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Donor-Acceptor reagents derived from 4-chloro-2-trimethylstannyl-1-butene, application to the total syntheses… Karunaratne, Veranja 1985

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DONOR - ACCEPTOR REAGENTS DERIVED FROM 4-CHLORO-2-TRIMETHYLSTANNYL-1-BUTENE. APPLICATION TO THE TOTAL SYNTHESES OF (±)-A 9^ 2^-CAPNELLENE AND (i)-PENTALENENE by VERANJA KARUNARATNE B.Sc. (Hons.), U n i v e r s i t y of Colombo, S r i Lanka, 1978 A THESIS SUBMITTED IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY i n THE FACULTY OF GRADUATE STUDIES (DEPARTMENT OF CHEMISTRY) We accept t h i s t h e s i s as conforming to the required standard THE UNIVERSITY OF BRITISH COLUMBIA March 1985 f7) ^ Veranja Karunaratne In presenting t h i s thesis i n p a r t i a l f u l f i l m e n t of the requirements for an advanced degree at the University of B r i t i s h Columbia, I agree that the Library s h a l l make i t f r e e l y available for reference and study. I further agree that permission for extensive copying of t h i s thesis for scholarly purposes may be granted by the head of my department or by his or her representatives. I t i s understood that copying or publication of t h i s thesis for f i n a n c i a l gain s h a l l not be allowed without my written permission. Department of The University of B r i t i s h Columbia 1956 Main Mall Vancouver, Canada V6T 1Y3 Date ) • tf S i T ' i i ABSTRACT This t h e s i s describes the preparation of 4 - c h l o r o - 2 - t r i m e t h y l -stannyl-l-butene (84) and i t s conversion i n t o a number of s t r u c t u r a l l y i n t e r e s t i n g and s y n t h e t i c a l l y u s e f u l donor-acceptor reagents. Thus, transmetalation of (84) w i t h m e t h y l l i t h i u m produced 4 - c h l o r o - 2 - l i t h i o -1-butene (95), which reacted smoothly at -78°C i n tetrahydrofuran with aldehydes, ketones and a,B-unsaturated N,N',N'-trimethylcarboxhydrazides to provide the a d d i t i o n products (108)-(113) and (128)-(130). When the r e a c t i o n mixtures were t r e a t e d w i t h hexamethylphosphoramide and were then allowed to warm to room temperature, the 3-methylenetetrahydro-furan d e r i v a t i v e s (114)—(119) and the 3-methylenecyclopentanecarboxylic a c i d d e r i v a t i v e s (131)-(133) were produced i n good y i e l d s . Treatment of reagent (95) w i t h 1 equiv of phenylthiocopper or cuprous cyanide provided s o l u t i o n s of the corresponding cuprate reagents (179) and (180). Conjugate a d d i t i o n of the l a t t e r species to the c y c l i c enones (181)-(186) a f f o r d e d very good y i e l d s of the ketones (187)-(192), which, when t r e a t e d w i t h potassium hydride i n tetrahydro-fu r a n , provided the methylenecyclopentane annulation products (193)-(198), r e s p e c t i v e l y . This methylenecyclopentane annulation method served as a key process i n the t o t a l s y n t h e s i s of two s t r u c t u r a l l y i n t e r e s t i n g t r i q u i n a n e 9(12) sesquiterpenoids, (±)-A -capnellene (205) and (l)-pentalenene (251). Thus, copper bromide - d i m e t h y l s u l f i d e c a t a l y z e d a d d i t i o n of the Grignard reagent (233) to 2-methyl-2-cyclopenten-l^one (184), followed by i n t r a -molecular a l k y l a t i o n of the r e s u l t a n t chloro ketone (190), gave the annulation product (196). This m a t e r i a l was converted i n t o the enone i i i (231) , which was subjected to an annulation sequence i d e n t i c a l w i t h that used i n the conversion of (184) i n t o (196). Removal of the 9(12) carbonyl group from the r e s u l t a n t product (232) provided (±)-A capnellene (205). Transformation of the r e a d i l y a v a i l a b l e keto a c e t a l (287) i n t o the enone (284), followed by s u b j e c t i o n of the l a t t e r substance to the methylenecyclopentane annulation sequence, gave the t e t r a c y c l i c keto o l e f i n (285). Treatment of an a c e t i c a c i d s o l u t i o n of t h i s m a t e r i a l wit h hydrogen i n the presence o f platinum metal produced a mixture of the epimeric ketones (298) and (299), which was converted i n t o a mixture of (±)-pentalenene (251) and (±)-9-epi-pentalenene (269), r e s p e c t i v e l y . 84 95 233 PhSCu. 179 180 V v i i TABLE OF CONTENTS Page ABSTRACT i i TABLE OF CONTENTS ' v i i LIST OF TABLES i x ACKNOWLEDGEMENTS x ABBREVIATIONS x i INTRODUCTION 1 A. General 1 B. Problem 21 DISCUSSION 28 I P r e p a r a t i o n and Transmetalation of A-Chloro-2-t r i m e t h y l s t a n n y l - l - b u t e n e (84) : Reaction of 4 - C h l o r o - 2 - l i t h i o - l - b u t e n e (95) w i t h Aldehydes, Ketones, and a,6-Unsaturated N,N',N'-Trimethyl-carboxhydrazides 28 A. Pr e p a r a t i o n of 4- C h l o r o - 2 - t r i m e t h y l s t a n n y l -1-butene (84) 28 B. Transmetalation of 4-Chloro-2-trimethyl-stannyl-l-butene (84): The Reaction of 4 - C h l o r o - 2 - l i t h i o - l - b u t e n e (95) w i t h Various Aldehydes, Ketones, and a,8-Unsaturated N,N',N'-Trimethylcarboxhydrazides 35 v i i i II Conjugate Addition of Cuprate Species Derived from A-Chloro-2-lithio-l-butene (95) to Cyclic Enones: An Efficient Methylenecyclopentane Annulation Process 51 A. Introduction 51 B. Conjugate Addition of Lithium Phenylthio-and Cyano-[2-(4-chloro-l-butenyl)]cuprate to Cyclic Enones. Subsequent Cyclization of the Intermediate Chloro Ketones 62 . I l l Total Synthesis of the Linear Triquinane Sesquiterpenoid (±)-A9(12)_c ap n en e n e 73 A. Introduction 73 9(12) B. Total Synthesis of (±)-A -Capnellene . . . . 79 IV Total Synthesis of the Angular Triquinane Sesquiterpenoid (±)-Pentalenene 94 A. Introduction 94 B. Total Synthesis of (±)-Pentalenene 101 EXPERIMENTAL 1 1 7 REFERENCES 193 i x LIST OF TABLES Page Table I Conversion of Aldehydes and Ketones i n t o 3-Methylenetetrahydrofuran D e r i v a t i v e s 38 Table I I C y c l i z a t i o n of a Number of Chloro A l c o h o l s w i t h Potassium hydride 39 Table I I I The Reaction of 4 - C h l o r o - 2 - l i t h i o - l -butene With N,N',N'-Trimethylcarbox-hydrazides 43 Table IV P r e p a r a t i o n of Methylenecyclopentane Annulation Products 66 X ACKNOWLEDGEMENTS S c i e n t i f i c research can seldom be done by one person alone, and, re q u i r e s considerable input from other i n s p i r e d minds. Therefore , i t i s a pleasure to acknowledge the meticulous guidance given by Pro f e s s o r Ed P i e r s during the course of my s t u d i e s . I t was indeed a p o s i t i v e t o n i c to be i n h i s company. I owe a debt of g r a t i t u d e to my w i f e , Nedra, f o r her u n f a i l i n g support and encouragement throughout the course of t h i s work. For t h e i r p a t i e n c e , i d e a s , cooperation, and good cheer, may I thank a l l the members of P r o f e s s o r P i e r s ' research group; p a r t i c u l a r l y Anderson Maxwell f o r t a k i n g the time to teach chemistry among other t h i n g s . I am indebted to Grace Jung, Anissa Yeung, B r i a n Keay, N e i l Moss, Ashwin Gavai and Nimal Rajapakse f o r t h e i r c a r e f u l p roofreading. Thanks are als o extended to Mrs. Rani Theeparajah f o r the care d i s p l a y e d i n the typ i n g of t h i s manuscript. x i ABBREVIATIONS The f o l l o w i n g a b b r e v i a t i o n s have been used throughout t h i s t h e s i s : Ac = A c e t y l AIBN = 2 , 2 ' - a z o b i s i s o b u t y r o n i t r i l e Bu = B u t y l m-CPBA = meta-Chloroperbenzoic Acid DBU = l,5-Diazabicyclo[5.4.0]undecane-5 DMF = N,N-dimethylformamide Et = E t h y l equiv = eq u i v a l e n t s g l c = g a s - l i q u i d chromatography nmr = proton n u c l e a r magnetic resonance HMPA = Hexamethylphosphoramide i r = i n f r a r e d IDA = L i t h i u m Diisopropylamide Me = Methyl mp = m e l t i n g p o i n t PCC = P y r i d i n i u m Chlorochromate Ph = Phenyl Py = P y r i d i n e r t = room temperature TEBA = Triethylbenzylammonium c h l o r i d e THF = Tetrahydrofuran t i c = t h i n - l a y e r chromatography Ts = para-Toluenesulfonyl X I I TO MY PARENTS w i t h a f f e c t i o n and respect - 1 -INTRODUCTION A. General The past decade of organic chemistry may be described as a p e r i o d of sound growth i n new s y n t h e t i c methods. The continuous quest f o r more e f f i c i e n t s y n t h e t i c reagents has l e d the s y n t h e t i c organic chemist to new f r o n t i e r s . One area i n which there has been much recent a c t i v i t y i n v o l v e s the p r e p a r a t i o n and u t i l i z a t i o n of b i f u n c t i o n a l reagents i n organic s y n t h e s i s . Indeed, w i t h i n a r e l a t i v e l y short p e r i o d of time , these reagents have gained a prominent place i n the a r s e n a l of s t r a t e g i e s used i n organic s y n t h e s i s . Although the chemical l i t e r a t u r e i s r e p l e t e w i t h reagents that correspond to synthons possessing one donor (d) or one acceptor (a) Corey defines synthons as " s t r u c t u r a l u n i t s w i t h i n a molecule which are r e l a t e d to p o s s i b l e s y n t h e t i c o p e r a t i o n s " [E.J. Corey, Pure. Appl. Chem. 14, 19 (1967)]. For example, the molecule A can be prepared by the combination of substances that are equivalent to the substrate synthon B and the formyl synthon C (see reference 1 ). o - < = » O + { H X H A B C 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 s k e l e t o n , i . e . acceptor p r o p e r t i e s (attack by donor species) at carbons and donor Droperties (attack by acceptor reagents) at carbons the heteroatom X i t s e l f i s a donor center (d°) (see reference 1 ). V »<L . ^  . . X = 0,N ± i. A s i t e , reagents that are equivalent to synthons possessing two donor or two acceptor s i t e s , or a combination of donor and acceptor carbon atoms are 2 q u i t e r a r e . Reagents w i t h two r e a c t i v e s i t e s are commonly r e f e r r e d to as 6 2 b i f u n c t i o n a l c onjunctive reagents. ' The term conjunctive reagents was introduced by T r o s t ^ to focus on those reagents that are incorporated i n whole or i n part i n t o a more complex system and to d i f f e r e n t i a t e them from reagents that react w i t h but are not normally incorporated i n t o a s u b s t r a t e . For example, methyl v i n y l ketone would be a conjunctive reagent and chromic a c i d would be a simple reagent. Seebach has r e c e n t l y d efined the nature of b i f u n c t i o n a l reagents and p r e f e r s to c a l l them m u l t i p l e c o u p l i n g reagents (MCR).^ He argues t h a t , i n a convergent s y n t h e s i s , i f one hopes to combine two p r e v i o u s l y synthesized components A and B i n a key step to form a t a r g e t molecule, i t i s u s u a l l y necessary to a c t i v a t e e i t h e r A or B, or both. However such a c t i v a t i o n can be avoided, i f a h i g h l y r e a c t i v e c oupling reagent i s used to j o i n the non-activated A and B. These reagents are designed to couple two or more such reagents and hence the name MCR. The mere presence of both donor and acceptor s i t e s i n a s i n g l e reagent i s , i n general, a n t i t h e t i c a l to i t s s u c c e s s f u l deployment i n organic r e a c t i o n s . However, s e l f - a n n i h i l a t i o n of these d,a reagents can be prevented by TT complexation of the reagent to t r a n s i t i o n 3 metals or by masking one r e a c t i v e s i t e w h i l e the other i s being deployed. On the other hand, acceptor, acceptor or donor, donor reagents do not pose such fundamental problems. However some d,d and 4 5 a,a reagents do contain r e a c t i v e s i t e s that are p rotected. ' The c r u c i a l p r o p e r t i e s of a b i f u n c t i o n a l reagent, as d e l i n e a t e d - 3 -by Seebach, are the f o l l o w i n g . ^ (a) The carbon skeleton and the f u n c t i o n a l i t y p a t t e r n that i t renders must be a par t of many ta r g e t molecules. (b) I t must be capable of s e l e c t i v e , s e q u e n t i a l (or simultaneous) i n t e r m o l e c u l a r formation of two or more new bonds. (c) I f i t has h e t e r o t o p i c s i t e s , they must be w e l l d i f f e r e n t i a t e d . (d) I f the r e a c t i v e s i t e s are d i a s t e r e o t o p i c , no mixtures of diastereomers must be obtained upon r e a c t i o n . Some b i f u n c t i o n a l reagents have the a b i l i t y to undergo c y c l i z a t i o n s . On such occasions the reagent r e a c t s w i t h a b i f u n c t i o n a l substrate by an i n t e r m o l e c u l a r c o u p l i n g step followed by an i n t r a m o l e c u l a r step.^ Such reagents are of primary i n t e r e s t to t h i s t h e s i s . The ensuing s e c t i o n s of t h i s i n t r o d u c t i o n deal w i t h s e l e c t e d examples of b i f u n c t i o n a l reagents w i t h s p e c i a l reference to those reagents that p a r t i c i p a t e i n * r i n g annulations. Perhaps the best known examples of b i f u n c t i o n a l reagents are 1,3-d i t h i a n e s (d^,d^)^ and d i a l k y l malonates ( d \ d * ) . 9 These reagents, over the y e a r s , have rendered i n v a l u a b l e s e r v i c e to organic s y n t h e s i s . For example, the 1,3 d i t h i a n e (1) has been used e f f e c t i v e l y as a d \ d ^ synthon i n the pr e p a r a t i o n of c y c l i c compounds of the general s t r u c t u r e (3) (equation 1). Recently, 1,1-dibromocyclopropane (4) and 1,1-dibromo-cyclobutane (5) have been a r r i v e d at i n two steps from diethylmalonate 9 (6) by Paquette. Treatment of diethylmalonate (6) w i t h 1,2-dibromo-For a general d i s c u s s i o n on r i n g annulations see: M.E. Jung, Tetrahedron 32, 3 (1976). For recent reports regarding cyclopentane-annulations see: L.A. Paquette, F o r t s c h r . Chem. Forsch. 119, 1 (1984); M. Ramaiah, Synthesis ]_, 529 (1984). - u -n=2-7 ethane and 1,3-dibromopropane i n aqueous sodium hydroxide c o n t a i n i n g triethylbenzylammonium c h l o r i d e (TEBA) at room temperature afforded (7) and (8) , r e s p e c t i v e l y , a f t e r a c i d i f i c a t i o n . Double Hunsdiecker degradation of the gem-diacids (7) and (8) proceeded smoothly upon heating these substances w i t h mercuric oxide and bromine i n d i c h l o r o -methane s o l u t i o n , to produce (4) and (5) (equations 2 and 3). This example i l l u s t r a t e s the u t i l i t y of diethylmalonate as a d \ d * synthon i n the e f f i c i e n t p r e p a r a t i o n of s y n t h e t i c a l l y u s e f u l intermediates (4) and (5). 6 7 4 - 5 -C r 4 C H ^ B V ^ 5 H * V > ^ h E S ^ ^ (3) Br 8 The one-step Reformatsky r e a c t i o n of e t h y l 2-bromomethylacrylate (9) w i t h aldehydes and ketones a f f o r d s a-methylene-y-butyrolactones (10) (equation 4 ) ; ^ (9) i n t h i s case acts as an a^ , d" synthon. ct-Methylene-y-butyrolactones, apart from t h e i r numerous b i o l o g i c a l a c t i v i t i e s ^ are valuable s y n t h e t i c intermediates. White has e x p l o i t e d 12 t h i s type of compound i n h i s synthesis of (-)-acorenone (11). E t h y l 2-bromomethylacrylate was condensed w i t h the aldehyde (12) i n the presence of zinc to a f f o r d the a-methylene-y-butyrolactone (13) , which was converted i n t o (-)-acorenone (11) (equation 5). — j - RR'co Z n » STL m C02Et ^ THF R / \ A ) (V 9 10 - 6 -(5) 12 9 13 The n i t r o dione (14) , prepared by the a c y l a t i o n of the l i t h i u m enolate of cyclohexanone w i t h 4 - n i t r o b u t a n o y l c h l o r i d e (15) (scheme 1), 13 can be c y c l i z e d w i t h sodium bicarbonate to y i e l d the n i t r o k e t o l (16). This example demonstrates the use of 4-nitrobutanoyl c h l o r i d e (15) as 1 4 an a ,d synthon. K e t a l i z a t i o n of (16), followed by c a t a l y t i c hydro-genation of the n i t r o group of the r e s u l t a n t product, f u r n i s h e s the amino a l c o h o l (17). The l a t t e r substance when allowed to react w i t h aqueous, a c i d i c , sodium n i t r i t e undergoes a Tiffeneau-Demjanow rearrange-ment to a f f o r d (18). This sequence of r e a c t i o n s serves to c a r r y out a r i n g expansion of a c y c l i c ketone w i t h "simultaneous" annulative formation of a five-membered r i n g . 14 The use of ( t r i m e t h y l s i l y l ) a l l e n e s (19) as equiv a l e n t s to the 3 1 15 a ,d synthons (20) was demonstrated by Danheiser i n 1981. Thus, a,B-unsaturated ketones were t r e a t e d w i t h v a r i o u s ( t r i m e t h y l s i l y l ) a l l e n e s i n the presence of T i C l ^ to generate, i n i t i a l l y , the e n o l a t e - c a t i o n (21) (scheme 2). The impetus f o r the s t e r e o s e l e c t i v e e l e c t r o p h i l i c s u b s t i t u t i o n at C-3 of the a l l e n e i s provided by the r e s u l t a n t v i n y l - 7 -15 14 NGH.COa-Hj,0 • 18 Scheme 1 19 20 c a t i o n (21) being s t a b i l i z e d by i n t e r a c t i o n w i t h the adjacent carbon-s i l i c o n bond. A 1,2 s h i f t of the t r i m e t h y l s i l y l group a f f o r d s an isomeric v i n y l c a t i o n which i s i n t e r c e p t e d by the t i t a n i u m enolate to generate a new five-membered r i n g (22). Such a process c o n s t i t u t e s a ( t r i m e t h y l -s i l y l ) cyclopentene annulation. 22 - 9 -The a b i l i t y of 2-ethoxy-3-acetoxy-l-propene (23) to f u n c t i o n as the 2 2' equivalent of ana ,d synthon of type (24) has been u t i l i z e d i n the 16 synth e s i s of the enedione (25) (scheme 3). Palladium (O)-catalyzed c o u p l i n g of 2-ethoxy-3-acetoxy-l-propene (23) w i t h 2-methyl-l,3-cyclopentanedione produced the enol ether (26). Treatment of (26) w i t h N-bromosuccinimide and water aff o r d e d the bromo ketone (27) which was converted i n t o the enedione (25) by formation of the phosphonium s a l t (28), generation of the y l i d e (29) w i t h aqueous potassium carbonate, and c y c l i z a t i o n at 40°C. In an elegant s y n t h e s i s of (±)-coriolin (30), Trost and coworkers*^ made use of 3 - i o d o - 2 - ( t r i m e t h y l s i l y l m e t h y l ) p r o p e n e (31) as an equ i v a l e n t of of the "trimethylenemethane" a,d synthon (32). Conjugate a d d i t i o n of methanethiol to the enedione (25) followed by chemoselective k e t a l i z a t i o n gave (33). Monosulfenylation of (33) afforded (34) which was c l e a n l y a l k y l a t e d w i t h the i o d i d e (31) to y i e l d (35). Oxidation of (35) to the d i s u l f o n e followed by f l u o r i d e - i n d u c e d c y c l i z a t i o n produced (36). The l a t t e r substance was converted i n t o (±)-coriolin by a s e r i e s of standard r e a c t i o n s (scheme 4). 23 24 - 10 -29 27 X = Br + 28 X-fV*" Scheme 3 31 32 - 11 -, . SMe 2|iolH' b e n Z e n e' 25 P - T S O H 33 KH,MeSSMe,DME • Dm- CPBA,CH2Cl2 2)U-eu\NF,THF The reagents (37) and (38) a l s o act as sources of the " t r i -methylenemethane" a,d synthon (32) and have been used w i t h great success i n palladium mediated cyclopentane annulations and three-carbon r i n g expansion r e a c t i o n s , r e s p e c t i v e l y . Equations 6 to 8 show some r e a c t i o n s of (37) w i t h v a r i o u s e l e c t r o n -d e f i c i e n t o l e f i n s i n the presence of a c a t a l y t i c amount of (Ph„P),Pd. - 12 -37 38 toluene , 80-ltO°C 37 P c K P h ^ P U 37 4- [ M T H F , A 37 - j - M e O ^ ^ T H F , A - 13 -Reagent (38) on the other hand, has been, shown to be a useful agent to effect a three-carbon ring expansion as depicted in scheme 5. -SOgPh —HflU N Q I , D M E , 6 5 C Me, SC^ Ph 42 38 43 n-Bu4NF,THF,55C Scheme 5 Reaction of (38) with the sodium enolate of a 8-keto sulfone (42) in the presence of sodium iodide in DME affords the C-alkylated product (43) . Fluoride-induced cyclization of the latter substance yields (44) , which either directly or, upon treatment of the corresponding - 14 -a l c o h o l w i t h KH i n the presence of 18-crown-6 leads to fragmentation to give the ring-expanded product (45). In some cases, (45) undergoes concomitant e l i m i n a t i o n of the elements of b e n z e n e s u l f i n i c a c i d to y i e l d (46). (±)-Muscone (47) proved to be a good ta r g e t molecule to t e s t the a p p l i c a t i o n of t h i s concept. Treatment of (48) w i t h a c a t a l y t i c q u a n t i t y of f l u o r i d e i o n l e d d i r e c t l y to the ring-expansion product (49). C a t a l y t i c hydrogenation and d e s u l f o n y l a t i o n produced (±)-muscone (47) (scheme 6). 6iMe3 48 49 47 Scheme 6 Trost has developed a m u l t i p l e annulation sequence based upon the use of 2-bromomethyl-3-(trimethylsilylmethyl)-l,3-butadiene (50) as a formal e q u i v a l e n t to the a,d synthon (51).^ Br 50 51 Treatment of the sodium enolate of the keto sulfone (52) w i t h (50) a f f o r d s (53). C y c l i z a t i o n of (53) occurs smoothly w i t h t e t r a - n - b u t y l -ammonium f l u o r i d e or e t h y l aluminum d i c h l o r i d e to give the 2,3-di-substituted-1,3-butadiene (54). F a c i l e D i e l s - A l d e r r e a c t i o n of (54) w i t h dimethyl a c e t y l e n e d i c a r b o x y l a t e gives mainly the adduct (55) (scheme 7). Seebach^ has r e c e n t l y demonstrated the c l e v e r use of p i v a l o y l o x y nitropropene (56) as an equivalent to the b i f u n c t i o n a l a,a synthon (57). A d d i t i o n of a n u c l e o p h i l e to (56) a f f o r d s the n i t r o n a t e anion (58) (scheme 8) which then looses the p i v a l o y l o x y group to give the n i t r o o l e f i n (59). Subsequently, a d d i t i o n of a second n u c l e o p h i l e to (59) provides (61). A l t e r n a t i v e l y , the n i t r o o l e f i n (59) can serve as a good d i e n o p h i l e and undergo D i e l s - A l d e r r e a c t i o n s to give (62). - 16 -Si Me , N o H . D M E S O j P h Br 52 50 53 U-Bu \NF,THF,55C Or EtAlCI 2,CH 2a 2,-78°C - 17 -61 60 62 Scheme 8 The nitro group i s a versatile functional group which can be converted readily into amines, ketones, alcohols and olefins. Equation 9 shows the reaction between pivaloyloxy nitropropene (56) and the lithiodithiane (63) to yield the nitro olefin (64). The subsequent reactions between (64) and the lithium enolate of ethyl acetate and 2,3-dimethylbutadiene are shown in equations 10 and 11, respectively. In order to combine the properties of a vinyl bromide (which can be converted into a Grignard reagent or undergo lithium-halogen exchange) and an allylsilane (which has nucleophilic properties), Trost prepared 4 20 2-bromo-3-(trimethylsilyl)propene (67). ' This reagent proved to be an efficient functional equivalent to the d,d synthon (68). The - 18 -(10) (11) 66 remarkable v e r s a t i l i t y of (67) i s amply demonstrated by the f o l l o w i n g a p p l i c a t i o n s . P r e p a r a t i o n of the Grignard reagent (69) from (67), followed by copper c a t a l y z e d conjugate a d d i t i o n of the former species to 3-methyl-2-cyclopenten-l-one produces (70) (equation 12). Treatment of the - 19 -S M e , 67 68 conjugate a d d i t i o n adduct (70) w i t h e t h y l aluminum d i c h l o r i d e i n toluene at 0°C a f f o r d s the b i c y c l o [ 2 . 2 . l ] h e p t a n e system (71). C u l B ~ ether,-78t S i M e 3 (12) 69 70 I t i s a l s o p o s s i b l e to reverse the order of unmasking of the two n u c l e o p h i l i c s i t e s . For example, T i C l ^ c a t a l y z e d conjugate a d d i t i o n of the a l l y l s i l a n e (67) to 1-acetylcyclopentene produces a mixture of adducts (72) and (73). Adduct (72), upon treatment w i t h l i t h i u m metal c o n t a i n i n g 1% sodium, undergoes an i n t r a m o l e c u l a r B a r b i e r r e a c t i o n to give the cyclopentanol (74) (equations 13 and 14). ^ S i M e , T i C I 4 CH2CI2,-78°c (13) 67 7 2 7 3 Li-l%No T H F H i (14) 72 74 The r e a c t i o n of (67) w i t h aldehydes and ketones i n the presence of T i C l ^ a f f o r d s the corresponding a l c o h o l which on treatment w i t h (Ph^P) 2 ^ 1 ( 0 0 ) 2 and t r i e t h y l a m i n e y i e l d s a-methylene-y-butyrolactones. For example, the b i c y c l i c ketone (75) i s converted i n t o (77) usi n g t h i s procedure (equation 15). - 21 -+ 67 TiCUJHF -7B°C (Ph,P)Ni(CO)| E1SN,THF,A (15) 75 76 77 B. Problem Previous work in our laboratory had shown that a,8-acetylenic esters (78) can be converted, stereoselectively and ef f i c i e n t l y , into either (E_)- or (Z^)-B-trimethylstannyl a,B-unsaturated esters ((79) and exercise to exploit the use of some of these substances to prepare reagents which would be of use in organic synthesis. In particular, ethyl (E)-3- trimethylstannyl -2-butenoate (81) appeared to be a precursor of considerable promise. For example, treatment of the enolate anion of (81) with acetic acid at low temperature would be expected to produce the deconjugated ester (82) (scheme 9). Reduction of (82) would afford the corresponding alcohol (83), which would be a suitable precursor of A-chloro-2-(trimethyl-stannyl)- 1-butene (84). (80), respectively). 21 Therefore we f e l t that i t might be a worthwhile - 22 -R CO Et R H R-C=C-CO,Et Me C O B X' X x Me3Sn H Me^Sn CO^ Et Me3Sn H 78 79 80 81 82 83 84 Scheme 9 22 23 In l i g h t of the f a c i l e t r a n s m e t a l a t i o n of vinylstannanes ' to the corresponding v i n y l l i t h i u m reagents, i t seemed reasonable to propose 2 4 that (84) could serve as an equivalent to the 1-butene d ,a synthon (85). - 23 -In 1959, Rosenthal reported the pr e p a r a t i o n of 3-bromo-3-buten-l-2 4 25 o l (86), a p o t e n t i a l d ,a synthon. L a t e r , Boeckman developed a general method f o r the synthesis of 2-bromo-l-alkenes. However, i t 26 remained f o r Magnus and coworkers to u t i l i z e (86) e f f e c t i v e l y , as an 2 4 equi v a l e n t of the 1-butene d ,a synthon, i n a synt h e s i s of (±)-hirsutene. Their s t r a t e g y , which i s shown i n scheme 10, encompasses the c r u c i a l a d d i t i o n of the cuprate reagent derived from (87), to the enone (88). Compound (89) thus obtained, was t r e a t e d w i t h Et 3BzN +Cl~/KF to a f f o r d the a l c o h o l (90). Conversion of the a l c o h o l (90) i n t o the p-toluene-- 24 -sulfonate e s t e r and treatment of the l a t t e r m a t e r i a l w i t h l i t h i u m b i s ( t r i m e t h y l s i l y l ) a m i d e y i e l d e d the t r i c y c l i c ketone (91). Reduction of the ketone (91) produced the corresponding a l c o h o l (92). Deoxygenation of the a l c o h o l (92) furnished (±)-hirsutene (94). E t s B z N C I / K F 2 H 2 0 M e C N , 60°C 1 9 2 93 94 Scheme 10 - 25 -I t i s evident from the above example that the use of a l c o h o l (86) 2 4 as a 1-butene d , a reagent r e q u i r e s a number of transformations ( p r o t e c t i o n of the a l c o h o l , conjugate a d d i t i o n , deprotection of the a l c o h o l , t o s y l a t i o n ) before the i n t r a m o l e c u l a r a l k y l a t i o n can be c a r r i e d out. On the other hand; s u c c e s s f u l use of the c h l o r i d e (84) as an equivalent to the synthon (85) would i n v o l v e fewer steps and thus, i t was of considerable i n t e r e s t to determine whether or not i t would be p o s s i b l e to deploy both donor and acceptor centers of (84) simultaneously i n a "one - p o t " process. For example, tr a n s m e t a l a t i o n of (84) at low temperature would produce the v i n y l l i t h i u m reagent (95). This s p e c i e s , on treatment w i t h aldehydes and ketones, would a f f o r d the intermediate (96) which may indeed c y c l i z e d i r e c t l y to produce methylenetetrahydro-furan d e r i v a t i v e s of the general s t r u c t u r e (97) (equation 16). A l t e r -n a t i v e l y , the conversion of the v i n y l l i t h i u m reagent (95) to a c o r r e s -ponding cuprate, followed by r e a c t i o n of the l a t t e r substance w i t h an enone, would a f f o r d the intermediate enolate (98) which could c y c l i z e to f u r n i s h (99). Such a process would c o n s t i t u t e an e f f i c i e n t methylenecyclopentane annulation (equation 17). While we were pursuing these i d e a s , a discovery was made i n our l a b o r a t o r y which gave us access to a more expedient route f o r the p r e p a r a t i o n of 3 - t r i m e t h y l s t a n n y l - 3 - b u t e n - l - o l (83). I t was found that a d d i t i o n of the ( t r i m e t h y l s t a n n y l ) c o p p e r reagent (100) to 1-alkynes 27 produced predominantly compounds of general s t r u c t u r e (101). By using t h i s methodology i t i s p o s s i b l e to add the ( t r i m e t h y l s t a n n y l ) c o p p e r reagent (100) to 3-butyn-l-ol to f u r n i s h the a l c o h o l (83) which could be converted r e a d i l y i n t o the c h l o r i d e (84). - 26 -Polycondensed cyclopentanoid n a t u r a l products have sparked the i n t e r e s t of many s y n t h e t i c organic chemists. Not only have we seen a p l e t h o r a of syntheses of these n a t u r a l products i n the l a s t few years, but a l s o the l i t e r a t u r e records many general approaches f o r the formation of five-membered r i n g s . I t i s i n these e x c i t i n g times that we sought to apply the above mentioned methodology toward the c o n s t r u c t i o n of five-membered r i n g s . - 28 -DISCUSSION I Preparation and Transmetalation of 4 - C h l o r o - 2 - t r i m e t h y l s t a n n y l - l -butene ( M ) : Reaction of 4 - C h l o r o - 2 - l i t h i o - l - b u t e n e (Jj5_) w i t h  Aldehydes, Ketones and a,B-Unsaturated N,N' ,N' - T r i m e t h y l - carboxhydrazides A. P r e p a r a t i o n of 4-Chloro-2-trimethylstannyl-l-butene (84) During the course of our s t u d i e s we have gained access to two d i f f e r e n t routes f o r the pr e p a r a t i o n of (84). The a p p l i c a b i l i t y of the f i r s t route hinges upon the s u c c e s s f u l conversion of e t h y l ( E ) - 3 - t r i -methylstannyl-2-butenoate (81) i n t o e t h y l 3-trimethylstannyl-3-butenoate The pr e p a r a t i o n of (81) can be r e a l i z e d i n a s t r a i g h t f o r w a r d manner, by d i r e c t a p p l i c a t i o n of methodology developed p r e v i o u s l y i n our l a b o r a t o r y . S p e c i f i c a l l y , i t was found that many a , B _ a c e t y l e n i c e s t e r s could be transformed h i g h l y s t e r e o s e l e c t i v e l y i n t o the corresponding (E)-3-t r i m e t h y l s t a n n y l - 2 - a l k e n o a t e s (79) (equation 18) usi n g the ( t r i m e t h y l -(82). CQ, Et 81 82 - 29 -stannyl)copper reagent (100) or i n t o the ( Z ) - 3 - t r i m e t h y l s t a n n y l - 2 -alkenoates (80) (equation 19) using the (phenylthio)cuprate (102). Me3SnCu-Me2S [Me^nCuSPh] Li 100 102 R — = — C 0 2 R .—•> ) — ' ( 1 8 ) R CO 2R Me3Sn R —== C02R 102 79 Me3Sn C0 2R 0 9 ) 80 Thus, when a c o l d (-78°C) tetra h y d r o f u r a n s o l u t i o n of the ( t r i m e t h y l -stannyl) copper reagent (100) (1.3 equiv) was allowed to react w i t h e t h y l 2-butynoate f o r 3 h, (81) was produced i n 76% y i e l d (equation 20). With ample q u a n t i t i e s of (81) i n hand, we embarked on the prepara-t i o n of (82) by deconjugation of (81). In 1972, Rathke published a paper concerning the deconjugative p r o t o n a t i o n , a l k y l a t i o n and a l d o l -type condensation of enolate anions derived from a,B-unsaturated - 30 -Me—HE—CO Et Me3SnCu«Me2S COgEt (20) THF, -78°C 81 28 I t was f i r m l y e s t a b l i s h e d by Rathke that such enolate anions e s t e r s . react predominantly at the alpha carbon. 28 Encouraged by these i n i t i a l f i n d i n g s , many organic chemists have i n v e s t i g a t e d the a p p l i c a t i o n s of t h i s r e a c t i o n f u r t h e r , thus r e v e a l i n g i t s true s y n t h e t i c p o t e n t i a l . Among these s t u d i e s , Kende's work on the stereochemical outcome of the deconjugative a l k y l a t i o n s and protonations of the d i e n o l a t e anions derived from pure geometric isomers of 2-alkenoate e s t e r s i s p a r t i c u l a r l y 29 noteworthy. Conversion of compound (81) i n t o the corresponding enolate anion by treatment of the former substance w i t h two equiv of l i t h i u m d i i s o -propylamide at 0°C, followed by quenching of the enolate species w i t h saturated aqueous ammonium c h l o r i d e at -78°C provided a 2.5:1 mixture of the deconjugated e s t e r (82) and (103) (geometric isomer of the 30 s t a r t i n g m a t e r i a l (81)). This i n i t i a l r e s u l t not only i n d i c a t e d the f e a s i b i l i t y of the deconjugative p r o t o n a t i o n process i n the pr e p a r a t i o n of (82), but als o demonstrated the s t a b i l i t y of the t r i m e t h y l s t a n n y l group toward excess l i t h i u m diisopropylamide. We f e l t t hat inverse quenching of the enolate anion derived from (81) w i t h g l a c i a l a c e t i c - 31 -ac i d at a temperature lower than -78°C might improve the y i e l d of (82). Indeed, when a c o l d (-78°C) s o l u t i o n of the enolate anion of (81) i n tet r a h y d r o f u r a n , derived using two equiv of l i t h i u m d i i s o p r o p y l a m i d e , was t r a n s f e r r e d i n t o a co l d (-95°C) s o l u t i o n of g l a c i a l a c e t i c a c i d i n dry e t h e r , a mixture of the B,y-unsaturated e s t e r (82) (94%) and the a,B-unsaturated e s t e r (103) (geometric isomer of the s t a r t i n g m a t e r i a l (81)) ( 6%) was obtained (equation 21). I t i s p e r t i n e n t to poi n t out that there i s evidence i n the l i t e r a t u r e that exposure of a,B-unsaturated e s t e r s to excess hindered amide bases r e s u l t s i n the 28 q u a n t i t a t i v e formation of the corresponding enolate anions. Since i t i s h i g h l y l i k e l y t hat the deconjugated e s t e r (82) was s t a b l e to the quenching and the workup sequence, i t i s reasonable to assume that the recovered a,B-unsaturated e s t e r (103) represents the product C02ET |)|_DA,THF, -78 C,J/rnO°C,2h I 2 X Me3Sn 2)H0Ac,-95oC,ether ^ + M e ^ / \ ^ He H A (21) 81 82 103 obtained from y p r o t o n a t i o n of the enolate anion. Compounds (82) and (103) were separated by su b j e c t i o n of the mixture to column chromatography on s i l i c a g e l . The e s t e r (82) shows an i r absorption at 1724 cm (the conjugated e s t e r (81)•shows a carbonyl absorption at 1712 cm * ) , i n d i c a t i n g the non-conjugated nature of the e s t e r carbonyl group. The 100 MHz *H nmr spectrum of t h i s m a t e r i a l i n d i c a t e d that i t contained one t r i m e t h y l s t a n n y l group (9-proton s i n g l e t at 6 0.16 w i t h s a t e l l i t e peaks due to Sn-H c o u p l i n g , _J = 54 Hz) and an a l l y l i c methylene group (2-proton doublet of doublets at 6 3.28, J = 2, 1 Hz, J = 48 Hz). The c o u p l i n g constants Sn—H as s o c i a t e d w i t h the coupling of the o l e f i n i c protons (H^ and H^) w i t h the 1 1 7 S n and **^Sn n u c l e i were a l s o v i s i b l e . These observed J_ values may be i n t e r p r e t e d as being due to the presence of the t r i m e t h y l s t a n n y l * group c i s ( J g n _ H = 66 Hz) to and trans ( J ^ ^ = 1 3 8 H z ) t o H A -Reduction of the e s t e r (82) to the corresponding a l c o h o l proceeded smoothly when the former substance was allowed to react w i t h l i t h i u m aluminum hydride i n dry ether at -78°C (equation 22). The a l c o h o l (83) thus produced i n 95% y i e l d showed the d i a g n o s t i c 0-H s t r e t c h i n g absorption i n i t s i r spectrum at 3350 cm ^. Treatment of t h i s substance w i t h triphenylphosphine-carbon t e t r a c h l o r i d e i n the presence of t r i e t h y l a m i n e a f f o r d e d 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 (84). The a d d i t i o n of t r i e t h y l a m i n e was found t o be c r i t i c a l i n t h i s r e a c t i o n . In the absence of t r i e t h y l a m i n e , undesirable by-products were formed. The c h l o r i d e (84) e x h i b i t e d s p e c t r a l data i n f u l l agreement w i t h i t s s t r u c t u r e . The ^H nmr spectrum of (84) showed a broad t r i p l e t at 6 2.69 I t i s known that w i t h organotin 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 i n k a g e , J.Sn-H ^ s n^ch l a r g e r when they are trans to each other than when they are c i s to each other. " ( J = 7 Hz, J . „ = 48 Hz) f o r the a l l y l i c methylene protons. The -CH C l o n — n Z protons gave r i s e to a t r i p l e t at 6 3.53 ( J = 7 Hz). The two o l e f i n i c protons Hj and H^ appeared as a p a i r of doublet of t r i p l e t s at 6 5.29 ( J = 2.4, 1 Hz, J c „ = 70 Hz) and 6 5.76 ( J = 2.4, 1 Hz, J . „ = 142 Hz)* r e s p e c t i v e l y . 82 83 84 Although the value of J _ f o r trans v i c i n a l c o u p l i n g i n 3 - t r i -bn—H al k y l s t a n n y l - 2 - a l k e n o a t e s i s approximately 120 Hz, a value of 142 Hz (or higher) i s expected f o r an o l e f i n without e l e c t r o n -withdrawing groups. - 34 -The f e a s i b i l i t y of a d d i t i o n of the (t r i m e t h y l s t a n n y l ) c o p p e r reagent (100) to 1-alkynes to produce 2 - t r i m e t h y l s t a n n y l - l - a l k e n e s , was demonstrated i n our l a b o r a t o r y by work done concurrently w i t h that 27 o u t l i n e d i n t h i s t h e s i s . This r e a c t i o n provided a second route f o r the p r e p a r a t i o n of the c h l o r i d e (84). The r e a c t i o n of the ( t r i m e t h y l -stannyl) copper reagent (100) (2 equiv) w i t h 3 - b u t y n - l - o l , i n the presence of methanol (60 equiv) f o r 12 h at -63°C produces, i n 81% y i e l d , a mixture of 3 - t r i m e t h y l s t a n n y l - 3 - b u t e n - l - o l (83) (91%) accompanied by a small amount of the isomeric a l c o h o l (10 4) ( 9 % ) . In order to gain access to large q u a n t i t i e s of the a l c o h o l (83) i t was necessary to modify the r e a c t i o n c o n d i t i o n s of t h i s process, which, p r i o r to our work, had been t e s t e d only f o r small s c a l e conversions. Thus, the (t r i m e t h y l s t a n n y l ) c o p p e r reagent (100) (49.2 mmol) was allowed to react w i t h 3 - b u t y n - l - o l (21.4 mmol) i n the presence of 1 mol of methanol i n i t i a l l y at -78°C f o r 2.5 h and then at 0°C f o r 3 h to a f f o r d a mixture of the des i r e d a l c o h o l (83) and the isomeric a l c o h o l (104) (90:10) i n 69% y i e l d (equation 23). Although t h i s v a r i a t i o n s u f f e r s from lower y i e l d s , i t c e r t a i n l y precludes the operation of a low temperature bath (-63°C) f o r a prolonged period of time (12 h ) , a cumbersome task e s p e c i a l l y with l a r g e s c a l e r e a c t i o n s . The isomeric a l c o h o l s (83) and (104) were separated by s u b j e c t i n g the mixture to column chromatography on s i l i c a g e l . The a l c o h o l (83) was converted i n t o the c h l o r i d e (84) w i t h triphenylphosphine-carbon t e t r a c h l o r i d e i n the presence of t r i e t h y l a m i n e , as o u t l i n e d p r e v i o u s l y . - 35 -Me3SnCu»Me2S 100 O H O H H-C=C- Me3Sn (23) OH MeOH T H F , -78°C—«-0°C 83 104 B. Transmetalation of 4-Chloro-2-trimethylstannyl-l-butene (84): The Reaction of 4 - C h l o r o - 2 - l i t h i o - l - b u t e n e Q9-5.) with Various Aldehydes, Ketones, and a,B-Unsaturated N,N',N'-Trimethylcarboxhydrazides. 32 Many years a f t e r Gilman reported h i s work on the transmetalation of t e t r a p h e n y l t i n w i t h excess n - b u t y l l i t h i u m to prepare t e t r a - n - b u t y l t i n (equation 24), Seyferth published the p r e p a r a t i o n of v i n y l l i t h i u m , a reagent h i t h e r t o unknown, by r e a c t i o n of p h e n y l l i t h i u m w i t h t e t r a -22 v i n y l t i n (equation 25). n-Bu4Sn -f 4 PhU (24) (CH2=CH^Sn + 4PhLi 4CH2=CHLi - f Ph4Sn (25) - 36 -33 No t e w o r t h i l y , Corey took the above process a step f u r t h e r by the p r e p a r a t i o n of the f u n c t i o n a l i z e d vinylstannane (106) v i a hydro-stannation of the te r m i n a l acetylene (105). Transmetalation of (106) wit h n - b u t y l l i t h i u m at low temperature (-78°C) r e s u l t e d i n the formation of the l i t h i o species (107) (Scheme 11) which has been used e f f e c t i v e l y as a n u c l e o p h i l i c v i n y l a t i n g agent. H = CH20THP n - B u 3 S n H , AIBN , A* n - B u 3 S n V -OTHP 105 106 n-BuLi,THF,-78C Scheme 11 Li V -OTHP 107 The l i t e r a t u r e records an extensive l i s t of recent examples of 23 v i n y l l i t h i u m reagents a c c e s s i b l e v i a t r a n s m e t a l a t i o n of vinylstannanes. This process has become popular among s y n t h e t i c organic chemists f o r 34 the f o l l o w i n g reasons: (a) The r e a c t i o n u s u a l l y proceeds smoothly at low temperatures (below -50°C), (b) the r e a c t i o n i s completely stereo-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 c o o r d i n a t i v e l y 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 w i t h the r e a c t i o n s of - 37 -the v i n y l l i t h i u m s p e c ies. With the methodology f o r the p r e p a r a t i o n of 4 - c h l o r o - 2 - t r i m e t h y l -stannyl-1-butene (84) having been developed, the task at hand was to study the t r a n s m e t a l a t i o n of t h i s substance. Success awaited us at t h i s p o i n t , f o r the t r a n s m e t a l a t i o n of (84) proceeded smoothly and c l e a n l y at -78°C. Thus, when a tetrahydrofuran s o l u t i o n of (84) was exposed to 1.1 equiv of m e t h y l l i t h i u m at -78°C f o r 5 min, a l i g h t yellow s o l u t i o n of 4 - c h l o r o - 2 - l i t h i o - 1 - b u t e n e (95) was obtained. The r e a c t i o n of the v i n y l l i t h i u m reagent (95) w i t h various aldehydes and ketones at -78°C, followed by appropriate workup, produced the i n t e r -mediate c h l o r o a l c o h o l s (108) - (113) . A l t e r n a t i v e l y and i m p o r t a n t l y , when the c o l d s o l u t i o n s derived from the r e a c t i o n of aldehydes and ketones w i t h (95) were t r e a t e d w i t h 1.4 equiv of hexa-methylphosphoramide, and then allowed to warm to room temperature, the 3-methylenetetrahydrofuran d e r i v a t i v e s (1_14_)- (1_19_) were formed i n good y i e l d . Table I summarizes the r e s u l t s of the above processes. The crude products obtained a f t e r workup i n both of these r e a c t i o n s were qu i t e pure (by g l c and t i c ) , except f o r the presence of a small amount of the s t a r t i n g carbonyl compound. P u r i f i c a t i o n of a l l these compounds was accomplished conveniently by s u b j e c t i n g the crude product obtained a f t e r workup to p r e p a r a t i v e t h i n l a y e r chromatography on s i l i c a g e l ( e l u t i o n w i t h petroleum e t h e r - e t h e r ) . Not s u r p r i s i n g l y , when the chloro a l c o h o l s (108), (109), (111), and (112) were allowed to react w i t h potassium hydride i n t e t r a h y d r o -furan at room temperature, the corresponding 3-methylenetetrahydrofuran d e r i v a t i v e s (114), (115), (117). and (118) were formed (Table I I ) . The spectroscopic data ( i r , ''H nmr, h i g h - r e s o l u t i o n mass spectra) - 38 -TABLE I. Conversion of aldehydes and ketones i n t o 3-methylene-tetrahydrofuran d e r i v a t i v e s . Carbonyl Compound Chloro A l c o h o l 3 Y i e l d b % C y c l i z e d Product C Y i e l d b % OH cr o y OH Cr O Y OH S° c r o v O H ^C l 7=° >V (108) 76 X ; (114) 63 H H J H T (109) 64 Cr^^ ( I i i) 56 (110) 67 (116) 51 (111) 69 \JY d i 7 ) 58 (112) 69 V JV ( U S ) 62 (113) 72 / Y J (119) 62 3 ( i ) A s o l u t i o n of 0.83 equiv of reagent (95) was t r e a t e d w i t h 1.0 equiv of the aldehyde or ketone, and the s o l u t i o n was s t i r r e d at -78°C f o r 1.5-2 h. ( i i ) The r e a c t i o n mixture was t r e a t e d w i t h N H 4 C I - H 2 O at -78°C. b Y i e l d of p u r i f i e d , d i s t i l l e d product. ( i ) As i n (a) ( i ) . ( i i ) Hexamethylphosphoramide (1.4 equiv) was added, and the r e a c t i o n mixture was warmed to room temperature, 2-3 h. - 39 -TABLE I I . C y c l i z a t i o n of a number of c h l o r o a l c o h o l s w i t h potassium hydride. Chloro A l c o h o l C y c l i z e d Product Y i e l d % (108) (114) 84 (109) (115) 78 (111) (117) 81 (112) (118) 88 A s o l u t i o n ( t e t r a h y d r o f u r a n , room temperature) of the c h l o r o a l c o h o l was t r e a t e d w i t h 1.2 equiv of potassium hydride and the mixture was s t i r r e d f o r 2 - 3 h. Y i e l d of p u r i f i e d , d i s t i l l e d product. - 40 -of a l l these compounds f u l l y corroborated the assigned s t r u c t u r e s . For example, the *H nmr spectrum of the chloro a l c o h o l (111) e x h i b i t e d a broad t r i p l e t at 6 2.62 ( J = 7 Hz) due to the a l l y l i c methylene protons while the -CT^Cl protons gave r i s e to a normal t r i p l e t at 6 3.70 ( J = 7 Hz). Furthermore, the somewhat broad s i n g l e t at 6 4.94 was assigned to H ( trans to the a l l y l i c methylene protons) and the s i n g l e t at & 5.24 was assigned to Hg. The i r spectrum of (111) showed the 0-H s t r e t c h i n g absorption band at 3375 cm On the other hand, the 3-methylenetetrahydrofuran d e r i v a t i v e (117) showed a doublet of doublet of t r i p l e t s at 6 2.58 ( J = 1.5, 2, 7 Hz) f o r the a l l y l i c methylene protons while the -OC^- protons appeared as a t r i p l e t a t 6 3.79 ( J = 7 Hz). The o l e f i n i c protons gave r i s e to a p a i r of t r i p l e t s at 6 4.74 ( H A , J = 2 Hz) and 6 4.89 ( 1 ^ , J = 1.5 Hz). a, (^-Unsaturated N,N ' ,N'-trimethylcarboxhydrazides which have an e x c e p t i o n a l l y u n r eactive carbonyl group, undergo conjugate a d d i t i o n 35 w i t h simple a l k y l l i t h i u m reagents. Furthermore, the derived l i t h i u m 36 enolates can be a l k y l a t e d w i t h various a l k y l h a l i d e s (equation 27). These r e a c t i o n s form the b a s i s f o r a "one-pot" s y n t h e t i c operation where two carbon-carbon bonds are formed. - 41 -Recently, i t was shown i n our l a b o r a t o r y that the v i n y l l i t h i u m reagents (120) and (121) prepared v i a t r a n s m e t a l a t i o n of the correspond-i n g t r i - n - b u t y l s t a n n y l d e r i v a t i v e s , add c l e a n l y to the a,B-unsaturated N,N',N'-trimethylcarboxhydrazide (122) i n a conjugate fashion 37 (equations 28 and 29) to y i e l d (123) and (124), r e s p e c t i v e l y . 121 122 124 - 42 -I t was the p o s i t i v e nature of these r e s u l t s that prompted us to examine the r e a c t i o n of the v i n y l l i t h i u m reagent (95) w i t h v a r i o u s a,B-unsaturated N,N' ,N'-trimethylcarboxhydrazides. Pre p a r a t i o n of the a,B-unsaturated N , N ' , N ' - t r i m e t h y l c a r b o x h y d r a z i d e s (125) - (127) was accomplished by treatment of t r i m e t h y l h y d r a z i n e w i t h the corresponding a c i d c h l o r i d e s at -78°C i n dichloromethane i n the 38 presence of t r i e t h y l a m i n e . When the b u t e n y l l i t h i u m reagent (95) was allowed to react w i t h each of the N , N ' , N ' - t r i m e t h y l c a r b o x h y d r a z i d e s (125) - (127) ( t e t r a h y d r o f u r a n , -78°C, 1 h ) , and, i n each case, the r e a c t i o n mixture was t r e a t e d at -78°C w i t h saturated aqueous ammonium c h l o r i d e , the a c y c l i c hydrazides (128) - (130) were obtained. On the other hand, when each of the c o l d (-78°C) r e a c t i o n mixtures, derived from the a d d i t i o n of the a,B-unsaturated N , N ' , N ' - t r i m e t h y l c a r b o x -hydrazides (125) - (127) to the l i t h i o species (95),, was t r e a t e d w i t h 1.4 equiv of hexamethylphosphoramide, and was then warmed to room temperature and allowed to s t i r at t h i s temperature f o r a f u r t h e r 2 h, the s u b s t i t u t e d 3-methylenecyclopentanecarboxylic a c i d d e r i v a t i v e s (131) - (133) were produced. The r e s u l t s of t h i s methylenecyclopentane ann u l a t i o n i n which two carbon-carbon bonds are formed i n a "one-pot" process are summarized i n Table I I I . S p e c t r a l c h a r a c t e r i s t i c s ( i r , nmr, h i g h - r e s o l u t i o n mass spectra) of these compounds confirmed the assigned s t r u c t u r e s . I n t e r e s t i n g l y , the nmr spectra of these rather simple compounds e x h i b i t e d , i n many cases, w e l l d i f f e r e n t i a t e d s i g n a l s thus a l l o w i n g f o r t h e i r proper i d e n t i f i c a t i o n by i r r a d i a t i o n s t u d i e s . The s a l i e n t f e a t u r e s of the decoupling experiments performed on these compounds are discussed below. - 43 -TABLE I I I . The r e a c t i o n of 4 - c h l o r o - 2 - l i t h i o - l - b u t e n e w i t h a,8-unsaturated N,N',N'-trimethylcarboxhydrazides R R A c y c l i c Y i e l d % b C y c l i z e d Y i e l d % b Hydrazide Product (125) H H (128) 65 (131) 60 (126) Me H (129) 75 (132) 62 (127) H Me (130) 65 (133) 60 ( i ) A s o l u t i o n ( t e t r a h y d r o f u r a n , -78°C) of 0.83 equiv.of reagent(95) was tr e a t e d w i t h the a,^-unsaturated N,N',N'-trimethylcarboxhydrazides and the s o l u t i o n was s t i r r e d f o r 1 h. ( i i ) The r e a c t i o n mixture was treat e d w i t h NH4C1 -H 20, -78°C. Y i e l d of p u r i f i e d , d i s t i l l e d product. ( i ) As i n (a) . ( i ) . ( i i ) The r e a c t i o n mixture was trea t e d w i t h 1.4 equiv of hexamethylphosphoramide and then warmed to room temperature, 2 h. - 44 -In the 400 MHz *H nmr spectrum of compound (128) the protons H^ appeared as a broad t r i p l e t at 6 2.32 (J = 8 Hz) while the protons H„ gave r i s e to a normal t r i p l e t at 6 2.68 ( J = 8 Hz). I r r a d i a t i o n of r -the s i g n a l due to H caused the H_ t r i p l e t to c o l l a p s e i n t o a broad E F s i n g l e t . Although the broad t r i p l e t due to the protons H (6 2.52, 128 _J = 8 Hz) was p a r t i a l l y obscured by the intense s i x - p r o t o n s i g n a l of the -NtMe^ group (6 2.50), i r r a d i a t i o n of the s i g n a l due to protons H ( t r i p l e t at 6 3.62, J = 8 Hz) c o l l a p s e d the 6 2.52 s i g n a l i n t o a broad s i n g l e t . S i m i l a r l y , i r r a d i a t i o n of the Hg s i g n a l c o l l a p s e d the H^ t r i p l e t i n t o a sharp s i n g l e t . In the 400 MHz "^H nmr spectrum of (131) the highest f i e l d m u l t i p l e t at 5 1.79 - 1.98 was a t t r i b u t e d to H A and H^t . Furthermore, H appeared as an overlapped f i v e - l i n e m u l t i p l e t at 6 3.51. Protons G HT>> H , , H_ and H, gave r i s e to m u l t i p l e t s at 6 2.24 - 2.37 (IH) and B B E F 6 2.44 - 2.54 (3H). The o l e f i n i c protons produced a m u l t i p l e t at 6 4.82 - 4.88. I r r a d i a t i o n of the m u l t i p l e t at 6 1.79 - 1.98 (H and The broadness of the t r i p l e t due to the protons H E may a r i s e due to unresolved a l l y l i c c o u pling w i t h the o l e f i n i c protons. - 45 -H^t ) s i m p l i f i e d the m u l t i p l e t at 6 2.24 - 2.37 i n t o a broad doublet (J = 16 Hz) while the s i g n a l due to Hfi c o l l a p s e d i n t o a doublet of doublets (J = 10, 8 Hz). A d d i t i o n a l l y , i r r a d i a t i o n of the m u l t i p l e t at S 2.24 - 2. 37 s i m p l i f i e d the m u l t i p l e t (6 4.82 - 4.88) due to the o l e f i n i c protons i n t o a p a r t i a l l y overlapped p a i r of broad s i n g l e t s . This data not only confirm our assignment of the protons H^ and H^,, but al s o show that the one-proton m u l t i p l e t at S 2.24 - 2.37 i s due to e i t h e r Hg or rig, . Proton H_ appeared as an overlapped doublet of a doublet of a quartet (appearing as a hextet, = 8,8,8 Hz) at 6 3.54 i n the 400 MHz *H nmr spectrum of (129). The highest f i e l d s i g n a l , due to the secondary methyl group, appeared as a doublet at 6 1.06 (J = 8 Hz). When the 6 3.54 s i g n a l was i r r a d i a t e d , the secondary methyl doublet was transformed i n t o a sharp s i n g l e t . M e N . 2 \ H - H A M e 2 N x 129 In compound (132), decoupling s t u d i e s c l e a r l y supported our assignment of protons H^ , and H^ , as a p a i r of broad doublets at 6 2.49 and 6 2.74 (J = 16 Hz). I r r a d i a t i o n of the doublet at 6 2.74 caused —hi the doublet at 6 2.49 to c o l l a p s e i n t o a broad s i n g l e t . - 46 -132 The 400 MHz H nmr spectrum of (133) e x h i b i t e d a doublet at 6 1.04 (J = 6 Hz) f o r the secondary methyl group. In a d d i t i o n , the broad unresolved s i g n a l (Wu = 24 Hz) at 6 2.69 - 2.80 was a t t r i b u t e d to H_, while H e x h i b i t e d a doublet of doublet of doublets at 6 3.20 ( J = 12, G 10, 8 Hz). I r r a d i a t i o n of the secondary methyl doublet at 6 1.04 changed d r a m a t i c a l l y the apparently uninformative broad s i g n a l at 6 2.69-2.80 i n t o a c l e a r l y d i s c e r n i b l e doublet ( J L ^ = 12 Hz). On the other Gr hand, i r r a d i a t i o n of t h i s broad s i g n a l (at 6 2.69- 2.80) caused c o l l a p s e of the doublet at 6 1.04 i n t o a s i n g l e t and not s u r p r i s i n g l y , transformed 133 - 47 -the s i g n a l at 6 3.20 i n t o a overlapped doublet of doublets ( J = 10, 8 Hz). Compound (133) c o n s i s t e d of a s i n g l e diastereomer and, although the r e l a t i v e c o n f i g u r a t i o n of t h i s substance was not e s t a b l i s h e d r i g o r o u s l y , the magnitude of the coupling constant (12 Hz) lends credence to the — b r proposed s t r u c t u r e , i n which the two s u b s t i t u e n t s on the five-membered r i n g have a trans r e l a t i o n s h i p . I t i s evident from the r e a c t i o n s of the b u t e n y l l i t h i u m reagent (95) w i t h v a r i o u s carbonyl compounds and a,B-unsaturated N,N' , N ' - t r i -methylcarboxhydrazides, that i t i s indeed a v i a b l e s y n t h e t i c equivalent 2 4 to the 1-butene d ,a synthon (85). Notwithstanding the s t a b i l i t y demonstrated by (95) at -78°C, we f e l t that i t might be u s e f u l to i n v e s t i g a t e i t s thermal s t a b i l i t y at higher temperatures. To t h i s end, three separate experiments were c a r r i e d out as f o l l o w s . Three tetrahydrofuran s o l u t i o n s of (95) prepared i n the normal f a s h i o n at -78°C, were warmed to -63°, -48° and -20°C and allowed to s t i r at these temperatures f o r ^ h. Each of these s o l u t i o n s were recooled to -78°C, t r e a t e d w i t h cyclohexanone (1.2 e q u i v ) , and the r e s u l t i n g mixtures were allowed to s t i r at -78°C f o r 1.5 h. Then a l l three s o l u t i o n s were worked up i n the usual way w i t h saturated - 48 -aqueous ammonium c h l o r i d e . The i s o l a t e d y i e l d s ( a f t e r chromatography and d i s t i l l a t i o n ) of the ch l o r o a l c o h o l (111) (equation 30) provided us w i t h a q u a l i t a t i v e e s t i m a t i o n of the s t a b i l i t y of (95) at the various temperatures employed. At -63°C the ch l o r o a l c o h o l (111) was obtained i n a 60% y i e l d , w h i le at -48°C (111) was obtained i n 42% y i e l d . The f i n a l experiment, at -20°C, f a i l e d to produce the product (111). I t should be noted a l s o that at -20°C no compound other than cyclohexanone was detected i n the crude mixture obtained a f t e r workup. In the absence of any experimental evidence as to the outcome of t h i s r e a c t i o n at -20°C, one can only speculate that (95) had undergone complete s e l f - a n n i h i l a t i o n , to produce a compound or compounds of high v o l a t i l i t y , which escaped d e t e c t i o n . The formation of methylene-cyclopropane (134) (equation 31), which has a bp of 10°C*^ seems a l o g i c a l pathway f o r the "disappearance" of (95). I t i s evident from these r e s u l t s that whereas the b u t e n y l l i t h i u m reagent (95) i s a (30) 95 I! - 49 -•Li ~-20°C Y (31) 95 134 2 4 v i a b l e 1-b'utene d ,a synthon at -78 and -63°C, i t s usefulness diminishes r a p i d l y at higher temperatures. A bromide group at C-4 of (84), i n s t e a d of the c h l o r i d e group, would serve as a b e t t e r l e a v i n g group. Thus, i t was w i t h the i n t e n t of enhancing the acceptor s i t e (C-4) r e a c t i v i t y of (84), that we embarked on the prep a r a t i o n of the corresponding bromide (135). Treat-ment of the a l c o h o l (83) w i t h triphenylphosphine-dibromide i n aceto-n i t r i l e i n the presence of excess t r i e t h y l a m i n e produced the bromide (135) i n 75% y i e l d (equation 32). Transmetalation of (135) i n t e t r a -hydrofuran at -78°C followed by treatment of the r e s u l t a n t s o l u t i o n w i t h cyclohexanone (1.2 equiv) f a i l e d to produce the adduct (136). S i m i l a r l y , when the same r e a c t i o n was c a r r i e d out at -95°C, the methylenetetrahydrofuran d e r i v a t i v e (117) was formed, but i n only ~4% y i e l d . I t was c l e a r from these r e s u l t s that the b u t e n y l l i t h i u m reagent (137) has a very short h a l f - l i f e , even at very low temperatures, and that i t probably s e l f - a n n i h i l a t e s before i t can be i n t e r c e p t e d by cyclohexanone. That i t may have formed methylenecyclopropane (134), i n doing so, i s again pure s p e c u l a t i o n . - 50 -(32) 137 136 117 - S i -l l Conjugate A d d i t i o n of Cuprate Species Derived from A-Chloro-2- l i t h i o - l - b u t e n e (95) to C y c l i c Enones: An E f f i c i e n t Methylene- cyclopentane Annulation Process A. I n t r o d u c t i o n Organocopper reagents have played a p i v o t a l r o l e i n the synthesis of many n a t u r a l products. The usefulness of these reagents can be a t t r i b u t e d to t h e i r a b i l i t y to connect two carbon u n i t s under r e l a t i v e l y 39 m i l d c o n d i t i o n s (e.g., at or below room temperature). Very o f t e n these transformations are e i t h e r d i f f i c u l t or impossible to accomplish using other reagents. I t i s due to the r e a l i z a t i o n (by the community of s y n t h e t i c organic chemists) of the uniqueness of organocopper reagents that has l e d to the phenomenal growth of research done i n t h i s area. 40 Gilman f i r s t reported the p r e p a r a t i o n of methylcopper i n 1936. 41 Kharasch , i n 1941, observed the 1,4-addition of organomagnesium compounds to cyclohexenones, i n the presence of a c a t a l y t i c amount of cuprous i o n s . In 1952, Gilman announced the pr e p a r a t i o n of dimethyl-42 ' c o p p e r l i t h i u m ( l i t h i u m dimethylcuprate). Not u n t i l the mid-1960's, however, d i d systematic research, done mainly by House and co-workers, r e v e a l the true s y n t h e t i c p o t e n t i a l o f organocopper reagents. Organocopper reagents are most commonly used f o r (a) a d d i t i o n s to carbon-carbon double and t r i p l e bonds, and (b) s u b s t i t u t i o n of 39 organic h a l i d e s and a l c o h o l d e r i v a t i v e s . These s y n t h e t i c a l l y v a l u a b l e processes are not without c o m p l i c a t i o n s . The major s h o r t -43 comings of organocopper reagents are the f o l l o w i n g : (a) homocuprates, - 52 -R^CuLi, waste one R group i n most a p p l i c a t i o n s ; (b) heterocuprates, RCuXLi (X = l i g a n d bonded to copper v i a a heteroatom) are thermally 44 unstable and must be used at low temperatures; (c) a c e t y l e n i c mixed cuprates, RCuR'Li (R' = 1-alkynyl l i g a n d ) , are much l e s s r e a c t i v e 45 than the corresponding homocuprates. Because of t h e i r high r e a c t i v i t y toward oxygen and water, organocopper reagents have to be prepared i n an i n e r t solvent (ether or tetrahydrofuran) and under an i n e r t atmosphere. In order t h a t organocopper reagents be i d e a l reagents i n organic s y n t h e s i s they should have high thermal s t a b i l i t y coupled w i t h high r e a c t i v i t y . I t i s a l s o very important that these r e a c t i o n s proceed i n high y i e l d w i t h but one equivalent of R (heterocuprates). The l a t t e r property i s p a r t i c u l a r l y d e s i r a b l e i f cuprate r e a c t i o n s are to be used to make c r u c i a l C-C bonds i n convergent syntheses. For example, 47 i n a number of p r o s t a g l a n d i n syntheses, the o p t i c a l l y a c t i v e (and therefore v a l u a b l e ) side chains are attached by using homocuprates (R^CuLi). I t would be of c o n s i d e r a b l e importance i f t h i s process could be achieved v i a heterocuprates. A r i g o r o u s survey of organocopper reagents i s beyond the scope of t h i s t h e s i s . The ensuing pages deal w i t h s e l e c t e d examples of organocopper reagents and a few of t h e i r more u s e f u l a p p l i c a t i o n s i n organic s y n t h e s i s . L i t h i u m dimethylcuprate, M e ^ u L i , i s by f a r the most widely used organocuprate i n organic s y n t h e s i s . The l a s t 25 years have been House summarizes the s y n t h e t i c organic chemist's predicament most s u c c i n c t l y : "Thus, the r e a c t i o n temperatures r e q u i r e d to form and use (RoCuLi) n reagents are often approximately the same temperatures as the temperatures where thermal decomposition becomes a serious competing r e a c t i o n " (see reference 46). - 53 -witness to the v e r s a t i l i t y of t h i s remarkably simple reagent. A more recent a p p l i c a t i o n of Me^CuLi in v o l v e s the e f f i c i e n t s y n t h e s i s of 48 (±)-isocomene (138). When the t r i c y c l i c enone (139) was allowed to react with Me^CuLi, a s i n g l e ketone (140) was produced. The methyl group i n (140) had been d e l i v e r e d e x c l u s i v e l y from the e x t e r i o r of the molecule, due to the s t e r i c a l l y encumbered endo-surface of the conjugated double bond. The ketone (140) was subjected to Wolff-Kishner reduction w i t h hydrazine hydrate and potassium carbonate to a f f o r d (±)-isocomene (138) (equation 33). (33) 139 140 138 49 Heathcock's e f f i c i e n t s y n t h e s i s of (±)-lycopodine (141), i n v o l v e d the c r e a t i v e a p p l i c a t i o n of the homocuprate (142). A d d i t i o n of t h i s species to the enone (143) r e s u l t s i n the formation of (144), i n which the C-3 and C-5 s u b s t i t u e n t s have a trans r e l a t i o n s h i p (equation 34). The remarkably good s t e r e o c o n t r o l i n t h i s organocopper a d d i t i o n can be a t t r i b u t e d to s t e r e o e l e c t r o n i c f a c t o r s , l e a d i n g almost e x c l u s i v e l y to a x i a l attachment"^ of the new carbon-carbon .bond. The conjugate a d d i t i o n product (144) was transformed i n t o the secondary amine (145) by a s e r i e s of standard r e a c t i o n s . Intramolecular Mannich - 54 -c y c l i z a t i o n of (145) a f f o r d e d a s i n g l e t r i c y c l i c amino ketone (146). C a t a l y t i c debenzylation of (146) afforded the a l c o h o l (147), which underwent Oppenauer o x i d a t i o n (benzophenone, _t-C^HgOK, C^A^, r e f l u x ) w i t h subsequent i n t r a m o l e c u l a r a l d o l i z a t i o n and dehydration y i e l d i n g racemic dehydrolycopodine (148). C a t a l y t i c hydrogenation of the l a t t e r substance produced ( l ) - l y c o p o d i n e (141) (Scheme 12). 143 142 144 141 148 Scheme 12 147 - 55 -During the I960's many s y n t h e t i c organic chemists, both academic and i n d u s t r i a l , pioneered the synth e s i s of n a t u r a l and s t r u c t u r a l l y modified p r o s t a g l a n d i n s . These e f f o r t s l e d to the accumulation of an impressive array of s y n t h e t i c methods designed f o r the l a b o r a t o r y 47 51 c o n s t r u c t i o n of cyclopentanoid p r o s t a g l a n d i n systems. ' Organocopper reagents have been widely used f o r the c o n s t r u c t i o n of the long chain 47 s u b s t i t u e n t s on the five-membered r i n g system of p r o s t a g l a n d i n s . Of 47c d the many syntheses of pr o s t a g l a n d i n d e r i v a t i v e s , Stork's s y n t h e s i s ' of PGF„ (158) stands out f o r i t s m a s t e r f u l manipulation of organd-cuprates. Thus, a d d i t i o n of the homocuprate (150) (obtained from the v i n y l i o d i d e (149)) (equation 35) to the enone (151), followed by treatment of the r e s u l t i n g enolate anion w i t h formaldehyde gave a 1.3:1 mixture of (152) and (153), r e s p e c t i v e l y . The mixture of (152) and (153) was converted i n t o the corresponding mesylates by treatment w i t h excess methanesulfonyl c h l o r i d e i n p y r i d i n e . The l a t t e r mixture, when exposed to d i i s o p r o p y l e t h y l a m i n e , furnished the c r u c i a l methylene-cyclopentanone (154). A d d i t i o n of the d i v i n y l c u p r a t e (156) from the v i n y l i o d i d e (155) (equation 36) to the enone (154), followed by removal o f the ethoxyethyl p r o t e c t i n g group and o x i d a t i o n of the r e s u l t a n t primary a l c o h o l provided the cyclopentanone a c i d (157). S t e r e o s e l e c t i v e r e d u c t i o n of the ketone f u n c t i o n i n (157) , followed by removal of the a l c o h o l p r o t e c t i n g groups, afforded a mixture of two epimers of PGF^^. The more p o l a r isomer, separated by chromatography on s i l i c a g e l was i d e n t i f i e d as the authentic (±)-PGF„ (158) (Scheme 13). In a synthesis of (±)-g-himachalene (159), the phenylthiocuprate 52 reagent (160) has been u t i l i z e d w i t h great e f f i c a c y . Lithium-halogen - 56 -152+153 1) MeS02Cl,Py1QC 2) (i-Pr)2E1N 154 1) l56r45c--io0c 2) 5 0 % AcOH,rt 3) Cr03-H2S0A OH ±=? >—C09H 1) U§ec-Bu)3BH 2) No,NH,,ElOH 158 Scheme 13 157 - 57 -exchange of the bromocyclopropane (161), followed by a d d i t i o n of s o l i d phenylthiocopper and warming of the r e s u l t a n t mixture to -20°C, furnished a reddish-brown s o l u t i o n of the cuprate reagent (160) (equation 37). Reaction of the l a t t e r species w i t h 3-iodo-2-cyclohexen-l-one (162) gave the s u b s t i t u t e d cyclohexenone (163) i n n e a r l y q u a n t i t a t i v e y i e l d (Scheme 1A). Compound (163) underwent smooth Cope rearrangement, when r e f l u x e d i n xylene, to produce the b i c y c l i c dienone (16A), which Was converted i n t o (±)-B-himachalene (159) by a s e r i e s of standard r e a c t i o n s . Li ether-THF , -78°C 2) PhSCu (37) 161 160 162 163 xylene t reflux 159 Scheme 1A 164 - 58 -The s u b t l e s h i f t from cuprous h a l i d e based organocuprates (P^CuLi) to cuprous cyanide (CuCN) derived species leads to a new c l a s s of h i g h l y r e a c t i v e and thermally s t a b l e reagents of the general 53 45 54 formula R 2 C u ( C N ) L i 2 and RCu(CN)Li. ' The l a t t e r species can be obtained by r e a c t i n g equimolar q u a n t i t i e s of organolithium (RLi) and 53 CuCN, while the former i s prepared by mixing 2 equiv of RLi with 1 equiv of CuCN. Cuprous cyanide i s an e x c e l l e n t source of Cu(I) 53a c o n t a i n i n g a n o n t r a n s f e r a b l e , "dummy" l i g a n d attached to copper. 53a L i p s h u t z o u t l i n e s the advantages of CuCN as f o l l o w s : (a) i t i s f a r l e s s expensive than cuprous i o d i d e ; (b) i t i s not hygroscopic; (c) i t i s qui t e s t a b l e as the Cu ''I) o x i d a t i o n s t a t e ; and,(d) i t i s not l i g h t s e n s i t i v e . 53b The higher order cuprates R^CuCCN^Li^ react w e l l w i t h epoxides, 53a d 53c unactivated secondary a l k y l h a l i d e s ' and enones (equations 38 -40). n - P r ) g C u ( C N ) L i 2 T H F , -20°C ' OH (38) - 59 -(-^pu(CN)Li THF,0°C (39) The r e g i o s e l e c t i v e a d d i t i o n of heterocuprates R Cu(CN)Li to cycloalkene epoxides has been stud i e d e x t e n s i v e l y by Marino (equation r,5 41)." For example, the mixed cyanocuprates RCu(CN)Li (R = Me, Ph) add s t e r e o s e l e c t i v e l y (100% trans) and r e g i o s e l e c t i v e l y (1,4 a d d i t i o n >95%) to the epoxide (165) i n ether at low temperatures, to y i e l d the a l l y l i c a l c o h o l s (166). Although, RCu(CN)Li i s q u i t e e f f e c t i v e f o r the above process, i t does not r i n g open epoxides as w e l l as the higher order cuprates R2Cu(CN)Li2 [see (a) R.D. Acker, Tetrahedron L e t t . 3407 (1977); (b) R.D. Acker, i b i d . , 2399 (1978)]. - 60 -L e v i s a l l e s , i n 1973, reported the conjugate a d d i t i o n of RCu(CN)Li to enones. H i s was a study designed to compare the e f f i c i e n c y of a d d i t i o n of RCu(CN)Li and R 2CuLi to enones under i d e n t i c a l r e a c t i o n c o n d i t i o n s . For example, when Me 2CuLi and MeCu(CN)Li were allowed to react w i t h 2-cyclohexen-l-one s e p a r a t e l y f o r 5 min at -59°C (Cu(I) : enone, 1 : 1 ) , 3-methylcyclohexanone was produced i n y i e l d s of 97% and 44%, r e s p e c t i v e l y . In a paper a p p r o p r i a t e l y t i t l e d "Organocopper conjugate a d d i t i o n r e v i s i t e d " , Noyori described an extremely e f f i c i e n t conjugate a d d i t i o n procedure based on the use of organocopper reagents d e r i v e d from mixing equimolar amounts of cuprous i o d i d e and an organolithium compound with 2-3 eq u i v a l e n t s of t r i - n - b u t y l p h o s p h i n e . The organocopper reagents thus produced react w i t h enones (1 : 1 r a t i o ) i n ether at -78°C -0°C to produce, a f t e r quenching w i t h aqueous ammonium c h l o r i d e , conjugate a d d i t i o n products i n very good y i e l d s . U n l i k e many homo-cuprates these reagents avoid the wastage of one R group. The value of copper-catalyzed conjugate a d d i t i o n of Grignard 57 58 reagents to enones i s w e l l documented. Recently, H e l q u i s t and - 61 -coworkers have developed 5-membered and 6-membered annulation sequences based upon the use of Grignard reagents of the general s t r u c t u r e (168) . 167 168 Treatment of the bromides (169) and (170) with anhydrous magnesium d i c h l o r i d e and potassium i n tetrahydrofuran at room temperature generated the Grignard reagents (171) and (172). When 2-cyclohexen-l-one was allowed to react w i t h (171) and (172) at -78°C i n the presence of 0.25 equiv of copper bromide-dimethylsulfide complex, the conjugate a d d i t i o n products (173) and (174), respectively,were obtained. Exposure of these keto a c e t a l s (173) and (174) to h y d r o c h l o r i c a c i d induced s e q u e n t i a l a c e t a l h y d r o l y s i s , i n t r a m o l e c u l a r a l d o l condensation, and dehydration, thus a f f o r d i n g the b i c y c l i c a n n ulation products (175) and (176) (Scheme 15). - 62 -169 171 173 175 170 172 174 176 Scheme 15 R . Conjugate A d d i t i o n of L i t h i u m P h e n y l t h i o - and Cyano-[2-(4-chloro-1-butenyl)]cuprate to C y c l i c Enones. Subsequent C y c l i z a t i o n of  the Intermediate Chloro Ketones. A f t e r having demonstrated the v i a b i l i t y of A - c h l o r o - 2 - l i t h i o -1-butene (95) as the equivalent of the 1-butene d ,a synthon, the important task at hand was to generate cuprate species from (95) i n order to accomplish the methylenecyclopentane annulation sequence o u t l i n e d i n equation 17. - 63 -(17) I t was d e s i r a b l e to generate heterocuprates of the general s t r u c t u r e (177) r a t h e r than bis-homocuprates (178) , i n order to save one equiv of the b u t e n y l l i t h i u m reagent i n the process. I t was eq u a l l y important to s e l e c t a proper a u x i l i a r y l i g a n d so as to enable us to perform conjugate a d d i t i o n r e a c t i o n s at low temperatures (due to the i n s t a b i l i t y of (95) at temperatures above -48°C). Both phenylthiocopper and cuprous cyanide proved to be u s e f u l non-transferable l i g a n d s , e s p e c i a l l y f o r small s c a l e r e a c t i o n s . A d d i t i o n of s o l i d phenylthiocopper (1 equiv) to a c o l d (-78°C) s o l u t i o n of 4 - c h l o r o - 2 - l i t h i o - l - b u t e n e (95) i n tet r a h y d r o f u r a n y i e l d e d a y e l l o w s l u r r y which was s t i r r e d at -78°C f o r 5 min and at -63°C f o r 15 min to a f f o r d a yellow s o l u t i o n of the l i t h i u m phenylthiocuprate (179). S i m i l a r l y , the cyanocuprate (180) was prepared by adding cuprous cyanide (1 equiv) to a c o l d (-78°C) s o l u t i o n of (95) i n t e t r a -hydrofuran. The yellow s l u r r y thus produced was allowed to react at -78°C f o r 5 min and then at -63°C f o r 15 min to produce a ye l l o w s o l u t i o n of (180). Importantly, reagents (179) and (180) were s u f f i c i e n t l y s t a b l e 179 180 to a l l o w f o r r e a c t i o n w i t h c y c l i c enones, to a f f o r d good to e x c e l l e n t y i e l d s of the corresponding conjugate a d d i t i o n products. S p e c i f i c a l l y , the c y c l i c enones (181) - (186) were allowed to react w i t h tetrahydro-furan s o l u t i o n s of (179) (-78°C, 2-3 h) or (180) (-78°C, 1 h; -48°C, 1.5 h), and the r e s u l t a n t s o l u t i o n s were t r e a t e d w i t h saturated aqueous ammonium c h l o r i d e , to produce the chloro ketones (187) - (192). These chloro ketones, when t r e a t e d w i t h potassium hydride i n tetrahydrofuran at room temperature, were converted i n t o the annulated products (193) -(198). The r e s u l t s of t h i s o v e r a l l methylenecyclopentane annulation - 65 -are summarized i n Table IV. In a l l cases s t u d i e d , the annulation sequence was q u i t e e f f i c i e n t and experimentally s t r a i g h t f o r w a r d . I n t e r e s t i n g l y , the p h e n y l t h i o - and cyanocuprates ((17 9) and (180), r e s p e c t i v e l y ) gave comparable y i e l d s i n the conjugate a d d i t i o n process. One minor d i f f i c u l t y arose when i t was found that treatment of 3-methyl-2-cyclopenten-l-one (185) w i t h e i t h e r of the reagents (179) or (180), under the c o n d i t i o n s described above, f a i l e d to produce the d e s i r e d a d d i t i o n product. However, t h i s s i t u a t i o n was remedied when the s o l u t i o n c o n t a i n i n g reagents (179) and (180) were t r e a t e d w i t h approximately 1 equiv of boron t r i f l u o r i d e - e t h e r a t e p r i o r t o a d d i t i o n of the enone 59 (185). Under these c o n d i t i o n s the conjugate a d d i t i o n r e a c t i o n proceeded smoothly (reagent (179), -48°C, 1 h; -20°C, 1 h; reagent (180), -78°C, 2 h). In each case, the cyclopentane d e r i v a t i v e (191) was obtained i n e x c e l l e n t y i e l d . In each case, the crude product obtained a f t e r the a d d i t i o n of the reagents (179) and (180) to the enones (181) - (186) c o n s i s t e d 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. These m a t e r i a l s were separated e a s i l y by s u b j e c t i o n of the crude mixture to column chromatography on s i l i c a g e l ( e l u t i o n w i t h petroleum e t h e r - e t h e r ) . On r a r e occasions, the crude products obtained a f t e r workup (from both (179) and (180)) contained a small amount (2-4%) of a by-product. This compound, which was r a t h e r non-polar, e l u t e d almost w i t h the solvent f r o n t upon column chromatography (on s i l i c a gel) of the crude product ( e l u t i o n w i t h petroleum e t h e r ) . The same product was obtained e x c l u s i v e l y by d e l i b e r a t e l y a l l o w i n g s o l u t i o n s of each of the cuprate reagents (179) and (180) to warm to room temperature. Based on the f o l l o w i n g s p e c t r a l data, t h i s substance was c h a r a c t e r i z e d - 66 -TABLE IV. Preparation of methylenecyclopentane annulation products En one Conjugate A d d i t i o n Annulation Product Product and Y i e l d , % a' b and Y i e l d , % b (j) (1^ 1) (—} 8 3' 8 0 ( 1 9 3 ) 7 5 o o ( j f ( i 8 2 ) ^H-\f — } 7 7 ' 7 8 ( — } 7 5 0 ,C. 0 H (Ml) Q.,,/ (il9) 75, 77 9, _ Q \ (185) ^ ^° (191) 80C,78C ^ > H (195) 68 (i8«) (—) 7 7'7 5 (~ 7 5 (197) 70d Cf)=o (186) CjC^ 0 (192) 70» 72 03=° (198) 65 The appropriate enone (1.2 equiv) was allowed to react i n tetrahydro-furan w i t h 1.0 equiv of reagent (179) (-78CC, 2-3 h) or (180) (-78°C, 1 h; -A8°C, 1.5 h ) . In each case, the two y i e l d s r e f e r to those obtained by the use of reagents (179) and (180), r e s p e c t i v e l y . b Y i e l d r e f e r s to the p u r i f i e d , d i s t i l l e d product. C In these cases, i t was necessary to c a t a l y z e the r e a c t i o n s w i t h boron t r i f l u o r i d e - e t h e r a t e . d In t h i s case, the r e a c t i o n was not complete a f t e r 2.5 h, and the mixture was th e r e f o r e s t i r r e d f o r an a d d i t i o n a l 5 h. - 67 -as the coupling product (199). 45 For example, the mass + spectrum of (199) showed the molecular i o n ( M ) at m/e 178. The i r spectrum of (199) showed peaks at 1595 and 900 cm"1. The 80 MHz *H nmr spectrum e x h i b i t e d a broad t r i p l e t at 6 2.75 ( J = 7 Hz) f o r the a l l y l i c methylene protons. Furthermore, the t r i p l e t at 6 3.62 ( = 7 Hz) was a t t r i b u t e d to the - C ^ C l protons while the o l e f i n i c protons appeared as a p a i r of s i n g l e t s (2H each) at 6 5.25 and 6 5.40. The g l c and the t i c analyses of the c h l o r o ketones (187), (189), (191), and (192) i n d i c a t e d that they c o n s i s t e d of e s s e n t i a l l y one component. 199 187 189 191 192 - 68 -Furthermore, the s p e c t r a l data ( i r , *H nmr, h i g h - r e s o l u t i o n mass) agreed w e l l w i t h the assigned s t r u c t u r e s . For example, the i r spectrum of (191) showed a carbonyl absorption at 1730 cm ^. Furthermore, the 80 MHz *H nmr spectrum of (191) e x h i b i t e d a s i n g l e t at 6 1.18 f o r the t e r t i a r y methyl group. A d d i t i o n a l l y , the a l l y l i c methylene protons appeared as a broad t r i p l e t at 6 2.55 ( J = 7.4 Hz) w h i l e the -CH^Cl protons gave r i s e to a t r i p l e t at 6 3.63 (J = 7.4 Hz). The proton H (6 4.88) which appeared as a t r i p l e t e x h i b i t e d a l a r g e r value (1 Hz) as compared to H_ which showed a s i n g l e t at 6 4.98. Not unexpectedly, each of the products (188) and (190) were found to c o n s i s t of a mixture of two epimers. A c c o r d i n g l y , g l c a n a l y s i s of (188) showed the r a t i o of the two isomers to be 96 : 4. This observation was supported by the H^ nmr spectrum of (188) , i n which the secondary methyl groups of the two epimers gave r i s e to a p a i r of doublets ( r a t i o -96 : 4, J = 6 Hz i n each case) at 6 1.00 and 6 0.95, r e s p e c t i v e l y . On the other hand, based on g l c a n a l y s i s , (190) was a 3:2 mixture of two components. In the ^H nmr spectrum of t h i s m a t e r i a l , the secondary methyl groups of the two isomers produced two doublets ( r a t i o ~3 : 2, - 69 -J = 7 Hz i n each case) at 6 0.95 and. 6 1.07, r e s p e c t i v e l y . Although the annulated products obtained a f t e r the c y c l i z a t i o n of the r e s p e c t i v e chloro ketones were devoid of any s t a r t i n g m a t e r i a l , they were a l s o subjected to column chromatography on s i l i c a g e l ( e l u t i o n w i t h petroleum e t h e r - e t h e r ) , i n order tro separate the yellow c o l o r e d i m p u r i t i e s that were u s u a l l y present i n the crude product. The s p e c t r a l p r o p e r t i e s of these compounds corroborated w e l l w i t h the proposed s t r u c t u r e s . For example, compound (197) showed a carbonyl absorption at 1712 cm * i n i t s i r spectrum. The highest f i e l d s i n g l e t (<5 1.27) i n 196 195 197 198 193 the 400 MHz *H nmr spectrum of (197) was assigned to the t e r t i a r y methyl group. The proton H^ appeared as a m u l t i p l e t at 6 2.45-2.56 while the lowest f i e l d s i g n a l ( m u l t i p l e t , 6 4.90-4.98) was a t t r i b u t e d to the o l e f i n i c protons. On the b a s i s of l i t e r a t u r e p r e c e d e n t , ^ there i s l i t t l e doubt that k i n e t i c a l l y c o n t r o l l e d i n t r a m o l e c u l a r a l k y l a t i o n s of the chloro ketones (187) - (192) w i l l provide b i c y c l i c (or t r i c y c l i c ) products possessing c i s - f u s e d r i n g systems. In theory, products (193), (195), (197) and (198) could have undergone subsequent e p i m e r i z a t i o n . However, - 70 -trans-fused bicyclo[3.3.0]octane systems are very s t r a i n e d and, there-f o r e , the stereochemistry of each of compounds (195), (197) and (198) i s undoubtedly as shown i n s t r u c t u r a l formulas. In the case of compound (193), the f o l l o w i n g *H nmr data appear to i n d i c a t e that i t i s a l s o c i s - f u s e d . For example, the doublet of t r i p l e t s (J = 8, 6 Hz) at <5 2.73 was assigned to H„ while the broad s i g n a l (W, = 14 Hz) at 6 2.97 was B -5 a t t r i b u t e d to H.. I f i n f a c t H. and H„ are t r a n s , one would expect A A B them to d i s p l a y a value l a r g e r than 8 Hz. However, the l a r g e s t c o u p l i n g constant a s s o c i a t e d w i t h H,, i s 8 Hz, thus i n d i r e c t l y supporting the B presence of a c i s - r i n g j u n c t i o n i n (193). Admittedly, the methylenecyclopentane a n n u l a t i o n sequence o u t l i n e d above would be p a r t i c u l a r l y a t t r a c t i v e i f one could accomplish i t by way of a "one-pot" process, without the i s o l a t i o n of the intermediate chloro ketone. In t h i s connection, a d d i t i o n of 1.5 equiv of hexamethyl-phosphoramide to the c o l d (-78°C) s o l u t i o n s derived from the a d d i t i o n of the phenylthiocuprate (179) to the enones (181) and (183) , followed by warming the r e s u l t a n t mixtures to room temperature and f u r t h e r r e a c t i o n at t h i s temperature f o r another 3 h, provided d i r e c t l y the annulated products (193) and (195) i n 55 and 60%, r e s p e c t i v e l y (equations 42 and 43). However, when each of the r e a c t i o n mixtures obtained from the a d d i t i o n of the phenylthiocuprate (179) to the enones (182), (184) and (185) was subjected to the same r e a c t i o n c o n d i t i o n s as above, product a n a l y s i s (by g l c ) i n d i c a t e d that the annulated products (194), (196) and (197) (70-85%) and a considerable amount (15-30%) of the u n c y c l i z e d chloro ketones (188), (190) and (191) were present i n the crude m a t e r i a l obtained a f t e r workup (equations 44 - 4 6 ) . These r e s u l t s i m p l i e d t h a t , when d e a l i n g w i t h s u b s t i t u t e d enones, the two-step - 71 -182 194 81% 188 19% - 72 -annulative procedure would be more e f f i c i e n t i n comparison w i t h the more appealing "one-pot" process. Be that as i t may, there was s t i l l great promise i n t h i s o v e r a l l a n n ulation sequence which warranted i t s a p p l i c a t i o n toward syn t h e s i s of n a t u r a l products. - 73 -I I I T o t a l Synthesis of the Linear Triquinane Sesquiterpenoid 9 C12") (±)-A v '-Capnellene A. I n t r o d u c t i o n Soft c o r a l s ( a l c y o n a r i n s ) are marine s e s s i l e c o e l e n t e r a t e s which belong to the subclass O c t o c o r a l l i a » The a b i l i t y of these organisms to ward o f f a l g a l and m i c r o b i a l growth i s a w e l l known 61 phenomenon. Chemical s t u d i e s have confirmed the s p e c u l a t i o n that 62 s o f t c o r a l s might produce novel organic compounds. During the l a t e 63 1970's, D j e r a s s i reported the s t r u c t u r a l e l u c i d a t i o n of f i v e sesquiterpene a l c o h o l s (200)-(204) and two hydrocarbons (205) and (206), a l l i s o l a t e d from the s o f t c o r a l Capnella i m b r i c a t a (Quoy and Gaimard 1833), c o l l e c t e d o f f the coast of Sewaru, L e t i I s l a n d , Indonesia and Liang I s l a n d l o c a t e d on the north coast of New Guinea. The s t r u c t u r e s of the a l c o h o l s (200)-(204) and the hydrocarbon (205) are based on the 9(12) s e s q u i t e r p e n o i d s k e l e t o n , capnellane (A). The hydrocarbon (-)-A capnellene (205) may indeed be the b i o g e n e t i c precursor of the a f o r e s a i d sesquiterpene a l c o h o l s . 9(12) The sesquiterpene hydrocarbon A -capnellene (205) has 64 captured the imagination of many s y n t h e t i c organic chemists. The r e s u l t s of some of the c r e a t i v e approaches toward the synthesis of t h i s substance are summarized below. 64a b 64c L i t t l e ' and Paquette reported c o n c u r r e n t l y , i n 1981, t h e i r syntheses of (+)-(205). L i t t l e ' s s o l u t i o n to the problem u t i l i z e d a 1 , 3 - d i y l t r a p p i n g r e a c t i o n as the c r u c i a l step of the s t r a t e g y . Despite the rather low o v e r a l l y i e l d of t h i s s y n t h e t i c sequence, i t must be noted that s e v e r a l new features of the d i y l - 74 -200 R3=R5=R4=H-, R = R8=0H A 201 R3=R4=H-,R2:R5:RB=0H 202 R*.RS.RtH» R3=R8:0H 203 R 2^R 5=HS R5=R8--R4=OH 204 R2=R3=R"H? R5.R8= OH 206 205 trapping r e a c t i o n were discovered during the course of h i s s t u d i e s . The diazene (207) was synthesized i n a s t r a i g h t f o r w a r d manner from r e a d i l y a v a i l a b l e s t a r t i n g m a t e r i a l s . When a tetrahydrofuran s o l u t i o n of the diazene (207) was heated at r e f l u x , a mixture of o l e f i n s (208)-(210) was obtained (1.6:1:6, r e s p e c t i v e l y ) . Subjection of the mixture to a h y d r o b o r a t i o n - o x i d a t i o n sequence provided a mixture of ketones (211) , (212) and (213), i n i s o l a t e d y i e l d s of 15, 6 and 40%, r e s p e c t i v e l y . 9(12) W i t t i g o l e f i n a t i o n of the ketone (211) , gave (±)-A -capnellene, thus confirming the e l s , a n t i , c i s r i n g - f u s e d nature of the former - 75 -207 208 209 210 2 0 8 , 2 0 9 , 2 1 0 ^ ^ 3)PCC 211 212 213 64c substance. The synthesis of (±)-(205) by Paquette"""" i n v o l v e d the successive annulation of two of the three f i v e membered r i n g s onto a p r e - e x i s t i n g cyclopentenylcarboxaldehyde. Conversion of the cyclopentenylcarbox-aldehyde (214) i n t o the v i n y l c a r b i n o l f o l l o w e d by o x i d a t i o n of the l a t t e r m a t e r i a l gave the somewhat unstable dienone (215). Nazarov c y c l i z a t i o n of (215) provided the enone (216) which was conveniently transformed i n t o the trimethylbicyclo[3.3.0]octanone (217), by conjugate 205 Scheme 16 222 - 77 -a d d i t i o n of l i t h i u m dimethylcuprate. Upon condensation w i t h l i t h i u m a c e t y l i d e , (217) gave the propargyl a l c o h o l (218) . Rupe rearrangement of (218) gave r i s e to the l e s s e r s u b s t i t u t e d enone (219). Reaction of (219) w i t h vinylmagnesium bromide i n the presence of cuprous i o d i d e i n tetrahydrofuran at -78°C, provided a s i n g l e compound possessing s t r u c t u r e (220). The r e l a t i v e stereochemistry of the v i c i n a l a c e t y l and v i n y l s u b s t i t u e n t s i n (220) were not r i g o r o u s l y e s t a b l i s h e d at t h i s p o i n t . Ozonolysis of (220) followed by s u b j e c t i o n of the r e s u l t a n t keto aldehyde (221) to a l d o l condensation and dehydration gave (222). C a t a l y t i c hydrogenation of (222) , f ollowed by W i t t i g o l e f i n a t i o n , 9(12) f u r n i s h e d (±)-A v -capnellene (205) (Scheme 16). Oppolzer's ingenious s y n t h e s i s ^ ' * of (±)-(205) centered about two i n t r a m o l e c u l a r "magnesium-ene" processes (Scheme 17). The a l l y l i c c h l o r i d e (223) was prepared i n short order by a l l o w i n g v i n y l l i t h i u m to react w i t h the known aldehyde (224), followed by treatment of the r e s u l t i n g a l l y l i c a l c o h o l w i t h t h i o n y l c h l o r i d e at room temperature. Slow a d d i t i o n of (223) to a s t i r r e d suspension of magnesium powder i n ether at room temperature, h e a t i n g of the thus obtained 2-alkenylmagnesium c h l o r i d e s o l u t i o n at 60°C f o r 23 h, and subsequent a d d i t i o n of a c r o l e i n (2 equiv, -10°C room temperature) afforded the cyclopentane d e r i v a t i v e (225). I t should be noted i n passing that t h i s c r u c i a l step (223) -> (225) invo l v e d the f i r s t reported s u c c e s s f u l "magnesium-ene" a d d i t i o n to a non-activated 1 , 1 - d i s u b s t i t u t e d o l e f i n , thereby c l o s i n g the s t e r i c a l l y congested C-4, C - l l bond [see (225)] w i t h high stereochemical c o n t r o l . The a l l y l i c c h l o r i d e (226) was obtained as a s i n g l e stereoisomer upon r e a c t i o n of (225) with t h i o n y l c h l o r i d e , thus s e t t i n g the stage f o r the second "magnesium-ene" r e a c t i o n . When the Grignard reagent Scheme 17 - 79 -prepared from (226) (magnesium powder, ether, room temperature) was s t i r r e d at room temperature f o r 20 h, c y c l i z a t i o n proceeded smoothly, to a f f o r d , a f t e r t r a p p i n g w i t h a 3:2 mixture of the stereoisomeric a l c o h o l s (227). Oxidation of the primary a l c o h o l s (227) to the corresponding c a r b o x y l i c a c i d s , followed by r e a c t i o n of the l a t t e r substances with m e t h y l l i t h i u m afforded the methyl ketones (220). The f i n a l transformations [(220) -»• (205)] were patterned a f t e r the s y n t h e t i c p r o t o c o l p r e v i o u s l y used by Paquette i n h i s s y n t h e s i s of (±)-(205). Not s u r p r i s i n g l y , the c r i t i c a l a l d o l condensation of (221) transformed both isomers i n t o the c i s , a n t i , c i s - t r i q u i n a n e (222) , v i a based-induced e p i m e r i z a t i o n at C-6 and/or at C-10. 9(12) B. T o t a l Synthesis of (±)-A -Capnellene 9(12) The s y n t h e t i c planning f o r the t o t a l s ynthesis of (±)-A capnellene was somewhat s i m p l i f i e d by the f a c t that the target had been chosen w i t h two key steps i n mind. R e t r o s y n t h e t i c a n a l y s i s of capnellene made i t abundantly c l e a r that one could assemble the molecule e x p e d i t i o u s l y v i a the s y n t h e t i c combination of substances eq u i v a l e n t to synthons (85), (228) and (229) (equation 47). E q u a l l y apparent was the l o g i c that w h i l e the nove l cuprate reagents (179) or (180) could serve d i r e c t l y as e f f i c i e n t e q u i v a l e n t s to the 1-butene 2 4 d ,a synthon (85), proper s y n t h e t i c manipulation (e.g. cyclopropanation-hydrogenolysis) of the double bond i n (85) would make cuprate reagents 2 4 (179) and (180) equivalent to the 2-methylbutane d ,a synthon (229) as w e l l . - 80 -* r 'Of (47) 205 85 228 229 l79,X=5Ph I807X = CN .a .a d or 85 229 A p o t e n t i a l equivalent to the synthon (228) i s 2-methyl-2-cyclo-penten-l-one (184). Subjection of t h i s m a t e r i a l to the methylenecyclo-pentane annulation would a f f o r d the b i c y c l i c ketone (196) , which upon cyclopropanation-hydrogenolysis would provide the ketone (230). Pr e p a r a t i o n of the enone (231) from- (230) would then set the stage f o r - 81 -the second methylenecyclopentane annulation. Successful a d d i t i o n of e i t h e r cuprate [ (179) or (180)] followed by c y c l i z a t i o n , would produce the t r i c y c l i c ketone (232). F i n a l l y , deoxygenation of the ketone 9(12) f u n c t i o n a l i t y on the c e n t r a l r i n g would f u r n i s h (±)-A -capnellene (205) (Scheme 18). H < 205 Scheme 18 - 82 -At the outset, i t was c l e a r that success of the whole e x e r c i s e would r e s t h e a v i l y on our a b i l i t y to prepare s u f f i c i e n t q u a n t i t i e s of the keto o l e f i n (196). I t was soon discovered that cuprates (179) and (180) were not e n t i r e l y s u i t a b l e f o r the l a r g e s c a l e p r e p a r a t i o n of (196). R e p r o d u c i b i l i t y of the y i e l d of the conjugate a d d i t i o n product (190) obtained a f t e r the r e a c t i o n of (179) or (180) w i t h (184) was problematic, since the y i e l d s ranged from 10-80%. This d i f f i c u l t y i m p l i e d that a l t e r n a t i v e r e a c t i o n c o n d i t i o n s should be i n v e s t i g a t e d . The conjugate a d d i t i o n of organomagnesium species to enones i n the presence of a c a t a l y t i c amount of cuprous i o n i s q u i t e a v i a b l e 57 58 process. ' Thus, we turned our a t t e n t i o n to the formation of the corresponding Grignard reagent (233) from the l i t h i o species (95). To t h i s end, s o l i d , anhydrous magnesium bromide was added to a c o l d (-78°C), tetr a h y d r o f u r a n s o l u t i o n of the b u t e n y l l i t h i u m reagent (95). When the r e s u l t i n g c l e a r s o l u t i o n was allowed to r e a c t w i t h 2-methyl-2-cyclopenten-1-one (184) i n the presence of copper bromide-dimethylsulfide complex 59 (0.25 equiv) and boron t r i f l u o r i d e - e t h e r a t e (1 e q u i v ) , the chloro ketone (190) was produced i n 80% y i e l d (equation 48). Furthermore, t h i s method was s u i t a b l e f o r the l a r g e s c a l e p r e p a r a t i o n of (190). For example, when 1.9 mmol of the l i t h i o species was subjected to the above r e a c t i o n c o n d i t i o n s the conjugate a d d i t i o n product (190) was obtained, q u i t e c o n s i s t e n t l y , i n -80% y i e l d . Thus, by means of s e v e r a l r e p e t i t i o n s of the r e a c t i o n on the same s c a l e , i t was p o s s i b l e to accumulate a considerable amount of the chloro ketone (190). Upon exposure to potassium hydride (2.5 equiv) i n tetrahydrofuran at room temperature, compound (190) c y c l i z e d smoothly to provide the b i c y c l i c ketone (196) (equation 49). - 83 -0 (49) 190 196 The H nmr spectrum of the keto o l e f i n (196) was c o n s i s t e n t w i t h the proposed 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 6 1.12 while the proton showed a broad s i g n a l at 6 2.75. The two 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 A.95. The i r spectrum of (196) showed an absorption at 1730 cm \ i n d i c a t i n g the presence of the carbonyl group. The next step i n the synt h e s i s was to convert the e x o c y c l i c - 84 -double bond of (196) i n t o a c y c l o p r o p y l group. In 1968, Furukawa and c o - w o r k e r s ^ published a report concerning the cyclopropanation of alkenes using diethylzinc-methylene i o d i d e . In view of the w e l l known high s e n s i t i v i t y of d i e t h y l z i n c toward oxygen, these cyclopropanation r e a c t i o n s were c a r r i e d out under a n i t r o g e n atmosphere. I r o n i c a l l y , three years l a t e r , M i y a n o ^ discovered that cyclopropanation of o l e f i n s by the diethylzinc-methylene i o d i d e system was g r e a t l y a c c e l e r a t e d by oxygen. Since then, the Miyano m o d i f i c a t i o n of t h i s cyclopropanation procedure has been used i n organic s y n t h e s i s w i t h •A v , 6 7 a considerable success. When the keto o l e f i n (196) was heated w i t h diethylzinc-methylene iod i d e i n toluene at 60°C, i n an atmosphere of dry a i r , the correspond-i n g keto cyclopropane (234) was produced, but i n low y i e l d (about 25-30%) (equation 50). C a p i l l a r y g l c a n a l y s i s of the crude product obtained a f t e r workup i n d i c a t e d the presence of higher r e t e n t i o n - t i m e by-products along w i t h the d e s i r e d compound (234). Although, these by-products were not i s o l a t e d and c h a r a c t e r i z e d , i t seemed l i k e l y t h at they were formed due to the r e a c t i o n of the ketone f u n c t i o n i n (196) w i t h the cyclopropanating agent. C l e a r l y , t h i s problem warranted c o n s i d e r a t i o n of a l t e r n a t i v e plans f o r the p r e p a r a t i o n of (234). S p e c i f i c a l l y , i t was f e l t that the corresponding a l c o h o l (235) obtained by the reduction of the keto o l e f i n (196), might be a b e t t e r substrate f o r the cyclopropanation r e a c t i o n . Subsequent hydrogenolysis of the cyclopropane r i n g i n (236) followed by o x i d a t i o n of the r e s u l t a n t a l c o h o l (237) would produce the corresponding ketone (230). Treatment of the keto o l e f i n (196) w i t h l i t h i u m aluminum hydride i n dry ether at -78°C a f f o r d e d , a f t e r workup w i t h saturated aqueous - 85 -Et2Zn-CH2l2 toluene, dry air,60 C (50) 196 234 ammonium c h l o r i d e , a mixture (87 : 13 by g l c ) of a l c o h o l s (235) i n 95% y i e l d (equation 51). 196 LiAiH 4 ether, -78 C (51) 235 The i r spectrum of (235) showed the re q u i r e d 0-H s t r e t c h i n g absorption at 3320 cm G r a t i f y i n g l y , the cyclopropanation of the o l e f i n i c a l c o h o l (235) proceeded c l e a n l y and smoothly under the c o n d i t i o n s described above to a f f o r d the t r i c y c l i c a l c o h o l (236) i n 76% y i e l d (equation 52). C a p i l l a r y g l c a n a l y s i s of (236) i n d i c a t e d that i t was an 88 : 12 mixture of two components. The i r spectrum of (236) showed bands at 3350 and 3045 cm ^ (O-H and cyclopropyl-hydrogen s t r e t c h i n g - 86 -(52) absorptions, r e s p e c t i v e l y ) . Furthermore, the c y c l o p r o p y l protons of (236) gave r i s e to a m u l t i p l e t at 6 0.28 - 0.48 i n i t s - nmr spectrum. 67b Hydrogenolysis of the l e a s t hindered c y c l o p r o p y l bond of (236) was accomplished by treatment of a s o l u t i o n of the former substance i n g l a c i a l a c e t i c a c i d w i t h a c a t a l y t i c amount of platinum oxide under an atmosphere of hydrogen (2.5 atm). The t r i m e t h y l b i c y c l o -[3.3.0]octanol (237) thus produced ( i n 95% y i e l d ) was o x i d i z e d to the corresponding ketone (230) by treatment of the former substance w i t h 68 p y r i d i n i u m chlorochromate i n the presence of sodium acetate (equation 53). The nmr spectrum of (230) showed three sharp s i n g l e t s at 236 237 230 - 87 -6 0.90, 1.05 and 1.19 f o r the three t e r t i a r y methyl groups while the i r spectrum e x h i b i t e d the ketone carbonyl absorption band at 1720 cm In order to carry out the second methylenecyclopentane annulation sequence, i t was necessary to convert the ketone (230) i n t o the enone (231). A perusal of the l i t e r a t u r e i n d i c a t e s that there are many methods f o r the conversion of a ketone i n t o the corresponding enone. One of the general approaches to a,B-unsaturated ketones i n v o l v e s 69 d i r e c t dehydrogenation of the corresponding saturated ketone. However, u n s a t i s f a c t o r y y i e l d s of the des i r e d enones are commonly encountered i n many of these methods. On the other hand, i n d i r e c t methods 7^ ^ f o r the conversion of a ketone i n t o an enone are c l e a r l y more v i a b l e since they impart considerable p r e p a r a t i v e r e s p e c t a b i l i t y to t h i s process. Common to a l l these approaches i s the f a c t that they take no l e s s than two steps to c a r r y out the o v e r a l l t ransformation. Two of the methods t h a t are q u i t e f r e q u e n t l y used i n v o l v e conversion of the saturated ketone i n t o the corresponding enolate anion and treatment of the l a t t e r species w i t h e i t h e r bromine or ph e n y l s e l e n y l c h l o r i d e . The a-bromide obtained i n the former case can be dehydrobrominated to produce the corresponding enone by treatment w i t h l i t h i u m carbonate i n dimethylformamide. 7^ On the other hand, the a-phenylselenide produced i n the l a t t e r case, i s o x i d i z e d w i t h a p e r a c i d to the corresponding selenoxide which e i t h e r e l i m i n a t e s d i r e c t l y or upon heating to a l s o produce the corresponding 71 enone. 72 In 1978,Saegusa and co-workers published a v e r s a t i l e procedure f o r the prep a r a t i o n of a,B-unsaturated carbonyl compounds (238) by the r e a c t i o n of s i l y l enol ethers (239) w i t h p a l l a d i u m ( I I ) - 88 -acetate i n a c e t o n i t r i l e (equation 54). The intermediate o x o - n - a l l y l -p a l l a d i u m ( I I ) complex (240) may be in v o l v e d i n t h i s r e a c t i o n . RCH2CH=CR OSiMej Pd(OAc), R—C< ;HCH2R ^ • Q A c RCH=CHCR (54) II 0 239 240 238 A l l three of the two-step methods o u t l i n e d above, can be perceived to be a p p l i c a b l e to the conversion of (230) i n t o (231). However, c o n s i d e r a t i o n was given to Saegusa's procedure, i n view of i t s s u p e r i o r y i e l d s and r e l a t i v e l y s t r a i g h t f o r w a r d experimental procedure. To t h i s end, the s i l y l e nol ether (241) was prepared by treatment of a s o l u t i o n of the b i c y c l i c ketone (230) i n methylene c h l o r i d e 74 with t r i m e t h y l s i l y l i o d i d e i n the presence of excess t r i e t h y l a m i n e at -78°C (equation 55). 230 241 - 89 -1 The 400 MHz H nmr spectrum of the crude t r i m e t h y l s i l y l enol ether (241) , i s o l a t e d a f t e r workup w i t h saturated aqueous sodium, bicarbonate, e x h i b i t e d a 9-proton s i n g l e t at 6 0.20 f o r the t r i m e t h y l s i l y l (-SiMe^) protons and a one proton t r i p l e t at 6 4.37 ( J = 2.5 Hz) f o r the H^ proton. Treatment of the crude (241) w i t h 1.2 equiv of p a l l a d i u m ( I I ) acetate i n dry a c e t o n i t r i l e f u r n i s h e d the a,g-unsaturated ketone (231) [74% from (230)] (equation 56). The i r spectrum of (231) showed a carbonyl s t r e t c h i n g band at 1675 cm"1. The doublet of doublets at 6 6.13 (J = 6, 2.6 Hz) i n the 400 MHz 1H nmr spectrum of (231) was assigned to H z > while the lowest f i e l d s i g n a l (doublet of doublets at 6 7.13, J_ = 6, 3.6 Hz) was a t t r i b u t e d to the proton H^. On the b a s i s of s t e r i c c o n s i d e r a t i o n s , conjugate a d d i t i o n of a n u c l e o p h i l i c species to the enone (231) would be expected to take place from the convex s i d e of the molecule. Indeed, when the Grignard reagent (233) prepared from the corresponding b u t e n y l l i t h i u m (95), was allowed to react w i t h the enone (231), i n the presence of copper bromide-dimethylsulfide (0.25 equiv) at -78°C, a s i n g l e conjugate - 90 -a d d i t i o n product (242) was produced i n 79% y i e l d (equation 57). As expected, potassium hydride induced c y c l i z a t i o n of the chloro ketone (242) proceeded smoothly to a f f o r d the t r i c y c l i c ketone (232) i n 86% y i e l d (equation 58). The i r spectrum of (232) showed a carbonyl absorption at 1720 cm *. The 400 MHz "^H nmr spectrum of (232) e x h i b i t e d a doublet of doublet of doublets at 6 2.74 ( J = 10, 8, 4 Hz) f o r H^ and a broad doublet at 6 2.92 ( J = 10 Hz) f o r Hy. The o l e f i n i c protons gave r i s e to a p a i r of m u l t i p l e t s at 6 4.91 and 4.99. (57) 233 242 KH, THF 0 (58) 242 232 - 91 -With the de s i r e d l i n e a r t r i q u i n a n e system (232) pr o p e r l y 9(12) assembled, completion of the t o t a l s ynthesis of (±)-A -capnellene (205) required the removal of the carbonyl group from the c e n t r a l r i n g . The most widely used method f o r d i r e c t l y reducing a ketone to a methylene group i s the Wolff-Kishner reduction. 7"' A recent m o d i f i c a t i o n of the Wolff-Kishner procedure i n v o l v e s reduction of a ketone t o s y l -hydrazone with sodium cyanoborohydride.^ However, the l i t e r a t u r e i n d i c a t e d that a p p l i c a t i o n of these methods to the red u c t i o n of (232) to (205) might be expected to proceed i n low y i e l d . For example, when the tosylhydrazone (243) was reduced w i t h sodium cyanoborohydride, the endo-hirsutene (244) was obtained i n only 8% y i e l d (equation 59) 7^  (59) Consequently, the t r i c y c l i c ketone (232) was reduced to the des i r e d hydrocarbon (205) v i a a sequence of r e a c t i o n s based on a method developed by Barton and co-workers. 7 7 The ketone (232) was tr e a t e d w i t h l i t h i u m aluminum hydride i n dry ether at -78°C to produce the a l c o h o l (245) as a mixture (1 : 1) of epimers. This compound e x h i b i t e d the expected 0-H s t r e t c h i n g absorption at 3350 cm i n i t s i r spectrum. The a l c o h o l (245) was converted i n t o the - 92 -corresponding methyl xanthate d e r i v a t i v e (246) by treatment w i t h sodium hydride i n tetrahydrofuran followed by exposure of the r e s u l t i n g a l koxide anion to carbon d i s u l f i d e and methyl i o d i d e . A s o l u t i o n of the xanthate (246) i n benzene, when t r e a t e d w i t h t r i - n - b u t y l t i n hydride i n the presence of 2 , 2 ' - a z o b i s i s o b u t y r o n i t r i l e (AIBN) at r e f l u x , f u r n i s h e d (±)-A9^12^-capnellene (205) i n 56% y i e l d [from (232)] (Scheme 19). The s y n t h e t i c m a t e r i a l , p u r i f i e d by column chromatography on s i l i c a g e l ( e l u t i o n w i t h petroleum ether) and d i s t i l l a t i o n , e x h i b i t e d s p e c t r a l data 1 1 3 * ( i r , H and C nmr) i d e n t i c a l w i t h those of a sample of (±)-(205). 205 Scheme 19 246 We are very g r a t e f u l to P r o f e s s o r R.D. L i t t l e f o r a sample of (±)-(205) and f o r copies of i r , 1H nmr and 13c nmr of t h i s m a t e r i a l and to Pr o f e s s o r L.A. Paquette f o r s p e c t r a l data of n a t u r a l (205). In summation, the t o t a l s ynthesis of (±)-A -capnellene (205) was achieved i n 10% o v e r a l l y i e l d from 2-methyl-2-cyclopenten-l-one (184). The s y n t h e t i c sequence used i n t h i s s y n t h e s i s amply demonstrated' the v i a b i l i t y of employing the newly developed methylenecyclopentane a n n u l a t i o n method i n the syn t h e s i s of l i n e a r t r i q u i n a n e s . - 94 -IV T o t a l Synthesis of the Angular Triquinane Sesquiterpenoid  (±)-Pentalenene A. I n t r o d u c t i o n A number of' Streptomyces species produce the metabolites penta-78 79 80 lenolactone (2 58), p e n t a l e n i c a c i d (247), pentalenolactones E (248) , G ( 2 4 9 ) , ^ and H (250) ? ^ Recently, the oxygen-free parent of t h i s pentalenolactone f a m i l y of a n t i b i o t i c s was i s o l a t e d from Streptomyces 82 griseochromogenes to possess s t r u c t u r e (251) This n a t u r a l product, (+)-pentalenene, was shown 82 80 83 84 Evidence from s e v e r a l b i o s y n t h e t i c s t u d i e s ' ' i n d i c a t e that pentalenolactone (258) and i t s co-metabolites may a r i s e v i a the c y c l i z a t i o n of humulene (252), w i t h pentalenene (251) s e r v i n g as a ..H 02H 249 - 95 -c r u c i a l intermediate. On t h i s b a s i s , pentalenene (251) i s considered to be b i o g e n e t i c a l l y r e l a t e d to other c l a s s e s of humulene-derived 85 sesquiterpenes. I l l u d o i d sesquiterpenes are suggested to be b i o -s y n t h e t i c a l l y derived from humulene (252) through p r o t o i l l u d y l c a t i o n 8 6 (257) (equation 60). In a b i o g e n e t i c a l l y modelled experiment designed 83 to mimic t h i s process, Matsumoto and co-workers heated the e x o - c y c l i c o l e f i n (254) and the epimeric t e r t i a r y a l c o h o l s (255) i n formic a c i d . In each case, there was i s o l a t e d i n high y i e l d a mixture of the t r i c y c l i c bridged formate (256) and pentalenene (251) i n a 7 : 3 r a t i o (equation 61). — - illudoids (60) The formation of (256) and (251) was c o n v i n c i n g l y i n t e r p r e t e d as being due to two conformations f(257a) and (257b) 1 f o r , the p r o t o i l l u d y l c a t i o n - 96 -83 85 (Scheme 20). ' The favorable s t e r e o e l e c t r o n i c alignment of the l a t e r a l (A) cyclobutane bond w i t h the vacant carbocation o r b i t a l i n (257a) permits a f a c i l e Wagner-Meerwein s h i f t w i t h concomitant capture of formate ion to produce (256). Scheme 20 On the other hand, i n (257b), s t e r e o e l e c t r o n i c f a c t o r s favour the fragmentation of the c e n t r a l cyclobutane bond (B) w i t h a concurrent 1,2 hydride s h i f t to y i e l d the t r a n s - c y c l o o c t e n y l c a t i o n (259). Subsequently, (259) can c y c l i z e to a f f o r d pentalenene (251). I m p l i c i t i n the above r a t i o n a l e f o r the conversion of (257b)„ i n t o (251) i s the f a c t that (because of the s t e r e o d i s p o s i t i o n of the hydride group that migrates) the stereochemistry of the secondary methyl group i n pentalenene (251) becomes f i x e d d u r i n g the process. Consequently, no informa t i o n regarding the more s t a b l e c o n f i g u r a t i o n about t h i s center can be derived from 85 b i o s y n t h e t i c c o n s i d e r a t i o n s . Nevertheless, t h i s data lend considerable credence to the suggested b i o s y n t h e t i c pathway f o r - 97 -pentalenene (251) from humulene (252). A few years a f t e r the f o r t u i t o u s s y n t h e s i s of pentalenene (251) 83 85 by Matsumoto, Paquette reported the f i r s t d i r e c t e d s y n t h e s i s of t h i s n a t u r a l product. C e n t r a l to h i s s y n t h e s i s , which i s shown i n Scheme 21, was the c r u c i a l conjugate a d d i t i o n of l i t h i u m d i - 3 - b u t e n y l -cuprate to the enone (260). Compound (261) was t r e a t e d w i t h methyl-magnesium bromide to produce a p a i r of epimeric c h l o r o h y d r i n s (262) (chromatographically separable). Independent o z o n o l y s i s and a c e t a l formation of (262) l e d to the formation of epimeric c h l o r o h y d r i n s (263). Reductive e l i m i n a t i o n of e i t h e r c h l o r o h y d r i n produced the o l e f i n a c e t a l (264). Treatment of (264) w i t h p y r i d i n i u m t o s y l a t e i n aqueous acetone gave the aldehyde (265). Lewis a c i d c a t a l y z e d P r i n s r e a c t i o n of (265) with s t a n n i c c h l o r i d e i n benzene at 5-10°C and o x i d a t i o n of the r e s u l t a n t endo a l c o h o l a f f o r d e d c l e a n l y the ketone (266). The s y n t h e t i c plan at t h i s p o i n t c a l l e d f o r the formation of the dienone (267), so that the r e q u i r e d secondary methyl group at C-9 could be introduced v i a a conjugate a d d i t i o n r e a c t i o n . The conversion of (266) i n t o (267) was e a s i l y accomplished by means of known methods.^ S u r p r i s i n g l y , a d d i t i o n of l i t h i u m dimethylcuprate to the enone (267) , followed by Wolff-Kishner r e d u c t i o n of the r e s u l t a n t ketone (268), produced (±)-9-epi-pentalenene (269) i n good y i e l d . Thus, d e l i v e r y of the methyl group during the conjugate a d d i t i o n had occurred from the B-face of the molecule. Organocuprate a d d i t i o n s to enones are k i n e t i c a l l y c o n t r o l l e d r e a c t i o n s . Therefore, i n order to o b t a i n information about the r e l a t i v e s t a b i l i t y of (251) and i t s C-9 epimer (269), (268) was converted i n t o (270) v i a a sequence of r e a c t i o n s i d e n t i c a l w i t h that used f o r the - 98 -CuLi 260 MeMgBr THF Py.TsOH H 20)Qceione 265 OSnCl 4,benzene 2)PCC , H | )LDA,PhSeCl 266 264 N a , N H , 267 Me2CuLi | )LDA,PhSeCI 2)H202 263 268 NHgNHg, K 2 C O j 269+ 25! •H OEtsSiH ^P" 3P ) 3 RhCI 2) NHgNHg, 270 269 Scheme 21 - 99 -conversion of (266) to (267). Reduction of the dienone (270) w i t h l i t h i u m i n l i q u i d ammonia, provided e x c l u s i v e l y (268). Based on these observations Paquette came to the conclusion that the C-9 methyl group i n t h i s t r i c y c l i c ketone (268) st r o n g l y p r e f e r s the B-c o n f i g u r a t i o n . He argued f u r t h e r that the non-bonded methyl-hydrogen i n t e r a c t i o n i n (268) must be considerably l e s s than the methyl-hydrogen i n t e r a c t i o n that e x i s t s i n (271). Unexpectedly, when ( P ^ P ^ R h C l / E t - j S i H was used to reduce the enone (270), a mixture (2.24 : 1) of (268) and (271) was produced. F i n a l l y , (i)-pentalenene (251) was obtained as a minor product by Wolff-Kishner reduction of the mixture of ketones (268) and (271) , followed by separation of the two epimers (269) and (251) by p r e p a r a t i v e g a s - l i q u i d chromatography. 87 A very recent s y n t h e s i s of (±)-pentalenene by Pattenden i n v o l v e d , as the key step, t r a n s a n n u l a t i o n of the bicyclo[6.3.0]undeca-From a stereochemical p o i n t of view, metal-ammonia reductions of b i - and p o l y c y c l i c enones g e n e r a l l y provide a large predominance of the thermodynamically more s t a b l e product. The chemical l i t e r a t u r e p o i n t s out s e v e r a l exceptions to t h i s " r u l e " , however (see D. Caine, Organic Reactions, V o l . 23, Chapter 1, John Wiley and Sons, Inc. 1976). - 100 -- 101 -diene (277) (Scheme 22). Thus, a d d i t i o n of Me^CuLi^ to the t r i c y c l i c ketone (273) (prepared from Meldrum's a c i d d e r i v a t i v e (272)) r e s u l t e d i n the stereo-s e l e c t i v e formation of the t e r t i a r y a l c o h o l (274). This compound, upon treatment w i t h h y d r o f l u o r i c a c i d i n aqueous tetrahydrofuran at 25°C, produced the keto o l e f i n (275). W i t t i g o l e f i n a t i o n of (275) afforded (276) , which upon treatment w i t h rhodium c h l o r i d e t r i h y d r a t e was isomerized c l e a n l y to provide (277). Treatment of the 1,5-diene (277) w i t h boron t r i f l u o r i d e etherate i n methylene c h l o r i d e (25°C, 5 min) r e s u l t e d i n a s t e r e o s e l e c t i v e t r a n s a n n u l a t i o n , v i a the carbocation (278), y i e l d i n g (i)-pentalenene (251). I t should be noted that t h i s elegant approach to (±)-(251) circumvents the s t e r e o c h e m i c a l ^ problematic i n t r o -duction of the C-9 methyl group encountered i n the e a r l i e r s y n t h e s i s . B. T o t a l Synthesis of (t)-Pentalenene Upon c l o s e examination of the carbon framework of (±)-pentalenene (251), i t appeared l i k e l y that a major p a r t of the molecule could be assembled by the s y n t h e t i c combination of the d,a synthon (279) w i t h the s u b s t r a t e synthon (280) (equation 62). Such a plan c o u l d , t h e r e f o r e , (62) 280 BrMg 233 279 - 102 -e n t a i l the methylenecyclopentane annulation sequence described e a r l i e r . E x p l i c i t l y , a d d i t i o n of the Grignard reagent (233) to the b i c y c l i c enone (281), i n the presence of copper bromide-dimethylsulfide complex, would be expected to proceed i n the desired stereochemical sense, to produce the corresponding conjugate a d d i t i o n product (282) (equation 63). Presumably, the l a t t e r substance could be c y c l i z e d to a f f o r d the t r i -c y c l i c ketone (283). (63) 233 281 282 283 Paquette's s y n t h e s i s of (251) a l l u d e d to the f a c t that the C-9 methyl group i n pentalenene p r e f e r s to be on the B face of the molecule. I f t h i s i s indeed the case, hydroboration of the e x o c y c l i c double bond of (283), followed by o x i d a t i o n of the r e s u l t a n t primary a l c o h o l and base induced e p i m e r i z a t i o n of the aldehyde thus produced, would give the 8-aldehyde. Wolff-Kishner reduction of the aldehyde would introduce the methyl group at C-9 w i t h the undesired 6-configura-t i o n . On the other hand, c a t a l y t i c hydrogenation of the e x o c y c l i c double bond appeared to be a more a t t r a c t i v e way to introduce the r e q u i s i t e a-methyl group. Such a r e a c t i o n became even more appealing i n view of the methodology planned to introduce the geminal methyl groups - 103 -at C-6. S p e c i f i c a l l y , s u c c e s s f u l methylenecyclopentane annulation on the t r i c y c l i c enone (284) would produce the t e t r a c y c l i c keto o l e f i n (285) (equation 64). Hydrogenolysis-hydrogenation of (285) would not only introduce the geminal methyl groups at C-6, but would a l s o reduce the carbon-carbon double bond. Exposure of the ketone (286) to m e t h y l l i t h i u m f o l lowed by dehydration would then generate the C-2,3 double bond i n the d e s i r e d f a s h i o n . The keto a c e t a l (287) appeared to be a s u i t a b l e s t a r t i n g m a t e r i a l f o r the s y n t h e s i s of the t r i c y c l i c enone (284). This compound could be prepared r e a d i l y by a l l o w i n g equimolar q u a n t i t i e s of the diketone * 88a * (289) , and the b i s - a c e t a l (288) to e q u i l i b r a t e i n benzene, i n the presence of a c a t a l y t i c q u a n t i t y of p - t o l u e n e s u l f o n i c a c i d (equation 65). The mixture of (288), (287) and (289) ( 1 : 2 : 1) thus obtained was e a s i l y separated by column chromatography on s i l i c a g e l ( e l u t i o n w i t h petroleum e t h e r - e t h e r , 2 : 1 ) . S u f f i c i e n t q u a n t i t i e s of the keto a c e t a l (287) prepared i n t h i s manner were used i n the next s e r i e s of transformations. We are very g r a t e f u l to Mr. N e i l Moss f o r a generous supply of compounds (288) and (289). - 104 -The next step i n the syn t h e s i s c a l l e d f o r the conversion of the ketone f u n c t i o n a l i t y i n (287) i n t o an e x o c y c l i c double bond, which would l a t e r be transformed i n t o the c y c l o p r o p y l group. Treatment of (287) w i t h a s o l u t i o n of methylenetriphenylphosphorane i n tetrahydrofuran at room temperature a f f o r d e d the o l e f i n i c a c e t a l (290) i n 84% y i e l d , (equation 66). The 400 MHz *H nmr spectrum of t h i s m a t e r i a l e x h i b i t e d a 6-proton s i n g l e t (6 0.96) f o r the t e r t i a r y methyl groups. The o l e f i n i c protons appeared as a t r i p l e t ( J = 2 Hz) at 6 4.81. Consideration was next given to the i n t r o d u c t i o n of the c y c l o -propane r i n g . In our hands, cyclopropanation of the o l e f i n i c a c e t a l (290) using diethylzinc-methylene i o d i d e ^ p r o d u c e d the d e s i r e d m a t e r i a l (291) i n a y i e l d of l e s s than 25%, thus making the r e a c t i o n - 105 -s y n t h e t i c a l l y unacceptable (equation 67). Although the other by-products which appeared i n the crude product mixture along w i t h the d e s i r e d (291) were not i d e n t i f i e d , i t i s l i k e l y that they were formed due to the r e a c t i o n of the a c e t a l f u n c t i o n w i t h the cyclopropanating agent. I t was thus c l e a r that the cyclopropanation had to be performed on e i t h e r the keto o l e f i n (292) or the corresponding a l c o h o l (293). To t h i s end, the a c e t a l group of (290) was removed by a l l o w i n g an acetone s o l u t i o n of the o l e f i n i c a c e t a l to s t i r i n the presence of aqueous s u l f u r i c a c i d (0.1% W/V) (equation 68). The i r spectrum of the keto o l e f i n (292) thus obtained i n 82% y i e l d showed a d i a g n o s t i c carbonyl absorption at 1710 cm ^. I n t e r e s t i n g l y , there was no i n d i c a t i o n of i s o m e r i z a t i o n of the e x o c y c l i c double bond i n (292) under these c o n d i t i o n s . Although we had encountered problems i n attempting the c y c l o -9(12) propanation of an o l e f i n i c ketone i n the synthesis of (±)-A -capnellene (vide supra), i t was n e v e r t h e l e s s thought worthwhile to i n v e s t i g a t e the cyclopropanation of (292) w i t h diethylzinc-methylene i o d i d e . Not unexpectedly, treatment of the keto o l e f i n (292) w i t h (67) r 290 291 - 106 -i-S^f: J l%H2S04-H20 J~\y^ Et2Zn-CH2l2 r~Cl •zL^S— ^ ocetone ** " ^ ^ s / toluene,dry air,55cf — (68) 290 292 295 65 66 diethylzinc-methylene i o d i d e ' i n toluene at 55°C i n the presence of dry a i r produced (295), but i n a y i e l d of only -30%. I t was there f o r e apparent that the cyclopropanation had to be c a r r i e d out on the corresponding a l c o h o l of (292). Reduction of the ketone (292) was accomplished c l e a n l y by a l l o w i n g t h i s compound to react w i t h l i t h i u m aluminum hydride i n ether (equation 69). The r e s u l t i n g a l c o h o l , obtained i n 94% y i e l d , c o n s i s t e d of one component ( c a p i l l a r y g l c a n a l y s i s ) . One would expect t h a t the hydride i o n had been d e l i v e r e d from the more open face of (292), and the r e f o r e the product was assigned the stereo-ether,-78°C 292 293 107 chemistry shown i n (293). The i r spectrum of (293) showed an -0-H s t r e t c h i n g absorption at 3300 cm 1 . A d d i t i o n a l l y , the 80 MHz 1H nmr spectrum of (293) e x h i b i t e d a q u i n t e t at 6 4.12 (J = 6.4 Hz) f o r the -CHOH proton. With ample q u a n t i t i e s of (293) i n hand, cyclopropanation of t h i s a l c o h o l was attempted. F o r t u n a t e l y , cyclopropanation of (293) proceeded smoothly when t h i s m a t e r i a l was exposed to r e a c t i o n c o n d i t i o n s i d e n t i c a l w i t h those described above (equation 70). The r e s u l t i n g t r i c y c l i c a l c o h o l (294), obtained i n 81% y i e l d , e x h i b i t e d i r s t r e t c h i n g absorptions at 3300 and 3050 cm ^  ( f o r the 0-H and the c y c l o p r o p y l protons, r e s p e c t i v e l y ) . The 100 MHz *H nmr spectrum of (294) showed a m u l t i p l e t at 6 0.18-0.64 f o r the four c y c l o p r o p y l protons. r—^I Et2Zn-CH2l2 /—<^ VH (70) ^L^y_j''OH toluene,dry oir,55C* T ^ \ 3 293 294 Treatment of (294) w i t h p y r i d i n i u m chlorochromate i n the presence of sodium acetate produced the t r i c y c l i c ketone (295) i n 87% y i e l d (equation 71). The i r spectrum of t h i s m a t e r i a l e x h i b i t e d a carbonyl s t r e t c h i n g absorp-t i o n at 1725 cm The three-step sequence ( r e d u c t i o n , cyclopropana-t i o n and o x i d a t i o n ) used to convert the keto o l e f i n (292) i n t o the - 108 -H •OH PCC, NaOAc, CH 2CI 2 (71) 294 295 c y c l o p r o p y l ketone (295) produced the l a t t e r m a t e r i a l i n 66% o v e r a l l y i e l d . I t should be noted that the same t r i c y c l i c ketone (295) was produced by d i r e c t cyclopropanation of (292) , but i n r a t h e r low y i e l d In order to ca r r y out the key methylenecyclopentane annulation sequence, we focussed our a t t e n t i o n on the p r e p a r a t i o n of the t r i c y c l i c enone (284). In view of the s u c c e s s f u l i n t r o d u c t i o n of an enone double bond i n t o a cyclopentanone i n our e a r l i e r s ynthesis of method f o r the conversion of (2 95) i n t o (284). Thus, treatment of a s o l u t i o n of the ketone (295) i n methylene c h l o r i d e w i t h f r e s h l y 74 prepared t r i m e t h y l s i l y l i o d i d e i n the presence of excess t r i e t h y l a m i n e at -78°C affo r d e d the s i l y l enol ether (296) (equation 72). Admittedly, the success of the subsequent o x i d a t i o n of (296) w i t h palladium acetate could not be assured due to the s t r a i n e d nature of the double bond being introduced i n (284). To our d e l i g h t , however, treatment of a s o l u t i o n of the crude s i l y l enol ether (296) i n dry a c e t o n i t r i l e w i t h palladium acetate produced, i n 63% o v e r a l l y i e l d from (295), the (-30%). (±)-A 9(12) -capnellene (vide supra), the d e c i s i o n was made to use the same - 109 -desired enone (284). N o t e w o r t h i l y , no s t a r t i n g m a t e r i a l was encountered i n the m a t e r i a l obtained at the end of the r e a c t i o n sequence. In consonance with i t s s t r u c t u r e , the i r spectrum of (284) showed a carbonyl absorption at 1690 cm . Furthermore, the 400 MHz H nmr spectrum of (284) showed a m u l t i p l e t at 6 0.55-0.69 f o r the c y c l o -p r o p y l protons, w h i l e the o l e f i n i c proton appeared as a m u l t i p l e t at 6 6.17. With the p r e p a r a t i o n of the t r i c y c l i c enone (284) , the stage was set f o r e l a b o r a t i o n of the t h i r d five-membered r i n g . Thus, to a co l d (-78°C) s o l u t i o n of 4- c h l o r o - 2 - t r i m e t h y l s t a n n y l - l - b u t e n e (84) i n t etrahydrofuran was added, s u c c e s s i v e l y , m e t h y l l i t h i u m (1.1 e q u i v ) , anhydrous magnesium bromide (1.2 e q u i v ) , copper bromide-dimethylsulfide (0.3 e q u i v ) , and the enone (284) (0.84 e q u i v ) . A f t e r the r e s u l t a n t s o l u t i o n had been s t i r r e d at -78°C f o r 1.5 h, i t was t r e a t e d w i t h saturated aqueous ammonium c h l o r i d e (equation 73). The r e s u l t a n t conjugate a d d i t i o n product (297), obtained i n 83% y i e l d , was homogeneous by both t i c and c a p i l l a r y g l c . The i r spectrum of t h i s m a t e r i a l showed the required carbonyl s t r e t c h i n g absorption at 1735 cm ^. The - 110 -80 MHz *H nmr spectrum of (297) showed a m u l t i p l e t at 6 0.52 f o r the c y c l o p r o p y l protons. A d d i t i o n a l l y , the -CH^Cl protons appeared as a t r i p l e t at 6 3.67 (J = 7.6 Hz). A t r i p l e t at 6 A.90 (J = 1.6 Hz) was a t t r i b u t e d to H while a s i n g l e t at 6 5.02 was assigned to H . (73) The chloro ketone (297) was subjected to i n t r a m o l e c u l a r a l k y l a t i o n w i t h potassium hydride i n tet r a h y d r o f u r a n at room temperature, y i e l d i n g the required angular t r i q u i n a n e system (285) i n 80% y i e l d (equation 7A). The t e t r a c y c l i c ketone (285) showed an i r absorption at 1720 cm f o r the carbonyl group. (7A) 297 285 - I l l -The c r u c i a l hydrogenation-hydrogenolysis of (285) was c a r r i e d out by treatment of a s o l u t i o n of t h i s compound i n g l a c i a l a c e t i c a c i d w i t h hydrogen i n the presence of platinum. The r e s u l t i n g product, formed i n 96% y i e l d , c o n s i s t e d of a mixture of t r i c y c l i c ketones (298) and (299) , i n a r a t i o of 42 :58, r e s p e c t i v e l y (equation 75). Attempts to increase the r e l a t i v e amount of the des i r e d epimer (298) by use of other hydrogenation c o n d i t i o n s proved to be f r u i t l e s s . For example, treatment of a s o l u t i o n of (285) i n hexane with hydrogen (2.5 atm) i n the presence of palladium-on-carbon (which hydrogenated only the double bond), followed by hydrogenolysis of the c y c l o p r o p y l r i n g w i t h hydrogen and platinum, y i e l d e d a 22 : 78 mixture of (298) and (299), r e s p e c t i v e l y . I n t e r e s t i n g l y , hydrogenation-hydrogenolysis of the endocyclic alkene (300) [obtained by a c i d c a t a l y z e d i s o m e r i z a t i o n of (285)] ** (Scheme 23) produced n e a r l y e n t i r e l y the 6-methyl d e r i v a t i v e (299) The stereochemistry of the C-9 methyl group i n (298) and (299) were proved l a t e r by transforming the mixture of (298) arid (299) i n t o (±)-pentalenene (251) and (±)-9-epi-pentalenene (269), r e s p e c t i v e l y . The 95 : 5 mixture of (299) and (298) was l a t e r transformed i n t o (±)-9-epi-pentalenene (269). - 112 -[(299) : (298) - 95 :5; 80% y i e l d from (285)]. 299 298 Scheme 23 In another attempt to c o n t r o l the stereochemistry at C-9, the hydrogenation-hydrogenolysis of the a l c o h o l (301) was i n v e s t i g a t e d . Thus, l i t h i u m aluminum hydride r e d u c t i o n of the t e t r a c y c l i c ketone (285) produced the a l c o h o l (301) as a 20 : 80 mixture of epimers (Scheme 24). On the b a s i s of molecular models, i t appeared that the a t t a c k of the hydride ion on (285) would take place predominantly from the a side of the molecule, thus p r o v i d i n g mainly the g-alcohol. Hence, i t seemed reasonable to assume that the major epimer (80%) was the g-alcohol. - 113 -Subjection of the mixture of a l c o h o l s (301) to hydrogenation-hydrogenolysis us i n g platinum-on-carbon i n hexane, followed by o x i d a t i o n of the r e s u l t a n t a l c o h o l s w i t h p y r i d i n i u m chlorochromate, produced (298) and (299) i n a r a t i o of 45 :55, r e s p e c t i v e l y ( o v e r a l l y i e l d from (285) ~79%). The l a c k of a s i g n i f i c a n t improvement i n the amount of (298) produced (as compared to d i r e c t hydrogenation-hydrogenolysis of (285)) i n the above sequence, made t h i s longer route s y n t h e t i c a l l y u n j u s t i f i a b l e . There are examples i n the l i t e r a t u r e which i n d i c a t e that a hydroxyl group i n clo s e p r o x i m i t y to a double bond can stereochemically d i r e c t hydrogenation of the double bond, p a r t i c u l a r l y when a non-p o l a r solvent i s employed as the r e a c t i o n medium (see CH. Heathcock, R.A. Badger, and J.W. P a t t e r s o n , J. Am. Chem. Soc. _89, 4133 (1967); J.E. McMurry, J . Org. Chem., 36, 2826 (1971)); G.Stork and D.E.Kahne, J . Am. Chem. Soc. 105, 1072(1983). - 114 -I t was c l e a r that d i r e c t hydrogenation of the carbon-carbon double bond i n (285) d i d not b r i n g about high s t e r e o c o n t r o l i n the i n t r o d u c t i o n of the C-9 methyl group. I t was f e l t , however, that i t would be best to complete the d e s i r e d s y n t h e s i s using the 42 : 58 mixture of (298) and (299) [obtained by the hydrogenation-hydrogenolysis of (285) w i t h P t , I ^ j HOAc], since a l t e r n a t i v e methods f o r the i n t r o d u c t i o n of the C-9 methyl group would increase c o n s i d e r a b l y the number of steps i n the o v e r a l l s y n t h e s i s . Furthermore, a l t e r n a t i v e routes would not guarantee good s t e r e o c o n t r o l nor respectable o v e r a l l y i e l d s (see page 102). Treatment of the 42 : 58 mixture of (298) and (299) w i t h m e t h y l l i t h i u m gave the d e s i r e d a l c o h o l (302), but t h i s m a t e r i a l was accompanied by s u b s t a n t i a l amounts of the s t a r t i n g m a t e r i a l s (298) and (299). The f a c t that the a d d i t i o n r e a c t i o n d i d not proceed to completion was, presumably, because enolate anion formation was i n competition w i t h the 89 d e s i r e d process. Exposure of the mixture of (302), (298) and (299) to m e t h y l l i t h i u m l e d to a mixture of a l c o h o l s (302) (~82% by g l c ) , and the s t a r t i n g m a t e r i a l s (298) and (299) (1% and 17%, r e s p e c t i v e l y , by g l c ) (Scheme 25). When a s o l u t i o n of t h i s mixture i n dry benzene c o n t a i n -i n g a s mall amount of p - t o l u e n e s u l f o n i c a c i d was heated at r e f l u x under a Dean-Stark t r a p , there was produced a mixture of compounds c o n t a i n i n g mainly (t)-pentalenene (251) and (±)-9-epi-pentalenene (269). This crude mixture, when subjected t o column chromatography on s i l i c a g e l impregnated w i t h s i l v e r n i t r a t e ( e l u t i o n w i t h petroleum ether) f u r n i s h e d (269) [33% from (299)] and (251) [32% from (298)]. The s p e c t r a l data 1 13 ( i r , H nmr, C nmr) of (l)-pentalenene (251) thus obtained, were i d e n t i c a l i n a l l respects w i t h those reported f o r t h i s m a t e r i a l , - 115 -Scheme 25 synthesized by Paquette . S i m i l a r l y , the s p e c t r a l data of (±)-(269) 85 were i d e n t i c a l w i t h those reported by Paquette. When the 95 : 5 mixture of (299) and (298) [obtained by the red u c t i o n of the e n d o c y c l i c o l e f i n (300) w i t h H^. P t , HOAc] was subjected to an i d e n t i c a l sequence of ope r a t i o n s , (±)-9-epi-pentalenene (269) was obtained i n 68% y i e l d . In summary, the t o t a l s y n t h e s i s of (±)-pentalenene (251) was We are very g r a t e f u l to Profess o r Paquette f o r h i s a s s i s t a n c e i n making t h i s comparison p o s s i b l e . - 116 -accomplished i n 6% o v e r a l l y i e l d from the keto a c e t a l (287). The value of the s y n t h e t i c approach l i e s not only on the v i a b i l i t y of the methylenecyclopentane annulation i n t h i s case, but a l s o i n i t s p o t e n t i a l a p p l i c a t i o n to other angular t r i q u i n a n e s of i n t e r e s t . - 117 -EXPERIMENTAL General M e l t i n g p o i n t s were determined using a Fisher-Johns m e l t i n g po i n t apparatus and are uncorrected. B o i l i n g p o i n t s are a l s o uncorrected and those i n d i c a t e d as a i r - b a t h temperatures r e f e r to short path (Kugelrohr) d i s t i l l a t i o n s . I n f r a r e d ( i r ) s p e c t r a were recorded on a Perkin-Elmer model 710B spectrometer, as l i q u i d f i l m s , and were c a l i b r a t e d w i t h the 1601 cm * band of the polystyrene f i l m . 1 13 Proton and carbon-13 n u c l e a r magnetic resonance ( H and C nmr) spe c t r a were done i n deuterochloroform s o l u t i o n s . The ^ H nmr spectra were recorded using Varian Associates models T-60, HA-100 or XL-100 and Bruker 13 models WP-80 and WH-400 spectrometers. C nmr spectra were recorded on Bruker models WH-400 and WP-80. S i g n a l p o s i t i o n s are given i n 6 u n i t s , w i t h t e t r a m e t h y l s i l a n e (TMS) as the i n t e r n a l standard. In cases of compounds w i t h 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 90 (6 7.25). The m u l t i p l i c i t y , number of protons, c o u p l i n g constants, and assignments (where p o s s i b l e ) are i n d i c a t e d i n parentheses. The t i n - p r o t o n c oupling constants ( J ) are given as an average of the bn—H coupling constants of the two isotopes ( J _ i i 7 g n _ H and ^ 119g n_jj) l j O W r e s o l u t i o n mass spectra were recorded w i t h a Varian/MAT CH4B mass spectrometer while the high r e s o l u t i o n mass spectra were recorded w i t h a Kratos/AEl MS 50 or MS 902 mass spectrometer. In cases of compounds wi t h t r i m e t h y l s t a n n y l groups the molecular weight determinations (high 120 r e s o l u t i o n mass spectrometry) were based on Sn and were made on the - 118 -+ 91 (M -15) peak. A n a l y t i c a l g a s - l i q u i d chromatography ( g l c ) was performed on a Hewlett-Packard model 5832A gas chromatograph using a 6 f t x 0.125 i n s t a i n l e s s s t e e l column packed w i t h 3-5% OV-17 on 80-100 mesh Chromosorb W(HP) (column A) and a thermal c o n d u c t i v i t y d e t e c t o r , or on a Hewlett-Packard model 5880 gas chromatograph using a 25 m x 0.21 mm fused s i l i c a column coated with c r o s s - l i n k e d SE-54 (column B) and a flame i o n i z a t i o n d e t e c t o r . T h i n - l a y e r chromatography ( t i c ) was c a r r i e d out on commercial p l a s t i c - b a c k e d s i l i c a g e l p l a t e s (Eastman Chromatogram Sheet Type 13181) or on aluminum-backed p l a t e s (E. Merck, Type 5554). P r e p a r a t i v e t i c was done on 20 x 20 cm g l a s s p l a t e s coated w i t h 0.7 mm of s i l i c a g e l (E. Merck, S i l i c a Gel 60). Conventional column chromatography was done on 70-230 mesh s i l i c a g e l (E. Merck, S i l i c a Gel 60) while f l a s h 92 chromatography was done on 230-400 mesh s i l i c a g e l (E. Merck, S i l i c a Gel 60). Unless otherwise s t a t e d , a l l r e a c t i o n s were c a r r i e d out under an atmosphere of dry argon using c a r e f u l l y flame-dried glassware. Cold temperatures were maintained by the use of the f o l l o w i n g 93 94 baths: aqueous calcium chloride/CO^ (-20°C), a c e t o n i t r i l e / C O ^ (-48°C), chloroform/C0 2 (-63°C), acetone/C0 2 (-78°C) and methanol/N (-98°C). Solvents and Reagents Solvents and reagents were p u r i f i e d and d r i e d using e s t a b l i s h e d p r o c e d u r e s . ^ ' ^ A l l s o l v e n t s were d i s t i l l e d before use. The - 119 -petroleum ether used was the f r a c t i o n w i t h a b o i l i n g range ca. 30-60°C. Hexamethylditin was obtained from the A l f a D i v i s i o n of the Ventron Corporation or from Organometallics, Inc. So l u t i o n s 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 Co., Inc. 97 and were standardized using the d o u b l e - t i t r a t i o n procedure of Gilman. Phenylthiocopper was prepared using the m o d i f i c a t i o n of the method 98 of Posner. Thus, a mixture of cuprous oxide (46 g, 0.32 mol) and thiophenol (79 g, 0.72 mol) i n absolute ethanol (1400 mL) was heated under r e f l u x f o r seven days. The r e s u l t a n t y e l l o w s l u r r y was s u c t i o n f i l t e r e d , and the c o l l e c t e d s o l i d was washed thoroughly w i t h ethanol and e t h e r , and then d r i e d f o r s e v e r a l days under high vacuum. Cuprous cyanide was purchased from J.T. Baker Co. and used without f u r t h e r p u r i f i c a t i o n . Copper bromide-dimethyl s u l f i d e complex was prepared by the 99a method of House, a f t e r washing the commercial cuprous bromide w i t h methanol. 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 saturated aqueous ammonium c h l o r i d e . L i t h i u m diisopropylamide (LDA) 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 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 (1.1 equiv) i n anhydrous tetrahydrofuran at -78°C. The r e s u l t i n g s l i g h t l y y ellow s o l u t i o n was then s t i r r e d at 0°C f o r 10 min before , 100 being used. T r i - n - b u t y l t i n hydride was p r e p a r e d ^ * by l i t h i u m aluminum hydride reduction of t r i - n - b u t y l t i n c h l o r i d e . - 120 -Prepa r a t i o n of E t h y l 3-Trimethylstannyl-3-butenoate (82) C02Et ,C02Et M e 3 S n C02Et He HA 81 103 82 To a c o l d (-78°C), s t i r r e d s o l u t i o n of l i t h i u m diisopropylamide (5 mmol) i n 10 mL of dry THF was added a s o l u t i o n of 0.69 g (2.5 mmol) of e t h y l (_E)-3-trimethylstannyl-2-butenoate (81) i n 2 mL of anhydrous THF. The b r i g h t y e l l o w s o l u t i o n was s t i r r e d at -78°C f o r 30 min and then at 0°C f o r 1 h. The s o l u t i o n was cooled to -78°C and t r a n s f e r r e d i n t o a c o l d (-98°C) s o l u t i o n of g l a c i a l a c e t i c a c i d (0.4 mL) i n ether. Saturated aqueous sodium bicarbonate (10 mL) and ether (25 mL) were added and the mixture was allowed to warm to room temperature. The la y e r s were separated and the aqueous l a y e r was e x t r a c t e d w i t h ether. The combined e x t r a c t s were washed w i t h saturated aqueous ammonium c h l o r i d e ( 2 x 5 mL) and d r i e d over anhydrous magnesium s u l f a t e . Removal of the sol v e n t and d i s t i l l a t i o n ( a i r - b a t h temperature » 85-90°C/12 Torr) af f o r d e d 0.55 g (80%) of a c l e a r , c o l o r l e s s o i l . Glc a n a l y s i s of t h i s mixture showed that i t c o n s i s t e d of a 94 : 6 mixture of two components. These were separated by f l a s h chromatography on s i l i c a g e l (30 g, e l u t i o n w i t h petroleum e t h e r - e t h e r , 100 : 1). The minor component was i d e n t i f i e d by i t s chromatographic ( g l c and t i c ) and s p e c t r a l (*H nmr) - 121 -p r o p e r t i e s as the (Z)-butenoate (103) (6% according to g l c ) . S i m i l a r l y , the major component (94% according to g l c ) was i d e n t i f i e d as e t h y l 3-trimethylstannyl-3-butenoate (82) (0.5 g, 72%). This m a t e r i a l e x h i b i t e d i r ( f i l m ) : 1724, 1325, 1190, 780 cm" 1; *H nmr (100 MHz, CDC1 3) 6: 0.16 ( s , 9H, -Sn(Me) 0, J_ „ = 54 Hz), 1.26 ( t , 3H, -0CHoCH., J = j bn—n / -J 7 Hz), 3.28 (d of d, 2H, a l l y l i c methylene protons, J = 2, 1, 2 S n _ H = 48 Hz), 4.18 (q, 2H, -0CK.CH-, J = 7 Hz), 5.36 (broad s, H,,, J c „ = 66 Hz), Z j — li bn—n 120 5.82 (broad s, l i . , J„ „ = 138 Hz). Exact Mass c a l c d . f o r CDH. _0„ Sn ' A' —Sn-H 8 15 2 (M +-CH 3): 263.0094; found: 263.0085. Prep a r a t i o n of 3-Tr i m e t h y l s t a n n y l - 3 - b u t e n - l - o l (83) To a co l d (-78°C), s t i r r e d s o l u t i o n - s u s p e n s i o n of l i t h i u m aluminum hydride (0.10 g, 2.62 mmol) i n 10 mL of dry ether was added a s o l u t i o n of 1.0 g (3.59 mmol) of e t h y l 3-trimethylstannyl-3-butenoate (82) i n 5 mL of anhydrous ether. The r e a c t i o n mixture was s t i r r e d at -78°C f o r 1.5 h. Saturated aqueous ammonium c h l o r i d e (2 mL) and ether (30 mL) were added and the mixture was allowed to warm to room temperature. The r e s u l t i n g white s l u r r y was f i l t e r e d ( e l u t i n g w i t h ether) through - 122 -a column of F l o r i s i l (-20 g). The elu a t e was d r i e d over anhydrous magnesium s u l f a t e and the solvent was removed under reduced pressure. D i s t i l l a t i o n ( a i r - b a t h temperature 70°C/12 Torr) of the residue gave 0.8 g (95%) of the a l c o h o l (83) as a c l e a r , c o l o r l e s s o i l . This m a t e r i a l e x h i b i t e d i r ( f i l m ) : 3350, 920, 770 cm" 1; *H nmr (80 MHz, CDC1 3) 6: 0.18 (s, 9H, -Sn(Me)., J = 53 Hz), 1.35 ( t , 1H, -OH, J = 6 Hz), 5 — Sn-H — — 2.55 (broad t , 2H, a l l y l i c methylene protons, J = 6 Hz, J =51 Hz), bn—H 3.65 (d of t , 2H, -0CH 2-, J = J' = 6 Hz), 5.30 (d of t , 1H, H^, J = 1.2, 1 Hz, J c „ = 70 Hz), 5.77 (d of t , 1H, H , J = 1.2, 1 Hz, J c „ = 148 Hz), bn—n B bn—H Exact Mass c a l c d . f o r C,H.,012°Sn (M +-CH„): 220.9989; found: 220.9989. fa 1 J 5 A d d i t i o n of (Trimethylstannyl)copper (100) to 3 - B u t y n - l - o l . P r e p a r a t i o n  of 3 - T r i m e t h y l s t a n n y l - 3 - b u t e n - l - o l (83) To a c o l d (-78°C), s t i r r e d s o l u t i o n of the ( t r i m e t h y l s t a n n y l ) -copper reagent (100) (49.2 mmol) i n 25 mL of dry THF was added a THF s o l u t i o n (5 mL) of 3-b u t y n - l - o l (1.5 g, 21.4 mmol) fol l o w e d by 27 anhydrous methanol (41 mL, 1 mol). The dark red r e a c t i o n mixture thus - 123 -obtained was s t i r r e d at -78°C f o r 2.5 h and at 0°C f o r 3 h. Saturated basic aqueous ammonium c h l o r i d e (10 mL) was added and the mixture was allowed to warm to room temperature w i t h vigorous s t i r r i n g . S t i r r i n g was maintained u n t i l the aqueous phase became deep blue. The l a y e r s were separated and the aqueous phase was ex t r a c t e d w i t h ether (2 x 15 mL). The combined organic e x t r a c t s were washed w i t h saturated b a s i c ammonium c h l o r i d e (3 x 10 mL), and d r i e d over anhydrous magnesium s u l f a t e . The crude o i l thus obtained showed, on c a p i l l a r y g l c a n a l y s i s the presence of hexamethylditin and a 90 : 10 mixture of two products. The crude o i l was subjected to f l a s h chromatography on s i l i c a g e l (100 g, e l u t i o n w i t h petroleum e t h e r - e t h e r , 3 : 1 ) . The major product was i s o l a t e d by concentration 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 70°C/12 Torr) of the r e s i d u a l m a t e r i a l . The c o l o r l e s s o i l obtained (3.45 g, 69%) e x h i b i t e d s p e c t r a l data ( i r , *H nmr) i d e n t i c a l w i t h those of the a l c o h o l (83). The l a t e r - e l u t e d f r a c t i o n y i e l d e d on d i s t i l l a t i o n ( a i r - b a t h temperature 70°C/12 (104) 300 mg (6%) of the a l c o h o l (124) as a c l e a r , c o l o r l e s s o i l . This m a t e r i a l e x h i b i t e d s p e c t r a l data ( i r , *H nmr) i d e n t i c a l to those of the a l c o h o l (10 4) , prepared i n our l a b o r a t o r y v i a the same route. - 124 -Preparation of 4-Chloro-2- t r i m e t h y l s t a n n y l -1-butene (84) To a s o l u t i o n of triphenylphosphine (1.3 g, 5.0 mmol) i n carbon t e t r a c h l o r i d e (15 mL) was added a s o l u t i o n of 0.8 g (3.4 mmol) of the 102 a l c o h o l (83) i n carbon t e t r a c h l o r i d e (3 mL) and t r i e t h y l a m i n e (0.7 mL, 5 mmol). The r e s u l t a n t s o l u t i o n was r e f l u x e d f o r 18 h. Petroleum ether (30 mL) was added and the r e s u l t i n g white s l u r r y was f i l t e r e d ( e l u t i n g w i t h petroleum ether) through a column of F l o r i s i l (25 g). Evaporation of the solvent from the combined el u a t e f o l l o w e d by d i s t i l l a t i o n of the residue ( a i r - b a t h temperature 60°C/12 Torr) aff o r d e d 0.60 g (70%) of the c h l o r i d e (84) as a c l e a r , c o l o r l e s s o i l . This m a t e r i a l e x h i b i t e d i r ( f i l m ) : 1615, 925, 780 cm" 1; XH nmr (80 MHz, CDC1 3) 6: 0.24 ( s , 9H, -Sn(Me) 0, J„ „ = 53 Hz), 2.69 (broad t , 2H, a l l y l i c methylene protons, j —Sn — ri J = 7 Hz, J c „ = 48 Hz), 3.53 ( t , 2H, -CH.Cl, J = 7 Hz), 5.29 (d of t , —bn—H Z. 1H, Hg, J = 2.4, 1 Hz, J . S n _ H = 70 Hz), 5.76 (d of t , 1H, R , J = 2.4, 35 120 + 1 Hz, J „ = 142 Hz). Exact Mass c a l c d . f o r C,H.„ CI Sn (M -CH,): — Sn—H o 1/ J 238.9650; found: 238.9648. - 125 -Prepa r a t i o n of A-Bromo-2- t r i m e t h y l s t a n n y l -1-butene (135) To a c o l d (0°C), s t i r r e d s o l u t i o n of triphenylphosphine (0.65 g, 2.5 mmol) i n 10 mL of dry a c e t o n i t r i l e was added bromine v i a a sy r i n g e , u n t i l the s o l u t i o n became pale yellow. A f t e r the s o l u t i o n had been s t i r r e d f o r 5 min, t r i e t h y l a m i n e (0.7 mL, 5 mmol) and 0.4 g (1.7 mmol) 103 of the a l c o h o l (83) were added, s u c c e s s i v e l y . The r e s u l t a n t s o l u t i o n was allowed to s t i r at 0°C f o r 20 min. Petroleum ether (15 mL) was added and•the r e s u l t i n g white s l u r r y was f i l t e r e d through a column of F l o r i s i l (15 g, e l u t i o n w i t h petroleum e t h e r ) . Evaporation of the solvent from the combined e l u a t e f o l l o w e d by d i s t i l l a t i o n of the residue ( a i r - b a t h temperature 70-75 CC/12 Torr) aff o r d e d 332 mg (76%) of the bromide (135) as a c l e a r , c o l o r l e s s o i l . This m a t e r i a l e x h i b i t e d i r ( f i l m ) : 915, 750 cm"1; *H nmr (100 MHz, CDC1 3) 5: 0.18 ( s , 9H, -Sn(Me) 3 > J„ u = 53 Hz), 2.80 (broad t , 2H, a l l y l i c methylene protons, J = 7 Hz, J„ T 7 = 46 Hz), 2.40 ( t , 2H, -CH Br, J = 7 Hz), 5.30, 5.75 ( p a i r of —Sn-H 2 — 120 broad s, IH each, o l e f i n i c p rotons). Exact Mass c a l c d . f o r CgH^Br Sn ( M + - C H 3 ) : 269.0301; found: 269.030. - 126 -General Procedure A: Transmetalation of 4 - C h l o r o - 2 - t r i m e t h y l s t a n n y l - l - butene (84) and Reaction of the Intermediate 4 - C h l o r o - 2 - l i t h i o - l - b u t e n e  (95) w i t h Carbonyl E l e c t r o p h i l e s To a c o l d (-78°C), s t i r r e d s o l u t i o n of 4 - c h l o r o - 2 - t r i m e t h y l -stannyl-1-butene (84) (100 mg, 0.39 mmol) i n 3 mL of anhydrous THF was added m e t h y l l i t h i u m (0.42 mmol) as a s o l u t i o n i n ether. The r e s u l t i n g l i g h t y e l l o w s o l u t i o n was s t i r r e d at -78°C f o r 5 min. The appropriate carbonyl e l e c t r o p h i l e (0.46 mmol) was added and the r e a c t i o n mixture was s t i r r e d at -78°C f o r 1 h. Saturated aqueous ammonium c h l o r i d e (0.4 mL) and ether (20 mL) were added and the mixture was allowed to warm to room temperature. The organic l a y e r was washed w i t h saturated aqueous ammonium c h l o r i d e ( 3 x 5 mL), d r i e d over anhydrous magnesium s u l f a t e , and concentrated under reduced pressure. The r e s u l t i n g o i l was subjected to p r e p a r a t i v e t i c and d i s t i l l a t i o n to a f f o r d pure product. 84 95 - 127 -General Procedure B: One-step C y c l i z a t i o n of Intermediates Derived from  the Reaction of A - C h l o r o - 2 - l i t h i o - l - b u t e n e (95) w i t h Carbonyl E l e c t r o - p h i l e s To a c o l d (-78°C), s t i r r e d s o l u t i o n of A - c h l o r o - 2 - l i t h i o - l -butene (95) (0.39 mmol, prepared as o u t l i n e d i n general procedure A) was added the appropriate carbonyl e l e c t r o p h i l e (0.46 mmol) and the r e s u l t a n t s o l u t i o n was s t i r r e d at -78°C f o r 1 h. Hexamethylphosphoramide (0.54 mmol) was added and the r e a c t i o n mixture was allowed to warm to room tempera-ture and s t i r r e d f o r a f u r t h e r 3 h. Saturated aqueous copper s u l f a t e (~3 mL) and ether (20 mL) were added and the mixture was s t i r r e d v i g o r o u s l y at room temperature f o r 10 min. The organic l a y e r was washed s u c c e s s i v e l y w i t h saturated aqueous copper s u l f a t e ( 3 x 3 mL) and saturated b r i n e (5 mL). The organic l a y e r was d r i e d over anhydrous magnesium s u l f a t e and the solvent was removed under reduced pressure. The r e s u l t i n g o i l was subjected to p r e p a r a t i v e t i c and d i s t i l l a t i o n t o a f f o r d pure product. General Procedure C: C y c l i z a t i o n of the Chloro A l c o h o l s (108), (109), (111), and (112) using Potassium Hydride. To a s o l u t i o n of the appropriate chloro a l c o h o l (0.20 mmol) i n 2 mL of anhydrous THF was added potassium hydride (30 mg, 0.75 mmol) as a suspension i n 1 mL of anhydrous THF. The r e s u l t a n t yellow mixture was s t i r r e d at room temperature f o r 3 h. Saturated aqueous ammonium c h l o r i d e (3 mL) and ether (10 mL) were added and the mixture was s t i r r e d at room temperature f o r 10 min. The l a y e r s were separated and the - 128 -aqueous l a y e r was e x t r a c t e d w i t h ether ( 2 x 4 mL). The combined ether e x t r a c t s were washed w i t h saturated b r i n e ( 2 x 2 mL) and d r i e d over anhydrous magnesium s u l f a t e . Solvent removal under reduced pressure followed 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 afforded the corresponding c y c l i c ether. P r e p a r a t i o n of 4-Chloro-2-(l-hydroxycyclohexyl)-l-butene (111) F o l l o w i n g the general procedure A described above, cyclohexanone (42 uL, 0.46 mmol) was allowed to react w i t h a s o l u t i o n of 4-chloro-2-l i t h i o - l - b u t e n e (95) (0.39 mmol) at -78°C. The c o l o r l e s s o i l obtained a f t e r workup" was subjected to p r e p a r a t i v e t i c ( e l u t i n g s o l v e n t : petroleum e t h e r - e t h e r , 5:2). D i s t i l l a t i o n ( a i r - b a t h temperature 55-65°C/ 0.2 Torr) of the m a t e r i a l obtained from the major band aff o r d e d (111) as a c o l o r l e s s o i l (51 mg, 69%). This m a t e r i a l e x h i b i t e d i r ( f i l m ) : 3375, 1060, 920 cm"1; lK nmr (100 MHz, CDC1 3) 6: 1.50-1.76 (m, 11H), 2.62 (broad t , 2H, a l l y l i c methylene protons, 1 = 7 Hz), 3.70 ( t , 2H, -CH0C1 , J = 7 Hz), 4.94 (broad s, IH, H.), 5.24 ( s , IH, H„). Exact A B 35 Mass c a l c d . f o r C H 0 C l : 188.0968; found: 188.0975. - 129 -Preparation of A-Methylene-l-oxaspiro[A.5]decane (117) Fol l o w i n g the general procedure B o u t l i n e d above, cyclohexanone (A2 uL, 0.A6 mmol) was allowed to react w i t h A - c h l o r o - 2 - l i t h i o - l - b u t e n e (95). Normal workup followed by p r e p a r a t i v e t i c ( e l u t i n g s o l v e n t : petroleum e t h e r - e t h e r , 5 : 1 ) and d i s t i l l a t i o n ( a i r - b a t h temperature 52-58°C/0.2 Torr) of the r e s u l t i n g o i l , y i e l d e d 3A mg (58%) of (117) as a c l e a r , c o l o r l e s s o i l . This m a t e r i a l e x h i b i t e d i r ( f i l m ) : 1150, 760 cm" 1; *H nmr (100 MHz, CDC1 3) 6: 1.41-1.77 (m, 10H), 2.58 (d of d of t , 2H, a l l y l i c methylene protons, J = 2, 1.5, 7 Hz), 3.79 ( t , 2H, -OCH„-, J = 7 Hz), 4.74 ( t , 1H, H A, J = 2 Hz), A.89 ( t , 1H, H , J = 1.5 Z — A — U — Exact Mass c a l c d . f o r CL.H^O: 152.1201; found: 152.1201. J.U I D F o l l o w i n g the general procedure C o u t l i n e d above, there was obtained 2A mg (81%) of (117) from 37 mg (0.2 mmol) of the chloro a l c o h o l (111). 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 to that reported above. - 130 -Prepa r a t i o n of 3- ( 2 - C h l o r o e t h y l ) - l - ( 2 - c y c l o p e n t e n y l ) - 3 - b u t e n - 2 - o l (109) Fo l l o w i n g the general procedure A o u t l i n e d above, (2 - c y c l o p e n t e n y l ) -ethanal (50 mg, 0.46 mmol) was allowed to react w i t h the b u t e n y l l i t h i u m reagent (95). Normal workup f o l l o w e d by p r e p a r a t i v e t i c ( e l u t i n g s o l v e n t : petroleum e t h e r - e t h e r , 5 : 2) and d i s t i l l a t i o n ( a i r - b a t h temperature 60-62°C/0.2 Torr) a f f o r d e d the a l c o h o l (109) (51 mg, 64%). This m a t e r i a l e x h i b i t e d i r ( f i l m ) : 3400, 3045, 910 cm"1; XH nmr (100 MHz, CDC1 3) 6: 1.13-1.73 (m, 4H), 1.93-2.45 (m, 3H), 2.55 (broad t , 2H, H c, J * 7 Hz), 2.55-2.90 (m, IH, H^), 3.66 ( t , 2H, -CH C l , J = 7 Hz), 4.17 (broad t , IH, -CHOH, J = 7 Hz), 4.93 (broad s, IH, H^), 5.15 (s , IH, H_), 5.71 (m, 2H, cyc l o p e n t e n y l o l e f i n i c p r o t o n s ) . Exact Mass c a l c d . a f o r C 1 1 H 1 7 0 3 5 C 1 200.0968; found: 200.0970. - 131 -Pre p a r a t i o n of 2-(2-Cyclopentenylmethyl)-3-methylenetetrahydrofuran (115) Fol l o w i n g the general procedure B o u t l i n e d above, ( 2 - c y c l o p e n t e n y l ) -ethanal (50 mg, 0.46 mmol) was converted i n t o the methylenetetrahydro-furan d e r i v a t i v e (115). Normal workup followed by p r e p a r a t i v e t i c ( e l u t i n g s o l v e n t : petroleum e t h e r - e t h e r , 5 : 1) and d i s t i l l a t i o n ( a i r -bath temperature 58-60°C/0.2 Torr) y i e l d e d (115) (36 mg, 56%) as a c l e a r , c o l o r l e s s o i l . This m a t e r i a l e x h i b i t e d i r ( f i l m ) : 890, 740 cm 1H nmr (100 MHz, CDC1 3) 6: 1.25-1.61 (m, 4H)1.83-2.32 (m, 3H), 2.32-2.63 (m, 2H, H , H^), 3.49-3.96 (m, 2H, -0CH_2-), 4.03-4.33 (broad s , IH, -CH0-), 4.83 (d of d of d, IH, H , J = 2.2, 2.2, 2 Hz), 4.97 (d of d of d, IH, H_, J = 2.2, 2, 2 Hz), 5.75 (m, 2H, cyclopentenyl o l e f i n i c B protons). Exact Mass c a l c d . f o r C n H 1 6 0 : 164.1201; found: 164.1206. Fo l l o w i n g the general procedure C o u t l i n e d above., there was obtained 26 mg (78%) of (115) from 40 mg (0.2 mmol) of the chloro a l c o h o l (109). 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 to that reported above. - 132 -Preparation of 4-Chloro-2-(l-hydroxycyclopentyl)-l-butene (110) Following the general procedure A o u t l i n e d above, cyclopentanone (40 uL, 0.46 mmol) was converted i n t o the a l c o h o l (110). The crude m a t e r i a l obtained a f t e r workup was subjected to p r e p a r a t i v e t i c ( e l u t i n g s o l v e n t : petroleum e t h e r - e t h e r , 5 : 2) and d i s t i l l a t i o n ( a i r - b a t h temperature 55-60°C/ 0.2 Torr) to a f f o r d compound (110) as a c l e a r , c o l o r l e s s o i l (46 mg, 67%). This m a t e r i a l e x h i b i t e d i r ( f i l m ) : 3360, 920 cm"1; *H nmr (100 MHz, CDClg) 6: 1.37-2.01 (m, 9H), 2.59 (broad t , 2H, a l l y l i c methylene protons, J_ = 8 Hz), 3.67 ( t , 2H, -CH 2C1, J = 8 Hz), 4.88 (broad s, IH, H^), 5.21 ( s , IH, Eg). Exact Mass c a l c d . f o r C g H 1 5 0 3 5 C l : 174.0811; found: 174.0811. - 133 -Preparation of 4-Methylene-l-oxaspiro[4.4]nonane (116) Fol l o w i n g the general procedure B described above, cyclopentanone (40 uL, 0.46 mmol) was converted i n t o the methylenetetrahydrofuran d e r i v a t i v e (116). Normal workup f o l l o w e d by p r e p a r a t i v e t i c ( e l u t i n g s o l v e n t : petroleum e t h e r - e t h e r , 5:1) and d i s t i l l a t i o n ( a i r - b a t h tempera-ture 52-58°C/0.2 Torr) of the crude m a t e r i a l a f f o r d e d 27 mg (51%) of compound (116) as a c l e a r , c o l o r l e s s o i l . This m a t e r i a l e x h i b i t e d i r ( f i l m ) : 1220, 760 cm"1; 1E nmr (100 MHz, CDC1 3) 6: 1.44 (m, 8H), 2.60 (d of d of t , 2H, a l l y l i c methylene protons, _J = 2, 1.6, 7 Hz), 3.77 ( t , 2H, -0CH 2-, J = 7 Hz), 4.83 ( t , IH, H A > J = 2 Hz), 4.92 ( t , IH, Hg, J = 1.6 Hz). Exact Mass c a l c d . f o r C H . O : 138.1045; found: 138.1045. - 134 -P r e p a r a t i o n of 4-Chloro-2-(l-hydroxybenzyl)-l-butene (108) F o l l o w i n g the general procedure A o u t l i n e d above, benzaldehyde (46 uL, 0.46 mmol) was allowed to react w i t h the b u t e n y l l i t h i u m reagent (95). Normal workup f o l l o w e d by p r e p a r a t i v e t i c ( e l u t i n g s o l v e n t : petroleum e t h e r - e t h e r , 7:3) and d i s t i l l a t i o n ( a i r - b a t h temperature 54-58°C/0.2 Torr) of the crude m a t e r i a l y i e l d e d 58 mg (76%) of the a l c o h o l (108) as a c l e a r , c o l o r l e s s o i l . This m a t e r i a l e x h i b i t e d i r ( f i l m ) : 3340, 1600, 1090 cm" 1; *H nmr (80 MHz, CDC1 3) 6: 2.0 (m, IH, -OH), 2.40 (broad t , 2H, a l l y l i c methylene protons, _J = 7 Hz), 3.53 ( t , 2H, -CH 2C1, J = 7 Hz), 5.08 (broad s, IH, -CH0H), 5.20, 5.35 ( p a i r of broad s, IH each, H., H ), 7.32 (broad s, 5H, aromatic protons). A B 35 Exact Mass c a l c d . f o r C H O CI: 196.0665; found: 196.0650. - 135 -Prepa r a t i o n of 3-Methylene-2-phenyltetrahydrofuran (114) Following the general procedure B o u t l i n e d above, benzaldehyde (46 uL, 0.46 mmol) was converted i n t o 3-methylene-2-phenyltetrahydro-furan (114). Normal workup f o l l o w e d by p r e p a r a t i v e t i c ( e l u t i n g s o l v e n t : petroleum e t h e r - e t h e r , 7 : 3) and d i s t i l l a t i o n ( a i r - b a t h temperature 52-55°C/0.2 Torr) afforded (114) (40 mg, 63%) as a c l e a r , c o l o r l e s s o i l . This m a t e r i a l e x h i b i t e d i r ( f i l m ) : 1635, 1608, 760 cm *H nmr (100 MHz, CDC1 3) 6: 2.73 (broad t , 2H, a l l y l i c methylene protons, J = 7 Hz), 3.79-4.31 (m, 2H, -0CH_2-) , 4.75 (d of d of d, IH, H., J = 2, 2, 1.5 Hz), 5.08 (d of d of d, IH, H_, J = 2, 1.5, 1.5 Hz), A D 5.18 (broad s, IH, -0CH-), 7.25-7.38 (m, 5H, aromatic protons). Exact  Mass calcd..for C^H^O: 160.0888; found: 160.0890. F o l l o w i n g the general procedure C o u t l i n e d above, there was obtained 27 mg (84%) of the c y c l i c ether (114) from 39 mg (0.2 mmol) of the chloro a l c o h o l (108). 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 to that reported above. - 136 -Prepa r a t i o n of 4-Chloro-2-(l-hydroxycycloheptyl)-l-butene (112) Following the general procedure A o u t l i n e d above, cycloheptanone (54 uL, 0.46 mmol) was converted i n t o the a l c o h o l (112). Normal workup followed by p r e p a r a t i v e t i c ( e l u t i n g s o l v e n t : petroleum e t h e r - e t h e r , 5 : 2 ) , and d i s t i l l a t i o n ( a i r - b a t h temperature 60-63°C/0.2 Torr) of the crude m a t e r i a l a f f o r d e d 54 mg (69%) of the a l c o h o l (112). This m a t e r i a l e x h i b i t e d i r ( f i l m ) : 3375, 1610, 1440, 1015 cm"1; XH nmr (80 MHz, CDC1 ) 6: 1.32 ( s , IH, -011), 1.38-2.0 (m, 12H), 2.60 (broad t , 2H, a l l y l i c methylene protons, _J = 7.5 Hz), 3.68 ( t , -CH 2C1, J = 7.5 Hz), 4.80 (broad s, IH, H ), 5.17 ( s , IH, Hg). Exact Mass c a l c d . f o r C n H i g 0 3 5 C l : 202.1124; found: 202.1127. - 137 -Preparation of 4-Methylene-l-oxaspiro[4.6]undecane (118) Fol l o w i n g the general procedure B o u t l i n e d above, cycloheptanone (54 yL, 0.46 mmol) was allowed to re a c t w i t h 4 - c h l o r o - 2 - l i t h i o - l - b u t e n e (95). Normal workup f o l l o w e d by p r e p a r a t i v e t i c ( e l u t i n g s o l v e n t : petroleum et h e r - e t h e r , 5:1) and d i s t i l l a t i o n ( a i r - b a t h temperature 57-60°C/0.2 Torr) of the crude m a t e r i a l gave 40 mg (62%) of compound (118). This m a t e r i a l e x h i b i t e d i r ( f i l m ) : 920, 740 cm" 1; *H nmr (100 MHz, CDC1 3) 6: 1.43-1.81 (m, 12H), 2.59 (t of t,,2H, a l l y l i c methylene protons, J = 7, 2 Hz), 3.79 ( t , 2H, -OCH -, J = 7 Hz), 4.82, 4.87 ( p a i r of t , IH each, H , YL^, J = 2 Hz). Exact Mass c a l c d . f o r C n H l g 0 : 166.1358; found: 166.1362. Fo l l o w i n g the general procedure C o u t l i n e d above, there was obtained 28 mg (88%) of (118) from 40 mg (0.2 mmol) of the chloro a l c o h o l (112). 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 to that reported above. - 138 -Preparation of 4-Chloro-2-(l-hydroxy-2-cyclohexenyl)-l-butene (113) F o l l o w i n g the general procedure A o u t l i n e d above, 2-cyclohexen-l-one (41 uL, 0.46 mmol) was allowed to r e a c t w i t h 4 - c h l o r o - 2 - l i t h i o - l -butene (95). Normal workup fo l l o w e d by p r e p a r a t i v e t i c ( e l u t i n g s o l v e n t : petroleum e t h e r - e t h e r , 5 : 3) and d i s t i l l a t i o n ( a i r - b a t h tempera-ture 58-62°C/0.2 Torr) of the crude m a t e r i a l a f f o r d e d 52 mg (72%) of the a l c o h o l (113). This m a t e r i a l e x h i b i t e d i r ( f i l m ) : 3380, 1620, 1160 cm"1; lE nmr (100 MHz, CDC1 3) 6: 1.23 ( s , IH, OH), 1.59-1.81 (m, 4H, n o n - a l l y l i c cyclohexenyl p r o t o n s ) , 1.89-2.11 (m, 2H, a l l y l i c c y c l o -hexenyl p r o t o n s ) , 2.57 (broad t , 2H, H^ ,, J_ = 8 Hz) , 3.67 ( t , 2H, -CH 2C1, J = 8 Hz), 4.94 (broad s, IH, H^), 5.18 ( s , IH, Hg), 5.55 (d of t , IH, cyclohexenyl C-2 v i n y l proton, j ; = 10.5, 0.8 Hz), 5.91 (d of t , IH, cyclohexenyl C-3, v i n y l p roton, = 10.5, 4 Hz). Exact Mass c a l c d . f o r C H 0 3 5 C 1 : 186.0811; found: 186.0812. - 139 -Prepa r a t i o n of 4-Methylene-l-oxaspiro[4.5]dec-6-ene (119) Foll o w i n g the general procedure B o u t l i n e d above, 2-cyclohexen-l-one (41 uL, 0.46 mmol) was converted i n t o the methylenetetrahydrofuran d e r i v a t i v e (119). P r e p a r a t i v e t i c ( e l u t i n g s o l v e n t : petroleum ether-e t h e r , 5 : 2) and d i s t i l l a t i o n ( a i r - b a t h temperature 55-59°C/0.2 Torr) of the crude m a t e r i a l obtained a f t e r workup, y i e l d e d 37 mg (62%) of compound (119). This m a t e r i a l e x h i b i t e d i r ( f i l m ) : 1075, 770 cm lU nmr (100 MHz, CDCl.^) 6: 1.54-1.81 (m, 4H, n o n - a l l y l i c cyclohexenyl p r o t o n s ) , 1.88-2.11 (m, 2H, a l l y l i c cyclohexenyl p r o t o n s ) , 2.63 (d of d of t , 2H, H c, J = 2, 1.8, 8 Hz), 3.86 ( t , 2H, -0CH 2-, J = 8 Hz), 4.80 ( t , IH, H A, J = 2 Hz), 4.97 ( t , IH, Hg, J = 1.8 Hz), 5.45 (d of t , IH, cyclohexenyl C-2 v i n y l protons, j ; = 10.5, 0.8 Hz), 5.89 (d of t , IH, cyclohexenyl C-3 v i n y l proton, ,J = 10.5, 3 Hz). Exact Mass c a l c d . f o r C 1 Q H 1 A 0 : 150.1045; found: 150.1045. - 140 -General Procedure D: Pre p a r a t i o n of A c y c l i c N,N' ,N'-Trimethylcarbox- hydrazides To a c o l d (-78°C), s t i r r e d s o l u t i o n of 4- c h l o r o - 2 - l i t h i o - 1 - b u t e n e (95) (0.39 mmol) i n 3 mL of THF was added the appropriate a,g-unsatura-38 ted N,N',N'-trimethylcarboxhydrazide (0.46 mmol). The r e s u l t i n g s o l u t i o n was allowed to s t i r at -78°C f o r 2 h. Saturated aqueous ammonium c h l o r i d e (~3 mL) and ether (15 mL) were added and the mixture was allowed to warm to room temperature. The l a y e r s were separated and the aqueous l a y e r was ext r a c t e d w i t h ether. The combined e x t r a c t s were washed w i t h saturated 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 solvent under reduced pressure a f f o r d e d an o i l which, on the b a s i s of g l c a n a l y s i s contained the de s i r e d product and some s t a r t i n g m a t e r i a l . Subjection of the m a t e r i a l to column chromatography on s i l i c a g e l (15 g, e l u t i o n w i t h petroleum e t h e r - e t h e r , 1 : 1) gave, a f t e r c o n c e n t r a 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 of the combined r e s i d u a l m a t e r i a l , the corresponding a c y c l i c N,N',N'-trimethylcarboxhydrazide. - 141 -General Procedure E: Pre p a r a t i o n of N,N',N'-Trimethylcarboxhydrazides  of 3-Methylenecyclopentanecarboxylic A c i d D e r i v a t i v e s To a c o l d (-78°C), s t i r r e d s o l u t i o n of 4 - c h l o r o - 2 - l i t h i o -butene (95) (0.39 mmol) i n 3 mL of THF was added the appropriate a,3-unsaturated N,N',N'-trimethylcarboxhydrazide (0.46 mmol). The r e s u l t i n g s o l u t i o n was allowed to s t i r at -78°C f o r 2 h. Hexamethyl-phosphoramide (0.54 mmol) was added and the r e a c t i o n mixture was allowed to warm to room temperature,and s t i r r e d f o r a f u r t h e r 3 h. Saturated aqueous copper s u l f a t e (~2 mL) and ether (20 mL) were added and the mixture was s t i r r e d v i g o r o u s l y a t room temperature f o r 10 min. The l a y e r s were separated and the aqueous l a y e r was ex t r a c t e d w i t h ether. The combined e x t r a c t s were washed w i t h saturated aqueous copper s u l f a t e ( 2 x 3 mL) and saturated aqueous 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 . The o i l obtained a f t e r the removal of solvent was subjected to column chromatography on s i l i c a g e l (15 g, e l u t i o n w i t h petroleum ether-ether, 2 : 1 ) . Concentration 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 r e s i d u a l m a t e r i a l a f f o r d e d the corresponding 3-methylenecyclopentanecarboxylic a c i d - 142 -d e r i v a t i v e . P r e p a r a t i o n of the N,N',N'-Trimethylcarboxhydrazide of 4- ( 2 - C h l o r o e t h y l ) -3-methyl-4-pentenoic Acid (130) Foll o w i n g the general procedure D o u t l i n e d above, the N,N',N'-trimethylcarboxhydrazide of (E)-2-butenoic a c i d (127) (65 mg, 0.46 mmol) was converted i n t o the a c y c l i c t r i m e t h y l h y d r a z i d e (130). Normal workup, followed by column chromatography on s i l i c a g e l (15 g, petroleum ether-ether, 1 : 1) and d i s t i l l a t i o n ( a i r - b a t h temperature 98-105°C/12 Torr) of the crude r e s i d u e , f u r n i s h e d 59 mg (65%) of (130) as a c l e a r , c o l o r l e s s o i l . 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, 1650, 1440 cm" 1; 1H nmr (400 MHz,CDCl 3) 6: 1.08 (d, 3H, secondary methyl group, J = 6 Hz), 2.47-2.57 ( p a r t i a l l y obscured m, 4H, H , H_), 2.49 ( s , 6H, -N(Me)„), 2.64-2.79 (m, IH, Hp,), 2.86 ( s , 3H, -CONMe), 3.64 ( 6 - l i n e m, 2H, -CH 2C1), 4.82, 4.92 (s, s, 2H, o l e f i n i c protons). Exact Mass c a l c d . f o r C l l H 2 1 N 2 ° 3 5 c i : 2 3 2 - 1 3 4 2 5 found: 232.1345. - 143 -Preparation of the N,N',N'-Trimethylcarboxhydrazide of 2-Methyl-3- methylenecyclopentanecarboxylie Acid (133) Following general procedure E o u t l i n e d above, the N,N',N'-tri-methylcarboxhydrazide of (E)-2-butenoic a c i d (127) (65 mg, 0.46 mmol) was converted i n t o the 3-methylenecyclopentanecarboxylic a c i d d e r i v a t i v e (133). Normal workup followed by column chromatography on s i l i c a g e l (15 g, petroleum e t h e r - e t h e r , 3 : 2) and d i s t i l l a t i o n ( a i r - b a t h temperature 93-98°C/12 Torr) of the crude residue afforded 46 mg (60%) of (133) as a c l e a r , c o l o r l e s s o i l . 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, 1645, 1400 cm" 1; XH nmr (400 MHz, CDC1 3) 6: 1.04 (d, 3H, secondary methyl group, 1 = 6 Hz), 1.64 ( 5 - l i n e m, IH), 1.86-1.97 (m, IH), 2.30-2.43, 2.50-2.60 (m, m, 2H, H , H ) a a 2.49, 2.51 (two s, 6H, -N(Me) 0), 2.69-2.80 (broad m, IH, H_) , 2.89 ( s , 2 r 3H, -CONMe), 3.20 (d of d of d, IH, H_, J = 12, 10, 8 Hz), 4.88, 4.95 (two d, 2H, J_ = 2 Hz, o l e f i n i c p r o tons). Exact Mass c a l c d . f o r C 1 1 H 2 0 N 2 0 : 1 9 6 - 1 5 7 5 ; found: 196.1575. - 144 -Preparation of the N,N*,N'-Trimethylcarboxhydrazide of 4-( 2 - C h l o r o e t h y l ) - 4-pentenoic Acid (128) Following the general procedure D o u t l i n e d above the N,N',N'-trimethylcarboxhydrazide of propenoic a c i d (125) (50 mg, 0.46 mmol) was allowed to react w i t h 4 - c h l o r o - 2 - l i t h i o - l - b u t e n e (95). Normal workup followed by column chromatography on s i l i c a g e l (15 g, e l u t i o n w i t h petroleum e t h e r - e t h e r , 1:1) and d i s t i l l a t i o n ( a i r - b a t h temperature 90-96°C/12 Torr) of the r e s i d u a l m a t e r i a l y i e l d e d 55 mg (65%) of (128) as a c l e a r , c o l o r l e s s o i l . This m a t e r i a l e x h i b i t e d i r ( f i l m ) : 3010, 1640, 1430, 905 cm"1; XH nmr (400 MHz, CDC1 3) 6: 2.32 (broad t , 2H, H , J = 8 Hz), 2.52 ( p a r t i a l l y obscured t , 2H, H^, J_ = 8 Hz), 2.50 (s, 6H, -N(Me)„), 2.68 ( t , 2H, H^, J = 8 Hz), 2.86 ( s , 3H, -CONMe), 3.62 ( t , 2H, -CH 2C1, J = 8 Hz), 4.85, 4.89 (two s i n g l e t s , 2H, o l e f i n i c 35 protons). Exact Mass c a l c d . f o r C 1 0 H 1 9 N 2 ° C 1 2 1 8 - 1 1 8 6 ; found: 218.1186. - 145 -Preparation of the N,N',N'-Trimethylcarboxhydrazide of 3-methylenecyclo- pentanecarboxylic Acid (131) F o l l o w i n g the general procedure E o u t l i n e d above, N,N',N'-trimethyl-carboxyhydrazide of propenoic a c i d (125) (58 mg, 0.46 mmol) was converted i n t o the 3-methylenecyclopentanecarboxylic a c i d d e r i v a t i v e , ( 1 3 1 ) . The residue obtained a f t e r workup was subjected to column chromatography on s i l i c a g e l (15 g, e l u t i o n w i t h petroleum e t h e r - e t h e r , 3 : 2) and d i s t i l l a t i o n ( a i r - b a t h temperature 89-92°C/12 Torr) to a f f o r d 42 mg (60%) of (131) as a c l e a r , c o l o r l e s s o i l . This m a t e r i a l e x h i b i t e d i r ( f i l m ) : 3010, 1630, 1440, 900, 760 cm - 1; *H nmr (400 MHz, CDC1 3) 6: 1.79-1.98 (m, 2H, H , H , ) , 2.24-2.37 (m, IH), 2.44-2.54 ( p a r t i a l l y A A obscured m, 3H), 2.49, 2.50 (two s i n g l e t s , 6H, -N(Me) 2), 2.88 (s, 3H, -CONMe), 3.51 ( 5 - l i n e m, IH, H j , 4.82-4.88 (m, 2H, o l e f i n i c p rotons). Exact Mass c a l c d . f o r C 1 0 H 1 8 N 2 0 : 182.1419; found: 182.1410. - 146 -Prepa r a t i o n of the N,N',N'-Trimethylcarboxhydrazide of 4 - ( 2 - c h l o r o e t h y l ) - 2-methyl-4-pentenoic Acid (129) Following the general procedure D o u t l i n e d above, the N,N',N'-trimethylcarboxhydrazide of 2-methylpropenoic a c i d (126) (65 mg, 0.46 mmol) was converted i n t o the a c y c l i c trimethylcarboxhydrazide (129). Normal workup followed by column chromatography on s i l i c a g e l (15 g, e l u t i o n w i t h petroleum e t h e r - e t h e r , 1:1) and d i s t i l l a t i o n ( a i r - b a t h tempera-ture 94-99°C/12 Torr) of the crude m a t e r i a l a f f o r d e d 68 mg (75%) of (129) as a c l e a r , c o l o r l e s s o i l . 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, 1645, 900 cm"1; lE nmr (400 MHz, CDC1 3) <$: 1.06 (d, 3H, secondary methyl group, J = 8 Hz), 2.02, 2.41 (two d of d, 2H, H_, H^, J = 14, 8 Hz), 2.50 ( p a r t i a l l y obscured t , 2H, Hg, J = 7.2 Hz), 2.51, 2.52 (s , s, 6H, -N(Me) 2), 2.86 ( s , 3H, -CONMe), 3.54 (d of d of q, IH, Hg, J = 8, 8, 8 Hz), 3.62 ( t , 2H, H^, J = 7.2 Hz), 4.84, 4.88 ( s , s, 2H, 35 o l e f i n i c p r otons). Exact Mass c a l c d . f o r c 1 1 H 2 l N 2 ° C 1 : 232.1343; found: 232.1334. - 147 -Preparation of the N,N',N'-Trimethylcarboxhydrazide of 1-Methyl-3- methylenecyclopentanecarboxylic A c i d (132) Following the general procedure E o u t l i n e d above, N , N ' ^ ' - t r i -methylcarboxhydrazide of 2-methylpropenoic a c i d (126) (65 mg, 0.46 mmol) was allowed to react w i t h the b u t e n y l l i t h i u m reagent (95). Column chromatography on s i l i c a g e l (15 g, e l u t i o n w i t h petroleum ether-ether, 3 : 2) and d i s t i l l a t i o n ( a i r - b a t h temperature 96-103°C/12 Torr) of the crude m a t e r i a l obtained a f t e r workup y i e l d e d 47 mg (62%) of the 3-methylenecyclopentanecarboxylic a c i d d e r i v a t i v e (132). This m a t e r i a l e x h i b i t e d i r ( f i l m ) : 3050, 1630, 1450, 1380, 740 cm" 1; *H nmr (400 MHz, CDC1 3) <$: 1.26 ( s , 3H, t e r t i a r y methyl group), 1.84-1.92, 2.05-2.14 (two m, 2H, H , H , ) , 2.33-2.43 (m, 2H, H , H , ) , 2.49, 2.74 (two broad d, 2H, A A JJ B H_, H^, J = 16 Hz), 2.50 ( s , 6H, -N(Me)„) , 2.83 ( s , 3H, -CONMe), 4.83, E F Z 4.88 (two broad s, 2H, o l e f i n i c protons). Exact Mass c a l c d . f o r C11 H20 N2° : 1 9 6 - 1 5 7 5 » found: 196.1575. - 148 -General Procedure F: Reaction of L i t h i u m P h e n y l t h i o [ 2 - ( 4 - c h l o r o - l - b u t e n y l j c u p r a t e (179) w i t h C y c l i c Enones To a c o l d (-78°C), s t i r r e d s o l u t i o n of 4 - c h l o r o - 2 - l i t h i o - l -butene (95) (0.39 mmol, prepared as o u t l i n e d i n general procedure A) i n 3 mL of anhydrous THF was added i n one p o r t i o n , s o l i d p h e n y l t h i o -copper (67 mg, 0.39 mmol). The r e s u l t i n g y e l l o w s l u r r y was s t i r r e d at -78°C f o r 5 min, then a t -63°C f o r 15 min, to a f f o r d a y e l l o w s o l u t i o n of l i t h i u m phenylthiocuprate (179). The s o l u t i o n was cooled to -78°C and the appropriate c y c l i c enone (0.46 mmol) was added and the mixture was s t i r r e d f o r 2-3 h. Saturated aqueous ammonium c h l o r i d e (-2 mL) and ether (15 mL) were added and the mixture was allowed to warm to room temperature. The r e s u l t i n g s l u r r y was f i l t e r e d through a column of F l o r i s i l (10 g, e l u t i o n w i t h e t h e r ) . The combined el u a t e was d r i e d over anhydrous magnesium s u l f a t e and the solvent was removed under reduced pressure. Column chromatography on s i l i c a g e l (15 g, e l u t i o n w i t h petroleum ether-ether) 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 afforded pure product. - 149 -General Procedure G: Reaction of Lithium C y a n o [ 2 - ( 4 - c h l o r 6 - l - b u t e n y l ) ] - cuprate (180) w i t h C y c l i c Enones To a co l d (-78°C), s t i r r e d s o l u t i o n of 4 - c h l o r o - 2 - l i t h i o - l -butene (95) (0.39 mmol) i n 3 mL of anhydrous THF was added i n one p o r t i o n , s o l i d cuprous cyanide (34 mg, 0.39 mmol). The r e s u l t i n g mixture was s t i r r e d at -78°C f o r 5 min, then at -63°C f o r 15 min to a f f o r d a ye l l o w s o l u t i o n of the l i t h i u m cyanocuprate (180). The s o l u t i o n was cooled to -78°C and the appropriate c y c l i c enone (0.46 mmol) was added. The r e s u l t i n g s o l u t i o n was s t i r r e d at -78°C f o r 1 h, warmed to -48°C, and s t i r r e d at t h i s temperature f o r 1 h. Saturated aqueous ammonium c h l o r i d e (~2 mL) and ether (15 mL) were added and the mixture was allowed to warm to room temperature. The r e s u l t i n g s l u r r y was f i l t e r e d through a column of F l o r i s i l (10 g, e l u t i o n w i t h ether). The combined e l u a t e was d r i e d over anhydrous magnesium s u l f a t e and the solvent was removed under reduced pressure. Column chromatography on s i l i c a g e l (15 g, e l u t i o n w i t h petroleum ether-ether) and d i s t i l l a -t i o n of the crude residue afforded pure product. - 150 -General Procedure H: C y c l i z a t i o n of the Intermediate Chloro Ketones  Derived from the Conjugate A d d i t i o n of the Cuprate Reagents (179) and  (180) to C y c l i c Enones To a s o l u t i o n of the appropriate chloro ketone (0.25 mmol) i n 2 mL of anhydrous THF was added potassium hydride (30 mg, 0.75 mmol) as a suspension i n 1 mL of anhydrous THF. The r e s u l t a n t yellow mixture was s t i r r e d at room temperature f o r 2.5-7.5 h. Saturated aqueous ^ammonium c h l o r i d e (3 mL) and ether (10 mL) were added and the mixture was s t i r r e d at room temperature f o r 10 min. The l a y e r s were separated and the aqueous l a y e r was ex t r a c t e d w i t h ether ( 2 x 4 mL). The combined ether e x t r a c t s were washed w i t h saturated b r i n e ( 2 x 2 mL) and d r i e d over anhydrous magnesium s u l f a t e . Solvent removal under reduced pressure f o l l o w e d 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 afforded the corresponding b i c y c l i c ketone. Preparation of 3-[2-(4-Chloro-l-butenyl)]cyclopentanone (189) 0 - 151 -a) Using the phenylthiocuprate (17 9) Following the general procedure F o u t l i n e d above, 2-cyclopenten-1-one (183) (37 mg, 0.46 mmol) was converted i n t o the c h l o r o ketone (189). Normal workup followed by column chromatography on s i l i c a g e l (15 g, e l u t i o n w i t h petroleum e t h e r - e t h e r , 5 : 2) and d i s t i l l a t i o n ( a i r -bath temperature 58-60°C/0.2 Torr) of the crude m a t e r i a l y i e l d e d 50 mg (75%) of (189) as a c l e a r , c o l o r l e s s o i l . This m a t e r i a l e x h i b i t e d i r ( f i l m ) : 1714, 1435 cm"1; ' H n i r (80 MHz, CDC1 3) 6: 2.10-2.41 (m, 6H), 2.53 (broad t , 2H, a l l y l i c methylene protons, J = 7 Hz), 2.67-3.06 (m, IH, H A ) , 3.62 ( t , 2H, -CH_2C1, J = 7 Hz), 4.90 (broad s, 2 H , o l e f i n i c 35 protons). Exact Mass c a l c d . f o r C H O CI: 172.0654; found: 172.0653. b) Using the cyanocuprate (180) Fo l l o w i n g the general procedure G, there was obtained 52 mg (77%) of the c h l o r o ketone (189) from 37 mg (0.46 mmol) of 2-cyclopenten-1-one (1S3). 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 described above. - 152 -Pre p a r a t i o n of £la-6-Me.thylenebicyclo [3. 3. 0] octan-2-one (195) Foll o w i n g the general procedure H o u t l i n e d above, the chloro ketone (189) (43 mg, 0.25 mmol) was converted i n t o the b i c y c l i c ketone (195). Normal workup followed by column chromatography on s i l i c a g e l (15 g, e l u t i o n w i t h petroleum e t h e r - e t h e r , 5 : 1) and d i s t i l l a t i o n ( a i r - b a t h temperature 53-55°C/0.2 Torr) of the crude m a t e r i a l afforded 23 mg (68%) of the b i c y c l i c ketone (195) as a c l e a r , c o l o r l e s s o i l . This m a t e r i a l e x h i b i t e d i r ( f i l m ) : 1712, 740 cm "*"; ^ nmr (80 MHz, CDC1 3) 6: 1.85-2.46 (m, 8H) , 2.50-2.82, 3.02-3.37 (two m, 2H, H A, H B ) , 4.86-5.01 (m, 2H, o l e f i n i c p r otons). Exact  Mass c a l c d . f o r CgH^O: 136.0888; found: 136.0888. - 153 -One-step c y c l i z a t i o n of the Intermediate Derived from the Reaction of  the Phenylthiocuprate (179) w i t h 2-Cyclopenten-l-one (183) To a c o l d (-78°C) s o l u t i o n of the phenylthiocuprate (179) (0.39 mmol, prepared as o u t l i n e d i n general procedure F) was added 37 mg (0.46 mmol) of 2-cyclopenten-l-one (183). The r e s u l t a n t y e l l o w s o l u t i o n was s t i r r e d at -78°C f o r 3 h. Hexamethylphosphoramide (0.64 mmol) was added and the mixture was allowed to warm to room temperature, and s t i r r e d f o r a f u r t h e r 3 h. Ether (15 mL) was added and the r e s u l t a n t mixture was f i l t e r e d through a column of F l o r i s i l (10 g, e l u t i o n w i t h e t h e r ) . The combined eluate was d r i e d over anhydrous magnesium s u l f a t e and the solvent was removed under reduced pressure. Column chromatography on s i l i c a g e l (15 g, e l u t i o n w i t h petroleum ether-ether, 5 : 1) gave 29 mg (55%) of the b i c y c l i c ketone (195). 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 to that reported above. Pr e p a r a t i o n of the Chloro Ketone (190) 0 - 154 -a) Using the phenylthiocuprate (179) Fol l o w i n g the general procedure F described above, 2-methyl-2-104 cyclopenten-l-one (184) (44 mg, 0.46 mmol) was allowed to react w i t h the phenylthiocuprate (179). Normal workup fo l l o w e d by s u b j e c t i o n of the crude product to column chromatography on s i l i c a g e l (15 g, e l u t i o n ) w i t h petroleum e t h e r - e t h e r , 3 : 2) and d i s t i l l a t i o n ( a i r - b a t h tempera-ture 60-63°C/0.2 Torr) gave 56 mg (77%) of a clear, c o l o r l e s s o i l . G l c a n a l y s i s of t h i s o i l showed th a t i t c o n s i s t e d of two components i n the r a t i o of 3 : 2, which on t i c a n a l y s i s (developing s o l v e n t , petroleum e t h e r - e t h e r , 3 : 2) gave one spot. The nmr spectrum of t h i s m a t e r i a l i n d i c a t e d that i t was a mixture of epimers (3 : 2). This mixture e x h i b i t e d i r ( f i l m ) : 1725, 1625, 440 cm"1; *H nmr (80 MHz, CDC1 3) 6: 0.90, 1.07 (two d, 3H, secondary methyl group, r a t i o 3 :2, = 7 Hz), 1.95-2.67 (m, 8H), 3.67 ( t , 2H, -C H j C l , J = 7 Hz), 4.85-5.07 (m, 2H, 35 o l e f i n i c p r otons). Exact Mass c a l c d . f o r C^H^O C l : 186.0811; found: 186.0810. b) Using the cyanocuprate (180) Foll o w i n g the general procedure G o u t l i n e d above, there was obtained 53 mg (75%) of (190) as a c l e a r , c o l o r l e s s o i l . Glc a n a l y s i s of t h i s o i l showed that i t c o n s i s t e d of a ~3 : 2 mixture of two components which e x h i b i t e d s p e c t r a l data ( i r , H^ nmr) i d e n t i c a l w i t h those reported above. - 155 -Pre p a r a t i o n of jiis_-l-Methyl-6-methylenebicyclo[3.3.0]octan-2-one (196) Fol l o w i n g the general procedure H o u t l i n e d above, the mixture of chloro ketones (190) (46 mg, 0.25 mmol) was converted i n t o the b i c y c l i c ketone (196). Normal workup followed by column chromatography on s i l i c a g e l (15 g, e l u t i o n w i t h petroleum ether-ether, 1 : 5 ) . and d i s t i l l a t i o n ( a i r - b a t h temperature 58-60°C/0.2 Torr) of the crude m a t e r i a l y i e l d e d 28 mg (75%) of the b i c y c l i c ketone (196) as a c l e a r , c o l o r l e s s o i l . This m a t e r i a l e x h i b i t e d i r ( f i l m ) : 1730, 1460, 890 cm 1 ; lR nmr (400 MHz, CDC1 3) &: 1.12 (s, 3H, t e r t i a r y methyl group), 1.50-1.60, 1.95-2.03 (two m, 2H), 1.80-1.90, 2.09-2.21 (two m, 2H), 2.23-2.34, 2.38-2.48 (two m, 4H), 2.75 (broad s, IH, H ), 4.95 (broad s, 2H, o l e f i n i c p r otons). Exact Mass c a l c d . f o r C ^ Q H ^ O : 150.1044; found: 150.1039. 0 - 156 -P r e p a r a t i o n of 3-[2-(4-Chloro-l-butenyl)]-3-methylcyclopentanone (191) a) Using the phenylthiocuprate (179) To a s o l u t i o n of the phenylthiocuprate (179) (prepared as o u t l i n e d i n general procedure F) was added boron t r i f l u o r i d e - e t h e r a t e (47 uL, 0.39 mmol) followed by 3-methyl-2-cyclopenten-l-one, (185) (44 mg, 0.46 mmol). The r e s u l t i n g deep y e l l o w s o l u t i o n was warmed to -48°C and s t i r r e d at t h i s temperature f o r 1 h and then at -20°C f o r 1 h. Normal workup followed by column chromatography on s i l i c a g e l (15 g, e l u t i o n w i t h petroleum e t h e r - e t h e r , 3 : 2) and d i s t i l l a t i o n ( a i r - b a t h temperature 60-62°C/0.2 Torr) of the crude residue afforded 59 mg (80%) of the chloro ketone (191) as a c l e a r , c o l o r l e s s o i l . This m a t e r i a l e x h i b i t e d i r ( f i l m ) : 1730, 1622, 1162, 905 cm"1; *H nmr (80 MHz, CDC13) &: 1.18 ( s , 3H, t e r t i a r y methyl group), 1.80-2.40 (m, 6H), 2.55 (broad t , 2H, a l l y l i c methylene protons, _J = 7.4 Hz), 3.63 ( t , 2H, -CH^Cl, J = 7.4 Hz), 4.88 ( t , IH, H^, J = 1 Hz), 4.98 ( s , IH, H c ) . Exact Mass c a l c d . f o r c 1 0 H i 5 ° 3 5 c l : 186.0811; found: 186.0805. - 157 -b) Using the cyanocuprate (180) Following the general procedure G o u t l i n e d above the cyanocuprate (180) was t r e a t e d with 1 equivalent of boron t r i f l u o r i d e - e t h e r a t e p r i o r to a d d i t i o n of the enone as i n (a) above, 3-methyl-2-cyclopenten-1-one (185) (44 mg, 0.46 mmol) was converted i n t o the chloro ketone (191) (57 mg, 78%). 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 w i t h that of the m a t e r i a l described above. Pre p a r a t i o n of cis-5-Methyl-6-methylenebicyclo[3.3.0]octan-2-one (197) Foll o w i n g the general procedure H o u t l i n e d above, the chloro ketone (191) (46 mg, 0.25 mmol) was allowed to react w i t h a suspension of potassium hydride i n THF f o r 7.5 h. Normal workup followed by column chromatography on s i l i c a g e l (15 g, e l u t i o n w i t h petroleum et h e r - e t h e r , 5 : 1) and d i s t i l l a t i o n ( a i r - b a t h temperature 58-60°C/0.2 Torr) of the crude m a t e r i a l a f f o r d e d 26 mg (70%) of the b i c y c l i c ketone (197). This m a t e r i a l e x h i b i t e d i r ( f i l m ) : 1712, 890 cm - 1; *H nmr (400MHz, CDC1„) 6: 1.27 (s, 3H, t e r t i a r y methyl group), 1.83-1.99 - 158 -(m, 3 H ) , 2 . 0 6 - 2 . 3 9 (m, 5 H ) , 2 . 4 5 - 2 . 5 6 (m, I H , H _ ) , 4 . 9 0 - 4 . 9 8 (m, 2 H , a o l e f i n i c protons). Exact Mass c a l c d . f o r C ^ Q H 0 : 1 5 0 . 1 0 4 4 ; found: 1 5 0 . 1 0 4 0 . P r e p a r a t i o n of . c i s - 1 - [ 2 - ( 4 - c h l o r o - l - b u t e n y l ) ] b i c y c l o [ 3 . 3 . 0 ] o c t a n - 3 - o n e ( 1 a) Using the phenylthiocuprate (179) F o l l o w i n g the general procedure F described above, b i c y c l o [ 3 . 3 . 0 ] -oct-l-en-3-one ( 1 8 6 ) ( 5 6 mg, 0.46 mmol) was allowed to r e a c t w i t h the phenylthiocuprate (179). Normal workup followed by column chromatography on s i l i c a g e l (15 g, e l u t i o n w i t h petroleum ether-ether, 5 : 2) and d i s t i l l a t i o n ( a i r - b a t h temperature 68-72°C/0.2 Torr) of the crude m a t e r i a l afforded 59 mg (70%) of (192) as a c l e a r , c o l o r l e s s o i l . This m a t e r i a l e x h i b i t e d i r ( f i l m ) : 1725, 1625, 1165, 900, 760 cm"1; XH nmr (400 MHz, CDC1 3) 6 : 1.45-1.55 (m, IH), 1.66-1.93 (m, 3H), 2.01-2.16 (m, 2H), 2.22, 2.52 (AB q> 2 H , H^, H , J = 18 Hz), 2.50-2.59 ( p a r t i a l l y obscured m, 2H, H^, H^), 2.52 ( t , 2H, a l l y l i c methylene protons, J = 8 Hz), 2.74 (m, IH, H^), 3.66 ( t , 2H, -CH 2C1, J = 8 Hz), - 159 -4.89, 4.99 (two s, o l e f i n i c protons). Exact Mass c a l c d . f o r 35 C 1 2 H 1 ? 0 CI: 212.0968; found: 212.0968. b) Using the cyanocuprate (180) Fol l o w i n g the general procedure G o u t l i n e d above, there was obtained 61 mg (72%) of the chloro ketone (192) from 56 mg (0.46 mmol) •> of bicyclo[3.3.0]oct-l-en-3-one (186). S p e c t r a l p r o p e r t i e s ( i r , nmr) of t h i s m a t e r i a l were i d e n t i c a l w i t h those reported above. 4 8 Preparation of 7-Methylenetricyclo[6.3.0.0 ' ]undecan-3-one (198) H F o l l o w i n g the general procedure H described above, the ch l o r o ketone (192) (53 mg, 0.25 mmol) was converted i n t o the t r i c y c l i c ketone (198). Normal workup followed by column chromatography on s i l i c a g e l (15 g, e l u t i o n w i t h petroleum e t h e r - e t h e r , 5 : 1) and d i s t i l l a t i o n ( a i r - b a t h temperature 64-67°C/0.2 Torr) fu r n i s h e d 28 mg (65%) of (198) as a c l e a r , c o l o r l e s s o i l . This m a t e r i a l e x h i b i t e d i r ( f i l m ) : 1712, 1620, 900 cm"1; *H nmr (400 MHz, CDC1 3) 6: 1.39-1.48 - 160 -(m, IH), 1.67-2.32 ( s e r i e s of m, 9H), 2.34-2.48 (m, 3H) , 2.52 ( t , IH, H. J_ = 9 Hz), 4.92 (broad s, 2H, o l e f i n i c protons). Exact Mass c a l c d . f o r C._H1,0: 176.1201; found: 176.1199. 12 16 ' Preparation of 3-[2-(4-Chloro-l-butenyl)]cyclohexanone (187) 4 / a) Using the phenylthiocuprate (179) Fo l l o w i n g the general procedure F o u t l i n e d above, 2-cyclohexen-1-one (181) (44 mg, 0.46 mmol) was converted i n t o the chloro ketone (187). The crude m a t e r i a l obtained a f t e r workup was subjected to column chromatography on s i l i c a g e l (15 g, e l u t i o n w i t h petroleum ether-ether, 3 : 2) and d i s t i l l a t i o n ( a i r - b a t h temperature 60-62°C/0.2 Torr) a f f o r d e d 61 mg (83%) of (187) as a c l e a r , c o l o r l e s s o i l . This m a t e r i a l e x h i b i t e d i r ( f i l m ) : 1710, 1640, 760 cm"1; *H nmr (100 MHz, CDC1 3) 6: 1.40-1.84 (m, 2H), 1.84-2.17 (m, 2H), 2.22-2.38 (m, 5H), 2.50 (broad t , 2H, a l l y l i c methylene protons, = 7 Hz), 3.60 ( t , 2H, -CH 2C1, jJ = 7 Hz), 4.91, 4.96 (two s, 2H, o l e f i n i c p r o tons). Exact Mass c a l c d . f o r C._H. C0 3 5C1: 186.0811; found: 186.0809. - 161 -b) Using the cyanocuprate (180) Following the general procedure G o u t l i n e d above, there was obtained 58 mg (80%) of (187) from 44 mg (0.46 mmol) of 2-cyclohexen-l-one (181). 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 w i t h that reported above. Pr e p a r a t i o n of nJLs.-7-methylenebicyclo [4 .3. 0]nonan-2-one (193) Foll o w i n g the general procedure H described above, the chloro ketone (187) (46 mg, 0.25 mmol) was converted i n t o the b i c y c l i c ketone (193). The crude m a t e r i a l obtained a f t e r workup was subjected to column chromatography on s i l i c a g e l (15 g, e l u t i o n w i t h petroleum e t h e r - e t h e r , 5 : 1) and d i s t i l l a t i o n ( a i r - b a t h temperature 57-59°C/0.2 T o r r ) , thus a f f o r d i n g 28 mg (75%) of (193) as a c l e a r , c o l o r l e s s o i l . This m a t e r i a l e x h i b i t e d i r ( f i l m ) : 1700, 890 cm"1; *H nmr (400 MHz, CDC1 3) 6: 1.60-1.70 (m, IH), 1.74-1.96 (m, 4H), 2.14-2.24 (m, IH), 2.27-2.41 (m, 4H), 2.73 (d of t , IH, H_, J = 8, 6 Hz), 2.97 (broad s, IH, H A ) , 4.83, 4.91 (two m, 2H, o l e f i n i c p r otons). Exact Mass c a l c d . - 162 -f o r C.„H,.0: 150.1044; found: 150.1044. 10 14 One-step C y c l i z a t i o n of the Intermediate Derived from the Reaction of  the Phenylthiocuprate (179) w i t h 2-Cyclohexen-l-one (181) To a c o l d (-78°C) s o l u t i o n of the phenylthiocuprate (179) (0.39 mmol, prepared as o u t l i n e d i n general procedure F) was added 44 mg (0.46 mmol) of 2-cyclohexen-l-one (181). The r e s u l t a n t y e l l o w s o l u t i o n was s t i r r e d at -78°C f o r 3 h. Hexamethylphosphoramide (0.64 mmol) was added and the mixture was allowed to warm to room temperature and s t i r r e d f o r a f u r t h e r 3 h. Ether (15 mL) was added and the r e s u l t a n t mixture was f i l t e r e d through a column of F l o r i s i l (10 g, e l u t i o n w i t h e t h e r ) . The combined e l u a t e was d r i e d over anhydrous magnesium s u l f a t e and the solvent was removed under reduced pressure. Column chromatography on s i l i c a g e l (15 g, petroleum e t h e r - e t h e r , 5 : 1) gave 33 mg (56%) of the b i c y c l i c ketone (193). 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 to that reported above. Preparation of the Chloro Ketone (188) - 163 -a) Using the phenylthiocuprate (179) Foll o w i n g the general procedure F o u t l i n e d above, 2-methyl-2-cyclohexen-l-one (182) (50 mg, 0.46 mmol) was allowed to react w i t h the cuprate reagent (179). Normal workup followed by column chromato-graphy on s i l i c a g e l (15 g, e l u t i o n w i t h petroleum e t h e r - e t h e r , 3 : 2) and d i s t i l l a t i o n ( a i r - b a t h temperature 61-63°C/0.2 Torr) of the crude residue afforded (188) (61 mg, 77%) as a c l e a r , c o l o r l e s s o i l . Glc a n a l y s i s of t h i s m a t e r i a l showed that i t c o n s i s t e d of a 96 : 4 mixture of two components. This m a t e r i a l showed one spot on t i c a n a l y s i s (developing solvent,petroleum e t h e r - e t h e r , 3 : 2 ) . The *H nmr spectrum i n d i c a t e d that i t c o n s i s t e d of a "96 : 4 mixture of two epimers. This mixture e x h i b i t e d i r ( f i l m ) : 1700, 1640, 920 cm" 1; *H nmr (400 MHz, CDC1 3) 6 : 0.95, 1.00 (two d, 3H, secondary methyl group, r a t i o -96 :4, J_ = 6 Hz), 1.64-1.90 (m, 4H), 1.98-2.08 (m, IH), 2.22-2.31 (m, IH), 2.43 (broad t , 2H, a l l y l i c methylene protons, J = 7.2 Hz), 2.41-2.60 (m, IH, H £ ) , 2.61 (m, IH, H ), 3.59 ( t , 2H, - C H ^ l , _J = 7.2 Hz), 4.83, 5.20 (two s, ~ 35 2H, o l e f i n i c protons). Exact Mass c a l c d . f o r C jH 0 C l : 200.0968; found: 200.0976. b) Using the cyanocuprate (180) Following the general procedure G o u t l i n e d above, there was obtained 62 mg (78%) of (188) as a c l e a r c o l o r l e s s o i l from 50 mg (0.46 mmol) 2-methyl-2-cyclohexen-1-one (182). Glc a n a l y s i s of t h i s m a t e r i a l showed that i t c o n s i s t e d of a 97 : 3 mixture of two components. This mixture e x h i b i t e d s p e c t r a l data ( i r , *H nmr) i d e n t i c a l w i t h those reported above. - 164 -Preparation of ju^-l-Methyl-7-methylenebicyclo[4.3.0]nonan-2-one (194) Fol l o w i n g the general procedure H o u t l i n e d above, the mixture of chloro ketones (188) (50 mg, 0.25 mmol) was converted i n t o the b i c y c l i c ketone (194). Normal workup f o l l o w e d by column chromatography on s i l i c a g e l (15 g, e l u t i o n w i t h petroleum e t h e r - e t h e r , 5 : 1) and d i s t i l l a t i o n ( a i r - b a t h temperature 58-61°C/0.2 Torr) of the crude m a t e r i a l gave 30 mg (75%) of (194) as a c l e a r , c o l o r l e s s o i l . This m a t e r i a l e x h i b i t e d i r ( f i l m ) : 1700, 1640, 890 cm" 1; 1H nmr (400 MHz, CDC1 3) 6: 1.21-1.31 (m, IH), 1.22 ( s , 3H, t e r t i a r y methyl group), 1.74-2.00 (m, 4K), 2.24-2.48 (m, 5H), 2.54 (broad s, IH, H ) , 4.82, 4.92 (two m, 2H, o l e f i n i c p rotons). Exact Mass c a l c d . f o r C^H^O: 164.1201; found: 164.1206. 0 - 165 -Large Scale Preparation of _ cxs-l-Methyl-6-methylenebicyclo[3.3.0]octan-2-one (196) To a co l d (-78°C), s t i r r e d s o l u t i o n of 4 - c h l o r o - 2 - l i t h i o - l - • butene (95) (1.9 mmol, prepared as o u t l i n e d i n general procedure A) was added 386 mg (2.1 mmol) of anhydrous magnesium bromide. A f t e r the r e s u l t i n g mixture had been s t i r r e d at t h i s temperature f o r 15 min, copper bromide-dimethylsulfide complex (110 mg, 0.54 mmol), boron t r i f l u o r i d e - etherate (232 u'L, 1.9 mmol), and 2-methyl-2-cyclo-penten-l-one (184) (153 mg, 1.6 mmol) were added s u c c e s s i v e l y . The deep yellow s o l u t i o n thus obtained was s t i r r e d at -78°C f o r 1.5 h. Saturated, b a s i c (pH 8 ) , aqueous ammonium c h l o r i d e (-5 mL) and ether (30 mL) were added and the r e s u l t i n g mixture was allowed to warm to room temperature w i t h vigorous s t i r r i n g . S t i r r i n g was maintained u n t i l the aqueous phase became deep blue. The organic l a y e r was separated, washed w i t h s a t u r a t e d , b a s i c (pH 8) 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 . Evaporation of the s o l v e n t , followed by d i s t i l l a t i o n ( a i r - b a t h temperature 60-63°C/0.2 Torr) afforded 238 mg (80%) of the mixture of c h l o r o ketones (190) (3 : 2 ) . 166 -Fo l l o w i n g the general procedure H, the mixture of chloro ketones (190) (238 mg, 1.2 mmol) were converted i n t o the b i c y c l i c ketone (196). Normal workup fo l l o w e d by d i s t i l l a t i o n ( a i r - b a t h temperature 58-63°C/0.2 Torr) of the crude m a t e r i a l afforded 145 mg (75%) of (196) as a c l e a r , c o l o r l e s s o i l . P r e p a r a t i o n of £jLs_-l-Methyl-6-methylenebicyclo [3. 3. 0]octan-2-ol (235) To a c o l d (-78°C), s t i r r e d - s o l u t i o n suspension of l i t h i u m aluminum hydride (0.19 g, 5.0 mmol) i n 15 mL of dry ether was added a s o l u t i o n of 1.50 g (10.0 mmol) of the b i c y c l i c ketone (196) i n 4 mL of anhydrous ether. The r e a c t i o n mixture was s t i r r e d at -78°C f o r 1.5 h. Saturated aqueous ammonium c h l o r i d e (3 mL) and ether (20 mL) were added and the mixture was allowed to warm to room temperature. The r e s u l t i n g white s l u r r y was f i l t e r e d ( e l u t i n g w i t h ether) through a column of F l o r i s i l (-20 g). The eluate was d r i e d over anhydrous magnesium s u l f a t e and the solvent was removed under reduced pressure. D i s t i l l a t i o n ( a i r - b a t h temperature 54-57°C/0.4 Torr) of the crude residue afforded 1.45 g (95%) of the a l c o h o l (235). Glc a n a l y s i s - 167 -of t h i s m a t e r i a l showed that i t co n s i s t e d of an 86 : 14 mixture of two components. This m a t e r i a l e x h i b i t e d i r ( f i l m ) : 3320, 3035, 1625, 1090, 890 cm"1; 1H nmr (400 MHz, CDC1 3) 6: 1.03 (s, 3H, t e r t i a r y methyl group), 1.31 (m, IH), 1.40-1.50 (m, IH), 1.50-1.64 (m, 2H), 1.76-1.92 (m, 3H), 2.33-2.43 (m, 3H, H^, Hg, Hc),- 3.78-3.86 (m, IH, -CHOH), 4.73, 4.83 (two broad s, 2H, o l e f i n i c protons). Exact Mass c a l c d . f o r C10 H16° : 1 5 2 - 1 2 0 1 ; found: 152.1198. Preparation of the T r i c y c l i c A l c o h o l (236) H O To a w e l l s t i r r e d , heated (55°C) s o l u t i o n of the a l c o h o l (235) (1.35 g, 8.8 mmol) i n 2 mL of anhydrous toluene was added s u c c e s s i v e l y 9.9 mL (12.3 mmol) of a s o l u t i o n of d i e t h y l z i n c i n toluene (15% W/V) and 1.02 mL (12.3 mmol) of methylene i o d i d e . Dry a i r was passed through t h i s mixture slowly f o r 1.5 h. The r e a c t i o n mixture was cooled to room temperature and 5 mL of h y d r o c h l o r i c a c i d (5%) was added. The l a y e r s were separated and the aqueous l a y e r was e x t r a c t e d w i t h ether (2 x 10 mL). The combined organic e x t r a c t s were washed w i t h 5% h y d r o c h l o r i c a c i d ( 2 x 3 mL), saturated b r i n e ( 2 x 2 mL) and d r i e d - 168 -over anhydrous magnesium s u l f a t e . Evaporation of the solvent gave an o i l which was subjected to column chromatography on s i l i c a g e l (65 g, e l u t i o n with petroleum e t h e r - e t h e r , 3 : 2 ) . D i s t i l l a t i o n ( a i r - b a t h temperature 55-60°C/0.4 Torr) of the crude m a t e r i a l obtained by concentration of the appropriate f r a c t i o n s y i e l d e d 1.12 g (76%) of the t r i c y c l i c a l c o h o l (236). Glc a n a l y s i s of t h i s m a t e r i a l i n d i c a t e d that i t was an 88 : 12 mixture of two components. This m a t e r i a l e x h i b i t e d i r ( f i l m ) : 3350, 3045, 1445, 1090 cm"1; *H nmr (400MHz, CDC1 3) 6: 0.28-0.48 (m, 4H, c y c l o p r o p y l p r o t o n s ) , 1.19 ( s , 3H, t e r t i a r y methyl group), 1.30-1.46 (m, 3H), 1.46-1.62 (m, 4H), 1.67-1.76 (m, IH), 1.78-1.86 (m, IH), 1.90-1.98 (m, 111), 3.80 (broad t , IH, -CHOH, J = 6 Hz). Exact Mass c a l c d . f o r C^H.-O: 11 lo 166.1358; found: 166.1344. Prep a r a t i o n of _c±s.-l,6,6-Trimethylbicyclo[3. 3.0]octan-2-ol (237) To a s o l u t ion of the t r i c y c l i c a l c o h o l (236) (1.070 g, 6.4 mmol) i n 10 mL of g l a c i a l a c e t i c a c i d was added 0.14 g (0.64 mmol) of - 169 -platinum oxide. The r e s u l t a n t suspension was shaken mechanically under an atmosphere of hydrogen (2.5 atm) at room temperature f o r 8 h. Saturated aqueous sodium bicarbonate was added to t h i s mixture u n t i l i t was b a s i c and the r e s u l t a n t aqueous s l u r r y was e x t r a c t e d w i t h ether (2 x 20 mL) and the combined ether e x t r a c t s were washed w i t h saturated bri n e ( 2 x 3 mL) and d r i e d over anhydrous magnesium s u l f a t e . Evaporation of the solvent f o l l o w e d by d i s t i l l a t i o n ( a i r - b a t h temperature 52-55°C/ 0.4 Torr) of the crude residue a f f o r d e d 1.028 g (95%) of the a l c o h o l (237). C a p i l l a r y g l c a n a l y s i s of t h i s m a t e r i a l showed that i t was an 87 : 13 mixture of two components. This m a t e r i a l e x h i b i t e d i r ( f i l m ) : 3360 cm"1; *H nmr (80 MHz, CDC1 3) 6: 0.92, 1.00, 1.12 (s, s, s, 3H each, t e r t i a r y methyl groups), 1.16-2.06 (m, 9H), 3.70 (broad t , IH, -CH0H, J = 8 Hz). Exact Mass c a l c d . f o r C n H 2 ( ) 0 : 168.1514; found: 168.1514. Pr e p a r a t i o n of .c_i&-l,6,6-Trimethylbicyclo[3.3.0]octan-2-one (230) To a s t i r r e d s l u r r y of p y r i d i n i u m chlorochromate (1.80 g, 8.4 mmol) and sodium acetate (137 mg, 1.68 mmol) i n 15 mL of dry - 170 -methylene c h l o r i d e was added a s o l u t i o n of the a l c o h o l (237) (0.95 g, 5.6 mmol) i n 2 mL of anhydrous methylene c h l o r i d e . The r e a c t i o n mixture, which turned dark almost immediately, was s t i r r e d f o r 2 h at room temperature. E t h e r ( 20 mL) was added and the mixture was f i l t e r e d through a column of F l o r i s i l (15 g). The column was e l u t e d w i t h ether. The solvent was removed from the eluate and the residue was d i s t i l l e d ( a i r - b a t h temperature 52-56°C/0.4 Torr) to a f f o r d 0.807 g (86%) of the b i c y c l i c ketone (230). This m a t e r i a l e x h i b i t e d i r ( f i l m ) : 1720, 1450 cm"1; *H nmr (400 MHz, CDC1 ) 6: 0.90, 1.05, 1.19 ( s , s, s, 3H each, t e r t i a r y methyl groups), 1.34-1.50 (m, 2H), 1.55-1.71 (m, 2H), 1.89-2.00 (m, 3H), 2.14-2.24 (m, IH), 2.31.-2.41 (m, IH); 1 3C nmr (20 MHz, CDC1 3) 6: 20.29, 25.10, 24.81, 29.02, 34.72, 37.39, 39.95, 42.18, 56.30, 58.44, 226.56. Exact Mass c a l c d . f o r C^H.-O: 166.1358; 11 lo found: 166.1358. Pr e p a r a t i o n of ,c_is_-l,6,6-Trimethylbicyclo [3.3. 0]oct-3-en-2-one (231) 241 231 - 171 -To a c o l d (-78°C), s t i r r e d s o l u t i o n of 0.70 g (4.2 mmol) of the ketone (230) and 3.5 mL (25 mmol) of dry t r i e t h y l a m i n e i n 20 mL of dry methylene c h l o r i d e was added, dropwise A.3 mL (21 mmol) of f r e s h l y prepared t r i m e t h y l s i l y l i o d i d e . 7 ^ The r e s u l t i n g orange s l u r r y was s t i r r e d f o r 15 min at t h i s temperature. Saturated aqueous sodium bicarbonate (~5 mL) was added and the mixture was allowed to warm to room tempera-t u r e . The l a y e r s were separated and the aqueous l a y e r was washed w i t h ether (3 x 10 mL). The combined ether e x t r a c t s were 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 a yellow o i l . Glc a n a l y s i s of t h i s o i l i n d i c a t e d the presence of the s i l y l enol ether (2A1) (98%) and the ketone (230) (~2%). An a l i q u o t of t h i s o i l e x h i b i t e d i r ( f i l m ) : 1625, 12A5 cm" 1; *H nmr (A00 MHz, CDC1 3) 6: 0.20 ( s , 9H, - S i ( M e ) 3 > 0.91, 0.99, 1.15 ( s , s, s, 3H each, t e r t i a r y methyl groups), 1.31-1.41 (m, 3H), 1.69-1.78 (m, 2H) , 2.OA (d of d of d, IH, H., J A 1 3 = 16, J A V = A, J . _ = 2.5 Hz), 2.21 (d of d A A B AX Ac. of d, IH, H B, = 16, J B X = 8, J f i Z = 2.5 Hz), A.37 ( t , IH, Hz, J = 2.5 Hz). Exact Mass c a l c d . f o r C,,H 0,0Si: 238.1753; found: 238.1756. 14 ZD The s i l y l enol ether (241) was d i s s o l v e d i n 15 mL of dry a c e t o n i t r i l e and the r e s u l t i n g s o l u t i o n was s t i r r e d at room temperature w i t h 1.12 g (5.0 mmol) of palladium ( I I ) acetate f o r 3 h. The mixture was f i l t e r e d through a short column of s i l i c a g e l (15 g) to remove the m e t a l l i c palladium and much of the colo r e d m a t e r i a l . A f t e r thoroughly washing the column with e t h e r , the combined eluate was concentrated to a f f o r d a brown viscous o i l . Column chromatography of t h i s m a t e r i a l on s i l i c a g e l (100 g, e l u t i o n w i t h petroleum e t h e r - e t h e r , 1 : 1) followed by d i s t i l l a t i o n ( a i r - b a t h temperature 57-61°C/0.4 Torr) of the o i l thus obtained afforded 0.511 g [74% from (230)] of the b i c y c l i c - 172 -enone (231). This m a t e r i a l e x h i b i t e d i r ( f i l m ) : 1675, 1580, 900 cm"1; XH nmr (400 MHz, CDC1 3) 6: 1-03, 1.12, 1.22 (s, s, s, 3H each, t e r t i a r y methyl groups), 1.25 ( p a r t i a l l y obscured d of d of d, IH, J_ = 14, 7.2, 7.2 Hz), 1.35 (d of d of d, IH, J = 14, 7.2, 3 Hz), 1.65 (d of d of d, IH, J = 14, 7.2, 7.2 Hz), 1.89 (d of d of d, IH, J = 14, 7.2, 3 Hz), 2.49 (broad s, IH, -1^) , 6.13 (d of d, IH, H z > J z y = 6, J z x = 2.6 Hz), 7.13 (d of d, IH, H^, J y z = 6, J y x = 3.6 Hz). Exact Mass c a l c d . f o r C n H 1 6 0 : 164.1201; found: 164.1206. Pr e p a r a t i o n of 4 - [ 2 - ( 4 - C h l o r o - 1 - b u t e n y l ) ] - l , 6 , 6 - t r i m e t h y l b i c y c l o [ 3 . 3 . 0 ] - octan-2-one (242) To a c o l d (-78°C), s t i r r e d s o l u t i o n of 4 - c h l o r o - 2 - l i t h i o - l -butene (95) (1.9 mmol, prepared as o u t l i n e d i n general procedure A) was added 386 mg (2.1 mmol) of anhydrous magnesium bromide. The r e s u l t i n g mixture was s t i r r e d at t h i s temperature f o r 15 min and copper bromide-dimethyl s u l f i d e complex (110 mg, 0.54 mmol) was added followed by 262 mg (1.6 mmol) of the enone (231). The deep y e l l o w s o l u t i o n thus obtained was s t i r r e d at -78°C f o r 1.5 h. Saturated, - 173 -basic (pH 8) aqueous ammonium c h l o r i d e (~5 mL) and ether (30 mL) were added and the r e s u l t i n g mixture was allowed to warm to room temperature w i t h vigorous s t i r r i n g . S t i r r i n g was maintained u n t i l the aqueous phase became deep blue. The organic l a y e r was separated, washed w i t h saturated,basic (pH 8) 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 . Evaporation of solvent followed by d i s t i l l a t i o n ( a i r -bath temperature 65-70°C/0.4 Torr) afforded 320 mg (79%) of the chloro ketone (242). This m a t e r i a l e x h i b i t e d i r ( f i l m ) : 1715, 1640 cm 1 ; *H nmr (80 MHz, CDC1 3) 6: 0.97, 1.10, 1.25 ( s , s, s, 3H each, t e r t i a r y methyl groups), 1.38-1.77 (m, 5H), 1.85-2.08 (m, 2H), 2.37-2.55 ( p a r t i a l l y obscured m, IH), 2.53 ( p a r t i a l l y obscured broad t , 2H, a l l y l i c methylene protons, J = 7 Hz), 3.66 ( t , 2H, C1CH -, J = 7 Hz), 4.93, 4.97 ( s , s, 35 IH each, o l e f i n i c protons). Exact Mass c a l c d . f o r ^ 5 ^ 2 3 ^ ^1: 254.1438: found: 254.1432. Preparation of the T r i c y c l i c Ketone (232) - 174 -Foll o w i n g the general procedure G o u t l i n e d above, 300 mg (1.18 mmol) of the chloro ketone (242) was allowed to react w i t h 116 mg (2.9 mmol) of potassium hydride i n 8 mL of THF. Normal workup followed by d i s t i l l a t i o n ( a i r - b a t h temperature 62-67°C/0.4 Torr) of the residue afforded 221 mg (86%) of the t r i c y c l i c ketone (232). This m a t e r i a l e x h i b i t e d i r ( f i l m ) : 1720, 890 cm"1; *H nmr (400 MHz, CDC1 3) 6: 0.96, 1.14, 1.15 (s, s, s, 3H each, t e r t i a r y methyl groups), 1.33-1.43 (m, IH), 1.46-1.68 (m, 2H), 1.81-1.95 (m, 3H), 1.98-2.07 (m, IH), 2.15-2.26, 2.3-2.4 (m, m, 2H, a l l y l i c methylene p r o t o n s ) , 2.74 (d of d of d, IH, H^, J = 10, 8, 4 Hz), 2.92 (broad d, IH, E^, J - 10 Hz), 4.91, 4.99 (m, m, IH each, o l e f i n i c p r otons). Exact Mass c a l c d . f o r (-,i^22°'' 218.1670; found: 218.1667. Pr e p a r a t i o n of the T r i c y c l i c a l c o h o l (245) To a cold (-78°C), s t i r r e d s o lution-suspension of l i t h i u m aluminum hydride (16 mg, 0.42 mmol) i n 8 mL of dry ether was added 190 mg (0.87 mmol) of the t r i c y c l i c ketone (232) i n 2 mL of dry ether. The r e a c t i o n mixture was allowed to s t i r at -78°C f o r 1.5 h. Saturated - 175 -aqueous ammonium c h l o r i d e (1 mL) and ether (15 mL) were added and the mixture was allowed to warm to room temperature. The r e s u l t i n g white s l u r r y was f i l t e r e d ( e l u t i n g with ether) through a column of F l o r i s i l (~10 g). The eluate was d r i e d over anhydrous magnesium s u l f a t e and the solvent was removed under reduced pressure. D i s t i l l a t i o n ( a i r - b a t h temperature 62-67°C/0.4 Torr) of the crude residue afforded 168 mg (88%) of the a l c o h o l (245). Glc a n a l y s i s of t h i s m a t e r i a l showed that i t con s i s t e d of a 1 : 1 mixture of two components. This m a t e r i a l e x h i b i t e d i r ( f i l m ) : 3350, 3050, 1640, 1460, 1170, 890 cm" 1; *H nmr (100 MHz, CDC1 3) 6: 1.00-1.30 (m, 9H, t e r t i a r y methyl groups), 1.38-2.02 (m, 8H), 2.30-2.78 (m, 3H), 2.38, 2.80 (broad d and m r e s p e c t i v e l y , IH, CHOH), 4.74-5.80 (m, 2H, o l e f i n i c protons). Exact Mass c a l c d . f o r C^^L^O: 220.1827; found: 220.1824. 9(12) P r e p a r a t i o n of (±)-A -Capnellene (205) 246 205 To a s o l u t i o n of 40 mg (0.18 mmol) of the a l c o h o l (245) i n 3 mL of dry THF was added a suspension of sodium hydride (12 mg,-0.54 mmol) - 176 -i n 1 mL of dry THF. The r e s u l t a n t suspension was s t i r r e d at room temperature f o r 2 h. Carbon d i s u l f i d e (271 uL, 4.5 mmol) and methyl i o d i d e (89 yL, 1.4 mmol) were added s u c c e s s i v e l y . The r e s u l t a n t deep yel l o w mixture was s t i r r e d at room temperature f o r 18 h. Ether (30 mL) and saturated aqueous ammonium c h l o r i d e (5 mL) were added and the mixture was allowed to s t i r at room temperature f o r 10 min. The l a y e r s were separated and the aqueous l a y e r was washed w i t h ether (2 x 10 mL). The combined organic e x t r a c t s were washed w i t h saturated b r i n e (3 mL) and dr i e d over anhydrous magnesium s u l f a t e . Evaporation of the solvent afforded the crude xanthate (246) as a yel l o w o i l . T i c a n a l y s i s (developing solvent, petroleum e t h e r , ~ 0.5) of t h i s m a t e r i a l showed one spot. This crude m a t e r i a l e x h i b i t e d i r ( f i l m ) : 1710, 1635, 1220, 1190, 815, 740 cm"1; *H nmr (80 MHz, CDC1 3) 6: 0.75-1.90 ( s e r i e s of m, 17H), 2.26-2.52 (m, 3H), 2.54, 2.57 (s , s, 3H, -SMe ), 4.70-4.97 (m, 2H, o l e f i n i c p r o t o n s ) , 5.60-5.85 (m, IH, -CHO-CSSMe ). To a s o l u t i o n of the xanthate (246) i n 2 mL of dry toluene was added 78 mg (2.7 mmol) of f r e s h l y prepared t r i - n - b u t y l t i n hydride followed by 4 mg (0.018 mmol) of 2 , 2 ' - a z o b i s i s o b u t y r o n i t r i l e and the r e s u l t a n t mixture was heated at r e f l u x f o r 4 h. A f t e r evaporation of most of the toluene, the crude residue was chromatographed on s i l i c a g e l (15 g, e l u t i n g solvent, petroleum e t h e r ) . Concentration 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 58-60°C/0.4 Torr) of 9 (12) the r e s i d u a l m a t e r i a l a f f o r d e d 24 mg (64%) of (±)-A -capnellene (205) as a c l e a r , c o l o r l e s s o i l . C a p i l l a r y g l c a n a l y s i s of t h i s m a t e r i a l showed that i t c o n s i s t e d of one component. Furthermore, i t was homo-geneous by t i c a n a l y s i s (developing solvent,petroleum ether, R^ = 0.9). This m a t e r i a l e x h i b i t e d i r ( f i l m ) : 3045, 1640, 1450, 1369, 1361, 870cm" 1; - 177 -*H nmr (400 MHz, CDC13) <5 : 0.98, 1.07, 1.15 (s, s, s, 3H each, t e r t i a r y methyl groups), 1.42-1.78 ( s e r i e s of m, 9H), 2.30-2.68 (m, 13 4H), 4.78, 4.89 (broad s, broad s, IH each, o l e f i n i c p r o t o n s ) ; C nmr (100 Mlz, CDC13) 6: 26.08, 29.22, 30.84, 31.69, 31.79, 40.65, 41.77, 42.37, 46.07, 48.13, 52.36, 53.59, 69.27, 104,90, 150.75. Exact Mass c a l c d . f o r C H : 204.1878; found: 204.1882. These s p e c t r a l data were i d e n t i c a l i n a l l respects w i t h those of synthesized ( i ) - c a p n e l l e n e . - 178 -Preparation of the Keto A c e t a l (287) 289 287 288 To a s o l u t i o n of the diketone (289) (2.2 g, 15.9 mmol) i n 10 mL of dry benzene was added 4.95 g (15.9 mmol) of the b i s - a c e t a l (288) i n 5 mL of dry benzene. To the r e s u l t a n t s o l u t i o n was added 86 mg (0.5 mmol) of p - t o l u e n e s u l f o n i c a c i d and the s o l u t i o n was r e f l u x e d f o r 3 h. The r e a c t i o n mixture was cooled to room temperature and washed w i t h saturated aqueous sodium bicarbonate (3 mL). The organic l a y e r was separated and d r i e d over anhydrous magnesium s u l f a t e . Glc a n a l y s i s of the residue obtained a f t e r evaporation of solvent showed the presence of compounds (288), (287) and (289) i n the r a t i o of 1 :2 : 1. Column chromatography on s i l i c a g e l (100 g, e l u t i o n w i t h petroleum e t h e r - e t h e r , 2 : 1) gave 3.2 g of the keto a c e t a l (287). The f r a c t i o n s c o n t a i n i n g the other two components were combined and r e c y c l e d twice to provide a t o t a l of 5.8 g (80%) of the c r y s t a l l i n e (m.p. 48°C) keto a c e t a l (287). This m a t e r i a l e x h i b i t e d *H nmr (400 MHz, CDC1 3) 6: 0.97 ( s , 6H, t e r t i a r y methyl groups), 1.82 (d of d, 2H, J = 14, 4 Hz), 2.18 (d of d, 2H, J - 14, 4 Hz), 2.30 (d of d, 2H, J = 18.5, 8 Hz), 2.48 (d of d, 2H, J = 18.5, 8 Hz), 2.83 (m, 2H), 3.45, 3.49 (s, s, 2H each, -0CH 2CMe 2CH 20-). These ^ nmr - 179 -s p e c t r a l data were i d e n t i c a l i n a l l r e spects to that of the keto 88a,88b a c e t a l (287) prepared p r e v i o u s l y i n our l a b o r a t o r y . P r e p a r a t i o n of the O l e f i n i c Acetal (290) To a s t i r r e d suspension of methyltriphenylphosphonium bromide (4.1 g, 11.6 mmol) i n 10 mL of anhydrous THF was added a s o l u t i o n of n - b u t y l l i t h i u m (11.6 mmol) i n hexane. S t i r r i n g was continued f o r 20 min at room temperature. The r e s u l t i n g y ellow s o l u t i o n of methylenetriphenyl-106 phosphorane was cooled to -78°C and a s o l u t i o n of the keto a c e t a l (287) (2.0 g, 8.9 mmol) i n 5 mL of dry THF was added. The c o o l i n g bath was removed a f t e r a few minutes and the r e a c t i o n mixture was s t i r r e d f o r 3 h at room temperature. Petroleum ether (40 mL) was added and the r e s u l t i n g suspension was f i l t e r e d through a column of F l o r i s i l (20 g, e l u t i o n w i t h e t h e r ) . Evaporation of the solvent from the el u a t e and d i s t i l l a t i o n ( a i r - b a t h temperature 105-110°C/10 Torr) of the residue afforded 1.66 g (84%) of the alkene (290) as a c l e a r , c o l o r l e s s o i l . 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, 1647, 1115, 895 cm" 1; Vnir (400 MHz, CDC1-) 6: 0.96 ( s , 6H, t e r t i a r y methyl groups), 1.50 (d of d, - 180 -2H, J = 12, 6 Hz), 2.06 (broad d, 2H, J = 14 Hz), 2.30 (d of d, 2H, J = 12, 8 Hz), 2.42-2.60 (m, 4H), 3.44, 3.48 ( s , s, 2H each, -OCH 2CMe 2CH 20-), 4.81 ( t , 2H, o l e f i n i c protons, J. = 2 Hz). Exact Mass ca l c d . f o r C..H..O,: 222.1619; found: 222.1617. 14 11 2 ' P r e p a r a t i o n of cis-7-Methylenebicyclo[3.3.0]octan-3-one (292) To a s o l u t i o n of the o l e f i n i c a c e t a l (290) (1.8 g, 8.1 mmol) i n 15 mL of acetone was added 15 mL of aqueous s u l f u r i c a c i d (0.1%, w/v). The r e s u l t a n t mixture was allowed to s t i r at room temperature f o r 8 h. Saturated aqueous sodium bicarbonate (5 mL) and ether (25 mL) were added and the mixture was v i g o r o u s l y s t i r r e d f o r 5 min at room temperature. The l a y e r s were separated and the aqueous l a y e r was washed w i t h ether (2 x 10 mL). The combined e x t r a c t s were d r i e d over anhydrous magnesium s u l f a t e and the solvent was removed under reduced pressure. The residue was subjected to column chromatography on s i l i c a g e l (75 g, e l u t i o n w i t h petroleum e t h e r - e t h e r , 2 : 1 ) . Concentration 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 75-80°C/10 Torr) of the residue f u r n i s h e d 0.94 g (82%) of the keto o l e f i n (292). This - 181 -m a t e r i a l e x h i b i t e d i r . ( f i l m ) : 3045, 1710, 1640, 1415, 1400, 1160, 1140 cm" 1; *H nmr (400 MHz, CDC1 3) 6: 2.05 (d of d, 2H, J = 19.2, 4 Hz), 2.14 (broad d of d, 2H, J = 16, 2 Hz), 2.40 (d of d, 2H, J = 19.2, 8 Hz), 2.58-2.71 (m, 2H), 2.71-2.85 (m, 2H), 4.89 ( t , 2H, o l e f i n i c protons, J = 2 Hz); 1 3C nmr (20 MHz, CDC13) 6: 39.37, 39.52, 43.49, 107.59, 151.53, 221.16. Exact Mass c a l c d . f o r C g H ^ O : 136.0888; found: 136.0883. Preparation of the O l e f i n i c A l c o h o l (293) H To a c o l d (-78°C), s t i r r e d s olution-suspension of l i t h i u m aluminum hydride (0.118 g, 3.1 mmol) i n 12 mL of anhydrous ether was added a s o l u t i o n o f 0.85 g (6.25 mmol) of the keto o l e f i n (292) i n 3 mL of anhydrous ether. The r e a c t i o n mixture was allowed to s t i r at -78°C f o r 1.5 h. Saturated aqueous ammonium c h l o r i d e (2 mL) and ether (15 mL) were added and the mixture was allowed to warm to room temperature. The r e s u l t i n g white s l u r r y was f i l t e r e d through a column of F l o r i s i l (20 g, e l u t i o n w i t h e t h e r ) . The eluate was d r i e d over anhydrous magnesium s u l f a t e and the solvent was removed under reduced pressure. D i s t i l l a t i o n ( a i r - b a t h temperature 78-82°C/ 10 Torr) of the crude residue afforded - 182 -0.82 g (94%) of the o l e f i n i c a l c o h o l (293). C a p i l l a r y g l c a n a l y s i s of t h i s m a t e r i a l showed that i t c o n s i s t e d of one component. This m a t e r i a l e x h i b i t e d i r ( f i l m ) : 3300, 3050, 1645, 1100, 895 cm" 1; *H nmr (80 MHz, J = 6.4 Hz), 4.83 (broad s, 2H, o l e f i n i c protons). Exact Mass c a l c d . f o r C.H.,0: 138.1045; found: 138.1042. 9 14 ' Preparation of the T r i c y c l i c A l c o h o l (294) To a w e l l s t i r r e d , heated (55°C) s o l u t i o n o f the o l e f i n i c a l c o h o l (293) (0.6 g, 4.3 mmol) i n 2 mL of anhydrous toluene was added successive-l y 4.79 mL (5.85 mmol) of a s o l u t i o n of d i e t h y l z i n c i n toluene (15% w/v) and 0.488 mL (5.85 mmol) of methylene i o d i d e . Dry a i r was passed through t h i s mixture s l o w l y f o r 1.5 h. " The r e a c t i o n mixture was cooled to room temperature and 4 mL of h y d r o c h l o r i c a c i d (5%) was added. The la y e r s were separated and the aqueous l a y e r was e x t r a c t e d w i t h ether (2 x 10 mL). The combined e x t r a c t s were washed with h y d r o c h l o r i c a c i d (5%, 2 x 3 mL), saturated b r i n e and d r i e d over anhydrous magnesium s u l f a t e . Evaporation of the solvent gave an o i l which was subjected to CDC1 3) 6: 1.02-1.45 (m, 3H), 1.90-2.70 (m, 8H), 4.12 ( q u i n t e t , IH, -CH0H> H - 183 -column chromatography on s i l i c a g e l (45 g, e l u t i o n w i t h petroleum ether-ether, 3 : 2 ) . D i s t i l l a t i o n ( a i r - b a t h temperature 80-84°C/10 Torr) of the m a t e r i a l obtained from the appropriate f r a c t i o n s a f f o r d e d 0.535 g (81%) of the t r i c y c l i c a l c o h o l (294). This m a t e r i a l e x h i b i t e d i r ( f i l m ) : 3300, 3050, 1084, 1100 cm" 1; *H nmr (100 MHz, CDC1 3) 6: 0.18-0.64 (m, 4H, c y c l o p r o p y l p r o t o n s ) , 1.14-2.65 ( s e r i e s of m, 11H), 4.15 (m, IH, -CHOH). Exact Mass c a l c d . f o r C^H^O: 152.1201; found: 152.1193. Prep a r a t i o n of the T r i c y c l i c Ketone (295) To a s t i r r e d s l u r r y of p y r i d i n i u m chlorochromate (1.03 g, 4.8 mmol) and sodium acetate (65 mg, 0.8 mmol) i n 10 mL of dry methylene c h l o r i d e was added a s o l u t i o n of the t r i c y c l i c a l c o h o l (294) (0.5 g, 3.3 mmol) i n 2 mL of anhydrous methylene c h l o r i d e . The r e a c t i o n mixture, which turned dark almost immediately, was s t i r r e d f o r 2 h at room temperature. Ether (~15 mL) was added and Che mixture was f i l t e r e d through a column of F l o r i s i l (10 g). The column was e l u t e d w i t h ether. The solvent was removed from the elu a t e and the residue was d i s t i l l e d ( a i r - b a t h tempera-ture 80-85°C/10 Torr) to a f f o r d 0.429 g (87%) of the t r i c y c l i c ketone - 184 -(295). This m a t e r i a l e x h i b i t e d i r ( f i l m ) : 3047, 1725, 1400, 1165, 1010 cm"1; Hi nmr (400 MHz, CDC1 3) 6: 0.38-0.47, 0.47-0.55 (m, m, 2H each, c y c l o p r o p y l p r o t o n s ) , 2.31 (d of d, 2H, J = 14, 4 Hz), 1.92 (d of d, 2H, J = 14, 8 Hz), 2.16 (d of d, 2H, J = 19, 4 Hz), 2.48 (d of d, 2H, J = 19, 8 Hz), 2.87 (m, 2H). Exact Mass c a l c d . f o r C^H^O: 150.1045; found: 150.1042. Preparation of the Enone (284) 296 284 To a c o l d (-78°C), s t i r r e d s o l u t i o n of 0.4 g (2.6 mmol) of the ketone (295) and 2.2 mL (15.9 mmol) of dry t r i e t h y l a m i n e i n 15 mL of dry methylene c h l o r i d e was added, dropwise, 2.92 mL (14.3 mmol) of f r e s h l y prepared t r i m e t h y l s i l y l i o d i d e . The r e s u l t i n g orange s l u r r y was allowed to s t i r f o r 15 min at t h i s temperature. Saturated aqueous sodium bicarbonate (4 mL) was added and the mixture was allowed to warm to room temperature. The l a y e r s were separated and the aqueous l a y e r was washed with ether (3 x 10 mL). The combined ether e x t r a c t s were d r i e d over anhydrous magnesium s u l f a t e . Removal of the solvent afforded a yellow o i l . Glc a n a l y s i s of t h i s o i l i n d i c a t e d the presence - 185 -of the s i l y l enol ether (296) (96%) and the ketone (295) (~4%). An a l i q u o t of t h i s o i l e x h i b i t e d i r ( f i l m ) : 3025, 1625, 1240, 860, 840 cm"1; ^ nmr (100 MHz, CDC1 3) 6: 0.20-0.78 (m, 4H, c y c l o p r o p y l p r o t o n s ) , 0.36 ( s , 9H, - S i ( M e ) 3 ) , 4.76 (d of t , IH, H^, J = 2, 2 Hz). Exact Mass c a l c d . f o r C ^ H ^ O S i : 222.1440; found: 222.1444. The s i l y l enol ether (296) was d i s s o l v e d i n 10 mL of dry aceto-n i t r i l e and the r e s u l t i n g s o l u t i o n was s t i r r e d at room temperature w i t h 0.873 g (3.9 mmol) of palladium ( I I ) acetate f o r 3 h. The r e s u l t i n g mixture was f i l t e r e d through a short column of s i l i c a g e l (10 g) to remove the m e t a l l i c palladium and much of the c o l o r e d m a t e r i a l . A f t e r thoroughly washing the column w i t h e t h e r , the combined el u a t e was concentrated to a f f o r d a brown viscous o i l . Column chromatography of t h i s m a t e r i a l on s i l i c a g e l (45 g, e l u t i o n w i t h petroleum ether-ether, 2 : 3 ) , followed by d i s t i l l a t i o n ( a i r - b a t h temperature 83-87°C/10 Torr) of the m a t e r i a l thus obtained afforded 0.288 g (73%) of the t r i c y c l i c enone (284). This m a t e r i a l e x h i b i t e d i r ( f i l m ) : 3025, 1690, 1620 cm"1; *H nmr (400 MHz, CDC1 3) 6: 0.55-0.69 (m, 4H, c y c l o p r o p y l p r o t o n s ) , 1.55-1.68 (m, 2H), 2.19 (d of d, IH, J = 18, 4 Hz), 2.44, 2.74 (broad AB p a i r of d, 2H, H^, Hg, J = 18 Hz), 2.61 (d of d, IH, J = 18, 6 Hz), 3.29 (m, IH, H c ) , 6.17 (m, IH, H^). Exact Mass c a l c d . f o r C 1 0 H 1 2 0 : 148.0888; found: 148.0893. - 186 -Preparation of the Chloro Ketone (297) To a c o l d (-78°C), s t i r r e d s o l u t i o n of A - c h l o r o - 2 - l i t h i o - l -butene (95) (1.9 mmol, prepared as o u t l i n e d i n general procedure A) was added 386 mg (2.1 mmol) of anhydrous magnesium bromide. A f t e r the r e s u l t i n g mixture had been s t i r r e d at t h i s temperature f o r 15 min, copper bromide-dimethylsulfide complex (110 mg, 0.54 mmol) and the t r i c y c l i c enone (284) (0.25 g, 1.6 mmol) were added s u c c e s s i v e l y . The deep yel l o w s o l u t i o n thus obtained was s t i r r e d at -78°C f o r 1.5 h. Saturated, b a s i c (pH 8),aqueous ammonium c h l o r i d e (~5 mL) and ether (30 mL) were added and the r e s u l t i n g mixture was allowed to warm to room temperature wit h vigorous s t i r r i n g . S t i r r i n g was maintained u n t i l the aqueous phase became deep blue. The organic l a y e r was separated, washed w i t h s a t u r a t e d , b a s i c (pH 8), 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 . Evaporation of the s o l v e n t , followed by d i s t i l l a t i o n ( a i r - b a t h temperature 100-105°C/10 Torr) afforded 0.333 g (83%) of the c h l o r o ketone (297). This m a t e r i a l e x h i b i t e d i r ( f i l m ) : 3045, 3050, 1735, 1610, 1440, 1400, 1165, 900 cm"1; *H nmr (80 MHz, CDC1-) 6: 0.52 ( s , 4H, c y c l o p r o p y l p r o t o n s ) , 1.31-3.12 ( s e r i e s of m, - 187 -11H), 3.67 ( t , 2H, -CH 2C1, J = 7.6 Hz), 4.90 ( t , IH, H^, J = 1.6 Hz), 35 5.02 ( s , IH, Hg). Exact Mass c a l c d . f o r C^H^O C l : 238.1124; found: 238.1129. Preparation of the T e t r a c y c l i c O l e f i n i c Ketone (285) He F o l l o w i n g the general procedure G, 280 mg (1.18 mmol) of the chloro ketone (297) was allowed to r e a c t w i t h 116 mg (2.9 mmol) of potassium hydride i n 8 mL of dry THF. Normal workup followed by d i s t i l l a t i o n ( a i r - b a t h temperature 92-96°C/10 Torr) of the crude residue a f f o r d e d 190 mg (80%) of t e t r a c y c l i c ketone (285). This m a t e r i a l e x h i b i t e d i r ( f i l m ) : 3035, 1720, 1623, 895 cm" 1; ^ nmr (400 MHz, CDC1 3) 6: 0.51 (m, 4H, c y c l o p r o p y l p r o t o n s ) , 2.20-2.36 (m, 2H), 2.61, 3.12 (d, d, IH each, Hfi, H c > J = 12.8 Hz), 2.81-3.00 (m, 2H), 3.15-3.68 ( s e r i e s of m, 6H), 4.96, 5.02 ( t , t , IH each, o l e f i n i c protons, J = 1.6 Hz). Exact Mass c a l c d . f o r C..H..0: 202.1357; found: 202.1357. - 188 -Preparation of the T e t r a c y c l i c Ketone (300) To a s o l u t i o n of the e x o c y c l i c alkene (285) (80 mg, 0.39 mmol) i n 3 mL of dry methylene c h l o r i d e was added 6 mg (0.039 mmol) of p - t o l u e n e s u l f o n i c a c i d and the r e s u l t a n t s o l u t i o n was s t i r r e d at room temperature f o r 24 h. Ether (~10 mL) was added and the s o l u t i o n was washed w i t h saturated aqueous sodium bicarbonate ( 2 x 2 mL). The organic l a y e r was d r i e d over anhydrous magnesium s u l f a t e and the solvent was removed under reduced pressure. D i s t i l l a t i o n ( a i r - b a t h temperature 95°C/10 Torr) of the residue a f f o r d e d 70 mg (88%) of the endocyclic alkene (300). Glc a n a l y s i s of t h i s m a t e r i a l i n d i c a t e d that i t was a s i n g l e component. T h i s ' m a t e r i a l e x h i b i t e d i r ( f i l m ) : 3046, 1715 cm"1; *H nmr (80 MHz, CDC1 3) 6: 0.47 (broad s, 4H, c y c l o p r o p y l protons), 1.10-1.52 (m, 2H), 1.70 (broad d, 3H, =CMe, J = 2 Hz), 1.82-2.80 ( s e r i e s of m, 8H), 5.25 (broad s, 111, o l e f i n i c p r oton). Exact Mass c a l c d . f o r C..H 0: 202.1358; found: 202.1358. - 189 -Preparation of the T r i c y c l i c Ketones (298) and (299) :0 298 299 To a s o l u t i o n of the t e t r a c y c l i c ketone (285) (65 mg, 0.32 mmol) i n 2 mL of g l a c i a l a c e t i c a c i d was added 14 mg (0.064 mmol) of platinum oxide. The r e s u l t a n t suspension was shaken mechanically under an atmosphere of hydrogen (3 atm) at room temperature f o r 8 h. Saturated aqueous sodium bicarbonate was added to t h i s mixture u n t i l i t was basi c and the r e s u l t a n t aqueous s l u r r y was e x t r a c t e d w i t h ether ( 3 x 5 mL). The ether e x t r a c t s were washed w i t h saturated b r i n e (2 mL) and d r i e d over anhydrous magnesium s u l f a t e . Evaporation of the solvent followed by d i s t i l l a t i o n ( a i r - b a t h temperature 90-95°C/10 Torr) of the residue afforded 63 mg (96%) of (298) and (299) as a c l e a r c o l o r l e s s o i l . C a p i l l a r y g l c a n a l y s i s of t h i s m a t e r i a l showed that i t c o n s i s t e d of a 42 : 58 mixture of two components. This mixture gave one spot on t i c a n a l y s i s (developing s o l v e n t , petroleum e t h e r - e t h e r , 5 : 1 ) . This m a t e r i a l e x h i b i t e d i r ( f i l m ) : 1718, 1445 cm"1; *H nmr (400 MHz, CDC1 3) 6: 0.98, 1.01 (d, d, 3H, secondary methyl group, J_ = 6, 4 Hz, respect-i v e l y ) , 1.03, 1.035 (s, s, 3H each, t e r t i a r y methyl groups), 1.17-2.70 ( s e r i e s of m, 13H). Exact Mass c a l c d . f o r C H 0: 206.1670; found: - 190 -206.1667. Subjection of the t e t r a c y c l i c ketone (300) (45 mg, 0.22 mmol) to hydrogenation-hydrogenolysis as described above, y i e l d e d a f t e r normal workup 41 mg (91%) of (298) and (299) as a c l e a r , c o l o r l e s s o i l . C a p i l l a r y g l c a n a l y s i s of t h i s m a t e r i a l showed the presence of the same two components as above (5 : 95, r e s p e c t i v e l y ) . Preparation of (i)-Pentalenene (251) and (±)-9-epi-Pentalenene (269) To a c o l d (-78°C) s o l u t i o n of the t r i c y c l i c ketones (2 98) and (299) ( r a t i o 42 :58, r e s p e c t i v e l y ) (50 mg, 0.24 mmol) i n 1.5 mL of anhydrous ether was added m e t h y l l i t h i u m (0.28 mmol) as a s o l u t i o n i n ether. The r e s u l t a n t mixture was allowed to s t i r at -78°C f o r 1.5 h. Saturated aqueous ammonium c h l o r i d e (1 mL) and ether (5 mL) were added and the mixture was allowed to warm to room temperature. The l a y e r s were separated and the aqueous l a y e r was washed with ether ( 2 x 3 mL). The combined organic e x t r a c t s were washed w i t h saturated b r i n e (2 mL) and d r i e d over anhydrous magnesium s u l f a t e . Evaporation of the solvent a f f o r d e d an o i l which, on the b a s i s of c a p i l l a r y g l c a n a l y s i s , c o n s i s t e d - 191 -of a mixture of the t r i c y c l i c ketones (299) and (298) ( r a t i o =28 : 12, r e s -p e c t i v e l y ) and two other components ( r a t i o ~31 :29). This o i l was exposed m e t h y l l i t h i u m twice as described above, to a f f o r d a c l e a r , c o l o r l e s s o i l . C a p i l l a r y g l c a n a l y s i s of t h i s crude m a t e r i a l showed the presence of the mixture of t r i c y c l i c ketones (299) and (298) (17 : 1) and the same two components as seen above, i n the r a t i o of 42 : 40. These two major components were i d e n t i f i e d as the mixture of t e r t i a r y a l c o h o l s (302) based on the f o l l o w i n g data: i r ( f i l m ) : 3310 cm ms m/e 222 (M +) , 204 (M + - H 20). The c l e a r , c o l o r l e s s o i l thus obtained was d i s s o l v e d i n 5 mL of dry benzene c o n t a i n i n g p - t o l u e n e s u l f o n i c a c i d (14 mg, 0.08 mmol). The s o l u t i o n was heated at r e f l u x under a Dean-Stark trap f o r 1.5 h. The r e a c t i o n mixture was cooled to room temperature .and washed w i t h saturated aqueous sodium bicarbonate (1 mL). The organic phase was d r i e d over anhydrous magnesium s u l f a t e and most of the solvent was evaporated under reduced pressure. The crude residue thus obtained was subjected . 108 to column chromatography on s i l i c a g e l impregnated w i t h s i l v e r n i t r a t e (15 g, e l u t i o n w i t h petroleum e t h e r ) . The f i r s t - e l u t e d f r a c t i o n provided, upon d i s t i l l a t i o n ( a i r - b a t h temperature 76-80°C/10 T o r r ) , 16 mg (33%) of (±)-9-ep_i-pentalenene (269) as a c l e a r , c o l o r l e s s o i l . This m a t e r i a l was one component by g l c and t i c analyses and e x h i b i t e d i r ( f i l m ) : 3020, 1440, 1375, 1360 cm" 1; *H nmr (400 MHz, CDC1 3) 6: 0.94 (d, 3H, J = 7 Hz), 1.23-1.70 (m, 15H), 1.62 (broad s, 3H), 2.64 (broad d, IH, J = 9 ) , 2.90 (m, IH), 5.21 ( s , IH); 1 3 C nmr (100 MHz, CDC1 3) 6: 13.41, 15.22, 28.52, 29.13, 31.45, 32.96, 39.75, 45.01, 46.23, 50.52, 54.81, 63.44, 131.30, 140.58. Exact Mass c a l c d . f o r C ^ H ^ : 204.1878; found: 204.1880. These s p e c t r a l data are i d e n t i c a l i n a l l respects with those of (±)-9-epi-pentalenene reported by Paquette and Annis. The l a t e r - e l u t e d f r a c t i o n y i e l d e d on d i s t i l l a t i o n ( a i r - b a t h temperature 75-80°C/10 Torr) 15 mg (32%) of (±)-pentalenene (251) as a c l e a r , c o l o r l e s s o i l . This m a t e r i a l was homogeneous by g l c and t i c analyses, and e x h i b i t e d i r ( f i l m ) : 3040, 1445, 1362, 1350 cm "*"; *H nmr (400 MHz, CDC1 3) 6: 0.91 (d, 3H, J = 7 Hz), 0.990, 0.995 ( s , s, 3H each), 1.14-1.88 ( s e r i e s of m, 9H), 1.63 (broad s, 3H), 2.56 (broad d, IH, J = 9 Hz), 2.66 (m, IH), 5.19 (broad s, IH) ; 1 3 C nmr (100 MHz, CDC1 3) 6: 15.41, 16.94, 27.64, 29.13, 29.98, 33.59, 40.51, 44.61, 46.90, 48.98, 59.39, 62.14, 64.77, 129.53, 140.63. Exact Mass c a l c d . f o r C ^ H ^ : 204.1878; found: 204.1892. These s p e c t r a l data are i d e n t i c a l i n a l l 85 respects to those of (±)-(251) synthesized by Paquette. 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