UBC Theses and Dissertations

UBC Theses Logo

UBC Theses and Dissertations

Methylenecyclohexane annulations : total syntheses of axane-type sesquiterpenoids Yeung, Bik Wah Anissa 1986

Your browser doesn't seem to have a PDF viewer, please download the PDF to view this item.

Item Metadata

Download

Media
831-UBC_1987_A1 Y48.pdf [ 6.66MB ]
Metadata
JSON: 831-1.0059450.json
JSON-LD: 831-1.0059450-ld.json
RDF/XML (Pretty): 831-1.0059450-rdf.xml
RDF/JSON: 831-1.0059450-rdf.json
Turtle: 831-1.0059450-turtle.txt
N-Triples: 831-1.0059450-rdf-ntriples.txt
Original Record: 831-1.0059450-source.json
Full Text
831-1.0059450-fulltext.txt
Citation
831-1.0059450.ris

Full Text

METHYLENECYCLOHEXANE ANNULATIONS. TOTAL SYNTHESES OF AXANE-TYPE SESQUITERPENOIDS BY BIK WAH ANISSA YEUNG B.Sc, The Chinese U n i v e r s i t y of Hong Kong, 1979 A THESIS SUBMITTED IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY IN THE FACULTY OF GRADUATE STUDIES (DEPARTMENT OF CHEMISTRY) We accept t h i s thesis as conforming to the required standard THE UNIVERSITY OF BRITISH COLUMBIA October 1986 ® Bik Wan Anissa Yeung In presenting this thesis in partial fulfilment of the requirements for an advanced degree at the University of British Columbia, I agree that the Library shall make it freely available for reference and study. I further agree that permission for extensive copying of this thesis for scholarly purposes may be granted by the head of my department or by his or her representatives. It is understood that copying or publication of this thesis for financial gain shall not be allowed without my written permission. Department of The University of British Columbia 1956 Main Mall Vancouver, Canada V6T 1Y3 DE-6(3/81) i i ABSTRACT This thes i s descr ibes the preparat ion of 5 - ch loro-2 - t r imethy l -s tannyl - l -pentene (111) and i t s conversion into 5 - c h l o r o-2 - l i t h i o - l -pentene (112). The l a t t e r reagent, which reacts smoothly with cyclohex-anone at - 7 8 ° C to give 5-chloro-2-(1-hydroxycyclohexyl)-1-pentene (132), was found to be thermal ly unstable at temperatures higher than - 6 3 ° C . Reagent (112) was transformed into the Grignard reagent (144) and the organocopper-phosphine complex reagent (145). Conjugate a d d i t i o n of reagents (144) and/or (145) to c y c l i c enones under appropriate condi t ions fo l lowed by c y c l i z a t i o n of the r e s u l t a n t products , e f fec ted u s e f u l methylenecyclohexane annulat ion sequences [(104) -+ (116)]. This methylenecyclohexane annulat ion method served as one of the two key steps i n the syntheses of ( ± ) - a x a m i d e-1 (174), ( ± ) - a x i s o -n i t r i l e-1 (173), and the corresponding C-10 epimers. Thus, copper(I) -ca ta lyzed a d d i t i o n of the Grignard reagent (144) to 2-methyl-2-cyclo-penten- l -one (152), fol lowed by c y c l i z a t i o n of the r e s u l t a n t chloro ketone (159), gave the annulat ion product (170), which was converted in to the enone (203). The other key step i n the pro jec t ed synthes is , which invo lved T i C l ^ - c a t a l y z e d conjugate a d d i t i o n of the b i s ( t r i m e t h y l -s i l y l ) ketene a c e t a l (226) to the enone (203), provided a mixture of the keto ac ids (222) and (223). With appropriate f u n c t i o n a l group manipula-t i o n s , (222) was converted in to ( ± ) - a x a m i d e-1 (174) and ( ± ) - a x i s o n i t r i l e (173), whi le (223) was converted in to (±)-10-epi-axamide-1 (224) and (±)-10 - e p i - a x i s o n i t r i l e - l (225). i i i iv TABLE OF CONTENTS Page ABSTRACT i i TABLE OF CONTENTS i v LIST OF TABLES v i LIST OF FIGURES v i i ABBREVIATIONS ix ACKNOWLEDGEMENTS x i INTRODUCTION 1 A. General 2 B. Problem 19 DISCUSSION 25 I . Preparat ion and Transmetalat ion of 5 - C h l o r o - 2 - t r i -methyls tannyl - l -pentene (111): React ion of 5 -Chloro-2 - l i t h i o - l - p e n t e n e (112) with Cyclohexanone . . . 26 A. Preparat ion of 5 - C h l o r o - 2 - t r i m e t h y l -s tanny l - 1-pentene (111) 26 B. Transmetalat ion of 5 - C h l o r o - 2 - t r i m e t h y l s t a n n y l -1-pentene (111): the React ion of 5 -Chloro-2-l i t h i o - l - p e n t e n e (112) with Cyclohexanone . . 30 V I I . Conjugate A d d i t i o n of Cuprate Species Derived from 5 - C h l o r o - 2 - l i t h i o - l - p e n t e n e (112) to C y c l i c Enones: An E f f i c i e n t Methylenecyclohexane Annulat ion Sequence 36 I I I . T o t a l Syntheses of the Sesquiterpenoids ( ± ) - A x a m i d e - 1 , ( ± ) - A x i s o n i t r i l e - 1 , and the Corresponding C-10 Epimers 55 A. In troduct ion 55 B. T o t a l Syntheses of ( ± ) - A x a m i d e - 1 , ( ± ) - A x i s o n i t r i l e - 1 , and the Corresponding C-10 Epimers 60 EXPERIMENTAL 121 REFERENCES 192 v i LIST OF TABLES Table Page I The Thermal S t a b i l i t y of 5 - C h l o r o - 2 - l i t h i o -1-pentene (112) 34 II Methylenecyclohexane Annulat ion of C y c l i c Enones 42 III E q u i l i b r a t i o n of the Annulated Product(s) . . . 54 IV P a r t i a l nmr Spec tra l Data for Compounds (204), (205), (222), (223), (187) and (193) . . 105 v i i LIST OF FIGURES Figure Page 1 The 400 MHz 1 H nmr spectrum of (204) 80 2 The homonuclear sp in decoupling experiments with (204): (a) the normal 400 MHz 1 H nmr spectrum expanded for the reg ion 51.8-3.0, and the spectra with i r r a d i a t i o n s at (b) 8 0.95 ( i sopropy l methyl groups), (c) 8 2.65 (HQ), and (d) 5 2.86 (H D) 82 3 The nOe d i f f erence experiment with (204): (a) the normal 400 MHz ^H nmr spectrum, and (b) the d i f ference spectrum with i r r a d i a t i o n at 5 1.01 ( r i n g j u n c t i o n methyl group) 84 4 The 400 MHz ^H nmr spectrum of (205) 85 5 The homonuclear sp in decoupling experiments with (205): (a) the normal 400 MHz -^H nmr spectrum for the reg ion 8 0.8-3.0, and the spectra with i r r a d i a t i o n s at (b) 8 0.92 ( i sopropy l methyl groups) , and (c) 5 1.91 (Hg) . . 87 6 The nOe d i f f erence experiment with (205): (a) the normal 400 MHz ^H nmr spectrum, and (b) the d i f f erence spectrum with i r r a d i a t i o n at 6 1.03 ( r i n g j u n c t i o n methyl group) 89 7 The 400 MHz X H nmr spectrum of (222) 93 8 The homonuclear sp in decoupling experiments wi th (222): (a) the normal 400 MHz X H nmr spectrum expanded for the reg ion 8 1.8-2.9, and the spectra with i r r a d i a t i o n s at (b) 8 2.62 (HQ) , and (c) 5 2.78 (H D) 95 v i i i 9 The 400 MHz L H nmr spectrum of (223) 97 10 The homonuclear sp in decoupling experiments with (223): (a) the normal 400 MHz X H nmr spectrum expanded for the reg ion 5 1 .8-2.8 , and the spectra with i r r a d i a t i o n s at (b) 5 0.95 ( i sopropy l methyl groups) , (b) S 1.92 (Hg), and (c) 5 2.32 (H c ) 99 11 The 400 MHz ^H nmr spectrum of ( ± ) - a x a m i d e - 1 (174) 113 12 The 400 MHz % spectrum of ( ± ) - 1 0 - e p i -axamide-1 (224) 115 13 The 400 MHz -^H nmr spectrum of synthet ic ( ± ) - a x i s o n i t r i l e - 1 (173) 116 14 The 400 MHz nmr spectrum of n a t u r a l ( + ) - a x i s o n i t r i l e - 1 118 15 The 400 MHz ^H nmr spectrum of synthet ic ( ± ) - 1 0 - e p i - a x i s o n i t r i l e - 1 (225) 119 i x ABBREVIATIONS The following abbreviations have been used throughout t h i s t h e s i s . Ac = a c e t y l A1BN = 2,2'-azobisisobutyronitrile br = broad Bu = but y l CD = c i r c u l a r dichroism d = doublet DEG «•> diethylene g l y c o l DME = 1,2-dimethoxyethane DMF = N,N-dimethylformamide equiv = equivalent(s) Et = eth y l 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 LHMDS = li t h i u m hexamethyldisilazide m = mu l t i p l e t MCPBA = meta-chloroperbenzoic a c i d Me = methyl X min = minute(s) mp = melt ing po in t Ms = methanesulfonate NBS = N-bromosuccinimide nmr = nuclear magnetic resonance nOe = nuclear Overhauser e f f ec t Ph = phenyl Pr = propy l py = p y r i d i n e q = quartet s = s i n g l e t t = t r i p l e t TBAF = tetra-n-butylammonium f l u o r i d e THF = te trahydrofuran THP = te trahydropyranyl TMS = t r i m e t h y l s i l y l t i c = t h i n - l a y e r chromatography p_-TsOH = para - to luenesu l fon ic a c i d x i ACKNOWLEDGEMENTS I would l i k e to thank Professor Edward P iers for h i s exce l l ent guidance and encouragement throughout the course of my s tud ies . I t i s a pleasure to work with him. I would a l so l i k e to thank the members of Professor P i e r s ' research group for t h e i r h e l p f u l d i scuss ions and shared ideas . I am indebted to Yee Fung L u , Peter Marrs , and John Wai for t h e i r c a r e f u l proofreading . Thanks are a l so extended to the var ious serv ices i n the department for t h e i r e f f i c i e n t cooperat ion and to Mrs. Rani Theeparajah for her c a r e f u l and e f f i c i e n t typing of t h i s t h e s i s . x i i To My Parents with a f f e c t i o n - 1 -CHAPTER I INTRODUCTION - 2 -INTRODUCTION A. General Ring annulat ion i s a demanding and an important process i n organic synthes i s . The term "annulation"-'- i s used to descr ibe the process of b u i l d i n g a r i n g onto a p r e - e x i s t i n g system, c y c l i c or n o n - c y c l i c . The two new carbon-carbon bonds invo lved i n annulat ion can be formed s imul-taneously, consecut ive ly i n a one-pot process , or separate ly . The added r i n g may be of any s i ze although f i v e - and six-membered r ings are most commonly formed. In a broad sense, the methods of annulat ion inc lude D i e l s - A l d e r r e a c t i o n s , ^ a c i d - c a t a l y z e d o l e f i n i c c y c l i z a t i o n s , ^ and r a d i c a l , ^ photochemical^ and thermal^ c y c l i z a t i o n s . However, i n a general sense, a l k y l a t i o n s or Michael addi t ions fol lowed by c y c l i z a t i o n s are more of ten thought of as the methods of annulat ion . Cons ider ing the formation of a six-membered r i n g which i s a common s t r u c t u r a l u n i t i n terpenes, s t e r o i d s , and a l k a l o i d s , the The i n c o r r e c t l y s p e l l e d word annelat ion has been used qui te often i n the l i t e r a t u r e . Here, the less used but c o r r e c t l y s p e l l e d word annulat ion w i l l be used (see reference 1). Since five-membered r i n g annulations are not the primary i n t e r e s t of t h i s t h e s i s , no d i s c u s s i o n about them w i l l be given here. However, a few exce l l en t reviews concerning five-membered r i n g annulat ions are a v a i l a b l e for c o n s u l t a t i o n (see reference 7 ) . - 3 -Robinson annulat ion r e a c t i o n i s commonly evoked. This process involves base ca ta lyzed Michael a d d i t i o n of a ketone enolate (2) to an a l k y l v i n y l ketone [e .g . (3)] fol lowed by a c i d - or base -ca ta lyzed a l d o l condensation, as i l l u s t r a t e d i n Scheme lA>^a D i f f e r e n t f u n c t i o n a l i t y patterns on the cyclohexenone products (8) can be der ived by modifying the s t ruc tures of the s t a r t i n g m a t e r i a l s . This s a l i e n t feature increases the u t i l i t y of the Robinson annulat ion r e a c t i o n . 8 7 6 5 Scheme 1 However, the po lymer iza t ion of the v i n y l ketones, which leads to lower y i e l d s of the des i red cyclohexenone products , cons t i tu te s a ser ious drawback of the Robinson annulat ion . The problem of polymeri -z a t i o n was p a r t l y overcome by the use of a quaternized Mannich base [e .g . (9)]^ i n place of the v i n y l ketone (equation 1) . Treatment of - 4 -t h i s Mannich base with strong base converts i t in to the corresponding v i n y l ketone [e .g . (3)] i n s i t u . Using t h i s procedure, the y i e l d of the product i s u s u a l l y improved. The use of enamines-^ h a s a l so produced good y i e l d s i n annulat ion r e a c t i o n s . For example, the enamine of cyclohexanone (12) reacts with methyl v i n y l ketone (3) to give a mixture of (13) and (14). A f t e r h y d r o l y s i s of the l a t t e r substance, a mixture of isomers (15) and (16) was produced i n 67% y i e l d (Scheme 2) . NaOAc HOAc H ? 0 15 16 Scheme 2 - 5 -a - T r i a l k y l s i l y l enones [e .g . (18)] have a l so been used to react with ketone enolates 1-'- (Scheme 3). The t r i e t h y l s i l y l group i n (19) s t a b i l i z e s somewhat the i n i t i a l negative charge formed by a d d i t i o n of the enolate ion to the enone, and, more important ly , provides s t e r i c hindrance which slows down anionic po lymer iza t ion . The t r i e t h y l s i l y l group can be removed from the a ' - t r i e t h y l s i l y l enone (20) with base a f t er the annulat ion process i s complete. Scheme 3 Besides the annulat ion methods mentioned above, numerous modif ied r e a c t i o n condi t ions and reagents r e l a t e d to (1) and (3) have been developed and used. ' ° They serve to improve the y i e l d s and to produce var ious s t r u c t u r a l patterns for the products from the Robinson annula-t i o n r e a c t i o n s . - 6 -Reagents (3), (9) and (18) can be c l a s s i f i e d as b i f u n c t i o n a l conjunct ive reagents conta in ing both a donor and an acceptor s i t e and can be considered as synthet ic equivalents to the synthon*** (22). 'X a d^a* synthon 22 Conjunct ive reagents are those reagents that are incorporated i n whole or i n part into a more complex system. The term "conjunc-t ive" i s used to d i f f e r e n t i a t e these reagents from those that react with but are not normally incorporated in to a substrate (see reference 12). Heteroatoms, present i n many organic molecules , 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 p a t t e r n upon the carbon ske le ton , i . e . acceptor proper t i e s (attack by donor reagents) at I O C carbons Q± •->.->... ^ a n ( j donor proper t i e s (attack by acceptor reagents) at carbons c^-^-^-... The heteroatom X i t s e l f i s a donor center ( d ° ) (see reference 13) . a^UA$^\6 X=0,N d d d Corey defines synthons as " s t r u c t u r a l un i t s w i t h i n a molecule which are r e l a t e d to poss ib le synthet ic operations" (see reference 14). A r e l a t e d , annulat ion method, a lso making use of the Michael reac-t i o n , involves the a d d i t i o n of an organometal l ic reagent, u s u a l l y a cuprate , to an enone, fol lowed by c y c l i z a t i o n . This method can be c a r r i e d out i n two ways, depending on whether the s i t e necessary for c y c l i z a t i o n i s incorporated in to the enone or in to the organometal l ic reagent before the conjugate a d d i t i o n . In the synthesis of valerane (29) reported by Posner et a l . 15 (Scheme 4 ) , a d d i t i o n of the Grignard reagent (23) , a synthet i c equiva-OTHP 2A 25 OTHP 1) H* 2) MsCl,Py 3) LiBr Acetone DMe,CuLi,0°C 2)HMPA 27 28 29 OTHP MgCI 23 / a 30 Scheme 4 - 8 -l e n t to the butane d^.a^ synthon (30), to the keto enol ether (24) gave, a f t e r a c i d h y d r o l y s i s , the enone (25). Deprotect ion of the a l c o h o l , mesylat ion , and displacement of the mesylate anion with bromide provided (26). Conjugate a d d i t i o n of l i t h i u m dimethylcuprate to the enone (26), fo l lowed by intramolecular a l k y l a t i o n i n the presence of HMPA, af forded the b i c y c l i c ketone (28) . Deoxygenation of t h i s b i c y c l i c ketone produced valerane (29). In t h i s synthes i s , the acceptor s i t e (the carbon bear ing Br) invo lved i n c y c l i z a t i o n was incorporated into the enone molecule before conjugate a d d i t i o n of the cuprate . Two i n t e r e s t -ing features have to be mentioned here. F i r s t l y , the methyl group from the cuprate reagent was introduced trans to the i s o p r o p y l group. Secondly, the c y c l i z a t i o n h i g h l y favored the c i s - l - d e c a l o n e system. In the l i g h t of these two p o i n t s , the product was formed with the d e s i r e d s t e r e o s e l e c t i v i t y . A s i m i l a r s trategy has been descr ibed by Naf et a l . ^ (Scheme 5). Treatment of the keto enol ether (31) with the Grignard reagent (32), a synthet i c equivalent to the d^, a)- synthon (36), fo l lowed by a c i d h y d r o l y s i s , provided the enone (33). L i th ium dimethylcuprate was added to the enone (33) at - 6 0 ° C and the mixture was s t i r r e d at that temperature for 90 min and then at 0°C for a fur ther 1 h . A f t e r workup of the mixture, the hydroxydecalone (35) was produced. Thus, again, the s i t e (the carbonyl group) necessary for c y c l i z a t i o n was present i n the conjugate a d d i t i o n substrate p r i o r to the a d d i t i o n r e a c t i o n . The s tereochemistry of the r i n g j u n c t i o n i n the decalone product was c i s . A c l o s e l y r e l a t e d r e a c t i o n sequence has been reported by Oshima^ (Scheme 6). Here, the organoaluminum reagent (38) conjugate ly trans-f e r r e d the PhS moiety to the enone (37). Subsequent a l d o l i z a t i o n of the r e s u l t a n t intermediate (39) af forded (40). Conversion of (40) into (41) was achieved by ox idat ive e l i m i n a t i o n of the phenyl th io group. The d ian ion (43), s y n t h e t i c a l l y equivalent to the d^,a^- synthon (49), has been employed by T a k a h a s h i ^ i n h i s synthes is of ( ± ) - 1 4 -norfuranoeudesmane-4,6-dione (47) (Scheme 7). The d ian ion (43) was allowed to react with 3-methoxy-2-cyclohexen-l-one (42) and the r e s u l t a n t product was subjected to a c i d h y d r o l y s i s to give the a c i d - 10 -(44). Treatment of the es ter (45), der ived from (44), with l i t h i u m dimethylcuprate at 0°C for 45 h gave ( ± ) - 1 4 - n o r f u r a n o e u d e s m a n e - 4 , 6 - d i o n e (47). The nmr spectrum of t h i s m a t e r i a l showed that i t cons i s ted of an e q u i l i b r i u m mixture of the tautomers (47) and (48), i n a r a t i o of 3:7, r e s p e c t i v e l y . Once more, the s i t e (the ester) invo lved i n c y c l i z a -t i o n was present i n the enone before conjugate a d d i t i o n of the cuprate . Heathcock-'-^ has synthesized the d i th iane (50) and used i t as an equiva lent of the d^.a^ synthon (53) (Scheme 8). The anion of (50) was added conjugate ly to 4-methyl-2-cyclohexen- l -one i n the presence of HMPA to provide (51). The l a t t e r substance, upon treatment with a c i d , underwent h y d r o l y s i s and a l d o l i z a t i o n - d e h y d r a t i o n to give the enone - 11 -Scheme 7 - 12 -Scheme 8 (52). In t h i s case, the s i t e (the aldehyde carbonyl group) for c y c l i z a t i o n was incorporated in to the b i f u n c t i o n a l conjunct ive reagent (50) before conjugate a d d i t i o n to the substrate . Helquist^O has employed the reagent (54) [ s y n t h e t i c a l l y equivalent to the d ^ . a 1 synthon (57)] , which a l so contained a s i t e (carbonyl group) 13 -s u i t a b l e for c y c l i z a t i o n (Scheme 9 ) . Compound (54) was converted into the corresponding Grignard reagent and the l a t t e r species was added conjugate ly to 2-cyclohexen-l -one i n the presence of a copper(I) s a l t to produce the a c e t a l ketone (55) . A c i d h y d r o l y s i s of (55) with concommitant a l d o l i z a t i o n - d e h y d r a t i o n gave the enone (56). 54 57 56 Scheme 9 In the synthesis of ( ± ) - 8 , 9 - d e o x y a l l i a c o l B (66) reported by Raphael et a l . . ^ 1 5-nitro-2-pentanone (58) was used as an equivalent of the d^,a^ synthon (68) (Scheme 10). Conjugate a d d i t i o n of the anion of (58) to 5 ,5-dimethyl-2-cyclopenten-1-one (59), fo l lowed by a c i d ca ta lyzed a l d o l condensation and dehydrat ion, produced the b i c y c l i c n i t r o ketone (61). Subject ion of (61) to the Nef r e a c t i o n gave the four - 14 -- 15 -products (62), (63), (64) and (65). Heating the mixture of (63), (64) and (65) wi th p_-toluenesulfonic a c i d gave the s ing l e r e q u i r e d conjugated diketone product (65). Th i s diketone was converted, v i a a s er i e s of transformat ions , into ( ± )-8 , 9 - d e o x y a l l i a c o l B (66) and the d ias tereo-meric lactone (67) i n a r a t i o of 1:3, r e s p e c t i v e l y . Incorporat ion of the carbonyl group ( s i t e for c y c l i z a t i o n ) in to the b i f u n c t i o n a l conjunc-t i v e reagent (58) was once again employed i n t h i s synthes i s . In each of the examples given above, the Michael r e a c t i o n played a key r o l e i n the o v e r a l l annulat ion sequence. Since the primary focus of the work descr ibed i n t h i s thes i s was the development of a methylene-cyclohexane annulat ion method v i a a Michae l - type r e a c t i o n , a s ec t i on concerning previous achievements i n methylenecyclohexane annulat ions i s necessary. The Grignard reagent (70), a synthet ic equivalent to a d^a-*-synthon (70a) , was used by F i c i n i i n her synthesis of eremophilone (75).22 A d d i t i o n of (70) to the enone (69) i n the presence of a copper(I) s a l t produced, a f t er a c i d h y d r o l y s i s of the r e s u l t a n t product , the ketone (71) with the stereochemistry as shown (see Scheme 11). Appropr iate f u n c t i o n a l group manipulations were employed to convert (71) in to (72). Oxidat ion of (72) fol lowed by base -ca ta lyzed a l d o l condensation gave the a l d o l (74). Conversion of (74) in to (75) was c a r r i e d out v i a a few synthet ic steps. In h i s synthesis of the subs t i tu ted c i s - d e c a l i n (82), Ley2^ used a d i f f e r e n t Gr ignard reagent (78) as a synthet ic equivalent to the 1-pentene d^,a2 synthon (76a) (Scheme 12). A d d i t i o n of (78) to the enone (77) i n the presence of a copper(I) s a l t , fol lowed by trapping of - 16 -Scheme 11 - 17 -77 + T M S — = -78 4r<r<-82 •Mgl 1)CV Et 20 * ? 2)CIC0Me 79 1) AgN03 2) KCN CCS Me Znl-PhCH< 80 TMS- •Mgl = 78 Scheme 12 76a the r e s u l t a n t enolate anion with methyl chloroformate, provided the keto es ter (79). D e s i l y l a t i o n of (79) and subsequent c y c l i z a t i o n of the r e s u l t a n t product (80) i n the presence of z inc iodide produced the keto es ter (81). Keto es ter (81) was converted into (82) v i a a sequence of transformat ions . In B u c h i ' s ^ synthesis of y3-agarofuran (91), 5 - iodo- l -pentyne (86) was employed to e f f ec t the methylenecyclohexane annulat ion (Scheme 13). - 18 -Scheme 13 19 (-)-Carvone (83) was subjected to success ive hydrat ion and hydrogenation to obta in the hydroxy ketone (85) . A l k y l a t i o n of the l a t t e r substance with the iodide (86) produced the hydroxy ketone (87) which, upon treatment with phosphorus pentach lor ide , provided the chloro ether (88). T r i m e t h y l s i l y l a t i o n of the terminal acetylene of (88) , fo l lowed by r i n g c losure of the r e s u l t a n t product (89) v i a a free r a d i c a l process , y i e l d e d the t r i c y c l i c ether (90). D e s i l y l a t i o n of (90) af forded agarofuran (91). A recent synthesis of ( ± ) - isoamij i o l (98) by Pattenden^-* d i s c l o s e d another method for methylenecyclohexane annulat ion (Scheme 14). A l k y l a -t i o n of the b i c y c l i c ketone (92) with the iod ide (93), fo l lowed by methylat ion and d e s i l y l a t i o n , provided a 4:1 mixture of (96) and (95), r e s p e c t i v e l y . Intramolecular reduct ive coupl ing of the terminal acety-l e n i c ketone (96) i n the presence of sodium naphthalenide af forded the t r i c y c l i c a l c o h o l (97). Treatment of (97) with selenium dioxide i n the presence of t -buty lhydroperoxide gave ( ± ) - i s o a m i j i o l (98). B. Problem Previous work i n our laboratory had shown^a that 4 -ch loro -2 -l i t h i o - l - b u t e n e (100), obtained by the transmeta lat ion of 4 - ch loro -2 -tr imethy ls tannyl -1 -butene (99) with methyl l i th ium (equation 2) , can be used as an equivalent to the 1-butene d^,a^ synthon (103). The cuprate reagents (101) and (102) der ived from (100) have been shown to be use fu l species i n a five-membered r i n g annulat ion sequence.^6b Thus, conjugate - 20 -Scheme 14 - 21 -Me3Sn 99 MeLi, THF ^ -78°C, 10 min 100 (2) 101 M = [CuSPh]l_i 102 M=[CuCN]Li 103 a d d i t i o n of the cuprates (101) and/or (102) to c y c l i c enones (104) prov ided the chloro ketones (105). The l a t t e r substances could be c y c l i z e d r e a d i l y to the b i c y c l i c ketones (106) by treatment with potassium hydride i n THF (equation 3) . A p p l i c a t i o n of t h i s annulat ion (CH9) 104 + 101 M = [CuSPh]Li 102 M=[CuCN]Li n=2,3 R1=H,CH3 R2 = H,CH3 THF > ( C H 2 ) n •78 C 105 (CH,) (3) 105 - 22 -method to the synthesis of the s t r u c t u r a l l y i n t e r e s t i n g sesquiterpenoids ( ± ) - A ^ ( ^ ) - c a p n e l l e n e ^ and ( ± ) - p e n t a l e n e n e 2 * * has fur ther demonstrated the u t i l i t y of the process . In f a c t , i n these syntheses, reagents der ived from (100) served as e f f i c i e n t synthet ic equivalents to the three donor-acceptor synthons (103), (107) and (108). V / >Z 103 107 108 A p o t e n t i a l l y important extension to the methodology o u t l i n e d above i s to prepare homologs of the reagents (100)-(102). I f the above sequences cou ld be c a r r i e d out with these homologs, b i c y c l i c r i n g systems with v a r y i n g r i n g s i zes and with d i f f e r e n t subst i tuent patterns would be obtained. One of the homologs of compound (99) i s 5 -ch loro-2 -t r i m e t h y l s t a n n y l - l - p e n t e n e (111). This m a t e r i a l had been prepared i n our l abora tory v i a the a d d i t i o n of the ( tr imethyls tannyl )copper reagent (110) to 5 -ch loro - l -pentyne (109) (equation 4 ) . 2 9 Since the reagent (111) i s r e a d i l y a c c e s s i b l e , i t was of i n t e r e s t to determine whether or not (111) could be transmetalated to give the l i t h i o species (112) (equation 5) . I f t h i s transmeta lat ion were to be s u c c e s s f u l , the convers ion o f (112) in to reagents (113) and (114) could - 23 -113 M = [CuSPh]Li 7 6 1 H M=[CuCN]Li be s tud ied . Conjugate a d d i t i o n of (113) and/or (114) to c y c l i c enones, fol lowed by in tramolecu lar a l k y l a t i o n of the r e s u l t a n t products as shown i n equation 6, would cons t i tu te an e f f i c i e n t methylenecyclohexane 116 - 24 -annulat ion process . Thus, reagents (113) and (114) would serve as the synthe t i c equivalents to the 1-pentene d^,a^ synthon (76). Since the methylenecyclohexane s t r u c t u r a l u n i t i s qui te common i n n a t u r a l products , p a r t i c u l a r l y i n terpenoids , the development of an e f f i c i e n t method to give t h i s type of r i n g system i s important. The proposed sequence, conjugate a d d i t i o n of the reagents (114) and/or (115) to enones, fol lowed by c y c l i z a t i o n , could serve as an e f f i c i e n t and a s t e r e o s e l e c t i v e methylenecyclohexane annulat ion method. CHAPTER II DISCUSSION - 26 DISCUSSION I . Preparat ion and Transmetalat ion of 5 - C h l o r o - 2 - t r i m e t h y l s t a n n y l - l -pentene (111): React ion of 5 - C h l o r o - 2 - l i t h i o - l - p e n t e n e (112) with Cyclohexanone A. Preparat ion of 5 -Chloro -2 - t r imethy l s tanny l - l -pentene (111) When the work descr ibed i n t h i s thes i s was begun, i t was not obvious how the preparat ion of 5 - c h l o r o - 2 - t r i m e t h y l s t a n n y l - l - p e n t e n e (111) was to be accomplished. Hydrostannation of a 1-alkyne, a widely used method for prepar ing v iny ls tannanes , near ly always gives a mixture of products with the 2 - t r i a l k y l s t a n n y l - l - a l k e n e as a minor p r o d u c t . ^ For example, r e a c t i o n of 1-hexyne (117) with t r i m e t h y l t i n hydride af fords a 2:29:69 mixture of the alkenes (118), (119), and (120), r e s p e c t i v e l y (equation 7 ) . ^ 117 118 119 (7) 120 27 -Since 4 - c h l o r o - 2 - t r i m e t h y l s t a n n y l - l - b u t e n e (99) had been prepared i n our laboratory v i a a 4-step r e a c t i o n s e q u e n c e , o n e p o s s i b l e method for prepar ing (111) would be to homologate (99) (equation 8) . However, the use of a mul t i s tep sequence to prepare a " s t a r t i n g mater ia l" i s not a d e s i r a b l e mode of operat ion i n organic synthes i s . For tunate ly , during the course of s tudying the react ions of ( t r i -a lky l s tanny l ) copper reagents with ace ty l en i c compounds, simple methods l ead ing to the chloro vinylstannane (111) were e s t a b l i s h e d . * The f i r s t method invo lved the r e a c t i o n of the ( tr imethyls tannyl )copper reagent (110) (1.3 equiv) with 5-chloro-1-pentyne (109) (1 equiv) at - 7 8 ° C for 6 h to prov ide , i n 58% y i e l d , the des i red compound (111) (equation 9).^9 - 28 -In t h i s r e a c t i o n , the isomeric c h l o r i d e (122) was produced together with the c h l o r i d e (111) i n a r a t i o of about 11:89, r e s p e c t i v e l y . Another procedure with improved y i e l d of (111) was found l a t e r . ^ Thus, r e a c t i o n of the copper reagent (110) (2 equiv) with 5-chloro-1-pentyne (109) (1 equiv) i n the presence of methanol (60 equiv) at - 6 3 ° C for 12 h produced the des i red c h l o r i d e (111) i n 79% y i e l d (equation 10). A small amount of the isomer (122) was a l so produced. THF H-=- (CH ? h-CI + Me3SnCu.Me2S — > /S>nMe3 2 3 1 * 1 Me0H(60 equiv) ^ -63°C,12h 109 110 111 Me3Sn SnMe-^  CI 89 Although the l a t t e r procedure has the advantage of producing (111) i n h igher y i e l d , i t s u t i l i t y i s deterred by the necess i ty of operat ing at a low temperature ( - 6 3 ° C ) for a prolonged p e r i o d of time (12 h ) , a cumbersome task e s p e c i a l l y with large scale r e a c t i o n s . Consequently, the former procedure was adopted for large sca le preparat ions of 5 - c h l o r o - 2 - t r i m e t h y l s t a n n y l - l - p e n t e n e (111). The ( t r i m e t h y l s t a n n y l ) -copper reagent (110) (38.3 mmol) was allowed to react with 5 - c h l o r o - l -pentyne (109) (30.2 mmol) i n THF at - 7 8 ° C for 6 h to produce, on the bas i s of a g l c a n a l y s i s , a mixture of the des i red c h l o r i d e (111) and the isomeric c h l o r i d e (122) i n a r a t i o of 85:15, r e s p e c t i v e l y . The mixture 29 -was subjected to (slow) column chromatography on s i l i c a ge l to a f f o r d the d e s i r e d c h l o r i d e (111) i n 68% y i e l d . The isomeric c h l o r i d e (122) was not recovered from the chromatography column even though a more p o l a r so lvent was employed for e l u t i o n . Thus, i t appeared that when the chromatography was c a r r i e d out s lowly (dropwise e l u t i o n ) , compound (122) was destroyed on the s i l i c a ge l column. I n t e r e s t i n g l y , i f the mixture was subjected to f l a s h column chromatography, the two isomeric compounds (111) and (122) were both recovered from the column, but were not separated c l e a n l y . The i s o l a t e d , pure c h l o r i d e (111) exh ib i t ed s p e c t r a l data i n f u l l agreement with the s t r u c t u r a l assignment. The 1-H nmr spectrum of (111) showed a qu inte t at S 1.85 (J = 7 Hz) for the -CH2CH2CH2CI protons , a broad t r i p l e t at 6 2 AO (J = 7 Hz) for the a l l y l i c protons , and a t r i p l e t at 6 3.50 (J = 7 Hz) for the -CH2CI protons . The two o l e f i n i c protons Hg and H A appeared as a p a i r of doublet of t r i p l e t s at S 5.20 (J = 2.5, 1 Hz, J S n . H = 7 0 H z ) a n d 5 - 7 0 (I = 2.5, 1.5 Hz, J _ S n _ H = 150 H z ) , * r e s p e c t i v e l y . I t i s known that with organot in compounds i n which a t i n atom and a hydrogen atom are v i c i n a l on an o l e f i n i c l inkage , isn-H ^ s m u c n l a r g e r when they are trans to each other than when they are c i s to each other . 30 -B. Transmetalat ion of 5 -Ch loro -2 - t r imethy l s tanny l - l -pentene (111): the React ion of 5 - C h l o r o - 2 - l i t h i o - l - p e n t e n e (112) with Cyclohexan-one G i l m a n J Z f i r s t showed that the r e a c t i o n of t e t r a p h e n y l t i n and excess n - b u t y l l i t h i u m could be used to prepare t e t r a - n - b u t y l t i n (equation 11). L a t e r , Seyferth and W e i n e r ^ prepared v i n y l l i t h i u m , which had been i n a c c e s s i b l e u n t i l that time, by r e a c t i o n of phenyl-l i t h i u m with t e t r a v i n y l t i n (equation 12). Ph 4 Sn + 4n-BuLi > n - B ^ S n + 4PhLi (11) (CH 2 =CH) 4 Sn + 4PhLi > Ph 4 Sn + 4(CH 2 =CH)Li (12) A large number of v i n y l l i t h i u m reagents, prepared v i a the trans-meta lat ion of v inylstannanes with a l k y l l i t h i u m s , have been reported-^ s ince the work of Seyferth and Weiner . -^ Thus, the transmeta lat ion process has become a va luable t o o l for organic synthes i s , e s p e c i a l l y for the synthes is of v i n y l l i t h i u m reagents i n a c c e s s i b l e by other routes . There are severa l features of the transmeta lat ion process that c o n t r i -bute to i t s usefulness: (a) the r e a c t i o n u s u a l l y proceeds e f f i c i e n t l y at low temperatures (below - 5 0 ° C ) , (b) the r e a c t i o n i s completely s t e r e o s p e c i f i c and (c) the by-product of the r e a c t i o n i s a coord inate ly saturated t e t r a a l k y l t i n which does not i n t e r f e r e with the reac t ions of the v i n y l l i t h i u m spec ies . For example, the two v inyls tannanes (125) and (126), obtained by s t e r e o s p e c i f i c r e t r o - D i e l s - A l d e r react ions of (123) and (124), r e s p e c t i v e l y , could be transmetalated with n - b u t y l -- 31 -l i t h i u m at - 7 8 ° C without loss of stereochemistry.^^ The r e s u l t a n t l i t h i u m species (127) and (128) could be trapped with 2-methylpropanal to give the a lcohols (129) and (130), r e s p e c t i v e l y (Scheme 15). With the r e a d i l y access ib le 5 - c h l o r o - 2 - t r i m e t h y l s t a n n y l - l - p e n t e n e (111) at hand, the transmetalat ion r e a c t i o n of t h i s m a t e r i a l was c a r r i e d out. The v inylstannane (111) was allowed to react with methyl l i th ium (1.2 equiv) at - 7 8 ° C for 15 min. A c l e a r , c o l o r l e s s s o l u t i o n of 5 - c h l o r o - 2 - l i t h i o - l - p e n t e n e (112) was produced (equation 13). Me^Sn 111 THF -78°C, 15 min (13) 112 The v i n y l reagent (112) was allowed to react with cyclohexanone (131) (1.1 equiv) at - 7 8 ° C to give 5 -ch loro-2 - (1 -hydroxycyc lohexy l ) -1 -pentene (132) as a s ing le product (equation 14). The crude product , 32 Scheme 15 - 33 -which contained a small amount of the s t a r t i n g m a t e r i a l (131), was subjected to column chromatography on s i l i c a ge l to a f f o r d the pure a l c o h o l (132) i n 84% y i e l d . The spectroscopic data obtained from the ch loro a l c o h o l (132) f u l l y confirmed the s t r u c t u r a l assignment. The i r spectrum of (132) showed an 0-H s t r e t c h i n g absorpt ion at 3431 cm" 1 , and an absorpt ion due to the C - CH2 moiety at 902 cm" 1 . The 1 H nmr spectrum of (132) contained a quintet at 6 1.98 (J = 7 Hz) due to the -CH2CH2CI protons , a t r i p l e t at S 2.24 (J = 7 Hz) due to the a l l y l i c methylene protons , and a t r i p l e t at S 3.56 (J = 7 Hz) due to the -CH2CI protons . The o l e f i n i c protons gave r i s e to two s i n g l e t s at 5 4.82 and 5.14. Since the l i t h i o species (112) seemed to be qui te s table at - 7 8 ° C , i t was of i n t e r e s t to determine i t s s t a b i l i t y at h igher temperatures. Therefore , three a d d i t i o n a l experiments were c a r r i e d out. In these experiments, the so lut ions of the l i t h i o reagent (112) were s t i r r e d at - 6 3 ° C , - 4 8 ° C , and - 2 0 ° C for 30 minutes. Each s o l u t i o n was then recooled to - 7 8 ° C , and cyclohexanone was added. A f t e r a p e r i o d of 3 h , each mixture was subjected to a standard workup procedure. The r e s u l t s of these experiments are summarized i n Table I . From a perusa l of the data given i n Table I , i t can be seen that the v i n y l l i t h i u m species (112) i s not p a r t i c u l a r l y s table at temperatures higher than approximately - 6 0 ° C . At - 4 8 ° C , (112) appears to decompose s lowly, while at - 2 0 ° C , i t decomposes completely w i t h i n 30 minutes. The fa te of the l i t h i o species (112) at h igher temperatures was not e x p l i c i t l y determined. However, ( Z ) - 5 - c h l o r o - 3 - l i t h i o - 2 - p e n t e n e (134), which has been prepared i n our laboratory v i a transmeta lat ion of reagent - 34 -Table I : The Thermal S t a b i l i t y of 5 - C h l o r o - 2 - l i t h i o - l - p e n t e n e (112) Entry Condi t ion , [A] Y i e l d (%)b 1 - 84 2 - 6 3 ° C , 30 min 76 3 - 4 8 ° C , 30 min 58 4 - 2 0 ° C , 30 min 0 C a 1.1 equiv of cyclohexanone was used and the r e s u l t a n t mixture was s t i r r e d at - 7 8 ° C for 3 h . b Y i e l d of i s o l a t e d , pure (132). c Only cyclohexanone was recovered. - 35 -(133) with methy l l i th ium, was found to c y c l i z e r a p i d l y even at - 7 8 ° C to give ethyl idenecyclopropane (135). The l a t t e r substance was trapped with 2 , 4 - d i n i t r o p h e n y l s u l f e n y l c h l o r i d e to give, compound (136) (Scheme Scheme 16 I t seems l i k e l y that , at higher temperatures, the l i t h i o species (112) would c y c l i z e to give methylenecyclobutane (137) (equation 15). The l a t t e r substance (bp 4 2 ° C ) ^ i s very v o l a t i l e and vigorous proof for i t s formation was not c a r r i e d out. 36 -I I . Conjugate Addition of Cuprate Species Derived from 5-Chloro-2-l i t h i o - l - p e n t e n e (112) to C y c l i c Enones: An E f f i c i e n t Methylene-cyclohexane Annulation Sequence Organocopper reagents are a very important and use fu l c la s s of organometal l ic reagents for carbon-carbon bond formation i n n a t u r a l product syntheses. ^ 8 The usefulness of these reagents i s due to t h e i r ease of p r e p a r a t i o n and t h e i r a b i l i t y to e f f e c t c e r t a i n transformations which are d i f f i c u l t or impossible to accomplish e f f e c t i v e l y with any other reagents. There are two general types of react ions of organocop-per reagents: (a) addi t ions to carbon-carbon double and t r i p l e bonds,^9 and (b) s u b s t i t u t i o n of organic ha l ides and a l c o h o l d e r i v a t i v e s . ^ These reac t ions are u s u a l l y h i g h l y s t e r e o s e l e c t i v e , r e g i o s e l e c t i v e , and chemoselect ive. Despite t h e i r widespread a p p l i c a t i o n s i n organic synthes i s , organocopper reagents are not without l i m i t a t i o n s : ^ 1 (a) homocuprates, - 37 -R^CuLi , u s u a l l y waste one R group i n r e a c t i o n s , (b) heterocuprates , RCuXLi (X = l i g a n d bonded to copper v i a a heteroatom), are often thermal ly unstable and must be used at low t e m p e r a t u r e s , ^ ( c ) the a c e t y l e n i c mixed cuprates , RCuR'Li (R' = 1 -a lkynyl l i g a n d ) , are less r e a c t i v e than the homocuprates, R2CuLi .^^ To circumvent these l i m i t a t i o n s , a number of new organocopper r e a g e n t s , ^ e .g . d i c y c l o h e x y l -phosphido l i g a n d based heterocuprates [ R C u ( P c y 2 ) L i ] ^ and higher order cuprates [RR' Cu(CN)Li2]^~', have been prepared and shown to be of higher s t a b i l i t y and r e a c t i v i t y . A f t e r the transmeta lat ion of 5 - c h l o r o - 2 - t r i m e t h y l s t a n n y l - l - p e n t e n e (111) wi th methy l l i th ium had been shown to be s u c c e s s f u l , the next important task was to prepare cuprate reagents der ived from 5-ch loro-2 -l i t h i o - l - p e n t e n e (112), i n order to perform the methylenecyclohexane annulat ion sequence as shown i n equation 16. 0 112 138 139 140 This formulat ion , and those of other organocopper reagents , are not meant to imply ac tua l s tructures but are used to show sto ichiometry and for convenience. - 38 -The generat ion and use of e i t h e r a heterocuprate with the general s t ruc ture (138) or a s t o i c h i o m e t r i c organocopper compound with the s t ruc ture (141) would be more des i rab le than. format ion and use of the bishomocuprate (142). I f the l a t t e r reagent were to be employed, one CI CI CI equiva lent of the reagent (112) would be l o s t . I t was equa l ly important to choose appropriate organocopper reagents that could be generated and added conjugate ly to enones at low temperatures, owing to the i n s t a b i l -i t y of reagent (112) at temperatures higher than - 6 0 ° C . Since the l i t h i u m phenyl th io- and cyano[2- (4 -ch loro-1-butenyl ) ] cuprates (101) and (102) had been prepared and used s u c c e s s f u l l y for conjugate a d d i t i o n react ions with c y c l i c enones, ° D i t was expected that e i t h e r phenyl th io or cyano would be a s u i t a b l e a u x i l i a r y l i g a n d for the cuprate (138) (X = SPh or CN). Because of i t s non-hygroscopic and s tab le n a t u r e , ^ 7 the commercially a v a i l a b l e cuprous cyanide was se lec ted to prepare the cuprate (143). 39 -A d d i t i o n of cuprous cyanide (1 equiv) to a s o l u t i o n of 5 -ch loro-2-l i t h i o - l - p e n t e n e (112) (1 equiv) i n dry THF at - 7 8 ° C , fol lowed by the a d d i t i o n of 2-cyclohexen-l -one (146), gave 3 - [ 2 - ( 5 - c h l o r o - l - p e n t e n y l ) ] -cyclohexanone (153) i n 30% y i e l d (equation 17). In attempts to improve 112 143 153 the y i e l d of t h i s r e a c t i o n , the use of a number of d i f f e r e n t r e a c t i o n condi t ions was i n v e s t i g a t e d . A l l of these attempts, i n c l u d i n g the use of boron t r i f l u o r i d e - e t h e r a t e to cata lyze the r e a c t i o n , f a i l e d to provide b e t t e r y i e l d s of (153). Therefore , d i f f e r e n t methods, e .g . use of d i f f e r e n t l igands and d i f f e r e n t types of organocopper reagents, to e f f e c t the conjugate t r a n s f e r of the 2 - ( 5 - c h l o r o - l - p e n t e n y l ) group to enones were s tudied . E v e n t u a l l y , two procedures were e s tab l i shed as being reasonably s a t i s -f a c t o r y . The f i r s t procedure (method A) invo lved copper ( I ) - ca ta lyzed conju-gate a d d i t i o n of the Grignard reagent obtained by the treatment of (112) with magnesium bromide-etherate (equation 18). S p e c i f i c a l l y , magnesium bromide-etherate (1.2 equiv) was added to a c o l d ( - 7 8 ° C ) , s t i r r e d s o l u t i o n of 5 - c h l o r o - 2 - l i t h i o - l - p e n t e n e (112) (1 equiv) i n dry THF and the r e s u l t i n g milky mixture was s t i r r e d at t h i s temperature for 20 minutes to give the Grignard reagent (144). S o l i d copper bromide-40 -dimethyl s u l f i d e complex (0.25 equiv) was added i n one p o r t i o n to give a pale yel low mixture. The c y c l i c enone (1 equiv) was added. The reac-t i o n mixture was s t i r r e d at - 7 8 ° C for 3 h , and then was t rea ted with saturated aqueous ammonium c h l o r i d e . Further s u i t a b l e workup provided the corresponding conjugate a d d i t i o n product . The second procedure (method B) was modelled on work done by Noyori and c o - w o r k e r s ^ (equation 19). S o l i d copper bromide-dimethyl s u l f i d e complex (1.1 equiv) was added to a s t i r r e d s o l u t i o n of t r i - n -butylphosphine (2 equiv) i n dry ether at room temperature. The mixture was s t i r r e d for 10 min to give a c o l o r l e s s s o l u t i o n . The s o l u t i o n was R1=H,CH3 R2=H,CH3 112 U 5 n=2,3 1 1 5 R1=H,CH3 R2=H,CH3 - 41 -cooled to - 7 8 ° C and then was t r a n s f e r r e d (cannula) to a c o l d ( - 7 8 ° C ) , s t i r r e d s o l u t i o n of 5 - c h l o r o - 2 - l i t h i o - l - p e n t e n e (112) (1 equiv) i n dry THF to provide a pale yel low s o l u t i o n of (145). The c y c l i c enone (1 equiv) was added and the r e s u l t i n g mixture was s t i r r e d at - 7 8 ° C for 1 h and at - 4 8 ° C for 2 h . A s u i t a b l e workup procedure gave the des i red conjugate a d d i t i o n product . The r e s u l t s of conjugate addi t ions v i a methods A and B are summa-r i z e d i n Table I I . In general , the y i e l d s of the conjugate a d d i t i o n react ions [(146)-(152) -* (153)-(159), r e spec t ive ly ] us ing methods A and/or B were s a t i s f a c t o r y , though not very h i g h . For some hindered enones [e .g . 3 , 5 , 5 - t r imethy l -2 - cyc lohexen- l -one (149)], the 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 (1.2 e q u i v ) ^ 9 immediately a f t e r the a d d i t i o n of the enones provided the corresponding chloro ketones [e .g . (156)] i n y i e l d s h igher than those der ived from s i m i l a r react ions without the Lewis a c i d . In each case, the crude mater ia l obtained from the copper(I ) -ca ta lyzed conjugate a d d i t i o n of the Grignard reagent (144) to the enones (146)-(152) cons i s t ed e s s e n t i a l l y of the conjugate a d d i t i o n product and a small amount of the enone. The pure chloro ketone could be obtained by subjec t ion of the mixture to column chromatography on s i l i c a g e l . On the other hand, the crude m a t e r i a l obtained from a d d i t i o n of the reagent (145) to the enones (146)-(152) cons i s ted , i n each case, of the conjugate a d d i t i o n product , a small amount of enone and t r i - n - b u t y l -phosphine. In each case, t h i s mixture was subjected to chromatography on s i l i c a g e l , us ing mixtures of petroleum ether and ether (20:1 to 7:1) as e luent . In t h i s fash ion , the pure chloro ketone was r e a d i l y obtained. - 42 -Table I I : Methylenecyclohexane Annulat ion of C y c l i c Enones Conjugate a d d i t i o n Entry Enone product C y c l i z e d product(s) [method, 3 y i e l d (%)b] [ r a t i o , c y i e l d (%)b] 150 157 167 168 - 43 -Method A: 112 1) MgBr 2 (1.2 equiv ) , - 7 8 ° C , 20 min 2) CuBr-Me 2S (0.25 equiv) 3) enone (1 equiv ) , - 7 8 ° C , 3 h 4) NH 4 C1, H 2 0 conjugate a d d i t i o n product 1) n-Bu 3 P (2 equiv ) , CuBr-Me 2S (1.1 equiv) con]ugate • ——>• a d d i t i o n 2) enone (1 equiv ) , - 7 8 ° C , 1 h; - 4 8 ° C , 2 h product 3) NH 4 C1, H 2 0 112 b b d Y i e l d of d i s t i l l e d , p u r i f i e d product ( s ) . Rat ios were determined by g a s - l i q u i d chromatography. B F 3 . E t 2 0 (1.2 equiv) was added immediately a f t er a d d i t i o n of the enone. The r e a c t i o n time was 4.5 h . - 44 -On rare occas ions , a by-product (2-10%) was observed i n the crude products . This m a t e r i a l could be separated i n pure form from the conjugate a d d i t i o n product by chromatography. On the bas i s of i t s s p e c t r a l p r o p e r t i e s , t h i s substance was assigned s t ruc ture (171). The mass spectrum of t h i s m a t e r i a l (171) exh ib i t ed the molecular ion at m/e CI CI 171 206 (based on - ^ C l ) The i r spectrum showed peaks at 1570 and 890 cm* 1 . The nmr spectrum of (171) showed a quinte t of doublets (J = 7, 2 Hz) centered at 5 1.90 a t t r i b u t a b l e to the -CH 2CH2C1 protons , a broad t r i p l e t (J = 7 Hz) at 8 2.42 a t t r i b u t a b l e to the a l l y l i c protons , and a t r i p l e t (J = 7 Hz) at 8 3.52 a t t r i b u t a b l e to the -CH2CI protons . Furthermore, the o l e f i n i c protons gave r i s e to two broad s i n g l e t s at 5 5.00 and 5.25. Analyses (g l c , t i c ) of the chloro ketones (153), (154), and (156)-(158) obtained from methods A and/or B i n d i c a t e d that each of them cons i s t ed of e s s e n t i a l l y one component. Furthermore, i n each case, the spectra ( i r , ^H nmr, h igh r e s o l u t i o n mass) agreed w e l l with the assigned s t r u c t u r e . For example, the i r spectrum of (154) showed a carbonyl absorpt ion at 1700 cm" 1 and a peak at 900 cm" 1 for the ^C=CH 2 absorpt ion . The 400 MHz 1H nmr spectrum of (154) e x h i b i t e d a s i n g l e t at 8 1.11 due to the t e r t i a r y methyl proton, and a t r i p l e t at 8 3.59 (J = 7 - 45 153 154 156 157 158 Hz) due to the -CH2CI protons . A d d i t i o n a l l y , the o l e f i n i c protons gave r i s e to two s i n g l e t s at 6 4.87 and 4.93. As expected, each of the chloro ketones (155) and (159) was found to c o n s i s t of two epimers. Thus on the bas i s of g lc analyses , (155) der ived from method A cons i s ted of a 12:1 mixture of epimers, while (155) obtained from method B cons i s ted of a 6:1 mixture of the same diastereomers. The -^H nmr spectra of (155) supported these observa-t i o n s . Thus, the spectrum of (155) obtained from method A showed two doublets ( r a t i o 12:1, J = 7 Hz i n each case) at 5 0.95 and 1.00, 155 159 - 46 -r e s p e c t i v e l y , due to the secondary methyl groups. In the nmr spectrum of (155) obtained from method B, these two s igna l s were i n a r a t i o of 6:1. • On the other hand, g lc analyses of the ch loro ketone (159) i n d i c a t e d that mixtures of epimers i n r a t i o s of 4:1 and 2:1 were obtained from methods A and B, r e s p e c t i v e l y . The nmr spectrum of (159) obtained from method A exh ib i t ed two doublets ( r a t i o 4:1, J = 7 Hz i n each case) at 5 1.05 and 0.88, r e s p e c t i v e l y , a t t r i b u t a b l e to the secondary methyl groups. In the -^ H nmr spectrum of (159) obtained from method B, these two s igna l s were i n a r a t i o of 2:1. The chloro ketones (153)-(159) were c y c l i z e d smoothly by t r e a t -ment with potassium hydride (-2.5 equiv) i n dry THF at room temperature for 2 h to give the annulated products (160)-(170). The r e s u l t s of these c y c l i z a t i o n s are summarized i n Table I I . The y i e l d s of the c y c l i z e d products were e x c e l l e n t . As expected, when no subsequent e q u i l i b r a t i o n was poss ib l e (entr ies 3 and 7) , the k i n e t i c products [(164), (170)] having a c i s - f u s e d r i n g j u n c t i o n were produced as the sole products (g lc analyses ) . The spectra ( i r , -*-H nmr, h igh r e s o l u t i o n mass) der ived from compounds (164) and (170) agreed w e l l with the s t r u c t u r a l assignments. For example, the i r spectrum of (164) exh ib i t ed a carbonyl absorpt ion at 1695 cm"-'- and a ^C=CH2 absorpt ion at 895 cm"-'-. The ^H nmr spectrum of (164) e x h i b i t e d a s i n g l e t at 6 1.10 due to the t e r t i a r y methyl protons , while the o l e f i n i c protons gave r i s e to two t r i p l e t s at 5 4.69 (J - 1.5 Hz) and 4.72 (J = 2 Hz) . The c i s s tereochemistry of the r i n g j u n c t i o n was confirmed by a nOe d i f f erence experiment . -^ Thus, i r r a d i a t i o n at S 1.10 (bridgehead methyl s i n g l e t ) - 47 -caused enhancement of the one-proton s i g n a l at 6 2.25 (d of d, J = 12, 6 Hz) . On the bas i s of the chemical s h i f t and s p i n - s p i n coupl ing pa t t ern , the l a t t e r resonance was assigned to H^. 0 0 164 170 In other cases (entr ies 1, 2, 4-6) v a r y i n g degrees of e q u i l i b r a t i o n occurred under the condi t ions employed for r i n g c l o s u r e . Thus, a mixture of (160) and (161) i n a r a t i o of 1:2 (^H nmr spectroscopy) , r e s p e c t i v e l y , was produced from the c y c l i z a t i o n of compound (153) (equation 20). Subject ion of t h i s mixture to column chromatography on s i l i c a ge l provided pure samples of (160) and (161). The ^H nmr spectrum of (160) exh ib i t ed two s igna l s due to o l e f i n i c protons , a one-proton t r i p l e t at 6 4.66 (J = 1.5 Hz) and a one-proton s i n g l e t at 6 4.69. In the ^H nmr spectrum of (161), two s i n g l e t s , one proton each, appeared at 5 4.69 and 4.75, due to the o l e f i n i c protons . However, no 0 CI 153 - 48 f u r t h e r informat ion with respect to the stereochemistry at the r i n g j u n c t i o n of (160) and (161) could be obtained by means of nmr spectroscopy. For tunate ly , e q u i l i b r a t i o n experiments i n v o l v i n g compounds (160) and (161) d i d provide information regarding the stereochemistry at the r i n g j u n c t i o n of these substances. Thus, when a methanol s o l u t i o n of a mixture of (160) and (161) ( r a t i o 1:2, r e s p e c t i v e l y ) was heated to r e f l u x for 18 h i n the presence of sodium methoxide, (161) was produced as the so le product . When each of (160) and (161) was e q u i l i b r a t e d under the same cond i t i ons , (160) was completely converted in to (161), while (161) was recovered unchanged. Therefore , the e q u i l i b r i u m (160) (161) favored e x c l u s i v e l y (161). Since the t rans - fused isomer would be expected to be more s table than the c i s - f u s e d isomer, these substances were assigned s tructures (161) and (160), r e s p e c t i v e l y . C y c l i z a t i o n of the compound (154) furnished a mixture of (162) and (163) i n a r a t i o of 3 .5:1 , r e s p e c t i v e l y (g lc ana lys i s ) (equation 21). Compounds (162) and (163) were very d i f f i c u l t to separate by column chromatography on s i l i c a g e l . However, p a r t i a l separat ion was accom-p l i s h e d by subjec t ion of the mixture to column chromatography on 25% 0 CI THF KH (21) 154 162 163 - 49 -s i l v e r n i t r a t e impregnated s i l i c a g e l . - ^ gy t h i s means, a n a l y t i c a l l y pure samples of (162) and (163) were obtained. The nmr spectrum of (162) showed the t e r t i a r y methyl s i n g l e t at 5 1.17, while the o l e f i n i c protons gave r i s e to two s i n g l e t s at 6 4.73 and 4.76. In a nOe d i f f erence experiment, i r r a d i a t i o n at S 1.17 (bridgehead methyl s i n g l e t ) caused enhancement of two one-proton s igna l s at 5 4.73 (s) and at S 2.15 (d of d, J = 10, 4 Hz) . On the bas i s of the chemical s h i f t and s p i n - s p i n coupl ing p a t t e r n , the s i g n a l at S 2.15 was assigned to B.Q. Furthermore, i t was evident from the nOe experiment that the s i g n a l at 6 4.73 was der ived from H A , and there fore , the s i g n a l at 6 4.76 could be assigned to Hg. The nOe experiment a l so showed that (162) possessed a c i s - f u s e d r i n g j u n c t i o n . In the ^H nmr spectrum of (163), which should be the trans isomer, the t e r t i a r y methyl group gave r i s e to a s i n g l e t at 6 0.95, while the two o l e f i n i c protons appeared as a m u l t i p l e t at 5 4 .70-4.76. The assignment of stereochemistry at the r i n g j u n c t i o n of compounds (162) and (163) was fur ther v e r i f i e d by e q u i l i b r a t i o n experiments. When each of (162) and (163) was e q u i l i b r a t e d (MeONa/MeOH, r e f l u x , 18 h) a mixture of (162) and (163) i n a r a t i o of 1:2.8, r e s p e c t i v e l y , (glc ana lys i s ) was obtained i n each case. Thus, the e q u i l i b r i u m (162);=* (163) favored the more s table trans isomer (163). A mixture of (165) and (166) i n a r a t i o of 8:1 (glc a n a l y s i s ) , r e s p e c t i v e l y , was obtained from the c y c l i z a t i o n of compound (156) (equation 22). Again , p a r t i a l separat ion of (165) and (166) was achieved by subjec t ion of t h i s mixture to column chromatography on s i l i c a ge l impregnated with 25% s i l v e r n i t r a t e . A n a l y t i c a l l y pure - 50 -samples of (165) and (166) were obtained i n t h i s manner. The nmr spectrum of (165) exh ib i t ed three t e r t i a r y methyl s i n g l e t s at 6 1.05, 1.06 and 1.26, while the two o l e f i n i c protons gave r i s e to a quartet (J = 1.5 Hz) at 6 4.77 and a broad s i n g l e t at 5 4.80. In a nOe d i f f erence experiment, i r r a d i a t i o n at 5 1.26 (a t e r t i a r y methyl s i n g l e t ) caused enhancement of the s igna l s at 5 1.06 (3H, s ) , 2.13 (d of d, 1H, J = 8, 4.5 Hz) , and 4.80 (br s ) . Since only the bridgehead methyl group was c lose enough to cause nOe enhancement of the o l e f i n i c proton at S 4.80, the s i g n a l at 8 1.26 was assigned to MeG and the resonance at 8 4.80 was assigned to Hg. The other o l e f i n i c proton HQ was assigned to the s i g n a l at 6 4.77. Furthermore, the s igna l s at 8 1.05 and 1.06 were a t t r i b u t e d to Mep and Meg, r e s p e c t i v e l y . F i n a l l y , the resonance at 6 2.13 could be assigned to H^. From the nOe exper i -ment, i t was concluded that (165) contained a c i s - c u s e d r i n g j u n c t i o n . In the 1-H nmr spectrum of (166), the trans isomer, three s i n g l e t s due to the three t e r t i a r y methyl groups appeared at 8 1.04, 1.10 and 1.14, while the o l e f i n i c protons gave r i s e to two broad s i n g l e t s at 8 4.70 and 4.73, r e s p e c t i v e l y . E q u i l i b r a t i o n experiments supported the stereochemistry assignments - 51 -for (165) and (166). Thus, when a methanol s o l u t i o n of the mixture of (165) and (166) ( r a t i o 8:1, r e s p e c t i v e l y ) was heated to r e f l u x for 18 h i n the presence of sodium methoxide, a mixture of (165) and (166) i n a r a t i o of 1:2, r e s p e c t i v e l y , (glc ana lys i s ) was obtained. Therefore , the e q u i l i b r i u m (165) (166) favored the more s table trans isomer (166). C y c l i z a t i o n of the compound (157) provided a mixture of (167) and (168) i n a r a t i o of - 5 : 1 , r e s p e c t i v e l y (glc ana lys i s ) (equation 23). Column chromatography of t h i s mixture on s i l i c a ge l impregnated with 25% s i l v e r n i t r a t e gave a small amount of pure (167). Compound (168) could not be separated i n pure form by t h i s method. o c ' 157 The 1H nmr spectrum of (167) exh ib i t ed two s i n g l e t s at 5 4.79 and 4.80, a t t r i b u t a b l e to the o l e f i n i c protons . In a nOe d i f f erence exper i -ment, i r r a d i a t i o n of a one-proton s i g n a l at 6 2.95 (d of t , J = 7, 7 Hz) caused enhancement of the s i g n a l at 8 4.79 ( s ) . On the bas i s of the chemical s h i f t s , prox imity i n space and/or s p i n - s p i n coupl ing p a t t e r n , the resonances at 5 2.95 and 4.79 were assigned to H A and Hg, r e s p e c t i v e l y . Consequently, H c was assigned to the s i g n a l at S 4 .80. The nmr of a mixture of (167) and (168) showed that the alkene protons of (168) resonated at 6 4.66 (s) and 4.77 (br s ) . - 52 -When a mixture of (167) and (168) ( r a t i o 84:16, r e s p e c t i v e l y ) was e q u i l i b r a t e d (MeONa/MeOH, r e f l u x , 18 h ) , a mixture of (167) and (168) i n a r a t i o of 82:18, r e s p e c t i v e l y , (g lc ana lys i s ) was obtained. When a pure sample of (167) was e q u i l i b r a t e d under the same c o n d i t i o n s , a 85:15 mixture of (167) and (168), r e s p e c t i v e l y , (glc ana lys i s ) was obtained. On the bas i s of the r e s u l t s of the e q u i l i b r a t i o n experiments and the f a c t that the c i s - f u s e d product would be the f i r s t - f o r m e d ( k i n e t i c ) product from the r i n g c losure r e a c t i o n , ( 1 6 7 ) was ass igned to be the c i s isomer and (168) was assigned to be the trans isomer. I n t e r e s t i n g l y , the c y c l i z a t i o n of compound (158) produced only one compound (169) (equation 24). The nmr spectrum of (169) showed a 158 169 s i n g l e t at 8 1.34 due to the t e r t i a r y methyl group while o l e f i n i c protons gave r i s e to two s i n g l e t s at 8 4.77 and 4.81. Attempted e q u i l i b r a t i o n of a methanol s o l u t i o n of (169) i n the presence of sodium methoxide ( r e f l u x , 18 h) gave no detectable change i n the crude product . Re f lux ing (18 h) a s o l u t i o n of (169) i n MeOD i n the presence of sodium methoxide gave a t r i d e u t e r i o compound (171) (equation 25) (mass spectrum molecular i on at m/e 167). The nmr spectrum of (171) a lso showed the t e r t i a r y methyl s i n g l e t at 5 1.34 and the s igna l s due to the o l e f i n i c protons at 5 4.77 (s) and 4.81 ( s ) . From the r e s u l t s of e q u i l i b r a t i o n 53 -° H NaOMe ° D MeOD reflux > D (25) 169 171 experiments and the f a c t that the k i n e t i c product of the c y c l i z a t i o n process would be the c i s - f u s e d b i c y c l i c ketone, -*® the annulat ion product der ived from (158) was assigned s t ruc ture (169). The r e s u l t s of the e q u i l i b r a t i o n experiments descr ibed above are summarized i n Table I I I . Not unexpectedly, the t rans - fused compounds [(161), (163), (166)] were found to be more s table than the corresponding c i s - f u s e d epimers i n the b i c y c l o [ 4 . 4 .0 ] d e c a l o n e s e r i e s . On the other hand, the c i s - f u s e d isomers [(167), (169)] were found to be predominant for the b icyc lo[4 .3.0 ]nonanones . In summary, the o v e r a l l y i e l d s of the methylenecyclohexane annula-t i o n sequences summarized i n Table II v a r i e d from 40% (entry 4) to 70% (entry 1) . Cons ider ing the b r e v i t y of the r e a c t i o n sequence and the f a c t that the methylenecyclohexane moiety i s qui te commonly found i n members of the terpenoid fami ly of n a t u r a l products , the annulat ion process descr ibed above should f i n d use i n organic synthes i s . - 54 -Table I I I : E q u i l i b r a t i o n of the Annulated Product(s) Entry C y c l i z e d product(s) r a t i o 3 a f t e r e q u i l i b r a t i o n 1 3 <1:>99 1:2.8 1:2 -5:1 no change 169 Rat ios were determined by g a s - l i q u i d chromatography. E q u i l i b r a t i o n was c a r r i e d out by r e f l u x i n g (18 h) a methanol so lu -t i o n of the c y c l i z e d product(s) i n the presence of sodium methoxide. - 55 -I I I . T o t a l Syntheses of the Sesquiterpenoids ( ± ) - A x a m i d e-1 , ( ± ) - A x i s o -n i t r i l e-1, and the Corresponding C-10 Epimers A. In troduct ion The i s o n i t r i l e func t ion i s a very rare feature i n nature . Most of the n a t u r a l l y o c c u r r i n g i s o n i t r i l e s d iscovered so far are of marine o r i g i n . In general , terpenoid i s o n i t r i l e s i s o l a t e d from marine sources have carbon skeletons that are qui te d i f f e r e n t from the carbon skeletons of terpenoids from t e r r e s t r i a l sources. The f i r s t n a t u r a l l y occurr ing i s o n i t r i l e , x a n t h o c i l l i n (172),-^ was i s o l a t e d from cu l tures of p e n i c i l l i u m notatum West l ing by Rothe i n 1950. HO—<^^— CH=C— C=CH—<^^0H 172 I t was not u n t i l 1973 that a second n a t u r a l i s o n i t r i l e , (+)-axiso-n i t r i l e - 1 (173),-^ was i s o l a t e d and charac ter i zed by S i ca and co-workers. ( + ) - A x i s o n i t r i l e - 1 (173), the f i r s t i socyano-conta in ing sesqui terpenoid i s o l a t e d from marine sources, was obtained from the sponge A x i n e l l a cannabina. A number of i s o n i t r i l e s i s o l a t e d from marine sources have been reported s ince that time.-'-' Most of these are sesquiterpenoids while a few of them are d i terpeno ids ; most of them are monofunct ional ized while a few of them are p o l y f u n c t i o n a l i z e d . - 56 -12 173 R* NsC 1 7 6 1 7 7 174 R= NCHO H 175 R= N=C=S I t i s i n t e r e s t i n g to po in t out that most of the i s o n i t r i l e s found i n nature co-occur with the corresponding isothiocyano and formamido d e r i v a t i v e s . For example, (+)-axamide-1 (174)-^ and (+) -axisothio-cyanate-1 (175)-^ were i s o l a t e d from the same marine sponge that produced ( + ) - a x i s o n i t r i l e - 1 (173). ( + ) - A x i s o n i t r i l e - 1 (173)-^ was shown to possess an axane (176) carbon ske le ton , which i s a l so present i n the n a t u r a l product oppos i to l (177) .^ 7 This carbon framework has not been encountered among t e r r e s t r i a l n a t u r a l products . Compound (173) e x h i b i t e d mp 4 3 - 4 5 ° C and [ a ] D +22.6 (CHCI3) , and was found to have a s t r u c t u r a l formula C]_6H25N (elemental ana lys i s and mass spectrum). From the i r and nmr of (173), the fo l l owing s t ruc ture un i t s were i n d i c a t e d : a secondary i s o n i t r i l e f u n c t i o n (^max 2130 cm"-'- and a one-proton m u l t i p l e t at 6 3.13, ^CH-NC), an exocyc l i c methylene u n i t ( ^ m a x 3050, 1640, 895 cm" 1 , a two-proton s i n g l e t at S 4 .75) , a t e r t i a r y methyl group ( a three-proton s i n g l e t at 6 0 .99) , and two secondary methyl groups probably - 57 -be longing to an i s o p r o p y l group ( i / m a x 1385 and 1375 cm"-'-, two doublets at 5 0.85 and 1.03, J = 6 Hz i n each case) . From these f a c t s , ( + ) - a x i s o n i t r i l e - 1 should be a b i c y c l i c sesqui terpenoid i s o n i t r i l e . Chemical transformations were c a r r i e d out to provide fur ther informat ion concerning the s t ruc ture of ( + ) - a x i s o n i t r i l e - 1 (173) (Schemes 17 and 18). Thus, ( + ) - a x i s o n i t r i l e - 1 (173) was t rea ted with l i t h i u m aluminum hydride to give the amine (178) . Hofmann exhaustive m e t h y l a t i o n - e l i m i n a t i o n on (178) provided a diene (179), which was shown \ ^ M e i to conta in a .CH-CH = C u n i t by i t s -"-H nmr spectrum. Hence, the u n i t / \Me ^CH-CH(NC)-CHMe 2 should be present i n (173). Scheme 17 Removal of the i s o n i t r i l e func t ion could be achieved by treatment of (173) with sodium i n l i q u i d ammonia. The product of t h i s r e a c t i o n was compound (180). Ozonolysis of (180) gave the ketone (181), which was shown to have a ketone func t ion on a six-membered r i n g (^max 1707 cm"-') . The ketone (181), upon being subjected to B a e y e r - V i l l i g e r o x i d a t i o n , a f forded the lactone (182). In the ^H nmr spectrum of (182), - 58 184 183 182 Scheme 18 I a doublet at 5 3.72 (1H, J = 5 Hz, H-C-O) was present . A l k a l i n e h y d r o l y s i s of (182) gave the hydroxy a c i d (183) , which contained the I u n i t H-C-OH (6 3.25, 1H, J = 6.5 Hz) . Jones' o x i d a t i o n of (183) gave a cyclopentanone compound (184) ( ^ m a x 1738 cm" 1 ) . On the bas i s of these r e s u l t s and those reported e a r l i e r , s t ruc ture (173) was proposed for ( + ) - a x i s o n i t r i l e - 1 . However, at t h i s stage, the s tereochemistry of t h i s n a t u r a l product was not known. The r e l a t i v e and absolute stereochemistry of ( + ) - a x i s o n i t r i l e - 1 (173) were e s ta b l i s h e d by M. A d i n o l f i et a l . 5 8 i n 1977. (+)-Axiso-- 59 n i t r i l e - 1 (173) was converted in to the c r y s t a l l i n e p_-bromophenylthiourea d e r i v a t i v e (185). The r e l a t i v e c o n f i g u r a t i o n of (185), as shown, was determined by X - r a y d i f f r a c t o m e t r i c measurements. The absolute conf igu-r a t i o n of ( + ) - a x i s o n i t r i l e - 1 was determined by means of a CD measurement performed on the ketone (181). This measurement showed that (+)-axiso-n i t r i l e - 1 possesses the absolute c o n f i g u r a t i o n shown i n s t r u c t u r e (173). H p-BrCcH/NSCN< 6 A H H 185 (+)-Axamide-l (174) was i s o l a t e d i n r e l a t i v e l y small amounts from the same sponge ( A x i n e l l a cannabina) that produced ( + ) - a x i s o n i t r i l e - 1 ( 1 7 3 ) . 5 6 Compound (174) { [a ] D + 1 0 . 0 ° (CHC1 3 ) , rj D 1.5087} was obtained as a c o l o r l e s s o i l , which was shown to have a s t r u c t u r a l formula <~16H27 N O (mass spectrum and elemental a n a l y s i s ) . The i r and nmr spectra of (174) showed that t h i s mater ia l possessed the fo l lowing s t r u c t u r a l u n i t s : a -NHCHO funct ion ( ^ m a x 3350-3150, 1687 cm" 1 ) , an e x o c y c l i c methylene group [^m a x 3050, 1640, 895 cm" 1 , S 4.68 (2H, bm)], a t e r t i a r y methyl group (s, 3H, S 0 .94) , and two secondary methyl groups, probably belonging to an i s o p r o p y l group (^max 1385 and 1375 cm" 1 , two doublets at 5 0.88 and 0.80, 3H each, J = 6 Hz i n each case) . A l l of these data i n d i c a t e d that there was a c lose s t r u c t u r a l r e l a t i o n s h i p between (+)-axamide-l and ( + ) - a x i s o n i t r i l e - 1 (173). This - 60 -was confirmed by hydrat ion of (173) to a f f o r d the corresponding formamide (equation 26), which showed p h y s i c a l , spectroscopic and chromatographic p r o p e r t i e s i d e n t i c a l with those e x h i b i t e d by (+)-ax-amide-1. Therefore , (+)-axamide-1 was shown to possess the s t ruc ture (174). 173 174 N a t u r a l l y o c c u r r i n g i s o n i t r i l e s u s u a l l y e x h i b i t i n v i t r o cy to tox ic p r o p e r t i e s as w e l l as ant i feedant a c t i v i t i e s . - ^ 9 ( + ) - A x i s o n i t r i l e - 1 (173) has been shown to possess t o x i c i t y , but no ant i feedant proper t i e s were d e t e c t e d . 5 5 J > 5 9 b B. T o t a l Syntheses of ( ± ) - A x a m i d e - 1 , ( ± ) - A x i s o n i t r i l e - 1 , and the Corresponding C-10 Epimers I t i s obvious that d e h y d r a t i o n ^ of axamide-1 (174) would provide a x i s o n i t r i l e - 1 (173), while the former substance could i n turn be prepared by f o r m y l a t i o n ^ 1 of the corresponding amine (186) (equation 27). Hence, the t o t a l syntheses of ( ± ) - a x a m i d e - 1 (174) and ( ± ) - a x i s o -n i t r i l e - 1 (173) would be reduced to the synthesis of the racemic - 61 -amine (186). Retrosynthet i c analyses revealed that two reasonable s t ra teg ie s could be envisaged to carry out the synthesis of the amine (186). Strategy A was based on the r e c o g n i t i o n that a major par t of the mole-cule could be assembled by a synthet ic combination of substances equiva-l ent to synthons (76) and (189) (Scheme 19). As had a lready been shown, the Grignard reagent (144) or the organocopper reagent (145) could serve Scheme 19 - 62 -as equivalents to the 1-pentene d^a-^ synthon (76). A p o t e n t i a l equivalent to the synthon (189) would be the enone (190). Thus, the methyenecyclohexane annulat ion sequence descr ibed e a r l i e r would be used to prepare the necessary carbon ske le ton. E x p l i c i t l y , r e a c t i o n of 190 189 e i t h e r reagent (144) or (145), under appropriate c o n d i t i o n s , with the enone (190) would be expected to proceed i n the d e s i r e d stereochemical sense to give the corresponding conjugate a d d i t i o n product (191) (equation 28). C y c l i z a t i o n of the l a t t e r substance would f u r n i s h (192) with the same r e l a t i v e stereochemistry as that of (186) at the three - 63 -carbon centers , C - l , C-8 and C-9 . Removal of the ketone f u n c t i o n ^ 2 from (192), with concommitant h y d r o l y s i s of the amide, fol lowed by a l k y l a -6 3 t i o n of the r e s u l t a n t c a r b o x y l i c a c i d with an i s o p r o p y l h a l i d e , would y i e l d the a c i d (187) and, presumably, the corresponding epimer (193). The a c i d (187) could be converted v i a the a c i d c h l o r i d e (194) in to the a c y l azide (195). Cur t ius rearrangement of the l a t t e r substance would g ive , a f t e r appropriate manipulat ion of the r e s u l t a n t isocyanate (196), the amine ( 1 8 6 ) . 6 4 194 R= COCl 195 R= CON 3196 R= N=C=0 With respect to the synthesis of the enone (190), i t was envis ioned that t h i s m a t e r i a l could be prepared by a'-alkylation^^ of the unsaturated ketone (198), fol lowed by hydride r e d u c t i o n - a c i d h y d r o l y s i s of the r e s u l t a n t product ( 1 9 7 ) 6 6 (Scheme 20). A l t e r n a t i v e l y , - 64 -a ' - a l k y l a t i o n " ' of (152), fol lowed by a 1 ,3 -carbonyl t r a n s p o s i t i o n " 8 on the r e s u l t a n t product (199) would a lso provide the enone (190) (Scheme 20) . An a l t e r n a t i v e approach to the synthesis of the amine (186) ( s trategy B) would involve a sequence conta in ing two key steps. One of the key steps would involve the synthet ic combination of substances equiva lent to the synthons (200) and (201) to assemble the carbon framework of (187) (Scheme 21). The 0- t r i m e t h y l s i l y l ketene ace ta l (202) would serve as a synthet ic equivalent to the synthon (201), while the enone (203) would correspond to the synthon (200). Michael a d d i t i o n ^ 9 o f (202) to the enone (203) would be expected to occur p r e f e r e n t i a l l y from the convex (/3) face of compound (203) to provide a - 65 -OTMS OEt X 202 201 200 product (204) with the c o r r e c t r e l a t i v e stereochemistry at C - l , C-8 and C-9 (equation 29). The corresponding epimer (205) would, presumably, be formed along with (204). Removal of the ketone f u n c t i o n 6 2 from (204), - 66 -accompanied by h y d r o l y s i s of the es ter , would give the a c i d (187). The a c i d (187) would be converted in to the requ ired amine (186) v i a the sequence of react ions o u t l i n e d p r e v i o u s l y . Compound (203) could be der ived from the corresponding ketone (170), which could i n turn be prepared by the other key convers ion i n the synthes i s , the methylenecyclohexane annulat ion sequence descr ibed e a r l i e r (Scheme 22). Thus, i t had a lready been shown that conjugate a d d i t i o n of e i t h e r reagent (144) or (145) to the enone (152), fol lowed by c y c l i z a t i o n of the r e s u l t a n t product , provided the c i s - fused b i c y c l i c ketone (170). 203 170 76 206 Scheme 22 A l l attempts to synthesize the amine (186) v i a s trategy A (Schemes 19 and 20) f a i l e d . For examples, r e a c t i o n of (207) with d i i s o b u t y l -aluminum hydride i n THF at - 7 8 ° C , fol lowed by a c i d h y d r o l y s i s of the Compound (207) was prepared (61%) by the a'-alkylation of 3-methoxy-2-methyl -2-cyc lopenten- l -one (198) (R=CH3) with N,N-diethylbromo-acetamide i n T H F . 6 5 67 152 205 r e s u l t a n t product mixture, provided the des i red enone (190) i n only 14% y i e l d . A l s o produced was the isomer (199) (34%) and an inseparable mixture of uncharacter ized compounds (19%) . On the other hand, t r e a t -ment of (207) with sodium borohydride i n the presence of cerium t r i c h l o r i d e hexahydrate i n ethanol at 6 5 ° C , / u gave the enone (190) i n only 18% y i e l d . Some s t a r t i n g mater ia l (207) (24%) was recovered. No detectable r e a c t i o n was observed at room temperature a f t e r 3 h. - 68 -Removal of the ketone funct ion from (192)* ( N H 2 N H 2 - H 2 0 , KOH, D E G ) 7 1 with concommitant h y d r o l y s i s of the amide, provided (79%) two insepara-b le ac ids i n a r a t i o of -8:1 (glc ana lys i s ) [ i r : ^ m a x 3400-2500 cm" 1 ( b r ) , 1705 cm" 1 ] . The nmr spectrum of t h i s mixture e x h i b i t e d three m u l t i p l e t s at 5 4.62, 4.75 and 5.36, with r e l a t i v e areas of -8 :8 :1 , r e s p e c t i v e l y . Thus, i t appeared that the Wol f f -Kishner reduct ion of (192) gave r i s e to a mixture of the des i red a c i d (188) and the isomer (208), i n a r a t i o of - 8 : 1 , r e s p e c t i v e l y . Furthermore, the r e l a t i v e amounts of (188) and (208) formed i n the r e d u c t i o n - h y d r o l y s i s r e a c t i o n v a r i e d from experiment to experiment. In f a c t , i n most of the exper i -ments, the r a t i o [(188):(208)] was cons iderably l e ss than 8:1. F i n a l l y , attempted a l k y l a t i o n (2.5 equivalents LDA, THF, HMPA; i s o p r o p y l i o d i d e 6 ^ ) of the mixture of acids (188) and (208) ( r a t i o 4:1, r e s p e c t i v e l y ) f a i l e d . The mater ia l recovered from the r e a c t i o n mixture 192 188 208 Compound (192) was prepared by the methylenecyclohexane annulat ion sequence descr ibed e a r l i e r . Thus, conjugate a d d i t i o n of 2-bromo-magnesio-5-chloro-1-pentene (144) to the enone (190) i n the presence of copper(I) s a l t and boron t r i f l u o r i d e - e t h e r a t e fo l lowed by c y c l i -z a t i o n , provided (192) i n 35% y i e l d . - 69 -was a mixture of the ac ids (188) and (208) ( r a t i o 4:1, r e s p e c t i v e l y , 75%). On the other hand, when the dianions der ived from the mixture of ac ids (188) and (208) ( r a t i o 2:1, r e s p e c t i v e l y ) were quenched with deuterium oxide, a 2:1 mixture of products (glc a n a l y s i s ) was obtained i n 71% y i e l d . On the bas i s of s p e c t r a l data [ i r : ^ m a x 3400-2500 cm" 1 ( b r ) , 1705 cm" 1 ; Exact Mass c a l c d . for C 1 3 H 1 9 0 2 D : 209.1527; found: 209.1523], t h i s mixture was concluded to c o n s i s t l a r g e l y of the corres -ponding mono-deuterated products of (188) and (208). At t h i s po in t s trategy A for the synthesis of the amine (186) was abandoned and an i n v e s t i g a t i o n of s trategy B (Schemes 21 and 22) was i n i t i a t e d . At the outset , i t was c l e a r that the synthesis of ( ± ) - a x a m i d e - 1 (174) and ( ± ) - a x i s o n i t r i l e - 1 (173) res ted h e a v i l y on the a c q u i s i t i o n of r e l a t i v e l y large q u a n t i t i e s of the ketone (170). Of the two methods p r e v i o u s l y employed for e f f e c t i n g a d d i t i o n of the 5 -ch loro- [2 -(1-pentenyl)] group to the enone (152), the modif ied Noyori procedure was d i scarded because, i n large sca le r e a c t i o n s , the necessary separat ion of t r i - n - b u t y l p h o s p h i n e from the des i red product proved to be quite ted ious . On the other hand, i n the e a r l i e r experiments, the y i e l d of (170) from the copper ( I ) - ca ta lyzed r e a c t i o n of the Grignard reagent (144) (1 equiv) with the enone (152) (1 equiv) was qui te low (33%). I t was found, however, that t h i s s i t u a t i o n could be remedied by us ing an excess of the Grignard reagent ( 1 4 4 ) . 7 2 Thus, when a 1.3:1 molar r a t i o of (144) to (152), r e s p e c t i v e l y , was used for the conjugate a d d i t i o n r e a c t i o n , the y i e l d of the r e a c t i o n was cons iderably improved. S o l i d magnesium bromide-etherate (7.3 mmol) was added to a s o l u t i o n - 70 -of 5 - c h l o r o - 2 - l i t h i o - 1 - p e n t e n e (112) (7.3 mmol) i n dry THF. Successive a d d i t i o n of copper bromide-dimethyl s u l f i d e complex (1.8 mmol), 2 -methyl -2-cyc lopenten- l -one (152) (5.6 mmol), and boron t r i f l u o r i d e -etherate (7.3 mmol) gave a b r i g h t yel low s o l u t i o n which was s t i r r e d at - 7 8 ° C for 3 h . Appropriate workup gave the chloro ketone (159) i n 89% y i e l d . Upon exposure to potassium hydride i n THF, the ch loro ketone (159) c y c l i z e d to produce the ketone (170) i n 96% y i e l d . Thus, the o v e r a l l y i e l d of the annulat ion sequence [(152) ->• (170)] had been increased to 85%. By r e p e t i t i o n of th i s procedure, q u a n t i t i e s of the ketone (170) s u f f i c i e n t to c a r r y out the p r o j e c t e d synthes is were obtained. 170 The -^ H nmr spectrum of (170) was cons i s tent with the assigned s t r u c t u r e . The t e r t i a r y methyl s i n g l e t appeared at 5 1.04 while the o l e f i n i c protons gave r i s e to a m u l t i p l e t at S 4 .76-4.83. The c i s r i n g j u n c t i o n of (170) was v e r i f i e d by a nOe d i f f erence experiment. Thus, i r r a d i a t i o n at 5 1.04 ( r i n g j u n c t i o n methyl s i n g l e t ) caused enhancement of a one-proton s i g n a l at 5 2.49 (d of d, J = 12, 8 Hz) . On the bas is of chemical s h i f t and the s p i n - s p i n coupl ing p a t t e r n , the l a t t e r reso-nance was assigned to H A . The i r spectrum of (170) showed an absorpt ion at 1730 cm" 1 , i n d i c a t i n g the presence of a carbonyl group. - 71 -In view of the presence of the exocyc l i c double bond i n (170), the convers ion of t h i s mater ia l in to the enone (203) was not expected to be s t ra igh t forward . Thus, one might expect that exposure of the product (203) to a c i d i c or bas i c medium could r e s u l t i n i somer iza t ion of the e x o c y c l i c double bond to give the f u l l y conjugated product (209). A p e r u s a l of the l i t e r a t u r e i n d i c a t e d that three p o t e n t i a l methods might be m i l d enough for conversion of the ketone (170) in to the enone (203) without the compl icat ion mentioned above. 203 209 The f i r s t and commonly used method i s the bromination of a t r i -m e t h y l s i l y l enol ether with bromine or N-Bromosuccinimide to give the corresponding a-bromo ketone. The l a t t e r substance can be dehydrobromi-nated to produce the corresponding enone by treatment with a mixture of l i t h i u m bromide and l i t h i u m carbonate i n r e f l u x i n g N,N-dimethyl-formamide. 7 ^ The second method makes use of organoselenium chemistry. Treatment of an enolate anion obtained from a ketone with phenylse lenenyl c h l o r i d e provides the corresponding a-phenylse lenide . The l a t t e r substance can be o x i d i z e d with a s u i t a b l e oxidant to the se lenoxide , which undergoes an e l i m i n a t i o n r e a c t i o n to produce the corresponding e n o n e . ^ The t h i r d and most recent method, reported by Saegusa, involves - 72 -r e a c t i o n of a t r i m e t h y l s i l y l enol ether with pa l ladium(II ) acetate i n a c e t o n i t r i l e to give the corresponding enone d i r e c t l y . 7 5 I n i t i a l l y , attempts were made to convert (170) in to the enone (203) v i a the second and t h i r d methods. However, the y i e l d of the enone (203) produced by the a-phenylse lenide method was low (-20%). Furthermore, use of the Saegusa procedure provided , i n only 15% y i e l d , a 72:28 mixture of the ketone (170) and the enone (203) r e s p e c t i v e l y . Since these two methods turned out to be u n s a t i s f a c t o r y , the f i r s t method (bromination-dehydrobromination) was inves t i ga ted . Treatment of the ketone (170) with LDA i n THF at - 7 8 ° C fol lowed by the a d d i t i o n of t r i m e t h y l s i l y l c h l o r i d e gave, a f t e r a non-aqueous workup, the t r i m e t h y l s i l y l enol ether (210) i n 99% y i e l d (equation 3 0 ) . 7 6 a The nmr spectrum of (210) showed a n ine -proton s i n g l e t at 5 0.21 due to the t r i m e t h y l s i l y l (-SiMe3) protons and a one-proton t r i p l e t at 5 4.48 (J = 2 Hz) due to the proton H A . React ion of the t r i m e t h y l s i l y l enol ether (210) with N-bromosucci-nimide i n dry THF at 0 ° C , gave the a-bromo ketone (211) (92%) as an 85:15 mixture (g lc ana lys i s ) (equation 3 1 ) . 7 ^ The i r spectrum of (211) e x h i b i t e d an absorpt ion at 1740 cm" 1 , i n d i c a t i n g the presence of a carbonyl group. - 73 -210 211 A so lut ion-suspens ion of the a-bromo ketone (211), l i t h i u m bromide, and l i t h i u m carbonate i n N,N-dimethylformamide was heated under r e f l u x for 3 h to provide the enone (203) i n 84% y i e l d (equation 3 2 ) . 7 ^ e 211 203 I n t e r e s t i n g l y , no i somer iza t ion of the e x o c y c l i c double bond was observed under the condi t ions employed. The i r spectrum of (203) showed an absorpt ion at 1700 cm" 1 , i n d i c a t i n g the presence of a cyclopentenone-type carbonyl group. The nmr spectrum of (203) e x h i b i t e d a s i n g l e t at S 1.12 due to the t e r t i a r y methyl group, a one-proton broad s i n g l e t at 5 3.23 due to the proton EQ, and two one-proton s igna l s at S 6.20 (d of d, J = 5.5, 2 Hz) and 7.48 (d of d, J = 5.5, 2.5 Hz) due to the protons H A and Hg, r e s p e c t i v e l y . A d d i t i o n a l l y , the two exocyc l i c methylene protons gave r i s e to two s i n g l e t s at 6 4.92 and 4.90. The c i s r i n g j u n c t i o n of (203) was, again , confirmed by a nOe d i f f erence experiment, i n which i r r a d i a t i o n at 5 1.12 ( t e r t i a r y methyl s i n g l e t ) - 74 -caused enhancement of the s i g n a l at 6 3.23 (H^). The next stage of the projec ted synthesis invo lved conjugate a d d i t i o n of the ketene a c e t a l (202) to the enone (203) to give (204) and/or (205). I t was evident from an examination of molecular models that t h i s conjugate a d d i t i o n would occur p r e f e r e n t i a l l y from the convex (/?) face of the enone molecule (equation 33). In t h i s manner, each of the c h i r a l centers C - l , C-8 and C-9 i n the products (204) and/or (205) would possess the des i red r e l a t i v e s tereochemistry. Whether or not the p r e f e r e n t i a l formation of (204) would be observed i n t h i s process was open to quest ion . Recent ly , Heathco ck?7 proposed an open t r a n s i t i o n state model to account for h i s observations of h igh s t e r e o s e l e c t i v i t y i n Lewis a c i d 75 -mediated Michae l addi t ions of s i l y l ketene aceta l s and/or enol s i l y l ethers to enones. For example, a d d i t i o n of the s i l y l ketene a c e t a l (212) to the a c y c l i c enone (213) i n the presence of t i tan ium t e t r a c h l o -r i d e produced, a f t e r base h y d r o l y s i s , a 96:4 mixture of (214) and (215), r e s p e c t i v e l y (equation 3 4 ) . 7 7 a The h igh s t e r e o s e l e c t i v e formation of + I •SiO D TiC(4 213 y 2) NaOH HO 212 214 + HO (34) 215 (214) was expla ined by p o s t u l a t i n g that the r e a c t i o n proceeded p r i m a r i l y v i a a t r a n s i t i o n s tate der ived from arrangement (216) ra ther than v i a a t r a n s i t i o n s tate der ived from (217) (equation 35). 214 216 u i f ^ © > 215 (35) I f one were to "apply" t h i s t r a n s i t i o n - s t a t e model to the r e a c t i o n of (203) wi th (202), one would a n t i c i p a t e that the d e s i r e d substance - 76 -(204) would be the major product der ived from t h i s transformat ion . The preference for the formation of (204) r e l a t i v e to (205) would be due to the f a c t that the s t e r i c hindrance present i n (219) would be greater than that present i n (218) (Scheme 23). However, s ince most of the s i l y l ketene aceta l s and enones used by Heathcock were s t e r i c a l l y quite demanding and s ince most of the enones he used were a c y c l i c compounds that were qui te d i f f e r e n t from compound (203), the v a l i d i t y of us ing t h i s open t r a n s i t i o n state model for the a d d i t i o n summarized i n equation 29 i s quest ionable . Treatment of the ester (220) wi th IDA i n THF, fo l lowed by a d d i t i o n of t r i m e t h y l s i l y l c h l o r i d e , provided a mixture of the (E) - and Scheme 23 - 77 -( Z ) - t r i m e t h y l s i l y l ketene a c e t a l s , (202) and (221), i n a r a t i o of 95:5, r e s p e c t i v e l y (g lc ana lys i s ) (equation 36). The •LH nmr spectrum of (202) e x h i b i t e d a n ine-proton s i n g l e t at 6 0.22 due to the t r i m e t h y l -s i l y l (-SiMe3) protons and a one-proton doublet at S 3.62 (J = 9 Hz) due to the v i n y l proton . / C 0 2 E t !)LDA,THF y \ 2JTMSCI 220 Treatment of the enone (203) with the t r i m e t h y l s i l y l ketene a c e t a l (202) i n r e f l u x i n g a c e t o n i t r i l e ^ b , c o r n i t r o m e t h a n e 6 ^ provided none of the conjugate a d d i t i o n products (204) and/or (205). Only the enone (203) was recovered from the r e a c t i o n mixtures . On the other hand, when a Lewis a c i d was present , the a d d i t i o n r e a c t i o n proceeded smoothly. I t i s known that treatment of an es ter with LDA i n THF, fol lowed by t rapping of the r e s u l t a n t enolate anion with t r i m e t h y l s i l y l c h l o r i d e , gives the corresponding ( E ) - t r i m e t h y l s i l y l ketene a c e t a l predominantly. On the other hand, the geometr ica l ly isomeric ( Z ) - t r i m e t h y l s i l y l ketene a c e t a l forms p r e f e r e n t i a l l y when the so lvent i s changed to 23% HMPA i n THF (see reference 78). The stereochemistry of the t r i m e t h y l s i l y l ketene ace ta l s was deduced from the ^H nmr spec tra . In general , the v i n y l proton of the ( E ) - t r i m e t h y l s i l y l ketene a c e t a l resonates at lower f i e l d than that of the ( Z ) - t r i m e t h y l s i l y l ketene a c e t a l (see reference 79). - 78 -Thus, a d d i t i o n of the t r i m e t h y l s i l y l ketene a c e t a l (202) to a mixture of the enone (203) and t i tan ium t e t r a c h l o r i d e i n dichloromethane furnished a mixture (-1:1, g lc ana lys i s ) of the conjugate a d d i t i o n products (204) and (205) i n 88% y i e l d (Scheme 24). When boron t r i f l u o r i d e - e t h e r a t e was used as Lewis a c i d i n the a d d i t i o n r e a c t i o n , an approximately 1:1 mixture (g lc ana lys i s ) of (204) and (205) was produced i n 83% y i e l d (Scheme 24). The use of s tannic t e t r a c h l o r i d e for the a d d i t i o n r e a c t i o n prov ided , again, a mixture (-1:1, g lc ana lys i s ) of (204) and (205) i n 50% y i e l d . In a d d i t i o n , 20% of the enone (203) was recovered (Scheme 24). M f m Lewis acid 0TMS > OEt 203 202 C H 2 C l 2 -78'C 2h C0 2E t 205 Lewis a c i d Rat io T i C l 4 S n C l 4 B F 3 - E t 2 0 46:54 46:54 48:51 Rat ios of (204) to (205) were determined by g lc a n a l y s i s . Scheme 24 Fol lowing I re land ' s p r o c e d u r e , ' 0 a 43:57 mixture of the (E) - and ( Z ) - t r i m e t h y l s i l y l ketene aceta l s (202) and (221), r e s p e c t i v e l y , (glc - 79 -a n a l y s i s ) was obtained (77%) by treatment of the es ter (220) with LDA i n 23% HMPA-THF, fo l lowed by the a d d i t i o n of t r i m e t h y l s i l y l c h l o r i d e . * The •'-H nmr spectrum of the mixture (202) and (221) showed that the v i n y l proton of (221) resonated at 6 3.33 (d, J = 8.5 Hz) . This mixture of t r i m e t h y l s i l y l ketene aceta l s (202) and (221) was al lowed to reac t with the enone (203) i n the presence of t i tanium t e t r a c h l o r i d e to g ive , i n 86% y i e l d , a mixture of (204) and (205) i n a r a t i o of 68:32, respec-t i v e l y (g lc a n a l y s i s ) . The experimental r e s u l t s summarized above i n d i c a t e d that Lewis a c i d - c a t a l y z e d a d d i t i o n of the t r i m e t h y l s i l y l ketene a c e t a l (202) to the enone (203) d i d not show any s t e r e o s e l e c t i v i t y with respect to the newly formed c h i r a l center i n the s ide c h a i n . However, the use of a 43:57 mixture of (202) and (221) d i d r e s u l t i n a s l i g h t preference for product (204) r e l a t i v e to (205). The mixture of (204) and (205) was p a r t i a l l y separated by us ing a combination of (slow) column chromatography on s i l i c a ge l and m u l t i p l e development preparat ive t i c ( e l u t i o n with 10:1 petroleum e t h e r - e t h e r ) . In t h i s way, pure samples of (204) and (205) were obtained for c h a r a c t e r i z a t i o n . The keto es ter (204) (mp 8 0 - 8 1 ° C , r e c r y s t a l l i z a t i o n from petroleum ether) e x h i b i t e d a carbonyl absorpt ion at 1730 cm"-'- i n i t s i r spectrum. The 1 H nmr spectrum of (204) (Figure 1) e x h i b i t e d a p a i r of doublets at 5 0.94 and 0.95 ( i sopropy l methyl groups, J = 7 Hz i n each case) , a s i n g l e t at 5 1.01 ( t e r t i a r y methyl group), a t r i p l e t at 5 1.23 See footnote on p. 77. - 81 -(-OCH2CH3, J = 7 Hz) , a p a r t i a l l y obscured one-proton m u l t i p l e t at 5 1.82-1.95 ( H B ) , a one-proton doublet of doublets at 5 1.94 (Hp, J = 18.5, 11.5 Hz) , a p a r t i a l l y obscured one-proton doublet at 6 2.15 (Hp, J = 11 Hz) , a p a r t i a l l y obscured one-proton doublet of doublets at 5 2.20 ( H c , J = 10, 4.5 Hz) , a one-proton doublet of doublets at S 2.65 (HQ, J = 1 8 . 5 , 7.5 Hz) , a one-proton m u l t i p l e t at S 2.79-2.93 ( H D ) , a two-proton m u l t i p l e t at 6 3.92-4.06 (-OCH2CH3), and a broad s i n g l e t and a t r i p l e t (J = 2 Hz) at S 4.72 and 4.77, r e s p e c t i v e l y (=CH 2 ) . The assignment of the s igna l s at S 1.94 (d of d, J = 18.5, 11.5 Hz) and 2.65 (d of d, J = 18.5, 7.5 Hz) to the s t rong ly coupled geminal protons Hp and HQ, r e s p e c t i v e l y , were based p a r t i a l l y on an examination of a molecular model, which showed that , i n what appears to be the most s tab le conformation of (204), the Hp-Hp d i h e d r a l angle approximates 1 8 0 ° whereas the HQ-H^ d i h e d r a l angle i s c lose to 3 0 ° . The mutual coupl ing between the protons Hp and HQ was confirmed by a decoupling experiment. Thus, i r r a d i a t i o n at S 2.65 (HQ) s i m p l i f i e d the s i g n a l at 5 1.94 (Hp) to an "imperfect" doublet (J = 11.5 Hz) (Figure 2) . In the same In t h i s decoupl ing experiment, the s i g n a l due to Hp should have c o l l a p s e d to a doublet (J = 1 1 . 5 Hz) . However, an "imperfect" doublet was obtained due to incomplete decoupl ing. - 82 -2-86 2-65 2-20 1-94 Fig. 2: The homonuclear spin decoupling experiments with (204): (a) the normal 400 MHz *H nmr spectrum expanded for the region 6 1.8-3.0, and the spectra with irradiations at (b) 6 0.95 (isopropyl methyl groups), (c) S 2.65 (H G), and (d) 6 2.86 (H D). - 83 -decoupl ing experiment, the m u l t i p l e t due to Hp (5 2.79-2.93) a lso s i m p l i f i e d . When Hp was decoupled, the s igna l s due to Hp and HQ at 5 1.94 and 2.65 co l l apsed to doublets ( J = 18.5 Hz i n each case) (Figure 2 ) . In the same decoupling experiment, the p a r t i a l l y obscured doublet of doublets due to H c at 5 2.20 co l l apsed to a doublet ( J = 4.5 Hz) while the p a r t i a l l y obscured doublet due to Hp at S 2.15 c o l l a p s e d to a s i n g l e t . In what appears to be the most s table conformation of (204), the d i h e d r a l angle between the t r a n s - r e l a t e d protons Hp and Hp i s c lose to 180° and, thus, the observed coupl ing constant (JED = 1 1 **Z) -*-S cons i s tent with the assigned stereochemistry. When the i s o p r o p y l methyl doublets at S 0.95 and 0.94 were both decoupled, the p a r t i a l l y hidden m u l t i p l e t due to Hg at 6 1.82-1.95 c o l l a p s e d to a very broad s i n g l e t * (Figure 2 ) . Using a nOe d i f ference experiment, i n which the s i g n a l at 5 1.01 (bridgehead methyl s i n g l e t ) was i r r a d i a t e d , enhancement of the s i g n a l at S 2.15 (Hp) was observed (Figure 3 ) . Therefore , the expectat ion that (204) possessed a c i s r i n g fus ion was v e r i f i e d . The keto es ter (205) (mp 69-70°C, r e c r y s t a l l i z a t i o n from petroleum ether) e x h i b i t e d a carbonyl absorpt ion at 1728 cm" 1 i n i t s i r spectrum. The ^H nmr spectrum of (205) (Figure 4) exh ib i t ed a p a i r of doublets at S 0.91 and 0.95 ( i sopropy l methyl groups, J = 7 Hz i n each case) , a s i n g l e t at 6 1.03 ( t e r t i a r y methyl group), a t r i p l e t at 5 1.27 T h e o r e t i c a l l y , the s i g n a l due to Hg should have c o l l a p s e d to a doublet (coupl ing constant = Jgc) • However, because of the in ter ference of the p a r t i a l l y over lapping doublet of doublets (Hp), only a very broad s i n g l e t was observed. (b) (a) CH 2=CV. i i 50 Hi r Tertiary C H 3 (CH 3 ) 2 CH-F i g . 3: The nOe difference experiment with (204): (a) the normal 400 MHz *H spectrum, and (b) the nOe d i f f e r e n c e spectrum with i r r a d i a t i o n at 6 1.01 (ring j u n c t i o n methyl group) 00 •P-86 -( - O C H 2 C H 3 , J = 7 Hz) , a one-proton m u l t i p l e t at 5 1.84-2.00 ( H B ) , a p a r t i a l l y obscured one-proton doublet at 8 2.30 (Hp, J = 11 Hz) , two one-proton doublet of doublets at 8 2.28 (J = 10, 4 Hz) and 2.52 (J = 17, 7 Hz) (HQ and HQ, r e s p e c t i v e l y ) , a two-proton quartet at 8 4.16 (-OCH2CH3, J = 7 Hz) , and two one-proton t r i p l e t s at 8 4.84 (J = 1.5 Hz) and 4.94 (J = 2 Hz) (=CH 2 ) . Assignment of the s i g n a l at 8 2.52 (d of d, J = 17, 7 Hz) to HQ was based on the chemical s h i f t and coupl ing constants assoc ia ted with th i s resonance. In what appears to be the most s table conformation of ( 2 0 5 ) , the HQ-HQ d i h e d r a l angle i s about 30°, while the H p - H D d i h e d r a l angle i s c lose to 180°. The observed coupl ing constants (17 Hz-geminal coupl ing; 7 H z - v i c i n a l coupl ing) are cons i s tent with HQ having the c o n f i g u r a t i o n shown i n ( 2 0 5 ) . The other proton (Hp) adjacent to the ketone funct ion was not c l e a r l y observed i n the ^H nmr spectrum of (205) . H B 205 When the i s o p r o p y l methyl s igna l s at 8 0.91 and 0.95 were both decoupled, the m u l t i p l e t at 8 1.84-2.00 due to Hg co l l apsed to a doublet (J = 10 Hz) (Figure 5 ) . Decoupling Hg caused the s igna l s due to the i s o p r o p y l methyl groups at 8 0.91 and 0.95 to co l lapse to s i n g l e t s - 87 -30 20 10 F i g . 5: The homonuclear sp in decoupling experiments with (205): (a) the normal 400 MHz ^H nmr spectrum for the reg ion S 0 .8 -3 .0 , and the spectra with I r r a d i a t i o n s at (b) S 0.92 ( i so -p r o p y l methyl groups) , and (c) 5 1.91 (Hg). 88 -(Figure 5 ) . In the same experiment, the doublet of doublets due to HQ at 5 2.28 co l l apsed to a very broad s i n g l e t (Figure 5 ) . In a nOe d i f f erence experiment, i n which the s i g n a l at 5 1.03 (bridgehead methyl s i n g l e t ) was i r r a d i a t e d , enhancement of a s i g n a l at 6 2.30 (d, J = 11 Hz) , which was p a r t i a l l y obscured, was observed (Figure 6 ) . On the bas i s of chemical s h i f t and s p i n - s p i n coupl ing p a t t e r n , the l a t t e r resonance was assigned to Hp. Thus, the expectat ion that (205) possessed a c i s - fused r i n g j u n c t i o n was confirmed. The trans r e l a t i o n h s i p of protons Hp and Hp was i n d i c a t e d by the coupl ing constant , Jprj = 11 Hz. In what appears to be the most s table conformation of (205), the d i h e d r a l angle between the t r a n s - r e l a t e d protons Hp and HQ i s c lose to 180° and, thus, the observed coupl ing constant i s cons i s tent with the assigned stereochemistry. Up to t h i s p o i n t , assignment of the stereochemistry at C-10 for both compounds (204) and (205) was not p o s s i b l e . However, i t was found l a t e r that compound (204) was r e l a t e d c o n f i g u r a t i o n a l l y to ( ± ) - a x a m i d e - l (174) and ( ± ) - a x i s o n i t r i l e - 1 (173). Therefore , for the sake of c l a r i t y , s t r u c t u r a l formulas (204) and (205) show the c o r r e c t r e l a t i v e s tereo-chemistry of these two substances. T h e o r e t i c a l l y , the s i g n a l due to HQ should have c o l l a p s e d to a doublet (JQ D = 4 Hz) when Hg was decoupled. However, a very broad s i n g l e t was obtained due to i n s u f f i c i e n t r e s o l u t i o n i n the spectrum and, probably , the in ter ference of the other p a r t i a l l y over lapping m u l t i p l e t . (b) (a) CfJ2=cC C H 3 C H 2 0-A H E Tertiary C H 3 C H 3 C H 20-rr H G H C H E Hi B 00 ( C H 3 ) 2 C H -J 5 0 AO 30 20 F i g . 6: The nOe difference experiment with (205): (a) the normal 400 MHz *H nmr spectrum, and (b) the nOe diffe r e n c e spectrum with i r r a d i a t i o n at 5 1.03 ( r i n g j unction methyl group). - 90 -I t appeared that Wol f f -Kishner reduct ion would be a s u i t a b l e method for removal of the ketone func t ion from (204). Presumably, the r e a c t i o n condi t ions assoc ia ted with t h i s r e a c t i o n would cause concommitant h y d r o l y s i s of the ester group. React ion of the pure keto ester (204) with anhydrous hydrazine and potassium hydroxide i n ethylene g l y c o l 7 1 produced a mixture of ac ids i n 61% y i e l d [ i r : ^ m a x 3500-2500 cm" 1 (br ) , 1702 cm" 1 ] . In the 1 H nmr spectrum of t h i s mixture, the o l e f i n i c protons gave r i s e to a broad s i n g l e t at 6 4.67, a broad s i n g l e t at 5 4.74, and a t r i p l e t at S 4.80 (J = 2 Hz) . The r e l a t i v e in tegrated areas of these s igna l s were near ly equal . I t was found l a t e r that the s i g n a l at 5 4.67 was r e l a t e d to the o l e f i n i c protons of the a c i d (187), while the s igna l s at 5 4.74 and 4.80 were r e l a t e d to the o l e f i n i c protons of the a c i d (193). Therefore , a 1:2 mixture of the ac ids (187) and (193), r e s p e c t i v e l y , was produced from the Wol f f -Kishner reduct ion of (204) (equation 37). C l e a r l y , p a r t i a l ep imer izat ion at C-10 of (204) had occurred under the r e a c t i o n condi t ions employed. The two products (187) and (193) , could not be separated by column chromatography on s i l i c a g e l . Et02C 204 H N H 2 N H 2 K0H DEG > C00H (37) 187 193 - 91 -When a mixture of the e t h y l esters (204) and (205) ( r a t i o -1:1) was subjected to base h y d r o l y s i s (KOH, EtOH, r e f l u x , 2 days) , a mixture of two compounds was obtained (equation 38). The i r spectrum of th i s mixture e x h i b i t e d a broad absorpt ion at 3400-2500 cm" 1 , which was a t t r i b u t e d to the 0-H s t r e t c h i n g v i b r a t i o n of a c a r b o x y l i c a c i d . In the same i r spectrum, two carbonyl absorptions at 1735 cm" 1 and 1703 cm" 1 were observed. The former absorpt ion was a t t r i b u t e d to a cyclopentanone type carbonyl group, while the l a t t e r peak was a t t r i b u t e d to a carbox-y l i c a c i d type carbonyl group. In the -^ H nmr spectrum of the product mixture, the o l e f i n i c protons gave r i s e to a t r i p l e t at 5 4.76 (J = 1.5 Hz) , a broad s i n g l e t at S 4.80, a broad s i n g l e t at 5 4.88, and a t r i p l e t at 5 4.94 (J = 2 Hz) . The r e l a t i v e in tegrated areas of these s igna l s were 1:1:2:2, r e s p e c t i v e l y . I t was found l a t e r that the s igna l s at 5 4.76 and 4.80 were r e l a t e d to the o l e f i n i c protons of the keto a c i d (222), while the s igna l s at 6 4.88 and 4.94 were r e l a t e d to the o l e f i n i c protons of keto a c i d (223). Thus, a 1:2 mixture of the keto acids (222) and (223) was produced from the base h y d r o l y s i s of the 1:1 mixture of e s ters (204) and (205). Again , p a r t i a l ep imer iza t ion at C-10 of compound (204) had occurred. - 92 -For tunate ly , the mixture of (222) and (223) could be separated by a combination of (repeated) column chromatography on s i l i c a ge l ( e l u t i o n with 3:2 petroleum ether-ether) and f r a c t i o n a l c r y s t a l l i z a t i o n from ether , to give the pure keto a c i d (222) i n 21% y i e l d and the pure keto a c i d (223) i n 50% y i e l d . The remaining mater ia l (11%) cons i s ted of a mixture of (222) and (223). The i r spectrum of (222) (mp 1 7 2 - 1 7 3 ° C , r e c r y s t a l l i z a t i o n from ether) exh ib i t ed carbonyl absorptions at 1735 and 1703 cm" 1 and a broad 0-H s t r e t c h i n g absorpt ion at 3400-2500 cm" 1 . The -^ H nmr spectrum of (222) (Figure 7) was very s i m i l a r to that of the corresponding e t h y l e s ter (204) (Figure 1) . Thus, the fo l lowing s igna l s were observed i n the -^H nmr spectrum of (222): a p a i r of doublets at 5 0.93 and 1.05 ( i sopropy l methyl groups, J = 7 Hz i n each case) , a s i n g l e t at 6 1.00 ( t e r t i a r y methyl group), an.obscured one-proton m u l t i p l e t at 5 1.86-2.00 (Hg), a p a r t i a l l y obscured one-proton doublet of doublets at 6 1.94 (Hp, J = 18.5, 11.5 Hz) , a p a r t i a l l y obscured one-proton broad doublet at 6 2.16 (Hp, J = 10.5 Hz) , a p a r t i a l l y obscured one-proton doublet of doublets at 5 2.21 ( H c , J = 9.5, 4.5 Hz) , a one-proton doublet of 222 - 94 -doublets at S 2.62 (HQ, J = 18.5, 7.5 Hz) , and a one-proton m u l t i p l e t at 5 2.71-2.85 (Hp). Furthermore, the o l e f i n i c protons gave r i s e to a t r i p l e t at 5 4.76 (J = 1.5 Hz) and a broad s i n g l e t at 5 4.80. The s igna l s at 5 1.94 (d of d, J = 18.5, 11.5 Hz) and 2.62 (d of d, J = 1 8 . 5 , 7.5 Hz) were assigned to the s trong ly coupled geminal protons Hp and HQ, r e s p e c t i v e l y . These assignments were based p a r t i a l l y on an examination of a molecular model, which showed that , i n what appears to be the most s tab le conformation of (222), the Hp-Hp d i h e d r a l angle approximates 1 8 0 ° whereas the HQ-Hp d i h e d r a l angle i s c lose to 3 0 ° . The coupl ing between Hp and HQ was confirmed by a decoupling experiment. Thus, i r r a d i a t i o n at 6" 2.62 (HQ) s i m p l i f i e d the s i g n a l at 5 1.94 (Hp)* (Figure 8) . In the same decoupling experiment, the s i g n a l due to Hp at 6 2.71-2.85 a l so s i m p l i f i e d (Figure 8) . When H D was decoupled, the s igna l s due to Hp and HQ at 6 1.94 and 2.62 c o l l a p s e d to "imperfect" doublets (J = 18.5 Hz i n each case) (Figure 8) . In the same decoupl ing experiment, the s igna l s due to Hp and HQ c o l l a p s e d to broad When HQ was decoupled, the s igna l s due to Hp should have co l lapsed to a doublet dlpp H - 5 Hz) . However, s ince the s i g n a l due to Hg overlapped with that of Hp, the co l lapsed doublet of Hp was not d i s t i n c t l y observed. When Hp was decoupled, the s igna l s due to Hp and HQ should have c o l l a p s e d to doublets with JpQ = 18.5 Hz i n each case. However, the formation of "imperfect" doublets for Hp and HQ was due to incomplete decoupling i n the decoupling experiment. 2-78 2-62 2 16 1-94 F i g . 8: The homonuclear sp in decoupling experiments with (222): (a) the normal 400 MHz ^H spectrum expanded for the reg ion 6 1.8-2 .9 , and the spectra with i r r a d i a t i o n s at (b) 5 2.62 ( H G ) , and (c) 5 2.78 (Hp). - 96 -s i n g l e t s (Figure 8 ) . The observed coupl ing constant between Hg and Hp (Jgp = 10.5 Hz) was cons i s tent with the assigned stereochemistry s ince , i n what appears to be the most s table conformation of (222) , the d i h e d r a l angle between the t r a n s - r e l a t e d protons Hg and Hp i s c lose to 180° . The keto a c i d (223) (mp 120-121 ° C , r e c r y s t a l l i z a t i o n from petroleum ether-e ther) showed carbonyl absorptions at 1733 and 1703 cm" 1 and a broad 0 - H s t r e t c h i n g absorpt ion at 3400-2500 cm" 1 i n i t s i r spectrum. The 1 H nmr spectrum of (223) (Figure 9) exh ib i t ed a p a i r of doublets at S 0.95 and 0.96 ( i sopropy l methyl groups, J = 6.5 Hz i n each case) , a s i n g l e t at S 1.03 ( t e r t i a r y methyl group), a one-proton m u l t i p l e t at 6 1.86-1.99 (Hg), a one-proton broad doublet at S 2.22 (Hg, J = 10.5 Hz) , a one-proton doublet of doublets at 6 2.32 (HQ, J = 9.5, 3.5 Hz) and a three-proton m u l t i p l e t at 5 2.46-2.70. Furthermore, the o l e f i n i c 223 When Hp was decoupled, the s i g n a l due to HQ should have c o l l a p s e d to a doublet with JgQ = 4.5 Hz. However, because of the presence of a p a r t i a l l y over lapping m u l t i p l e t , the co l l apsed doublet of HQ was only seen as a very broad s i n g l e t . - 98 -protons gave r i s e to a broad s i n g l e t at 6 4.88 and a t r i p l e t (J = 2 Hz) at 5 4.94. When the i s o p r o p y l methyl groups were both i r r a d i a t e d , the s i g n a l at 5 1.86-1.99 due to H B c o l l a p s e d to a doublet (J = 9.5 Hz) (Figure 10). When Hg was decoupled, the doublets due to the i s o p r o p y l methyl groups at 8 0.95 and 0.96 co l l apsed to s i n g l e t s . In the same decoupl ing experiment, the s i g n a l due to HQ at 5 2.32 c o l l a p s e d to a very broad s i n g l e t (Figure 10). When HQ was decoupled, the s i g n a l due to Hg at 6 1.86-1.99 co l l apsed to a septet (J = 6.5 Hz) , and the three-proton m u l t i p l e t at 6 2 .46-2.70, which presumably contained the proton Hp, s i m p l i f i e d . The assignment of the s i g n a l at 6 2.22 to Hg was based on the chemical s h i f t and s p i n - s p i n coupl ing p a t t e r n of th i s resonance and on a comparison of the nmr spectrum of (223) with that of the corresponding e t h y l es ter (205). Once more, the observed coupl ing constant between Hg and Hp (Jgp = 10.5 Hz) was cons i s tent with the assigned stereochemistry s ince , i n what appears to be the most s table conformati on of (223), the d i h e d r a l angle between the trans -r e l a t e d protons Hg and Hp i s c lose to 1 8 0 ° . At t h i s stage, there was s t i l l no information a v a i l a b l e concerning the stereochemistry at C-10 for (222) and (223). Thus, the' assigned s tereochemistr ies were based on the fac t that (222) was eventual ly converted in to ( ± ) - a x a m i d e - l (174) and ( ± ) - a x i s o n i t r i l e - 1 (173), while (223) was converted in to the corresponding C-10-epi compounds (224) and (225), r e s p e c t i v e l y . When Hg was decoupled, the s i g n a l due to HQ should have co l lapsed to a doublet (JQP = 3.5 Hz) . - 99 -reg ion 5 1 .8-2.8 , and the spectra with i r r a d i a t i o n s at (b) S 0.95 ( i sopropy l methyl groups) , (b) 5 1.92 (Hg), and (c) S 2.32 ( H C ) . - 100 -Presumably, under condi t ions of the Wol f f -Kishner reduc t ion , ep imer iza t ion adjacent to a c a r b o x y l i c a c i d func t ion would be slower than that adjacent to the corresponding es ter . Therefore , i t would be d e s i r a b l e to generate the keto acids (222) and (223) d i r e c t l y from the enone (203) . I t was f e l t that t h i s transformation could be done by r e a c t i o n of the l a t t e r mater ia l with the b i s ( t r i m e t h y l s i l y l ) ketene a c e t a l (226). Although react ions of b i s ( t r i a l k y l s i l y l ) ketene aceta l s with a l d e h y d e s , a ^ • B l S c h i f f b a s e s 8 1 and h a l i d e s 8 2 i n the presence of Lewis a c i d were known, conjugate addi t ions of these reagents to enones were, to our knowledge, not c a r r i e d out p r i o r to our work. Recent ly , RajanBabu reported that 1 , 1 - b i s ( t r i m e t h y l s i l o x y ) - 1 - p r o p e n e d i d not add to 2-cyc lopenten- l -one i n nitromethane at room t e m p e r a t u r e . 6 9 d React ion of 3-methylbutanoic a c i d (227) with 2.2 equivalents of LDA i n THF, fo l lowed by successive a d d i t i o n of HMPA and t r i m e t h y l s i l y l c h l o r i d e , gave 3 - m e t h y l - l , 1 - b i s ( t r i m e t h y l s i l o x y ) - 1 - b u t e n e (226) i n 86% y i e l d (equation 39). The ^H nmr spectrum of (226) exh ib i t ed two n ine -proton s i n g l e t s at 5 0.20 and 0.22 for the two t r i m e t h y l s i l y l (-SiMe3) groups, while the v i n y l proton gave r i s e to a doublet at 6 3.42 (J = 8 Hz) . A d d i t i o n of the b i s ( t r i m e t h y l s i l y l ) ketene a c e t a l (226) to the 101 -1) 2LDA,THF 2) HMPA 3) TMSCl OTMS OTMS (39) 227 226 enone (203) i n the presence of t i tanium t e t r a c h l o r i d e gave a -3:2 mixture of the keto acids (222) and (223) i n 93% y i e l d (equation 40). The r a t i o of the two products was deduced from the nmr spectrum of OTMS 1)T iC l A OTMS 2 ) H 2 ° 203 226 the mixture by c a r e f u l i n t e g r a t i o n of the resonance s igna l s due to the o l e f i n i c protons . Thus, the spectrum exh ib i t ed four s igna l s at 6 4.76 ( t , J = 1.5) , 4.80 (br s ) , 4.88 (br s ) , and 4.94 ( t , J = 2 Hz) . The r e l a t i v e in tegrated areas of these resonances were found to be 3:3:2:2, r e s p e c t i v e l y . Since pure samples of compound (222) and (223) had been obtained p r e v i o u s l y (vide supra) , i t was known that the two s igna l s at 6 4.76 and 4.80 were due to the o l e f i n i c protons of the keto a c i d (222), whi le the s igna l s at 6 4.88 and 4.94 arose from the o l e f i n i c protons of the keto a c i d (223). The mixture of (222) and (223) was separated by a combination of (repeated) column chromatography on s i l i c a ge l ( e l u t i o n with 3:2 petro-- 102 -leum ether-e ther) and f r a c t i o n a l c r y s t a l l i z a t i o n from ether. In t h i s manner, the pure keto a c i d (222) was obtained i n 44% y i e l d , while the pure keto a c i d (223) was acquired i n 32% y i e l d . The remaining m a t e r i a l (12%) cons i s t ed of a mixture of (222) and (223) . The i s o l a t e d pure keto ac ids (222) and (223) exh ib i t ed nmr spectra i d e n t i c a l with those descr ibed before . Wol f f -Kishner r e d u c t i o n 7 1 of the pure keto a c i d (222) (NH 2 NH 2 , KOH, DEG) gave, i n 90% y i e l d , the pure a c i d (187) without any observable 187 ep imer iza t ion (^H nmr spectroscopy) . The a c i d (187) (mp 1 2 0 - 1 2 1 ° C , r e c r y s t a l l i z a t i o n from petroleum ether-ether) e x h i b i t e d a broad 0-H s t r e t c h i n g absorpt ion at 3500-2500 cm" 1 and a carbonyl absorpt ion at 1703 cm" 1 i n i t s i r spectrum. The 1 H nmr spectrum of (187) showed a p a i r of doublets at 6 0.96 and 0.97 ( i sopropy l methyl groups, J = 7 Hz i n each case) , a s i n g l e t at 8 0.94 ( t e r t i a r y methyl group), a s i x - p r o t o n m u l t i p l e t at 8 1.35-1.66, a one-proton broad doublet at 8 1.86 (Hg, J = 10.5 Hz) , a three-proton m u l t i p l e t at 5 1.90-2.07, a one-proton doublet of doublets at 8 2.10 (HQ , J — 9.5, 5 Hz) , and a one-proton m u l t i p l e t at 8 2.46-2.58 (Hp). A d d i t i o n a l l y , the o l e f i n i c protons gave r i s e to a broad s i n g l e t at 8 4.67. When Hp was decoupled, the s i g n a l due to Hg at 5 1.86 c o l l a p s e d to a s i n g l e t while the s i g n a l due to HQ at 8 2.10 - 103 -c o l l a p s e d to a doublet (J = 5 Hz) . In the same decoupling experiment, the m u l t i p l e t s at 8 1.35-1.66 and 8 1.90-2.07 s i m p l i f i e d . The keto a c i d (223) was converted in to the a c i d (193) (an o i l ) (90%) v i a the same r e a c t i o n condit ions as those employed for the trans-formation of (222) in to ( 1 8 7 ) . 7 1 The i r spectrum of (193) showed a broad 0-H s t r e t c h i n g absorpt ion at 3500-2500 cm" 1 and a carbonyl absorpt ion at 1702 cm" 1 . The 1 H nmr spectrum of (193) e x h i b i t e d a p a i r of doublets at 5 0.93 and 0.94 ( i sopropy l methyl groups, J - 7 Hz i n each case) , a s i n g l e t at 5 0.95 ( t e r t i a r y methyl group), a p a r t i a l l y obscured broad doublet at 8 1.91 ( H E , J •= 11 Hz) , a p a r t i a l l y obscured m u l t i p l e t at 5 1.96-2.08 (Hg), a doublet of doublets at 8 2.18 ( H c , J - 9, 5 Hz) , and a one-proton m u l t i p l e t at 8 2.40-2.50 (Hp). Furthermore, the o l e f i n i c protons gave r i s e to a broad s i n g l e t at 8 4.74 and a t r i p l e t ( J = 2 Hz) at 5 4.80. When the i s o p r o p y l methyl groups were both decoupled, the s i g n a l due to Hg at 8 1.96-2.08 co l l apsed to a doublet (J = 9 Hz) . When HQ was decoupled, the s igna l s due to Hp and Hg at 8 2.40-2.50 and 5 1.96-2.08 s i m p l i f i e d . When Hp was decoupled, the s i g n a l due to Hg at 5 1.91 c o l l a p s e d to a broad s i n g l e t and the s i g n a l due to H c at 8 2.18 c o l l a p s e d to a doublet (J - 9 Hz) . C00H 193 - 104 -At t h i s p o i n t , i t i s i n t e r e s t i n g to compare some of the nmr s p e c t r a l data of compounds (204), (222) and (187), with those of the corresponding epimers (205), (223) and (193), r e s p e c t i v e l y (Table IV) . The s igna l s due to Hg and H c (6 1.84-2.00 and 2.28, r e s p e c t i v e l y ) i n compound (205) have chemical s h i f t s very s i m i l a r to those (5 1.82-1.95 and 2.20, r e s p e c t i v e l y ) of Hg and HQ i n the corresponding epimer (204). S i m i l a r observations could be made for the other two p a i r s of epimers (222)-(223) and (187)-(193) (see Table I V ) . Of more i n t e r e s t , however, were the coupl ing constants JgQ and JQQ i n the two ser i e s of epimeric compounds. Thus, for compounds (204), (222) and (187) the coupl ing constants JgQ and JQQ were found to be 4.5-5 Hz and 9.5-10 Hz r e s p e c t i v e l y . On the other hand, for the ser i e s of epimeric compounds [(205), (223), (193), r e s p e c t i v e l y ] , JgQ and JQQ were found to be 9-10 Hz and 3.5-5 Hz, r e s p e c t i v e l y . A c a r e f u l examination of molecular models ind ica te s that the observed coupl ing constants can be r a t i o n a l i z e d on the bas i s of confor-mational a n a l y s i s . Furthermore, such an a n a l y s i s , along with the ^H data provides some evidence regarding the stereochemistry at C-10 of the two ser i e s of epimeric compounds. I t i s pos tu la ted that compounds (204), (222) and (187) e x i s t l a r g e l y i n the conformation shown i n (235), while the epimeric substances (205), (223) and (193) adopt p r i m a r i l y the conformation represented by (236). Thus, i t i s proposed that for both s er i e s of compounds, the p r e f e r r e d conformation i s that i n which the bulky i s o p r o p y l group i s a n t i to C-8 , with the methine proton (Hg) c lose to C-2 as shown i n (235) and (236). In (235), the H C - H D d i h e d r a l angle approximates 1 8 0 ° while the Hg-H G d i h e d r a l angle i s c lose to 6 0 ° . On - 105 -Table IV: P a r t i a l ± H nmr S p e c t r a l Data f o r Compounds (204), (205), (222), (223), (187) and (193).* R . R (204) (R=0, R'=Et) (205) (R=0, R'=Et) 5H B 1.82-1.95 (m) 1.84-2.00 (m) 5H C 2.20 (dd) 2.28 (dd) 5H D 2.79-2.93 (m) not c l e a r l y observed ^BC 4.5 10 ICD 10 4 (222) (R=0, R'=H) (223) (R=0, R'=H) 5H B 1.86-2.00 (m) 1.86-1.99 (m) 5H C 2.21 (dd) 2.32 (dd) 6H D 2.71-2.85 (m) not c l e a r l y observed ^BC 4.5 9.5 J-CD 9.5 3.5 (187) (R=CH 2, R'=H) (193) (R=CH 2, R'=H) 6H B not c l e a r l y observed 1.96-2.08 (m) 5H C 2.10 (dd) 2.18 (dd) 5H D 2.46-2.58 (m) 2.40-2.50 (m) ^BC 5 9 iCD 9.5 5 A l l coupl ing constants were given i n Hertz (Hz) and were determined by appropriate decoupling experiments (see t e x t ) . - 106 -the other hand, i n (236), the HQ-HQ d i h e d r a l angle approximates 60°, while the Hg-HQ d i h e d r a l angle i s c lose to 180°. Therefore , f or one ser i e s of compounds, represented by conformation (235), one would expect a r e l a t i v e l y large value for JQ^ and a small value for JgQ. On the other hand, for the compounds possess ing conformation (236), JQH and JgQ would be expected to be qui te small and r e l a t i v e l y l a r g e , r e s p e c t i v e l y . The f a c t that the magnitudes of the var ious coupl ing constants (see Table IV) were cons i s tent with these expectations provides reasonable evidence for the stereochemical assignments. Conversion of the c a r b o x y l i c acids (187) and (193) in to the corresponding amines would be achieved v i a a sequence of react ions o u t l i n e d i n Scheme 2 5 . ^ Recent ly , P o u l t e r 0 ^ reported that an isocyanate generated by Curt ius rearrangement of an a c y l azide could be trapped e f f i c i e n t l y with 2 - t r i m e t h y l s i l y l e t h a n o l . Treatment of the r e s u l t a n t carbamate with tetra-n-butylammonium f l u o r i d e af fords the corresponding amine i n good y i e l d . This m i l d and e s s e n t i a l l y n e u t r a l method for cleavage of the carbamate avoids use of the s t rong ly a c i d i c or s t rong ly b a s i c condi t ions that are normally requ ired for carbamate - 107 -RC00H 228 RCOCl 229 > RCON 3 230 •> RN=C=0 RNH< 233 acid or base 231 1 R'OH RNHCOR 232 Scheme 25 h y d r o l y s i s . Therefore , t h i s method was adopted for the synthesis of the amines (186) and (234). The c a r b o x y l i c a c i d (187) was converted v i a the a c i d c h l o r i d e (194) in to the a c y l azide (195). Curt ius rearrangement of the l a t t e r substance, fol lowed by treatment of the r e s u l t a n t isocyanate with 2 - t r i m e t h y l s i l y l e t h a n o l , a f forded the c r y s t a l l i n e carbamate (237) (mp 7 9 . 5 - 8 0 . 5 ° C , r e c r y s t a l l i z a t i o n from petroleum ether) i n a y i e l d of 89% from (187) (Scheme 26). A carbonyl absorpt ion at 1709 cm" 1 and a N-H s t r e t c h i n g absorpt ion at 3446 cm" 1 were observed i n the i r spectrum of (237) . The -^ H nmr spectrum of (237) exh ib i t ed a n ine -proton s i n g l e t at 5 0.05 (SiMe3 group), a p a i r of doublets at S 0.73 and 0.87 ( i sopropy l methyl groups, J = 7 Hz i n each case) , a s i n g l e t at S 0.91 ( t e r t i a r y methyl group), and a t r i p l e t at 5 0.97 ( - C H 2 C H 2 S i M e 3 , J = 8.5 Hz) , a m u l t i p l e t at S 1.77-1.88 (Hg), a m u l t i p l e t at S 2.20-2.31 ( H D ) , a t r i p l e t of doublets - 108 at 8 3.47 ( H c , J = 10, 4 Hz) , a m u l t i p l e t at 5 4.06-4.20 ( - C H 2 C H 2 S i M e 3 ) , and a broad doublet at 8 4.31 ( -NH-, J = 10 Hz) . A d d i t i o n a l l y , the o l e f i n i c protons gave r i s e to broad s i n g l e t s at 8 4.65 and 4.73. When the s i g n a l at 8 4.06-4.20 ( - C H 2 C H 2 S i M e 3 ) was decoupled, the s i g n a l at 8 0.97 due to - C H 2 C H 2 S i M e 3 protons co l lapsed to a s i n g l e t . When one of the i s o p r o p y l methyl groups at 5 0.73 was decoupled, the s i g n a l due to Hg at 8 1.77-1.88 s i m p l i f i e d . When Hg was decoupled, the s igna l s due to the i s o p r o p y l methyl groups at 8 0.73 and 0.87 co l l apsed to s i n g l e t s , and the s i g n a l due to HQ at 8 3.47 co l l apsed to a t r i p l e t (J = 10 Hz) . When HQ was decoupled, the s i g n a l due to Hg co l l apsed to a septet (J = 7 - 109 -Hz) and the s i g n a l due to Hp at 6 2.20-2.31 s i m p l i f i e d . When the proton attached to n i t rogen was decoupled, the s i g n a l due to HQ at 6 3.47 c o l l a p s e d to a doublet of doublets (J = 10, 4 Hz) . React ion of (237) with tetra-n-butylammonium f l u o r i d e prov ided , i n 72% y i e l d , the amine (186) (equation 41). The i r spectrum of (186) e x h i b i t e d two weak absorptions at 3397 and 3338 cm" 1 , i n d i c a t i n g the presence of an amino group. The ^H nmr spectrum of (186) showed a p a i r of doublets at 6 0.82 and 0.92. (J = 6.5 Hz i n each case) a t t r i b u t a b l e to the i s o p r o p y l methyl groups, while the t e r t i a r y methyl group gave r i s e to a s i n g l e t at 6 0.94. A doublet of doublets due to HQ appeared at 5 2.51 (J = 8.5, 3.5 Hz) , while a doublet due to H E could be found at 5 1.97 (J = 10 Hz) . A d d i t i o n a l l y , the o l e f i n i c protons gave r i s e to a broad s i n g l e t at S 4.77, while a m u l t i p l e t due to Hg appeared at 5 1.70-1.83. When one of the i sopropy l methyl groups at 5 0.82 was decoupled, the s i g n a l due to Hg at 5 1.70-1.83 s i m p l i f i e d . When HQ was decoupled, the s i g n a l due to Hg co l lapsed to a septet (J = 6.5 Hz) -and a three-proton m u l t i p l e t at 6 2.05-2.30, which presumably contained the proton Hp, s i m p l i f i e d . The assignment of the s i g n a l at 5 1.97 to Hg was based on the chemical s h i f t and coupl ing pa t t ern of t h i s resonance. 110 -Subjec t ion of the a c i d (193) to a sequence of react ions s i m i l a r to that used for the conversion of (187) in to (237) prov ided , i n 82% y i e l d , the c r y s t a l l i n e carbamate (240), mp 8 6 - 8 7 ° C ( r e c r y s t a l l i z a t i o n from petroleum ether) (Scheme 27). The i r spectrum of (240) showed a N-H s t r e t c h i n g absorpt ion at 3450 cm" 1 and a carbonyl absorpt ion at 1726 cm" 1 . The 1 H nmr spectrum of (240) exh ib i t ed a n ine -proton s i n g l e t at 5 0.05 (-SiMe3), a p a i r of doublets at 6 0.85 and 0.88 ( i s o p r o p y l methyl groups, J = 7 Hz i n each case) , a s i n g l e t at S 0.95 ( t e r t i a r y methyl group), a t r i p l e t at 5 0.99 (-OCH 2 CH 2 SiMe3, J = 8.5 Hz) , a m u l t i p l e t at S 2.25-2.36 ( H D ) , a doublet of doublet of doublets at 5 3.41 ( H c , J = 10.5, 7, 4 Hz) , a t r i p l e t at 6 4.16 ( - O C H 2 C H 2 S i M e 3 , J = 8.5 Hz) , a broad doublet at 5 4.43 ( -NH-, J = 10.5 Hz) , and two broad s i n g l e t s due to the C00H (C0CI)2 PhCH 3 COCl N a N 3 , H 2 0 Acetone ^ C 0 N 3 193 238 239 2) Me 3Si> A 1) NC0 2 (CH 2 ) 2 SiMe 3 240 Scheme 27 - I l l -o l e f i n i c protons at 6 4.77 and 4.81. When the s i g n a l at S 4.16 (-OCH2 cH2SiMe3) was decoupled, the s i g n a l due to -OCH2CH2SiMe3 protons at S 0.99 c o l l a p s e d to a s i n g l e t . When HQ was decoupled, the s igna l s due to HQ and -NH- (5 2.30 and 4.43, r e s p e c t i v e l y ) c o l l a p s e d to a t r i p l e t of doublets ( J «= 11, 5.5 Hz) and a broad s i n g l e t , r e s p e c t i v e l y . In the same decoupling experiment, a two-proton m u l t i p l e t at 6 1.59-1.74, which presumably contained the proton Hg, s i m p l i f i e d . When Hp was decoupled, the s i g n a l due to H c at 5 3.41 c o l l a p s e d to a doublet of doublets ( J = 10.5, 7 Hz) , and a two-proton m u l t i p l e t at 6 1.76-1.95 s i m p l i f i e d . Treatment of the carbamate (240) with tetra-n-butylammonium f l u o r i d e gave the amine (234) i n a y i e l d of 72% (equation 4 2 ) . The i r spectrum of (234) showed two weak absorpt ion at 3387 and 3307 cm"-'-, i n d i c a t i n g the presence of a primary amine f u n c t i o n . The nmr spectrum of (234) exh ib i t ed a p a i r of doublets at 6 0.86 and 0.89 ( i s o p r o p y l methyl groups, J = 6.5 Hz, i n each case) , a s i n g l e t at 5 0.97 ( t e r t i a r y methyl group), a broad doublet at 61.95 (Hg, J = 11 Hz) , and a doublet of doublets at 5 2.34 ( H c , J = 6.5, 3 Hz) . Furthermore, the o l e f i n i c protons gave r i s e to broad s i n g l e t s at S 4.62 and 4.75. The assignment of the s igna l s at S 1.95 and 2.34 to H E and HQ, r e s p e c t i v e l y , - 112 -was based on the chemical s h i f t s and/or the s p i n - s p i n coupl ing patterns of these resonances. Formylat ion of the amine (186) was a s t ra ight forward process . Thus, the a d d i t i o n of f r e s h l y prepared a c e t i c formic anhydride (241) to a s o l u t i o n of the amine (186) i n ether at room temperature provided the ( ± ) - a x a m i d e - 1 (174) i n 90% y i e l d . 6 1 The i r spectrum of (174) e x h i b i t e d an ff 8 CH3C0CH 241 absorpt ion at 3268 cm" 1 for the N-H s t r e t c h i n g v i b r a t i o n , a peak at 1660 cm" 1 f or the carbonyl absorpt ion , and a peak at 890 cm" 1 f or the C=CH2 group absorpt ion . The -^ H nmr spectrum of (174) (Figure 11) was rather compl icated .^ However, the appearance of two doublets due to formamide protons (H-C-) at 6 7.90 (J = 12 Hz) and 8.15 (J = 2 Hz) ( in tegrated area r a t i o - 2 : 3 , r e s p e c t i v e l y ) i n d i c a t e d that (174) cons i s ted of a mixture of trans and c i s rotamers i n a r a t i o of - 2 : 3 , r e s p e c t i v e l y . 8 4 cis 174 trans 174 Formylat ion of the amine (234) by treatment with a c e t i c formic anhydride (241) provided ( ± ) - 1 0 - e p i - a x a m i d e - 1 (224) i n 88% y i e l d . 6 1 The - 114 -i r spectrum of (224) exh ib i t ed an absorpt ion at 3288 cm" 1 f or the N-H s t r e t c h i n g v i b r a t i o n , a peak at 1659 cm" 1 for the carbonyl absorpt ion , and a peak at 896 cm" 1 for the ^C=CH2 group absorpt ion . In the -^ H nmr II spectrum of (224) (Figure 12), the formamide protons (H-C-) gave r i s e to a doublet at 6 7.97 (J = 12 Hz) and a broad s i n g l e t at 5 8.31 ( in tegrated area r a t i o - 1 : 1 , r e s p e c t i v e l y ) . Therefore , compound (224) cons i s t ed of a mixture of trans and c i s rotamers i n a r a t i o of about 1 : 1 . 8 4 Comparison of the ( l imi ted) s p e c t r a l data reported-* 6 for n a t u r a l (+)-axamide-l with those exh ib i t ed by compounds (174) and (224) d i d not l ead to an unambiguous conc lus ion regarding compound i d e n t i t i e s . cis 224 trans 224 Dehydration of (174) with p_-toluenesulfonyl c h l o r i d e i n p y r i d i n e a f forded , i n 86% y i e l d , the i s o n i t r i l e (173) , 8 ^ which e x h i b i t e d mp 4 5 - 4 6 ° C ( r e c r y s t a l l i z a t i o n from petroleum e t h e r ) . The i r spectrum of (173) showed an absorpt ion at 2136 c m , i n d i c a t i n g the presence of an i s o n i t r i l e f u n c t i o n . A l so observed i n the i r spectrum of (173) was an absorpt ion due to the }C=CH2 group at 899 cm" 1 and two peaks at 1376 and 1390 cm" 1 due to the i s o p r o p y l methyl groups. The 400 MHz 1 H nmr spectrum of (173) (Figure 13), as w e l l as the 117 chromatographic behavior (g lc , t i c ) , were found to be i d e n t i c a l with those of an authent ic sample of ( + ) - a x i s o n i t r i l e - 1 (Figure 14 for H 173 nmr spectrum). This comparison a l so confirmed that (174) was ( ± ) -axamide-1. The 75 MHz 1 3 C nmr spectrum of (173) exh ib i t ed a 1:1:1 t r i p l e t at S 155.535, 155.621, and 155.689 a t t r i b u t a b l e to the i s o n i t r i l e c a r b o n . 8 6 Furthermore, a 1:1:1 t r i p l e t due to the a-carbon adjacent to the i s o n i t r i l e func t ion appeared at 5 67.691, 67.763, and 6 7 . 8 2 4 . 8 6 b Dehydration of (224) af forded ( ± ) - 1 0 - e p i - a x i s o n i t r i l e - l (225) i n 87% y i e l d . 8 5 Compound (225) exh ib i t ed mp 5 3 - 5 4 ° C ( r e c r y s t a l l i z a t i o n from petroleum ether) and i t s i r spectrum showed an absorpt ion at 2135 cm"-'- due to the i s o n i t r i l e func t ion , an absorpt ion at 901 cm" 1 due to the /C=CH2 group, and two peaks at 1391 and 1377 cm" 1 due to the i s o p r o p y l methyl groups. The 400 MHz 1 H nmr spectrum of (225) (Figure 15), as w e l l as the chromatographic behavior ( g l c ) , were c l e a r l y d i f f e r e n t from those of n a t u r a l ( + ) - a x i s o n i t r i l e - 1 . We are very g r a t e f u l to Professor D. S i c a for a sample of (+)-axiso-n i t r i l e - 1 and for a copy of i t s 1 H nmr spectrum. F i g . 14: The 400 MHz 1 H nmr spectrum of n a t u r a l ( + ) - a x i s o n i t r i l e - 1 120 -In summary, the t o t a l synthesis of ( ± ) - a x i s o n i t r i l e - 1 (173) was achieved i n 13% o v e r a l l y i e l d from 2-methyl -2-cyclopenten- l -one (152). The o v e r a l l y i e l d of ( ± ) -10 -ep_ i -ax i son i tr i l e -1 (225) was 9%. The synthet i c sequences employed for these syntheses provided an example of the use of the newly developed methylenecyclohexane annulat ion method i n n a t u r a l product synthes i s . Furthermore, the e f f i c i e n t t i tan ium t e t r a -c h l o r i d e - c a t a l y z e d conjugate a d d i t i o n of 3 - m e t h y l - l , 1 - b i s ( t r i m e t h y l -s i loxy) -1 -butene (226) to the enone (203) provided an i n t e r e s t i n g example of the use of t h i s modif ied Mukaiyama r e a c t i o n i n a t o t a l synthes i s . - 121 -EXPERIMENTAL 122 -EXPERIMENTAL General M e l t i n g points were determined us ing a Fisher-Johns mel t ing po int apparatus and are uncorrected . B o i l i n g points are a l so uncorrected and those i n d i c a t e d as a i r - b a t h temperatures re f er to short path (Kugelrohr) d i s t i l l a t i o n s . In frared ( i r ) spectra were recorded e i t h e r on a P e r k i n -Elmer model 710B i n f r a r e d spectrophotometer us ing the 1601 cm"-'- band of polystyrene f i l m for c a l i b r a t i o n or on a Perkin-Elmer model 1710 F o u r i e r Transform Infrared (FTIR) spectrometer. Proton and carbon-13 nuclear magnetic resonance ( X H and • L J C nmr) spectra were recorded i n deutero-chloroform s o l u t i o n s . These spectra were recorded us ing a HXS-270 spectrometer, V a r i a n XL-300 spectrometer, and/or Bruker models WP-80 or WH-400 spectrometers. S igna l p o s i t i o n s are given i n parts per m i l l i o n (5) r e l a t i v e to t e tramethy l s i lane (TMS). In cases of compounds with t r i m e t h y l s t a n n y l and/or t r i m e t h y l s i l y l groups, the resonance p o s i t i o n s were determined r e l a t i v e to the chloroform s i g n a l (5 7 . 2 5 ) . 5 1 The m u l t i p l i c i t y , number of protons , coupl ing constants , and assignments (where poss ib le ) are i n d i c a t e d i n parentheses. The t i n - p r o t o n coupl ing constants ( isn-H) a r e g iven as J_\IJ /3-119 where the coupl ing Sn-H Sn-H constants for the two isotopes are d i s t i n c t and as an average of the two values where they are not d i s t i n c t . Low r e s o l u t i o n mass spectra were recorded with a Varian/MAT CH4B mass spectrometer while h igh r e s o l u t i o n mass spectra were recorded with a K r a t o s / A E l MS 50 mass spectrometer. - 123 -Glc-mass spectre-metric analyses were done us ing a Car lo ERBA GC ser ies 4160 chromatograph coupled with a Kratos MS 80 RFA mass spectrometer. In cases of compounds with t r imethy l s tanny l groups the molecular weight determinations (high r e s o l u t i o n mass spectrometry) were based on 1 2 0 S n and were made on the (M +-15) peak. A n a l y t i c a l g a s - l i q u i d chromatography (glc) was performed on a Hewlett-Packard model 5880 gas chromatograph equipped with a 12.5 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 (column B) or a 12.5 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 OV-101 (column A) and a flame i o n i z a t i o n detec tor . Glc was a l so performed on a Hewlett-Packard model 5990 gas chromatograph us ing a 12.5 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 (column B) and a flame i o n i z a t i o n detec tor . T h i n - l a y e r chromatography ( t i c ) was c a r r i e d out on commercial aluminum-backed s i l i c a ge l p la tes (E. Merck, Type 5554). Preparat ive t h i n - l a y e r chromatography was done on 20 cm x 20 cm p la tes coated with 2 mm of s i l i c a ge l (E. Merck, S i l i c a Gel 60). Conventional column chroma-tography was done on 70-230 mesh s i l i c a ge l (E. Merck, S i l i c a Gel 60) while f l a s h chromatography 8 7 was done on 230-400 mesh s i l i c a ge l (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 fo l lowing 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 de ionized water was added to 50 g of 70-230 mesh s i l i c a gel (E. Merck, S i l i c a Gel 60) 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 and the s i l i c a ge l was d r i e d under vacuum overnight at room temperature, with p r o t e c t i o n from l i g h t . The d r i e d s i l i c a ge l was 124 -s tored under argon i n a brown b o t t l e . Unless otherwise s ta ted , a l l react ions were c a r r i e d out under an atmosphere of dry argon us ing c a r e f u l l y f lame-dr ied glassware. Cold temperatures were maintained by the use of the fo l lowing b a t h s : 8 8 aqueous calc ium c h l o r i d e / C 0 2 ( - 2 0 ° C ) , 8 9 a c e t o n i t r i l e / C 0 2 ( - 4 8 ° C ) , ch loro form/C0 2 ( - 6 3 ° C ) , acetone/C0 2 ( - 7 8 ° C ) . Solvents and Reagents Tetrahydrofuran and d i e t h y l ether were d i s t i l l e d from sodium benzophenone k e t y l . Dichloromethane was d i s t i l l e d from phosphorus pentoxide. Di i sopropylamine , N,N-dimethylformamide, hexamethylphosphoramide (HMPA) and p y r i d i n e were d i s t i l l e d from calc ium hydride and s tored over a c t i v a t e d 4 A molecular s ieves . Toluene was d i s t i l l e d from sodium and s tored over a c t i v a t e d 4 A molecular s i eves . Methanol was d i s t i l l e d from magnesium methoxide and s tored over a c t i v a t e d 4 A molecular s ieves . A c e t i c anhydride was d i s t i l l e d from calc ium carb ide . Formic a c i d was re f luxed with p h t h a l i c anhydride for 6 h and then was d i s t i l l e d . T r i m e t h y l s i l y l c h l o r i d e was f r e s h l y d i s t i l l e d before use. Acetone was d i s t i l l e d and s tored over a c t i v a t e d 4 A molecular s i eves . - 125 -The petroleum ether used was the f r a c t i o n s with a b o i l i n g po int range of ca . 3 0 - 6 0 ° C . Hexamethyldit in was obtained from the A l f a D i v i s i o n of the Ventron Corporat ion or from Organometal l ics , Inc. So lut ions of m e t h y l l i t h i u m - l i t h i u m bromide complex i n ether and n - b u t y l l i t h i u m i n hexane were obtained from A l d r i c h Chemical C o . , Inc. and were s tandardized us ing the d o u b l e - t i t r a t i o n procedure of G i l m a n . 9 ^ Potassium hydride was obtained as a 35% suspension i n mineral o i l from the A l d r i c h Chemical Company, Inc. and was washed free of o i l (with dry THF) before use. Cuprous bromide-dimethyl s u l f i d e complex was prepared by the method of H o u s e , 9 1 a f t e r washing commercial cuprous bromide with m e t h a n o l . 9 2 Li th ium di isopropylamide was prepared by the a d d i t i o n of a s o l u t i o n of n - b u t y l l i t h i u m (1.0 equiv) i n hexane to a s o l u t i o n of d i i s o p r o p y l -amine (1.0 equiv) i n dry THF at - 7 8 ° C . The r e s u l t i n g s o l u t i o n was then s t i r r e d at 0°C for 10 min before being u s e d . 9 3 Saturated b a s i c aqueous ammonium c h l o r i d e (pH 8) was prepared by the a d d i t i o n of ~ 50 mL of aqueous ammonium hydroxide (58%) to 1 L of sa turated aqueous ammonium c h l o r i d e . Tetra-n-butylammonium f l u o r i d e 9 4 was prepared by the t i t r a t i o n of h y d r o f l u o r i c a c i d with tetra-n-butylammonium hydroxide , with subsequent removal of water under vacuum at room temperature. Boron t r i f l u o r i d e - e t h e r a t e 9 5 was p u r i f i e d by d i s t i l l a t i o n from calc ium hydride (1 g per 250 mL of boron t r i f l u o r i d e - e t h e r a t e ) under reduced pressure ( 6 0 ° C / 2 0 T o r r ) . p_-Toluenesulfonyl c h l o r i d e 9 6 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 - 126 -chloroform-petroleum ether . N-Bromosucc in imide 9 7 was r e c r y s t a l l i z e d from hot water. Magnesium bromide-etherate was prepared by the r e a c t i o n of 1,2-dibromoethane ( f r e s h l y d i s t i l l e d ) with magnesium metal i n dry ether , with subsequent removal of ether under vacuum at room temperature. 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 fur ther p u r i f i c a t i o n . Preparat ion of 5 -Chloro -2 - t r imethy l s tanny l - l -pentene (111) To a c o l d ( - 2 0 ° C ) , s t i r r e d s o l u t i o n of hexamethyldi t in (8.0 mL, 38.3 mmol) i n 250 mL of dry THF was added methy l l i th ium (40 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 yel low s o l u t i o n was s t i r r e d at - 2 0 ° C for 15 min and then was cooled to - 7 8 ° C . S o l i d cuprous bromide-dimethyl s u l f i d e complex (7.9 g, 38.3 mmol) was added i n one p o r t i o n to the c o l o r l e s s s o l u t i o n at - 7 8 ° C . The mixture was s t i r r e d at - 7 8 ° C for 10 min, was warmed to - 6 3 ° C , and then was s t i r r e d for an a d d i t i o n a l 15 min. The r e s u l t i n g reddish brown s o l u t i o n was recooled to - 7 8 ° C . 5-Chloro-1-pentyne (3.2 mL, 30.2 mmol) was added and the r e a c t i o n mixture was s t i r r e d at - 7 8 ° C for 6 h . A c e t i c a c i d (3 mL), 111 - 127 -methanol (3 mL), saturated aqueous ammonium c h l o r i d e (pH 8) (200 mL) and ether (100 mL) were added succes s ive ly . The mixture was al lowed to warm to room temperature and was s t i r r e d v i g o r o u s l y with exposure to a i r . The blue aqueous layer was separated and extracted twice with ether . The combined ether ex trac t was washed twice with saturated aquoeus ammonium c h l o r i d e (pH 8), d r i e d over anhydrous magnesium s u l f a t e , and concentrated under reduced pressure . The r e s i d u a l m a t e r i a l was subjected to column chromatography on s i l i c a ge l (450 g, e l u t i o n with petroleum e t h e r ) . D i s t i l l a t i o n ( a i r - b a t h temperature 8 0 - 8 5 ° C / 2 5 Torr) of the o i l obtained from the appropriate f r a c t i o n s provided 5.5 g (68%) of the c h l o r i d e (111) as a c o l o r l e s s o i l . Th 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 ) : 1440, 920, 770 c m - 1 ; T-H nmr (80 MHz, CDC1 3) 5: 0.15 (s, 9H, -SnMe 3 , J S n - H = 52/54 Hz) , 1.85 (quintet , 2H, - C H 2 C H 2 C H 2 C 1 , J = 7 Hz) , 2.40 (br t , 2H, - C H 2 C H 2 C H 2 C 1 , J = 7 Hz) , 3.50 ( t , 2H, - C H 2 C 1 , J = 7 Hz) , 5.20 (d of t , 1H, H B , J - 2.5, 1 Hz, J S n . H = 70 Hz) , 5.70 (d of t , 1H, H A , J = 2 .5 , 1.5 Hz, J S n _ H = 150 Hz) . Exact Mass c a l c d . for C 7 H 1 4 3 5 C l 1 2 0 S n ( M + - C H 3 ) : 252.9806; found: 252.9809. Preparat ion of 5 - C h l o r o - 2 - l i t h i o - l - p e n t e n e (112) by the Transmetalat ion of 5 - C h l o r o - 2 - t r i m e t h y l s t a n n y l - l - p e n t e n e (111) CI CI Li 111 112 - 128 -To a c o l d ( - 7 8 ° C ) , s t i r r e d s o l u t i o n of 5 - c h l o r o - 2 - t r i m e t h y l -s t a n n y l - 1-pentene (111) (1.0 equiv) i n dry THF [-1 mL per 0.1 mmol of (111)] was added methyl l i th ium (-1.2 equiv) as a s o l u t i o n i n ether . The r e s u l t i n g c o l o r l e s s s o l u t i o n was s t i r r e d at - 7 8 ° C for an a d d i t i o n a l 15 min before being used. General Procedure A: React ion of 5 - C h l o r o - 2 - l i t h i o - l - p e n t e n e (112) with Cyclohexanone at Various Temperatures. Preparat ion of 5 - C h l o r o - 2 -(1-hydroxycyclohexyl)-1-pentene (132) CI 112 132 A s t i r r e d s o l u t i o n of 5 - c h l o r o - 2 - l i t h i o - l - p e n t e n e (112) (0.37 mmol) i n dry THF (4 mL) at - 7 8 ° C was allowed to warm up to an appropriate temperature and then was s t i r r e d for an a d d i t i o n a l 30 min. The s o l u t i o n was recoo led to - 7 8 ° C . Cyclohexanone (43 / iL , 0.41 mmol) was added and the c o l o r l e s s r e a c t i o n mixture was s t i r r e d at - 7 8 ° C for 3 h . Saturated aqueous ammonium c h l o r i d e (5 mL) and ether (10 mL) were added and the r e s u l t i n g mixture was allowed to warm to room temperature. The organic l a y e r was washed with saturated aqueous ammonium c h l o r i d e (2 x 5 mL), d r i e d over anhydrous magnesium s u l f a t e and concentrated under reduced - 129 -pressure . Column chromatography of the res idue on 5 g s i l i c a ge l ( e l u t i o n with 3:2 petroleum ether-ether) fol lowed by d i s t i l l a t i o n of the m a t e r i a l obtained from the appropriate f r a c t i o n s , provided the pure product (132). (a) At - 7 8 ° C Fol lowing general procedure A descr ibed above, a s o l u t i o n of 5 - c h l o r o - 2 - l i t h i o - l - p e n t e n e (112) (0.37 mmol) i n dry THF (4 mL) was s t i r r e d at - 7 8 ° C for a fur ther 30 min before the a d d i t i o n of cyclohexa-none (43 /xL, 0.41 mmol). Normal workup, fol lowed by column chromato-graphy of the crude product and d i s t i l l a t i o n ( a i r - b a t h temperature 1 1 0 - 1 1 5 ° C / 0 . 2 Torr) of the o i l thus obtained, a f forded 64 mg (84%) of the a l c o h o l (132) as a c o l o r l e s s o i l . This m a t e r i a l exh ib i t ed i r ( f i l m ) : 3431, 3094, 1639, 902 c m - 1 ; -^H nmr (400 MHz, CDC1 3) 5: 1.12-1.30 (m, 2H), 1.50-1.70 (m, 9H), 1.98 (quintet , 2H, - C H 2 C H 2 C 1 , J = 7 Hz) , 2.24 ( t , 2H, - C H 2 C H 2 C H 2 C 1 , J = 7 Hz) , 3.36 ( t , 2H, - C H 2 C H 2 C 1 , J = 7 Hz) , 4.82, 5.14 (s, s, 1H each, o l e f i n i c protons ) . Exact Mass c a l c d . for C 1 1 H 1 9 0 3 5 C 1 : 202.1124; found: 202.1130. (b) At - 6 3 ° C Fol lowing general procedure A, a s o l u t i o n of reagent (112) (0.37 mmol) i n 4 mL of dry THF was s t i r r e d at - 6 3 ° C for 30 min and then was - 130 -recoo led to - 7 8 ° C p r i o r to a d d i t i o n of cyclohexanone (0.41 mmol). The a l c o h o l (132) was obtained i n 76% y i e l d (57 mg). The nmr spectrum of t h i s m a t e r i a l was i d e n t i c a l with that of the m a t e r i a l descr ibed above. (c) At - 4 8 ° C Fol lowing general procedure A, a s o l u t i o n of reagent (112) (0.37 mmol) i n 4 mL of dry THF was s t i r r e d at - 4 8 ° C for 30 min and then was recoo led to - 7 8 ° C p r i o r to a d d i t i o n of cyclohexanone (0.41 mmol). There was obtained 44 mg (58%) of the a l c o h o l (132). This m a t e r i a l exh ib i t ed a nmr spectrum i d e n t i c a l with that g iven above. (d) At - 2 0 ° C Fol lowing general procedure A, a s o l u t i o n of reagent (112) (0.37 mmol) i n 4 mL of dry THF was s t i r r e d at - 2 0 ° C for 30 min and then was recoo led to - 7 8 ° C p r i o r to a d d i t i o n of cyclohexanone (0.41 mmol). A n a l y s i s of the crude product (40 mg) by g lc and ^H nmr spectroscopy showed that i t contained none of the a l c o h o l (132), but cons i s t ed near ly e n t i r e l y of cyclohexanone. - 131 -General Procedure B: Reaction of 2-Bromomagnesio-5-chloro-l-pentene (144) with C y c l i c Enones, Catalyzed by Cuprous Bromide-Dimethyl Su l f i d e To a c o l d ( - 7 8 ° C ) , s t i r r e d s o l u t i o n of 5 - c h l o r o - 2 - l i t h i o - l - p e n t e n e (112) (1.0 equiv) i n dry THF [-1.0 mL per 0.1 mmol of (112)] was added, i n one p o r t i o n , s o l i d magnesium bromide-etherate (-1.2 equ iv ) . The r e s u l t i n g mi lky s o l u t i o n was s t i r r e d at - 7 8 ° C for 20 min. S o l i d cuprous bromide-dimethyl s u l f i d e complex (-0.25 equiv) was added i n one p o r t i o n to t h i s mixture at - 7 8 ° C . To the s l i g h t l y yel low mixture was added the c y c l i c enone (1.0 equiv) and the r e s u l t i n g b r i g h t ye l low mixture was s t i r r e d at - 7 8 ° C for 2-3 h . Saturated aqueous ammonium c h l o r i d e (pH 8) (-5 mL) and ether (-10 mL) were added. The mixture was s t i r r e d r a p i d l y and was al lowed to warm to room temperature with exposure to a i r . The blue aqueous l ayer was separated and extracted twice with ether . The combined ether ex trac t was washed twice with saturated aqueous ammonium c h l o r i d e (pH 8) , d r i e d over anhydrous magnesium s u l f a t e and concentrated under reduced pressure . The residue was subjected to column chromato-graphy on s i l i c a ge l (- 5 g per 100 mg of crude product ) . Concentrat ion of the appropriate f r a c t i o n s and d i s t i l l a t i o n of the o i l thus obtained, provided pure product . 132 -General Procedure C: Reaction of 2-Bromomagnesio-5-chloro-l-pentene (144) with C y c l i c Enones, Catalyzed by Cuprous Bromide-Dimethyl S u l f i d e and Boron T r i f l u o r i d e - E t h e r a t e To a c o l d ( - 7 8 ° C ) , s t i r r e d s o l u t i o n of 5 - c h l o r o - 2 - l i t h i o - l - p e n t e n e (112) (1.0 equiv) i n dry THF [-1.0 mL per 0.1 mmol of (112)] was added, i n one p o r t i o n , s o l i d magnesium bromide-etherate (-1.2 equiv) and the r e s u l t i n g mi lky s o l u t i o n was s t i r r e d at - 7 8 ° C for 20 min. S o l i d cuprous bromide-dimethyl s u l f i d e complex (-0.25 equiv) was added i n one p o r t i o n . To the s l i g h t l y yel low mixture was added success ive ly c y c l i c enone (1.0 equiv) and boron t r i f l u o r i d e - e t h e r a t e (~ 1.2 equ iv ) . The r e s u l t i n g b r i g h t yel low mixture was s t i r r e d at - 7 8 ° C for 2-3 h . Saturated aqueous ammonium c h l o r i d e (pH 8) (-5 mL) and ether (-10 mL) were added. The mixture was s t i r r e d r a p i d l y and was allowed to warm to room temperature with exposure to a i r . The blue aqueous l ayer was separated and extrac ted twice with ether . The combined ether ex trac t was washed twice with saturated aqueous ammonium c h l o r i d e (pH 8) , d r i e d over anhydrous magnesium s u l f a t e and concentrated under reduced pressure . The residue was subjected to column chromatography on s i l i c a ge l (- 5 g per 100 mg of crude m a t e r i a l ) . D i s t i l l a t i o n of the mater ia l obtained from the appropriate f r a c t i o n s af forded pure product . - 133 -General Procedure D: React ion of the Organocopper-phosphine Complex Reagent (145) with C y c l i c Enones CI (n-Bu3P)2-Cu H5 S o l i d cuprous bromide-dimethyl s u l f i d e complex (1.1 equiv) was added to a s t i r r e d s o l u t i o n of t r i - n - b u t y l p h o s p h i n e (2.0 equiv) i n dry ether (-1.0 mL per 0.1 mmol of cuprous bromide-dimethyl s u l f i d e com-plex) . A f t e r the mixture had been s t i r r e d at room temperature for 10 min, a l l of the s o l i d had d i s s o l v e d . The s o l u t i o n was cooled to - 7 8 ° C and then was t r a n s f e r r e d v i a a cannula to a c o l d ( - 7 8 ° C ) , s t i r r e d s o l u t i o n of 5 - c h l o r o - 2 - l i t h i o - 1 - p e n t e n e (112) (1.0 equiv) i n dry THF [-1.0 mL per 0.1 mmol of (112)]. The r e s u l t i n g l i g h t yel low s o l u t i o n was s t i r r e d at - 7 8 ° C for 20 min. Enone (1.0 equiv) was added and the r e s u l t i n g b r i g h t yel low s o l u t i o n was s t i r r e d at - 7 8 ° C for 1 h and then at - 4 8 ° C for 2 h . Saturated aqueous ammonium c h l o r i d e (pH 8) (5 mL) and ether (10 mL) were added. The mixture was s t i r r e d v i g o r o u s l y and was allowed to warm to room temperature with exposure to a i r . The blue aqueous l ayer was extracted twice with ether . The combined ether ex trac t was washed twice with saturated aqueous ammonium c h l o r i d e (pH 8) , and then was d r i e d over anhydrous magnesium s u l f a t e . Removal of the so lvent under reduced pressure , fol lowed by column chromatography of the crude m a t e r i a l on s i l i c a gel (-5 g per 100 mg of crude m a t e r i a l , e l u t i o n - 134 -with 20:1 to 7:1 petroleum ether-ether) and d i s t i l l a t i o n of the o i l obtained from the appropriate f r a c t i o n s , a f forded pure product . General Procedure E : React ion of the Organocopper-phosphine Complex Reagent (145) with C y c l i c Enones, Catalyzed by Boron T r i f l u o r i d e -Etherate CI (n-Bu 3 P) 2 -Cu 145 S o l i d cuprous bromide-dimethyl s u l f i d e complex (1.1 equiv) was added to a s t i r r e d s o l u t i o n of t r i - n - b u t y l p h o s p h i n e (2.0 equiv) i n dry ether (-1.0 mL per 0.1 mmol of cuprous bromide-dimethyl s u l f i d e complex) at room temperature. The mixture was s t i r r e d for 10 min to give a c o l o r l e s s s o l u t i o n . This s o l u t i o n was cooled to - 7 8 ° C and then was t r a n s f e r r e d (cannula) to a c o l d ( - 7 8 ° C ) , s t i r r e d s o l u t i o n of 5 -ch loro-2 -l i t h i o - l - p e n t e n e (112) (1.0 equiv) i n dry THF [-1.0 mL per 0.1 mmol of (112)] . The r e s u l t i n g pale yel low s o l u t i o n was s t i r r e d at - 7 8 ° C for 20 min. Enone (1.0 equiv) and boron t r i f l u o r i d e - e t h e r a t e (1.2 equiv) were added succes s ive ly and the r e s u l t i n g b r i g h t yel low s o l u t i o n was s t i r r e d at - 7 8 ° C for 1 h and then at - 4 8 ° C for 2 h . Saturated aqueous ammonium c h l o r i d e (pH 8) (5 mL) and ether (10 mL) were added. The mixture was s t i r r e d v i g o r o u s l y and was allowed to warm to room temperature with - 135 -exposure to a i r . The blue aqueous l ayer was extracted twice with ether. The combined ether extract was washed twice with saturated aqueous ammonium c h l o r i d e (pH 8) , and then was d r i e d over anhydrous magnesium s u l f a t e . Evaporat ion of solvent under reduced pressure , fo l lowed by column chromatography of the crude product on s i l i c a ge l (~5 g per 100 mg of crude m a t e r i a l , e l u t i o n with 20:1 to 7:1 petroleum ether-ether) and d i s t i l l a t i o n of the o i l obtained from the appropriate f r a c t i o n s , a f forded pure product . Preparat ion of 3 - [2 - (5 -Chloro- l -penteny l ) ] -cyc lohexanone (153) 0 CI 153 (a) Using the Grignard Reagent (144) Fo l lowing general procedure B, 2-cyclohexen-l -one (146) was converted in to the conjugate a d d i t i o n product (153). The fo l lowing amounts of reagents were used: 5 - c h l o r o - 2 - l i t h i o - l - p e n t e n e (112) (0.37 mmol) i n 4 mL of dry THF; magnesium bromide-etherate (113 mg, 0.44 mmol); cuprous bromide-dimethyl s u l f i d e complex (18.3 mg, 0.088 mmol) and 2-cyclohexen- l -one (146) (40 /xL, 0.41 mmol). Workup, fo l lowed by - 136 -column chromatography of the crude product on s i l i c a ge l (4 g, e l u t i o n with 3:2 petroleum ether-ether) and d i s t i l l a t i o n ( a i r - b a t h temperature 8 2 - 8 5 ° C / 0 . 2 Torr ) of the o i l obtained from the appropriate f r a c t i o n s , provided 60 mg (81%) of the chloro ketone (153) as a c o l o r l e s s o i l . Th 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 ) : 3050, 1700, 1630, 900 cm" 1 ; lE nmr (400 MHz, CDC1 3) 6: 1.52-1.74 (m, 2H), 1.85-2.0 (m, 3H), 2.02-2.14 (m, 1H), 2.15-2.24 ( t , 2H, - C H 2 C H 2 C H 2 C 1 , J = 7 Hz) , 2.24-2.49 (m, 5H), 3.54 ( t , 2H, - C H 2 C 1 , J = 7 Hz) , 4.85 (br s, 2H, o l e f i n i c pro tons ) . Exact  Mass c a l c d . for C 1 1 H 1 7 0 3 5 C 1 : 200.0969; found: 200.0963. (b) Using the Organocopper Reagent (145) Fo l lowing general procedure D, 2-cyclohexen-l -one (146) was converted in to the conjugate a d d i t i o n product (153). The fo l lowing amounts of reagents were used: a s o l u t i o n of cuprous bromide-dimethyl s u l f i d e complex (83.5 mg, 0.41 mmol) and t r i - n - b u t y l p h o s p h i n e (0.18 mL, 0.73 mmol) i n 4 mL of dry ether; 5 - c h l o r o - 2 - l i t h i o - l - p e n t e n e (112) (0.36 mmol) i n 3.6 mL of dry THF; 2-cyclohexen-l -one (146) (35 fih, 0.36 mmol). Workup, fo l lowed by column chromatography of the crude product on s i l i c a ge l (6 g, e l u t i o n with 20:1 to 7:1 petroleum ether-e ther) and d i s t i l l a -t i o n ( a i r - b a t h temperature 8 2 - 8 5 ° C / 0 . 2 Torr) of the o i l obtained from the appropriate f r a c t i o n s , a f forded 44 mg (61%) of the chloro ketone (153). The ^H nmr spectrum of t h i s mater ia l was i d e n t i c a l with that of the m a t e r i a l descr ibed above. - 137 Preparat ion of 3 - [2 - (5 -Chloro- l -penteny l ) ] - cyc lopentanone (157) 157 (a) Using the Grignard Reagent (144) Fo l lowing general procedure B, 2-cyc lopenten- l -one (150) was converted in to the conjugate a d d i t i o n product (157). The fo l lowing amounts of reagents were used: 5 - c h l o r o - 2 - l i t h i o - l - p e n t e n e (112) (0.39 mmol) i n 4 mL of dry THF; magnesium bromide-etherate (121 mg, 0.47 mmol); cuprous bromide-dimethyl s u l f i d e complex (19 mg, 0.096 mmol); 2 -cyc lopenten- l -one (150) (38 / iL , 0.39 mmol). Normal workup, fol lowed by column chromatography of the crude product on s i l i c a gel (4 g, e l u t i o n with 3:1 petroleum ether-ether) and d i s t i l l a t i o n ( a i r - b a t h temperature 9 0 - 9 5 ° C / 0 . 2 Torr) of the o i l obtained from the appropriate f r a c t i o n s , provided 38.7 mg (54%) of the chloro ketone (157). This m a t e r i a l e x h i b i t e d i r ( f i l m ) : 3050, 1735, 1630, 900 cm" 1 ; X H nmr (400 MHz, CDC1 3) 5: 1.72-1.86 (m, 1H), 1.93-2.01 (quintet , 2H, - C H 2 C H 2 C H 2 C l , J = 7 Hz) , 2.08-2.32 (m, 5H), 2.34-2.50 (m, 2H), 2.89 (m, 1H), 3.58 ( t , 2H, - C H 2 C 1 , J = 7 Hz) , 4.86 (br s, 2H, o l e f i n i c protons ) . Exact Mass c a l c d . f or C 1 0 H 1 5 0 3 5 C 1 : 186.0812; found: 186.0815. - 138 -(b) Us ing the Organocopper Reagent (145) Fo l lowing general procedure D, the conjugate a d d i t i o n product (157) was prepared from 2-cyclopenten- l -one (150). The fo l lowing amounts of reagents were used: a s o l u t i o n of cuprous bromide-dimethyl s u l f i d e complex (75 mg, 0.36 mmol) and t r i - n - b u t y l p h o s p h i n e (160 juL, 0.66 mmol) i n 4 mL of dry ether; 5 - c h l o r o - 2 - l i t h i o - l - p e n t e n e (112) (0.33 mmol) i n 3.5 mL of dry THF; 2-cyclopenten- l -one (150) (28 fiL, 0.33 mmol). Workup, fo l lowed by column chromatography of the crude m a t e r i a l on s i l i c a ge l (6 g, e l u t i o n with 20:1 to 7:1 petroleum ether-e ther) and d i s t i l l a t i o n ( a i r - b a t h temperature 9 0 - 9 5 ° C / 0 . 2 Torr) of the o i l obtained from the appropriate f r a c t i o n s , a f forded 39.9 mg (65%) of the chloro ketone (157). The ^H nmr spectrum of t h i s m a t e r i a l was i d e n t i c a l with that of the m a t e r i a l descr ibed above. Preparat ion of 3- [2-(5-Chloro-1-pentenyl) ] -2-methylcyclohexanone (155) 0 CI 155 (a) Using the Grignard Reagent (144) Fo l lowing general procedure C, 2-methyl-2-cyclohexen-l -one (148) - 139 -was converted in to the conjugate a d d i t i o n product (155) . The fo l lowing amounts of reagents were used: 5 - c h l o r o - 2 - l i t h i o - l - p e n t e n e (112) (0.18 mmol) i n 2 mL of dry THF; magnesium bromide-etherate (56 mg, 0.22 mmol); cuprous bromide-dimethyl s u l f i d e complex (14 mg, 0.067 mmol); 2-methyl-2-cyc lohexen- l -one (148) (21 mg, 0.19 mmol); boron t r i f l u o r i d e - e t h e r a t e (27 fiL, 0.22 mmol). Workup, fol lowed by column chromatography of the r e s i d u a l m a t e r i a l on s i l i c a ge l (3 g, e l u t i o n with 3:1 petroleum ether-ether) and d i s t i l l a t i o n ( a i r - b a t h temperature 9 3 - 9 8 ° C / 0 . 2 Torr) of the o i l obtained from the appropriate f r a c t i o n s , a f forded 21.8 mg (56%) of the chloro ketone (155) as a c o l o r l e s s o i l . A n a l y s i s of t h i s o i l by g lc (column B) showed that i t cons i s ted of two components i n a r a t i o of -12:1 , while ana lys i s by t i c (3:1 petroleum ether-e ther) showed one spot . The ^H nmr spectrum of t h i s m a t e r i a l a lso i n d i c a t e d an epimeric mixture ( r a t i o -12:1) . This m a t e r i a l exh ib i t ed i r ( f i l m ) : 3070, 1700, 1635, 900 cm" 1 ; % nmr (400 MHz, CDCI3) 5: 0.95, 1.00 (d, d, 3H t o t a l , secondary methyl protons , r a t i o -1:12, r e s p e c t i v e l y , J = 7 Hz i n each case) , 1.65-1.80 (m, 2H), 1.80-1.97 (m, 3H), 1.97-2.21 (m, 3H), 2.21-2.32 (m, 1H), 2.44-2.60 (m, 2H), 2.60-2.70 (m, 1H,)CHCH 3 ) , 3.55 ( t , 2H, - C H 2 C 1 , J = 7 Hz) , 4.75, 4.98 (br s, br s, - 0 .9 H each, o l e f i n i c protons of major isomer), 4.86, 4.89 (br s, br s, - 0 .1 each, o l e f i n i c protons of minor isomer). I r r a d i a t i o n at 6 1.00 caused the s i g n a l at 6 2.60-2.70 to co l l apse to a d (J = 7 Hz) . Exact Mass c a l c d . for c 1 2 H 1 9 ° 3 5 c l : 214.1126; found: 214.1124. - 140 -(b) Using the Organocopper Reagent (145) Fo l lowing general procedure D, ch loro ketone (155) was obtained from 2-methyl-2-cyclohexen-l -one (148). The fo l lowing amounts of reagents were used: a s o l u t i o n of cuprous bromide-dimethyl s u l f i d e complex (40 mg, 0.19 mmol) and t r i - n - b u t y l p h o s p h i n e (91 pL, 0.36 mmol) i n 2 mL of dry ether; 5 - c h l o r o - 2 - l i t h i o - l - p e n t e n e (112) (0.18 mmol) i n 2 mL of dry THF; 2-methyl-2-cyclohexen-l -one (148) (20 mg, 0.18 mmol). Workup, fol lowed by column chromatography of the crude m a t e r i a l on s i l i c a ge l (5 g, e l u t i o n with 20:1 to 7:1 petroleum ether-e ther) and d i s t i l l a t i o n ( a i r - b a t h temperature 9 3 - 9 8 ° C / 0 . 2 Torr) of the o i l obtained from the appropriate f r a c t i o n s , provided 22.5 mg (58%) of the chloro ketone (155). A n a l y s i s of t h i s o i l by g lc (column B) and nmr spectroscopy showed that i t cons i s ted of an epimeric mixture i n the r a t i o of - 6 : 1 . The -"-H nmr spectrum of t h i s mixture was very s i m i l a r to that of the m a t e r i a l descr ibed above. Preparat ion of 3 - [2- (5-Chloro- l -pentenyl ) ] -3-methylcyc lohexanone (154) 154 - 141 -(a) Using the Grignard Reagent (144) Fo l lowing general procedure C, 3-methyl-2-cyclohexen- l -one (147) was converted in to the conjugate a d d i t i o n product (154). The fo l lowing amounts of reagents were used: 5 - c h l o r o - 2 - l i t h i o - l - p e n t e n e (112) (0.20 mmol) i n 2 mL of dry THF; magnesium bromide-etherate (61.8 mg, 0.24 mmol); cuprous bromide-dimethyl s u l f i d e complex (10 mg, 0.049 mmol); 3-methyl-2-cyclohexen- l -one (147) (23 /uL, 0.20 mmol); boron t r i f l u o r i d e -etherate (27 ^ L . 0.22 mmol). Normal workup, fol lowed by column chromatography of the crude product on s i l i c a ge l (3 g, e l u t i o n with 3:1 petroleum ether-e ther) and d i s t i l l a t i o n ( a i r - b a t h temperature 8 5 - 9 0 ° C / 0 . 2 Torr ) of the o i l obtained from the appropriate f r a c t i o n s , a f forded 15.7 mg (37%) of the chloro ketone (154) as a c o l o r l e s s o i l . This m a t e r i a l exh ib i t ed i r ( f i l m ) : 3050, 1700, 1620, 900 cm" 1 ; 1 H nmr (400MHz, CDC1 3) 6: 1.11 (s, 3H, t e r t i a r y methyl protons ) , 1.57-1.67 (m, 1H), 1.67-1.80 (m, 1H), 1.80-1.90 (m, 1H), 1.90-2.10 (m, 3H), 2.10-2.36 (m, 5H), 2.60 (br d, 1H, J - 14 Hz) , 3.59 ( t , 2H, - C H 2 C 1 , J = 7 Hz) , 4.87, 4.93 (s, s, 1H each, o l e f i n i c protons ) . Exact Mass c a l c d . for C 1 2 H 1 9 0 3 5 C 1 : 214.1126; found: 214.1119. (b) Using the Organocopper Reagent (145) Fo l lowing general procedure D, conjugate adduct (154) was obtained from 3-methyl-2-cyclohexen- l -one (147). The fo l lowing amounts of reagents were used: a s o l u t i o n of cuprous bromide-dimethyl s u l f i d e - 142 -complex (131 mg, 0.63 mmol) and t r i - n - b u t y l p h o s p h i n e (280 ^ L , 1.1 mmol) i n 6.3 mL of dry ether; 5 - c h l o r o - 2 - l i t h i o - l - p e n t e n e (112) (0.57 mmol) i n 6.0 mL of dry THF; 3-methyl-2-cyclohexen-l -one (147) (65 A * L , 0.57 mmol). Workup, fo l lowed by column chromatography of the crude m a t e r i a l on s i l i c a ge l (10 g, e l u t i o n with 20:1 to 7:1 petroleum ether-e ther) and d i s t i l l a t i o n ( a i r - b a t h temperature 8 5 - 9 0 ° C / 0 . 2 Torr) of the o i l obtained from the appropriate f r a c t i o n s , y i e l d e d 62 mg (55%) of the ch loro ketone (154). The ^H nmr spectrum of t h i s m a t e r i a l was i d e n t i c a l with that of the m a t e r i a l g iven above. Preparat ion of 3- [2- (5-Chloro- l -pentenyl ) ] -2-methylcyc lopentanone (159) 159 (a) Using the Grignard Reagent (144) Fol lowing general procedure C, 2-methyl -2-cyclopenten- l -one (152) was converted in to the conjugate a d d i t i o n product (159). The fo l lowing amounts of reagents were used: 5 - c h l o r o - 2 - l i t h i o - l - p e n t e n e (112) (0.18 mmol) i n 2 mL of dry THF; magnesium bromide-etherate (55.7 mg, 0.22 mmol); cuprous bromide-dimethyl s u l f i d e complex (13.2 mg, 0.064 mmol); - 143 -2-methyl -2-cyc lopenten- l -one (152) (18 uL, 0.18 mmol); boron t r i -f l u o r i d e - e t h e r a t e (26 jiL, 0.22 mmol). A f t e r normal workup, column chromatography of the crude mater ia l on s i l i c a ge l (3 g, e l u t i o n with 3:1 petroleum ether-ether) and d i s t i l l a t i o n ( a i r - b a t h temperature 9 0 - 9 5 ° C / 0 . 2 T o r r ) , a f forded 12 mg (33%) of the ch loro ketone (159) as a c o l o r l e s s o i l . A n a l y s i s of t h i s m a t e r i a l by g lc (column B) and nmr spectroscopy showed that i t cons i s ted of a mixture of epimers i n the r a t i o of - 4 : 1 . Th i s m a t e r i a l exh ib i t ed i r ( f i l m ) : 3060, 1730, 1635, 900 cm" 1 ; l-H nmr (400 MHz, CDC1 3) 6: 1.05, 0.88 (d, d, 3H t o t a l , secondary methyl protons , r a t i o -4:1 r e s p e c t i v e l y , J •= 7 Hz i n each case) , 1.60-2.50 (m, -9 .25H) , 2.78-2.88 (m, -0 .75H, s i g n a l r e l a t e d to the major isomer), 3.52-3.63 (m, 2H, - C H 2 C 1 ) , 4.78, 4.94 (s, s, - 0 . 7 5 H e a c h , o l e f i n i c protons of the major isomer), 4.89-4.92 (m, - 0 . 5 H , o l e f i n i c protons of the minor isomer) . Exact Mass c a l c d . for C^^H^yO^^Cl: 200.0969; found: 200.0975. (b) Us ing the Organocopper Reagent (145) Fo l lowing general procedure D, ch loro ketone (159) was obtained from 2-methyl -2-cyclopenten- l -one (152). The fo l l owing amounts of reagents were used: a s o l u t i o n of cuprous bromide-dimethyl s u l f i d e complex (45.4 mg, 0.22 mmol) and t r i - n - b u t y l p h o s p h i n e (98 pL, 0.39 mmol) i n 2.2 mL of dry ether; 5 - c h l o r o - 2 - l i t h i o - l - p e n t e n e (112) (0.19 mmol) i n 2 mL of dry THF; 2-methyl -2-cyclopenten- l -one (152) (20 uL, 0.2 mmol). Workup, fo l lowed by column chromatography of the crude m a t e r i a l on 144 -s i l i c a ge l (5 g, e l u t i o n with 20:1 to 7:1 petroleum ether-ether) and d i s t i l l a t i o n ( a i r - b a t h temperature 9 0 - 9 5 ° C / 0 . 2 Torr) of the o i l obtained from the appropriate f r a c t i o n s , provided 26.2 mg (67%) of the chloro ketone (159). Glc ana lys i s (column B) of t h i s m a t e r i a l showed that i t cons i s t ed of a -2:1 mixture of epimers. The nmr spectrum of t h i s m a t e r i a l was very s i m i l a r to that of the m a t e r i a l descr ibed above. Preparat ion of 3 - [2 - (5 -Chloro- l -pentenyl ) ] -3 -methylcyc lopentanone (158) 158 (a) Using the Grignard Reagent (144) Fo l lowing general procedure C, 3-methyl -2-cyclopenten- l -one (151) was converted in to the conjugate a d d i t i o n product (158). The fo l lowing amounts of reagents were used: 5 - c h l o r o - 2 - l i t h i o - l - p e n t e n e (112) (0.21 mmol) i n 2 mL of dry THF; magnesium bromide-etherate (65.1 mg, 0.25 mmol); cuprous bromide-dimethyl s u l f i d e complex (10.7 mg, 0.052 mmol), 3 -methyl -2-cyc lopenten- l -one (151) (21 fiL, 0.21 mmol); boron t r i -f l u o r i d e - e t h e r a t e (30 pL, 0.25 mmol). Normal workup, fol lowed by column chromatography of the crude m a t e r i a l on s i l i c a ge l (3 g, e l u t i o n with 3:1 petroleum ether-ether) and d i s t i l l a t i o n ( a i r - b a t h temperature - 145 7 6 - 8 5 ° C / 0 . 2 Torr ) of the o i l obtained from the appropriate f r a c t i o n s , a f forded 22.5 mg (54%) of the chloro ketone (158) as a c o l o r l e s s o i l . This m a t e r i a l exh ib i t ed i r ( f i l m ) : 3070, 1730, 1630, 900 cm" 1 ; -^H nmr (400 MHz, GDCI3) 6: 1 .20 (s, 3H, t e r t i a r y methyl protons ) , 1 .85-2.50 (m, 10H), 3.59 ( t , 2H, - C H 2C1, J = 7 Hz) , 4.82 (br s, 1H, o l e f i n i c proton) , 4.88 (s, 1H, o l e f i n i c proton) . Exact Mass c a l c d . for C 1 1 H 1 7 0 3 5 C 1 : 200.0969; found: 200.0969. (b) Using the Organocopper Reagent (145) Fol lowing general procedure E , ch loro ketone (158) was obtained from 3-methyl -2-cyclopenten- l -one (151). The fo l lowing amounts of reagents were used: a s o l u t i o n of cuprous bromide-dimethyl s u l f i d e complex (43 mg, 0.21 mmol) and t r i - n - b u t y l p h o s p h i n e (95 pL , 0.38 mmol) i n 2.1 mL of dry ether; 5 -ch l oro-2-1 i th io-1-pentene (112) (0.19 mmol) i n 2 mL of dry THF; 3-methyl-2-cyclopenten- l -one (151) (19 J I L , 0.19 mmol); boron t r i f l u o r i d e - e t h e r a t e (28 fiL, 0.23 mmol). Workup, fol lowed by column chromatography of the crude m a t e r i a l on s i l i c a ge l (5 g, e l u t i o n with 20:1 to 7:1 petroleum ether-ether) and d i s t i l l a t i o n ( a i r - b a t h temperature 7 6 - 8 5 ° C / 0 . 2 Torr) of the o i l obtained from the appropriate f r a c t i o n s , gave 14.3 mg (38%) of the chloro ketone (158). The 1 H nmr spectrum of t h i s mater ia l was i d e n t i c a l with that of the m a t e r i a l given above. - 146 -Preparat ion of 3 - [2 - (5 -Chloro - l -penteny l ) ] -3 , 5 , 5 - t r imethy lcyc lohexanone (156) (a) Using the Grignard Reagent (144) Fol lowing general procedure C, 3 , 5 ,5 - t r imethy l -2 - cyc lohexen- l -one (149) was converted in to the conjugate a d d i t i o n product (156). The fo l l owing amounts of reagents were used: 5 - c h l o r o - 2 - l i t h i o - l - p e n t e n e (112) (0.39 mmol) i n 4 mL of dry THF; magnesium bromide-etherate (120.5 mg, 0.47 mmol); cuprous bromide-dimethyl s u l f i d e complex (22.5 mg, 0.11 mmol), 3 , 5 , 5 - t r imethy l -2 - cyc lohexen- l -one (149) (58 ^ L , 0.39 mmol); boron t r i f l u o r i d e - e t h e r a t e (58 uL, 0.47 mmol). The r e s u l t a n t mixture was s t i r r e d at - 7 8 ° C for 4.5 h . Normal workup, fo l lowed by column chromatography of the crude m a t e r i a l on s i l i c a ge l (5 g, e l u t i o n with 3:1 petroleum ether-e ther) and d i s t i l l a t i o n ( a i r - b a t h temperature 8 2 - 8 6 ° C / 0 . 2 Torr) of the o i l obtained from the appropriate f r a c t i o n s , a f forded 42.6 mg (45%) of the chloro ketone (156) as a c o l o r l e s s o i l . This m a t e r i a l exh ib i t ed i r ( f i l m ) : 3070, 1700, 1630, 900 c m - 1 ; % nmr (400 MHz, CDC1 3) 5: 0.97, 1.04, 1.16 (s, s, s, 3H each, t e r t i a r y methyl pro tons ) , 1.58 (d, 1H, J - 14 Hz) , 1.90-2.05 (m, 3H), 2.13-2.25 (m, 5H), 2.76 (d, 1H, J = 14 Hz) , 3.59 ( t , 2H, - C H 2 C 1 , J = 7 Hz) , 4 .81, 5.04 (br 0 CI 156 - 147 -s, br s, 1H each, o l e f i n i c protons ) . Exact Mass c a l c d . for C^4H230 3 5 C1: 242.1437; found: 242.1436. (b) Using the Organocopper Reagent (145) Fo l lowing general procedure E , chloro ketone (156) was prepared from 3 ,5 ,5 - t r imethy l -2 - cyc lohexen- l -one (149). The fo l lowing amounts of reagents were used: a s o l u t i o n of cuprous bromide-dimethyl s u l f i d e complex (44 mg, 0.21 mmol) and t r i - n - b u t y l p h o s p h i n e (97 / iL , 0.39 mmol) i n 2.1 mL of dry ether; 5 - c h l o r o - 2 - l i t h i o - l - p e n t e n e (112) (0.19 mmol) i n 2.0 mL of dry THF; 3 ,5 ,5 - t r imethy l -2 - cyc lohexen- l -one (149) (29 pL, 0.19 mmol); boron t r i f l u o r i d e - e t h e r a t e (29 fiL, 0.23 mmol). Workup, fol lowed by column chromatography of the crude m a t e r i a l on s i l i c a gel (5 g, e l u t i o n with 20:1 to 7:1 petroleum ether-ether) and d i s t i l l a t i o n ( a i r -bath temperature 8 2 - 8 6 ° C / 0 . 2 Torr) of the o i l obtained from the appropriate f r a c t i o n s , provided 10 mg (21%) of the chloro ketone (156). This m a t e r i a l e x h i b i t e d a ^H nmr spectrum i d e n t i c a l with that of the m a t e r i a l descr ibed above. General Procedure F: C y c l i z a t i o n of the Chloro Ketones Derived from the Conjugate A d d i t i o n of Reagents (144) and/or (145) to C y c l i c Enones To a s o l u t i o n of the chloro ketone (1.0 equiv) i n dry THF (~1 mL per 0.1 mmol of the chloro ketone) was added potassium hydride (~ 2.5 - 148 -equiv) as a suspension i n dry THF (- 1 mL per mmol of potassium hydride) at room temperature. The r e s u l t a n t yel low mixture was s t i r r e d at room temperature for 2 h . Saturated aqueous ammonium c h l o r i d e (5 mL) and ether (10 mL) were added. The aqueous layer was separated and extracted twice with ether . The combined ether extract was washed once with br ine and d r i e d over anhydrous magnesium s u l f a t e . Solvent removal under reduced pressure fol lowed by d i s t i l l a t i o n of the r e s i d u a l o i l provided the product . Preparat ion of c i s -7 -Methylenebicyc lo[4 .4 .0 ]decan-2-one (160) and trans -7-Methvlenebicvc lo \4.4 .0]decan-2-one (161) 160 161 Fol lowing general procedure F , the chloro ketone (153) (44 mg, 0.22 mmol) i n 2 mL of dry THF was allowed to react with potassium hydride (22 mg, 0.55 mmol) i n 0.5 mL of dry THF. Workup, fol lowed by d i s t i l l a t i o n ( a i r - b a t h temperature 1 0 0 - 1 2 0 ° C / 3 3 Torr) of the crude m a t e r i a l , af forded 31 mg (86%) of a c o l o r l e s s o i l . This m a t e r i a l showed one peak by g lc ana lys i s (column B) and two spots by t i c ana lys i s (3:1 petroleum ether-ether) . The ^H nmr spectrum of t h i s m a t e r i a l showed that i t cons i s ted - 149 -of a mixture of c i s and trans isomers i n a r a t i o of 1:2, r e s p e c t i v e l y . Column chromatography of t h i s mixture on s i l i c a ge l (10 g, e l u t i o n with 12:1 petroleum e t h e r - e t h e r ) , fol lowed by concentrat ion of the appropr i -ate f r a c t i o n s prov ided , i n order of e l u t i o n , 8 mg of the c i s isomer (160) as a c o l o r l e s s o i l ( d i s t i l l a t i o n temperature 95-100°C/33 Torr ) and 17 mg of the trans isomer (161) as a white s o l i d (mp 2 8 - 2 9 ° C , r e c r y s t a l l i z a t i o n from petroleum e ther ) . The c i s ketone (160) exh ib i t ed i r ( f i l m ) : 3040, 1700, 1630, 895 c m - 1 ; LU nmr (400 MHz, CDC1 3) 8: 1.31-1.45 (m, 1H), 1.45-1.64 (m, 2H), 1 .64-1.79 (m, 1H), 1.79-1.94 (m, 2H), 2.00-2.19 (m, 3H), 2 .19-2 .30 (m, 2H), 2 .36-2.55 (m, 2H), 2 .63-2 .72 (m, 1H), 4.66 ( t , 1H, o l e f i n i c proton, J = 1.5 Hz) , 4 .69 (s, 1H, o l e f i n i c proton) . Exact Mass c a l c d . for C 1 1 H 1 6 0 : 164.1202; found: 164.1205. The trans ketone (161) exh ib i t ed i r (CHCI3) : 1700, 1635, 900 cm" 1 ; 1 H nmr (400 MHz, CDCI3) 6: 1.20-1.36 (m, 1H) , 1 .36-1 .52 (m, 1H) , 1 .60-1 .78 (m, 2H), 1 .83-2 .09 (m, 6H), 2 .09-2.21 (m, 1H), 2 .23-2.45 (m, 3H), 4 . 69 , 4.75 (s, s, 1H each, o l e f i n i c protons) ; 1 3 C nmr (20 MHz, CDCI3) 5: 24.99, 25.30, 26.27, 27.61, 35 . 76 , 41.26, 48.10, 55.53, 75 .42 , 77.02, 78.62, 105.74, 151.57, 212.45. Exact Mass c a l c d . f or C 1 1 H l g 0 : 164.1202; found: 164.1202. - 150 -Preparat ion of c i s - l - M e t h y l - 7 - m e t h y l e n e b i c y c l o [ 4 . 4 . 0 ] d e c a n - 2 - o n e (164) Fo l lowing general procedure F , a s o l u t i o n of the mixture of chloro ketones (155) (21.7 mg, 0.1 mmol) i n 1 mL of dry THF was allowed to react with potassium hydride (11 mg, 0.26 mmol) i n 0.3 mL of dry THF. Workup, fo l lowed by d i s t i l l a t i o n ( a i r - b a t h temperature 8 5 - 9 2 ° C / 2 2 Torr) of the crude m a t e r i a l , a f forded 14 mg (78%) of the b i c y c l i c ketone (164) as a c o l o r l e s s o i l . This m a t e r i a l cons i s ted of one component as shown by g lc (column B) ana lys i s and ^H nmr spectroscopy. This m a t e r i a l e x h i b i t e d i r ( f i l m ) : 3050, 1695, 1635, 895 cm" 1 ; X H nmr (400 MHz, CDC1 3) 6: 1.10 (s, 3H, t e r t i a r y methyl protons) , 1.19-1.28 (m, 1H) , 1.55-1.76 (m, 4H), 1.98-2.37 (m, 7H), 2.55-2.67 (m, 1H), 4.69 ( t , 1H, o l e f i n i c proton , J = 1.5 Hz) , 4.72 ( t , 1H, o l e f i n i c proton, J = 2 Hz) . In a nOe d i f f erence experiment, i r r a d i a t i o n at 5 1.10 caused enhancement of a s i g n a l at 6 2.25 (d of d, J = 12, 6 Hz) . Exact Mass c a l c d . for C 1 2 H 1 8 0 : 178.1358; found: 178.1357. 0 164 - 151 -Preparat ion of c i s -6-Methyl -7-methylenebicyc lo[4 .4 .0]decan-2-one (162) and trans-6-Methvl-7-methvlenebicvcloT4.4 .01decan-2-one (163) 0 u a? 163 Fol lowing general procedure F , a s o l u t i o n of 22 rag (0.1 mmol) of the ch loro ketone (154) i n 1 mL of dry THF was allowed to react with potassium hydride (10 mg, 0.25 mmol) i n 0.3 mL of dry THF. Normal workup, fo l lowed by d i s t i l l a t i o n ( a i r - b a t h temperature 1 0 0 - 1 1 3 ° C / 3 3 Torr ) of the crude m a t e r i a l , a f forded 15 mg (82%) of a c o l o r l e s s o i l . A n a l y s i s of t h i s o i l by g lc (column B) showed that i t cons i s t ed of a mixture of c i s and trans isomers i n a r a t i o of 3 .5:1 , r e s p e c t i v e l y . Column chromatography on s i l i c a ge l impregnated with 25% s i l v e r n i t r a t e (6 g, e l u t i o n with 25:1 petroleum e t h e r - e t h e r ) , fol lowed by concentra-t i o n of the appropriate f r a c t i o n s and d i s t i l l a t i o n a f forded , i n order of e l u t i o n , 5 mg of the c i s isomer (162) and 2 mg of the trans isomer (163), both as c o l o r l e s s o i l s . A mixture (5 mg) of (162) and (163) was a l so recovered. The c i s ketone (162) ( d i s t i l l a t i o n temperature 1 0 6 - 1 0 9 ° C / 3 3 Torr) e x h i b i t e d i r ( f i l m ) : 3060, 1700, 1630, 900 c m - 1 ; -^H nmr (400 MHz, CDCI3) 8: 1.17 (s, 3H, t e r t i a r y methyl protons) , 1.28-1.47 (m, 2H) , 1.61-1.70 (m, 1H), 1.75-2.05 (m, 4H), 2.15 (d of d, 1H, H c , J = 10, 4 Hz) , - 152 -2.18-2.40 (m, 4H), 2.43-2.53 (m, 1H), 4.73 (s, 1H, o l e f i n i c proton , H A ) , 4.76 (br s, 1H, o l e f i n i c proton, Hg). In a nOe d i f f erence experiment, i r r a d i a t i o n at 8 1.17 caused enhancement of the s igna l s at 8 4.73 (s) and 8 2.15 (d of d, J = 10, 4 Hz) . Exact Mass c a l c d . for C 1 2 H 1 8 0 : 178.1358; found: 178.1359. The trans ketone (163) ( d i s t i l l a t i o n temperature 1 0 2 - 1 0 5 ° C / 3 3 Torr) e x h i b i t e d i r (CHC1 3 ) : 3060, 1700, 1630, 895 cm" 1 ; % nmr (400 MHz, CDCI3) 8: 0.95 (s, 3H, t e r t i a r y methyl protons) , 1.20-1.35 (m, 1H), 1.50-1.75 (m, 2H), 1.84-2.40 (m, 10H), 4.70-4.76 (m, 2H, o l e f i n i c pro tons ) . Exact Mass c a l c d . for C 1 2 H 1 8 0 : 178.1358; found: 178.1355. Preparat ion of c i s -7 -Methy lene -4 .4 ,6 - t r imethy lb i cyc lo [4 .4 .0 ]decan-2 -one (165) and trans -7 -Methy lene -4 .4 .6 - t r imethv lb icvc lo \4 .4 .0 ]decan-2 -one (166) Fo l lowing general procedure F , a s o l u t i o n of the chloro ketone (156) (76.7 mg, 0.32 mmol) i n 3.2 mL of dry THF was allowed to react with potassium hydride (33 mg, 0.79 mmol) i n 1 mL of dry THF. Workup, fo l lowed by d i s t i l l a t i o n ( a i r - b a t h temperature 7 0 - 8 6 ° C / 2 4 Torr) of the crude m a t e r i a l , a f forded 58 mg (89%) of a c o l o r l e s s o i l . A n a l y s i s of - 153 -t h i s o i l by g lc (column B) showed that i t cons i s ted of a mixture of c i s and trans isomers i n a r a t i o of 8:1, r e s p e c t i v e l y . Column chromato-graphy of t h i s m a t e r i a l on s i l i c a gel impregnated with 25% s i l v e r n i t r a t e (12 g, e l u t i o n with 25:1 petroleum e t h e r - e t h e r ) , fo l lowed by concentra t ion of the appropriate f r a c t i o n s , provided 5.7 mg of the c i s isomer (165) as a white s o l i d , mp 56-56.5°C ( r e c r y s t a l l i z a t i o n from petroleum e t h e r ) , and 46 mg of a mixture of (165) and (166). The trans isomer (166) was c h a r a c t e r i z e d a f t e r e q u i l i b r a t i o n of the mixture as descr ibed l a t e r . The c i s ketone (165) exh ib i t ed i r (CDC1 3): 3070, 1690, 1620, 900 c m - 1 ; 1 H nmr (400 MHz, CDCI3) 6: 1 .05 (s, 3H, M e F ) , 1.06 (s, 3H, Meg), 1.26 (s, 3H, bridgehead methyl protons) , 1.33 (d, 1H, J = 15 Hz) , 1.43 (m, 1H), 1 .63-1 .76 (m, 2H), 1 .92-2 .03 (m, 1H), 2 .08 (d of d of d, 1H, J = 14, 1.5, 1.5 Hz) , 2.13 (d of d, 1H, H A , J = 8, 4.5 Hz) , 2 .23-2 .37 (m, 3H), 2.43 (d, 1H, J = 14 Hz) , 4.77 (q, 1H, H c , J = 1.5 Hz) , 4 .80 (br s, 1H, Hg). In a nOe d i f f erence experiment, i r r a d i a t i o n at S 1.26 caused enhancement of the s igna l s at 6 1 .06, 2 .13 and 4 .80 . Exact Mass c a l c d . for C 1 4 H 2 2 0 : 206.1672; found: 206.1680. The trans ketone (166), a c o l o r l e s s o i l ( d i s t i l l a t i o n temperature 72-75°C/24 T o r r ) , exh ib i t ed i r ( f i l m ) : 3060, 1700, 1623, 900 cm" 1 ; % nmr (400 MHz, CDCI3) 6: 1 .04, 1.10, 1 .14 (s, s, s, 3H each, t e r t i a r y methyl pro tons ) , 1 .19-1.34 (m, 1H), 1.49-1.72 (m, 2H), 1 .76-1 .91 (m, 2H), 2.01 (d, 1H, J =13.5 Hz) , 2 .08-2.20 (m, 2H), 2.20-2.43 (m, 3H), 4 . 70 , 4.73 (br s, br s, 1H each, o l e f i n i c protons ) . Exact Mass c a l c d . for C 1 4 H 2 2 0 : 206.1671; found: 206.1675. - 154 -Preparation of cis -2-Methylenebicyclo [4 .3.0]nonan-7-one (167) and trans -2-Methylenebicyclo14.3.0]nonan-7-one (168) Fol lowing general procedure F , a s o l u t i o n of 36.8 mg (0.2 mmol) of the ch loro ketone (157) i n 2 mL of dry THF was allowed to react with potassium hydride (20 mg, 0.5 mmol) i n 0.5 mL of dry THF. Workup, fo l lowed by d i s t i l l a t i o n ( a i r - b a t h temperature 7 0 - 8 5 ° C / 2 3 Torr ) of the crude m a t e r i a l , a f forded 24.8 mg (84%) of a c o l o r l e s s o i l . A n a l y s i s of t h i s o i l by g l c (column B) showed that i t cons i s t ed of a mixture of the isomers (167) and (168) i n a r a t i o of - 5 : 1 , r e s p e c t i v e l y . The ^H nmr spectrum of t h i s o i l a lso i n d i c a t e d a mixture of epimers ( -5:1) . Column chromatography of the mixture on s i l i c a ge l impregnated with 25% s i l v e r n i t r a t e (6 g, e l u t i o n with 20:1 petroleum e t h e r - e t h e r ) , fol lowed by d i s t i l l a t i o n ( a i r - b a t h temperature 7 5 - 8 0 ° C / 2 3 Torr) of the o i l obtained from the appropriate f r a c t i o n s , provided 4 mg of the c i s isomer (167) as a c o l o r l e s s o i l . A mixture (11 mg) of (167) and (168) was a lso recovered. The c i s ketone (167) exh ib i t ed i r ( f i l m ) : 3050, 1730, 1635, 895 c m - 1 ; % nmr (400 MHz, CDCI3) 6: 1.42-1.60 (m, 2H) , 1.62-1.80 (m, 2H)', 1.85-1.97 (m, 1H), 2.05-2.14 (m, 1H), 2.15-2.37 (m, 3H), 2.37-2.41 (m, 2H),2 .95(d of t , 1H, H A , J = 7, 7 Hz) , 4.79 (s, 1H, Hg), 4.80 (br s, 1H, 0 H 168 155 -HQ ) . In a nOe d i f f erence experiment, i r r a d i a t i o n at 5 2.95 caused enhancement of the s igna l s at 5 A.79 (s) and 2.37-2.41 (m). Exact Mass c a l c d . f or C 1 0 H 1 4 0 : 150.1046; found: 150.1039. The •'-H nmr spectrum of a mixture of the c i s and trans ketones [(167) and (168)] showed that the alkene protons of the trans isomer (168) resonated at S 4.66 (s) and 4.77 (br s ) . Exact Mass c a l c d . for ^10H14^ : 150.1046; found (glc-mass spectroscopy): 150.1066. Preparat ion of c i s -6-Methyl -2-methylenebicvc lo \4 .3 .01nonan-7-one (170) Fol lowing general procedure F , a s o l u t i o n of the mixture of ch loro ketones (159) (37 mg, 0.18 mmol) i n 1.8 mL of dry THF was allowed to reac t with potassium hydride (18 mg, 0.45 mmol) i n 0.5 mL of dry THF. Workup, fo l lowed by d i s t i l l a t i o n ( a i r - b a t h temperature 6 8 - 7 3 ° C / 2 3 Torr) of the crude o i l a f forded 27.4 mg (90%) of the b i c y c l i c ketone (170) as a c o l o r l e s s o i l . This o i l cons i s ted of one component as shown by g lc (column B) and t i c (3:1 petroleum ether-ether) ana lys i s and by ^H nmr spectroscopy. This mater ia l exh ib i t ed i r ( f i l m ) : 3050, 1730, 1635, 900 cm" 1 ; 1 H nmr (400 MHz, CDCI3) 6: 1.04 (s, 3H, t e r t i a r y methyl protons) , 1.18-1.27 (m, 1H), 1.43-1.56 (m, 2H), 1.60-1.72 (m, 1H), 1.83-1.95 (m, 0 170 - 156 -1H), 1.98-2.12 (m, 1H) , 2.12-2.28 (m, 3H), 2.43-2.55 (m, 2H), 4.76-4.83 (m, 2H, o l e f i n i c protons ) . In a nOe d i f f erence experiment, i r r a d i a t i o n at S 1.04 caused enhancement of the s i g n a l at 6 2.49 (d of d, J = 12, 8 Hz) . Exact Mass c a l c d . for C 1 ; L H 1 6 0 : 164.1202; found: 164.1205. Preparat ion of c i s -1-Methyl -2-methylenebicyclo \4 .3 .01nonan-7-one (169) Fol lowing general procedure F , a s o l u t i o n of the ch loro ketone (158) (32.7 mg, 0.16 mmol) i n 1.6 mL of dry THF was al lowed to react with potassium hydride (17 mg, 0.43 mmol) i n 0.5 mL of dry THF. Workup, fo l lowed by d i s t i l l a t i o n ( a i r - b a t h temperature 7 2 - 7 6 ° C / 2 3 Torr) of the crude m a t e r i a l , a f forded 21.7 mg (83%) of the b i c y c l i c ketone (169) as a c o l o r l e s s o i l . A n a l y s i s of t h i s o i l by g lc (column B) , t i c (3:1 petro-leum ether-e ther) and nmr spectroscopy i n d i c a t e d that i t cons i s t ed of one component. This mater ia l exh ib i t ed i r ( f i l m ) : 3070, 1735, 1635, 900 c m - 1 ; X H nmr (400 MHz, CDCI3) 5: 1.15-1.30 (m, 1H), 1.34 (s, 3H, t e r t i a r y methyl protons ) , 1.50-1.61 (m, 3H), 1.97-2.10 (m, 2H), 2.10-2.33 (m, 4H), 2.45 (m, 1H), 4.77, 4.81 (s, s, 1H each, o l e f i n i c pro tons ) . Exact Mass c a l c d . for C 1 1 H 1 6 0 : 164.1202; found: 164.1208. ° H 169 - 157 -General Procedure G: E q u i l i b r a t i o n of B i c y c l i c Ketones Derived from the C y c l i z a t i o n of the Chloro Ketones Sodium metal (10 mg, 0.43 mmol) was added to 0.5 mL of s t i r r e d , dry methanol at room temperature. A f t e r a l l of the sodium had reacted , a s o l u t i o n of appropriate b i c y c l i c ketone i n dry methanol (~0.5 mL per 0.1 mmol of b i c y c l i c ketone) was added and the mixture was re f luxed for 18 h . Saturated aqueous ammonium c h l o r i d e (2 mL) and ether (4 mL) were added. The aqueous l ayer were separated and washed twice with ether. The combined ether extract was washed once with b r i n e and d r i e d over anhydrous magnesium s u l f a t e . Removal of the so lvent under reduced pressure and d i s t i l l a t i o n of the r e s i d u a l o i l provided the product . E q u i l i b r a t i o n of c i s -7-Methylenebicyc lo[4 .4 .01decan-2-one (160) and trans-7-Methylenebicyc lo \4 .4 .0 ]decan-2-one (161) 0 H 9 H H 160 161 (a) Use of a Mixture of the B i c y c l i c Ketones (160) and (161) Fo l lowing general procedure G, a mixture of the c i s and trans 158 -b l c y c l i c ketones (160) and (161) ( r a t i o 1:2, r e s p e c t i v e l y ) (20 mg, 0.12 mmol) was e q u i l i b r a t e d with sodium methoxide i n r e f l u x i n g dry methanol (1.1 mL). Workup, fol lowed by d i s t i l l a t i o n ( a i r - b a t h temperature 1 1 0 - 1 2 0 ° C / 3 3 Torr) of the crude m a t e r i a l , provided 18 mg (90%) of a white s o l i d . The nmr spectrum of t h i s mater ia l was i d e n t i c a l with that of the trans isomer (161). (b) Use of the Pure c i s Ketone (160) Fol lowing general procedure G, the pure c i s ketone (160) (10 mg, 0.061 mmol) was t rea ted with sodium methoxide i n r e f l u x i n g dry methanol (0.8 mL). Workup, fol lowed by d i s t i l l a t i o n ( a i r - b a t h temperature 1 1 0 - 1 2 0 ° C / 3 3 Torr ) of the res idue , a f forded 7 mg (70%) of a white s o l i d . Th i s m a t e r i a l exh ib i t ed nmr spectrum i d e n t i c a l with that of the trans ketone (161). (c) Use of the Pure trans Isomer (161) Fol lowing general procedure G, 13.4 mg (0.088 mmol) of the pure trans ketone (161) was treated with sodium methoxide i n r e f l u x i n g dry methanol (0.9 mL). Workup, fol lowed by d i s t i l l a t i o n ( a i r - b a t h tempera-ture 1 1 0 - 1 2 0 ° C / 3 3 Torr) of the res idue , af forded 10 mg (75%) of a white s o l i d . This mater ia l exh ib i t ed % nmr spectrum i d e n t i c a l with that of the trans ketone (161). - 159 -E q u i l i b r a t i o n of c i s -6-Methyl -7-methylenebicyc lof4 .4 .01decan-2-one (162) and trans -6-Methyl-7-methvlenebicvclo"4.4.01decan-2-one (163) (a) Use of the Pure c i s Ketone (162) Fol lowing general procedure G, the pure c i s ketone (162) (11 mg, 0.062 mg) was e q u i l i b r a t e d with sodium methoxide i n r e f l u x i n g dry methanol (0.8 mL). Workup, fol lowed by d i s t i l l a t i o n ( a i r - b a t h tempera-ture 1 0 0 - 1 1 3 ° C / 3 3 Torr) of the crude m a t e r i a l , a f forded 7 mg (64%) of a c o l o r l e s s o i l . A n a l y s i s of t h i s o i l by g lc (column B) showed that i t cons i s t ed of the isomers (162) and (163) i n a r a t i o of 1:2.8, r e s p e c t i v e l y . (b) Use of the Pure trans Ketone (163) Fol lowing general procedure G, the pure trans ketone (163) (18 mg, 0.1 mmol) was e q u i l i b r a t e d with sodium methoxide i n r e f l u x i n g dry methanol (1 mL). Workup and d i s t i l l a t i o n ( a i r - b a t h temperature 1 0 0 - 1 1 3 ° C / 3 3 Torr) of the residue provided 14 mg (77%) of a c o l o r l e s s - 160 -o i l . A n a l y s i s of t h i s o i l by g lc (column B) i n d i c a t e d that i t cons i s ted of (162) and (163) i n a r a t i o of 1:2.8, r e s p e c t i v e l y . E q u i l i b r a t i o n of c i s -7 -Methy lene -4 ,4 ,6 - t r imethy lcyc lo [4 .4 .0 ]decan-2 -one (165) and t rans -7 -Methy lene -4 ,4 ,6 - t r imethy lb icyc lo [4 .4 .0 ]decan-2 -one (166) Fo l lowing general procedure G, a mixture of the ketones (165) and (166) ( r a t i o 8:1, r e s p e c t i v e l y ) (53.8 mg, 0.26 mmol) was e q u i l i b r a t e d with sodium methoxide i n r e f l u x i n g dry methanol (2.5 mL). Workup af forded 50 mg (93%) of crude m a t e r i a l . A n a l y s i s of t h i s mater ia l by g lc (column B) showed that i t cons i s ted of a mixture of (165) and (166) i n a r a t i o of 1:2, r e s p e c t i v e l y . Column chromatography of t h i s mixture on s i l i c a ge l impregnated with 25% s i l v e r n i t r a t e (12 g, e l u t i o n with 90:1 to 20:1 petroleum e t h e r - e t h e r ) , fol lowed by concentrat ion of the appropriate f r a c t i o n s , a f forded, i n order of e l u t i o n , 10.9 mg of the c i s ketone (165) as a white s o l i d , 16 mg of a mixture of (165) and (166), and 16.8 mg of trans ketone (166) ( d i s t i l l a t i o n temperature 7 2 - 7 5 ° C / 2 4 T o r r ) as a c o l o r l e s s o i l . 161 -E q u i l i b r a t i o n of c i s -2-Methylenebicyc lo[4 .3 .0]nonan-7-one (167) and trans-2-Methylenebicyclo[4 .3 .0]nonan-7-one (168) (a) Use of a Mixture of (167) and (168) Fo l lowing general procedure G, a mixture of ketones (167) and (168) ( r a t i o 84:16, r e s p e c t i v e l y ) (15 mg, 0.091 mmol) was e q u i l i b r a t e d with sodium methoxide i n r e f l u x i n g dry methanol (0.7 mL). Workup, fol lowed by d i s t i l l a t i o n ( a i r - b a t h temperature 7 0 - 8 5 ° C / 2 3 Torr) of the crude m a t e r i a l , a f forded 12 mg (80%) of a c o l o r l e s s o i l . This o i l cons i s ted of a mixture of the ketones (167) and (168) i n the r a t i o of 82:18, r e s p e c t i v e l y , as determined by g lc (column B) a n a l y s i s . (b) Use of the Pure c i s Ketone (167) Fo l lowing general procedure G, the pure c i s ketone (167) (15 mg, 0.091 mmol) was e q u i l i b r a t e d with sodium methoxide i n r e f l u x i n g dry methanol (0.7 mL) . Workup and d i s t i l l a t i o n ( a i r - b a t h temperature 7 0 - 8 5 ° C / 2 3 Torr ) of the crude product provided 10 mg (67%) of a c o l o r l e s s o i l . This o i l was shown by g lc (column B) ana lys i s to cons i s t - 162 -of a mixture of ketones (167) and (168) i n the r a t i o of 85:15, r e s p e c t i v e l y . E q u i l i b r a t i o n of c i s - l -Methy l -2 -methy lenebicyc lo [4 .3 .0 ]nonan-7-one (169) Fol lowing general procedure G, 11 mg (0.066 mmol) of the pure c i s b i c y c l i c ketone (169) was e q u i l i b r a t e d with sodium methoxide i n r e f l u x i n g dry methanol (0.8 mL). Workup, fol lowed by d i s t i l l a t i o n ( a i r - b a t h temperature 7 2 - 7 6 ° C / 2 3 Torr ) of the crude m a t e r i a l , a f forded 10 mg (91%) of a c o l o r l e s s o i l . This mater ia l showed one peak by g lc (column B) ana lys i s and e x h i b i t e d a nmr spectrum i d e n t i c a l with that of the pure c i s ketone (169). Large Scale Preparat ion of 6-Methyl-2-methylenebicyclo[4.3 .0]nonan-7-one (170) <i H 169 170 - 163 -To a c o l d ( - 7 8 ° C ) , s t i r r e d s o l u t i o n of 5 - c h l o r o - 2 - t r i m e t h y l -stannyl-1-pentene (111) (1.96 g, 7.3 mmol) i n 30 mL of dry THF was added methy l l i th ium (9.1 mmol) as a s o l u t i o n i n ether and the c o l o r l e s s s o l u t i o n was s t i r r e d at - 7 8 ° C for 15 min. S o l i d magnesium bromide-etherate (1.88 g, 7.3 mmol) was added i n one p o r t i o n and the milky mixture was s t i r r e d at - 7 8 ° C for 20 min. S o l i d cuprous bromide-dimethyl s u l f i d e complex (376 mg, 1.8 mmol) was added i n one p o r t i o n to th i s mixture at - 7 8 ° C . To the pale yel low mixture was added success ive ly a s o l u t i o n of 2-methyl -2-cyclopenten- l -one (152) (541 mg, 5.6 mmol) i n 5 mL of dry THF and boron t r i f l u o r i d e - e t h e r a t e (0.9 mL, 7.3 mmol). The r e s u l t i n g b r i g h t yel low mixture was s t i r r e d at - 7 8 ° C for 3 h . Saturated aqueous ammonium c h l o r i d e (pH 8) (25 mL) and ether (30 mL) were added and the mixture was allowed to warm to room temperature with vigorous s t i r r i n g and exposure to a i r . The blue aqueous layer was separated and extracted twice with ether . The combined ether ex trac t was washed twice with saturated aqueous ammonium c h l o r i d e (pH 8) , d r i e d over anhydrous magnesium s u l f a t e , and concentrated under reduced pressure . The residue was subjected to f l a s h chromatography on s i l i c a ge l (80 g, e l u t i o n with 4:1 petroleum e t h e r - e t h e r ) . D i s t i l l a t i o n ( a i r - b a t h temperature 9 0 - 9 5 ° C / 0 . 2 Torr ) of the o i l obtained from the appropriate f r a c t i o n s af forded 996 mg (89%) of the mixture of chloro ketones (159) ( r a t i o - 2 : 1 ) . Fo l lowing general procedure F , a s o l u t i o n of the mixture of chloro ketones (159) (996 mg, 5.0 mmol) i n 5 mL of dry THF was allowed to react with 498 mg (12.4 mmol) of potassium hydride i n 5 mL of dry THF. Normal workup, fo l lowed by d i s t i l l a t i o n ( a i r - b a t h temperature 6 8 - 7 3 ° C / 2 3 Torr) - 164 -of the crude m a t e r i a l , a f forded 789 mg (96%) of the b i c y c l i c ketone (170) as a c o l o r l e s s o i l . Preparat ion of 6 - M e t h y l - 2 - m e t h y l e n e - 7 - t r i m e t h y l s i l o x y b i c y c l o [ 4 . 3 . 0 ] -non-7-ene (210) To a c o l d ( - 7 8 ° C ) , s t i r r e d s o l u t i o n of LDA (2.3 mmol) i n 2.3 mL of dry THF was added a s o l u t i o n of 6-methyl-2-methylenebicyclo[4.3 .0]nonan-7-one (170) (310 mg, 1.9 mmol) i n 2 mL of dry THF. The s o l u t i o n was s t i r r e d at - 7 8 ° C for 40 min, during which time a white s o l i d was formed. T r i m e t h y l s i l y l c h l o r i d e (310 ^ L , 2.5 mmol) was added at - 7 8 ° C and, a f ter 5 min, the mixture was allowed to warm to room temperature and then was s t i r r e d for a fur ther 1.5 h . During t h i s time, the i n i t i a l l y formed white p r e c i p i t a t e d i s s o l v e d and then, a f t er a short time, was replaced by another p r e c i p i t a t e . The mixture was d i l u t e d with 5 mL of dry ether and then was f i l t e r e d . A f t e r the f i l t r a t e had been concentrated under reduced pressure , the residue was treated with 2 mL of dry ether and the r e s u l t a n t mixture was f i l t e r e d again . Removal of so lvent from the f i l t r a t e under reduced pressure , fol lowed by d i s t i l l a t i o n ( a i r - b a t h temperature 8 2 - 8 8 ° C / 2 5 Torr) of the r e s i d u a l m a t e r i a l , a f forded 446 mg 210 - 165 -(99%) of the s i l y l enol ether (210) as a c o l o r l e s s o i l . This mater ia l e x h i b i t e d i r ( f i l m ) : 3050, 1630, 1252, 1235, 920, 895, 845 cm" 1 ; X H nmr (400MHz, CDC1 3) 8: 0.21 [s, 9H, - S i ( C H 3 ) 3 ] , 0.97 (s, 3H, t e r t i a r y methyl pro tons ) , 1.24-1.65 (m, 4H), 2.09-2.26 (m, 4H), 2.42 ( t , 1H, bridgehead proton , J = 9 Hz) , 4.48 ( t , 1H, H A , J = 2 Hz) , 4.70 (br s, 2H, ) c=CH 2 ) . Exact Mass c a l c d . for C ^ H ^ O S i : 236.1597; found: 236.1599. Preparat ion of 8-Bromo-6-methyl-2-methylenebicyclo[4.3.0]nonan-7-one (211) A s o l u t i o n of N-bromosuccinimide (355 mg, 2.0 mmol) i n 6 mL of dry THF was added dropwise to a s o l u t i o n of the s i l y l enol ether (210) (446 mg, 1.9 mmol) i n 3 mL of dry THF at 0 ° C . A f t e r the mixture had been s t i r r e d for 15 min at 0 ° C , 15 mL of water and 15 mL of t e t r a c h l o r o -methane were added. The aqueous l ayer was separated and extracted twice with tetrachloromethane. The combined organic l ayer was washed once with water, d r i e d over anhydrous magnesium s u l f a t e , and concentrated under reduced pressure . D i s t i l l a t i o n ( a i r - b a t h temperature 4 8 - 5 2 ° C / 0 . 2 Torr ) of the r e s i d u a l o i l a f forded 425 mg (92%) of the bromo ketone (211) - 166 -as a c o l o r l e s s o i l with very sweet smel l . A n a l y s i s of t h i s o i l by g lc (column B) showed that i t cons i s ted of a mixture of epimers i n a r a t i o of 85:15. The major epimer (211a) exh ib i t ed i r ( f i l m ) : 3050, 1740, 1640, 1060, 900 c m - 1 ; LE nmr (400 MHz, CDCI3) 5: 1.24 (s, 3H, t e r t i a r y methyl protons ) , 1.29-1.78 (m, 4H), 2.05-2.18 (m, 1H), 2.14 (d of d of d, 1H, Hg, J = 15, 6.5, 1 Hz) , 2.18-2.28 (m, 1H), 2.55 (d of d of d, 1H, H c , J = 15, 11.5, 6.5 Hz) , 2.96 (d of d, 1H, bridgehead proton, J = 11.5, 6.5 Hz) , 4.42 (d of d, 1H, H A , J = 6.5, 1 Hz) , 4.87, 4.90 (br s, br s, 1H each, o l e f i n i c protons ) . I r r a d i a t i o n at 5 2.55 caused the s i g n a l at 5 4.42 to sharpen, and the s igna l s at S 2.96 and 2.14 to s i m p l i f y ; i r r a d i a t i o n at 6 2.96 caused the resonance at S 2.55 to co l l apse to a d of d (J = 15, 6.5 Hz) and the s i g n a l at 6 2.14 to s i m p l i f y ; i r r a d i a t i o n at 5 4.42 caused the s igna l s at 5 2.14 and 2.55 to c o l l a p s e , i n each case, to a d of d (J *= 15, 6.5 and 15, 11.5 Hz, respect-i v e l y ) . Exact Mass c a l c d . for C 1 1 H 1 5 0 7 9 B r : 242.0306; found: 242.0303. Preparat ion of 6-Methyl-2-methylenebicyclo[4 .3 .0]non-8-en-7-one (203) 203 A s o l u t i o n of the bromo ketone (211) (425 mg, 1.76 mmol) i n 5 mL of - 167 -dry DMF was added to a s l u r r y of l i t h i u m bromide (315 mg, 3.6 mmol) and l i t h i u m carbonate (401 mg, 5.4 mmol) i n 4 mL of dry DMF. The mixture was re f luxed for 3 h and then was cooled and f i l t e r e d . The c o l l e c t e d s a l t was washed with 20 mL of e ther . The combined f i l t r a t e was washed wi th water (3 x 15 mL), d r i e d over anhydrous magnesium s u l f a t e , and concentrated under reduced pressure . D i s t i l l a t i o n ( a i r - b a t h temperature 9 0 - 1 0 0 ° C / 2 5 Torr ) of the res idue provided 239 mg (84%) of the enone (203) as a c o l o r l e s s o i l . This mater ia l exh ib i t ed i r ( f i l m ) : 3050, 3025, 1700, 1640, 900, 820 cm" 1 ; 1 H nmr (400 MHz, CDCI3) 5: 1.12 (s, 3H, t e r t i a r y methyl protons ) , 1.34-1.58 (m, 3H), 1.65 (m, 1H), 2.09 (m, 1H), 2.22 (m, 1H), 3.23 (br s, 1H, H c ) , 4.92, 4.90 (br s, br s, 1H each, )C=CH 2), 6.20 (d of d, 1H, H A , J - 5.5, 2 Hz) , 7.48 (d of d, 1H, H B , J = 5.5, 2.5 Hz) . In a nOe d i f f erence experiment, i r r a d i a t i o n at 5 1.12 caused enhancement of the s i g n a l at 8 3.23. Exact Mass c a l c d . for C 1 1 H 1 4 0 : 162.1045; found: 162.1046. Preparat ion of (E)-1-Ethoxy- 3 -me t h y 1 - 1 - t r ime thy1s i loxybut-1-ene (202) To a c o l d ( - 7 8 ° C ) , s t i r r e d s o l u t i o n of LDA (2.76 mmol) i n 2.8 mL of 202 - 168 -dry THF was added e t h y l 3-methylbutanoate (299 mg, 2.3 mmol) i n 2 mL of dry THF. The mixture was s t i r r e d at - 7 8 ° C for 30 min. To t h i s s o l u t i o n , t r i m e t h y l s i l y l c h l o r i d e (410 (xL, 3.2 mmol) was added. The s o l u t i o n was al lowed to warm to room temperature and then was s t i r r e d for 1.5 h . The mixture was d i l u t e d with 5 mL of dry ether and then was f i l t e r e d . A f t e r removal of the solvent from the f i l t r a t e (reduced p r e s s u r e ) , the res idue was treated with 2 mL of dry ether and the f i l t r a t i o n was repeated. Removal of the solvent from the f i l t r a t e , fo l lowed by d i s t i l l a t i o n ( a i r - b a t h temperature 6 0 - 6 5 ° C / 2 5 Torr ) of the r e s i d u a l o i l provided 419 mg (90%) of the s i l y l ketene a c e t a l (202) as a c o l o r l e s s o i l . A n a l y s i s of t h i s mater ia l by g lc (column B) i n d i c a t e d that i t cons i s t ed of a mixture of (E) and (Z) isomers i n a r a t i o of 95:5, r e s p e c t i v e l y . This mater ia l was used immediately for the next r e a c t i o n without fur ther p u r i f i c a t i o n . This m a t e r i a l e x h i b i t e d i r ( f i l m ) : 1678, 1369, 1255, 1064, 891, 848 c m - 1 ; LE nmr (80 MHz, CDC1 3) 6: 0.22 [s, 9H, - S i ( C H 3 ) 3 ] , 0.95 [d, 6H, - C H ( C H 3 ) 2 , J = 7 Hz] , 1.22 ( t , 3H, - O C H 2 C H 3 , J = 7 Hz) , 2.25-2.80 [m, 1H, - C H ( C H 3 ) 2 ] , 3.62 (d, 1H, v i n y l proton , J = 9 Hz) , 3.82 (q, 2H, - O C H 2 C H 3 , J = 7 Hz) . - 169 -Preparat ion of the B i c y c l i c Keto Esters (204) and (205) To a c o l d ( - 7 8 ° C ) , s t i r r e d s o l u t i o n of the b i c y c l i c enone (203) (198 mg, 1.23 mmol) i n 2 mL of dry dichloromethane was added t i tan ium t e t r a c h l o r i d e (150 / iL , 1.36 mmol) and the s o l u t i o n was s t i r r e d for a fur ther 5 min. To the r e s u l t a n t orange red s o l u t i o n was added a so lu -t i o n of the s i l y l ketene a c e t a l (202) (311 mg, 1.5 mmol) i n 2 mL of dry dichloromethane. The c o l o r of the s o l u t i o n turned to dark red immedi-a t e l y . A f t e r the mixture had been s t i r r e d at - 7 8 ° C for 2 h , i t was t rea ted with 8 mL of water and the r e s u l t a n t mixture was extracted with ether (3 x 15 mL). The organic layer was d r i e d over anhydrous magnesium s u l f a t e and concentrated under reduced pressure . F l a s h chromatography of the res idue on s i l i c a gel (80 g, e l u t i o n with 3:1 petroleum ether-ether) prov ided , a f t e r concentrat ion of the appropriate f r a c t i o n s , 322 mg (89%) of a white s o l i d . Ana lys i s of t h i s mater ia l by g lc (column B) and nmr spectroscopy showed that i t cons i s ted of a mixture of (204) and (205) i n a r a t i o of - 1 : 1 . By us ing a combination of c a r e f u l column chromatography on s i l i c a gel (10 g of s i l i c a gel per 10 mg of mixture, e l u t i o n with 10:1 petroleum ether-e ther , slow dr ipping) and mul t ip l e development preparat ive t i c (11 times, 10:1 petroleum e t h e r - e t h e r ) , pure - 170 -samples of (204) and (205) were obtained for c h a r a c t e r i z a t i o n . The keto es ter (204), mp 8 0 - 8 1 ° C ( r e c r y s t a l l i z a t i o n from petroleum e t h e r ) , e x h i b i t e d i r (CHC1 3 ) : 3080, 3035, 1730, 1645, 1374, 1181, 902 cm" 1 ; 1 H nmr (400 MHz, CDCI3) 8: 0.94, 0.95 [d, d, 3H each, - C H ( C H 3 ) 2 , J = 7 Hz i n each case] , 1.01 (s, 3H, t e r t i a r y methyl protons ) , 1.23 ( t , 3H, - O C H 2 C H 3 , J = 7 Hz) , 1.20-1.30 (obscured m, 1H), 1.40-1.63 (m, 2H), 1.68-1.78 (m, 1H) , 1.82-1.95 ( p a r t i a l l y obscured m, 1H, Hg), 1.94 (d of d, 1H, Hp, J - 18.5, 11.5 Hz) , 2.07-2.15 (m, 1H), 2.15 ( p a r t i a l l y obscured d, 1H, Hp, J = 11 Hz) , 2.20 ( p a r t i a l l y obscured d of d, 1H, H c , J = 10, 4.5 Hz) , 2.18-2.31 (m, 1H), 2.65 (d of d, 1H, H G , J - 18.5, 7.5 Hz) , 2.79-2.93 (m, 1H, H D ) , 3.92-4.06 (m, 2H, - O C H 2 C H 3 ) , 4.72 (br s, 1H, o l e f i n i c proton) , 4.77 ( t , 1H, o l e f i n i c proton, J = 2 Hz) . I r r a d i a t i o n at 8 2.86 caused the s igna l s at 8 1.94, 2.15, 2.20, and 2.65 to co l lapse to a d (J = 18.5 Hz) , a s, a d (J = 4.5 Hz) , and a d (J = 18.5 Hz) , r e s p e c t i v e l y ; i r r a d i a t i o n at 5 2.65 caused the resonance at 5 1.94 to co l l apse to an "imperfect" doublet (J = 11.5 Hz) and the s i g n a l at 5 2.86 to s i m p l i f y ; i r r a d i a t i o n at 8 0.95 caused the m u l t i p l e t at 5 1.83-1.94 to co l l apse to a broad s i n g l e t ; i n a nOe d i f f erence exper i -ment, i r r a d i a t i o n at 5 1.01 caused a weak enhancement of the s i g n a l at 8 2.15 (d, J = 11 Hz) . Exact Mass c a l c d . for C 1 8 H 2 8 0 3 : 292.2039; found: 292.2045. The keto es ter (205), mp 6 9 - 7 0 ° C ( r e c r y s t a l l i z a t i o n from petroleum e t h e r ) , e x h i b i t e d i r (CHCI3) : 3070, 3028, 1728, 1645, 1377, 1188, 1152, 1029, 903 cm" 1 ; LE nmr (400 MHz, CDCI3) 8: 0.91, 0.95 [d, d, 3H each, -CH(CH.3)2, J = 7 Hz i n each case] , 1.03 (s, 3H, t e r t i a r y methyl pro tons ) , 1.27 ( t , 3H, - O C H 2 C H 3 , J = 7 Hz) , 1.22-1.30 (obscured m, 1H), - 171 -1.45-1.55 (m, 2H), 1.67-1.77 (m, 1H), 1.84-2.00 (m, 1H, Hg), 2.03-2.17 (m, 1H), 2.30 ( p a r t i a l l y obscured d, 1H, H E , J = 11 Hz) , 2.18-2.28 (m, 1H), 2.28 (d of d, 1H, H c , J - 10, 4 Hz) , 2.52 (d of d, 1H, H G , J - 17, 7 Hz) , 2.56-2.74 (m, 2H), 4.16 (q, 2H, - O C H 2 C H 3 , J = 7 Hz) , 4.84 ( t , 1H, o l e f i n i c proton , J = 1.5 Hz) , 4.94 ( t , 1H, o l e f i n i c proton, J = 2 Hz) . I r r a d i a t i o n at 8 0.92 caused the m u l t i p l e t at 8 1.84-2.00 to co l lapse to a d (J = 10 Hz); i r r a d i a t i o n at 8 1.91 caused both of the doublets at S 0.91 and 0.95 to co l l apse to s i n g l e t s , and the d of d at 8 2.28 to co l l apse to a very broad s i n g l e t ; i n a nOe d i f f erence experiment, i r r a d i a t i o n at 8 1.03 caused enhancement of the s i g n a l at 8 2.30 (d, J = 11 Hz) . Exact Mass c a l c d . for C 1 8 H 2 8 0 3 : 292.2039; found: 292.2041. Preparat ion of 3 - M e t h y l - l , l - b i s ( t r i m e t h y l s i l o x y ) - l - b u t e n e (226) To a c o l d ( - 7 8 ° C ) , s t i r r e d s o l u t i o n of LDA (1.78 mmol) i n 1.8 mL of dry THF was added 3-methylbutanoic a c i d (227) (82.8 mg, 0.81 mmol) i n 2 mL of dry THF. A f t e r 5 min, the s o l u t i o n was warmed to 0°C and then was s t i r r e d at t h i s temperature for 1.5 h . A white p r e c i p i t a t e formed. HMPA (0.31 mL, 1.78 mmol) was added and the mixture was s t i r r e d for 15 min at 0 ° C . During t h i s time, the white s o l i d d i s s o l v e d . To the c l e a r , pale ye l low s o l u t i o n was added 0.25 mL (1.97 mmol) of t r i m e t h y l s i l y l ch lo-226 - 1 7 2 -r i d e . The s o l u t i o n was allowed to warm to room temperature and then was s t i r r e d for 1.5 h . Aqueous sodium bicarbonate (5%, 10 mL) and pentane (10 mL) were added. The organic layer was separated and washed with 5% aqueous sodium bicarbonate (4 x 10 mL), and d r i e d over anhydrous magnesium s u l f a t e . Removal of the solvent under reduced pressure , fo l lowed by d i s t i l l a t i o n ( a i r - b a t h temperature 8 0 - 9 0 ° C / 2 5 Torr ) of the res idue , provided 172 mg (86%) of the b i s ( t r i m e t h y l s i l y l ) ketene a c e t a l (226) as a c o l o r l e s s o i l . This mater ia l was used immediately for the next r e a c t i o n without any fur ther p u r i f i c a t i o n . This m a t e r i a l exh ib i t ed i r ( f i l m ) : 1670, 1255, 1060, 890, 840, 760 cm" 1 ; X H nmr (270 MHz, CDC1 3) 5: 0.20, 0.22 [s, s, 18H, - S i ( C H 3 ) 3 groups] , 0.91 [d, 6H, - C H ( C H 3 ) 2 , I = 7 Hz] , 2.41 [m, 1H, - C H ( C H 3 ) 2 ] , 3.42 (d, 1H, v i n y l proton , J = 8 Hz) . Preparat ion of the B i c y c l i c Keto Acids ( 2 2 2 ) and ( 2 2 3 ) (a) V i a Conjugate A d d i t i o n of the Ketene A c e t a l ( 2 2 6 ) to Enone ( 2 0 3 ) Titanium t e t r a c h l o r i d e ( 6 9 / J L , 0 . 6 3 mmol) was added to a s t i r r e d s o l u t i o n of the enone ( 2 0 3 ) ( 9 3 mg, 0.57 mmol) i n 1 mL of dry d i c h l o r o -- 173 -methane at - 7 8 ° C and the s o l u t i o n was s t i r r e d for 5 min. To t h i s c o l d ( - 7 8 ° C ) , orange red s o l u t i o n was added slowly a s o l u t i o n of the ketene a c e t a l (226) (168 mg, 0.68 mmol) i n 1 mL of dry dichloromethane. The c o l o r of the s o l u t i o n turned to reddish brown immediately. The mixture was allowed to s t i r at - 7 8 ° C for 2 h. Water (10 mL) was added and the mixture was allowed to warm to room temperature with s t i r r i n g . A f t e r 5 min, the s o l u t i o n became c o l o r l e s s . The mixture was extracted with ether (3 x 15 mL). The combined ether extract was d r i e d over anhydrous magnesium s u l f a t e and concentrated under reduced pressure to a f f o r d 150 mg of crude m a t e r i a l . The nmr spectrum of t h i s crude m a t e r i a l i n d i c a t e d that i t cons i s ted of a mixture of (222) and (223) i n the r a t i o of -3 :2 , r e s p e c t i v e l y . This mixture was subjected to a combination of (repeated) column chromatography on s i l i c a ge l (20 g per 100 mg of sample, e l u t i o n with 3:2 petroleum ether-ether) and f r a c t i o n a l c r y s t a l l -i z a t i o n from ether . Eventua l ly there was obtained 66 mg (44%) of the pure keto a c i d (222) and 48 mg (32%) of the pure keto a c i d (223), along with 18 mg (12%) of a mixture of (222) and (223). A n a l y t i c a l l y pure sample of the keto a c i d (222) ( r e c r y s t a l l i z a t i o n from ether) e x h i b i t e d mp 1 7 2 - 1 7 3 ° C ; i r (CHC1 3 ) : 3400-2500 ( b r ) , 3030, 1735, 1703, 1646, 1375, 901 cm" 1 ; -^H nmr (400 MHz, CDCI3) 6: 0.93, 1.05 [d, d, 3H each, -CH(CH 3 )2 , J = 7 Hz i n each case] , 1.00 (s, 3H, t e r t i a r y methyl pro tons ) , 1.23 (br d, 1H, J = 12 Hz) , 1.38-1.59 (m, 2H), 1.66-1.75 (m, 1H), 1.86-2.00 (obscured m, 1H, Hg), 1.94 (d of d, 1H, H F , J = 18.5, 11.5 Hz) , 2.06-2.15 (m, 1H), 2.16 ( p a r t i a l l y obscured br d, 1H, H E , J = 10.5 Hz) , 2.21 ( p a r t i a l l y obscured d of d, 1H, H c , J = 9.5, 4.5 Hz) , 2.20-2.30 (m, 1H), 2.62 (d of d, 1H, H G , J = 18.5, 7.5 Hz) , 2.71-- 174 -2.85 (m, 1H, H D ) , 4.76 ( t , 1H, o l e f i n i c proton, J = 1.5 Hz) , 4.80 (br s, 1H, o l e f i n i c proton) , 10.5-11.2 (br, 1H, -C00H). I r r a d i a t i o n at 5 2.62 caused the s i g n a l s at 8 2.71-2.85 and 1.86-2.0 to s i m p l i f y ; i r r a d i a t i o n at 6 2.78 caused the s igna l s at 8 2.62, 2.16, 2.21 and 1.94 to co l lapse to a d (J = 18.5 Hz) , a br s, a br s, and an "imperfect" doublet (J = 18.5 Hz) , r e s p e c t i v e l y ; 1 3 C nmr (100 MHz, CDC1 3) 8: 17.12, 18.58, 21.48, 22.90, 28.50, 30.32, 34.51, 40.85, 51.18, 55.52, 58.84, 113.03, 144.97, 179.54, 218.00. Exact Mass c a l c d . f or C 1 6 H 2 4 0 3 : 264.1726; found: 264.1726. A n a l y t i c a l l y pure sample of the keto a c i d (223) ( r e c r y s t a l l i z a t i o n from petroleum e t h e r - e t h e r ) , exh ib i t ed mp 1 2 0 - 1 2 1 ° C ; i r (CHCI3): 3400-2500 ( b r ) , 3030, 1733, 1703, 1646, 1376, 907 cm" 1 ; 1 H nmr (400 MHz, CDCI3) 5: 0.95, 0.96 [d, d, 3H each, - C H ( C H 3 ) 2 , J = 6.5 Hz i n each case ] , 1.03 (s, 3H, t e r t i a r y methyl protons ) , 1.21-1.30 (m, 1H), 1.42-1.57 (m, 2H), 1.66-1.77 (m, 1H), 1.86-1.99 (m, 1H, Hg), 2.01-2.04 (m, 1H), 2.17-2.23 (1 obscured H) , 2.22 (br d, 1H, H E > J = 10.5 Hz) , 2.32 (d of d, 1H, H c , J - 9.5, 3.5 Hz) , 2.46-2.70 (m, 3H), 4.88 (br s, 1H, o l e f i n i c pro ton) , 4.94 ( t , 1H, o l e f i n i c proton, J «= 2 Hz) . I r r a d i a t i o n at 8 1.92 caused the doublets at 8 0.95 and 0.96 to sharpen and the s i g n a l at 8 2.32 to co l lapse to a br s; i r r a d i a t i o n at 6 2.32 caused the s i g n a l at 8 1.86-1.99 to co l lapse to a septet (J = 6.5 Hz) and the s i g n a l at 8 2.46-2.70 to s i m p l i f y ; i r r a d i a t i o n at 5 0.95 caused the s i g n a l at 8 1.86-1.99 to co l lapse to a d (J = 9.5 Hz) . 1 3 C nmr (75 MHz, CDCI3) 8: 18.83, 20.27, 21.37, 22.82, 28.69, 28.94, 30.65, 34.68, 37.57, 50.80, 52.25, 55.52, 113.76, 143.63, 178.93, 219.89. Exact Mass c a l c d . for C 1 6 H 2 4 0 3 : 264.1726; found: 264.1727. 175 -(b) V i a Hydro lys i s of the Keto Esters (204) and (205) A mixture of the keto esters (204) and (205) ( r a t i o -1:1) (318 mg, 1.1 mmol) and potassium hydroxide (600 mg, 10.9 mmol) i n 1.5 mL of ethanol and 0.5 mL of water was re f luxed for 48 h . The s o l u t i o n was washed with ether ( 2 x 5 mL) and then was a c i d i f i e d with IN h y d r o c h l o r i c a c i d . The r e s u l t a n t mixture was extracted with ether (3 x 10 mL). The combined ether ex trac t was d r i e d over anhydrous magnesium s u l f a t e and concentrated under reduced pressure . The res idue was subjected to a combination of (repeated) column chromatography on s i l i c a gel (20 g per 100 mg of sample, e l u t i o n with 3:2 petroleum ether-ether) and f r a c t i o n a l c r y s t a l l i z a t i o n from ether to a f f o r d 61.6 mg (21%) of the keto a c i d (222), 146 mg (50%) of the keto a c i d (223) and 32 mg (11%) of a mixture of (222) and (223). The i s o l a t e d pure samples of (222) and (223) e x h i b i t e d ^H nmr spectra i d e n t i c a l with those of the mater ia l s descr ibed above. Preparat ion of the B i c y c l i c A c i d (187) A s t i r r e d s o l u t i o n of the keto a c i d (222) (40 mg, 0.15 mmol) i n anhydrous hydrazine (48 pL, 1.5 mmol) i n 0.3 mL of d iethylene g l y c o l was H, C 187 - 176 -heated at 1 1 0 ° C for 3 h . The mixture was then heated at 1 9 0 ° C for 30 min, dur ing which time excess hydrazine and water were allowed to d i s t i l l from the s o l u t i o n . A f t e r the s o l u t i o n had been cooled to room temperature, 43 mg (0.75 mmol) of potassium hydroxide was added and the mixture was heated at 1 9 0 ° C for 6 h . Gas evo lu t ion was observed. The mixture was cooled to room temperature, was d i l u t e d with 5 mL of water, and then was a c i d i f i e d with IN h y d r o c h l o r i c a c i d . E x t r a c t i o n of the r e s u l t a n t mixture with ether ( 3 x 5 mL), dry ing (MgS0 4) of the combined e x t r a c t , and evaporat ion of the solvent under reduced pressure gave a white s o l i d . This m a t e r i a l was p u r i f i e d by column chromatography on s i l i c a ge l (8 g, 4:1 petroleum e t h e r - e t h e r ) . D i s t i l l a t i o n ( a i r - b a t h temperature 1 0 8 - 1 1 2 ° C / 0 . 3 Torr) of the m a t e r i a l obtained from the appropriate f r a c t i o n s af forded 34 mg (90%) of the a c i d (187) as a white s o l i d . R e c r y s t a l l i z a t i o n of t h i s mater ia l from petroleum ether-e ther af forded white needles , mp 1 2 0 - 1 2 1 ° C ; i r (CHCI3) : 3500-2500 ( b r ) , 3071, 1703, 1644, 1390, 1374, 1219, 894 cm" 1 ; 1 H nmr (400 MHz, CDCI3) 6: 0.96, 0.97 [d, d, 3H each, -CH(CH 3 )2 , J = 7 Hz i n each case ] , 0.94 (s, 3H, t e r t i a r y methyl protons) , 1.16-1.24 (m, 1H), 1.35-1.66 (m, 6H), 1.86 (br d, 1H, H E , J = 10.5 Hz) , 1.90-2.07 (m, 3H), 2.10 (d of d, 1H, H c , J = 9.5, 5 Hz) , 2.13-2.24 (m, 1H), 2.46-2.58 (m, 1H, H D ) , 4.67 (br s, 2H, o l e f i n i c pro tons ) . I r r a d i a t i o n at 5 2.50 caused the s i g n a l at 6 1.86 to co l l apse to a s, the s i g n a l at 6 2.10 to co l lapse to a d (J = 5 Hz) and the s igna l s at 8 1.35-1.66 and 1.90-2.07 to s i m p l i f y . Exact Mass c a l c d . for C 1 6 H 2 6 0 2 : 250.1934; found: 250.1934. 177 Preparat ion of the B i c y c l i c A c i d (193) COOH 193 A s t i r r e d s o l u t i o n of the keto a c i d (223) (30 mg, 0.11 mmol) i n anhydrous hydrazine (35 / iL , 1.1 mmol) i n 0.2 mL of d iethylene g l y c o l was heated at 1 1 0 ° C for 3 h . This mixture was then heated at 1 9 0 ° C for 30 min, during which time excess hydrazine and water were allowed to d i s t i l l from the s o l u t i o n . The mixture was cooled and 31 mg (0.55 mmol) of potassium hydroxide was added. The mixture was heated at 1 9 0 ° C for 6 h . During t h i s time, gas evo lu t ion was observed. The s o l u t i o n was cooled to room temperature, was d i l u t e d with 2 mL of water, and then was a c i d i f i e d with IN h y d r o c h l o r i c a c i d . The r e s u l t a n t mixture was extracted with ether ( 3 x 6 mL). The combined ether ex trac t was d r i e d over anhydrous magnesium s u l f a t e and concentrated under reduced pres-sure. The res idue was subjected to column chromatography on s i l i c a gel (5 g, 4:1 petroleum e t h e r - e t h e r ) . D i s t i l l a t i o n ( a i r - b a t h temperature 1 0 5 - 1 1 0 ° C / 0 . 3 Torr ) of the mater ia l obtained from the appropriate f r a c t i o n s af forded 25.6 mg (90%) of the b i c y c l i c a c i d (193) as a c o l o r l e s s o i l . This mater ia l exh ib i t ed i r ( f i l m ) : 3500-2500 (br ) , 3071, 1702, 1645, 1390, 1375, 1289, 1228, 1166, 895 c m - 1 ; 1 H nmr (400 MHz, CDC1 3) 6: 0.93, 0.94 [d, d, 3H each, - C H ( C H 3 ) 2 , J = 7 Hz i n each case] , - 178 -0.95 (s, 3H, t e r t i a r y methyl protons) , 1.16-1.22 (m, 1H), 1.34-1.55 (m, 4H), 1.57-1.66 (m, 1H), 1.79-1.90 (m, 2H), 1.91 ( p a r t i a l l y obscured br d, 1H, H E , J - 11 Hz) , 1.96-2.08 ( p a r t i a l l y obscured m, 1H, Hg), 2.05-2.15 (m, 2H), 2.18 (d of d, 1H, H c , J = 9, 5 Hz) , 2.40-2.50 (m, 1H, Hn). 4.74 (br s, 1H, o l e f i n i c proton) , 4.80 ( t , 1H, o l e f i n i c proton, J = 2 Hz) . I r r a d i a t i o n at 6 0.93 caused the s i g n a l at 6 1.96-2.08 to co l lapse to a d (J *= 9 Hz); i r r a d i a t i o n at S 2.18 caused the s igna l s at S 2.40-2.50 and S 1.96-2.08 to s i m p l i f y ; i r r a d i a t i o n at 5 2.45 caused the s i g n a l at S 1.91 to co l lapse to a s and the s i g n a l at 5 2.18 to co l lapse to a d (J = 9 Hz) . Exact Mass c a l c d . f or C i 6 H 2 6 0 2 : 250.1934; found: 250.1931. Preparat ion of the Carbamate (237) 194 R= C0CI 195 R= CON 3 237 R= NC0 2 (CH 2 ) 2 SiMe3 H To a s t i r r e d s o l u t i o n of the a c i d (187) (46 mg, 0.185 mmol) i n 1.5 mL of dry toluene, under an atmosphere of argon, was added o x a l y l c h l o r i d e (64 /xL, 0.74 mmol) and the mixture was s t i r r e d at room temperature. A f t e r 45 min, evo lu t ion of gas had ceased and the solvent was removed under reduced pressure . The r e s i d u a l pale ye l low o i l [the - 179 -a c i d c h l o r i d e (194)] exh ib i t ed i r ( f i l m ) : 3072, 1794, 1646, 1393, 1375, 894 cm" 1 . Th i s m a t e r i a l was d i s so lved i n 1 mL of dry acetone and the s o l u t i o n was added to a r a p i d l y s t i r r e d s o l u t i o n of sodium azide (50.5 mg, 0.74 mmol) i n 0.2 mL of water at 0 ° C . A f t e r 15 min, 10 mL of hexanes and 5 mL of water were added. The organic layer was removed and the aqueous l ayer was extracted with 3 mL of hexanes. The combined organic ex trac t was d r i e d over anhydrous magnesium s u l f a t e . Removal of the so lvent under reduced pressure provided the a c y l azide (195), which exh ib i t ed i r ( f i l m ) : 3070, 2271, 2130, 1714, 1644, 1373, 892 cm" 1 . This m a t e r i a l was d i s s o l v e d i n 0.2 mL of dry toluene and the s o l u t i o n was heated at 80°C with s t i r r i n g . E v o l u t i o n of n i t rogen began immediately. A f t e r 2 h , 80 jzL (0.55 mmol) of 2 - t r i m e t h y l s i l y l e t h a n o l was added and s t i r r i n g at 80°C was continued for 20 h . Most of the so lvent was removed under reduced pressure . The res idue was d i s s o l v e d i n 6 mL of ether and the s o l u t i o n was washed with 5 mL of aqueous sodium hydroxide (IN). The ether l ayer was d r i e d over anhydrous magnesium s u l f a t e . Removal of the solvent under reduced pressure , fo l lowed by column chromatography of the r e s i d u a l mater ia l on s i l i c a ge l (6 g, 6:1 petro-leum ether-e ther) and d i s t i l l a t i o n ( a i r - b a t h temperature 1 2 5 - 1 3 0 ° C / 0 . 3 Torr) of the m a t e r i a l obtained from the appropriate f r a c t i o n s , y i e l d e d 60 mg (89%) of carbamate (237) as a white s o l i d . An a n a l y t i c a l l y pure sample of (237), obtained by r e c r y s t a l l i z a t i o n from petroleum ether, e x h i b i t e d mp 7 9 . 5 - 8 0 . 5 ° C ; i r (CHC1 3 ) : 3446, 3072, 1709, 1644, 1515, 1465, 896 cm" 1 ; nmr (400 MHz, CDCI3) 8: 0.05 (s , 9H, - S i M e 3 ) , 0.73, 0.87 [s, s, 3H each, - C H ( C H 3 ) 2 , J = 7 Hz i n each case] , 0.91 (s, 3H, t e r t i a r y methyl protons) , 0.97 ( t , 2H, - C H 2 C H 2 S i M e 3 , ^ = 8 - 5 H z^> - 180 -1.13-1.23 (m, 1H), 1.36-1.51 (m, 5H), 1.59-1.68 (m, 1H), 1.77-1.88 (m, 1H, Hg), 1.90-2.00 (m, 2H), 2.00-2.16 (m, 2H), 2.20-2.31 (m, 1H, H D ) , 3.47 (t of d, 1H, H c , J = 10, 4 Hz) , 4.06-4.20 (m, 2 H , - C H 2 C H 2 S i M e 3 ) , 4.31 (br d, 1H, - N H - , J - 10 Hz) , 4.65, 4.73 (br s, br s, 1H each, o l e f i n i c pro tons ) . I r r a d i a t i o n at S 4.11 caused the t at 6 0.97 to co l l apse to a s; i r r a d i a t i o n at 6 0.73 caused the m at S 1.77-1.88 to s i m p l i f y ; i r r a d i a t i o n at 5 1.80 caused the s i g n a l at 5 3.47 to co l lapse to a t (J = 7 Hz) and the s igna l s at 6 0.73 and 0.87 to co l l apse to s i n g l e t s ; i r r a d i a t i o n at 5 3.47 caused the m u l t i p l e t at 6 1.77-1.88 to co l l apse to a septet (J = 7 Hz) and the m at 8 2.20-2.31 to s i m p l i f y ; i r r a d i a t i o n at S 4.31 caused the s i g n a l at 5 3.47 to co l l apse to a d of d (J = 10, 4 Hz) . Exact Mass c a l c d . for C 2 1 H 3 9 N O S i : 365.2752; found: 365.2742. Preparat ion of the Carbamate (240) 238 R= C0CI 239 R= CON3 240 R= N C 0 2 ( C H 2 ) 2 S i M e 3 To a s t i r r e d s o l u t i o n of the a c i d (193) (25 mg, 0.1 mmol) i n 1.0 mL of dry toluene, under an atmosphere of argon, was added o x a l y l c h l o r i d e (35 /J.L, 0.4 mmol) and the mixture was s t i r r e d for 45 min at room - 181 -temperature. A f t e r the evo lu t ion of gas had ceased, most of the solvent was removed under reduced pressure to give a pale yel low o i l [the a c i d c h l o r i d e (238)] which showed i r ( f i l m ) : 3072, 1795, 1645, 1464, 1392, 1335, 897 cm" 1 . This o i l was d i s s o l v e d i n 1 mL of dry acetone and the s o l u t i o n was added to a r a p i d l y s t i r r e d s o l u t i o n of sodium azide (27 mg, 0.4 mmol) i n 0.1 mL of water at 0 ° C . A f t e r 15 min, 5 mL of hexanes and 5 mL of water were added. The hexanes layer was separated and the aqueous l a y e r was washed with hexanes (5 mL). The combined organic ex trac t was d r i e d over anhydrous magnesium s u l f a t e . Removal of the so lvent under reduced pressure gave the a c y l azide (239) as a c o l o r l e s s o i l which e x h i b i t e d i r ( f i l m ) : 3070, 2267, 2129, 1712, 1644, 1389, 1376, 894 cm" 1 . Th i s o i l was d i s s o l v e d i n 0.2 mL of dry toluene and the s o l u t i o n was heated with s t i r r i n g at 8 0 ° C . E v o l u t i o n of gas began immediately. A f t e r 2 h , 57 (0.4 mmol) of 2 - t r i m e t h y l s i l y l e t h a n o l was added and heat ing at 80°C was continued for 20 h . A f t e r removal of the so lvent under reduced pressure , the res idue was d i s s o l v e d i n 5 mL of ether and the s o l u t i o n was washed with 3 mL of aqueous sodium hydroxide (IN). The organic layer was d r i e d over anhydrous magnesium s u l f a t e . Removal of the solvent under reduced pressure , provided a res idue that was subjected to column chromatography on s i l i c a ge l (6 g, 6:1 petroleum e t h e r - e t h e r ) . Concentrat ion of the appropriate 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 temperature 1 2 5 - 1 3 0 ° C / 0 . 3 Torr) of the r e s i d u a l mater ia l y i e l d e d 30 mg (82%) of carbamate (240) as a white s o l i d . R e c r y s t a l l i z a -t i o n of t h i s m a t e r i a l from petroleum ether gave an a n a l y t i c a l l y pure sample, which e x h i b i t e d mp 8 6 - 8 7 ° C ; i r ( C C 1 4 ) : 3450, 3073, 1726, 1643, 1464, 1375, 904 cm" 1 ; 1 H nmr (400 MHz, CDC1 3) 6: 0.05 (s , 9H, - 182 -- S i M e 3 ) , 0.85, 0.88 [d, d, 3H each, - C H ( C H 3 ) 2 , J = 7 Hz i n each case ] , 0.95 (s, 3H, t e r t i a r y methyl protons) , 0.99 ( t , 2H, - C H 2 C H 2 S i M e 3 , J = 8 . 5 Hz) , 1.17-1.24 (m, 1H), 1.29-1.55 ( ser ies of m u l t i p l e t s , 5H), 1.59-1.74 (m, 2H), 1.76-1.95 (m, 2H), 1.99-2.16 (m, 2H), 2.25-2.36 (m, 1H, H D ) , 3.41 (d of d of d, 1H, H c , J = 10.5, 7, 4 Hz) , 4.16 ( t , 2H, - O C H 2 C H 2 S i M e 3 , J = 8.5 Hz) , 4.43 (br d, 1H, - N H - , J = 10.5 Hz) , 4.77, 4.81 (br s, br s, 1H each, o l e f i n i c protons ) . I r r a d i a t i o n at 5 2.30 caused the m u l t i p l e t at 6 3.41 to co l l apse to a d of d (J = 10.5, 7 Hz) and the s i g n a l at S 1.76-1.95 to s i m p l i f y ; i r r a d i a t i o n at S 4.16 caused the s i g n a l at 6 0.99 to co l lapse to a s i n g l e t ; i r r a d i a t i o n at 6 0.85 caused par t of the m u l t i p l e t at 5 1.59-1.74 to s i m p l i f y ; i r r a d i a t i o n at 5 3.41 caused the s i g n a l at 6 4.43 to co l lapse to a broad s i n g l e t and the s i g n a l at 5 2.30 to co l lapse to a t of d (J = 11, 5.5 Hz) and the s i g n a l at 6 1.59-1.74 to s i m p l i f y . Exact Mass c a l c d . for C 2 ^H 3 gNOSi : 365.2752; found: 365.2754. Preparat ion of the Amine (186) A s o l u t i o n of the carbamate (237) (43.9 mg, 0.12 mmol) i n 1 mL of 186 183 -dry THF was added to a s t i r r e d s o l u t i o n of tetra-n-butylammonium f l u o r i d e (136.5 mg, 0.5 mmol) i n 0.5 mL of dry THF. The mixture was heated at 50°C for 35 min. A f t e r the mixture had been cooled to room temperature, the solvent was removed under reduced pressure . The res idue was d i s s o l v e d i n 5 mL of pentane. Water (4 mL) was added and the mixture was s t i r r e d v i g o r o u s l y for 10 min. The aqueous l a y e r was separated and extracted twice with pentane. The combined pentane ex trac t was washed once with aqueous ammonium c h l o r i d e and d r i e d over anhydrous magnesium s u l f a t e . Removal of the solvent under reduced pressure , fo l lowed by d i s t i l l a t i o n ( a i r - b a t h temperature 7 0 - 7 5 ° C / 0 . 3 Torr ) of the r e s i d u a l mater ia l y i e l d e d 17.7 mg (72%) of the amine (186) as a c o l o r l e s s o i l . This m a t e r i a l exh ib i t ed i r ( f i l m ) : 3397, 3338, 3067, 1641, 1376, 1365, 889 cm" 1 ; X H nmr (400 MHz, CDCI3) 6: 0.82, 0.92 [d, d, 3H each, - C H ( C H 3 ) 2 , I = 6.5 Hz i n each case] , 0.94 (s, 3H, t e r t i a r y methyl protons ) , 1.14-1.22 (br d, 1H), 1.20-1.35 (br s, 2H, - N H 2 ) , 1.32-1.60 ( ser ies of m u l t i p l e t s , 5H), 1.61-1.70 (m, 1H), 1.70-1.83 (m, 1H, Hg), 1.83-1.93 (m, 1H), 1.97 (d, 1H, H E , J = 10 Hz) , 2.05-2.30 (m, 3H), 2.51 (d of d, 1H, H c , J = 8.5, 3.5 Hz) , 4.77 (br s, 2H, o l e f i n i c protons ) . I r r a d i a t i o n at 5 2.51 caused the m u l t i p l e t at 5 1.70-1.83 to co l lapse to a septet (J = 6.5 Hz) and the m u l t i p l e t at S 2.05-2.30 to s i m p l i f y ; i r r a d i a t i o n at 5 0.82 caused the m u l t i p l e t at 6 1.70-1.83 to s i m p l i f y . Exact Mass c a l c d . for C 1 5 H 2 7 N : 221.2145; found: 221.2142. - 184 -Preparat ion of the Amine (234) NH 2 234 A s o l u t i o n of the carbamate (240) (26.9 mg, 0.074 mmol) i n 0.6 mL of dry THF was added to a s t i r r e d s o l u t i o n of tetra-n-butylammonium f l u o r i d e (78.1 mg, 0.3 mmol) i n 0.4 mL of dry THF. The mixture was heated at 50°C for 35 min; The solvent was removed under reduced pressure and the res idue was d i s s o l v e d i n 3 mL of pentane. Water (3 mL) was added and the mixture was s t i r r e d v i g o r o u s l y for 10 min. The aqueous l ayer was separated and extracted twice with pentane. The combined pentane extract was washed with saturated ammonium c h l o r i d e (3 mL) and d r i e d over anhydrous magnesium s u l f a t e . Removal of the solvent under reduced pressure and d i s t i l l a t i o n ( a i r - b a t h temperature 5 0 - 5 4 ° C / 0 . 3 Torr ) of the r e s i d u a l mater ia l a f forded 12 mg (73%) of the amine (234) as a c o l o r l e s s o i l . This m a t e r i a l exh ib i t ed i r ( f i l m ) : 3387, 3307, 3067, 1643, 1375, 890 cm" 1 ; LU nmr (400 MHz, CDCI3) 5: 0.86, 0.89 [d, d, 3H each, - C H ( C H 3 ) 2 , I = 6.5 Hz i n each case] , 0.97 (s, 3H, t e r t i a r y methyl protons ) , 1.17-1.24 (br d, 1H, J = 11 Hz) , 1.30-1.80 ( ser ies of m, 10H), 1.95 (br d, 1H, H £ , J = 11 Hz) , 2.02-2.15 (m, 2H), 2.23-2.34 (m, 1H), 2.34 (d of d, 1H, H c , J = 6.5, 3 Hz) , 4.62, 4.75 (br s, br s, 1H each, o l e f i n i c protons ) . Exact Mass c a l c d . f or C 15 H 27N: - 185 -221.2145; found: 221.2140. Preparat ion of A c e t i c Formic Anhydride (241) CH3COCH 241 Formic a c i d (0.1 mL, 2.65 mmol) and a c e t i c anhydride (0.25 mL, 2.6 mmol) were mixed together i n a three-necked f l a s k equipped with condenser and a septum. The mixture was heated at 55°C for two hours The r e q u i r e d amount of the mixture was removed by syr inge . - 186 -To a s t i r r e d s o l u t i o n of the amine (186) (17.7 mg, 0.08 mmol) i n 0.6 mL of dry ether was added a c e t i c formic anhydride (241) (24 / iL , 0.16 mmol) and the mixture was s t i r r e d at room temperature for 10 h . Ether (5 mL) and water (2 mL) were added to the mixture and the layers were separated. The aqueous l ayer was washed twice with ether . The combined ether ex trac t was d r i e d over anhydruos magnesium s u l f a t e . Removal of so lvent under reduced pressure , fol lowed by column chromatography of the res idue on s i l i c a ge l (5 g, e l u t i o n with 6:1 petroleum ether-e ther) and d i s t i l l a t i o n ( a i r - b a t h temperature 1 1 0 - 1 1 5 ° C / 0 . 3 Torr) o f the o i l obtained from the appropriate f r a c t i o n s , provided 18 mg (90%) of ( ± ) - a x a m i d e - 1 (174) as a c o l o r l e s s , v i scous o i l . This mater ia l e x h i b i t e d i r ( f i l m ) : 3268, 3067, 1660, 1383, 890 cm" 1 ; 1 H nmr (400 MHz, CDC1 3) 6: 0.79, 0.89 [d, d, t o t a l 3.6 H, - C H ( C H 3 ) 2 , c i s rotamer, J = 7 Hz i n each case] , 0.80, 0.88 [d, d, t o t a l 2.4 H, - C H ( C H 3 ) 2 , trans rotamer, J = 7 Hz i n each case] , 0.92 (s, 1.8 H, t e r t i a r y methyl protons , c i s rotamer), 0.94 (s, 1.2 H, t e r t i a r y methyl protons , trans rotamer), 1.14-1.27 (m, 1H), 1.30-1.57 (m, 5H), 1.58-1.69 (m, 1H) , 1.81-2.18 (m, 5H), 2.24 (q of d, 0.6 H, H D , c i s rotamer, J = 9.5, 5 Hz) , 2.31-2.42 (m, 0.4H, H D , trans rotamer), 2.96 (d of d of d, 0.4 H, H c , trans rotamer, J = 13, 8.5, 4 Hz) , 3.91 (t of d, 0.6 H, HQ, c i s rotamer, J = 10, 4 Hz) , 4.65, 4.82 (br s, t , 0.4 H each, o l e f i n i c protons , trans rotamer, J = 2 Hz) , 4.68, 4.75 ( t , t , 0.6 H each, o l e f i n i c protons , c i s rotamer, J = 2.5 Hz and J = 2 Hz, r e s p e c t i v e l y ) , 5.18 (br d, 0.6 H, - N H - , c i s rotamer, J = 10 Hz) , 5.38 (br t , 0.4 H, - N H - , trans rotamer, J = 13 Hz) , 7.90 (d, 0.4 H, -CHO, trans rotamer, J = 12 Hz) , 8.15 (d, 0.6 H, -CHO, c i s rotamer, J = 2 Hz) . Exact Mass c a l c d . for C 1 6 H 2 7 N O : - 187 -249.2094; found: 249.2091. Preparat ion of ( ± ) - 1 0 - e p J L - A x a m i d e - l (224) I II H 0 N-C / H cis 224 trans 224 To a s t i r r e d s o l u t i o n of the amine (234) (12 mg, 0.054 mmol) i n 1 mL of dry ether was added a c e t i c formic anhydride (241) (29 fj,L, 0.22 mmol) and the mixture was s t i r r e d at room temperature for 10 h . Ether (5 mL) and water (5 mL) were added. The aqueous l ayer was separated and washed twice with ether . The combined ether ex trac t was d r i e d over anhydrous magnesium s u l f a t e and concentrated under reduced pressure . Column chromatography of the res idue on s i l i c a ge l (5 g, e l u t i o n with 6:1 petroleum ether-ether) and d i s t i l l a t i o n ( a i r - b a t h temperature 1 0 4 - 1 1 0 ° C / 0 . 3 Torr) of the o i l obtained from the appropriate f r a c t i o n s , provided 11.8 mg (88%) of ( ± ) - 1 0 - e p i - a x a m i d e - l (224) as a c o l o r l e s s , v i scous o i l . This m a t e r i a l exh ib i t ed i r ( f i l m ) : 3288, 3068, 1659, 1385, 896 cm* 1 ; 1 H nmr (400 MHz, CDCI3) 6: 0.84-0.98 [unresolved doublets and s i n g l e t s due to two rotamers, 9H, -CH(CH.3)2 and t e r t i a r y methyl pro tons ] , 1.17-1.79 (m, 8H), 1.79-1.94 (m, 2H), 1.96-2.10 (m, 1H), 2.10-2.19 (m, 1H) , 2.30-2.46 (m, 1H, H D ) , 2.94 (d of d of d, 0.5H, H c , J - 188 -- 11, 8, 3 Hz) , 3.84 (d of d of d, 0.5H, H c , J - 11, 7, 3 Hz) , 4.59 (br s, 0.5H, o l e f i n i c proton) , 4.76 (br s, 0.5H, o l e f i n i c proton) , 4.79-4.84 (m, 1H, o l e f i n i c proton) , 5.25 (br d, 0.5H, - N H - , J - 11 Hz) , 5.42 (br t , 0.5H, - N H - , J - 11 Hz) , 7.97 (d, 0.5H, -CHO, trans rotamer, 12 Hz) , 8.31 (br s, 0.5H, c i s rotamer,-CHO). Exact Mass c a l c d . for C 1 6 H 2 7 N O : 249.2094; found: 249.2092. Preparat ion of ( ± ) - A x i s o n i t r i l e - 1 (173) S o l i d p_-toluenesulfonyl c h l o r i d e (29.5 mg, 0.15 mmol) was added to a s t i r r e d s o l u t i o n of ( ± ) - a x a m i d e - l (174) (12.5 mg, 0.05 mmol) i n 0.8 mL of dry p y r i d i n e and the mixture was s t i r r e d at room temperature for 3 h . A few chips of i ce was added and the mixture was poured in to ice water. The r e s u l t a n t mixture was extracted with pentane ( 2 x 5 mL). The combined pentane ex trac t was washed twice with c o l d water, d r i e d over anhydrous magnesium su l fa te and concentrated under reduced pressure . Column chromatography of the residue on s i l i c a ge l (3 g, 14:1 petroleum ether-e ther) and d i s t i l l a t i o n of the m a t e r i a l obtained from the appro-p r i a t e f r a c t i o n s af forded 10 mg (86%) of ( ± ) - a x i s o n i t r i l e - 1 (173) as a - 189 -white s o l i d . R e c r y s t a l l i z a t i o n of t h i s m a t e r i a l from petroleum ether prov ided an a n a l y t i c a l l y pure sample, which exh ib i t ed mp 4 5 - 4 6 ° C ; i r ( C C 1 4 ) : 3072, 2136, 1645, 1390, 1375, 899 cm" 1 ; X H nmr (400 MHz, CDCI3) 5: 0.88, 1.02 [d, d, 3H each, - C H ( C H 3 ) 2 , J = 6.5 Hz i n each case ] , 0.99 (s, 3H, t e r t i a r y methyl protons) , 1.19-1.29 (m, 1H), 1.40-1.59 (m, 5H), 1.59-1.71 (m, 1H), 1.94-2.13 (m, 3H), 2.14-2.23 (m, 2H), 2.47 (m, 1H, H D ) , 3.23 (t of t , 1H, H c , J = 7.5, 1.5 Hz) , 4.79-4.85 (m, 2H, o l e f i n i c pro tons ) . I r r a d i a t i o n at 5 2.47 caused the s i g n a l at S 3.23 to co l lapse to a br d (J = 7.5 Hz) and the m u l t i p l e t s at 5 2.14-2.23 and 1.94-2.14 to s i m p l i f y . 1 3 C nmr (75 MHz, CDCI3 , proton decoupled) 6: 19.068, 19.779, 24.371, 24.442, 27.719, 29.727, 31.279, 33.301, 39.638, 40.092, 45.167, 57.137, (67.691, 67.763, 67.824, t r i p l e t ) , 111.633, 148.299, (155.535, 155.621, 155.689, t r i p l e t ) . Exact Mass c a l c d . for C 1 6 H 2 5 N : 231.1989; found: 231.1993. The s p e c t r a l data der ived from the syn-t h e t i c m a t e r i a l were i d e n t i c a l with those of an authent ic sample of ( + ) - a x i s o n i t r i l e - 1 . We are very g r a t e f u l to Professor D. S i ca for a sample of (+)-axiso-n i t r i l e - 1 and for a copy of i t s •'-H nmr spectrum. - 190 -Preparat ion of ( ± ) - 1 0 -ejDi-A x i s o n i t r i l e - 1 (225) 225 S o l i d p . - to luenesulfonyl c h l o r i d e (26.1 mg, 0.14 mmol) was added to a s o l u t i o n of ( ± ) - 1 0 - e p i - a x a m i d e - l (224) (8.9 mg, 0.036 mmol) i n 0.36 mL of dry p y r i d i n e at room temperature and the mixture was allowed to s t i r for 3.5 h . A few chips of i ce was added and the mixture was poured into ice water. The r e s u l t a n t mixture was extracted with pentane ( 2 x 5 mL). The combined pentane ex trac t was d r i e d over anhydrous magnesium s u l f a t e , and concentrated under reduced pressure . Column chromatography of the res idue on s i l i c a ge l (3 g, e l u t i o n with 15:1 petroleum ether-e ther) and d i s t i l l a t i o n ( a i r - b a t h temperature 6 3 - 6 8 ° C / 0 . 3 Torr) of the m a t e r i a l obtained from the appropriate f r a c t i o n s af forded 7.2 mg (87%) of ( ± ) - 1 0 - e p i - a x i s o n i t r i l e - l (225) as a white s o l i d . An a n a l y t i c a l l y pure sample obtained by r e c r y s t a l l i z a t i o n of t h i s m a t e r i a l from petroleum ether , e x h i b i t e d mp 5 3 - 5 4 ° C ; i r (CC1 4 ) : 3070, 2135, 1644, 1391, 1377, 901 c m - 1 ; X H nmr (400 MHz, CDCl 3 ) 6: 0.92, 1.04 [d, d, 3H each, -CH(CH.3)2, I = 7 Hz i n each case] , 1.00 (s, 3H, t e r t i a r y methyl pro tons ) , 1.21-1.32 (m, 1H), 1.38-1.59 (m, 4H) , 1.59-1.75 (m, 2H) , 1.75-1.92 (m, 2H), 1.92-2.02 (m, 1H), 2.05 (d, 1H, H E , J = 11 Hz) , 2.14 (br d, J = 14 Hz) , 2.22-2.34 (m, 1H, H D ) , 3.18-3.25 (m, 1H, H c ) , 4.72 - 191 -( t , 1H, o l e f i n i c proton , J •= 2.25 Hz) , 4.80 ( t , 1H, o l e f i n i c proton , J = 2 Hz) . I r r a d i a t i o n at 8 2.28 caused the m u l t i p l e t at 5 3.18-3.25 to c o l l a p s e to a br d (J - 8 Hz) , the d at 8 2.05 to co l l apse to a br s and the m u l t i p l e t at 8 1.75-1.92 to s i m p l i f y . 1 3 C nmr (75 MHz, CDCI3, proton decoupled) 8: 19.423, 19.510, 22.941, 23.786, 24.621, 30.457, 31.406, 33.156, 39.995, 41.974, 43.175, 57.922, (63.912, 63.973, 64.046, t r i p l e t ) , 111.392, 146.862, (155.026, 155.097, 155.168, t r i p l e t ) . Exact  Mass c a l c d . f or C 1 6 H 2 5 N : 231.1988; found: 231.1981. The s p e c t r a l data der ived from t h i s synthet ic m a t e r i a l were qui te d i f f e r e n t from those of an authent ic sample of ( + ) - a x i s o n i t r i l e - 1 . We are very g r a t e f u l to Professor D. S i ca for a sample of (+)-axiso-n i t r i l e - 1 and for a copy of i t s ^H nmr spectrum. - 192 -REFERENCES - 193 REFERENCES 1. M . E . Jung, Tetrahedron. 32, 3 (1976). 2. (a) M . C . K l o e t z e l , Organic React ions . 4, 1 (1948). (b) H . L . Holmes, Organic React ions . 4, 60 (1948). (c) E . Ciganek, Organic React ions . 32, 1 (1984). (d) Alex G. F a l l i s , Can. J . Chem.. 62, 183 (1984). 3. (a) W.S. Johnson, Acc . Chem. R e s . . 1, 1 (1968). (b) M . F . A n s e l l and M.H. Palmer, Quart . Rev . . 18, 211 (1964). (c) K. Sutherland, J . Chem. S o c . Chem. Commun. . 526, 528 (1978). (d) K . - G . G e r l i n g , H. Wolf, Tetrahedron L e t t . . 1293 (1985). (e) S .P . T a n i s , P .M. H e r r i n t o n , L . A . Dixon, Tetrahedron L e t t . . 5347 (1985). 4. (a) M. J u l i a , Rec. Chem. P r o g . . 25, 3 (1964). (b) G .A . Molander, J . B . E t t e r , Tetrahedron L e t t . . 3281 (1984). (c) G. Stork, N . H . Baine, Tetrahedron L e t t . . 5927 (1985). (d) B. Giese , Angew. Chem. Int . Ed. E n g l . . 24, 553 (1985). 5. (a) W.L. D i l l i n g , Chem. Rev . . 66, 373 (1966); 69, 845 (1969). (b) P . E . Eaton, Acc . Chem. R e s . . 1, 50 (1968). (c) P. de Mayo, Acc . Chem. R e s . . 4, 41 (1971). 6. (a) J . M . Conia and P. Le Perchec, S y n . , 1, (1975). (b) M. Karpf , J . Huguet, and A . S . D r e i d i n g , Helv . Chim. A c t a . 65, 13 (1982). (c) W. Oppolzer and R. P i t t e l o u d , J . Am. Chem. Soc . . 104, 6478, (1982) . - 194 -7. (a) L . A . Paquette "Recent Synthet ic Developments i n Polyquinane Chemistry" i n Topics i n Current Chemistry. V o l . 119, S p r i n g e r - V e r l a g , B e r l i n Heide lberg , 1984. (b) M. Ramaiah, Syn . , 529 (1984). (c) B .M. T r o s t , Angew. Chem. Int . Ed. E n g l . . 25, 1 (1986). 8. (a) R . E . Gawley, Syn- , 777 (1976). (b) B . P . Mundy, J . Chem. E d . . 50, 110 (1973). (c) B . P . Mundy, Concept of Organic Synthesis: C a r b o c y c l i c  Chemistry. Marcel Dekker, New York, 1979, p . 40-50. (d) H.O. House, Modern Synthet ic React ions . W.A. Benjamin, P h i l l i p i n e s , 1972, p. 595-623. 9. J .W. Comforth and R. Robinson, J . Chem. S o c . 1855 (1949). 10. G. Stork, A. B r i z z o l a r a , H. Landesman, J . Szmuszkovicz, and R. T e r r e l l , J . Am. Chem. Soc . . 85, 207 (1963). 11. G. Stork and B. Ganem, J . Am. Chem. Soc . . 95, 6152 (1973). 12. B .M. T r o s t , Acc . Chem. R e s . . 11, 453 (1978). 13. D. Seebach, Angew. Chem. Int . Ed. E n g l . . 18, 239 (1979). 14. E . J . Corey, Pure A p p l . Chem.. 14, 19 (1967). 15. (a) G . H . Posner, C . E . Whitten, J . J . S t e r l i n g , and D . J . Brunne l l e , Tetrahedron L e t t . . 2591 (1974). (b) G . H . Posner, J . J . S t e r l i n g , C . E . Whitten, C M . Lentz , and D . J . Brunne l l e , J . Am. Chem. Soc . . 97, 107 (1975). 16. F . Naf, R. Decorzant, and W. Thommen, Helv . Chem. A c t a . 68, 1808 (1975). 17. A . I toh, S. Ozawa, K. Oshima, H. Nozaki , Tetrahedron L e t t . . 361 (1980). 18. M. Tada, Y. Sugimoto, and T. Takahashi , B u l l . Chem. Soc. Japan. 53, 2966 (1980). 19. J . A . Thomas, C . H . Heathcock, Tetrahedron L e t t . . 3235 (1980). 20. S .A. B a l , A. Marfat , and P. H e l q u i s t , J . Org. Chem.. 47, 5045 (1982) . - 195 -21. R . A . Raphael , S . J . T e l f e r , Tetrahedron L e t t . . 489 (1985). 22. J . F i c i n i and A . M . Touz in , Tetrahedron L e t t . . 1081 (1977). 23. W.P. Jackson and S.V. Ley, J . Chem. Soc. Perk in Trans . I . 1516 (1981). 24. G. Buchi and H. Wuest, J . Org. Chem.. 44, 546 (1979). 25. (a) G. Pattenden and G.M. Robertson, Tetrahedron. 42, 4001 (1985). (b) G. Pattenden and G.M. Robertson, Tetrahedron L e t t . . 399 (1986) . 26. (a) E . P iers and V. Karunaratne, J . Org. Chem.. 48, 1774 (1983). (b) E . P iers and V. Karunaratne, J . Chem. Soc , . Chem. Commun.. 935 (1983). 27. E . P ier s and V. Karunaratne, Can. J . Chem.. 62, 629 (1984). 28. E . P ier s and V. Karunaratne, J . Chem. S o c . Chem. Commun.. 959 (1984). 29. E . P ier s and J . M . Chong, J . Chem. S o c . Chem. Commun.. 934 (1983). 30. E . I . N e g i s h i , Organometal l ics i n Organic Synthes is . V o l . 1, John Wiley , New York, 1980, p . 410-412. 31. A . J . Lensink, H .A . Budding, and J .W. Marsman, J . Organomet. Chem.. 9, 285 (1967). 32. H. Gilman, F.W. Moore, and R . G . Jones, J . Am. Chem. Soc . . 63, 2482 (1941). 33. D. Seyferth and M.A. Weiner, Chem. Ind. (London). 402 (1959). 34. M. G i e l e n , "Recent developments i n the Syntheses, Propert i e s and Uses of Tetraorganot in Compounds", i n Reviews on S i l i c o n Germanium.  T i n and Lead Compounds. V o l . V, No. 2, Freund P u b l i s h i n g House, L t d . T e l - A v i v . 1981, p. 5. 35. G . J . McGarvey, J . S . Bajwa, J . Org. Chem.. 49, 4091 (1984). 36. E . P ier s and A . V . Gavai , personal communication. 37. W. Shand, J r . , V. Schomaker, and J . R . F i s c h e r , J . Am. Chem. Soc . , 66, 636 (1944). 38. G . H . Posner, An Introduct ion to Synthesis Using Organocopper Rea- gents . John Wiley and Sons, New York, 1980. - 196 -39. (a) G . H . Posner, "Conjugate A d d i t i o n Reactions of Organocopper Reagents" i n Organic React ions . 19, 1 (1972). (b) R . J . K . T a y l o r , Synthes is . 364 (1985). 40. G . H . Posner, "Subst i tu t ion Reactions Using Organocopper Reagents" i n Organic React ions . 22, 253 (1975). 41. S .H . B e r t z , G. Dabbagh, and G.M. V i l l a c o r t a , J . Am. Chem. S o c . . 104, 5824 (1982). 42. G . H . Posner, C . E . Whitten, and J . J . S t e r l i n g , J . Am. Chem. Soc . . 95, 7788 (1973). 43. W.H. Mandev i l l e , G.M. Whites ides , J . Org. Chem.. 39, 400 (1974). 44. (a) S .H. Bertz and G. Dabbagh, J . Org. Chem.. 49, 1119 (1984). (b) S . H . Bertz and G. Dabbagh, J . Chem. S o c . Chem. Commun. . 1030 (1982) . 45. (a) B . H . L i p s h u t z , R . S . Wilhelm, J . A . Kozlowski , Tetrahedron, 24, 5005 (1984). (b) B . H . L i p s h u t z , J . A . Kozlowski , D .A. Parker, S . L . Nguyen, and K . E . McCarthy, J . Organometal. Chem.. 285, 437 (1985). 46. (a) D .B . L e d l i e and G. M i l l e r , J . Org. Chem.. 44, 1006 (1979). (b) C R . Johnson and D.S . Dhanoa, J . Chem. Soc, , Chem. Commun.. 358 (1982). (c) T. Tsuda, T. Yazawa, K. Watanabe, T. F u j i i , and T. Saegusa, J . Org. Chem.. 46, 192 (1981). (d) Y. Yamamoto, S. Yamamoto, H. Yataga i , and K. Maruyama, J . Am.  Chem. S o c . 102, 2318 (1980). (e) Y. Yamamoto, S. Yamamoto, H. Yataga i , Y. I sh ihara , and K. Maruyama, J . Org. Chem.. 47, 119 (1982). 47. B . H . L ipshutz and R . S . Wilhelm, J . Am. Chem. S o c . . 103, 7672 (1981). 48. M. Suzuki , T. Suzuki , T. Kawagishi , and R. Noyor i , Tetrahedron  L e t t . , 1247 (1980). 49. (a) A . B . Smith, I I I , P . J . J e r r i s , J . Org. Chem.. 47, 1845 (1982). (b) B . H . L i p s h u t z , D .A. Parker , J . A . Kozlowski , and S . L . Nguyen, Tetrahedron L e t t . . 5959 (1984). - 197 -50. (a) J . M . Conia , F . Rouessac, Tetrahedron. 16, 45 (1961). (b) G .H. Posner, J . J . S t e r l i n g , C . E . Whitten, C M . Lentz , D . J . Brunne l l e , J . Am. Chem. Soc . . 97, 107 (1975). 51. D . H . Wil l iams and I . Fleming, Spectroscopic Methods i n Organic  Chemistry. 3rd E d . , McGraw-Hi l l , London, 1980, p . 74-152. 52. J . G . K i r c h n e r , "Thin- layer Chromatography" i n Techniques of Chem- i s t r y . E d i t o r : E . S . Perry , V o l . XIX, 2nd E d . , John Wiley and Sons, New York, 1978, p. 47, 80, 898-899. 53. I . Hagedorn and H. Tonjes , Pharmazie. 12, 567 (2957); Chem. A b s t r . , 52, 6362 (1958). 54. F . C a f i e r i , E . Fat torusso , S. Magno, C. Santacroce, and D. S i c a , Tetrahedron. 29, 4259 (1973). 55. (a) E . Fat torusso , S. Magno, L . Mayol , C. Santacroce, and D. S i c a , Tetrahedron. 30, 3911 (1974). (b) L . Mina le , R. R i c c i o and G. Sodano, Tetrahedron. 30, 1341 (1974) . (c) B . J . Burreson, P . J . Scheuer, J . F i n e r , and J . C l a r d y , J . Am.  Chem. S o c . 97, 4763 (1975). (d) B . J . Burreson and P . J . Scheuer, J . Chem. Soc . , Chem. Commun.. 1035 (1974). (e) B . J . Burreson, C. Christophersen and P . J . Scheuer, J . Am.  Chem. S o c . 97, 201 (1975). (f) B . J . Burreson, C. Christophersen and P . J . Scheuer, T e t r a - hedron. 31, 2015 (1975). (g) B. Di B l a s i o , E . Fat torusso , S. Magno, L . Mayol , C. Pedone, C. Santacroce, and D. S i c a , Tetrahedron. 32, 473 (1976). (h) A. Iengo, L . Mayol , and C. Santacroce, E x p e r i e n t i a . 33, 11 (1977). ( i ) P. C i m i n i e l l o , E . Fat torusso , S. Magno, and L . Mayol , J .  Org. Chem.. 49, 3949 (1984). (j) P. C i m i n i e l l o , E . Fat torusso , S. Magno, and L . Mayol , J . Nat.  P r o d . , 48, 64 (1985). (k) S . J . Wratten, D . J . Faulkner , K. H i r o t s u , and J . C l a r d y , Tetrahedron L e t t . . 4345 (1978). - 198 -(1) R. Kazlauskas, P . T . Murphy, R . J . Wel l s , and J . F . Blount , Tetrahedron L e t t . . 315 (1980). (m) H. Nakamura, J . Kobayashi , Y . Ohizumi, and Y . H i r a t a , T e t r a - hedron L e t t . . 5401 (1984). (n) C . W . J . Chang, A. Pa tra , D.M. R o l l , P . J . Scheuer, G .K. Matsumoto, and J . C lardy , J . Am. Chem. Soc . . 106, 4644 (1984). (o) A . P a t r a , C . W . J . Chang, P . J . Scheuer, G.D. van Duyne, G .K. Matsumoto, and J . C lardy , J . Am. Chem. Soc. . 106, 7981 (1984) . 56. E . Fat torusso , S. Magno, L . Mayol, C. Santacroce, and D. S i c a , Tetrahedron. 31, 269 (1975). 57. S .S . H a l l , D . J . Faulkner , J . Fayos, J . C lardy , J . Am. Chem. Soc . . 95, 7187 (1973). 58. M. A d i n o l f i , L . De N a p o l i , B. D i B l a s i o , A. Iengo, C. Pedone, and C. Santacroce, Tetrahedron L e t t . . 2815 (1977). 59. (a) J . E . Thompson, R.P .Walker , S . J . Wratten, and D . J . Faulkner , Tetrahedron. 38, 1865 (1982). (b) G. Cimino, S. De Rosa, S. De Stefano, and G. Sodano, Comp.  Biochem. P h y s i o l . . 73B, 471 (1982). 60. P. Hoffmann, G. Gokel , D. Marquarding, and I . U g i , " I s o n i t r i l e Syntheses", i n I s o n i t r i l e Chemistry. I . U g i , e d . , Academic Press , New York, 1971, p. 9. 61. C.W. Huffman, J . Org. Chem.. 23, 727 (1958). 62. D. Todd "The Wol f f -Kishner Reduction", i n Organic React ions . V o l . IV, p . 379. 63. (a) M. Rathke, D. S u l l l i v a n , Tetrahedron L e t t . . 4249 (1972). (b) P . E . P f e f f e r , L . S . S i l b e r t , E . K i n s e l , Tetrahedron L e t t . . 1163 (1973). (c) J . - A . MacPhee and J . - E . Dubois, Tetrahedron. 36, 775 (1980). (d) A . P . Krapcho, E . A . Dundul is , J . Org. Chem.. 45, 3236 (1980); (e) R . H . van der Veen and H. Cer fonta in , J . Org. Chem., 50, 342 (1985) . - 199 -(f) A . P . Krapcho, D .S . Kashdan, and E . G . E . Jahngen, J r . , J . Org.  Chem., 4 2 , 1189 (1977). (g) P . E . P f e f f e r , L . S . S i l b e r t , a n d J . M . C h i r i n k o , J r . , J . Org.  Chem. . , 3 7 , 451 (1972) . 64. P . A . S . Smith "The Curt ius React ion", i n Organic React ions . V o l . I l l , p . 337. 65. (a) G. Stork, R . L . Danheiser, J . Org. Chem.. 3 8 , 1775 (1973). (b) M . L . Quesada, R . H . Schless inger , and W.H. Parsons, J . Org.  Chem., 4 3 , 3968 (1978). (c) M. Koreeda, Y. L i a n g , and H. Akag i , J . Chem. S o c . Chem.  Commun., 449 (1979). 66. A . J . Barker and G. Pattenden, J . Chem. Soc. P erk in Trans . I . 1885 (1983). 67. B . H . Toder, S . J . Branca, R . K . D i e t e r , and A . B Smith, I I I , Syn.  Commun., 435 (1975). 68. D . G . M o r r i s , Chem. S o c Rev . . 397 (1982). 69. (a) K. Saigo, M. Osaki , and T. Mukaiyama, Chem. L e t t . . 163 (1976). (b) Y. K i t a , J . Segawa, J . Haruta, T . F u j i i , and Y. Tamura, Tetrahedron L e t t . . 3779 (1980). (c) Y . K i t a , J . Segawa, J . Haruta, H. Yasuda, and Y. Tamura, J .  Chem. S o c Perk in Trans . I . 1099 (1982). (d) T . V . RajanBabu, J . Org. Chem.. 4 9 , 2083 (1984). (e) R . A . Bunce, M . F . Schle'cht, W.G. Dauben, C . H . Heathcock, Tetrahedron L e t t . . 4943 (1983). 70. A . L . Gemal, a n d J . - L . Luche, J . Am. Chem. S o c . 1 0 3 , 5454 (1981). 71. S. Binns , J . S . G . Cox, E . R . H . Jones, and B . G . Ketcheson, J . Org.  Chem., 2 9 , 1161 (1964). 72. (a) G . H . Posner, "Conjugate A d d i t i o n Reactions of Organocopper Reagents", i n Organic React ions . V o l . 19, p . 1. (b) G . H . Posner, C . E . Whitten, and J . J . S t e r l i n g , J . Am. Chem.  Soc. , 9 5 , 7788 (1973). 73. (a) P . L . S to t t er and R . A . H i l l , J . Org. Chem.. 3 8 , 2576 (1973). 200 -(b) E . J . Corey, and A . G . Hartmann, J . Am. Chem. Soc . . 87, 5736 (1965). (c) R . H . Reuss and A. Hassner, J . Org. Chem.. 39, 1785 (1974). (d) L . Blano, P. Amice, a n d J . M . Conia , S y n . , 194 (1976). (e) G. V i d a r i , S. F e r r i n o , and P .A . Gr ieco , J . Am. Chem. Soc . . 106, 3539 (1984). 74. (a) H . J . Re ich , J . M . Renga, and I . L . Re ich , J . Am. Chem. Soc . . 97, 5434 (1975). (b) K . B . Sharpless , M.W. Young, and R . F . Lauer, Tetrahedron  L e t t . , 1979 (1973). (c) K . B . Sharpless , R. F . Lauer, and A . Y . T e r a n i s h i , J . Am. Chem.  Soc. . 95, 6137 (1973). 75. Y. I t o , T . H i r a o , and T. Saegusa, J . Org. Chem.. 43, 1011 (1978). 76. C. Ainsworth, F . Chen, and Y . - N . Kuo, J . Organomet. Chem.. 46, 59 (1972). 77. (a) C . H . Heathcock, M.H. Norman, and D . E . Ueh l ing , J . Am. Chem. Soc . , 2797 (1985). (b) C . H . Heathcock and D . E . Ueh l ing , J . Org. Chem.. 51, 280 (1986). 78. R . E . I r e l a n d , R . H . M u e l l e r , and A . K . W i l l a r d , J . Am. Chem. Soc . . 98, 2868 (1976). 79. (a) E . Nakamura, K. Hashimoto, and I . Kuwajima, Tetrahedron L e t t . , 2079 (1978). (b) T . H . Chan, T . A i d a , P.W.K. Lau, V. Gorys, and D.N. Harpp, Tetrahedron L e t t . . 4029 (1979). 80. J . - E . Dubois, G. A x i o t i s , and E . Bertounesque, Tetrahedron L e t t . . 4655 (1984). 81. J . - E . Dubois and G. A x i o t i s , Tetrahedron L e t t . . 2143 (1984). 82. H . A . Khan and I . Paterson, Tetrahedron L e t t . . 5083 (1982). 83. T . L . Capson and C D . Pou l t er , Tetrahedron L e t t . . 3515 (1984). 84. (a) T . Drakenberg and S. Forsen, J . Phys. Chem.. 74, 1 (1970). - 201 -(b) B . H . L i p s h u t z , K . E . McCarthy, and R.W. Hungate, J . Org.  Chem., 1218 (1984). (c) P. C i m i n i e l l o , E . Fat torusso , S. Magno, and L . Mayol , J .  Org. Chem.. 49, 3949 (1984). (d) B . J . Burreson, C. Chris tophersen, and P . J . Scheuer, T e t r a - hedron. 2015 (1974). 85. W.R. H e r t l e r and E . J . Corey, J . Org. Chem.. 23, 1221 (1958). 86. (a) G . C . Levy and G . L . Nelson, Carbon-13 Nuclear Magnetic Resonance for Organic Chemisi ts . John Wiley and Sons, 1972, p. 129. (b) I . Morishima, A. Mizuno, and T. Yonezawa, J . Chem. S o c . .  Chem. Commun.. 1321 (1970). 87. W.C. S t i l l , M. Kahn, and A. M i t r a , J . Org. Chem.. 43, 2923 (1978). 88. A . J . Gordon and R . A . Ford , The Chemist's Companion. John Wiley and Sons, New York, 1972, p. 451. 89. Y . P . Bryan and R . H . Byrne, J . Chem. E d . . 47, 361 (1970). 90. H. Gilman and F . K . Cart ledge , J . Organomet. Chem., 2, 447 (1964). 91. H .O. House, C . Y . Chu, J . M . Wilkens, and M . J . Umen, J . Org. Chem.. 40, 1460 (1975). 92. P . G . M . Wuts, Syn. Commun.. 11, 139 (1981). 93. R . J . Cregge, J . L . Herrmann, C . S . Lee, J . E . Richman, and R . H . Sch less inger , Tetrahedron L e t t . . 2435 (1973). 94. E . J . Corey, and A. Venkateswarlu, J . Am. Chem. Soc . . 94, 6190 (1972). 95. H . C . Brown, Organic Synthesis V i a Boranes. John Wiley and Sons, New York, 1975, p . 259. 96. S.W. P e l l e t i e r , Chem. I n d . . 1034 (1953). 97. H . J . Dauben, J r . , and L . L . McCoy, J . Am. Chem. Soc. . 81, 4863 (1959) . 

Cite

Citation Scheme:

        

Citations by CSL (citeproc-js)

Usage Statistics

Share

Embed

Customize your widget with the following options, then copy and paste the code below into the HTML of your page to embed this item in your website.
                        
                            <div id="ubcOpenCollectionsWidgetDisplay">
                            <script id="ubcOpenCollectionsWidget"
                            src="{[{embed.src}]}"
                            data-item="{[{embed.item}]}"
                            data-collection="{[{embed.collection}]}"
                            data-metadata="{[{embed.showMetadata}]}"
                            data-width="{[{embed.width}]}"
                            async >
                            </script>
                            </div>
                        
                    
IIIF logo Our image viewer uses the IIIF 2.0 standard. To load this item in other compatible viewers, use this url:
https://iiif.library.ubc.ca/presentation/dsp.831.1-0059450/manifest

Comment

Related Items