ph protons. The high r e s o l u t i o n mass spectrum of 223 80-90°C S 0 2 P h (93) 110 223 102 -showed a molecular ion at m/e 294.0744, consistent with a molecular formula of Ci^H-LgSC^Si. The sulfone 223 was treated with n-bu t y l l i t h i u m i n THF at -78°C. The r e s u l t a n t s o l u t i o n was treated successively with geranial (211) (-78°C, 3 h) and benzoyl chloride (-78°C to r t , 1.5 h) to a f f o r d the benzoyloxy phenylsulfone 230. The l a t t e r material was treated with sodium amalgam (4%) i n methanolic THF at -20°C f o r 3 h 7 3 to a f f o r d s t e r e o s e l e c t i v e l y the triene 221 (68% y i e l d from sulfone 223, equation 94). In the -^H nmr spectrum of 221, the o l e f i n i c signals appeared at 5 6.65 (dd, 1H, J = 11, 16 Hz, H A), 6.26 (d, 1H, J = 16 Hz, Hg), 5.90 (d, 1H, J = 11 Hz, H c) and 5.07 (br s, 1H, H D), i n d i c a t i n g that the newly formed carbon-carbon double bond had the desired E stereochemistry. This material was i d e n t i c a l with the major product obtained from the previously described W i t t i g reaction (see p. 99). S0 2Ph Me3Si-'**\0 S0£Ph 1 . n-BuLi, THF > 2. O H C - ^ V ^ ^ V ^ Me3Si 0 223 3. PhCOCl Na(Hg), MeOH-THF (94) 221 - 103 -The furan tr i e n e 221 was then used as a model to investigate the photosensitized oxygenation reaction. When a c o l d (-78°C) dichloro-methane s o l u t i o n of the furan triene 221, containing a c a t a l y t i c amount of tetraphenylporphin, was i r r a d i a t e d while oxygen was bubbled through the mixture, a t e r r i b l e mixture of products was obtained. Fortunately, when a c o l d (-78°C) methanolic s o l u t i o n of the furan t r i e n e 221, containing a c a t a l y t i c amount of Rose Bengal, was i r r a d i a t e d with a tungsten-halogen lamp (325W) through an aqueous sodium n i t r i t e f i l t e r , while oxygen was bubbled through the methanolic s o l u t i o n , ^ the 7-hydroxybutenolide 231 was obtained i n 70% y i e l d (equation 95). The i r spectrum of 231 exhibited a broad absorption at 3343 cm"1 due to the hydroxy group and a strong absorption at 1744 cm"1 due to the carbonyl group. The -41 nmr spectrum of 231 exhibited signals at 5 7.18 (dd, 1H, J = 11, 16 Hz, H A), 6.30 (d, 1H, J = 16 Hz, H f i), 6.23 (d, 1H, J - 8.5 Hz, H c), 6.00 (d, 1H, J = 11 Hz, H D), and 5.87 (s, 1H, H E) due to the protons on the diene butenolide moiety of 231. These chemical s h i f t s were almost exactly the same as those reported for the diene butenolide These r e a c t i o n conditions are i d e n t i c a l with those used for convert-ing 4-(chloromethyl)-2-trimethylsilylfuran (110)to the corresponding 7-hydroxybutenolide 109. 110 109 - 104 -moiety of palauolide (55) [5 7.16 (dd, J - 11, 15.5 Hz), 6.28 (d, J -15.5 Hz), 6.26 (s ) , 5.95 (d, J = 11 Hz), 5.83 ( s ) ] . 1 4 K. Reaction of the aldehyde 107 with the sulfone 223. Photosensitized  oxidation of the resultant triene 216 to (±)-palauolide (55) With s u i t a b l e conditions developed (section J) for the required o l e f i n a t i o n and photosensitized oxygenation, the stage was set to employ these reactions to e f f e c t a t o t a l synthesis of (±)-palauolide (55). To a s o l u t i o n of the sulfone 223 i n THF at -78°C was added a s o l u t i o n of n-butyllithium. The resultant s o l u t i o n was treated with the a,fi-unsaturated aldehyde 107 (-78°C, 3 h) and benzoyl ch l o r i d e (-78°C to room temperature, 1.5 h). The resultant benzoyloxy phenylsulfone 232 was allowed to react with sodium amalgam (4%) i n a 3:1 mixture of THF and methanol, r e s p e c t i v e l y , at -20°C f o r 3 h. Workup afforded the furan t r i e n e 216 (51% from the aldehyde 107, equation 96). 105 -The iH nmr spectrum of 216 exhibited s i n g l e t s at 5 7.58 and 6.76 due to the furan protons H A and Hg, re s p e c t i v e l y , and at 6 0.27 due to the t r i m e t h y l s i l y l group. The o l e f i n i c protons i n the side chain appeared at 6 6.56 (dd, 1H, J = 10, 16 Hz, H c), 6.30 (d, 1H, J = 16 Hz, H n), 5.89 (d, 1H, J - 10 Hz, H E), i n d i c a t i n g that the newly introduced carbon-carbon double bond i n the diene moiety possesses the desired E stereochemistry. The high r e s o l u t i o n mass spectrum of 216 showed the molecular ion at m/e 424.3161, which i s consistent with a formula of c 2 8 H 4 4 S i 0 -A c o l d (-78°C) dichloromethane-methanol s o l u t i o n of the furan t r i e n e 216, containing a c a t a l y t i c amount of Rose Bengal, was i r r a d i a t e d f o r 8 minutes with a halogen-tungsten lamp (325W) through an aqueous sodium n i t r i t e f i l t e r , while oxygen was bubbled through the mixture. The re s u l t a n t s o l u t i o n was purged with argon and kept at room temperature i n the dark f o r 3 h. Af t e r workup and column chromatography of the crude - 106 -The synthetic material was spe c t r o s c o p i c a l l y i d e n t i c a l with natural palauolide (Figs. 4 and 5). For comparison purposes, the 1H nmr sp e c t r a l data reported f o r the natural m a t e r i a l 1 4 and those derived from our synthetic material are compiled i n Table 1. Table 1: AH nmr sp e c t r a l data of natural palauolide and synthetic (±)-palauolide (55) Reported Data AH nmr (CDC13) 6: 7.16 (dd, 1H, J = 15.5, 11 Hz, H A), 6.28 (d, 1H, J = 15.5 Hz, Hg), 6.26 (s, 1H, H c), 5.95 (d, 1H, J - 11 Hz, H D), 5.83 (s, 1H, Hg), 4.51 (s, 2H, Hp), 1.86 (s, 3H, v i n y l methyl protons), 1.05 (s, 3H, methyl protons), 0.82 (d, 3H, J = 7 Hz, methyl protons), 0.74 (s, 3H, methyl protons). Our data AH nmr (400 MHz, CDCI3) 5: 7.14 (dd, 1H, J_ - 15.5, 11 Hz, H A) , 6.29 (d, 1H, J - 15.5 Hz, H B), 6.26 (d, J = 8.5 Hz, collapsed to s on D 20 exchange, H c), 5.97 (d, 1H, J = 11 Hz, H D), 5.87 (s, 1H, Hg), 4.51 (s, 2H, H F), 1.88 (s, 3H, v i n y l methyl protons), 1.06 (s, 3H, methyl protons), 0.82 (d, 3H, J •= 6 Hz, methyl protons), 0.74 (s, 3H, methyl protons). We are g r a t e f u l to Professor D.J. Faulkner f o r the AH nmr spectrum of palauolide (55) . F i g u r e 4 : The H nmr spectrum o f n a t u r a l p a l a u o l i d e - 109 -The work summarized above c o n s t i t u t e s t h e s u c c e s s f u l t o t a l s y n t h e s i s o f (±)-palauolide i n a t o t a l o f s e v e n t e e n s t e p s from 3 , 6 - d i m e t h y l - 2 -c y c l o h e x e n - 1 - o n e w i t h an o v e r a l l y i e l d o f 5% (see Scheme 25) and r e p r e s e n t s t h e f i r s t r e p o r t e d t o t a l s y n t h e s i s o f t h i s s t r u c t u r a l l y and b i o l o g i c a l l y i n t e r e s t i n g n a t u r a l p r o d u c t . 115 x i i i * ) 177 xiiil-*-) 187 xiv(-*) 107 i,n 183 R = H , R = H .0H 184 R = H . R'=0 185 R=Me .R '=H .0H 176 R=Me .R '=0 ixC-*-) 183 x ( - * )184 xi{-»-) 185 x ( - » 1 7 6 177 R=C02Et 187 R=CH20H 107 R = C H 0 Li f~ M e 3 S i - ^ 0 - ' 223a i v ( - » 1 7 3 v(-»> 180 vi(->)181 vii (•*) 174 viii(-*-) 175 173 R = C N 180 R=CH0 181 R = CH20H 174 R=CH20P0(NMe2)2 175 R = Me Scheme 25 109a -Reagents and conditions: i , 2-(5-chloropent-l-enyl)magnesium bromide, CuBr-Me2S, BF 3-Et 20, THF, -78°C, 3 h; NH 4Cl, H 20, 77%; i i , Bu^K, Bu^H, 30°C, 10 h, 82%; i i i , (p.-tolylsulphonyl)methyl isocyanide, Bu^K, Bu^ -OH-HMPA, 40-55°C, 3 days, 64%; i v , l i t h i u m diisopropylamide, THF-HMPA, 0°C; I[CH 2] 30CH 20Me, 0°C - room temp., 99%; v, Bu i 2AlH, DME, 60°C, 6 h; H0Ac-H20, THF, room temp., 10 h, 85%; v i , L 1 A I H 4 , E t 2 0 , room temp., 91%; v i i , B u n L i , DME-TMEDA; Cl 2P0NMe 2, room temp., 10 h; Me2NH, 0°C, 2 h, 88%; v i i i , L i , MeNH2, -20°C, 10 min, 81%; i x , pyridinium toluene-p_-sulphonate , Bu^ -OH, 70°C, 91%; x, pyridinium chlorochromate , NaOAc, CH 2C1 2, 99%; x i , MeLi, Et 2Q, 98%; x i i , [Et0 2CCHP0(0Et) 2]K, THF, room temp., 18 h, 88%; x i i i , Bu i 2AlH, E t 2 0 , -78 -+ 0°C, 98%; xi v , Mn02, hexane, room temp., 88%; xv, 223a, THF, -78°C, 3 h; PhCOCl, -78°C room temp.; Na(Hg), MeOH-THF, -20°C, 3 h, 51%; x v i , hu (tungsten halogen lamp, aqueous NaN02 f i l t e r , 0 2, Rose Bengal ( c a t a l y s t ) , Me0H-CH 2Cl 2, -78°C, 8 min; purge re a c t i o n mixture with argon and then keep at room temp, i n the dark for 3 h, 68%. - 110 -I I . T o t a l Synthesis of (±)-Isolinaridiol (64) and (±)-Isolinaridiol Diacetate (61) A. Retrosynthetic Analysis Our r e t r o s y n t h e t i c analysis of (±)-isolinaridiol (64) and (±)-isolinaridiol diacetate (61) was based on the methodology employed i n the construction of the d e c a l i n substructure of (±)-palauolide (55), as discussed i n a previous section of t h i s t h e s i s . Suitable r e t r o s y n t h e t i c f u n c t i o n a l group interconversions of the diacetate 61 would provide the d i o l 64. I t may be noted that San F e l i c i a n o et a l . ^ - 9 have reported the reduction of i s o l i n a r i d i a l (60) and the s a p o n i f i c a t i o n of the natural diacetate 61 to i s o l i n a r i d o l 64. Further r e t r o s y n t h e t i c f u n c t i o n a l group interconversions i n v o l v i n g 64 would provide the ester 223. Retrosynthetic disconnection of the carbon-carbon double bond i n the side chain of the l a t t e r substance, along with s u i t a b l e f u n c t i o n a l i z a t i o n of resultant fragments, would provide the aldehyde 234 and the phosphonate 235. Recently, S t i l l et a l . 7 4 have reported the use of the methyl b i s ( t r i f l u o r o e t h y l ) -phosphonoacetate 236 to e f f e c t h i g h l y s t e r e o s e l e c t i v e Z o l e f i n a t i o n of aldehydes. For example, rea c t i o n of the potassium s a l t of the phospho-nate 236 with n-heptanal i n THF at -78°C i n the presence of 18-crown-6 gave a 46:1 mixture of the Z and E esters, 237 and 238, r e s p e c t i v e l y (equation 97). I t was expected that the analogous phosphonate 235 should be preparable by monoalkylation of 239 with the iodide 240. Further, i t was hoped that the r e a c t i o n of the anion of 235 with - I l l -- 112 -( C F 3 C H 2 0 ) 2 P ( j H C 0 2 M e (236) 1 8 - c r o w n - 6 e t h e r , - 7 8 C 237 238 aldehyde 234 would give p r i m a r i l y the Z o l e f i n 223. Suitable r e t r o s y n t h e t i c f u n c t i o n a l group interconversions i n v o l v i n g the aldehyde 234 would provide the n i t r i l e 241. Disconnection at the carbon-carbon bond j o i n i n g the side chain and the b i c y c l i c system, along with the s u i t a b l e f u n c t i o n a l i z a t i o n of the fragments, would provide the n i t r i l e 112 and the iodide 240. A l k y l a t i o n of the n i t r i l e 112 had already been demonstrated to be completely s t e r e o s e l e c t i v e and the preparation of the n i t r i l e 112 had been developed for the synthesis of (±)-palauolide (55). B. Z S e l e c t i v e Horner-Wittig o l e f i n a t i o n s 1. O l e f i n a t i o n s with a c y c l i c b i s ( t r i f luoroethvDphosphonates Treatment of d i s t i l l e d trimethyl phosphonoacetate (242) with phosphorus p e n t a c h l o r i d e ^ 4 at room temperature f o r 1 h and at 75°C f o r 3 h, provided the d i c h l o r i d e 243 i n 99% y i e l d (equation 98). The l a t t e r material was treated with 2,2,2-trifluoroethanol i n benzene i n the presence of diisopropylethylamine at room temperature f o r 2 h. Column 113 -(MeO)2$CH2C02Me — > CI 2^CH2C02Me (98) 242 2 A 3 c h r o m a t o g r a p h y o f t h e cru d e p r o d u c t on s i l i c a g e l p r o v i d e d t he b i s ( t r i f l u o r o e t h y l ) p h o s p h o n a t e 239 (57%, e q u a t i o n 9 9 ) . The nmr sp e c t r u m o f 239 e x h i b i t e d a q u i n t e t a t 8 4.44 ( J = 8 Hz) due t o the 0 (CF3CH20)2P- p r o t o n s , a s i n g l e t a t 6 3.75 due t o t h e methoxy p r o t o n s , 0 and a d o u b l e t a t 8 3.15 ( J = 20 Hz) due t o t h e -PCH2- p r o t o n s . 0 C F 3 C H 2 O H (2.3 e q u i v . ) 0 CI2PCH2C02Me > (CRC^bPCHbCOjMf L i - P r 7 N E t , benzene c L 2 4 3 " 2 239 (99) R e a c t i o n o f 2 - c h l o r o e t h a n o l (244) w i t h c h l o r o m e t h y l m e t h y l e t h e r i n the p r e s e n c e o f d i i s o p r o p y l e t h y l a m i n e i n d i c h l o r o m e t h a n e a t room t e m p e r a t u r e gave 2 - c h l o r o - l - m e t h o x y m e t h o x y e t h a n e ( 8 0 %, see e q u a t i o n 100). T r eatment o f t h e l a t t e r m a t e r i a l w i t h an a c e t o n e s o l u t i o n o f sodium i o d i d e a t 60°C i n the d a r k f o r 30 h a f f o r d e d 2-iodo-1-methoxy-methoxyethane (240) (50%, e q u a t i o n 100). The ^ H nmr s p e c t r u m o f 240 C1CH_0CH7 2 3 „ NaT C l / \ / 0 H > C l ^ s / O ^ O ^ > (100) i . - P r 2 N E t a c e t o n e 1 v x 2AA C H 2 C I 2 2A0 - 114 -exhibited two s i n g l e t s at 6 4.68 and 6 3.40, due to the acetal and methoxy protons, re s p e c t i v e l y , and two t r i p l e t s at 6 3.82 (J = 6 Hz) and 5 3.30 (J - 6 Hz) due to the -OCH2CH2- and ICH2- protons, r e s p e c t i v e l y . The high r e s o l u t i o n mass spectrum of 240 showed a molecular ion at m/e 215.9649, consistent with a molecular formula of C^HgI02. The phosphonate 239 (0.63 mmol) was treated with sodium hydride (0.71 mmol) i n dimethylformamide (2 mL) at room temperature f o r 15 min. The r e s u l t a n t s o l u t i o n was treated with 18-crown-6 ether (47 umol)^^ and 2-iodo-l-methoxymethoxyethane (240) (0.47 mmol). The mixture was heated at 60°C f o r 4 h. Workup provided a 6 :20:1 mixture of the phosphonate 239, the mono-alkylated phosphonate 235, and the d i - a l k y l a t e d phosphonate 245, r e s p e c t i v e l y ( XH nmr spectroscopy, equation 1 0 1 ) . However, these compounds were not separable by chromatography on e i t h e r s i l i c a gel or alumina. I t was expected that employing 2-iodo-l-benzyloxymethoxyethane (246) as the a l k y l a t i n g reagent would provide a separable mixture of products. Treatment of 2-chloroethanol (244) with f r e s h l y d i s t i l l e d benzyl chloromethyl ether i n the presence of diisopropylethylamine i n dichloro-239 2. ICH 2CH 2OCH 2OCH 3 18-crown-6 e t h e r 239 R=R>H 235 R=H,R=CH2CH2OCH2OMe 245 R=R=CH2CH20CH20Me methane at room temperature provided 2-chloro-1-benzyloxymethoxyethane - 115 -(247) i n 86% y i e l d (see equation 102). The nmr spectrum of 247 exhibited two s i n g l e t s at 5 4.81 and 6 4.63 due to the benzyl and acetal protons, r e s p e c t i v e l y . In the AH nmr spectra of a number of compounds described i n t h i s thesis that contain the -OCH2OCH3 group, the chemical s h i f t s of the ace t a l protons i n v a r i a b l y appeared between 6 4.68 and S 4.56. The spectrum of 247 also showed two t r i p l e t s at 6 3.83 (J = 6 Hz) and 6 3.63 (J = 6 Hz) due to the C1CH2CH20- and C1CH2CH20- protons, r e s p e c t i v e l y . Treatment of 247 with sodium iodide i n acetone at 60°C f o r 40 h provided the iodide 246 i n 77% y i e l d (equation 102). The high r e s o l u t i o n mass spectrum of 246 showed a molecular ion at m/e 291.9966, corresponding to a molecular formula of C^oH^302I. 247 (102) P ^ X / O ^ O ^ P n 246 Following conditions i d e n t i c a l with those described i n the previous page, a dimethylformamide s o l u t i o n of the bis(trifluoroethyl)phosphonate 239 was treated successively with sodium hydride, 18-crown-6 ether, and the iodide 246. A f t e r workup and column chromatography of the crude product on s i l i c a g e l , pure mono-alkylated phosphonate 248 was i s o l a t e d i n 70% y i e l d (equation 103). The ^ H nmr spectrum of 248 exhibited a 5-proton m u l t i p l e t at 5 7.34 due to the aromatic protons, a s i n g l e t at d ^ S s / O H ClCH2OCH2Ph 244 - P r 2 N E t CH2C12 Nal, acetone 247 > - 116 -6 3.75 due to the methoxy protons, and a doublet of doublet of doublets 0 of doublets at S 3.39 (J = 4, 10, 22 Hz) due to the >CHP(0R) 2 proton. 9 1- N a H > D M F ^ % 9 (103) (CF,CH70)2F>CH2C02Me ' > (CF3CH20)2PCHC02Me 2' ^H 2CH 20CH 20CH 2Ph CH2CH20CH20CH2Ph 18-crown-6 ether *~ 2A8 With the desired substituted bis(trifluoroethyl)phosphonate 248 a v a i l a b l e , the use of t h i s reagent f o r the o l e f i n a t i o n of 3-methyl-butanal was investigated. Following S t i l l ' s procedure, 7 4 a s o l u t i o n of the phosphonate 248 (0.58 mmol) i n THF (10 mL) at 0°C was treated with potassium b i s ( t r i m e t h y l s i l y l ) amide (0.64 mmol), and 18-crown-6 .nC^CN complex7*" (0.74 g) . The resultant s o l u t i o n was cooled to -78°C and treated with 3-methylbutanal (0.46 mmol). The r e a c t i o n mixture was s t i r r e d at -78°C for 4 h. Workup provided a 3:1 mixture of the Z and E esters, 249 and 250, r e s p e c t i v e l y (87%, equation 104). Column C02Me I ^ 0 - ^ P h (CF3CH20)2PCHC02Me lm KN(TMS)2,THF CH2CH 20CH20CH ?Ph— — > + ( 1 0 A ) * ^ c c 2. 3-methylbutanal 248 18-crown-6 ether -78°C - 117 -chromatography of t h i s material on s i l i c a gel (4 g, 230-400 mesh, e l u t i o n with petroleum ether-ether, 9:1 v/v) afforded a pure sample of each compound f o r c h a r a c t e r i z a t i o n . The i r spectrum of the le s s polar Z ester 249 exhibited absorptions at 1719 and 1644 cm"'- due to the carbonyl and alkene groups, respec-t i v e l y . The ^H nmr spectrum of 249 showed a t r i p l e t at 6 6.01 (J = 7 Hz) due to the o l e f i n i c proton, and a t r i p l e t at S 2.35 (J = 7 Hz) due to the i-PrCH.2 protons. The i r spectrum of the more polar E ester 250 exh i b i t e d absorptions at 1713 and 1646 cm"^ - due to the carbonyl and o l e f i n groups, r e s p e c t i v e l y . The ^H nmr spectrum of 250 showed a t r i p l e t at 6 6.90 (J = 7 Hz) due to the o l e f i n i c proton, and a t r i p l e t at 5 2.12 (J = 7 Hz) due to the i-PrCH 2- protons. The assignment of stereochemistry was based on comparison of the chemical s h i f t s of the o l e f i n i c protons and the i-PrCH^- protons of the two isomers. The i-PrCH.2-protons of the Z isomer are deshielded by the c i s C^Me group and thus resonate at lower f i e l d than the corresponding protons of the E isomer. On the other hand, as expected, the o l e f i n i c proton of the E isomer produces a s i g n a l at lower f i e l d than the o l e f i n i c proton of the Z isomer. The Z s e l e c t i v i t y of the o l e f i n a t i o n of 3-methylbutanal with the bis(trifluoroethyl)phosphonate 248 (3:1, Z:E) was rather low. In contrast, S t i l l et a l . . 7 4 had reported that r e a c t i o n of the phosphonate 236 with various aldehydes gave high Z s e l e c t i v i t y (>30:1, Z:E). On comparison of the structures of the two phosphonates, 236 and 248, the lower s e l e c t i v i t y with 248 must be due to the presence of a more bulky side chain (Me vs C^Cl^OC^OCl^Ph) . I t was thought that reducing the - I n -e f f e c t i v e s i z e of t h i s side chain by using the phosphonate 251 might improve the Z s e l e c t i v i t y . (CF3CH20)2PCHC02Me Me 235 (CF 3CH 20) 2R (CF3CH20)2PCHC02Me CH2CH20CH20CH2Ph 248 251 2. O l e f i n a t i o n s with -y-lactone q-phosphonates I t was expected that the 7 -lactone phosphonate 251 would be preparable from the reaction of a-bromo -7-butyrolactone (252)* with t r i s ( 2 , 2 , 2 - t r i f l u o r o e t h y l ) p h o s p h i t e (253).* However, heating a mixture of these substances at 130°C for 2 days d i d not give any of the desired product and most of the bromo lactone 252 was recovered i n t a c t . (CF3CH20)3P 253 252 130°C no reaction I t was thought that 251 might be accessible from a-diethylphospho-no - 7-butyrolactone (254) by s u b s t i t u t i n g the ethoxy groups with Both 252 and 253 are commercially a v a i l a b l e from A l d r i c h Chemical Co. - 119 -t r i f l u o r o e t h o x y g r o u p s . Treatment o f t h e bromo l a c t o n e 252 w i t h t r i e t h y l p h o s p h i t e a t 140°C f o r 5 h p r o v i d e d t h e phosphonate 2 5 4 7 7 ( e q u a t i o n 1 0 5 ) . However, subsequent t r e a t m e n t o f t h e phosphonate 254 w i t h phosphorus p e n t a c h l o r i d e and t r i f l u o r o e t h a n o l d i d n o t p r o v i d e any o f t h e d e s i r e d phosphonate 251. E W 3 P + B r ^ , > ( E t O l j U L I 252 25A (105) S i n c e a t t e m p t s t o p r e p a r e t h e b i s ( t r i f l u o r o e t h y l ) p h o s p h o n a t e 251 were u n s u c c e s s f u l , i t was d e c i d e d t o i n v e s t i g a t e t h e use o f a s i m p l e r 7 - l a c t o n e phosphonate f o r a l d e h y d e o l e f i n a t i o n s , i n o r d e r t o d e t e r m i n e w h e t h e r h i g h Z s e l e c t i v i t y c o u l d be a c h i e v e d . R e c e n t l y , K i s h i e t a l . 7 8 r e p o r t e d t h a t t h e r a t i o o f Z and E e s t e r s o b t a i n e d f r o m H o r n e r - W i t t i g r e a c t i o n s o f a l d e h y d e s i s s e n s i t i v e t o t h e s t r u c t u r e o f t h e phosphonate r e a g e n t s , t h e n a t u r e o f t h e s o l v e n t and t h e r e a c t i o n t e m p e r a t u r e . F u r t h e r m o r e , Nagaoka and K i s h i 7 9 r e p o r t e d t h a t i n g e n e r a l , phosphonate r e a g e n t s 255 w i t h b u l k y R groups r e a c t w i t h a l d e h y d e s t o g i v e predomi-n a n t l y E a.^-unsaturated e s t e r s , w h i l e phosphonate r e a g e n t s 255 w i t h s m a l l R groups p r o v i d e p r e d o m i n a n t l y Z o . ^ - u n s a t u r a t e d e s t e r s . F o r example, r e a c t i o n o f t h e a l d e h y d e 256 w i t h t h e d i i s o p r o p y l p h o s p h o n a t e 257 p r o v i d e d a 1:9 m i x t u r e o f 258 and 259, r e s p e c t i v e l y ( see e q u a t i o n 1 0 6 ) . On t h e o t h e r hand, r e a c t i o n o f 256 w i t h t h e d i m e t h y l p h o s p h o n a t e 260 p r o v i d e d a 9:1 m i x t u r e o f 258 and 259, r e s p e c t i v e l y ( e q u a t i o n 106). Thus, o l e f i n a t i o n o f a l d e h y d e s w i t h d i m e t h y l 7 - b u t y r o l a c t o n e phosphonate - 120 -261 was investigated. [(R0)2PCC02Et]M+ 255 CH3 256 CHO (RO) PCHCO Et, THF Me tert-BuOK, -78 C C02Et 258 C02Et 259 257 R=jrPr 1 260 R=Me 9 9 1 (106) The phosphonate 261 was prepared by heating a mixture of a-bromo-7-butyrolactone (252) with p u r i f i e d trimethyl phosphite 262 at 150°C for 8 h. A bulb to bulb d i s t i l l a t i o n of the resultant o i l provided the crude product, which was subjected to column chromatography on s i l i c a gel to provide the pure phosphonate 261 (30%, equation 107). The i r OfcOjP •+- B r - J L 1 5°°C > W - O j y ^ (107) 262 252 261 spectrum of 261 showed a strong absorption at 1772 cm"1 due to the carbonyl group. The XH nmr spectrum of 261 exhibited two doublets at 5 0 3.77 (J = 10 Hz) and 5 3.73 (J = 10 Hz) due to the -P(0CH 3) 2 protons, 0 and a t r i p l e t of doublets at 6 3.03 (J - 8, 24 Hz) due to the -PCH< - 121 -proton. The high r e s o l u t i o n mass spectrum of 261 showed a molecular ion at m/e 194.0352, consistent with a molecular formula of C^il^O^. The r e a c t i o n of 3-methylbutanal with the 7-lactone phosphonate 261 (equation 108), under a v a r i e t y of experimental conditions, was i n v e s t i -gated. The r e s u l t s are summarized i n Table 2. 263 CHO ( M e O ) 2 P ^ ^ > 261 (108) = \ J 264 Table 2: Reaction of 3-methylbutanal with the 7 -lactone phosphonate 261 Reaction Product r a t i o 3 T o t a l i s o l a t e d Entry Conditions 263 : 264 y i e l d (%) 1 NaH/benzene/rt^5 64 : 36 69 2 tert-BuOK/THF/- 7 8 0 C c 73 : 27 81 3 te r t-BuOK/THF-HMPA/-7 8 0 C 77 : 23 80 4 KN(TMS) 2/THF/18-crown-6/-78°C d >99 : <1 86 The product r a t i o s were determined by glc analysis of the crude product mixtures, and were supported by ^H nmr spectroscopy. See reference 80. See reference 79. See reference 74. - 122 -Treatment of the phosphonate 261 with sodium hydride i n benzene, followed by a d d i t i o n of 3-methylbutanal, gave a 64:36 mixture of the Z and E lactones, 263 and 264, r e s p e c t i v e l y (Table 2, entry 1). The lactones were separated by column chromatography on s i l i c a g e l . The i r spectrum of the l e s s polar Z lactone 263 exhibited absorptions at 1752 and 1670 cm"1 due to the carbonyl group and the o l e f i n i c double bond, r e s p e c t i v e l y . The XH nmr spectrum of 263 showed a t r i p l e t of t r i p l e t s at 6 6.27 (J = 4.5, 7 Hz) due to the o l e f i n i c proton and a broad t r i p l e t at S 2.60 (J = 7 Hz) due to the i-PrCH^- protons. The i r spectrum of the more polar E lactone 264 exhibited absorptions at 1757 and 1681 cm"1 due to the carbonyl and alkene functions, r e s p e c t i v e l y . The XH nmr spectrum of 264 showed a t r i p l e t of t r i p l e t s at 6 6.78 (J = 3, 7 Hz) due to the o l e f i n i c proton and a broad t r i p l e t at S 2.09 (J = 7 Hz) due to the i-PrCH2- protons. When the r e a c t i o n of 3-methylbutanal with the phosphonate 261 was c a r r i e d out i n THF i n the presence of potassium tert-butoxide at -78°C, the Z s e l e c t i v i t y improved marginally to 73:27 (Table 2, entry 2). A d d i t i o n of hexamethylphosphoramide to the r e a c t i o n mixture r e s u l t e d i n a further s l i g h t improvement i n the Z:E r a t i o (77:23) (Table 2, entry 3). However, when potassium b i s ( t r i m e t h y l s i l y l ) a m i d e was used as the base and the r e a c t i o n was c a r r i e d out i n THF i n the presence of 18-crown-6 at -78°C for 4 h, only the Z lactone 263 could be detected i n the crude product. This material was i s o l a t e d i n 86% y i e l d (Table 2, entry 4). Employing re a c t i o n conditions i d e n t i c a l with those summarized i n Table 2, entry 4, the o l e f i n a t i o n of a number of aldehydes with the - 123 -7-lactone phosphonate 261 was investigated (equation 109). The r e s u l t s are summarized i n Table 3. (109) Table 3: Reaction of aldehydes with the 7-lactone phosphonate 261 Product r a t i o a T o t a l i s o l a t e d Entry Aldehyde Z lactone : E lactone y i e l d (%) 1 heptanal (267) b 265a : : 266a, >99:1 94% 2 cyclohexanecarbox-aldehyde (268) b 265b : : 266b, 83:17 68% 3 (E)-2-hexenal (269) c 265c : : 266c, 97:3 78% 4 benzaldehyde (270) b 265d : : 266d, 50:50 91% The product r a t i o s were determined by glc analysis of the crude product mixture, and were substantiated by nmr spectroscopy. These aldehydes were d i s t i l l e d (atmospheric pressure) j u s t p r i o r to use. This aldehyde was d i s t i l l e d under reduced pressure (bp 40-45°C/15 t o r r ) . 124 -In the reactions of the phosphonate 261 with the a l i p h a t i c aldehydes 267, 268 and 269 (Table 3, entry 1-3), under the conditions described, the products were formed with good to e x c e l l e n t Z s e l e c t i -v i t y . However, with benzaldehyde, no s e l e c t i v i t y was observed. I t i s i n t e r e s t i n g to note that Minami et al.^Q reported that r e a c t i o n of the sodium s a l t of the d i e t h y l phosphonate 254 with benzaldehyde i n benzene gave only the E lactone 266d (equation 110). The Z s e l e c t i v e o l e f i n a t i o n of a l i p h a t i c aldehydes with the 7 -lactone phosphonate 261 described above i s complimentary to the E s e l e c t i v e o l e f i n a t i o n of the a l i p h a t i c aldehyde 271 with the phospho-rane 272 reported recently by S e c r i s t et a l . * * 1 (equation 111). - 125 -A pure sample of each of the lactones 256b and 266b (Table 3, entry 2) was obtained by column chromatography of the crude product mixture on s i l i c a gel (70-230 mesh, e l u t i o n with petroleum ether-ether , 8:2 v/v). S i m i l a r l y , the lactones 265d and 266d (Table 3, entry 4) were r e a d i l y separable by column chromatography of the crude product mixture on s i l i c a gel (230-400 mesh, e l u t i o n with benzene-ether, 30:1 v/v). A pure sample of the E lactone 266a was obtained as follows. Treatment of the phosphonate 261 with a suspension of sodium hydride i n benzene, followed by a d d i t i o n of heptanal (267), gave a 1:1 mixture of the Z and E lactones, 265a and 266a. These substances were separated by column chromatography on s i l i c a g e l . S i m i l a r l y , r e a c t i o n of the sodium s a l t of the phosphonate 261 with (E)-2-hexenal (269) i n benzene provided a 1:3 mixture of the Z and E lactones, 265c and 266c. The pure E lactone 266c was obtained by subjection of the crude product mixture to column chromatography on s i l i c a g e l . The assignment of stereochemistry of the o l e f i n a t i o n products l i s t e d i n Table 3 was, i n each case, based on comparison of the chemical s h i f t s of the o l e f i n i c protons and/or the a l l y l i c 7 '-protons (see general structures A and B) of the two possible geometric isomers. A B Z-lactone general structure A E-lactone general structure B - 126 -The o l e f i n i c p r o t o n s o f t h e E i s o m e r s a r e d e s h i e l d e d by t h e c i s c a r b o n y l group o f t h e l a c t o n e m o i e t y and th u s r e s o n a t e a t l o w e r f i e l d t h a n t h e c o r r e s p o n d i n g p r o t o n s o f t h e Z i s o m e r s . On t h e o t h e r hand, f o r the Z i s o m e r s , t h e a l l y l i c 7 ' - p r o t o n s , i f p r e s e n t , r e s o n a t e a t l o w e r f i e l d t h a n t h o s e o f t h e E i s o m e r s . Some o f t h e s p e c t r o s c o p i c d a t a d e r i v e d from t h e o l e f i n a t i o n p r o d u c t s o b t a i n e d f r o m t h e e x p e r i m e n t s summarized i n T a b l e s 2 and 3 a r e t a b u l a t e d i n T a b l e 4 (page 127). I t i s p e r t i n e n t t o n o t e t h a t , i n t h e -^ H nmr s p e c t r a o f t h e l a c t o n e s , t h e o l e f i n i c p r o t o n s o f t h e E i s o m e r s r e s o n a t e a t -0.50-0.56 ppm l o w e r f i e l d t h a n t h e c o r r e s p o n d i n g p r o t o n s o f t h e Z i s o m e r s . I t i s a l s o i n t e r e s t i n g t o p o i n t o u t t h a t , i n t h e i r s p e c t r a o f t h e s e m a t e r i a l s , t h e c a r b o n - c a r b o n d o u b l e bond s t r e t c h i n g v i b r a t i o n s o f t h e E l a c t o n e s appear a t h i g h e r wavenumbers (-5-11 cm"'-) t h a n t h o s e o f t h e Z l a c t o n e s . On t h e o t h e r hand, t h e p o s i t i o n s o f t h e c a r b o n y l s t r e t c h i n g v i b r a t i o n s o f t h e Z and E i s o m e r s do n o t show any w e l l d e f i n e d d i f f e r e n c e s . C. S y n t h e s i s o f t h e a l d e h y d e 234 A 15:85 m i x t u r e o f t h e n i t r i l e s 112a and 112b, r e s p e c t i v e l y , was t r e a t e d w i t h l i t h i u m d i i s o p r o p y l a m i d e i n THF-HMPA a t 0°C f o r 15 min. l-Iodo-2-methoxymethoxyethane (240) was added and t h e r e s u l t a n t s o l u t i o n was s t i r r e d a t 0°C f o r 30 min and a t room t e m p e r a t u r e f o r 1 h. Workup p r o v i d e d t h e n i t r i l e 241 i n 99% y i e l d ( e q u a t i o n 112). - 127 -Table 4: P a r t i a l '•H nmr and i n f r a r e d data f o r o l e f i n a t i o n products derived from reactions of aldehydes with the 7-lactone phosphonate 261 Lactone 3 Chemical s h i f t s (5) i r absorptions (cm"') c o l e f i n i c proton a H y l i c 7 ' - p r o t o n ( s ) b uC=0 i/C=C 263 6.35 2.60 1752 1670 264 6.85 2.09 1757 1681 265a 6.24 2.70 1757 1672 266a 6.76 2.20 1757 1681 265b 6.03 3.45 1756 1669 266b 6.54 2.11 1757 1678 265c 6.57 d 1747 1647 266c 7.09 - 1751 1652 265d 7.02 d 1747 1641 266d 7.58 - 1742 1651 a A l l compounds exhibited one peak on g l c analysis and one spot by t i c an a l y s i s . See structures A and B. A l l i n f r a r e d spectra were recorded on a Perkin-Elmer model 1710 spectrophotometer with i n t e r n a l c a l i b r a t i o n . This compound contains no a l l y l i c 7 '-proton. 128 -CN C N 1. LDA, THF-HMPA (112) 2. ICH 2CH 2OCH 2OCH 3 (240) 112a 112b 241 15:85 The i r spectrum of 241 exhibited absorptions at 2228 and 1638 cm"1 due to the n i t r i l e and o l e f i n i c groups, r e s p e c t i v e l y . The XH nmr spectrum of 241 showed a s i n g l e t at 5 3.34 due to the methoxy protons, and a p a i r of broad t r i p l e t of doublets at 6 2.15 (J = 7, 15 Hz) and 2.09 (J - 7, 15 Hz) due to the -CH2CH20- protons. Treatment of the n i t r i l e 241 with diisobutylaluminum hydride i n dimethoxyethane at 60°C f o r 6 h afforded, a f t e r workup and a c i d catalyzed h y d r o l y s i s of the crude imine, the aldehyde 273 (92%, equation 113). The i r spectrum of 273 showed a strong absorption at 1713 cm"1 due to the carbonyl group, while the AH nmr spectrum exhibited a s i n g l e t at S 9.97 due to the aldehyde proton. 2. H0Ac-H20-THF, r t 1. DIBAL-H, DME, 60°C 273 (113) 241 - 129 -Reduction of the aldehyde 273 with l i t h i u m aluminum hydride i n ether at room temperature provided the alcohol 274 i n 95% y i e l d (equation 114). The i r spectrum of 274 showed a broad absorption at 3443 cm"'- due to the hydroxy group. The nmr spectrum of 274 showed a p a i r of doublets at 5 3.77 (J = 11 Hz) and 6 3.68 (J = 11 Hz) due to the -CH2OH protons. Successive treatment of a s o l u t i o n of the alcohol 274 i n a 4:1 mixture of dimethoxyethane and N,N,N',N'-tetramethylethylenediamine with n - b u t y l l i t h i u m (15 min, room temperature), dimethylaminophosphoro-d i c h l o r i d a t e (12 h, room temperature), and anhydrous dimethylamine (2 h, 0°C)-' J afforded, a f t e r column chromatography of the crude product on s i l i c a g e l , the phosphorodiamidate 275 (63%, equation 115). The '-H nmr - 130 -spectrum of 275 exhibited a p a i r of doublets of doublets at 6 4.00 (J = 0 4, 11 Hz) and S 3.94 (J = 4, 11 Hz) due to the -CH20P(NMe2)2 protons, and a p a i r of doublets at 6 2.67 (J = 6 Hz) and 2.65 (J = 6 Hz) due to 0 the -0P(NMe2)2 protons. These s p e c t r a l data showed that the phosphoro-diamidate group had been i n s t a l l e d . Treatment of the phosphorodiamidate 275 with an anhydrous methyl-amine s o l u t i o n of lithium, i n the absence of t e r t - b u t y l alcohol, at -20°C f o r 10 min gave the deoxygenated compound 276 i n 80% y i e l d (equation 116). The LH nmr spectrum of 276 exhibited two s i n g l e t s at 5 1.04 and 6 0.75, and a doublet at 6 0.85 (J' - 6 Hz) due to the methyl groups i n the d e c a l i n substructure. The ether 276 was treated with pyridinium p_-toluenesulfonate i n t e r t - b u t v l a l c o h o l 5 5 at 70°C f o r 12 h to give the alcohol 277 (91%, equation 117). The i r spectrum of 277 showed a broad absorption at 3375 cm"1. The XH nmr spectrum of 277 exhibited a broad s i n g l e t at S 4.50 due to the exocyclic o l e f i n i c protons, and a p a i r of doublet of t r i p l e t s at 6 3.61 (J = 5.5, 10 Hz) and 6 3.52 (J = 5.5, 10 Hz) due to the -CH20H protons. 131 -OH PPTS, t e r t - B u O H (117) 70°C, 12h > 276 277 When t h e a l c o h o l 277 was o x i d i z e d w i t h p y r i d i n i u m c h l o r o c h r o m a t e i n t h e p r e s e n c e o f anhydrous sodium a c e t a t e i n d i c h l o r o m e t h a n e a t room t e m p e r a t u r e , a m i x t u r e o f p r o d u c t s was o b t a i n e d . However, t r e a t m e n t o f the a l c o h o l 277 w i t h a d i c h l o r o m e t h a n e s o l u t i o n o f d i m e t h y l s u l f o x i d e -o x a l y l c h l o r i d e r e a g e n t a t -78°C, f o l l o w e d by a d d i t i o n o f t r i e t h y l a -m i n e , 8 ^ p r o v i d e d the a l d e h y d e 234 c l e a n l y ( 8 5 % , e q u a t i o n 1 1 8 ) . The i r s p e c t r u m o f 234 e x h i b i t e d a s t r o n g a b s o r p t i o n a t 1718 cm"'- due t o t h e c a r b o n y l group. The '-H nmr s p e c t r u m o f 234 showed a t r i p l e t a t 6 9.78 ( J = 3.5 Hz) due t o t h e a l d e h y d e p r o t o n , and a p a i r o f d o u b l e t o f d o u b l e t s a t S 2.41 ( J = 3.5, 14.5 Hz) and 6 2.29 ( J = 3.5, 14.5 Hz) due t o t h e -CH2CHO p r o t o n s . OH 1. DMSO, ( C 0 C 1 ) 2 C H 2 C 1 2 , -78°C CHO 2. E t 3 N , -78°C t o r t > (118) 277 234 132 -D. Synthesis of (±)-isolinaridiol (64) and i t s geometric isomer 278 With s u i t a b l e conditions developed f o r the required Z o l e f i n a t i o n (Section B) and with the a c q u i s i t i o n of the aldehyde 234 (Section C), the stage was set to e f f e c t the synthesis of (±)-isolinaridiol (64). A c o l d (0°C) THF (1.9 mL) s o l u t i o n of the phosphonate 261 (0.11 mmol) was treated with a toluene s o l u t i o n of potassium b i s ( t r i m e t h y l s i l y l ) a m i d e * (0.12 mmol) and then 18-crown-6.nCH^CN complex (0.16 g) was added. The re s u l t a n t s o l u t i o n was cooled to -78°C, a THF s o l u t i o n of the aldehyde 234 (85 /imol) was added, and s t i r r i n g was continued at -78°C f o r 4 h. Glc analysis of the crude product showed that i t consisted of a 3:1 mixture of the o l e f i n a t i o n products. Subjection of t h i s mixture to column chromatography on s i l i c a gel provided both the pure Z lactone 279 (58%) and the pure E lactone 280 (19%, equation 119). This reagent s o l u t i o n i s commercially a v a i l a b l e from A l d r i c h Chemical Co. - 133 -The i r spectrum of the less polar lactone 279 exhibited absorptions at 1753 cm"1 due to the carbonyl group and at 1666 and 1635 cm"1 due to the o l e f i n i c linkages. The XH nmr spectrum of 279 exhibited a 1-proton t r i p l e t of t r i p l e t s at 6 6.24 (J •= 2.8 Hz) due to the o l e f i n i c proton on the side chain, and a p a i r of t r i p l e t of doublet of doublets at S 2.89 and S 2.65 (J = 2.5, 8, 17 Hz) due to the -CH2CH= protons. The i r spectrum of the more polar lactone 280 showed absorptions at 1758 cm"1 due to the carbonyl group and at 1676 and 1635 cm"1 due to the carbon-carbon double bonds. The LH nmr spectrum of 280 exhibited a 1-proton t r i p l e t of t r i p l e t s at 8 6.76 (J - 2.5, 6.5 Hz) due to the o l e f i n i c proton on the side chain, and a p a i r of m u l t i p l e t s at 5 2.30-2.22 and 5 2.18-2.10 due to the -CH2CH= protons. Since a v i c i n a l o l e f i n i c proton on the same side of the double bond as the carbonyl group i n an a,/9-unsaturated ester would experience an ani s o t r o p i c magnetic deshielding e f f e c t from the carbonyl group, the lactone 279 was assigned the Z stereochemistry, while the lactone 280 was assigned the E stereochemistry. The Z s e l e c t i v i t y (3:1, Z:E) of the o l e f i n a t i o n of the aldehyde 234 with the potassium s a l t of the phosphonate 261 was not as high as those observed i n the o l e f i n a t i o n of 3-methylbutanal (>99% Z s e l e c t i v i t y , Table 2, entry 4) and heptanal (>99% Z s e l e c t i v i t y , Table 2, entry 1). Attempts to improve the Z s e l e c t i v i t y by changing the concentration of the potassium s a l t of the phosphonate 261, and that of the aldehyde 234 proved to be f r u i t l e s s . The Z lactone 279, upon treatment with diisobutylaluminum hydride i n THF at -78°C f o r 1 h and 0°C for 2 h, afforded (±)-isolinaridiol (64) i n - 134 -96% y i e l d (equation 120). The i r spectrum of 64 exhibited a broad absorption at 3328 cm"1 due to the hydroxy groups and absorptions at 1636 and 891 cm"1 due to the exocyclic terminal double bond. The XH nmr spectrum of t h i s material was shown to be i d e n t i c a l with that of a sample of natural i s o l i n a r i d i o l provided by Professor A. San F e l i c i a n o * (see Figs. 7 and 8). However, these XH nmr data are s l i g h t l y d i f f e r e n t from those reported by San F e l i c i a n o et a l . 1 9 For comparison purposes, the nmr s p e c t r a l data reported f o r natural i s o l i n a r i d i o l , l 9 those derived from the authentic sample provided by Professor San F e l i c i a n o , and those obtained from our synthetic (±)-isolinaridiol are compiled i n Table 5. Reduction of the E lactone 280 with diisobutylaluminum hydride i n THF afforded the d i o l 278 (89%, equation 121), which i s spectroscopi-c a l l y d i s t i n c t l y d i f f e r e n t from i s o l i n a r i d i o l 64. The XH nmr of the d i o l 64 (see F i g . 9) exhibited a 1-proton t r i p l e t at 6 5.52 (J = 7.5 Hz) due to the o l e f i n i c proton, a broad s i n g l e t at 6 4.05 due to the =CCH.20H * We are g r a t e f u l to Professor A. San F e l i c i a n o f o r a sample of i s o l i n a r i d i o l and for copies of i t s XH nmr, i r , and mass spectra. 137 T a b l e 5: 1 H nmr s p e c t r a l d a t a o f i s o l i n a r i d i o l (64) I . R e p o r t e d D a t a -41 nmr (200 MHz, CDC1 3) 8: 5.32 ( t , 1H, J = 7.5 Hz, o l e f i n i c p r o t o n ) , 4.49 ( d , 2H, J = 1.4 Hz , o l e f i n i c p r o t o n s ) , 3 3.68 ( t , 2H, J = 5.7 Hz, -CH 2CH 2OH), 2.34 ( t , 2H, 5.7 Hz, -CH 2CH 2OH), 2.10 (m, 2H, -CH 2CH=), b 1.04 ( s , 3H, m e t h y l p r o t o n s ) , 0.82 ( d , 3H, J = 6 Hz, m e t h y l p r o t o n s ) , 0.75 ( s , 3H, m e t h y l p r o t o n s ) . I I . D a t a d e r i v e d from t h e sample p r o v i d e d by P r o f e s s o r San F e l i c i a n o -41 nmr (400 MHz, CDCI3) 6: 5.36 ( b r t , 1H, J = 8 Hz, o l e f i n i c p r o t o n ) , 4.50 ( b r s, 2H, o l e f i n i c p r o t o n s ) , 4.18, 4.15 ( d , d, 1H eac h , J = 12 Hz, =CCH 20H), 3.74 ( b r t , 2H, J = 6 Hz, -CH 2CH 20H), 2.39 ( t , 2H, J = 6 Hz, -CH 2CH 20H), 2.09 (m, 2H, -CH 2CH=), 1.80 ( b r s, 2H, D 20 exchanged, -OH), 1.05 ( s , 3H, m e t h y l p r o t o n s ) , 0.83 ( d , 3H, J = 7 Hz, m e t h y l p r o t o n s ) , 0.77 ( s , 3H, m e t h y l p r o t o n s ) . I l l . D a t a d e r i v e d from our s y n t h e t i c m a t e r i a l 41 nmr (400 MHz, CDCI3) 5: 5.36 ( b r t , 1H, J = 8 Hz, o l e f i n i c p r o t o n ) , 4.50 ( b r s, 2H, o l e f i n i c p r o t o n s ) , 4.18, 4.15 ( d , d, 1H eac h , J = 12 Hz, =CCH 20H), 3.74 ( b r t , 2H, J = 6 Hz, -CH 2CH 20H), 2.39 ( t , 2H, J = 6 Hz, -CH 2CH 20H), 2.09 (m, 2H, -CH 2CH=), 1.80 ( b r s, 2H, D 20 exchanged, -OH), 1.05 ( s , 3H, m e t h y l p r o t o n s ) , 0.84 ( d , 3H, J = 7 Hz, m e t h y l p r o t o n s ) , 0.77 ( s , 3H, m e t h y l p r o t o n s ) . The s i g n a l s a t 6 4.2-4.1 were n o t r e p o r t e d , however t h e "41 nmr s p e c t r u m o f i s o l i n a r i d i o l p r o v i d e d by P r o f e s s o r San F e l i c i a n o showed t h a t t h e r e i s a b r o a d s i n g l e t a t -6 4.12. No h y d r o x y l p r o t o n s were r e p o r t e d . 139 -protons, a t r i p l e t at S 3.71 (J = 6 Hz) due to the -CH2CH2OH protons, and a t r i p l e t at S 2 A3 (J - 6 Hz), due to the -CH 2CH20H protons. E. Synthesis of (±)-isolinaridiol diacetate (61) Treatment of (±)-isolinaridiol (64) with a c e t i c anhydride i n p y r i d i n e containing a c a t a l y t i c amount of 4-N,N-dimethylaminopyridine provided the diacetate 61 i n 90% y i e l d (equation 122). The i r spectrum of 61 exhibited absorptions at 1742 and 1635 cm'1 due to the carbonyl groups and the exocyclic o l e f i n i c double bond. The XH nmr s p e c t r a l data (see F i g . 10) of our synthetic (±)-isolinaridiol diacetate (61) were F i g . 10 : The 300 MHz H nmr spectrum o f s y n t h e t i c i s o l i n a r i d i o l d i a c e t a t e - 141 -found to be somewhat d i f f e r e n t from those r e p o r t e d 1 9 for natural i s o l i n a r i d i o l diacetate (vide i n f r a ) . Treatment of the d i o l 278 with a c e t i c anhydride i n p y r i d i n e i n the presence of 4-N,N-dimethylaminopyridine ( c a t a l y s t ) gave the diacetate 281 (78%, equation 123). This material exhibited i r absorptions at 1747 and 1635 cm' • 1. The  LH nmr s p e c t r a l data (see F i g . 11) 281 were also d i f f e r e n t from those reported for natural i s o l i n a r i d i o l d i a c e t a t e . 1 9 For comparison, the 1H nmr s p e c t r a l data reported f o r natural i s o l i n a r i d i o l d i a c e t a t e , 1 9 and those derived from our synthetic (±)-iso-l i n a r i d i o l diacetate (61) and the diacetate 281 are compiled i n Table 6. Comparison of the AH nmr s p e c t r a l data reported f o r natural i s o l i n a r i d i o l diacetate with those derived from our synthetic (±)-iso-l i n a r i d i o l diacetate (61) and the racemic diacetate 281 does not show con c l u s i v e l y that one of our synthetic materials i s i d e n t i c a l with the n a t u r a l product. Thus f a r , we have not been successful i n our attempts to obtain a sample of natural i s o l i n a r i d i o l diacetate. However, we hope that Professor San F e l i c i a n o w i l l be able to send us a small amount of t h i s material so that a proper comparison can be c a r r i e d out. In any case, there seems to be l i t t l e doubt that the s t r u c t u r a l assignments of our synthetic materials are correct. - 143 -Table 6: i H nmr s p e c t r a l data reported f o r na t u r a l i s o l i n a r i d i o l d i -acetate, and those derived from our synthetic <±)-isolinari-d i o l diacetate (61) and the diacetate 281 I. Spectral data reported f o r natural i s o l i n a r i d i o l diacetate •4" nmr (50 MHz, CDCl 3) S: 5.45 (m, 1H, o l e f i n i c proton), 4.47 (s, 2H, =CCH20Ac), 4.43 (br s, 2H, o l e f i n i c protons), 4.04 ( t , 2H, J = 6 Hz, -CH 2CH 20Ac), 2.38 ( t , 2H, J = 6 Hz, -CH 2CH 2OAc), 1.97, 1.91 (s, s, 3H each, a c e t y l protons), 1.03 (s, 3H, methyl protons), 0.81 (br d , a 3H, methyl protons), 0.75 (s, 3H, methyl protons). I I . Data derived from our synthetic (±)-isolinaridiol diacetate (61) XH nmr (300 MHz, CDCI3) 5: 5.44 ( t , 1H, J = 7.5 Hz, o l e f i n i c proton), 4.61 (br s, 2H, =CCH 20Ac b), 4.49 (br s, 2H, o l e f i n i c p r o t o n s b ) , 4.13 (m, 2H, -CH2CH2OAc), 2.40 ( t , 2H, J - 7 Hz, -CH 2CH 20Ac), 2.06, 2.03 (s, s, 3H each, a c e t y l protons), 1.04 (s, 3H, methyl protons), 0.81 (d, 3H, J = 6 Hz, methyl protons), 0.75 (s, 3H, methyl protons). I l l . Data derived from the synthetic diacetate 281 '-H nmr (300 MHz, CDCI3) 8: 5.57 ( t , 1H, J = 7.5 Hz, o l e f i n i c proton), 4.50 (br s, 4H, =CCH20Ac and o l e f i n i c protons), 4.10 (t, 2H, J = 7.5 Hz, -CH 2CH 20Ac), 2.43 ( t , 2H, J - 7.5 Hz, -CH2CH2OAc), 2.06, 2.04 (s, s, 3H each, a c e t y l protons), 1.04 (s, 3H, methyl protons), 0.82 (d, 3H, J = 6 Hz, methyl protons), 0.77 (s, 3H, methyl protons). No coupling constant was given. The assignment i s based on the f a c t that the o l e f i n i c protons of compounds described i n t h i s thesis bearing the general structure C i n v a r i a b l y appear at 8 4.49 to 4.52 i n the ^H nmr spectra and the =CCH20Ac protons of compound 282 (prepared by reduction of the lactone 263, Table 2, followed by b i s - a c e t y l a t i o n of the product) appears at 6 4.63 ( s ) . general structure C 282 144 -F. Attempts to oxidize (±)-isolinaridiol (64) to (±)-Isolinaridial (60) Recently, i n connection with work di r e c t e d toward the t o t a l synthe-s i s of polygodial (284), Lallemand et a l . * * 3 employed the Swern oxidation to oxidize the d i o l 283 to the dialdehyde 284 (75%, equation 124). I t was expected that t h i s method could be employed to oxidize (±)-isolinaridiol (64) to (±)-isolinaridial (60). Diisobutylaluminum hydride reduction of the lactone 263 provided the d i o l 285 (85%, equation 125), which was employed for a model study of the oxidation of the d i o l 64 to the dialdehyde 60. The i r spectrum of 285 showed a broad absorption at 3336 cm"1 due to the hydroxy groups and a weak absorption at 1656 cm"1 due to the o l e f i n i c linkage. The -^H nmr spectrum of 285 exhibited a t r i p l e t at 8 5.42 (J — 6 Hz) due to the The preparation of the lactone 263 was described i n p. 116 of t h i s t h e s i s . - 145 -o l e f i n i c proton, a s i n g l e t at 6 4.15 due to the =CCH2OH protons, and two t r i p l e t s at « 3.73 (J = 6 Hz) and S 2.39 (J = 6 Hz) due to the -CH2CH2OH and -CH2CH2OH protons, r e s p e c t i v e l y . Treatment of the d i o l 285 with a dichloromethane s o l u t i o n of the Swern dimethylsulfoxide-oxalyl chloride reagent at -78°C, followed by add i t i o n of t r i e t h y l a m i n e ^ a n ( j column chromatography of the crude product mixture on s i l i c a g e l , provided the aldehyde 286 i n 58% y i e l d (equation 126). The i r spectrum of 286 showed absorptions at 1728 and 1674 cm"1 due to the saturated aldehyde and the aunsaturated aldehyde carbonyl groups, r e s p e c t i v e l y . The AH nmr spectrum of 286 exhibited a t r i p l e t at S 9.60 (J - 2 Hz) due to the -CH2CH0 proton, a s i n g l e t at S 9.48 due to the =CCH0 proton, and a t r i p l e t at S 6.83 (J = 8 Hz) due to the o l e f i n i c proton. 0 H 1. DMSO-(COCl) 2,CH 2Cl 2, -78°C ) v /CHO (126) 2. Et,N, -78°C to 0°C v _ r u n 285 X 0H 3 286 L M U - 146 -However, attempts to oxidize (±)-isolinaridiol (64) under the conditions described above p e r s i s t e n t l y provided a t e r r i b l e mixture of products. The i r spectrum of the crude product mixture showed absorp-tions at 1727 and 1673 cm"', suggesting that the desired dialdehyde had been generated. However, a l l attempts to p u r i f y the dialdehyde were not s u c c e s s f u l . Since, at t h i s stage of the work, a l l of the a v a i l a b l e d i o l 64 had been used, further attempts to prepare (±)-isolinaridial (60) were not possible. The work summarized above constitutes the successful t o t a l synthesis of (±)-isolinaridiol (64) i n a t o t a l of nine steps from the n i t r i l e 112 with an o v e r a l l y i e l d of 19% (see Scheme 26). B i s - a c e t y l a t i o n of (±)-isolinaridiol (64) provided (±)-isolinaridiol diacetate (61). The i d e n t i t y of t h i s material with natural 61 has not yet been established (see page 141). 146a H-*) 241 273 61 R=Ac Scheme 26 Reagents and c o n d i t i o n s : i , l i t h i u m d i i s o p r o p y l a m i d e , THF-HMPA, 0°C; I ( C H 2 ) 2 0 C H 2 0 M e , 0°C -+ room temp., 99%; i i , B u i 2 A l H , DME, 60°C, 6 h; HOAc-H 20, THF, room temp., 10 h, 92%; i i i , L i A l H ^ , E t 2 0 , room temp., 95%; i v , B u n L i , DME-TMEDA; Cl 2PONMe 2, room temp., 10 h; Me 2NH, 0°C, 2 h, 63%; v, L i , MeNH 2, -20°C, 10 min, 80%; v i , p y r i d i n i u m p.-to l u e n e s u l -f o n a t e , Bu t0H, 70°C, 91%; v i i , DMSO-(C0C1) 2, C H 2 C 1 2 , -78°C; E t 3 N , -78°C t o room temp., 85%; v i i i , d i m e t h y l - y - b u t y r o l a c t o n e phosphonate (261) , l i t h i u m b i s ( t r i m e t h y l s i l y l ) a m i d e , THF, 0°C; 18-crown-6•nCH 3CN complex, -78°C, 4 h, 58%; i x , B u i 2 A l H , THF, -78 -+ 0°C, 96%; x, A c 2 0 , DMAP, p y r i d i n e , 90%. - 147 I I I . M i s c e l l a n e o u s I n t h e c h e m i c a l l i t e r a t u r e , t h e r e a r e a f a i r l y l a r g e number o f r e p o r t e d d i t e r p e n o i d n a t u r a l p r o d u c t s b e a r i n g a g e n e r a l s t r u c t u r e i n w h i c h t h e d e c a l i n s u b s t r u c t u r e has an e n d o c y c l i c o l e f i n i c f u n c t i o n i n s t e a d o f an e x o c y c l i c d o u b l e bond as i n p a l a u o l i d e (55) and i s o l i n a r -i d i o l (64). Examples i n c l u d e k o l a v e n i c a c i d ( 2 8 7 ) , 8 4 k o l a v e n o l ( 2 8 8 ) , 8 5 t h e a c i d 289, 8 6 t h e f u r a n o - o l e f i n 290, 8 7 j u n c e i c a c i d ( 2 9 1 ) , 8 8 k o l a v - 3 - e n - 1 5 - o i c a c i d ( 2 9 2 ) , 8 9 and k o l a v e l o o l ( 2 9 3 ) . 8 5 287 R=C02H R'=H 288 R=CH20HR'=H 289 R=H R=C02H 290 R=Me 291 R=C02H - 148 -I n o r d e r t o employ the m e t h y l e n e c y c l o h e x a n e a n n u l a t i o n sequence u s e d i n o u r t o t a l s y n t h e s i s o f (±)-palauolide (55) and (±)-isolinaridiol (64) f o r t h e c o n s t r u c t i o n o f t h e d e c a l i n s u b s t r u c t u r e o f t h i s c a t e g o r y o f n a t u r a l p r o d u c t s , c o n d i t i o n s w o u l d have t o be d e v e l o p e d t o i s o m e r i z e t h e d o u b l e bond i n t o t h e r i n g (Scheme 2 8 ) . Scheme 28 - 149 -In connection with work di r e c t e d toward the t o t a l synthesis of avarol, Sarma et a l . 9 0 reported that rhodium (III) chloride catalyzed isomerization of a -2:1 mixture of 294 and 295 furnished e x c l u s i v e l y the dimethyl ether 294 (equation 127). MeO OMe MeO MeO OMe RhCl 3, EtOH r e f l u x 295 Attempts were made to isomerize the exocyclic double bond of a number of intermediates prepared during the course of the synthesis of palauolide (55) and i s o l i n a r i d i o l (64). When a s o l u t i o n of the decalone 114 i n ethanol was refluxed i n the presence of rhodium (III) c h l o r i d e 9 0 or of p_-toluenesulfonic acid, a complicated mixture of products was obtained i n each case (equation 128). RhCl 3, EtOH, r e f l u x or £-TsOH, EtOH, r e f l u x complicated mixture (128) Treatment of the alcohol 126 with potassium 3-aminopropylamide (KAPA) 9 i i n 3-aminopropylamine (APA), or with rhodium (III) c h l o r i d e 9 0 - 150 -i n ethanol, gave, i n each case, only recovered s t a r t i n g material. The same r e s u l t was observed when the n i t r i l e 112 was subjected to s i m i l a r r e a c t i o n conditions. During the i n v e s t i g a t i o n of the use of dimethylboron bromide^ to cleave the methoxymethyl group of compound 276, a 3:1 mixture of the desired material 277 and the isomerized material 296 was obtained (^ H nmr spectroscopy, equation 129). Thus, i t appeared that t h i s r e a c t i o n could be used to e f f e c t the desired double bond isomerization. Indeed, when a s o l u t i o n of the ether 276 i n dichloromethane was treated wtih dimethylboron bromide (6 equiv.) at -78°C for a prolonged period of time (6 h), the alcohol 296 was obtained i n 84% y i e l d (equation 130). The alcohol 296 exhibited an i r absorption at 3304 cm"' due to the hydroxy group. The 'H nmr spectrum of 296 showed a very broad s i n g l e t at 6* 5.18 due to the endocyclic o l e f i n i c proton, and a broad s i n g l e t at 8 1.57 due to the v i n y l methyl protons. The 'H nmr spectra also exhibited two s i n g l e t s at 8 1.00 and 0.73, and a doublet at 8 0.87 (J «= 6 Hz) due to the methyl substituents on the b i c y c l i c moiety. These chemical s h i f t s are very s i m i l a r to those reported f o r the corresponding protons i n the f u r a n o - o l e f i n 2 9 0 . 8 7 - 151 -1.56 br s 290 - 152 -EXPERIMENTAL G e n e r a l Proton nuclear magnetic resonance ( XH nmr) spectra were recorded on e i t h e r a Bruker model WP 80, Bruker model HXS 270, Varian model XL 300 or Bruker model WH 400 spectrometers using deuterochloroform as the solvent and tetramethylsilane (TMS) as the i n t e r n a l or external stan-dard. Signal p o s i t i o n s are given i n parts per m i l l i o n (5) from TMS. Coupling constants (J-values) are given i n Hz. The m u l t i p l i c i t y , number of protons, assignments ( i f p o s s i b l e ) , and coupling constants are given i n parentheses. Abbreviations used are: s, s i n g l e t ; d, doublet; t, t r i p l e t ; q, quartet; m, mu l t i p l e t ; br, broad; v, very. Carbon nuclear magnetic resonance ( i 3C nmr) spectra were recorded on a Bruker model WH 400 spectrometer at 100.6 Hz or on a Varian model XL 300 spectrometer at 75.3 Hz using deuterochloroform as the solvent and TMS as the i n t e r n a l standard. Signal p o s i t i o n s are given i n parts per m i l l i o n (5) from TMS. Infrared ( i r ) spectra were recorded e i t h e r on a Perkin-Elmer model 1710 Fourier transform spectrophotometer with i n t e r n a l c a l i b r a t i o n or on a Perkin-Elmer model 710B spectrophotometer using the 1601 cm"1 band of polystyrene f i l m f o r c a l i b r a t i o n . Low r e s o l u t i o n mass spectra (LRMS) were recorded on a Varian/MAT CH4B spectrometer. High r e s o l u t i o n mass spectra (HRMS) were recorded on a Kratos/AEl MS 50 or MS 902 spectrometer. In cases of compounds with - 153 -trimethylstannyl groups the molecular weight determinations (HRMS) were based on '20g n a n ( j w e r e m a d e on the (M+-15) peak. G a s - l i q u i d chromatography (glc) was performed on ei t h e r a Hewlett-Packard model 5880 or model 5890 c a p i l l a r y gas chromatograph, both using a flame i o n i z a t i o n detector and a 25 m x 0.21 mm fused s i l i c a column coated with c r o s s - l i n k e d SE-54. Thin layer chromatography ( t i c ) was performed on commercially a v a i l a b l e 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 iodine vapor, u l t r a v i o l e t l i g h t or a 5% s o l u t i o n of ammonium molybdate i n 10% aqueous s u l f u r i c a c i d (w/v). Conventional column chromatography was done on 70-230 mesh s i l i c a (E. Merck, S i l i c a Gel 60) while f l a s h chromatography 9^ w a s done on 230-400 mesh s i l i c a gel (E. Merck, S i l i c a Gel 60). S i l i c a gel impregnated with s i l v e r n i t r a t e was prepared according to the following procedure. A s o l u t i o n of 12.5 g of s i l v e r n i t r a t e i n 100 mL of d i s t i l l e d water was added to 50 g of 70-230 mesh s i l i c a gel with s t i r r i n g u n t i l the s l u r r y was homogeneous. Most of the water was removed under reduced pressure (20 t o r r ) and the s i l i c a gel was dried under reduced pressure (0.02 to r r ) over D r i e r i t e overnight at room temperature with p r o t e c t i o n from l i g h t . Melting points (uncorrected) were measured on a Fischer-Johns melting point apparatus. D i s t i l l a t i o n temperatures (uncorrected) are ind i c a t e d as air- b a t h temperatures of Kugelrohr d i s t i l l a t i o n s . Unless otherwise stated, a l l reactions were c a r r i e d out under an atmosphere of dry argon, with dry solvents i n flame d r i e d glassware. Cold temperatures were maintained by the use of the following baths: - 154 -aqueous calcium chloride/C0 2 (-20°C, -30°C, - 4 0 ° C ) , 9 3 a c e t o n i t r i l e / C 0 2 (-48°C), chloroform/C0 2 (-63°C), acetone/C0 2 (-78°C). A l l temperatures recorded were i n degrees C e l s i u s . Solvents and Reagents Petroleum ether r e f e r s to a hydrocarbon mixture with b.p. 30-60°C. Ether r e f e r s to d i e t h y l ether. Tetrahydrofuran, ether, dimethoxyethane and benzene were d i s t i l l e d from sodium benzophenone k e t y l . Dichloro-methane and carbon t e t r a c h l o r i d e were d i s t i l l e d from phosphorus pento-xide. Iodomethane was passed through a short colum of basic alumina ( a c t i v i t y I) before use. Diisopropylamine, triethylamine, pyridine, c o l l i d i n e , l u t i d i n e , hexamethylphosphoramide, dimethyl sulfoxide, and a c e t o n i t r i l e were d i s t i l l e d from calcium hydride and stored over a c t i v a t e d 4A molecular sieves. N,N,N',N'-Tetramethylethylenediamine, toluene and dimethylamine were d i s t i l l e d from sodium. Ethylamine was d i s t i l l e d from l i t h i u m . Ethanol and methanol were d i s t i l l e d from magnesium. t e r t - B u t v l a l c ohol was d r i e d over a c t i v a t e d powdered 3 A molecular s i e v e s . 9 4 Dimethylformamide was d r i e d over activ a t e d 4A molecular sieves and d i s t i l l e d before use. p_-Toluenesulfonyl chloride 9-* was p u r i f i e d by r e c r y s t a l l i z a t i o n from chloroform-petroleum ether. Phosphorus t r i c h l o r i d e and t r i m e t h y l s i l y l -c h l o r i d e were f r e s h l y d i s t i l l e d before use. Boron t r i f l u o r i d e - e t h e r a t e was d i s t i l l e d under reduced pressure (~55°C/16 t o r r ) . Benzyl chloro-- 155 -methyl ether was d i s t i l l e d under reduced pressure (-120°C/16 t o r r ) . Triethylphosphite and trimethylphosphite were d r i e d over sodium, decanted and d i s t i l l e d before use. Hexamethylditin was d i s t i l l e d and stored under argon. Copper(I) bromide-dimethyl s u l f i d e complex was prepared by the method described by Wats9*" and phenylthiocopper was prepared by the method described by Posner. 9 7 Magnesium bromide-etherate was prepared by the r e a c t i o n of 1,2-dibromoethane with magnesium metal i n ether, followed by removal of ether under reduced pressure (0.02 t o r r ) at room temperature. Triphenylphosphine was p u r i f i e d by r e c r y s t a l l i z a t i o n from methanol-e t h y l acetate. N-Bromosuccinimide was r e c r y s t a l l i z e d from hot water. 18-Crown-6 ether was r e c r y s t a l l i z e d from dry a c e t o n i t r i l e and dri e d under reduced pressure (0.02 t o r r ) . 7 * 1 Tetra-n-butylammonium f l u o r i d e , prepared by the t i t r a t i o n of hydro-f l u o r i c a c i d with tetra-n-butylammonium hydroxide, was c r y s t a l l i z e d at -0°C and freeze d r i e d under reduced pressure (0.02 t o r r ) . Dimethyl-aminophosphorodichloridate was prepared by the method described by Walsh op et a l . Phenoxythiocarbonyl chloride was prepared by the method described by M i y a z a k i . " Pyridinium p_-toluenesulf onate was prepared by the method described by Miyashita et a l . ' u ^ Methyl b i s ( t r i f l u o r o e t h y l ) -phosphonoacetate was prepared by the method described by S t i l l et a l . 7 4 Manganese(IV) oxide was prepared by the r e a c t i o n between potassium permanganate and manganese s u l f a t e . ' ^ ' Sodium amalgam (4%) was prepared by mixing sodium and mercury.'^2 - 156 -Solutions of methyllithium i n ether and n-butyl l i t h i u m i n hexanes were obtained from A l d r i c h Chemical Co., Inc. and were standardized using the procedure of Kofron et a l . ' u 3 Potassium hydride and sodium hydride were washed free of o i l with dry ether, d r i e d under a stream of argon and weighed before use. A l l other reagents were commercially a v a i l a b l e and were u t i l i z e d without further p u r i f i c a t i o n . Preparation of 3.6-dimethyl-2-cyclohexen-1-one (115) To a c o l d (-78°C) s o l u t i o n of diisopropylamine (8.4 mL, 60 mmol) i n THF (50 mL) was added n-butyllithium (42 mmol) as a s o l u t i o n i n hexanes. The r e s u l t i n g s o l u t i o n was s t i r r e d at 0°C for 15 min and recooled to -78°C. 3-Methyl-2-cyclohexen-l-one (4.5 mL, 40 mmol) was added dropwise and the mixture was s t i r r e d f o r 30 min at -78 CC. To the res u l t a n t white s l u r r y was added iodomethane (5 mL, 80 mmol), the re a c t i o n mixture was allowed to warm gradually to room temperature, and then was s t i r r e d overnight. The re a c t i o n mixture was d i l u t e d with pentane, and washed with water. The organic layer was separated and the aqueous layer was extracted twice with pentane. The organic extracts were combined, washed once with 2N hydrochloric a c i d and three times with brine, and - 157 -then were d r i e d (MgSO^), f i l t e r e d and concentrated. D i s t i l l a t i o n [bp 40-42°C/0.02 t o r r ( l i t . 3 0 bp 95-100°C/22 t o r r ) ] , of the remaining o i l y i e l d e d 4.6 g (93%) of the cyclohexenone 115. This material was homogeneous by glc analysis and exhibited i r ( f i l m ) : 3031, 1672, 1635 cm - 1; XH nmr (80 MHz) 5: 5.83 (m, lH, o l e f i n i c proton), 3.72 (m, 1H, H A), 2.50-1.40 (m, 4H, methylene protons), 1.96 (br s, 3H, v i n y l methyl protons), 1.13 (d, 3H, J = 7 Hz, methyl protons). Preparation of 5-chloro-2-trimethylstannvl-l-pentene (39) H B SnMe 3 To a c o l d (-20°C) s o l u t i o n of hexamethylditin (16 mL, 70 mmol) i n THF (500 mL) was added methyllithium (80 mmol) as a s o l u t i o n i n ether. The r e s u l t i n g pale yellow s o l u t i o n was s t i r r e d at -20°C f o r 20 min and then was cooled to -78°C. S o l i d copper(I) bromide-dimethylsulfide complex (14.8 g, 60 mmol) was added i n one por t i o n and the mixture was s t i r r e d at -78°C f o r 5 min and then at -63°C f o r 30 min. The r e s u l t i n g reddish brown s o l u t i o n was recooled to -78°C. 5-Chloro-1-pentyne (6.4 ml, 60 mmol) was added and the rea c t i o n mixture was s t i r r e d at -78°C f o r 6 h. A c e t i c a c i d (3.4 mL, 60 mmol) was added and the mixture was s t i r r e d f o r 10 min. Saturated aqueous ammonium c h l o r i d e (pH 8) and petroleum ether were added. The mixture was allowed to warm to room - 158 -temperature and was s t i r r e d vigorously with exposure to a i r . The blue aqueous layer was separated and extracted twice with petroleum ether. The combined extract was washed once with saturated aqueous ammonium chl o r i d e (pH 8) and twice with brine, and then was d r i e d (MgSO^), f i l t e r e d and concentrated. The r e s i d u a l material was subjected to column chromatography on s i l i c a gel (450 g, e l u t i o n with petroleum ether). D i s t i l l a t i o n [bp 95-100°C/15 t o r r ( l i t . 1 0 4 bp 80-85°C/25 t o r r ) ] of the o i l obtained from the appropriate f r a c t i o n s provided 9.6 g (62%) of the chlo r i d e 39 as a c o l o r l e s s o i l . This material was homogeneous by glc a n alysis and exhibited i r ( f i l m ) : 3040, 930 cm*1; XH nmr (80 MHz) 6: 5.71 (dt, 1H, J = 2.5, 1.2 Hz, J S n - H = 1 5 0 H z> HA>' 5.23 (dt, 1H, J = 2.5, 0.8 Hz, Isn-H = 7 0 H z> HB>• 3 - 5 1 2H, J = 7 Hz, -CH 2Cl), 2.43 (br t, 2H, J <= 7 Hz, a l l y l i c CH 2), 1.89 (quintet, 2H, J - 7 Hz, -CH 2CH 2CH 2C1), 0.15 (s, 9H, J S n - H = 52/54 Hz, -SnMe 3). Preparation of 5-f 2 -(5-Chloro-l-pentenvl)1-2.5-dimethvlcvclohexanone  (121) To a c o l d (-78°C) s o l u t i o n of 5-chloro-2-trimethylstannyl-l-pentene (39) (1.7 g, 6.4 mmol) i n THF (50 mL) was added a s o l u t i o n of methyllithium i n ether (7.1 mmol). A f t e r the mixture had been s t i r r e d - 159 -a t -78°C f o r 20 min, s o l i d magnesium b r o m i d e - e t h e r a t e (1.7 g, 6.6 mmol) was added i n one p o r t i o n and t h e r e s u l t i n g m i l k y s o l u t i o n was s t i r r e d f o r an a d d i t i o n a l 20 min. S o l i d c o p p e r ( I ) b r o m i d e - d i m e t h y l s u l f i d e complex (0.28 g, 1.4 mmol), b o r o n t r i f l u o r i d e - e t h e r a t e (0.71 mL, 5.8 mmol) and t h e k e t o n e 115 (0.75 mL, 5.3 mmol) were added s u c c e s s i v e l y . A f t e r t h e r e s u l t i n g b r i g h t y e l l o w m i x t u r e had been s t i r r e d a t -78°C f o r 3 h, s a t u r a t e d aqueous ammonium c h l o r i d e (pH 8) was added. The m i x t u r e was warmed t o room t e m p e r a t u r e and s t i r r e d v i g o r o u s l y w i t h e x p o s u r e t o a i r . The b l u e aqueous l a y e r was s e p a r a t e d and e x t r a c t e d t w i c e w i t h p e t r o l e u m e t h e r . The combined o r g a n i c e x t r a c t was washed once w i t h aqueous ammonium c h l o r i d e (pH 8) and t h r e e t i m e s w i t h b r i n e , and t h e n was d r i e d (MgSO^) and c o n c e n t r a t e d . D i s t i l l a t i o n ( a i r - b a t h t e m p e r a t u r e 88-89°C/0.02 t o r r ) o f t h e r e m a i n i n g o i l p r o v i d e d 0.93 g (77%) o f a c o l o r l e s s o i l . A n a l y s i s o f t h i s m a t e r i a l by g l c and nmr s p e c t r o s c o p y showed t h a t i t c o n s i s t e d o f a m i x t u r e o f epi m e r s o f 121 i n t h e r a t i o o f -2: 1 . T h i s m a t e r i a l e x h i b i t e d i r ( f i l m ) : 3098, 1705, 1640, 905 cm" 1; X H nmr (80 MHz) 6": 4.93 ( b r s, -1.3H, o l e f i n i c p r o t o n s o f t h e major i s o m e r ) , 4.80 (m, -0.7 H, o l e f i n i c p r o t o n s o f t h e mi n o r i s o m e r ) , 3.59 ( b r t , 2H, -CH 2C1), 2.9-1.2 (m, 11H), 1.15 ( s , -1H, t e r t i a r y m e t h y l o f m i n o r i s o m e r ) , 1.05 ( d , -2H, J = 7 Hz, -CHCH3 o f major i s o m e r ) , 1.03 ( s , -2H, t e r t i a r y m e t h y l o f major i s o m e r ) , 1.00 ( d , -1H, J = 7 Hz, -CHCH3) o f m i n o r i s o m e r ) . E x a c t Mass c a l c d . f o r C 1 3 H 2 i 3 5 C 1 0 : 228.1281; f o u n d : 228.1276. 160 -Preparation of the ketones 114 and 122 114 122 To a s o l u t i o n of potassium tert-butoxide (6.2 g, 55 mmol) i n t e r t -b u t y l alcohol (40 mL) was added a s o l u t i o n of the chloro ketone 121 (6.3 g, 27 mmol) i n tert-butanol (10 mL) and the s o l u t i o n was s t i r r e d at 30°C fo r 12 h. The r e a c t i o n mixture was n e u t r a l i z e d with 2N hydrochloric a c i d with c o o l i n g and the resultant mixture was extracted three times with petroleum ether. The combined extract was washed three times with brine and then was d r i e d (MgSO^) and concentrated. D i s t i l l a t i o n ( a ir-bath temperature 80-85°C/0.02 to r r ) of the remaining o i l y i e l d e d 4.6 g (89%) of a c o l o r l e s s o i l . Glc analysis of t h i s o i l showed that i t consisted of a mixture of two compounds i n a r a t i o of 94:6. A p o r t i o n of t h i s material was subjected to column chromatography, so that a pure sample of each compound was a v a i l a b l e for c h a r a c t e r i z a t i o n . Thus column chromatography of t h i s material (0.22 g) on s i l i c a gel impregnated with 25% s i l v e r n i t r a t e (25 g, e l u t i o n with petroleum ether-ether, 25:1, v/v) followed by concentration of the appropriate f r a c t i o n s provided 0.17 g of the trans ketone 114 and trace amounts of the l e s s polar c i s ketone 122. The trans ketone 114 exhibited i r ( f i l m ) : 3086, 1713, 1638, 895, 876 cm"1; XH nmr (400 MHz) 5: 4.70 (br s, 2H, o l e f i n i c protons), 2.40-2.04 (m, 5H), 1.96 (dt, 1H, J - 4 Hz, 13 Hz), 1.90-1.78 (m, 2H) , 1.69-1.50 (m, 3H), 1.32-1.15 (m, 1H), 0.99 (d, 3H, J = 6.0 Hz, methyl protons), - 161 -0.87 (s, 3H, angular methyl protons). 1 3 C nmr (100.6 MHz) 6: 204.46 (carbonyl carbon), 155.85 (quaternary o l e f i n i c carbon), 105.54 (second-ary o l e f i n i c carbon), 58.01, 44.51 ( t e r t i a r y carbons), 35.92 (quaternary carbon), 35.92, 32.19, 31.75, 26.61, 21.05 (secondary carbons), 18.91, 14.36 (methyl carbons). Exact Mass calcd. f o r C13H2oO: 192.1514; found: 192.1515. The c i s ketone 122 exhibited i r ( f i l m ) : 3084, 1708, 1639, 894, 874 cm'1; lti nmr (400 MHz) 8: 4.74, 4.63 (br s, br s, 1H each, o l e f i n i c protons), 2.39-2.25 (m, 4H), 2.17-2.08 (m, 2H), 1.92-1.55 (m, 6H), 1.31 (s, 3H, angular methyl protons), 0.98 (d, 3H, J - 6 Hz, methyl protons). Exact Mass calcd. f o r C 1 3H 2oO: 192.1514; found: 192.1517. Preparation of the alcohol 125 To a solution-suspension of l i t h i u m aluminum hydride (22 mg, 0.57 mmol) i n ether (2 mL) was added dropwise a s o l u t i o n of the trans ketone 114 (91 mg, 0.47 mmol) i n dry ether (0.5 mL). The re a c t i o n mixture was s t i r r e d f o r 3 h and then was treated with s o l i d sodium s u l f a t e decahy-drate u n t i l the evolution of gas ceased. The mixture was f i l t e r e d and the residue was washed three times with ether. The f i l t r a t e was concentrated and the re s i d u a l o i l was d i s t i l l e d (air-bath temperature - 162 -110-115°C/0.5 t o r r ) to y i e l d 76 mg (84%) of the alcohol 125. This material was homogeneous by glc analysis and exhibited i r ( f i l m ) : 3490 (br), 3075, 1637, 895 cm - 1; XH nmr (400 MHz) 5: 4.55 ( t , 1H, J = 1.5 Hz, o l e f i n i c proton), 4.53 (br s, 1H, o l e f i n i c proton), 3.56 (br s, 1H, H A), 2.40 (br dt, 1H J = 4, 12 Hz, Hg), 2.14 (br d, 1H, J 12 Hz, H c), 1.95-1.80 (m, 2H), 1.70-1.30 (m, 7H), 1.20 (br s, 2H), 1.17 (s, 3H, angular methyl protons), 0.98 (d, 3H, J = 6 Hz, methyl protons). Exact  Mass calcd. f o r C 1 3H 2 20: 194.1670; found: 194.1670. Preparation of the alcohol 126 L i q u i d ammonia (15 mL) was condensed into a cold (-78°C) d r i e d f l a s k containing calcium (55 mg, 14 mmol) and the mixture was s t i r r e d under r e f l u x (dry ice-acetone condenser) f o r 10 min. An ethereal s o l u t i o n of the trans ketone 114 (50 mg, 1.3 mmol) was added and the mixture was refl u x e d f o r 45 min. The rea c t i o n mixture was quenched with ethanol (150 ul,) and water (2 mL) and then was extracted three times with ether. The combined organic extract was washed three times with brine, d r i e d (MgSO^) and concentrated. D i s t i l l a t i o n (air-bath temperature 80-82°C/0.5 t o r r ) y i e l d e d 38 mg (75%) of the alcohol 126 which s o l i d i f i e d on cooling. R e c r y s t a l l i z a t i o n from ether afforded c o l o r l e s s - 163 -prisms, m.p. 129-130°C. This material was homogeneous by g l c analysis and e x h i b i t e d i r (CHC1 3): 3300 (br), 3080, 1642, 1035, 895 cm"1; ^ nmr (400 MHz) 5: 4.62 ( t , 1H, J = 1.7 Hz, o l e f i n i c proton), 4.59 ( t , 1H, J = 1.4 Hz, o l e f i n i c proton), 3.04 ( t , 1H, J = 9 Hz, H A), 2.35 (br dt, 1H, J = 4, 12 Hz, Hg), 2.14 (br d, 1H, J - 12 Hz, H c), 1.99 (m, 1H), 1.88 (m, 1H), 1.71-1.14 (m, 9H), 1.05 (d, 3H, J = 6 Hz, methyl protons), 0.98 (s, 3H, angular methyl protons). Exact Mass calcd. f o r C13H22O: 194.1670; found: 194.1670. Preparation of the tosylate 127 OTs A s o l u t i o n of the alcohol 126 (22 mg, 0.11 mmol), p.-toluenesulfonyl c h l o r i d e (26 mg, 0.13 mmol) and 4-N,N-dimethylaminopyridine (16 mg, 0.13 mmol) i n dichloromethane (2 mL) was s t i r r e d at room temperature f o r 12 h. The s o l u t i o n was d i l u t e d with ether, washed with saturated aqueous sodium bicarbonate and brine, and then was d r i e d (MgSO^) and concen-tr a t e d . The r e s i d u a l material was subjected to column chromatography on s i l i c a gel (4 g, e l u t i o n with petroleum ether-ether, 8:1 v/v). Concen-t r a t i o n of the appropriate f r a c t i o n s provided the tosylate 127 (32 mg, 83%) which exhibited one spot on t i c ; i r (CHCI3): 3089, 3032, 1638, 1600, 1496, 898 cm"1; XH nmr (80 MHz) 8: 7.75, 7.31 (d, d, 2H each, J -- 164 -8 Hz, aromatic protons), 4.60 (m, 2H, o l e f i n i c protons), 4.38 (m, 1H, CHOTs), 2.44 (s, 3H, aromatic methyl protons), 2.5-1.0 (m, 12H), 1.00 (s, 3H, angular methyl protons), 0.82 (d, 3H, J - 7.5 Hz, methyl protons). Exact Mass calcd. for C 2oH28°3 S : 348.1759; found: 348.1756. Preparation of n i t r i l e 112a A s o l u t i o n of the tosylate 127 (9 mg, 25 jimol) and sodium cyanide (2.5 mg, 52 /imol) i n dry HMPA (1 mL) was heated at 80°C f o r 3 h. The r e a c t i o n mixture was d i l u t e d with petroleum ether and washed once with water, twice with aqueous copper(II) s u l f a t e and twice with brine. The organic layer was d r i e d (MgSO,^ ) and concentrated and the residue was subjected to column chromatography on s i l i c a gel (1 g, e l u t i o n with petroleum ether-ether, 19:1 v/v). The appropriate f r a c t i o n s were c o l l e c t e d and concentrated. D i s t i l l a t i o n (air-bath temperature 65-68°C/0.02 t o r r ) of the remaining o i l y i e l d e d 2.3 mg (44%) of the n i t r i l e 112a as a c o l o r l e s s o i l which was homogeneous by g l c analysis and exhibited i r ( f i l m ) : 3070, 2225, 1638, 998, 895 cm"1; 1H nmr (400 MHz) 6: 4.61 ( t , 1H, J - 1.5 Hz, o l e f i n i c proton), 4.56 (br s, 1H, o l e f i n i c proton), 2.60 (dt, 1H, J = 1.3, 4.5 Hz, H A), 2.41 (tdt, 1H, J = 1.5, 5, 14.Hz, Hg), 2.16 (br d, 1H, J - 14 Hz, H c), 2.00-1.87 (m, 2H), 1.75-1.30 165 -(m, 8 H ) , 1.24 (s, 3H, angular methyl protons), 1.14 (d, 3H, J = 6.4 Hz, methyl protons). Exact Mass calcd. f o r C14H21N: 203.1674; found: 203.1676. Preparation of the n i t r i l e s 112a and 112b 112 b To a c o l d (0°C) s o l u t i o n of (p.-toluenesulfonyl) methyl isocyanide-*- 3 (2.9 g, 15 mmol) i n dry HMPA (17 mL) was added potassium tert-butoxide (4.0 g, 36 mmol) and the s o l u t i o n was s t i r r e d f o r 15 min. t e r t - B u t y l a l c o h o l (0.47 mL, 5 mmol) and the ketones 114 and 122 (0.96 g, 5 mmol; 94:6 r e s p e c t i v e l y ) , were added and the resultant mixture was s t i r r e d at room temperature f o r 1 h and at 45°C f o r 88 h. The re a c t i o n mixture was poured into cool IN hydrochloric a c i d and the mixture was extracted three times with petroleum ether. The combined extract was washed once with water, twice with aqueous copper(II) s u l f a t e and twice with brine and then was dr i e d (MgSO^) and concentrated. The r e s i d u a l o i l was subjected to f l a s h chromatography on s i l i c a gel (40 g, e l u t i o n with petroleum ether-ether, 19:1 v/v). The appropriate f r a c t i o n s were c o l l e c t e d and concentrated. D i s t i l l a t i o n ( air-bath temperature 65-68°C/0.02 t o r r ) of the remaining o i l y i e l d e d 0.69 g (68%) of a c o l o r l e s s o i l . Glc analysis of t h i s o i l showed that i t consisted of a - 166 -mixture of two compounds, 112a and 112b, i n a r a t i o of 15:85, respect-i v e l y . Column chromatography of a portion (0 . 1 g) of t h i s material on s i l i c a gel impregnated with 25% s i l v e r n i t r a t e (55 g, e l u t i o n with petroleum ether-ether, 25 : 1 , v/v) afforded pure samples of each compound for c h a r a c t e r i z a t i o n . The l e s s polar minor component exhibited spectra i d e n t i c a l with those of the a x i a l n i t r i l e 112a prepared previously (see above). The more polar component 112b exhibited i r ( f i l m ) : 3070, 2225, 1638, 998, 895 cm'1; 1H nmr (400 MHz) 6: 4 . 6 8 ( t , 1H, J •= 1.7 Hz, o l e f i n i c proton), 4.62 (br s, 1H, o l e f i n i c proton), 2.36 (br t, 1H, J = 12 Hz, Hg), 2.17 (br d, 1H, J - 12 Hz, H c), 2.08 ( t , 1H, J = 11.5 Hz, H A), 2.0-1.85 (m, 2 H ) , 1.78-1.25 (m, 8 H ) , 1.17 (d, 3H, J - 6 .2 Hz, methyl protons), 0.96 (s, 3H, angular methyl protons). Exact Mass calcd. f o r C14H21N: 203.1674; found: 203.1676. Preparation of 4-chloro-l-butvne (134) To dimethylformamide (50 mL) at room temperature was added, drop-wise, phosphorus t r i c h l o r i d e (2.5 mL, 69 //mol) and the mixture was s t i r r e d f o r 90 min. To the re s u l t a n t yellow s l u r r y was added 3-butyn-l - o l (6.7 mL, 0.2 mol) and s t i r r i n g was continued f or 40 min. The crude product was d i s t i l l e d (70-110°C) from the rea c t i o n mixture and c o l l e c t e d C I - 167 -as a c o l o r l e s s o i l , which was then f r a c t i o n a l d i s t i l l e d (bp 80-85°C/760 t o r r ) to a f f o r d 7 g (42%) of the chloride 134. I r (CH 2C1 2): 3300, 2120, 650 cm"1; 1H nmr (80 MHz) 6: 3.63 ( t , 2H, J = 7 Hz, -CH 2C1), 2.68 (dt, 2H, J = 2.5, 7 Hz, -CH 2CH 2C1), 2.11 ( t , 1H, J = 2.5 Hz, acetylenic proton). Exact Mass calcd. f o r C ^ ^ C l : 88.0079; found: 88.0074. Preparation of ethvl 5-chloro-2-pentvnoate (117) To a c o l d (-78°C) s o l u t i o n of 4-chloro-l-butyne (134) (4.4 g, 50 mmol) i n THF (100 mL) was added methyllithium (55 mmol) as a s o l u t i o n i n d i e t h y l ether. A f t e r the mixture had been s t i r r e d at -78°C f o r 10 min and at -20°C f o r 1 h, eth y l chloroformate (5.7 mL, 60 mmol) was added and the res u l t a n t mixture was s t i r r e d at -20°C f o r 1 h, and then at room temperature f o r an a d d i t i o n a l hour. The reac t i o n mixture was d i l u t e d with ether, washed twice with aqueous sodium bicarbonate and twice with brine, and then was dried (MgSO^) and concentrated. The residue was subjected to f l a s h column chromatography on s i l i c a gel (300 g, e l u t i o n with petroleum ether-ether, 9:1 v/v) and the appropriate f r a c t i o n s were c o l l e c t e d and concentrated. D i s t i l l a t i o n (air-bath temperature 80-82°C/ 0.02 tor r ) of the remaining o i l y i e l d e d 5.0 g (63%) of the pentynoate 117 as a c o l o r l e s s o i l which was homogeneous by glc analysis and - 168 -exhib i t e d i r ( f i l m ) : 2235, 1710, 1258, 1090, 760 cm"1; ' H nmr (80 MHz) 6: 4.20 (q, 2H, J - 7 Hz, -0CH 2-), 3.65 ( t , 2H, J = 7 Hz, C1CH2-)., 2.83 (t , 2H, J = 7 Hz, C1CH 2CH 2-), 1.32 ( t , 3H, J = 7 Hz, CH 3-). Exact Mass cal c d . f o r C 5H 40 3 5C10 (M +-0Et): 114.9950; found: 114.9950. Preparation of eth y l (Z)-5-chloro-3-trimethvlstannvl-2-pentenoate (116) To a c o l d (-20°C) s o l u t i o n of hexamethylditin (1.1 mL, 4.9 mmol) i n THF (50 mL) was added methyllithium (4.9 mmol) as a s o l u t i o n i n ether. The r e s u l t i n g pale yellow s o l u t i o n was s t i r r e d at -20°C f o r 20 min and then s o l i d phenylthiocopper (0.84 g, 4.9 mmol) was added. The r e s u l t i n g red s o l u t i o n was s t i r r e d at -20°C f o r an a d d i t i o n a l 15 min and then was cooled to -78°C. The chloro pentynoate 117 (0.74 g, 4.6 mmol) was added and the mixture was s t i r r e d at -78°C f o r 15 min and at -48°C f o r 4 h. Saturated aqueous ammonium chloride (pH 8) and petroleum ether (300 mL) were added, and the mixture was warmed to room temperature. The organic layer was separated, washed twice with brine and the dried (MgSO^), f i l t e r e d through a short pad of F l o r i s i l and concentrated. Glc analysis of the residue showed that i t consisted of a mixture of two compounds. Careful f r a c t i o n a l d i s t i l l a t i o n (air-bath temperature 60-62°C/0.02 to r r ) of t h i s material afforded 0.39 g (26%) of the more v o l a t i l e desired 169 e s t e r 116. T h i s m a t e r i a l e x h i b i t e d i r ( f i l m ) : 1704, 1603, 1207, 774 cm' 1; -^H nmr (80 MHz) 5: 6.43 ( t , 1H, J = 1.1 Hz, J S n _ H = H z > o l e f i n i c p r o t o n ) , 4.19 ( q , 2H, J = 7 Hz, -0CH 2-), 3.56 ( b r t , 2H, J = 7 Hz, C1CH 2-), 2.86 ( t , 2H, J = 7 Hz, C1CH 2CH 2-), 1-29 ( t , 3H, J = 7 Hz, C H 3 - ) , 0.21 ( s , 9H, J S n _ H = 52/54 Hz, -SnMe 3). E x a c t Mass c a l c d . f o r C 9 H 1 6 3 5 C 1 0 2 1 2 0 S n ( M + - C H 3 ) : 310.9859; f o u n d : 310.9866. The r e s i d u a l m a t e r i a l from t h e above d i s t i l l a t i o n was s u b j e c t e d t o f l a s h c h romatography on s i l i c a g e l (300 g, e l u t i o n w i t h p e t r o l e u m e t h e r - e t h e r , 100:1 v / v ) . C o n c e n t r a t i o n o f the a p p r o p r i a t e f r a c t i o n s and d i s t i l l a t i o n ( a i r - b a t h t e m p e r a t u r e 75-78°C/0.02 t o r r ) o f t h e r e m a i n i n g m a t e r i a l gave a s m a l l sample o f the l e s s v o l a t i l e p r o d u c t 136, w h i c h e x h i b i t e d i r ( f i l m ) : 1702, 1601, 1200, 770 cm" 1; lE (80 MHz) 5: 6.34 ( t , 1H, J = 1.1 Hz, J S n - H = 1 2 0 H z > o l e f i n i c p r o t o n ) , 4.18 ( q , 2H, J = 7 Hz, -0CH 2), 2.55 ( b r t , 2H, J = 7 Hz, a l l y l i c p r o t o n s ) , 1.28 ( t , 3H, J = 7 Hz, -0CH 2CH 3), 0.83 (m, 2H, -SnCH 2-), 0.22 ( s , 9H, J S n . H = 52/54 Hz, -SnMe 3), 0.12 ( s , 9H, J_sn-H = 50/52 Hz, -SnMe 3) . E x a c t Mass c a l c d . f o r c 1 2 H 2 5 ° 2 1 2 ° S n 2 ( M + - C H 3 ) : 440.9897; f o u n d : 440.9900. 1 36 - 170 -Preparation of l-tert-butyldimethylsilvloxy-3-butyne (137) A s o l u t i o n of 3-butyn-l-ol (3.8 mL, 50 mmol), tert-butyldimethyl-s i l y l c h l o r i d e (9 g, 60 mmol) and imidazole (8.5 g, 125 mmol) i n dimethylformamide (17 mL) was s t i r r e d at room temperature f o r 12 h. Aqueous sodium bicarbonate was added and the mixture was extracted three times with petroleum ether. The combined extract was washed twice with brine, d r i e d (MgSO,^ ) and concentrated. D i s t i l l a t i o n [bp 55-60°C/15 t o r r ( l i t . 4 1 bp 45-46°C/2.5 t o r r ) ] of the remaining o i l y i e l d e d 9 g (98%) of the s i l y l ether 137 which exhibited i r ( f i l m ) : 3300, 2100, 1110, 632 cm"1; 1H nmr (80 MHz) 6": 3.72 ( t , 2H, J = 7 Hz, -0CH 2-), 2.37 (dt, 2H, J = 2.5, 7 Hz, -CH2C=), 1.92 ( t , 1H, J = 2.5 Hz, a c e t y l e n i c proton), 0.90 (s, 9H, t e r t - b u t y l protons), 0.07 (s, 6H, methyl protons). Preparation of e t h y l 5-tert-butyldimethvlsilyloxv-2-pentvnoate (138) To a c o l d (-78°C) s o l u t i o n of the alkyne (137) (9.2 g, 50 mmol) i n - 171 -THF (180 mL) was added methyllithium (55 mmol) as a s o l u t i o n i n ether. A f t e r the s o l u t i on had been s t i r r e d at -78°C f o r 10 min and at -20°C f o r 1 h, e t h y l chloroformate (5.7 mL, 60 mmol) was added and the mixture was s t i r r e d at -20°C f o r 1 h, and at room temperature f o r 1 h. The reaction mixture was d i l u t e d with ether, washed twice with aqueous sodium bicarbo-nate and twice with brine, and then was dr i e d (MgSO^) and concentrated. D i s t i l l a t i o n (air-bath temperature 75-78°C/ 0.02 tor r ) of the remaining o i l y i e l d e d 11.5 g (90%) of the pentynoate 138 as a c o l o r l e s s o i l which exhi b i t e d i r ( f i l m ) : 2230, 1705, 1250, 1110, 1080 cm - 1; XH nmr (80 MHz) 6: 4.20 (q, 2H, J = 7 Hz, -OCH2CH3), 3.76 ( t , 2H, J = 7 Hz, Si0CH 2-), 2.52 ( t , 2H, J = 7 Hz, -,CH2Cs) , 1.28 ( t , 3H, J = 7 Hz, -0CH 2CH 3), 0.90 (s, 9H, t e r t - b u t y l protons), 0.07 (s, 6H, s i l y l methyl protons). Exact  Mass ca l c d . f o r C 1 2 H 2 1 0 3 S i (M +-CH 3): 241.1260; found: 241.1256. Preparation of eth y l (Z)-5-tert-butyldimethvlsilyloxv-3-trimethyl- stannyl-2-pentenoate (139) SnMe3 ^ i 0 ^ v A ^ C 0 2 E t To a c o l d (-20°C) s o l u t i o n of hexamethylditin (2.6 mL, 12 mmol) i n THF (120 mL) was added methyllithium (13 mmol) as a s o l u t i o n i n ether. The r e s u l t i n g pale yellow s o l u t i o n was s t i r r e d at -20°C f o r 20 min and then s o l i d phenylthiocopper (2.1 g, 12 mmol) was added. The red solu-- 172 -t i o n was s t i r r e d at -20°C f o r an a d d i t i o n a l 15 rain and then was cooled to r78°C. The pentynoate 138 (2.6 g, 10 mmol) was added and the mixture was s t i r r e d at -78°C for 15 min and at -40°C for 9 h. To the r e a c t i o n mixture, saturated aqueous ammonium chloride (pH 8) and petroleum ether were added, and the mixture was warmed to room temperature. More petroleum ether was added u n t i l most of the phenylthiocopper had p r e c i p i t a t e d and the organic layer became nearly c o l o r l e s s . The organic layer was separated, washed twice with brine, d r i e d (MgSO^), f i l t e r e d through a short pad of F l o r i s i l and concentrated. D i s t i l l a t i o n ( a i r -bath temperature 91-95°C/0.02 to r r ) of the remaining o i l y i e l d e d 3.8 g (91%) of the ester 139, which exhibited i r ( f i l m ) : 1700, 1600, 1110, 1052 cm - 1; ' H nmr (80 MHz) 5: 6.40 ( t , 1H, J = 1 Hz, J_Sn-H = 1 2 0 H z> o l e f i n i c proton), 4.18 (q, 2H, J - 7 Hz, -0CH 2CH 3), 3.63 ( t , 2H, J -6.5 Hz, Si0CH 2-), 2.63 (br t, 2H, J - 6.5 Hz, SiOCH 2CH 2-), 1.28 ( t , 3H, J = 7 Hz, -OCH2CH3-), 0.90 (s, 9H, t e r t - b u t y l protons), 0.18 (s, 9H, J S N _ H " 52/54 Hz, -SnMe3), 0.04 (s, 6H, s i l y l methyl protons). Exact  Mass c a l c d . f o r C 1 5 H 3 1 0 3 S i 1 2 0 S n (M +-CH 3): 407.1063; found: 407.1058. Preparation of (Z)-5-tert-butvldimethvlsilyloxv-3-trimethylstannyl-2- penten-l-ol (140) SnMe3 - 173 -To a c o l d (-78°C) s o l u t i o n of the pentynoate 138 (3.8 g, 9 mmol) i n THF (90 mL) was added a s o l u t i o n of diisobutylaluminum hydride (27 mmol) i n hexanes. A f t e r the mixture had been s t i r r e d at -78°C f o r 1 h and at 0°C f o r 1 h, i t was treated with aqueous ammonium chlo r i d e (1.6 mL) and d i l u t e d with ether. The mixture was s t i r r e d at room temperature f o r 5 min, d r i e d (MgSO/^), f i l t e r e d through F l o r i s i l and concentrated. D i s t i l -l a t i o n (air-bath temperature 104-105°C/0.02 to r r ) of the r e s i d u a l o i l y i e l d e d 3.3 g (96%) of the alcohol 140 which exhibited i r ( f i l m ) : 3350 (br), 1621, 1090, 1010 cm - 1; 1H nmr (80 MHz) 6: 6.26 (br t, 1H, J = 6 Hz, o l e f i n i c H), 4.08 ( t , 2H, J = 6 Hz, collapsed to a d on D2O ex-change, -CH20H), 3.57 ( t , 2H, J - 7 Hz, SiOCH 2-), 2.43 ( t , 2H, J - 7 Hz, SiOCH 2CH 2-), 1.18 ( t , 1H, J = 6 Hz, exchanged with D 20, -OH), 0.89 (s, 9H, t e r t - b u t y l protons), 0.19 (s, 9H, J S n . H = 52/54 Hz, -SnMe 3), 0.05 (s, 6H, s i l y l methyl protons). Exact Mass calcd. f o r C i 3 H 2 9 0 2 S i 1 2 0 S n (M +-CH 3): 365.0958; found: 365.0959. Preparation of (Z) - 5 - t e r t - b u t y l d i m e t h y l s i l v l o x y - 3 - t r i m e t h v l s t a n n v l - l - methoxymethoxv-2-pentene (141) / To a c o l d (-20°C) s o l u t i o n of the alcohol 140 (3.3 g, 8.7 mmol) and diisopropylethylamine (2.3 mL, 13 mmol) i n dichloromethane (25 mL) was - 174 -added chloromethyl methyl ether (1 mL, 13 mmol) and the mixture was s t i r r e d at room temperature f o r 12 h. The r e a c t i o n mixture was concen-t r a t e d under reduced pressure and the r e s i d u a l o i l was t r i t u r a t e d with petroleum ether. The organic s o l u t i o n was decanted and the remaining s o l i d was washed three more times (decantation) with petroleum ether. The combined extract was concentrated and the residue was f i l t e r e d through a short column of s i l i c a gel (75 g, e l u t i o n with petroleum ether-ether, 9:1 v/v). The f i l t r a t e was concentrated and d i s t i l l a t i o n ( a i r - b a t h temperature 90-93°C/0.02 to r r ) of the remaining o i l y i e l d e d 3.3 g (90%) of the diether 141, which exhibited i r ( f i l m ) : 1100, 1040 cm - 1; XH nmr (80 MHz) 5: 6.21 ( t , 1H, J - 6 Hz, o l e f i n i c proton), 4.63 (s, 2H, ac e t a l protons), 4.01 (d, 2H, J = 6 Hz, =CCH20-), 3.58 ( t , 2H, J - 7 Hz, Si0CH 2-), 3.38 (s, 3H, -OCH3), 2.45 ( t , 2H, J = 7 Hz, -CH2CH2C=), 0.91 (s, 9H, t e r t - b u t y l protons), 0.20 (s, 9H, I S n . H = 52/54 Hz, -SnMe3), 0.06 (s, 6H, s i l y l methyl protons). Exact Mass calcd. f o r c 1 5 H 3 3 ° 3 S i l 2 ° S n (M +-CH 3): 409.1220; found: 409.1228. Preparation of (E)-5-tert-butvldimethvlsilyloxv-3-methyl-1-methoxy- methoxy-2-pentene (142) / - 175 -To a c o l d (-78°C) s o l u t i o n of the vinylstannane 141 (3.3 g, 8 mmol) i n THF (65 mL) was added methyllithium (9 mmol) as a s o l u t i o n i n d i e t h y l ether. A f t e r the s o l u t i o n had been s t i r r e d at -78°C f o r 30 min, iodomethane (1.2 mL, 20 mmol) was added and the mixture was s t i r r e d f o r a furt h e r 90 min. The res u l t a n t s o l u t i o n was d i l u t e d with petroleum ether, washed three times with brine, d r i e d (MgSO,^ ) and concentrated. D i s t i l l a t i o n (air-bath temperature 81-83°C/0.02 to r r ) of the remaining o i l y i e l d e d 2 g (90%) of the alkene 142. This material was homogeneous by g l c analysis and exhibited i r ( f i l m ) : 2725, 1100, 1050 cm"1; 1H nmr (80 MHz) 6: 5.36 (br t, 1H, J - 7 Hz, o l e f i n i c proton), 4.61 (s, 2H, ace t a l protons), 4.04 (d, 2H, J - 7 Hz, =CCH20-), 3.68 ( t , 2H, J = 7 Hz, -Si0CH 2-), 3.35 (s, 3H, -0CH 3), 2.23 (t, 2H, J = 7 Hz, =CCH2CH2-), 1.69 (br s, 3H, v i n y l methyl protons), 0.88 (s, 9H, t e r t - b u t y l protons), 0.03 (s, 6H, s i l y l methyl protons). Exact Mass calcd. f o r C^2^25(-)^1 (M +-0CH 20CH 3): 213.1674; found: 213.1671. Preparation of (E)-3-methyl-5-methoxymethoxy-3-penten-l-ol (143) To a s o l u t i o n of tetra-n-butylammonium f l u o r i d e (5.6 g, 20 mmol) i n THF (35 mL) at room temperature was added a s o l u t i o n of the s i l y l ether 142 (2 g, 7.2 mmol) i n THF. Af t e r the s o l u t i o n had been s t i r r e d f or 40 - 176 -min, i t was d i l u t e d with ether, washed three times with brine, d r i e d (MgSC^) and concentrated. D i s t i l l a t i o n (air-bath temperature 81-83°C/ 0.02 t o r r ) of the remaining o i l y i e l d e d 1.1 g (98%) of the homoallylic alcohol 143 which exhibited i r ( f i l m ) : 3400 (br), 2760, 1040, 922 cm - 1; XH nmr (80 MHz) 6: 5.48 (br t, 1H, J - 7 Hz, o l e f i n i c proton), 4.65 (s, 2H, a c e t a l protons), 4.11 (d, 2H, J = 7 Hz, =CCH20), 3.73 ( t , 2H, J = 6.5 Hz, H0CH 2-), 3.40 (s, 3H, -0CH 3), 2.30 ( t , 2H, J - 6.5 Hz, ~CCH 2CH 2-), 1.72 (br s, 4H, v i n y l methyl and hydroxyl protons). Exact  Mass calcd. f o r C 6 H 1 1 0 2 (M +-CH 20CH 3): 115.0759; found: 115.0762. Preparation of (E)-3-methvl-5-methoxymethoxv-3-penten-l-yl tosylate  (1*4) A s o l u t i o n of the alcohol 143 (0.84 g, 5.3 mmol), p_-toluenesulfonyl c h l o r i d e (1.2 g, 6.3 mmol) and 4-N,N-dimethylaminopyridine (0.77 g, 6.3 mmol) i n dichloromethane (15 mL) was s t i r r e d at room temperature f or 12 h. The s o l u t i o n was d i l u t e d with ether, washed with saturated aqueous sodium bicarbonate and brine, d r i e d (MgSO^) and concentrated. The r e s i d u a l material was subjected to f l a s h column chromatography on s i l i c a g el (75 g, e l u t i o n with petroleum ether-ether, 1:1 v/v). C o l l e c t i o n and concentration of the appropriate f r a c t i o n s provided the tosylate 144 - 177 -(1.2 g, 75%) as a c o l o r l e s s o i l which exhibited i r ( f i l m ) : 1600, 1360, 1180, 1100 cm"1; '-H nmr (80 MHz) 6: 7.83, 7.37 (d, d, 2H each, J = 8 Hz, aromatic protons), 5.38 ( t , 1H, J = 6.5 Hz, o l e f i n i c proton), 4.64 (s, 2H, a c e t a l protons), 4.14 ( t , 2H, J = 7 Hz, -OCH2CH2-), 4-03 (d, 2H, J = 6.5 Hz, =CCH20-). 3.40 (s, 3H, -0CH 3), 2.48 (s, 3H, b e n z y l i c protons), 2.39 ( t , 2H, J - 7 Hz, -OCH2CH2-), 1-65 (s, 3H, v i n y l methyl protons). Exact Mass calcd. for C 1 4 H 1 8 0 4 S (M +-CH 40): 282.0926; found: 282.0930. This tosylate decomposed on heating under vacuum and slowly turned brown on storage under argon i n a freezer. Preparation of (E)-5-iodo-l-methoxvmethoxv-3-methyl-2-pentene (113) To a s o l u t i o n of the tosylate 144 (1.27 g, 4.04 mmol) i n dimethylfor-mamide (8 mL) was added sodium iodide (1 g, 6.6 mmol) and the resultant mixture was s t i r r e d at room temperature for 4 days with p r o t e c t i o n from l i g h t . Water was added and the mixture was extracted three times with pentane. The combined extract was washed twice with brine, d r i e d (MgS04) and concentrated. D i s t i l l a t i o n (air-bath temperature 48-51°C/ 0.02 t o r r ) of the remaining o i l y i e l d e d 1 g (91%) of the iodide 113 as a c o l o r l e s s o i l which was stored over copper dust i n a freezer. This material was homogeneous by glc analysis and exhibited i r ( f i l m ) : 2770, - 178 -1040 cm - 1; LE nmr (80 MHz) 6: 5.41 (br t, 1H, J = 7 Hz, o l e f i n i c proton), 4.63 (s, 2H, a c e t a l protons), 4.07 (d, 2H, J = 7 Hz, -CC^O), 3.38 (s, 3H, - 0 C H 3 ) , 3.23 ( t , 2H, J = 8 Hz, -CH 2I), 2.58 ( t , 2H, J = 8 Hz, -CH2CH2 I ) , 1.68 (br s, 3H, v i n y l methyl protons). Exact Mass calcd. f o r C 8 H 1 5 I 0 2 : 270.0116; found: 270 .0111. Preparation of the n i t r i l e 111 To a c o l d (-78°C) s o l u t i o n of diisopropylamine (0.17 mL, 1.2 mmol) i n THF (10 mL) was added n-butyllithium (1.2 mmol) as a s o l u t i o n i n hexanes and the mixture was s t i r r e d at 0°C for 15 min. HMPA (0.34 mL, 2 mmol) and a s o l u t i o n of a mixture of the n i t r i l e s 112a and 112b (0.2 g, 1 mmol; 15:85, resp e c t i v e l y ) i n THF were added and the s o l u t i o n was s t i r r e d at 0°C f o r 15 min. To the resultant yellow s o l u t i o n at 0°C was added the iodide 113 (0.35 g, 1.3 mmol). The s o l u t i o n was allowed to warm gradually to room temperature and was s t i r r e d overnight. The s o l u t i o n was d i l u t e d with petroleum ether, washed with water, aqueous copper(II) s u l f a t e , twice with brine, d r i e d (MgSO^) and concentrated. The r e s i d u a l o i l was subjected to f l a s h column chromatography on s i l i c a - 179 -gel (35 g, e l u t i o n with petroleum ether-ether, 3:1 v/v) and c o l l e c t i o n of the appropriate f r a c t i o n s afforded 0.24 g [94% based on recovery of 47 mg of the s t a r t i n g material and the n i t r i l e s , 112a and 112b, (60:40 (r e s p e c t i v e l y ) ] of the n i t r i l e 111 which exhibited i r ( f i l m ) : 3086, 2780, 2227, 1671, 1638, 1150, 1103, 1045, 2045, 895 cm'1; XH nmr (400 MHz) 6: 5 .35 ( t , 1H, J = 6 .5 Hz, H A), 4.62 (s, 2H, a c e t a l protons), 4.60, 4 . 5 5 (s, s, 1H each, exocyclic o l e f i n i c protons), 4.05 (d, 2H, J = 6 .5 Hz, <=CCH20-), 3.38 (s, 3H, - O C H 3 ) , 2.40 (br dt, 1H, J = 5 , 13 .5 Hz, Hg), 2.14 (br dd, 1H, J - 4 , 13 .5 Hz, H c), 2.0-1.82 (m, 5H) , 1.8 -1 .5 (m, 9 H ) , 1.68 (s, 3H, v i n y l methyl protons), 1.27 (s, 3H, angular methyl protons), 1.11 (d, 3H, J = 6 Hz, methyl protons). Exact Mass calcd. f o r C 2 2 H 3 5 N 0 2 : 345.2668; found: 345.2668. Preparation of the aldehyde 147 To a s o l u t i o n of the n i t r i l e 111 (0.17 g, 0.5 mmol) i n dimethoxy-ethane (7 mL) was added diisobutylaluminum hydride (2 mmol) as a s o l u t i o n i n hexanes and the mixture was heated at 60°C f o r 6 h. The re a c t i o n mixture was cautiously poured into water, and the re s u l t a n t K 'C 180 -mixture was n e u t r a l i z e d with IN hydrochloric a c i d and extracted three times with ether. The extracts were combined, washed with brine, d r i e d (Na2S0 4) and concentrated. The r e s i d u a l o i l was dissol v e d i n a mixture of THF-acetic acid-water (4 mL, 3:1:0.16 by volume) and s t i r r e d at room temperature f o r 12 h. A f t e r removal of the solvents under reduced pressure (0.02 t o r r ) , the residue was dissolved i n ether. The s o l u t i o n was washed with aqueous sodium bicarbonate and brine, then d r i e d (MgS04) and concentrated to a f f o r d 0.15 g (87%) of the aldehyde 147. This material was homogeneous by t i c analysis and exhibited i r ( f i l m ) : 3086, 2776, 2736, 1713, 1671, 1637, 1149, 893 cm'1; XH nmr (400 MHz) 6": 9.98 (s, 1H, aldehyde proton), 5.36 ( t , 1H, J = 7 Hz, H A), 4.62 (s, 2H, a c e t a l protons), 4.58 (br s, 2H, o l e f i n i c protons), 4.06 (d, 2H, J = 7 Hz, =CCH20-), 3.37 (s, 3H, -0CH 3), 2.27 (br dt, 1H, J = 5, 13 Hz, Hg), 2.12 (br d, 1H, J = 13 Hz, H c), 2.0-1.1 (m, 14H), 1.69 (s, 3H, v i n y l methyl protons), 1.03 (d, 3H, J = 7 Hz, methyl protons), 0.96 (s, 3H, angular methyl protons). Exact Mass calcd. f o r C22 H36°3 : 348.2664; found: 348.2658. Preparation of the alcohol 152 K 'C - 181 -To a solution-suspension of l i t h i u m aluminum hydride (16 mg, 0.42 mmol) i n ether (3 mL) was added an ethereal s o l u t i o n of the aldehyde 147 (99 mg, 0.28 mmol) and the mixture was s t i r r e d at room temperature f o r 1 h. Sodium s u l f a t e decahydrate was added i n small portions to the s t i r r e d mixture u n t i l evolution of gas ceased. The mixture was f i l t e r e d and the residue was washed three times with ether. The combined f i l t r a t e was concentrated to a f f o r d 92 mg (93%) of the alcohol 152 which exh i b i t e d i r ( f i l m ) : 3469 (br), 3085, 1669, 1635, 1150, 1103, 1043, 892 cm"1; XH nmr (400 MHz) 6: 5.47 ( t , 1H, J - 7 Hz, H A), 4.63 (s, 2H, ace t a l protons), 4.52 (br s, 2H, exocyclic o l e f i n i c protons), 4.06 (d, 2H, J = 7 Hz, =CCH20-), 3.80, 3.70 (dd, dd, 1H each, J = 6, 12 Hz; each collapses to d, J = 12 Hz on D 20 exchange, -CH20H), 3.38 (s, 3H, -0CH 3), 2.27 (br dt, 1H, J - 4, 14 Hz, Hg), 2.11 (br d, 1H, J = 14 Hz, H c), 1.93-1.40 (m, 12H), 1.71 (s, 3H, v i n y l methyl protons), 1.27-1.11 (m, 2H), 1.06 (s, 3H, angular methyl protons), 1.02 ( t , 1H, J = 6 Hz, D 20 exchanged, -CH20H), 0.94 (d, 3H, J = 6.5 Hz, methyl protons); nOe diff e r e n c e spectrum showed p o s i t i v e s i g n a l enhancement at 6" 3.80 and 3.70 (-CH20H) on i r r a d i a t i o n at 6 1.06 (angular methyl protons). Exact Mass c a l c d f o r C 2 ] H 3 5 0 2 (M +-0CH 3): 319.2637; found: 319.2636. - 182 -Preparation of the xanthate 153 H 'C To a s o l u t i o n of the alcohol 152 (67 mg, 0.2 mmol) i n dimethylforma-mide (1 mL) was added 1,8-diazabicyclo[5.4.0]undec-7-ene (0.17 mL, 1.3 mmol) and the s o l u t i o n was s t i r r e d at room temperature f o r 5 min. Carbon disulphide (0.93 mL, 15 mmol) was added and s t i r r i n g was c o n t i -nued at room temperature f o r 1 h. The resultant red s o l u t i o n turned yellow on ad d i t i o n of iodomethane (1.8 mL, 29 mmol). The s o l u t i o n was s t i r r e d f o r three more hours at room temperature. Excess reagents and solvent were removed under reduced pressure (0.02 t o r r ) , and the residue was subjected to column chromatography on s i l i c a gel (3 g, e l u t i o n with petroleum ether-ether, 6:4 v/v). C o l l e c t i o n and concentration of the appropriate f r a c t i o n s afforded 86 mg (100%) of the xanthate 153 as a viscous yellow o i l which exhibited i r ( f i l m ) : 3085, 1669, 1635, 1219, 894 cm"1; -^H nmr (400 MHz) 8: 5.36 ( t , 1H, J - 7 Hz, H A), 4.69, 4.64 (d, d, 1H each, J = 12 Hz, -CH 2 0CS2- ) , 4.63 (s, 2H, a c e t a l protons), 4 . 5 4 (br s, 2H, exocyclic o l e f i n i c protons), 4.07 (d, 2H, J •= 7 Hz, =CCH 2 0-) , 3.39 (s, 3H, - 0 C H 3 ) , 2 .57 (s, 3H, - S C H 3 ) , 2.29 (br dt, 1H, J = 5 , 13 .5 Hz, Hg), 2.13 (br d, 1H, J - 13 .5 Hz, H c), 1.97-1.48 (m, 11H) , 1.71 (s, 3H, v i n y l methyl protons), 1.35-1.15 (m, 3H) , 1.17 (s, 3H, angular - 183 -methyl protons), 0.93 (d, 3H, J = 6 Hz, methyl protons). Exact Mass cal c d . f o r C24H 4 00 3S2: 440.2419; found: 440.2410. Preparation of the thionocarbonate 155 A s o l u t i o n of the alcohol 152 (20 mg, 57 fimol), phenoxythiocarbonyl c h l o r i d e (10 ph, 68 umol) and 4-N,N-dimethylaminopyridine (15 mg, 0.13 mmol) i n a c e t o n i t r i l e (1 mL) was s t i r r e d at room temperature f or 48 h. The s o l u t i o n was d i l u t e d with ethyl acetate, washed twice with brine, d r i e d (MgSO^ and concentrated. The residue was subjected to column chromatography on s i l i c a gel (2 g, e l u t i o n with petroleum ether-ether, 9:1 v/v). C o l l e c t i o n and concentration of the appropriate f r a c t i o n s afforded 11 mg (40%) of the thionocarbonate 155 which exhibited i r ( f i l m ) : 3085, 1729, 1635, 1592, 1491, 894 cm"1; XH nmr (400 MHz) 6: 7.40 ( t , 2H, J - 8 Hz, aromatic protons), 7.27 ( t , 1H, J - 8 Hz, aromatic proton), 7.10 (d, 2H, J - 8 Hz, aromatic protons), 5.35 ( t , 1H, J = 7 Hz, H A), 4.65 (s, 2H, ac e t a l protons), 4.63, 4.52 (d, d, 1H each, J - 10 Hz, -CH20C0S-), 4.54 (br s, 2H, exo c y c l i c o l e f i n i c protons), 4.07 (d, 2H, J = 7 Hz, =CCH20-), 3.40 (s, 3H, -0CH 3), 2.28 (br dt, 1H, J = 4, - 184 -14 Hz, Hg), 2.13 (br d, 1H, J = 14 Hz, H c), 1.95-1.49 (m, 11H), 1.69 (s, 3H, v i n y l methyl protons), 1.35-1.18 (m, 3H), 1.09 (s, 3H, angular methyl protons), 0.89 (s, 3H, methyl protons). Preparation of the acetate 168 A s o l u t i o n of the alcohol 152 (10 mg, 29 /imol), a c e t i c anhydride (0.1 mL, 1 mmol) and 4-N,N-dimethylaminopyridine (2 mg, 16 /xmol) i n pyri d i n e (0.4 mL) was s t i r r e d at room temperature f or 90 min. Solvent and excess reagents were removed under reduced pressure (0.02 to r r ) and the residue was dissol v e d i n ether. The ethereal s o l u t i o n was washed twice with brine, d r i e d (MgSO^j and concentrated. The residue showed one spot on t i c and exhibited i r ( f i l m ) : 3086, 1741, 1669, 1635, 1240, 1150, 1104, 1044, 893 cm"1; XH nmr (270 MHz) 6: 5.35 ( t , 1H, J - 6.8 Hz, H A), 4.65 (s, 2H, ac e t a l protons), 4.54 (br s, 2H, exocyclic o l e f i n i c protons), 4.16 (s, 2H, -CH 20Ac), 4.07 (d, 2H, J = 6.8 Hz, =CCH20-), 3.40 (s, 3H, -0CH 3), 2.4-1.1 (m, 16H), 2.06 (s, 3H, a c e t y l methyl protons), 1.70 (s, 3H, v i n y l methyl protons), 1.09 (s, 3H, angular methyl protons), 0.90 (br s, 3H, methyl protons). - 185 -Preparation of the phosphorodiamidate 174 To a s o l u t i o n of the alcohol 152 (23 mg, 66 Ltmol) i n a mixture of dimethoxyethane (1 mL) and N,N,N',N'-tetramethylethylenediamine (0.25 mL) at 0°C was added a s o l u t i o n of n-butyllithium (73 /imol) i n hexanes. A f t e r the mixture had been s t i r r e d at room temperature for 30 min, dimethylaminophosphorodichloridate (40 LIL, 0.32 mmol) was added and the mixture was s t i r r e d at room temperature f o r 12 h. The reaction mixture was cooled to 0°C, and anhydrous dimethylamine (1 mL) was added. A f t e r the r e s u l t a n t mixture had been s t i r r e d at 0°C f o r 2 h, i t was d i l u t e d with ether, and then was washed twice with brine, d r i e d (MgS04) and concentrated. The residue was subjected to column chromatography on s i l i c a gel (2 g, e l u t i o n with ether-acetone 10:1 v/v). C o l l e c t i o n and concentration of the appropriate f r a c t i o n s gave the phosphorodiamidate 174 which exhibited i r ( f i l m ) : 3085, 1667, 1634, 1224, 1041, 994, 891 cm - 1; XH nmr (270 MHz) 6: 5.34 ( t , 1H, J = 6.8 Hz, H A), 4.63 (s, 2H, a c e t a l protons), 4.53 (s, 2H, exocyclic o l e f i n i c protons), 4.06 (d, 2H, J = 6.8 Hz, =CCH20-), 4.00 (br m, 2H, -P0 2CH 2-), 3.39 (s, 3H, -0CH 3), 2.69, 2.66 (br s, br s, 6H each, -N(CH 3) 2), 2.30-1.10 (m, 16H), 1.70 (s, 3H, v i n y l methyl protons), 1.08 (s, 3H, angular methyl protons), 0.93 (br s, 3H, methyl protons). - 186 -Preparation of 3-lodo-l-methoxvmethoxypropane (172) To a c o l d (-20°C) s o l u t i o n of 3-chloro-1-propanol (8.4 mL, 0.10 mol) and diisopropylethylamine (28 mL, 0.16 mol) i n dichloromethane (200 mL) was added chloromethyl methyl ether (11.4 mL, 0.15 mol). A f t e r the s o l u t i o n had been s t i r r e d at room temperature for 12 h, i t was d i l u t e d with dichloromethane and washed three times with IN hydrochloric acid, once with saturated aqueous sodium bicarbonate, twice with brine, and then was d r i e d (MgSO^). The s o l u t i o n was concentrated at atmospheric pressure v i a a Vigreux column (10 cm). D i s t i l l a t i o n (bp 73-80°C/15 t o r r ) of the remaining o i l afforded 11 g (80%) of 3-chloro-l-methoxy-methoxypropane. A s o l u t i o n of 3-chloro-l-methoxymethoxypropane (11 g, 80 mmol) and sodium iodide (47 g, 0.32 mol) i n acetone (150 mL) was s t i r r e d at 60°C fo r 30 h. The s o l u t i o n was d i l u t e d with petroleum ether, f i l t e r e d and concentrated at atmospheric pressure v i a a Vigreux column (10 cm). D i s t i l l a t i o n [bp 80-85°C/15 t o r r ( l i t . 5 4 bp 87-85°C/1.87 kPa)] of the remaining o i l y i e l d e d 13 g (70%) of the iodide 172 as a c o l o r l e s s o i l which was stored over copper dust under argon i n a freezer. This material was homogeneous by glc analysis and exhibited nmr (80 MHz) 6: 4.63 (s, 2H, a c e t a l protons), 3.60 ( t , 2H, J = 6 Hz, -CH 20-), 3.40 (s, 3H, methoxy protons), 3.30 ( t , 2H, J = 6 Hz, -CH 2I), 2.05 (quintet, 187 2H, J = 6 Hz, -CH 2CH 2CH 2I). Preparation of the n i t r i l e 173 C N H ft To a c o l d (-78°C) s o l u t i o n of diisopropylamine (0.24 mL, 1.7 mmol) i n THF (11 mL) was added n-butyllithium (1.5 mmol) as a s o l u t i o n i n hexanes and the s o l u t i o n was s t i r r e d at 0°C for 15 min. HMPA (0.4 mL, 2.2 mmol) and a s o l u t i o n of a mixture of the n i t r i l e s 112a and 112b (0.23 g, 1.1 mmol; 15:85, respectively) i n THF were added and the s o l u t i o n was s t i r r e d at 0°C for 15 min. To the re s u l t a n t yellow s o l u t i o n was added the iodide 172 (0.35 g, 1.5 mmol) and the s o l u t i o n was s t i r r e d at 0°C f o r 30 min and at room temperature f o r 1 h. The so l u t i o n was d i l u t e d with petroleum ether, washed with IN hydrochloric a c i d , twice with aqueous copper s u l f a t e and twice with brine and then was d r i e d (MgSO^, f i l t e r e d through a small pad of F l o r i s i l and concentrated under reduced pressure (0.02 tor r ) to a f f o r d 0.34 g (99%) of the desired n i t r i l e 173. This material was homogeneous by glc analysis and exhibited i r ( f i l m ) : 3086, 2766, 2228, 1638, 1153, 1112, 1039, 921, 894 cm - 1; 1H nmr (400 MHz) 6: 4.59 (br s, 3H, o l e f i n i c and - 188 -ace t a l protons), 4.55 (br s, 1H, o l e f i n i c proton), 3.43 ( t , 2H, J - 6 Hz, -CH 2CH 20-), 3.35 (s, 3H, -OCH3), 2.34 (br dt, 1H, J = 5, 12 Hz, H A), 2.14 (br d, 1H, J - 12 Hz, Hg), 2.00-1.20 (m, 14H), 1.27 (s, 3H, angular methyl protons), 1.11 (d, 3H, J = 6 Hz, methyl protons). Exact Mass cal c d . f o r C 1 9H 3 1N0 2: 305.2355; found: 305.2356. Preparation of the aldehyde 180 To a s o l u t i o n of the n i t r i l e 173 (0.34 g, 1.1 mmol) i n dimethoxy-ethane (11 mL) was added diisobutylaluminum hydride (4.4 mmol) as a s o l u t i o n i n hexanes and the s o l u t i o n was warmed at 60°C f o r 6 h. The re a c t i o n mixture was cautiously poured into water, and the resultant mixture was n e u t r a l i z e d with IN hydrochloric acid, and then was extracted three times with ether. The extracts were combined, washed with brine, d r i e d (Na2S0 4) and concentrated. The r e s i d u a l o i l was diss o l v e d i n a mixture of THF-acetic acid-water (8 mL, 1:1:0.16 by volume) and the s o l u t i o n was s t i r r e d at room temperature f o r 12 h. A f t e r removal of the solvent under reduced pressure (0.02 t o r r ) , the residue was dis s o l v e d i n ether and the res u l t a n t s o l u t i o n was washed - 189 -with aqueous sodium bicarbonate and brine, and then was d r i e d (MgSO^) and concentrated to a f f o r d 0.29 g (85%) of the aldehyde 180, which exh i b i t e d i r ( f i l m ) : 3086, 2766, 2740, 1713, 1636, 1153, 1112, 1039, 921, 893 cm - 1; '-H nmr (400 MHz) 6: 9.52 (s, 1H, aldehyde proton), 4.60 (s, 2H, a c e t a l protons), 4.58 (br s, 2H, o l e f i n i c protons), 3.50 (t, 2H, J - 6 Hz, -CH 20-), 3.35 (s, 3H, -OCH3), 2.26 (br dt, 1H, J - 5, 12 Hz, H A), 2.11 (br d, 1H, J = 12 Hz, Hg), 1.95-1.10 (m, 14H), 1.02 (d, 3H, J •= 6 Hz, methyl protons), 0.98 (s, 3H, angular methyl protons). Exact  Mass ca l c d . f o r C 1 9H320 3: 308.2351; found: 308.2359. Preparation of the alcohol 181 To a solution-suspension of l i t h i u m aluminum hydride (70 mg, 1.8 mmol) i n ether (10 mL) was added an ethereal s o l u t i o n of the aldehyde 180 (0.28 g, 0.9 mmol) and the mixture was s t i r r e d at room temperature fo r 1 h. Sodium s u l f a t e decahydrate was added i n small portions to the s t i r r e d mixture u n t i l evolution of gas ceased. The mixture was f i l t e r e d and the c o l l e c t e d material was washed three times with ether. The combined f i l t r a t e was concentrated to y i e l d 0.25 g (91%) of the alcohol - 190 -181 which exhibited i r ( f i l m ) : 3462 (br), 3085, 1635, 1152, 1111, 1039, 921, 891 cm*1; % nmr (400 MHz) 5: 4.62 (s, 2H, ace t a l protons), 4.51 (br s, 2H, o l e f i n i c protons), 3.78, 3.70 (d, d, 1H each, J - 12 Hz, -CH20H), 3.51 ( t , 2H, J - 6.5 Hz, -CH 2CH 20-), 3.37 (s, 3H, -0CH 3), 2.26 (br dt, 1H, 1 - 5 , 12 Hz, H A), 2.10 (br d, 1H, J - 12 Hz, Hg), 1.87 (br d, 1H, I - 12 Hz, H c), 1.70-1.10 (m, 14H), 1.06 (s, 3H, angular methyl protons), 0.94 (d, 3H, J = 6 Hz, methyl protons). Exact Mass calcd. f o r C 1 9 H 3 4 ° 3 : 310.2508; found: 310.2509. Preparation of the phosphorodiamidate 174 To a s o l u t i o n of the alcohol 181 (0.22 g, 0.7 mmol) i n a mixture of dimethoxyethane (6 mL) and N,N,N',N'-tetramethylethylenediamine (1.5 mL) at 0°C was added n-butyllithium (0.77 mmol) as a s o l u t i o n i n hexanes. A f t e r the mixture had been s t i r r e d f o r 15 min, dimethylaminophosphoro-d i c h l o r i d a t e (0.45 mL, 3.6 mmol) was added and the reac t i o n mixture was s t i r r e d at room temperature f o r 12 h. The reac t i o n mixture was cooled to 0°C, anhydrous dimethylamine (10 mL) was added, and s t i r r i n g was continued at 0°C f o r 2 h. The s o l u t i o n was d i l u t e d with ether, washed - 191 -twice with brine, d r i e d (MgS04) and concentrated. The residue was subjected to column chromatography on s i l i c a gel (10 g, e l u t i o n with ether-acetone 10:1 v/v). The appropriate f r a c t i o n s were combined and concentrated under reduced pressure (16 t o r r , then 0.02 t o r r ) to y i e l d 0.27 g (88%) of the phosphorodiamidate 174 as a c o l o r l e s s viscous o i l which exhibited i r ( f i l m ) : 3084, 1635, 1305, 1215, 1152, 1111, 1037, 920, 888 cm - 1; 1H nmr (400 MHz) 6: 4.60 (s, 2H, a c e t a l protons), 4.51 (s, 2H, o l e f i n i c protons), 4.00, 3.95 (dd, dd, 1H each, J - 4, 12 Hz, -CH 20P), 3.48 ( t , 2H, J = 6 Hz, -CH 2CH 20-), 3.35 (s, 3H, -OCH3), 2.66, 2.64 (d, d, 6H each, J = 4 Hz, -PNMe2), 2.26 (br dt, 1H, J = 5, 12 Hz, H A), 2.11 (br d, lH, J - 12 Hz, Hg), 1.9-1.1 (m, 14H), 1.06 (s, 3H, angular methyl protons), 0.93 (d, 3H, J = 6 Hz, methyl protons). Exact  Mass calcd. f or C 2 3H 4 5N 204P: 444.3117; found: 444.3119. Preparation of the ether 175 L i q u i d methylamine (7 mL) was condensed into a c o l d (-78°C) f l a s k containing l i t h i u m metal (9 mg, 1.3 mmol) and the mixture was s t i r r e d at -30°C for 30 min. To the resultant dark blue s o l u t i o n was added an - 192 -ethereal s o l u t i o n of the phosphorodiamidate 174 (99 mg, ' 0.2 mmol) and the mixture s t i r r e d at -20°C f or exactly 10 min. The rea c t i o n mixture was cau t i o u s l y but quickly treated with aqueous ammonium chloride and the r e s u l t a n t mixture was extracted three times with ether. The ethereal extracts were combined, washed with brine, d r i e d (MgS04) and concentrated. The residue was subjected to column chromatography on s i l i c a g el (4 g, e l u t i o n with petroleum ether-ether, 20:1 v/v). C o l l e c t i o n and concentration of the appropriate f r a c t i o n s afforded 48 mg (81%) of the ether 175 as a c o l o r l e s s o i l which exhibited i r ( f i l m ) : 3085, 2767, 1636, 1147, 1112, 1078, 1039, 922, 891 cm"1; XH nmr (400 MHz) 6: 4.60 (s, 2H, ace t a l protons), 4.49 (br s, 2H, o l e f i n i c protons), 3.44 ( t , 2H, J - 6 Hz, -CH 2CH 20-), 3.36 (s, 3H,-0CH3), 2.'28 (br dt, 1H, J = 5, 13.5 Hz, H A), 2.09 (br d, 1H, J = 13.5 Hz, Hg), 1.87 (br d, 1H, J - 12 Hz, H c), 1.63-1.00 (m, 13H), 1.04 (s, 3H, angular methyl protons), 0.80 (d, 3H, J - 6 Hz, methyl protons), 0.73 (s, 3H, methyl protons). I r r a d i a t i o n at 8 4.49 ( o l e f i n i c protons) caused the s i g n a l at 8 2.34-2.23 to sharpen; i r r a d i a t i o n at 5 2.28 (H A) caused the s i g n a l at 8 2.14-2.06 to collapse to a broad s i n g l e t and the s i g n a l at 8 1.91-1.82 to sharpen; i r r a d i a t i o n at 8 2.09 (Hg) caused the s i g n a l at 8 2.34-2.23 to collapse to a broad doublet ( J = 13.5 Hz) and the s i g n a l at 5 1.91-1.82 to sharpen to a q of d (J = 3.5 Hz, J = 12 Hz); i r r a d i a t i o n at 5 1.87 (HQ) caused the s i g n a l at 8 2.34-2.23 to collapse to a broad t r i p l e t ( J = 13.5 Hz) and the s i g n a l at 8 2.14-2.06 to sharpen to a d of d ( J - 4, 13.5 Hz). Exact Mass calcd. f o r C 1 9H 340 2: 294.2559; found: 294.2557. - 193 Preparation of the ether 182 Dry l i q u i d ethylamine (1 mL) was condensed into a c o l d (-78°C) f l a s k containing l i t h i u m metal (11 mg, 0.29 mmol) and the mixture was s t i r r e d at 0°C for 20 min. To the resultant dark blue s o l u t i o n was added a THF s o l u t i o n of the phosphorodiamidate 174 (13 mg, 29 pmol) and t e r t - b u t y l a l c ohol (0.11 mmol) and the mixture was s t i r r e d at 0°C f o r 20 min. The r e a c t i o n mixture was treated with aqueous ammonium ch l o r i d e and the r e s u l t a n t mixture was extracted three times with ether. The ethereal extracts were combined, washed with brine, d r i e d (MgSO^) and concen-trate d . The residue was subjected to column chromatography on s i l i c a gel (1 g, e l u t i o n with petroleum ether-ether, 30:2 v/v). C o l l e c t i o n and concentration of the appropriate f r a c t i o n s afforded 6.8 mg (80%) of the ether 182 as a colourless o i l which exhibited i r ( f i l m ) : 1463, 1383, 1151, 1112, 1039 cm - 1; XH nmr (400 MHz) 6: 4.62 (s, 2H, a c e t a l protons), 3.46 ( t , 2H, J - 7 Hz, -CH 2CH 20-), 1.8-0.8 (m, 20H), 0.78 (d, 3H, J - 7 Hz, methyl protons), 0.77 (s, 3H, methyl proton), 0.73 (d, 3H, J •= 7 Hz, methyl protons), 0.70 (s, 3H, methyl proton). Exact Mass calcd. for C 1 9 H 3 6 0 2 : 296.2715; found: 296.2707. 194 -Preparation of the alcohol 183 A mixture of the ether 175 (65 mg, 0.22 mmol) and pyridinium p_-toluenesulf onate (0.55 g, 2.2 mmol) i n t e r t - b u t y l a l c ohol (5 mL) was heated at 70°C f o r 12 h. A f t e r removal of solvent under reduced pressure (0.02 t o r r ) the residue was t r i t u r a t e d three times with dry ether. The ethereal s o l u t i o n was f i l t e r e d and concentrated, and the residue was subjected to column chromatography on s i l i c a gel (1 g, e l u t i o n with petroleum ether-ether, 7:3 v/v). C o l l e c t i o n and concentra-t i o n of the appropriate f r a c t i o n s provided 50 mg (91%) of the alcohol 183 as a c o l o r l e s s o i l which exhibited i r ( f i l m ) : 3319 (br) , 3085, 1635, 1055, 891 cm - 1; XH nmr (400 MHz) 5: 4.50 (br s, 2H, o l e f i n i c protons), 3.57 ( t , 2H, J = 6 Hz, -CH2CH2OH), 2.29 (br dt, 1H, J = 5, 12 Hz, H A), 2.10 (br d, 1H, J = 12 Hz, Hg), 1.87 (br d, 1H, J = 12 Hz, H c), 1.65-1.00 (m, 14H), 1.05 (s, 3H, angular methyl protons), 0.80 (d, 3H, J = 6 Hz, methyl protons), 0.75 (s, 3H, methyl protons). Exact Mass calcd. f o r C 1 7 H 3 0 0 : 250.2296; found: 250.2295. - 195 -Preparation of the aldehyde 184 CHO To a s t i r r e d solution-suspension of pyridinium chlorochromate (70 mg, 0.32 mmol) and anhydrous sodium acetate (5 mg, 61 /xmol) i n dichloromethane (5 mL) was added a s o l u t i o n of the alcohol 183 (60 mg, 0.24 mmol). A f t e r the mixture had been s t i r r e d at room temperature for 1 h, i t was d i l u t e d with dry ether, and then was f i l t e r e d through a short pad of F l o r i s i l . The f i l t r a t e was concentrated to a f f o r d 58 mg (99%) of the aldehyde 184 as a c o l o r l e s s o i l which exhibited i r ( f i l m ) : 3085, 2714, 1728, 1635, 892 cm"1; 1H nmr (400 MHz) 5: 9.74 ( t , 1H, J = 2 Hz, aldehyde proton), 4.50 (br s, 2H, o l e f i n i c protons), 2.30-2.16 (m, 3H, H A and -CH2CH0), 2.10 (br d, 1H, J = 12 Hz, Hg), 1.88 (br d, 1H, J = 12 Hz, H c), 1.70-1.15 (m, 11H), 1.05 (s, 3H, angular methyl protons), 0.81 (d, 3H, J = 6 Hz, methyl protons), 0.79 (s, 3H, methyl protons). Exact Mass calcd. f o r C 1 7H 280: 248.2140; found: 248.2145. - 196 -Preparation of the ketone 176 H A"" •0 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 aldehyde 184 (22 mg, 88 ^imol) i n ether (1 mL) was added methyllithium (0.28 mmol) as a s o l u t i o n i n ether. A f t e r the mixture had been s t i r r e d at room temperature f o r 3 h, sodium s u l f a t e decahydrate was added i n small portions u n t i l evolu-t i o n of gas ceased. The s o l u t i o n was d i l u t e d with ether, f i l t e r e d and concentrated to give a mixture of epimeric alcohols, which showed i r ( f i l m ) : 3349 (br), 3085, 1635, 891 cm"1. Exact Mass calcd. f o r C 1 8H 3 20: 264.2453; found: 264.2455. The mixture of alcohols obtained as described above was added to a solution-suspension of pyridinium chlorochromate (31 mg, 14 mmol) and sodium acetate (3 mg, 36 /xmol) i n dichloromethane (1 mL) at 0°C and the mixture was s t i r r e d at room temperature f o r 1 h. The re a c t i o n mixture was d i l u t e d with dry ether and then was f i l t e r e d through a short pad of F l o r i s i l . Concentration of the f i l t r a t e gave 22 mg (97%) of the ketone 176 which exhibited i r ( f i l m ) : 3085, 1718, 1635, 891 cm*1; XH nmr (400 MHz) 8: 4.51 (br s, 2H, o l e f i n i c protons), 2.28 (br dt, 1H, J = 5, 12 Hz, H A), 2.13 (s, 3H, -COCH3), 2.21-2.05 (m, 1H), 1.88 (br d, 1H, J - 12 Hz, H c), 1.65-1.10 (m, 13H), 1.05 (s, 3H, angular methyl protons), 0.80 (d, 3H, J = 7 Hz, methyl protons), 0.78 (s, 3H, methyl protons). Exact  Mass ca l c d . f o r C 1 8H 3 0O: 262.2297; found: 262.2298. - 197 -Preparation of the esters 186 and 177 Hi H A R 186 R=H. R=C0?Et 177 R=C02Et,R=H To a suspension of potassium hydride (30 mg, 0.75 mmol; washed with ether and d r i e d under a stream of argon) i n THF (3 mL) at room tempera-ture was added t r i e t h y l phosphonoacetate (140 uL, 0.7 mmol) and the mixture was s t i r r e d f o r 30 min. A s o l u t i o n of the ketone 176 (17 mg, 65 /jmol) i n THF was added and the mixture was s t i r r e d at room temperature f o r 15 h. The r e a c t i o n mixture was treated with sodium s u l f a t e decahy-drate, d i l u t e d with ether, and f i l t e r e d through C e l i t e . The f i l t r a t e was concentrated. Glc analysis of the r e s i d u a l o i l showed that i t consisted of a mixture of two compounds i n a r a t i o of 1:10. The two products were r e a d i l y separable by column chromatography on s i l i c a gel (2 g, e l u t i o n with petroleum ether-ether, 50:1 v/v). C o l l e c t i o n and concentration of the appropriate f r a c t i o n s afforded both the pure (Z) ester 186, 2.5 mg (11.6%) and the pure (Z) ester 177, 19 mg (88.3%). The l e s s polar (Z) ester 186 exhibited i r ( f i l m ) : 3085, 1718, 1648, 1151, 890 cm"1; XH nmr (400 MHz) 6: 5.60 (br s, 1H, o l e f i n i c proton), 4.50 (br s, 2H, terminal o l e f i n i c protons), 4.12 (q, 2H, J = 7.5 Hz, -0CH 2CH 3), 2.55 (br dt, 1H, J = 4, 12 Hz, H A), 2.32, 2.24 (br ddd, br ddd, 2H, J - 5, 12, 12 Hz, -CH 2(CH 3)C=), 2.11 (br d, 1H, J - 12 Hz, Hg), - 198 -1.90 (m, 1H, H c), 1.85 (d, 3H, J = 1.5 Hz, v i n y l methyl protons), 1 . 7 4 - 1 . 2 2 (m, 11H) , 1.25 ( t , 3H, J - 7.5 Hz, -OCH2CH3), 1.05 (s, 3H, angular methyl protons), 0.85 (d, 3H, J = 6 Hz, methyl protons), 0 .73 (s, 3H, methyl protons). Exact Mass calcd. f o r C22H36O2: 332.2715; found: 332.2721. The more polar (E) ester 177 exhibited i r ( f i l m ) : 3085, 1718, 1646, 1224, 1148, 892, 871 cm - 1; XH nmr (400 MHz) S: 5.63 (br s, 1H, o l e f i n i c proton), 4.51 (br s, 2H, terminal o l e f i n i c protons), 4.14 (q, 2H, J = 7.5 Hz, - 0 C H 2CH 3), 2.29 (br dt, 1H, J - 5, 13.5 Hz, H A), 2.14 (d, 3H, J = 1.5 Hz, v i n y l methyl protons), 2.15-2.07 (m, 1H, Hg), 2 .02-1.78 (m, 3H, -CH 2(CH 3)C= and H c), 1 . 6 6 - 1 . 2 2 (m, 11H) , 1.28 ( t , 3H, J = 7.5 Hz, - 0 C H 2CH 3), 1.05 (s, 3H, angular methyl protons), 0.81 (d, 3H, J = 6 Hz, methyl protons), 0 . 7 4 (s, 3H, methyl protons). Exact Mass calcd. f o r C 2 2 H 3 6 ° 2 : 332.2715; found: 332.2715. Preparation of the a l l y l i c alcohol 187 OH To a c o l d (-78°C) s t i r r e d s o l u t i o n of the (E) ester 177 (19 mg, 57 ^mol) i n ether (1 mL) was added diisobutylaluminum hydride (0.25 mmol) as a s o l u t i o n i n hexanes. A f t e r the s o l u t i o n had been s t i r r e d f o r 1 h - 199 -at -78°C and 2 h at 0°C, i t was treated with saturated aqueous ammonium chl o r i d e (0.1 mL) and then d i l u t e d with ether. The r e s u l t i n g mixture was s t i r r e d f o r 5 min at room temperature, dri e d (MgSO^ and f i l t e r e d through a pad of F l o r i s i l . Concentration of the f i l t r a t e gave 16 mg (98%) of the a l l y l i c alcohol 187 which exhibited i r ( f i l m ) : 3327 (br), 3085, 1668, 1636, 1000, 891 cm - 1; XH nmr (400 MHz) 6: 5.37 ( t , 1H, J -8 Hz, o l e f i n i c proton), 4.50 (br s, 2H, terminal o l e f i n i c protons), 4.12 (d, 2H, J = 8 Hz, •=CCH20H), 2.29 (br dt, 1H, J = 5, 13.5 Hz, H A) , 2.10 (br d, 1H, J - 13.5 Hz, Hg), 1.93-1.18 (m, 15H), 1.65 (br s, 3H, v i n y l methyl protons), 1.03 (s, 3H, angular methyl protons), 0.81 (d, 3H, J = 8 Hz, methyl protons), 0.72 (s, 3H, methyl protons). Exact Mass calcd. f o r C20H34O: 290.2610; found: 290.2614. Preparation of the aldehyde 107 A s o l u t i o n of the a l l y l i c alcohol 187 (15.8 mg, 55 /xmol) i n n-hexane (1.5 mL) was s t i r r e d at room temperature with manganese(IV) oxide (70 mg) f o r 3 h. The mixture was f i l t e r e d through a pad of C e l i t e . The c o l l e c t e d material was washed four more times with d i e t h y l ether. The - 200 -combined f i l t r a t e was concentrated to a f f o r d 14 mg (88%) of the aldehyde 107 as a c o l o r l e s s o i l which exhibited i r ( f i l m ) : 3084, 1676, 1633, 1611, 1195, 891 cm"1; 1H nmr (270 MHz) 8: 9.97 (d, 1H, J = 8 Hz, aldehyde proton), 5.86 (br d, 1H, J= 8 Hz, o l e f i n i c proton), 4.51 (br s, 2H, terminal o l e f i n i c protons), 2.16 (d, 3H, J = 0.8 Hz, v i n y l methyl protons), 2.4-1.1 (m, 16H), 1.06 (s, 3H, angular methyl protons), 0.81 (d, 3H, J = 8 Hz, methyl protons), 0.77 (s, 3H, methyl protons). Exact  Mass calcd. f o r C20H32O: 288.2453; found: 288.2446. Preparation of 2-trimethylsilvl-4-(chloromethyl)furan (110) 190X=OH, Y=SPh.Z=H 191 X=OTBDMS,Y=SPh,Z=H 192 X=0TBDMS,Y=SPh,Z=TMS 193 X=0TBDMS.Y=H, Z=TMS 194 X=0H, Y=H, Z=TMS 110 X=Cl, Y=H, Z=TMS 2-Trimethylsilyl-4-(chloromethyl)furan (110) was prepared from 3-furanmethanol as described by Goldsmith et a l 5 8 and Tanis et a l 5 9 v i a 190, 191, 192, 193, and 194. Compound 190 exhibited -^H nmr (80 MHz) 8: 7.59 (d, 1H, J = 2 Hz, furan a-proton), 7.25-7.15 (m, 5H, phenyl protons), 6.65 (d, 1H, J = 2 Hz, furan y3-proton), 4.66 (d, 2H, J = 5 Hz, -CH20H), 1.62 (t, 1H, J = 5 Hz, exchanged with D2O, -OH). Compound 191 exhibited lU nmr (80 MHz) 8: 7.55 (d, 1H, J = 2 Hz, - 201 -furan a-proton), 7.23-7.13 (m, 5H, phenyl protons), 6.61 (d, 1H, J = 2 Hz, furan 0-proton), 4.66 (s, 2H, -CH 20), 0.91 (s, 9H, t e r t - b u t y l protons), 0.07 (s, 6H, s i l y l methyl protons). Compound 192 exhibited -^H nmr (80 MHz) 8: 7.35-7.15 (m, 5H, phenyl protons), 6.85 (br s, 1H, furan proton), 4.70 (s, 2H, -CH 20), 0.99 (s, 9H, t e r t - b u t y l protons), 0.38 (s, 9H, s i l y l trimethyl protons), 0.13 (s, 6H, s i l y l methyl protons). Compound 193 exhibited XH nmr (80 MHz) 8: 7.56 (br s, 1H, furan a-proton), 6.60 (br s, 1H, furan /3-proton), 4.63 (br s, 2H, -CH 20-), 0.97 (s, 9H, t e r t - b u t y l protons), 0.30 (s, 9H, s i l y l trimethyl protons), 0.13 (s, 6H, s i l y l methyl protons). Compound 194 exhibited XH nmr (80 MHz) 8: 7.60 (br s, 1H, furan a-proton), 6.66 (br s, 1H, furan /9-proton), 4.55 (br s, 2H, -CH20H), 1.58 (br s, 1H, D 20 exchange, -OH), 0.30 (s, 9H, s i l y l methyl protons). Compound 110 exhibited 1H nmr (270 MHz) 8: 7.61 (br s, 1H, furan a-proton), 6.62 (s, 1H, furan 0-proton), 4.45 (s, 2H, -CH 2C1), 0.25 (s, 9H, s i l y l methyl protons). Preparation of the chloro butenolide 109 0 : 202 -While oxygen was bubbled through a cold (-78°C) s o l u t i o n of the furan d e r i v a t i v e 110 (2 g, 10 mmol) and a c a t a l y t i c amount of t e t r a -phenylporphin (1 mmol) i n dichloromethane (120 mL), i t was i r r a d i a t e d with a halogen-tungsten lamp (650 W, 110 V operated at 50 V) for 27 min. The disappearance of s t a r t i n g material was monitored by g l c . The s o l u t i o n was allowed to warm to room temperature and then was concen-trate d . The residue was dissolved i n methanol and the s o l u t i o n s t i r r e d at room temperature f o r 12 h. Af t e r removal of the solvent, the residue was subjected to f l a s h column chromatography on s i l i c a gel (250 g, e l u t i o n with petroleum ether-ethyl acetate, 6:5 v/v). C o l l e c t i o n and concentration of the appropriate f r a c t i o n s afforded 1.27 g (78%) of the butenolide 109, which exhibited i r ( f i l m ) : 3357 (br), 1763, 1660, 1139 cm"1; 1H nmr (80 MHz) 5: 6.21 (br s, 2H, H A and Hg), 4.80 (br s, 1H, exchanged with D2O, -OH), 4.37 (s, 2H, -CH2CI ). Exact Mass calcd. f o r C 5 H 4 3 5 C 1 0 3 ( M + - l ) : 146.9849; found: 146.9843. Preparation of the methoxy butenolide 197 A s o l u t i o n of the butenolide 109 (0.1 g, 0.67 mmol) and p_-toluenesul-fon i c a c i d monohydrate (30 mg, 0.16 mmol) i n dry methanol (10 mL) was 0 : OMe - 203 -s t i r r e d at room temperature f o r 2 days. The s o l u t i o n was concentrated and the residue was subjected to column chromatography on s i l i c a gel (5 g, e l u t i o n with petroleum ether-ethyl acetate 3:1 v/v). C o l l e c t i o n and concentration of the appropriate f r a c t i o n s afforded 0 .1 g (92%) of the methoxy butenolide 197 which exhibited i r ( f i l m ) : 3113, 2845, 1800, 1768, 1662, 1120 cm"1. 1H nmr (80 MHz) 6: 6 .20 (m, lH,' H A), 5.80 (br s, 1H, Hg), 4.31 (br s, 2H, -CH 2 C1) , 3.61 (s, 3H, -OCH3). Exact Mass cal c d . f o r C 6 H 6 3 5 C 1 0 3 (M+-1): 161.0005; found: 160.9999. Preparation of the phosphonium s a l t 188 A so l u t ion of the butenolide 197 (0.4 g, 2.5 mmol) and triphenylphos-phine (1 g, 3.9 mmol) i n benzene (8 mL) was refluxed f o r 2 days. The re s u l t a n t s l u r r y was centrifuged and the supernatant s o l u t i o n was decanted. The residue was washed three times with benzene and then was dr i e d under reduced pressure (0.02 torr) to a f f o r d 0.74 g (70%) of the phosphonium s a l t 188. This white f i n e s o l i d exhibited ^H nmr (80 MHz, CD 2C1 2) 6: 8.2-7.5 (m, 15H, aromatic protons), 6.00,5.98 (br s, br s, 1H each, H A and Hg), 5.80 (d, 2H, J = 16 Hz, -CH 2P), 3.30 (s, 3H, - O C H 3 ) . 0' H B - 204 -Hydrolysis of the methoxy butenolide 200 to the hydroxy butenolide 202 To a mixture of the butenolide 200 (0.13 g, 1 mmol) and aqueous sodium hydroxide (4 M, 1.1 mmol) was added a c e t o n i t r i l e u n t i l the s o l u t i o n was c l e a r (-7 ml). The so l u t i o n , which was s t i r r e d at room temperature f o r 0.5 h, gradually turned yellow. The res u l t a n t s o l u t i o n was treated with d i l u t e hydrochloric a c i d (2 M, 1.2 mmol) and the s o l u t i o n turned c o l o r l e s s . A f t e r removal of solvents, the residue was t r i t u r a t e d with ether. The ethereal s o l u t i o n was f i l t e r e d , d r i e d (MgS04) and concentrated to provide 68 mg (60%) of the hydroxybutenolide 2 0 2 6 3 which exhibited i r ( f i l m ) : 3350, 1730 cm - 1; -^H nmr (80 MHz) 6: 5.94 (br s, 1H, OCHOH), 5.79 (m, 1H, o l e f i n i c proton), 5.48 (v br s, 1H, D 20 exchanged, -OH), 2.06 (d, 3H, J = 2H, methyl protons). 200 202 - 205 -Preparation of the phosphonate 213 t0Et)2 0" Me A mixture of the butenolide (197) (0.11 g, 0.68 mmol) and p u r i f i e d t r i e t h y l p h o s p h i t e (5 mL) was heated at -150°C f o r 18 h. Excess tr i e t h y l p h o s p h i t e was removed under reduced pressure (0.02 tor r ) and the r e s i d u a l o i l was subjected to column chromatography on s i l i c a gel (10 g, e l u t i o n with ether). C o l l e c t i o n and concentration of the appropriate f r a c t i o n s afforded 0.14 g (78%) of the phosphonate 213 as a c o l o r l e s s o i l which exhibited i r ( f i l m ) : 3107, 2846, 1796, 1767, 1651, 1250 cm"1; XH nmr (400 MHz) 6: 6.11 (br d, 1H, J = 4.5 Hz, H A or Hg), 5.82 (br d, 1H, J - 3 Hz, Hg or H A), 4.15 (br quintet, 4H, J - 7 Hz, -0CH 2CH 3), 3.60 (s, 3H, -0CH 3), 3.01, 2.89 (dd, dd, 1H each, J - 16, 21 Hz, -CH 2P), 1.35 (dt, 6H, J = 2.7, 7 Hz, -0CH 2CH 3). Exact Mass calcd. f o r C 1 Q H 1 7 0 6 P : 264.0762; found: 264.0756. Preparation of the sulfone 223 Me3Si •S02Ph - 206 -A s t i r r e d mixture of the furan 110 (0.56 g, 2.95 mmol), sodium benzenesulfinate (0.58 g, 3.5 mmol) and dimethylformamide (2.5 mL) was heated at 80-90°C f o r 2.5 h. The resultant s o l u t i o n was d i l u t e d with ether, washed twice with brine, d r i e d (MgSo 4), f i l t e r e d and concen-trated. The residue was subjected to column chromatography on neutral alumina ( a c t i v i t y I I I , 20 g, e l u t i o n with petroleum e t h e r - d i e t h y l ether, 2:8 v/v). C o l l e c t i o n and concentration of the appropriate f r a c t i o n s afforded 0.62 g (72%) of the sulfone (223) which exhibited i r ( f i l m ) : 3065, 1681, 1587, 1479, 1448, 1310, 1251, 1152 cm"1; XH nmr (80 MHz) 8: 7.8-7.3 (m, 6H, aromatic protons), 6.45 (s, 1H, H A), 4.15 (s, 2H, -CH 2S0 2-), 0.25 (s, 9H, s i l y l methyl protons). Exact Mass ca l c d . for C 1 4 H 1 8 0 3 S S i : 294.0746; found: 294.0744. Preparation of the triene 216 To a c o l d (-78°C) s o l u t i o n of the sulfone 223 (25.5 mg, 87 Ltmol) i n THF (0.9 mL) was added a s o l u t i o n of n - b u t y l l i t h i u m (77 Ltmol) i n hexanes and the s o l u t i o n was s t i r r e d f or 20 min. A s o l u t i o n of the aldehyde 107 (10 mg, 35 Limol) i n THF was added and the s o l u t i o n was s t i r r e d at -78°C - 207 -f o r 3 h. Benzoyl chloride (10 uL, 87 umol) was added and the reaction mixture was allowed to warm to room temperature over a period of 1.5 h. The s o l u t i o n was d i l u t e d with ether, washed once with saturated sodium bicarbonate and twice with brine and then was d r i e d (MgSO^ and concentrated. The r e s i d u a l o i l was dissolved i n a mixture of THF-methanol (1 mL, 3:1 v/v) and the s o l u t i o n was cooled to -20°C. Sodium amalgam (4%, 23 mg) was added and the mixture was s t i r r e d at -20°C for 2 h. A d d i t i o n a l amalgam (13 mg) was added and s t i r r i n g was continued for 1 h. The mixture was d i l u t e d with pentane, washed twice with brine, d r i e d (MgSO^) and concentrated. The residue was subjected to column chromatography on neutral alumina (2 g, a c t i v i t y I I I , e l u t i o n with pentane-ether, 50:1 v/v). C o l l e c t i o n of the appropriate f r a c t i o n s afforded 7.5 mg (51%) of the desired t r i e n e 216, which e x h i b i t e d i r ( f i l m ) : 3085, 3034, 1635, 1250, 891, 844 cm"1; XH nmr (400 MHz) 6: 7.58 (s, 1H, H A), 6.76 (s, 1H, Hg), 6.56 (dd, 1H, J = 10, 16 Hz, H c), 6.30 (d, 1H, J - 16 Hz, H D), 5.89 (d, 1H, J = 10 Hz, Hg), 4.50 (br s, 2H, terminal o l e f i n i c protons), 2.30 (br dt, 1H, J «= 5, 13.5 Hz, Hp), 2.12 (br d, 1H, J = 13.5 Hz, H G), 1.97-1.20 (m, 14H), 1.80 (s, 3H, v i n y l methyl protons), 1.05 (s, 3H, angular methyl protons), 0.82 (d, 3H, J = 6 Hz, methyl protons), 0.74 (s, 3H, methyl protons), 0.27 (s, 9H, -SiMe 3). Exact Mass calcd. f or C 28H44Si0: 424.3161; found: 424.3161. - 208 -Prepararion of (±)-Palauolide (55) 0 HG1 A s o l u t i o n of .the triene 216 (7.5 mg, 17 /xmol) and a c a t a l y t i c amount of Rose Bengal (1.7 /imol) i n a mixture of methanol-dichloro-methane (1 mL, 10:3 v/v) was cooled to -78°C. While a stream of oxygen was bubbled through the solu t i o n , i t was i r r a d i a t e d f o r 8 min with a halogen-tungsten lamp (650 W, 110 V operated at 50 V) through an aqueous sodium n i t r i t e f i l t e r (74 g per l i t r e ) . The resultant s o l u t i o n was purged with argon and then was allowed to stand at room temperature i n the dark for 3 h. Removal of solvent provided a crude product which was subjected to column chromatography on s i l i c a gel (1.5 g, e l u t i o n with hexane-ethyl acetate, 7:3 v/v). C o l l e c t i o n of the appropriate f r a c t i o n s provided (±)-palauolide (4.4 mg, 68%) which exhibited i r . ( f i l m ) : 3340 (br), 3083, 1757, 1634, 1614, 890 cm - 1; 1H nmr (400 MHz) 6: 7.14 (dd, 1H, J = 11, 15.5 Hz, H A), 6.29 (d, 1H, J = 15.5 Hz, Hg), 6.23 (d, 1H, J = 8.5 Hz; collapsed to s on D 20 exchange, H c), 5.97 (d, 1H, J = 11 Hz, H D), 5.87 (s, 1H, H E), 4.51 (br s, 2H, terminal o l e f i n i c protons), 2.30 (br dt, 1H, J = 5, 13.5 Hz, Hp), 2.12 (br d, 1H, J = 13.5 Hz, H G), 2.07-1.10 (m, 15H), 1.88 (s, 3H, v i n y l methyl protons), 1.06 (s, 3H, angular methyl protons), 0.82 (d, 3H, J = 6 Hz, methyl protons), 0.75 (s, 3H, methyl protons). The ^H nmr spectrum of t h i s material was i d e n t i c a l to - 209 -that of the n a t u r a l l y occurring sesterterpene (+)-palauolide.* Exact  Mass calcd. f o r C25H 3 60 3: 384.2664; found: 384.2660. Preparation of 2-iodo-l-benzyloxvmethoxvethane (246) I ^ N / ° \ / 0 N / P h To a c o l d (0°C) s o l u t i o n of 2-chloroethanol (1.0 mL, 15 mmol) and diisopropylethylamine (5.2 mL, 30 mmol) i n dichloromethane (33 mL) was added benzyl chloromethyl ether (3.8 mL, 27 mmol) and the s o l u t i o n was s t i r r e d at room temperature f o r 12 h. The rea c t i o n mixture was d i l u t e d with ether, washed once with saturated aqueous sodium bicarbonate, twice with 2N hydrochloric acid, twice with saturated aqueous sodium bicarbo-nate and three times with brine, and then was dr i e d (MgSO^) and concentrated. D i s t i l l a t i o n (air-bath temperature 90-95°C/0.02 to r r ) of the remaining o i l y i e l d e d 2.6 g (86%) of 2-chloro-l-benzyloxymethoxy-ethane (247). The c h l o r i d e 247 exhibited i r ( f i l m ) : 3095, 3064, 3032, 1498, 1161, 1118, 1075, 1041, 1002 cm"1; XH nmr (270 MHz) 6: 7.35-7.20 (m, 5H, aromatic protons), 4.81 (s, 2H, benzyl protons), 4.63 (s, 2H, acetal We are g r a t e f u l to Professor D. John Faulkner f o r the -41 nmr spectrum of palauolide. - 210 -protons), 3.83 ( t , 2H, J = 6 Hz, -CH 20-), 3.63 ( t , 2H, J - 6 Hz, -CH 2C1). Exact Mass calcd. f o r C 1 0 H 1 3 3 5 c l o 2 : 200.0604; found: 200.0600. A s t i r r e d s o l u t i o n of the chloride 247 (2.0 g, 10 mmol) and sodium iodide (6 g, 40 mmol) i n acetone (20 mL) was heated at 60°C i n the dark f o r 40 h. The re s u l t a n t s o l u t i o n was concentrated and the re s i d u a l material was t r i t u r a t e d three times with petroleum ether. The organic solutions were combined, f i l t e r e d and concentrated. D i s t i l l a t i o n ( a i r - b a t h temperature 105-110°C/0.02 to r r ) of the remaining o i l y i e l d e d 2.5 g (77%) of 2-iodo-l-benzyloxymethoxyethane (246). The iodide 246 exhibited i r ( f i l m ) : 3095, 3064, 3030, 1497, 1455, 1152, 1114, 1066, 1027 cm"1; XH nmr (270 MHz) 8 7.35-7.20 (m, 5H, aromatic protons), 4.78 (s, 2H, benzyl protons), 4.63 (s, 2H, ace t a l protons), 3.83 ( t , 2H, J = 6 Hz, -CH 20-), 3.26 ( t , 2H, J = 6 Hz, -CH 2I). Exact Mass calcd. for C 1 0 H 1 3 I O 2 : 291.9959; found: 291.9966. Preparation of the phosphonate 248 0 To a s t i r r e d suspension of sodium hydride (35 mg, 1.46 mmol; washed with d i e t h y l ether and dried) i n dimethylformamide (4.4 mL) was added methyl bis(2,2,2-trifluoroethyl)phosphonoacetate (0.42 g, 1.32 mmol) and - 211 -the mixture was s t i r r e d at room temperature for 15 min. Then 18-crown-6 (25 mg, 95 j*mol) and 2-iodo-l-benzyloxymethoxyethane (246) (0.28 g, 0.98 mmol) were added. A f t e r the reac t i o n mixture had been heated at 60°C fo r 4 h, i t was d i l u t e d with anhydrous ether and f i l t e r e d through a small pad of F l o r i s i l . The f i l t r a t e was concentrated under reduced pressure (16 t o r r , then 0.02 t o r r ) . The residue was subjected to f l a s h column chromatography on s i l i c a gel (160 g, e l u t i o n with petroleum ether-ether, 4:6 v/v). C o l l e c t i o n and concentration of the appropriate f r a c t i o n s provided 0.45 g (70%) of the phosphonate 248 which exhibited i r ( f i l m ) : 1743, 1499, 1299, 1264, 1174, 1068, 964 cm - 1; XH nmr (400 MHz) 6: 7.34 (m, 5H, aromatic protons), 4.71, 4.70 (d, d, 1H each, J = 7 Hz, benzyl protons), 4.58, 4.57 (d, d, 1H, each, J = 11.5 Hz, acetal protons), 4.40 (ra, 4H, CF 3CH 20-), 3.75 (s, 3H, -OCH3), 3.64 (m, 2H, -CH 2CH 20-), 3.39 (ddd, 1H, J = 4, 10, 22 Hz, -PCH-), 2.25 (m, 2H, PCHCH2-). Exact Mass calcd. for C 1 0 H 1 4 F 6 0 6 P (M +-0CH 2^): 375.0432; found: 375.0425. Preparation of the phosphonate 261 A mixture of the commercially a v a i l a b l e a-bromo -7-butyrolactone (7 . 4 g, 45 mmol) and p u r i f i e d trimethylphosphite (8.3 g, 67 mmol) was heated - 212 -at 150°C for 8 h. Excess trimethylphosphite was removed under reduced pressure (0.02 t o r r ) and the crude product was obtained v i a a short path d i s t i l l a t i o n (air-bath temperature 120-160°C/0.02 to r r ) of the r e s i d u a l material. The crude product was subjected to f l a s h column chromatogra-phy on s i l i c a gel (150 g, e l u t i o n with ether-acetone, 7:3, v/v). The appropriate f r a c t i o n s were c o l l e c t e d and concentrated. D i s t i l l a t i o n ( a i r - b a t h temperature 120-130°C/0.02 to r r ) of the remaining o i l y i e l d e d 2.6 g (30%) of the phosphonate 261 which exhibited i r ( f i l m ) : 1772, 1236, 1034 cm"1; lti nmr (270 MHz) 6: 4.30 (m, 2H, -CH 20-), 3.77, 3.73 (d, d, 3H each, J = 10 Hz, -P(0CH 3) 2), 3.03 (td, 1H, J = 8, 24 Hz, -PCH-), 2.50 (m, 2H, -CH 2CH 20-). Exact Mass calcd. f o r C 6H 1 10 5P: 194.0344; found: 194.0352. General procedure A: reaction of the phosphonate s a l t s 248a and 261a  with aldehydes To a col d (0 CC) s t i r r e d s o l u t i o n of the required phosphonate 248 or 261 (0.57 mmol) i n THF (10 mL) was added a s o l u t i o n of potassium b i s ( t r i m e t h y l s i l y l ) a m i d e (0.63 mmol) i n toluene and 18-crown-6 .nC^CN complex (0.85 g). A f t e r the s o l u t i o n had been s t i r r e d f o r 15 min, i t 248a 261a - 213 -was cooled to -78°C and the required aldehyde (0.45 mmol) was added. S t i r r i n g was continued at -78°C for 4 h. The re s u l t a n t s o l u t i o n was treated with brine and then was extracted three times with ether. The combined extract was washed twice with brine, d r i e d (MgS04) and concentrated. The residue was subjected to column chromatography on s i l i c a gel (2 g, e l u t i o n with e i t h e r petroleum ether-ether, 8:2 v/v or benzene-ether, 30:1 v/v). C o l l e c t i o n and concentration of the appropri-ate f r a c t i o n s y i e l d e d pure sample(s) of the o l e f i n a t i o n product(s). General procedure B: reaction of the phosphonate s a l t 261b with  aldehyde ( M e 0 ) 2 P ~a^ - o N„e To a suspension of sodium hydride (14 mg, 0.58 mmol; washed with ether and d r i e d under a stream of argon) i n benzene (2.7 mL) at room temperature was added the phosphonate 261 (0.1 g, 0.53 mmol) and the s o l u t i o n was s t i r r e d at 50°C f o r 30 min. The appropriate aldehyde (0.42 mmol) was added and the s o l u t i o n was s t i r r e d at room temperature f o r 15 h. The r e a c t i o n mixture was d i l u t e d with petroleum ether, washed three times with brine, and was drie d (MgSO^ and concentrated. The residue was subjected to column chromatography on s i l i c a gel (2 g, e l u t i o n with - 214 -e i t h e r petroleum ether-ether, 8:2, v/v or benzene-ether, 30:1 v/v). C o l l e c t i o n and concentration of the appropriate f r a c t i o n s y i e l d e d pure sample(s) of o l e f i n a t i o n product(s). Preparation of the Z and E esters 249 and 250 Following the general procedure A, rea c t i o n of the potassium s a l t of the phosphonate 248 with isovaleraldehyde afforded a 3:1 mixture of the Z ester 249 and the E ester 250, re s p e c t i v e l y . The following amounts of reagents were used: the phosphonate 248 (0.58 mmol) i n THF (10 mL); potassium b i s ( t r i m e t h y l s i l y l ) a m i d e (0.64 mmol); 18-crown-6 .nC^CN complex (0.74 g); isovaleraldehyde (49 pL, 0.46 mmol). Workup, followed by column chromatography of the crude product on s i l i c a gel (2 g, e l u t i o n with petroleum ether-ether, 8:2 v/v) and c o l l e c t i o n , concentra-t i o n of the appropriate f r a c t i o n s afforded 122 mg (87%) of a c o l o r l e s s o i l . Both glc analysis and -^H nmr spectroscopy showed that t h i s material consisted of a mixture of the Z ester 249 and the E ester 250 i n a r a t i o of 3:1. Further column chromatography on s i l i c a gel (4 g, 230-400 mesh, e l u t i o n with petroleum ether-ether, 9:1 v/v) provided pure samples of each isomers. - 215 -The less polar Z ester 249 exhibited i r ( f i l m ) : 1719, 1644, 1498 cm"1; --H nmr (300 MHz) 6: 7.35 (m, 5H, aromatic protons), 6.01 ( t , 1H, J = 7 Hz, o l e f i n i c proton), 4.73 (s, 2H, benzylic protons), 4.58 (s, 2H, acet a l protons), 3.72 (s, 3H, methoxy protons), 3.68 ( t , 2H, J = 7 Hz, - C H 2 C H 2 O - ) , 2.57 ( t , 2H, J = 7 Hz, collapsed to s on i r r a d i a t i o n at 6 3.68, -CH 2CH 20-). 2.35 ( t , 2H, J = 7 Hz, Me2CHCH2C=), 1.69 (ra, 1H, isopropyl proton), 0.92 (d, 6H, J = 7 Hz, methyl protons). Exact Mass cal c d . f o r C 1 8 H 2 6 0 4 : 306.1831; found: 306.1826. The more polar E ester 250 exhibited i r ( f i l m ) : 1713, 1646, 1498 cm"1; '-H nmr (300 MHz) S: 7.35 (m, 5H, aromatic protons), 6.90 ( t , 1H, J = 7 Hz, o l e f i n i c proton), 4.75 (s, 2H, benzylic protons), 4.58 (s, 2H, ac e t a l protons), 3.73 (s, 3H, methoxy protons), 3.62 ( t , 2H, J = 7 Hz, -CH 2CH 20-). 2.64 ( t , 2H, J = 7 Hz, collapsed to a s i n g l e t on i r r a d i a t i o n at 6 3.62, -CH 2CH 20-), 2.12 ( t , 2H, J = 7 Hz, Me2CHCH2C=), 1.75 (m, 1H, isopropyl proton), 0.93 (d, 6H, J •= 7 Hz, methyl protons). Exact Mass calcd. f o r C 1 8 H 2 6 0 4 : 306.1831; found: 306.1835. Preparation of the Z and E lactones 263 and 264 263 - 216 -Procedure I Following the general procedure B, rea c t i o n of the sodium s a l t of the phosphonate 261 with isovaleraldehyde afforded, by glc analysis and •'•H nmr spectroscopy of the crude product, a 2:1 mixture of the Z lactone 263 and the E lactone 264, re s p e c t i v e l y . The following amounts of reagents were used: the phosphonate 261 (0.1 g, 0.53 mmol) i n benzene (2.7 mL); sodium hydride (14 mg, 0.58 mmol); isovaleraldehyde (45 /zL, 0.42 mmol). Workup followed by column chromatography of the crude product on s i l i c a gel (2 g, e l u t i o n with petroleum ether-ether, 8:2 v/v), and c o l l e c t i o n and concentration of the appropriate f r a c t i o n s afforded 30 mg (46%) of the Z lactone 263 and 15 mg (23%) of the E lactone 264. Procedure II To a c o l d (0°C) s o l u t i o n of the phosphonate 261 (0.11 g, 0.57 mmol) i n THF (3.8 mL) was added s o l i d potassium tert-butoxide (57 mg, 0.51 mmol) and the mixture was s t i r r e d at room temperature f o r 1 h. The re s u l t a n t s o l u t i o n was cooled to -78°C and isovaleraldehyde (30 /*L, 0.28 mmol) was added and s t i r r i n g was continued at -78°C for 4 h. The re a c t i o n mixture was d i l u t e d with petroleum ether, washed three times with brine, d r i e d (MgS04) and concentrated. Glc analysis of the residue showed that i t consisted of a mixture of the Z lactone 263 and the E lactone 264 i n a r a t i o of 73:27. This material was subjected to column chromatography on s i l i c a gel (2 g, e l u t i o n with petroleum ether-ether, - 217 8:2 v/v). C o l l e c t i o n and concentration of the appropriate f r a c t i o n s afforded 26 mg (61%) of the Z lactone 263 and 8.6 mg (20%) of the E lactone 264. Procedure I II To a c o l d (0°C) s o l u t i o n of the phosphonate 261 (0.11 g, 0.57 mmol) i n THF (3.3 mL) was added s o l i d potassium tert-butoxide (57 mg, 0.51 mmol) and the mixture was s t i r r e d at room temperature f o r 1 h. HMPA (0.6 mL) was added and the resultant s o l u t i o n was cooled to -78°C. Isovaleraldehyde (30 ul, 0.28 mmol) was added and the r e a c t i o n mixture was s t i r r e d at -78°C for 4 h, and then was d i l u t e d with petroleum ether. The r e s u l t a n t mixture was washed once with brine, three times with aqueous copper(II) s u l f a t e , and twice with brine and then was d r i e d (MgS0 4) and concentrated. Glc analysis of the residue showed that i t consisted of a 77:23 mixture of the Z lactone 263 and the E lactone 264, re s p e c t i v e l y . This material was subjected to column chromatography on s i l i c a g el (2 g, e l u t i o n with petroleum ether-ether, 8:2 v/v). C o l l e c -t i o n and concentration of the appropriate f r a c t i o n s afforded 27 mg (62%) of the Z lactone 263 and 7.7 mg (18%) of the E lactone 264. Procedure IV Following the general procedure A, rea c t i o n of the potassium s a l t of the phosphonate 261 with isovaleraldehyde afforded p r a c t i c a l l y pure Z lactone 263. The following amounts of reagents were used: the phospho-- 218 -nate 261 (0.57 mmol) i n THF (10 mL); potassium b i s ( t r i m e t h y l s i l y l ) a m i d e (0.62 mmol); 18-crown-6-nCH3CN complex (0.85 g); isovaleraldehyde (49 fih, 0.45 mmol). Glc analysis of the crude product a f t e r workup showed only the Z lactone 263. The crude product was then passed through a short pad of s i l i c a gel (1 g, e l u t i o n with petroleum ether-ether, 8:2 v/v). Concentration of the eluant afforded 60 mg (86%) of the Z lactone 263. The less polar Z lactone 263 exhibited i r ( f i l m ) : 1752, 1670 cm"1; '-H nmr (270 MHz) 8: 6.27 ( t t , 1H, J = 4.5 Hz, o l e f i n i c proton), 4.29 (t, 2H, J = 7 Hz, -CH 20-), 2.90 (br t, 2H, J = 7 Hz, -CH 2CH 20-), 2.60 (br t, 2H, J = 7 Hz, -CH2C=), 1.71 (quintet, 1H, J = 7 Hz, Me2CH-), 0.95 (d, 6H, J •= 7 Hz, methyl protons). Exact Mass calcd. f o r CgH]_402: 154.0994; found: 154.0995. The more polar E lactone 264 exhibited i r ( f i l m ) : 1757, 1681 cm"1; 1H nmr (270 MHz) 6: 6.78 ( t t , 1H, J = 3, 7 Hz, o l e f i n i c proton), 4.36 ( t , 2H, J = 7 Hz, -CH 20-), 2.85 (br t, 2H, J = 7 Hz, -CH 2CH 20-), 2.09 (br t, 2H, J = 7 Hz, -CH2C=), 1.71 (quintet, 1H, J - 7 Hz, Me2CH-), 0.95 (d, 6H, J = 7 Hz, methyl protons). Exact Mass calcd. f o r CgH^O;^: 154.0994; found: 154.0993. - 219 -P r e p a r a t i o n o f t h e Z and E l a c t o n e s 265a and 266a 0 O 265a 266a P r o c e d u r e I F o l l o w i n g t h e g e n e r a l p r o c e d u r e A, r e a c t i o n o f t h e p o t a s s i u m s a l t o f th e p h o sphonate 261 w i t h n - h e p t a n a l a f f o r d e d p r a c t i c a l l y p u r e Z l a c t o n e 265a. The f o l l o w i n g amounts o f r e a g e n t s were use d : t h e phosphonate 261 (0.57 mmol) i n THF (10 mL); p o t a s s i u m b i s ( t r i m e t h y l s i l y l ) a m i d e (0.62 mmol); 18-crown-6-nC^CN complex (0.85 g) ; n - h e p t a n a l (61 uL, 0.45 mmol). G l c a n a l y s i s o f t h e cr u d e p r o d u c t a f t e r workup showed o n l y t h e Z l a c t o n e 265a. The cru d e p r o d u c t was p a s s e d t h r o u g h a s h o r t pad o f s i l i c a g e l (1 g, e l u t i o n w i t h p e t r o l e u m e t h e r - e t h e r , 8:2 v / v ) . Concen-t r a t i o n o f t h e e l u a n t a f f o r d e d 78 mg (94%) o f t h e Z l a c t o n e 265a. P r o c e d u r e I I F o l l o w i n g t h e g e n e r a l p r o c e d u r e B, r e a c t i o n o f t h e sodium s a l t o f the phosphonate 261 w i t h n - h e p t a n a l a f f o r d e d , by g l c a n a l y s i s o f t h e cr u d e p r o d u c t , a 1:1 m i x t u r e o f t h e Z l a c t o n e 265a and E l a c t o n e 266a. The f o l l o w i n g amounts o f r e a g e n t s were use d : t h e phosphonate 261 (0.1 g, 0.53 mmol) i n benzene (2.7 mL); sodium h y d r i d e (14 mg, 0.58 mmol); - 220 -n-heptanal (57 (ML, 0.42 mmol). Workup, followed by column chromatogra-phy of the crude product (2 g, e l u t i o n with petroleum ether-ether, 8:2 v / v ) • gave, a f t e r c o l l e c t i o n and concentration of the appropriate f r a c t i o n s , 30 mg (39%) of the Z lactone 265a and 289 mg (36%) of the E lactone 266a. The l e s s pol ar Z lactone 265a exhibited i r ( f i l m ) : 1757, 1672 cm" , --H nmr (300 MHz) 6: 6.24 ( t t , 1H, J = 2.5, 7 Hz, o l e f i n i c proton), 4.30 (t , 2H, J = 7 Hz, -CH 20-), 2.90 (br t, 2H, J = 7 Hz, -CH 2CH 20-), 2.70 (br q, 2H, J - 7 Hz, -CH2C=), 1.50-1.20 (m, 8H), 0.90 ( t , 3H, J = 6 Hz, methyl protons). Exact Mass calcd. f o r c l l H l 8 0 2 • 182.1307; found: 182.1308. The more polar E lactone 266a exhibited i r ( f i l m ) : 1757, 1681 cm"1; 1H nmr (300 MHz) 6: 6.76 ( t t , 1H, J = 2.5, 7 Hz, o l e f i n i c proton), 4.38 (t , 2H, J = 7 Hz, -CH 20-), 2.88 (br t, 2H, J = 7 Hz, -CH 2CH 20-), 2.20 (br q, 2H, J - 7 Hz, -CH2C=), 1.70-1.20 (m, 8H), 0.90 ( t , 3H, J - 6 Hz, methyl protons). Exact Mass calcd. f o r C^H^sO^ 182.1307; found: 182.1307. Preparation of the Z and E lactones 265b and 266b 0 2 6 5 b 266b - 221 -Following the general procedure A, rea c t i o n of the potassium s a l t of the phosphonate 261 with cyclohexanecarboxaldehyde afforded, by glc analysis and nmr spectroscopy of the crude product, a 5:1 mixture of the Z lactone 265b and the E lactone 266b, r e s p e c t i v e l y . The following amounts of reagents were used: the phosphonate (261) (0.11 g, 0.57 mmol) i n THF (10 mL); potassium b i s ( t r i m e t h y l s i l y l ) a m i d e (0.62 mmol), 18-crown-6-nCl^CN complex (0.85 g) ; eye lohexanecarboxyal deny de (56 u~L, 0.45 mmol). A f t e r workup, the crude product was subjected to column chromatography on s i l i c a gel (2 g, e l u t i o n with petroleum ether-ether, 8:2 v/v). Concentration of the appropriate f r a c t i o n s afforded 45 mg (56%) of the Z lactone 265b and 10 mg (12%) of the E lactone 266b. The l e s s polar Z lactone 265b exhibited i r ( f i l m ) : 1756, 1669 cm"1; 1H nmr (270 MHz) 8: 6.03 (td, 1H, J = 2.5, 10 Hz, o l e f i n i c proton), 4.29 ( t , 2H, J - 8 Hz, -CH 20-), 3.45 (br m, 1H, a l l y l i c proton), 2.87 (dt, 2H, J = 2.5, 8 Hz, -CH 2CH 20-), 1.9-0.9 (m, 10H). Exact Mass calcd. for C 1 1 H 1 6 0 2 : 180.1150; found: 180.1150. The le s s polar E lactone 266b exhibited i r ( f i l m ) : 1757, 1678 cm"1; XH nmr (270 MHz) 8: 6.54 (td, 1H, J - 3, 10 Hz, o l e f i n i c proton), 4.29 (t, 2H, J •= 7 Hz, -CH 20-), 2.80 (dt, 2H, J = 3, 7 Hz, -CH 2CH 20-), 2.11 (br m, 1H, a l l y l i c proton), 1.9-0.9 (m, 10H). Exact Mass calcd. f o r C 1 1 H 1 6 0 2 : 180.1150; found: 180.1150. - 222 -Preparation of the Z and E lactones 265c and 266c H C H B ft Hg p 265c Procedure I Following the general procedure A, r e a c t i o n of the potassium s a l t of the phosphonate 261 with (E)-2-hexenal afforded, by glc analysis of the crude product, a 97:3 mixture of the Z lactone 265c and the E lactone 266c, r e s p e c t i v e l y . The following amounts of reagents were used: the phosphonate 261 (0.11 g, 0.57 mmol) i n THF (10 mL); potassium b i s ( t r i -t r i m e t h y l s i l y l ) a m i d e (0.62 mmol); 18-crown-6-nCH3CN complex (0.85 g); (E)-2-hexanal (52 pL, 0.45 mmol). A f t e r workup, the crude product was subjected to column chromatography on s i l i c a gel (2 g, e l u t i o n with petroleum ether-ether 8:2 v/v). Concentration of the appropriate f r a c t i o n s afforded 52 mg (78%) of the Z lactone 265c. Procedure II Following the general procedure B, re a c t i o n of the sodium s a l t of the phosphonate 261 with (E)-2-hexenal afforded, by glc analysis of the crude product, a 1:3 mixture of the Z lactone 265c and the E lactone 266c. The following amounts of reagents were used: the phosphonate 261 - 223 -(0.1 g, 0.53 mmol) i n benzene (2.7 mL); sodium hydride (14 mg, 0.58 mmol); (E)-2-hexenal (49 LIL, 0.42 mmol). Workup, followed by column chromato-graphy of the crude product on s i l i c a gel (2 g, e l u t i o n with petroleum ether-ether, 8:2 v/v), gave, a f t e r c o l l e c t i o n and concentra-t i o n of the appropriate f r a c t i o n s , 15 mg (21%) of the Z lactone 265c and 42 mg (60%) of the E lactone 266c. The le s s pol ar Z lactone 265c exhibited i r ( f i l m ) : 1747, 1647 cm ; XH nmr (270 MHz) 5: 7.42 (dd, 1H, J = 10, 16 Hz, H A), 6.57 (td, 1H, J = 2, 10 Hz, Hg), 6.00 (td, 1H, J = 7, 16 Hz, H c), 4.33 ( t , 2H, J = 7 Hz, -CH 2CH 20-), 2.95 ( t , 2H, J = 7 Hz, -CH 2CH 20-), 2.18 (q, 2H, J = 7 Hz, a l l y l i c protons), 1.47 (m, 2H, J = 7 Hz, CH 3CH 2CH 2-), 0.93 ( t , 3H, J = 7 Hz, CH 3-). Exact Mass calcd. f o r C 1 0 H 1 4 ° 2 : 166.0994; found: 166.0994. The more polar E lactone 266c exhibited i r ( f i l m ) : 1751, 1652 cm"1; % nmr (270 MHz) 5: 7.09 (td, 1H, J = 2.5, 10 Hz, Hg), 6.3-6.0 (m, 2H, H A and H c), 4.39 ( t , 2H, J = 7 Hz, -CH 2CH 20-), 2.96 (dt, 2H, J = 2.5, 7 Hz, -CH 2CH 20-), 2.19 (q, 2H, J = 7 Hz, a l l y l i c protons), 1.48 (m, 2H, J = 7 Hz, CH 3CH 2CH 2-), 0.93 ( t , 3H, J = 7 Hz, CH 3-). Exact Mass calcd. fo r C 1 0H 140 2: 166.0994; found: 166.0992. - 224 -Preparation of the Z and E lactones 265d and 266d 0 o 26 5d o 266d Following the general procedure A, reaction of the potassium s a l t of the phosphonate 261 with benzaldehyde afforded by g l c analysis and -^H nmr spectroscopy of the crude product, a 1:1 mixture of the Z lactone 265d and the E lactone 266d. The following amounts of reagents were used: the phosphonate 261 (0.11 g, 0.57 mmol) i n THF (10 mL); potassium b i s ( t r i - m e t h y l s i l y l ) a m i d e (0.62 mmol); 18-crown-6-nC^CN complex (0.85 g); benzaldehyde (46 juL, 0.45 mmol). A f t e r workup, the crude product was subjected to column chromatography on s i l i c a gel (2 g, 230-400 mesh, e l u t i o n with benzene-ether, 30:1 v/v). Concentration of the appropriate f r a c t i o n s afforded 38 mg (48%) of the Z lactone 265d and 34 mg (43%) of the E lactone 266d. The le s s polar Z lactone 265d exhibited i r ( f i l m ) : 1747, 1641 cm"1; XH nmr (300 MHz) 6: 7.82 (dd, 2H, J = 2, 7.5 Hz, H A), 7.42-7.32 (m, 3H, aromatic protons), 7.02 (t, 1H, J = 2.5 Hz, o l e f i n i c proton), 4.41 (t, 2H, J - 7 Hz, -CH 2CH 20-), 3.15 (dt, 2H, J = 2.5, 7 Hz, -CH 2CH 20-). Exact Mass calcd. f o r C 1 1 H 1 0 ° 2 : 174.0681; found: 174.0683. The more polar E lactone 266d exhibited i r ( f i l m ) : 1742, 1651 cm"1; LE nmr (300 MHz) 5: 7.58 ( t , 1H, J = 3 Hz, o l e f i n i c proton), 7.54-7.38 (m, 5H, aromatic protons), 4.48 ( t , 2H, J - 7 Hz, -CH 2CH 20-), 3.26 (dt, - 225 -2H, J - 3, 7 Hz, -CH 2CH 20-)- Exact Mass calcd. f or CnU1Q02: 174.0681; found: 174.0680. Preparation of 2-iodo-l-methoxymethoxyethane (240) To a c o l d (-20°C) s o l u t i o n of 2-chloroethanol (7.35 mL, 0.113 mol) and diisopropyethylamine (31.4 mL, 0.18 mol) i n dichloromethane (250 mL) was added chloromethyl methyl ether (12.8 mL, 0.168 mol). A f t e r the s o l u t i o n had been s t i r r e d at room temperature for 12 h, i t was d i l u t e d with dichloromethane washed three times with IN hydrochloric acid, once with saturated aqueous sodium bicarbonate, twice with brine, and then was d r i e d (MgS0 4). The s o l u t i o n was concentrated under atmospheric pressure v i a a Vigreux column (10 cm). D i s t i l l a t i o n (bp 50-54°C/15 t o r r ) of the remaining o i l afforded 11.2 g (80%) of 2-chloro-l-methoxymethoxyethane. A s o l u t i o n of 2-chloro-1-methoxymethoxyethane (4.0 g, 32 mmol) and sodium iodide (20 g, 0.13 mol) i n acetone (64 mL) was s t i r r e d at 60°C f o r 30 h with pr o t e c t i o n from l i g h t . The s o l u t i o n was d i l u t e d with pentane and f i l t e r e d . The f i l t r a t e was concentrated under atmospheric pressure v i a a Vigreux column (10 cm). D i s t i l l a t i o n (bp 58-60°C/15 to r r ) of the remaining o i l y i e l d e d 3.5 g (50%) of the iodide 240 as a - 226 -c o l o r l e s s o i l which was stored over copper dust under argon i n a free z e r . This material was homogeneous by glc analysis and exhibited i r ( f i l m ) : 1144, 1115, 1065, 1030 cm - 1; '-H nmr (270 MHz) 6: 4.68 (s, 2H, ac e t a l protons), 3.82 ( t , 2H, J = 6 Hz, -OCH2CH2-), 3.40 (s, 3H, -0CH 3), 3.30 ( t , 2H, J = 6 Hz, -CH 2I). Exact Mass calcd. for C 4H 9I0 2: 215.9646; found: 215.9649. Preparation of the n i t r i l e 241 To a c o l d (-78°C) s o l u t i o n of diisopropylamine (0.83 mL, 5.9 mmol) i n THF (40 mL) was added n-butyllithium (5.7 mmol) as a s o l u t i o n i n hexanes and the s o l u t i o n was s t i r r e d at 0°C f o r 15 min. HMPA (1.37 mL, 7.9 mmol) and a s o l u t i o n of a mixture of the n i t r i l e s 112a and 112b (0.89 g, 3.9 mmol; 15:85, respectively) i n THF were added and the s o l u t i o n was s t i r r e d at 0°C f o r 15 min. To the r e s u l t i n g yellow s o l u t i o n was added the iodide 240 (1.15 g, 5.5 mmol) and the s o l u t i o n was s t i r r e d at 0°C for 30 min and at room temperature f o r 1 h. The s o l u t i o n was d i l u t e d with petroleum ether, washed once with IN hydro-c h l o r i c acid, twice with aqueous copper s u l f a t e and twice with brine and then was dr i e d (MgS0 4), and f i l t e r e d through a small pad of F l o r i s i l . CN 0 \ / 0 \ H A " ' - 227 The f i l t r a t e was concentrated under reduced pressure (16 t o r r , then 0.02 to r r ) to a f f o r d 1.12 g (99%) of the desired n i t r i l e 241. This material was homogeneous by glc analysis and exhibited i r ( f i l m ) : 3086, 2228, 1638, 1153, 1110, 1070, 1041, 895 cm"1; '-H nmr (400 MHz) 5: 4.59 (br s, 1H, o l e f i n i c proton), 4.57 (s, 2H, ace t a l protons), 4.55 (br s, 1H, o l e f i n i c proton), 3.50 (m, 2H, -CH 2CH 20-), 3.34 (s, 3H, -0CH 3), 2.40 (br dt, 1H, J - 5.5, 13.5 Hz, H A), 2.15, 2.09 (br td, br td, 1H each, J - 7, 15 Hz, -CH 2CH 20-), 2.13-1.10 (m, 11H), 1.27 (s, 3H, angular methyl protons), 1.15 (d, 3H, J = 6 Hz, methyl protons). Exact Mass calcd. f o r C 1 8H 2 9N0 2: 291.2198; found: 291.2205. Preparation of the aldehyde 273 To a s o l u t i o n of the n i t r i l e 241 (1.12 g, 3.86 mmol) i n dimethoxy-ethane (40 mL) was added diisobutylaluminum hydride (15.4 mmol) as a s o l u t i o n i n hexanes and the s o l u t i o n was warmed at 60°C f o r 6 h. The re a c t i o n mixture was cautiously poured into water under a blanket of argon, and the res u l t a n t mixture was n e u t r a l i z e d with IN hydrochloric ac i d , and then was extracted three times with ether. The extracts were combined, washed with brine, dri e d (Na 2S0 4) and concentrated. The - 228 -r e s i d u a l o i l was dissolved i n a mixture of THF-acetic acid-water (100 mL, 1:1:0.16 by volume) and the s o l u t i o n was s t i r r e d at room temperature fo r 12 h. A f t e r removal of the solvent under reduced pressure (0.02 t o r r ) , the residue was dissolved i n ether and the res u l t a n t s o l u t i o n was washed with aqueous sodium bicarbonate and brine, and then was drie d (MgS04) and concentrated to a f f o r d 1.04 g (92%) of the aldehyde 273 which exhibited i r ( f i l m ) : 3086, 2767, 2737, 1713, 1637, 1153, 1109, 1044, 893 cm - 1; 1H nmr (400 MHz) 6: 9.97 (s, 1H, aldehyde proton), 4.56 (s, 2H, acet a l protons), 4.55 (br s, 2H, o l e f i n i c protons), 3.46 (m, 2H, -CH 2CH 20-), 3.32 (s, 3H, -0CH 3), 2.30-1.1 (m, 14H), 1.04 (d, 3H, J = 7 Hz, methyl protons), 0.99 (s, 3H, angular methyl protons). Exact Mass. calcd. f o r C 1 8 H 3 0 0 3 : 294.2195; found: 294.2200. Preparation of the alcohol 274 To a solution-suspension of l i t h i u m aluminum hydride (0.26 g, 6.8 mmol) i n ether (40 mL) was added an ethereal s o l u t i o n of the aldehyde 273 (1.04 g, 3.54 mmol) and the mixture was s t i r r e d at room temperature f o r 1 h. Sodium s u l f a t e decahydrate was added i n small portions to the s t i r r e d mixture u n t i l evolution of gas ceased. The mixture was f i l t e r e d H B ' - 229 -and the c o l l e c t e d material was washed three times with ether. The combined f i l t r a t e was concentrated to a f f o r d 1.0 g (95%) of the alcohol 274 which exhibited i r ( f i l m ) : 3443 (br) , 3085, 2775, 1635, 1152, 1108, 1039, 892 cm"1; 1H nmr (400 MHz) 8: 4.59 (s, 2H, ace t a l protons), 4.50 (br s, 2H, o l e f i n i c protons), 3.77, 3.68 (d, d, 1H each, J = 11 Hz, -CH20H), 3.50 (m, 2H, -CH 2CH 20-), 3.34 (s, 3H, -0CH 3), 2.27 (br dt, 1H, J = 5, 13.5 Hz, on i r r a d i a t i o n at 8 4.50, sharpened to a d of t, J = 5, 13.5 Hz, H A), 2.10 (br d, 1H, J - 12 Hz, Hg), 1.95-1.00 (m, 13H), 1.05 (s, 3H, angular methyl protons), 0.99 (d, 3H, J = 6 Hz, methyl protons). Exact Mass calcd. f o r C 1 8 H 3 2 0 3 : 296.2351; found: 296.2355. Preparation of the phosphorodiamidate 275 0 \ / 0 \ To a s o l u t i o n of the alcohol 274 (0.31 g, 1 mmol) i n a mixture of dimethoxyethane (4 mL) and N,N,N',N'-tetramethylethylenediamine (1 mL) at 0°C was adeed n-butyllithium (1.26 mmol) as a s o l u t i o n i n hexanes. A f t e r the mixture had been s t i r r e d f o r 15 min, dimethylaminophosphorodi-c h l o r i d a t e (0.4 mL, 3.2 mmol) was added and the re a c t i o n mixture was s t i r r e d at room temperature f o r 12 h. The reac t i o n mixture was cooled to 0°C, anhydrous dimethylamine (5 mL) was added, and s t i r r i n g was - 230 -continued at 0°C for 2 h. The s o l u t i o n was d i l u t e d with ether, washed with water, twice with brine, d r i e d (MgS04) and concentrated. The residue was subjected to f l a s h column chromatography on s i l i c a gel (30 g, e l u t i o n with ether-acetone, 10:1 v/v). The appropriate f r a c t i o n s were combined and concentrated under reduced pressure (16 t o r r , then 0.02 to r r ) to y i e l d 0.27 g (63%) of the phosphorodimmidate 275 as a c o l o r l e s s viscous o i l which exhibited i r ( f i l m ) : 3085, 1635, 1213, 895 cm"1; -^H nmr (400 MHz) 5: 4.58 (s, 2H, acetal protons), 4.51 (br s, 2H, o l e f i n i c protons), 4.00, 3.94 (dd, dd, 1H each, J = 4, 11 Hz, -CH 20P), 3.53, 3.45 (td, td, 1H each, J = 8, 10 Hz, -CH 2CH 20-). 3.33 (3H, s, -0CH 3), 2.67, 2.65 (d, d, 6H each, J - 6 Hz, -PNMe2), 2.27 (br dt, 1H, J =5, 14 Hz, H A), 2.11 (br d, 1H, J = 14 Hz, H f i), 1.93 ( t , 2H, J = 8 Hz, -CH 2CH 20-), 2.04-1.40 (m, 10H), 1.06 (s, 3H, angular methyl protons), 0.99 (d, 3H, J = 6 Hz, methyl protons). Exact Mass calcd. f o r C 2 2H 4 3N 20 4P: 430.2960; found: 430.2966. Preparation of the ether 276 0 \ / 0 x H B ; L i q u i d methylamine (10 mL) was condensed into a cold (-78°C) f l a s k containing l i t h i u m metal (12 mg, 1.7 mmol) and the mixture was s t i r r e d 231 -at -30°C f o r 30 min. To the res u l t a n t dark blue s o l u t i o n was added an ethereal s o l u t i o n of the phosphorodiamidate 275 (0.13 g, 0.3 mmol) and the mixture was s t i r r e d at -20CC for exactly 10 min. The reac t i o n mixture was cautiously but quickly treated with aqueous ammonium ch l o r i d e and the resultant mixture was extracted three times with ether. The ethereal extracts were combined, washed with brine, d r i e d (MgS04) and concentrated. The residue was subjected to column chromatography on s i l i c a g el (4 g, e l u t i o n with petroleum ether-ether, 100:8 v/v). C o l l e c t i o n and concentration of the appropriate f r a c t i o n s afforded 67 mg (80%) of the ether 276 as a c o l o r l e s s o i l which exhibited i r ( f i l m ) : 3085, 1636, 1149, 1109, 1078, 1040, 891 cm"1; *H nmr (400 MHz) 8: 4.57 (s, 2H, a c e t a l protons), 4.49 (br s, 2H, o l e f i n i c protons), 3.47, 3.38 (dt, dt, 1H each, J = 6, 10 Hz, -CH 2CH 20-), 3.34 (s, 3H, -OCH3), 2.29 (br t d t , 1H, J = 1.3, 5, 13.5 Hz, H A), 2.10 (br dd, 1H, J = 4, 13.5 Hz, Hg), 1.88 (br d, 1H, J - 12 Hz, H c), 1.72-1.20 (m, 11H), 1.04 (s, 3H, angular methyl protons), 0.85 (d, 3H, J = 6 Hz, methyl protons), 0.75 (s, 3H, methyl protons). I r r a d i a t i o n at 8 4.49 ( o l e f i n i c protons) caused the s i g n a l at 8 2.34-2.25 to sharpen to a d of t (J •= 5, 13.5 Hz); i r r a d i a t i o n at 6 2.29 (H A) caused the s i g n a l at 8 2.14-2.06 to collapse to a broad s i n g l e t and the s i g n a l at 8 1.93-1.83 to sharpen; i r r a d i a t i o n at 6 2.10 (Hg) caused the s i g n a l at 8 2.34-2.25 to collapse to a broad doublet (J = 13 Hz) and s i g n a l at 8 1.93-1.83 to sharpen to a q of d (J = 3, 12 Hz); i r r a d i a t i o n at 5 1.88 (H^) caused the si g n a l at 5 2.34-2.25 to collapse to a broad t r i p l e t (J •= 13 Hz) and si g n a l at 5 2.14-2.06 to sharpen to a d of d (J = 4, 13 Hz). Exact Mass calcd. f o r C 1 8 H 3 2 ° 2 : 280.2402; found: 280.2412. - 232 -Preparation of the alcohol 277 O H He-.. H B H A s o l u t i o n of the ether 276 (37 mg, 0.13 mmol) and pyridinium 2-toluenesulfonate (0.33 g, 1.3 mmol) i n t e r t - b u t y l alcohol (6 mL) was heated at 70°C f o r 12 h. A f t e r removal of solvent under reduced pressure (0.02 t o r r ) , the residue was t r i t u r a t e d three times with dry ether. The ethereal solutions were combined, f i l t e r e d , and concen-trate d . The residue was subjected to column chromatography on s i l i c a gel (4 g, e l u t i o n with petroleum ether-ether, 7:3 v/v). C o l l e c t i o n and concentration of the appropriate f r a c t i o n s afforded 25 mg (91%, based on recovery of 5 mg of s t a r t i n g material) of the alcohol 277 which exhibited i r ( f i l m ) : 3375 (br), 3085, 1636, 892 cm - 1; 1H nmr (300 MHz) 6: 4.50 (br s, 2H, o l e f i n i c protons), 3.61, 3.52 (dt, dt, lH each, J = 5.5, 10 Hz, -CH20H), 2.29 (tdt, 1H, J - 2, 5.5, 14 Hz, H A), 2.10 (tdd, 1H, J = 4.5, 4.5, 14 Hz, H f i), 1.88 (br d, 1H, J = 13 Hz, H c), 1.72-1.18 (m, 12H), 1.04 (s, 3H, angular methyl protons), 0.86 (d, 3H, J = 6 Hz, methyl protons), 0.75 (s, 3H, methyl protons). Exact Mass calcd. f o r C 1 6 H 2 8 0 : 236.2140; found: 236.2144. - 233 -P r e p a r a t i o n o f t h e a l d e h y d e 234 CHO He-. H B H To a c o l d (-78°C) s o l u t i o n o f d i m e t h y l s u l f o x i d e (5.6 mg, 71 /imol) i n d i c h l o r o m e t h a n e (0.6 mL) was added o x a l y l c h l o r i d e (9 mg, 66 /imol) and t h e m i x t u r e was s t i r r e d a t -78°C f o r 20 min. The a l c o h o l 277 (13 mg, 55 jumol) was added and the m i x t u r e was s t i r r e d a t -78°C f o r 30 min. T r i e t h y l a m i n e (35 /JL, 0.25 mmol) was added 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 s l o w l y t o room t e m p e r a t u r e and t h e n was c o n c e n t r a t e d u n d e r r e d u c e d p r e s s u r e (0.02 t o r r ) . The r e s i d u e was t r i t u r a t e d t h r e e t i m e s w i t h pentane and t h e pentane s o l u t i o n were combined, f i l t e r e d and c o n c e n t r a t e d t o a f f o r d 11 mg (85%) o f t h e a l d e h y d e 234 w h i c h e x h i b i t e d i r ( f i l m ) : 3085, 2724, 1718, 1636, 892 c m - 1 ; -^H nmr (300 MHz) 6: 9.78 ( t , 1H, J = 3.5 Hz, a l d e h y d e p r o t o n ) , 4.52 ( b r s, 2H, o l e f i n i c p r o t o n s ) , 2.41, 2.29 (dd, dd, 1H each, J = 3.5, 14.5 Hz, -CH 2CH0), 2.29 ( b r d t , 1H, J = 5, 13 Hz, H A ) , 2.11 ( b r d, 1H, J = 13 Hz, Hg), 1.89 ( b r d, 1H, J = 13 Hz, H c ) , 1.80-1.18 (m, 9H), 1.06 ( s , 3H, a n g u l a r m e t h y l p r o t o n s ) , 0.96 ( d , 3H, J - 6.6 Hz, m e t h y l p r o t o n s ) , 0.83 ( s , 3H, m e t h y l p r o t o n s ) . E x a c t Mass c a l c d . f o r C 1 6 H 2 6 0 : 234.1984; found: 234.1992. - 234 -Preparation of the Z and E lactones 279 and 280 To a c o l d (-0°C) s o l u t i o n of the phosphonate 261 (0.11 mmol) i n THF (1.9 mL) was,added potassium b i s ( t r i m e t h y l s i l y l ) a m i d e (0.12 mmol) as a s o l u t i o n i n toluene and 18-crown-6-nC^CN complex (0.16 g) . A f t e r the mixture had been s t i r r e d f o r 15 min, i t was cooled to -78°C, a THF s o l u t i o n of the aldehyde 234 (85 nmol) was added and the mixture was s t i r r e d at -78°C f o r 4 h. The res u l t a n t s o l u t i o n was treated with brine and then was extracted three times with petroleum ether. The combined extract was washed twice with brine, d r i e d (MgS04) and concentrated. Glc analysis of the crude material showed that i t consisted of two compounds i n a r a t i o of 3:1. The crude material was subjected to column chromatography on s i l i c a gel (2 g, e l u t i o n with petroleum ether-ether, 8:2 v/v). C o l l e c t i o n and concentration of the appropriate f r a c t i o n s afforded both the pure Z lactone 279, 15 mg (58%) and the pure E lactone 280, 5 mg (19%). The l e s s polar Z lactone 279 exhibited i r ( f i l m ) : 3084, 1753, 1666, 1635, 891 cm - 1; 1H nmr (400 MHz) 8: 6.24 ( t t , 1H, J - 2, 8 Hz, o l e f i n i c proton), 4.52 (br s, 2H, o l e f i n i c protons), 4.28 (br t, 2H, J = 7.5 Hz, -CH 20-), 2.91 (br t, 2H, J = 7.5 Hz, -CH 2CH 20-), 2.89, 2.65 (tdd, tdd, 1H each, J = 2.5, 8, 17 Hz, -CH2C=), 2.30 (br dt, 1H, J = 5, 13.5 Hz, - 235 -H A), 2.10 (br d, 1H, J - 13.5 Hz, Hg), 1.87 (br d, 1H, J - 12.5 Hz, H c), 1.7-1.1 (m, 9H), 1.05 (s, 3H, angular methyl protons), 0.87 (d, 3H, J = 6.5 Hz, methyl protons), 0.82 (s, 3H, methyl protons). Exact Mass calcd. f o r C20H30O2: 302.2246; found: 302.2239. The more polar E lactone 280 exhibited i r ( f i l m ) : 3084, 1758, 1676, 1635, 892 cm - 1; 1H nmr (400 MHz) 6: 6.76 ( t t , 1H, J = 2.5, 6.5 Hz, o l e f i n i c proton), 4.51 (br. s, 2H, o l e f i n i c protons), 4.36 ( t , 2H, J = 6 Hz, -CH 20-), 2.85 (br t, 2H, J = 6 Hz, -CH 2CH 20-), 2.27 (br dt, 1H, J = 5, 13 Hz, H A), 2.30-2.22, 2.18-2.10 (m, 1H each, -CH2C=), 2.11 (br d, 1H, J - 13 Hz, Hg), 1.87 (br d, 1H, J - 13 Hz, H c), 1.65-1.10 (m, 9H), 1.05 (s, 3H, angular methyl protons), 0.86 (d, 3H, J = 6.5 Hz, methyl protons), 0.82 (s, 3H, methyl protons). Exact Mass calcd. f o r C20H30O2: 302.2246; found: 302.2238. Preparation of (±)-isolinaridiol (64) and the d i o l 278 To a c o l d (-78°C) s o l u t i o n of the Z lactone 279 (15 mg, 50 umol) i n ether (1 mL) was added diisobutylaluminum hydride (0.2 mmol) as a s o l u t i o n i n hexanes. A f t e r the mixture had been s t i r r e d at -78°C f o r 1 h and at 0°C f o r 1 h, i t was treated with saturated aqueous ammonium - 236 -chl o r i d e (10 LIL) and then was d i l u t e d with ether. The mixture was s t i r r e d at room temperature for 5 min, dr i e d (MgS04) , f i l t e r e d through F l o r i s i l and concentrated to a f f o r d 14.5 mg (96%) of (±)-isolinaridiol (64) which exhibited i r ( f i l m ) : 3328 (br), 3086, 1636, 891 cm"1; 1H nmr (400 MHz) S 5.36 (br t, 1H, J - 8 Hz, o l e f i n i c proton), 4.50 (br s, 2H, o l e f i n i c protons), 4.19, 4.15 (d, d, 2H, J = 12 Hz, =CCH20H), 3.74 (br t, 2H, J = 6 Hz, -CH2CH20H), 2.39 ( t , 2H, J = 6 Hz, -CH2CH2OH), 2.30 (br dt, 1H, J - 6, 14 Hz, H A), 2.09 (m, 2H, -CH2C=), 1.9-1.0 (m, 7H), 1.78 (br s, 2H, D 20 exchanged,-OH), 1.05 (s, 3H, angular methyl protons), 0.83 (d, 3H, J = 7 Hz, methyl protons), 0.76 (s, 3H, methyl protons). The '•H nmr spectrum of t h i s material was i d e n t i c a l to that of natural i s o l i n a r i d i o l (64).* Exact Mass calcd. for C 2 0 H 3 2 0 (H +-H 20): 288.2453; found: 288.2451. S i m i l a r l y , the E lactone 280 (10 mg, 33 ^tmol) was reduced to the d i o l 278 (9 mg, 89%), which exhibited i r ( f i l m ) : 3309 (br), 3085, 1636, 891 cm - 1; 1H nmr (300 MHz) 6 5.52 (t, 1H, J = 7.5 Hz, o l e f i n i c proton), 4.51 (br s, 1H, o l e f i n i c protons), 4.05 (br s, 2H, =CCH20H), 3.71 ( t, 2H, J - 6 Hz, -CH 2CH 20-), 2.43 ( t , 2H, J - 6 Hz, -CH 2CH 20-), 2.30 (br dt, 1H, J = 5, 14 Hz, H A), 2.14-1.10 (m, 11H), 1.04 (s, 3H, angular methyl protons), 0.82 (d, 3H, J •= 6 Hz, methyl protons), 0.76 (s, 3H, methyl protons). The ^H nmr spectrum of t h i s material was very d i f f e r e n t from that of i s o l i n a r i d i o l (64). Exact Mass calcd. f o r C 2 0 H 3 2 0 (H +-H 20): 288.2453; found: 288.2448. We are g r a t e f u l to Professor A. San F e l i c i a n o f or a sample of natural i s o l i n a r i d i o l . - 237 -Preparation of the diacetate 61 and 281 OAc OAc OAc OAc HA" A s o l u t i o n of i s o l i n a r i d i o l (64) (4 mg, 13 umol), a c e t i c anhydride (5 /iL, 52 umol) and 4-N,N-dimethylaminopyridine ( c a t a l y s t ) i n pyridine (0.5 mL) was s t i r r e d at room temperature f o r 1.5 h. The resultant s o l u t i o n was d i l u t e d with e t h y l acetate and then was washed three times with brine, d r i e d (MgS04) and concentrated. The residue was subjected to column chromatography on s i l i c a gel (1 g, e l u t i o n with petroleum ether-ethyl acetate, 8:2 v/v). C o l l e c t i o n and concentration of appro-p r i a t e f r a c t i o n s afforded 4.5 mg (90%) of the diacetate (61) which exhibited i r ( f i l m ) : 3083, 1742, 1635, 1234, 892 cm'1; XH nmr (300 MHz) 6: 5.44 ( t , 1H, J = 7.5 Hz, o l e f i n i c proton), 4.61 (br s, 2H, =CCH20Ac), 4.49 (br s, 2H, o l e f i n i c protons), 4.13 (m, 2H, -CH 2CH 20Ac), 2.40 (t, 2H, J = 7 Hz, -CH 2CH 20Ac), 2.29 (br dt, 1H, J = 5, 13.5 Hz, H A), 2.16-1.96 (m, 3H) , 2.06, 2.03 (s, s, 3H each, a c e t y l protons), 1.84 (br d, 1H, J = 13.5 Hz, H c), 1.54-1.0 (m, 9H), 1.04 (s, 3H, angular methyl protons), 0.81 (d, 3H, J - 6 Hz, methyl protons), 0.75 (s, 3H, methyl protons). The ^H nmr sp e c t r a l data of t h i s material i s d i f f e r e n t from those reported by San F e l i c i a n o et a l 1 9 for i s o l i n a r i d i o l diacetate. Exact Mass calcd. f o r C 2 2 H 3 4 0 2 (M+-H0Ac): 330.2559; found: 330.2560. S i m i l a r l y , the d i o l 278 (4 mg, 14 umol) was converted into the - 238 -diacetate 281 (4 mg, 78%) which exhibited i r ( f i l m ) : 3085, 1747, 1635, 1230, 892 cm'1; XH nmr (300 MHz) 6: 5.57 ( t , 1H, J = 7.5 Hz, o l e f i n i c proton), 4.50 (br s, 4H, =CCH20Ac and o l e f i n i c protons), 4.10 ( t , 2H, J - 7.5 Hz, -CH 2CH 20Ac), 2.43 (t, 2H, J = 7.5 Hz, -CH 2CH 20Ac), 2.29 (br dt, 1H, J = 5, 13.5 Hz, H A), 2.15-2.02 (m, 3H), 2.06, 2.04 (s, s, 3H each, a c e t y l protons), 1.85 (br d, 1H, J = 13.5 Hz, H c), 1.56-1.1 (m, 9H), 1.04 (s, 3H, angular methyl protons), 0.82 (d, 3H, J = 6 Hz, methyl protons), 0.77 (s, 3H, methyl protons). The ^H nmr s p e c t r a l data of t h i s material i s d i f f e r e n t from those reported f o r i s o l i n a r i d i o l d i a c e t a t e . 1 9 Exact Mass calcd. for C 2 2H340 2 (M +-H0Ac): 330.2559; found: 330.2557. Preparation of the endocyclic alkene 296 To a c o l d (-78°C) s o l u t i o n of the exocyclic alkene 276 (20 mg, 71 umol) i n dichloromethane (1 mL) was added dimethylboron bromide (0.43 mmol) as a s o l u t i o n i n dichloromethane. A f t e r the s o l u t i o n had been s t i r r e d at -78°C for 6 h, i t was cannulated into a vigorously s t i r r e d mixture of THF and saturated aqueous sodium bicarbonate. The mixture was extracted three times with ether. The combined extracts was washed - 239 -with brine, d r i e d (MgSO^) and concentrated. The residue was subjected to column chromatography on s i l i c a gel (1 g, e l u t i o n with petroleum ether-ether, 7:3 v/v). C o l l e c t i o n and concentration of the appropriate f r a c t i o n s afforded 14 mg (84%) of the endocyclic alkene 296 which exhibited i r ( f i l m ) : 3304 (br) cm"1; '-H nmr (400 MHz) 6: 5.18 (v br s, 1H, o l e f i n i c proton), 3.62 (m, 2H, -CH20H), 1.57 (br s, 3H, v i n y l methyl protons), 2.1-1.1 (m, 13H), 1.00 (s, 3H, angular methyl protons), 0.87 (d, 3H, J = 6 Hz, methyl protons), 0.73 (s, 3H, methyl protons). Exact  Mass calcd. f o r C 1 6H 2 gO: 236.2140; found: 236.2143. - 240 -REFERENCES 1. E.J. Corey, Pure Appl. Chem.. 14, 19 (1967). 2. (a) E. Piers and V. Karunaratne, J . Org. Chem.. 48, 1774 (1983). (b) B.M. Trost, Acc. Chem. Res.. 11, 453 (1978). 3. (a) P. Deslongchamps, Aldrichim. Acta. 17, 59 (1984). (b) D. Seebach and P. Knochel, Helv. Chim. Acta. 67, 261 (1984). 4. (a) E.J. Corey and D. Seebach, Angew. Chem. Int. Ed. Engl.. 4, 1075, 1077 (1965). (b) D. Seebach, Synthesis. 17 (1969). (c) D. Seebach and A.K. Beck, Org. Svn.. 51, 76 (1971). 5. K.G. 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