Open Collections

UBC Theses and Dissertations

UBC Theses Logo

UBC Theses and Dissertations

Stereoselective total syntheses of tetracyclic sesquiterpenes: (±)-ishwarone and (±)-ishwarane Hall, Tse Wai 1978

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

Item Metadata

Download

Media
831-UBC_1978_A1 H33.pdf [ 9.07MB ]
Metadata
JSON: 831-1.0060956.json
JSON-LD: 831-1.0060956-ld.json
RDF/XML (Pretty): 831-1.0060956-rdf.xml
RDF/JSON: 831-1.0060956-rdf.json
Turtle: 831-1.0060956-turtle.txt
N-Triples: 831-1.0060956-rdf-ntriples.txt
Original Record: 831-1.0060956-source.json
Full Text
831-1.0060956-fulltext.txt
Citation
831-1.0060956.ris

Full Text

STEREOSELECTIVE TOTAL SYNTHESES OF TETRACYCLIC SESQUITERPENES : (±)-ISHWARONE AND (+)-ISHWARANE by TSE WAI HALL B.Sc.(Hons.), University of Guelph, 1972 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 this thesis as conforming to the required standard THE UNIVERSITY OF BRITISH COLUMBIA September 1978 © Tse Wai(Hall, 1978 In p r e s e n t i n g t h i s t h e s i s in p a r t i a l f u l f i l m e n t o f the requ i rement s f o r an advanced degree at the U n i v e r s i t y o f B r i t i s h Co lumb ia , I ag ree that the L i b r a r y s h a l l make i t f r e e l y a v a i l a b l e f o r r e f e r e n c e and s tudy . I f u r t h e r agree t h a t p e r m i s s i o n f o r e x t e n s i v e c o p y i n g o f t h i s t h e s i s f o r s c h o l a r l y purposes may be g r a n t e d by the Head o f my Department o r by h i s r e p r e s e n t a t i v e s . It i s u n d e r s t o o d that c o p y i n g o r p u b l i c a t i o n o f t h i s t h e s i s f o r f i n a n c i a l g a i n s h a l l not be a l l o w e d w i thout my w r i t t e n p e r m i s s i o n . Department o f The U n i v e r s i t y o f B r i t i s h Co lumbia 2075 Wesbrook P l a c e V a n c o u v e r , Canada V6T 1W5 - i i -ABSTRACT This thesis describes a stereoselective total synthesis of (±)-ishwarone 12_ and (±)-ishwarane _13_ via the trans-fused octalone 226 as the key intermediate. The f i r s t synthetic attempt toward the octalone 226 involved a Lewis acid-catalyzed Diels-Alder reaction between 1,3-butadiene and the unsaturated keto ester 258, obtained from the known diene ester 261 by selective hydrogenation and a l l y l i c oxidation. Two isomeric Diels-Alder adducts, 272 and 273, were isolated in moderate yield. The relative stereochemistry of these adducts was determinated by chemical correlation with compounds of known structure and stereo-chemistry . In a second approach to the synthesis of the octalone 226, 3,4-dimethyl-2-cyclohexen-l-one (227) was treated with vinyl magnesium bromide in the presence of cuprous iodide and dimethylsulfide to afford the adduct 142, which was converted into the aldehyde 304. Reaction of the latter with dibromomethylenetriphenylphosphorane afforded the dibromo olefin 305. Trapping the lithium acetylide generated from the dibromo olefin 305 with gaseous formaldehyde provided the ketal propargylic alcohol 306 which was elaborated into the keto a l l y l i c alcohol 291 by acid hydrolysis and hydrogenation. Mesylation of the keto a l l y l i c alcohol 306, followed by treatment of the resultant mesylate with excess potassium tert-butoxide gave the desired octalone 226. The ketone group of 226 was protected as the corresponding 5,5-dimethyl-1,3-dioxane derivative 324. Addition of dibromocarbene to the latter - i i i -compound gave the dibromocyclopropane derivative 325. Model studies were carried out with 7,7-dibromonorcarane (185) and i t s derivatives. Subjection of 185 to a sequence involving lithium-halogen exchange and alkylation afforded the benzyl ether 329. This compound was converted by hydrogenolysis into the bromohydrin 331, which upon mesylation gave the bromo mesylate 332. Treatment of 7-exo-bromo-7-endo-methylnorcarane 336 (obtained from dibromonorcarane 185) with an alkyllithium and methyl chloroformate produced the monoester 338. The lat t e r , upon reduction, provided the exo-hydroxymethyl derivative 339. Mesylation of this primary alcohol proved to be unsuccessful. When dibromonorcarane 185 was treated with two equivalents of an alkyllithium, followed by methyl chloroformate, the diester 359 was obtained. Reduction of this compound, followed by mesylation of the resultant d i o l 361 gave the dimesylate 362. The latter was converted into the dichloride 363 by treatment with lithium chloride in hexamethylphosphoramide. Conversion of the dibromocyclopropane derivative 325 into the benzyl ether 327 (R=PhCH2) or the diester 369 by means of reaction conditions used in the model studies were unsuccessful. However, compound 325 could be monomethylated to afford a mixture of exo and endo isomers 366 and 372. The exo-isomer 366 was converted into the endo-monoester 367. Reduction of the la t t e r , followed by deprotection of the ketone yielded the desired keto alcohol 368. Mesylation of 368 could not be achieved without decom-position. However, this alcohol underwent ester formation with p_-nitrobenzyl chloride to give the p_-nitrobenzoate derivative 380. Attempted intramole-cular alkylation of this keto jj-nitrobenzoate 380 to give (±)-ishwarone 12_ was unsuccessful. - i v -The ketal o l e f i n 324 reacted stereoselectively with the carbenoid derived from dimethyl diazomalonate to give the diester 369 as the only adduct. This compound was reduced to the d i o l 389. Hydrolysis of the ketal functionality, followed by mesylation of the resulting d i o l 383 afforded the keto dimesylate 384. Intramolecular alkylation of this keto dimesylate gave no recognizable product. When the dimesylate 384 was treated with anhydrous lithium chloride, the crystalline dichloride 391 was obtained. Base-promoted intramolecular alkylation of the latter provided the keto chloride 392 which was reduced immediately by means of lithium triethylborohydride. Oxidation of the resulting alcohol 393 gave (t)-ishwarone 12_ which upon Wolff-Kishner reduction furnished (±)-ishwarane 13. -V-TABLE OF CONTENTS Page TITLE PAGE . i ABSTRACT i i TABLE OF CONTENTS v ACKNOWLEDGEMENTS v i INTRODUCTION 1 I. Perspective 1 II. Isolation and Structure Elucidation of Ishwarone and Related Sesquiterpenoids 6 III. Synthesis of cis-4,10-Dimethyl Octalones and Related Systems 17 2 7 IV. Synthesis of Tricyclo[3.2.1.0 ]octane Systems and the Total Synthesis of Ishwarane 37 V. The Problem 49 DISCUSSION 51 I. General 51 II. Attempted Synthesis of the Keto Olefin 226 via a Diels-Alder Reaction 58 III. Synthesis of the Keto Olefin 226 via Intramolecular Alkylation 93 IV. Attempted Synthesis of (±)-ishwarone via Dibromocyclopropane Derivatives 108 A. Model Studies Employing Norcarane Derivatives 116 B. Attempted Synthesis of (±)-Ishwarone from Dibromocyclopropane Derivative 325 132 V. Total Synthesis of (±)-Ishwarone and (±)-Ishwarane 144 EXPERIMENTAL 155 BIBLIOGRAPHY 201 - v i -ACKNOWLEDGEMENT I would l i k e t o e x p r e s s my thanks t o Dr. Edward P i e r s f o r h i s encouragement, i n v a l u a b l e a d v i c e , and c o n s i s t e n t i n t e r e s t d u r i n g t h e c o u r s e o f t h i s r e s e a r c h and t h e p r e p a r a t i o n o f t h i s m a n u s c r i p t . I would a l s o l i k e t o thank a l l t h e members o f Dr. P i e r s ' r e s e a r c h group ( p a s t and p r e s e n t ) f o r h e l p f u l d i s -c u s s i o n s and s u g g e s t i o n s . S p e c i a l t h a n k s a r e due to Mr. Fuk Wah Sum f o r p r o o f r e a d i n g t h i s t h e s i s and t o Mrs. Anna Wong f o r h e r v e r y c a p a b l e t y p i n g . R e c e i p t o f a f i n a n c i a l award from a U n i v e r s i t y o f B r i t i s h C olumbia G r a d u a t e F e l l o w s h i p and a N a t i o n a l R e s e a r c h C o u n c i l o f Canada P o s t g r a d u a t e F e l l o w s h i p a r e g r a t e f u l l y acknowledged. INTRODUCTION I. P e r s p e c t i v e From t h e a c t i v e s t u d y on t h e c o n s t i t u e n t s o f t h e e s s e n t i a l o i l s o b t a i n e d from f r a g r a n t p l a n t s d u r i n g the t u r n o f t h e c e n t u r y , a f a m i l y o f n a t u r a l p r o d u c t s h a v i n g e m p i r i c a l f o r m u l a s c o n t a i n i n g a m u l t i p l e o f f i v e c a r b o n s has been r e c o g n i z e d . These compounds have been named t e r p e n o i d s . Thus, compounds c o n t a i n i n g two C ^ - u n i t s a r e c a l l e d monoterpenes t h r e e u n i t s , s e s q u i t e r p e n e s ; f o u r u n i t s , d i t e r p e n e s ; f i v e u n i t s , s e s t e r t e r -penes; s i x u n i t s , t r i t e r p e n e s ; and compounds h a v i n g more t h a n s i x u n i t s b e l o n g to t h e c a r o t e n o i d f a m i l y . Due to the e l e g a n t work, o f R u z i c k a and h i s colleagues"'' i t i s now known t h a t most t e r p e n o i d s have a r e m a r k a b l e f a m i l i a l r e s e m b l a n c e i n w h i c h t h e i r s t r u c t u r e s can be d i s s e c t e d i n t o i s o p e n t a n e s k e l e t a l u n i t s l i n k e d head t o t a i l . T h i s u n i q u e and s t r i k i n g p r o p e r t y has been f o r m u l a t e d as t h e " i s o p r e n e rule""'" and t h e l a t t e r has been used as a p o t e n t g u i d e i n t h e s t r u c t u r a l e l u c i d a t i o n o f new t e r p e n o i d s . The e a r l y work on t e r p e n o i d c h e m i s t r y was m a i n l y r e s t r i c t e d t o h y d r o c a r b o n monoterpenes and s i m p l e s e s q u i t e r p e n e s , p a r t l y due t o t h e i r v o l a t i l i t y w h i c h a l l o w e d them t o be s e p a r a t e d e a s i l y f r o m o t h e r more complex m o l e c u l e s m e r e l y by d i s t i l l a t i o n , and p a r t l y due to t h e r e l a t i v e s i m p l i c i t y o f t h e i r s t r u c t u r e s . However, i n the l a s t two decades, the c h e m i s t r y of t e r p e n o i d compounds has expanded v e r y r a p i d l y m a i n l y due t o t h e a v a i l a b i l i t y o f more s o p h i s t i c a t e d i s o l a t i o n t e c h n i q u e s ( g a s - l i q u i d chromatography, t h i n -l a y e r chromatography, h i g h p r e s s u r e l i q u i d chromatography, e t c . ) and modern p h y s i c a l methods f o r s t r u c t u r a l a n a l y s i s ( f o u r i e r - t r a n s f o r m n u c l e a r m a g n e t i c 13 r e s o n a n c e s p e c t r o s c o p y , C n u c l e a r m a g n e t i c r e s o n a n c e s p e c t r o s c o p y , x - r a y -2-crystallography, mass spectrometry, etc.). Many new compounds with novel structures have been obtained and identified by these techniques. One large group of terpenoids are the sesquiterpenes which are formed by linking three isoprene units together in various ways. Thus, more than 80 different carbon skeletons have been found in the sesquiterpene family of natural products. These skeletons vary from the rather simple acyclic system of farnesol 1_ to the complex polycyclic system of cyclo-sativene 2_. The degree of oxygenation also varies a great deal, ranging from hydrocarbons with no oxygen (e.g. cyclosativene 2) to compounds which are highly oxygenated (e.g. tutin _3). Recently, researchers have reported the isolation of sesquiterpenes containing functional groups which, up to the present time, have not been commonly found i n natural products (e.g. halogen in laurintend 4_, i s o n i t r i l e in 9-isocyanopupukeanone -3-However, the structure of the f i r s t member of this class, eremophilone 4 6_ (isolated by Simonsen and co-workers in 1932 ), puzzled chemists for several years. This bewilderment was mainly due to the fact that this compound did not obey the "isoprene rule" as originally formulated. The correct skeleton was eventually proposed by Penfold and Simonsen.^ About fifteen years later, the structure and stereochemistry of hydroxydihydro-eremophilone 7_, one of the congeners isolated with eremophilone 6_, were defined by means of x-ray crystallography^ and the original proposal"* regarding the carbon skeleton of eremophilane sesquiterpenoids was confirmed. 6 7 Valencane-type sesquiterpenoids, although very closely related in structure to the eremophilanes, are less frequently encountered in nature. In 1965, several new sesquiterpenes belonging to the valencane class, (for example, nootkatone j3, nootakene 9_ and valencene 10), were isolated and characterized.^ 8 9 10 The common structural features between the eremophilane- and valencane--4-type sesquiterpenoids are a pair of c i s - v i c i n a l methyl groups at and C,. of the b i c y c l i c system and a three carbon "isopropyl"-type unit as a side chain at C'^ *. The relative stereochemistry of this isopropyl-type moiety is cis with respect to the methyl groups in eremophilane-type sesquiterpenoids but is trans in the valencane family. To account for the biosynthesis of these two classes of sesquiter-penoids, a 1,2-methyl shift from a eudesmane-type precusor was f i r s t suggested by Robinson to Penfold and Simonsen as early as 1 9 3 9 . S i n c e then, various biogenetic schemes involving 1,2-alkyl migration have been g postulated. McSweeney and co-workers have postulated that the above mentioned stereochemical differences between the eremophilane- and valencane-type compounds is due to biogenetic-type cyclization of two different conformers of a substituted cyclodeca-1,6-diene, followed by appropriate 1,2-alkyl rearrangements (see scheme 1). The numbering system commonly employed for eremophilanes and valencanes is as shown below -5-e r e m o p h i l a n e V a l e n c a n e I n 1969, t h e s t r u c t u r a l e l u c i d a t i o n o f t h e f i r s t member o f a new c l a s s o f s e s q u i t e r p e n o i d s ( i s h w a r a n e - t y p e s e s q u i t e r p e n o i d s ) was r e p o r t e d . " ^ A l t h o u g h i t i s c l e a r t h a t t h i s new c l a s s i s s t r u c t u r a l l y r e l a t e d t o t h e e r e m o p h i l a n e - v a l e n c a n e t y p e t e r p e n o i d s , t h e i s hwaranes c o n t a i n a n o v e l t e t r a c y c l i c c a r b o n s k e l e t o n ]JL. I t i s r e a s o n a b l e to p o s t u l a t e t h a t the u n i q u e c a r b o n framework o f t h i s c l a s s o f compounds i s d e r i v e d b i o g e n e t i c a l l y - 6 -11 from the same intermediate which leads to the valencane sesquiterpenoids, with participation of the side chain in subsequent electrophilic cyclizations. Due to the unusual structural features present in the ishwaranes, studies concerning the chemistry and total synthesis of this group of compounds have been actively pursued by several research groups since the f i r s t reports appeared. II. Isolation and Structural Elucidation of Ishwarone and Related Sesquiterpenoids Ishwarone, the f i r s t member of a relatively small class of sesquiterpenoid with a unique tetracyclic structure, was originally isolated from the roots of Aristolochia indica and given i t s name by Rao 9 and co-workers as early as 1935. However, these researchers only recognized the ketonic nature of ishwarone and proposed i t s molecular formula as ^ 1 5 ^ 2 0 . * t s u n i q u e skeletal structure was not f u l l y revealed u n t i l the late sixties, when a f u l l structural elucidation was accomplished by means of chemical degradation and spectroscopic evidence.^ ^ Ishwarone and i t s parent hydrocarbon ishwarane, also a natural product isolated from 13 the roots of Aristolochia indica and from the dried petals of Cymbopetalum 14 penduliforum (Dunal) B a i l l , have been identified as _12_ and 13_ respectively. 12 13 Ishwarone was found to be resistant to hydrogenation even though the molecular formula, £^^22®' indicated five degrees of unsaturation. Therefore, after taking into account the presence of the ketone group (indicated by a strong absorption at 1706 cm ^ in the infrared spectrum), i t appeared that the molecule was tetracyclic in structure. Indeed, the absence of appropriate signals due to ethylenic unsaturation in infrared ( i . r . ) , proton nuclear magnetic resonance (p.m.r.) and Raman spectra supported the tetracyclic nature of ishwarone. The p.m.r. spectrum of ishwarone showed two 3-proton singlets at 60.75 and 61.15 which could be attributed to the presence of two tertiary methyl groups. There was also a 3-proton doublet at 60.85 with a coupling constant J=6.5 Hz, probably due to a secondary methyl group. Other than these distinct methyl signals, the most important information observed from the p.m.r. was a multiplet corresponding to one proton at 60.55. This resonance signal, in conjunction with the presence of absorption at 3020 cm ^ in Raman spectrum, strongly implied the presence of a cyclopropyl moiety. Indeed, this suggestion was supported by the fact that ishwarone was unstable to acid and exhibited a positive color reaction with tetranitromethane, even though the molecule contained no ol e f i n i c double bonds. In attempts to determine the position of the methyl groups, ishwarone 12_ was oxidized with oxygen i n the presence of potassium -8-t_-butoxide and t e r t i a r y b u t a n o l to a f f o r d t h e d i o s p h e n o l 14. When the a l l y l i c p r o t o n o f the c o r r e s p o n d i n g m e t h y l e t h e r 1_5 was exchanged f o r d e u t e r i u m (NaOCH^/CH^OD), b o t h o f t h e d o u b l e t s i n t h e p.m.r. spectrum, due t o the se c o n d a r y m e t h y l group and the o l e f i n p r o t o n , 16 R=H 17 R=Me c o l l a p s e d t o s i n g l e t s . When t h e ishwarone d i o s p h e n o l _14_ was f u r t h e r o x i d i z e d w i t h a l k a l i n e h ydrogen p e r o x i d e , a d i c a r b o x y l i c a c i d , i s h w a r i c a c i d 1_6, was i s o l a t e d . P y r o l y s i s of t h i s a c i d o r Dieckman c o n d e n s a t i o n -9-of the corresponding dimethyl ester 17_ (followed by hydrolysis and decarboxylation) furnished norishwarone _18, the latter compound contained a five membered ring ketone, as indicated clearly by a strong absorption at 1728 cm ^ i n the i . r . spectrum. Subsequently, this cyclopentanone underwent Barton oxidation (oxidation with oxygen in the presence of strong base such as potassium t-butoxide) smoothly to provide the corresponding diosphenol JL9. The p.m.r. of this enol ketone lacked the doublet signal due to the secondary methyl group in comparison to the diosphenol 14 obtained directly from ishwarone. Instead, a new signal at 61.87, which corresponded to a vinyl methyl group, was present. Oxidation of this new diosphenol with alkaline hydrogen peroxide led to a new dicarboxylic acid, norishwaric acid 20. Brief treatment of the latter with refluxing acetic anhydride, afforded norishwaric anhydride 21. The i . r . spectrum of this compound exhibited absorptions at 1760 and 1800 cm These absorption positions are identical with those found for glutaric anhydride. From these chemical and spectroscopic evidences, a 1,4-relationship between the secondary methyl group and the Ketone functionality was clearly demonstrated. When treated with dry hydrogen chloride in ethyl ether at 0°, followed by brief contact with boiling pyridine, ishwarone rearranged to two isomeric o l e f i n i c ketones via ring opening of the cyclopropyl moiety. Furthermore, one of the products, the exocyclic o l e f i n i c ketone 2_2, could be converted (p-toluenesulfonic acid in refluxing benzene) into the other isomeric product, the endocyclic olefin 23. The latter compound (named isoishwarone) reacted with osmium tetroxide to form the keto- d i o l 24 which -10-was then oxidized by the K i l i a n i reagent (prepared by the addition of 60 g of sodium dichromate to a solution of 80 g of cone, sulfuric acid in 270 g of water) to give the diketo alcohol 2_5_. The carbonyl absorptions in the i . r . spectrum of this compound indicated that one carbonyl group was like a normal cyclohexanone (1705 cm ^) while the other was reminiscent of a bicyclo[2.2.2]octanonesystem (1722 cm "*"). Further evidence for the latter point was obtained by cleavage of the keto d i o l 26^ (obtained by osmium tetroxide hydroxylation of the exocyclic ol e f i n 22) to the dione 27. The presence of bands at 1702 and 1726 cm ^ in.the i . r . spectrum of -11-27 tended to confirm the presence of a cyclohexanone-type carbonyl and a bicyclo[2.2.2.]octanone moiety. Even though the results described above indicated the presence of a bicyclo[2.2.2.]octene system in isoishwarone 23, the position of the vinyl methyl group was not yet secured. This problem was solved by periodate cleavage of the keto d i o l 24. The p.m.r. spectrum of the diketo-aldehyde 2J3, thus obtained, showed a 3-proton singlet at 62.17 for the methyl group of the acetyl moiety and a 1-proton singlet at 610.05 for the aldehyde proton. The lack of coupling in the downfield signal (610.05) clearly implied that the aldehyde group must be adjacent to a quaternary center as indicated in 28. At this stage, the relative stereochemistry of tne v i c i n a l methyl groups and the bicyclo[2.2.2.]octene moiety had not been established. Conclusive chemical evidence which unambiguously defined the stereochemistry was needed. One way in which this could be done would be to correlate isoishwarone with other sesquiterpenes of known structure and absolute stereochemistry. Therefore, isoishwarone 23 was subjected to ozonolysis to provide the diketo aldehyde 2_8 as well as the diketone 29. The. latter was found to be identical with an authentic sample of the same compound prepared from valerinol 30, the stereochemistry of which had been f u l l y established. -12-OH l)Cr03/HOAc Although the c l s - v i c i n a l relationship of the methyl groups at and C,. in isoishwarone had thus been ver i f i e d , the trans relationship between the acetyl group and the methyl groups in dione 29_ could not be accepted without question. Clearly, the S-acetyl function in 29_ could have been derived by equilibration, during the ozonolysis procedures, from the thermodynamically less stable a-acetyl isomer 3JL (acetyl group axial). 31 29 In order to c l a r i f y the stereochemistry at Cj, the ethylene ketal 32 of isoishwarone 23 was hydroborated to give the ketal alcohol 33. After removal of the ketal protecting group with aqueous acid, the 8-hydroxy ketone 34 was treated with base to provide keto aldehyde 3_5 via a retro-aldol reaction. The bicyclo[2.2.2.]octane bridge was therefore cleaved — . . The numbering system of isoishwarane and derivatives is -13-into a simple system without the poss i b i l i t y of affecting the stereo-chemistry at Cy. The bis-semicarbazone of this keto aldehyde was converted into a single hydrocarbon which was identical in a l l respects with an authentic sample of (+)-nootkatane 3_6_ obtained by hydrogenation of valencene 10. The latter is a naturally occurring sesquiterpene with f u l l y established structure and configuration. 36 10 From these results, the basic structure as well as the stereo-chemistry of isoishwarone 23 was completely solved. Therefore, ishwarone i t s e l f must be represented by structure 12_ or 37. However, no differentiation of these positional isomers could be made at this stage of the structural elucidation work. -14-12 37 Treatment o f ishwarone w i t h ozone a f f o r d e d a s m a l l amount o f oxoishwarone 3J3 h a v i n g two c a r b o n y l a b s o r p t i o n s i n t h e i . r . s p e c t r u m a t 1718 and 1689 cm \ The i . r . s t r e t c h i n g band a t 1689 cm ^ i n d i c a t e d t h a t t h e newly formed c a r b o n y l group s h o u l d be c o n j u g a t e d w i t h t h e c y c l o p r o p y l m o i e t y . Indeed, t h i s i n t e r p r e t a t i o n was s u p p o r t e d by t h e u l t r a v i o l e t (U.V.) spectrum which e x h i b i t e d A 210 nm (e5020) and X max max 290 nm (e 7 0 ) . H e a t i n g oxoishwarone 38_ w i t h c o n c e n t r a t e d h y d r o c h l o r i c a c i d , r e s u l t e d i n r i n g c l e a v a g e to y i e l d t h e m o n o c h l o r i d e _39_ which, upon exposure t o b a s e , c y c l i z e d back t o oxoishwarone. S i m i l a r l y , r e a c t i o n o f oxoishwarone 38_ w i t h hot h y d r o b r o m i c a c i d o r t r i f l u o r o a c e t i c a c i d gave t h mOnobromide 4JJ or the t r i f l u o r o a c e t a t e 41 r e s p e c t i v e l y . 38 39 X=C1 40 X=Br — 0 41 X=0CCF -15-I n each o f t h e p.m.r. s p e c t r a o f t h e m o n o c h l o r i d e _39_ and t h e monobromide 4p_, t h e proton, a d j a c e n t t o t h e h a l o g e n appeared as an 8 - l i n e s i g n a l w i t h c o u p l i n g c o n s t a n t s J=1.5, 4.5 and 7.5 Hz. These o b s e r v a t i o n s c o u l d be r a t i o n a l i z e d by p r o p o s i n g t h a t , i n each c a s e , t h e p r o t o n a d j a c e n t t o t h e h a l o g e n atom e x p e r i e n c e d two v i c i n a l c o u p l i n g s and one long-range W-type c o u p l i n g . On t h e o t h e r hand, i f ishwarone had p o s s e s s e d t h e s t r u c t u r e 37_, t h e c o r r e s p o n d i n g oxoishwarone would have been and t h e m o n o h a l i d e s would have p o s s e s s e d t h e s t r u c t u r e s 45 and 46 37_ 44 !zl X - C l 46 X=Br O b v i o u s l y , one would ex p e c t t h a t t h e p r o t o n s a d j a c e n t t o h a l o g e n i n t h e l a t t e r compounds would have g i v e n r i s e t o s i n g l e t s i n t h e p.m.r. s p e c t r a . In a d d i t i o n t o t h e s p e c t r o s c o p i c e v i d e n c e , t h e s t r u c t u r e o f monobromide 40 has been c o n f i r m e d by t h e x - r a y c r y s t a l l o g r a p h y t e c h n i q u e . T h e r e f o r e , ishwarone must be r e p r e s e n t e d by s t r u c t u r e 12_ i n s t e a d o f 37. The t r i f l u o r o a c e t a t e 41_ was h y d r o l y s e d w i t h a l c o h o l i c sodium h y d r o x i d e t o g i v e t h e d i k e t o - a l c o h o l 42. O x i d a t i o n o f t h i s a l c o h o l gave t h e t r i k e t o n e 43 w h i c h showed i n the i . r . s p e c trum a new c a r b o n y l s t r e t c h i n g a b s o r p t i o n a t 1745 cm \ t y p i c a l o f a five-membered r i n g k e t o n e . These c h e m i c a l t r a n s f o r m a t i o n s added a n o t h e r p i e c e o f e v i d e n c e t o s u p p o r t t h e s t r u c t u r e o f i s h w a r o n e . -16-In o r d e r to e n s u r e t h a t no rearrangement had been i n v o l v e d i n the ozone o x i d a t i o n o f ishwarone, oxoishwarone 3_8 was s u b j e c t e d t o W o l f f - K i s h n e r r e d u c t i o n . A s i n g l e h y d r o c a r b o n was i s o l a t e d and c h a r a c t e r i z e d as ishwarane 13, w h i c h had a l s o been o b t a i n e d from t h e r e d u c t i o n o f ishwarone i t s e l f . I t i s p e r t i n e n t t o n o t e t h a t i shwarane i s a l s o a n a t u r a l l y o c c u r r i n g compound, h a v i n g been o b t a i n e d from t h e 13 hexane e x t r a c t o f the r o o t s o f A r i s t o l o c h i a i n d i c a o r t h e d r i e d 14 p e t a l s o f Cymbopetalum p e n d u l i f o r u m (Dunal) B a i l l . 38 13 12 In 1973 t h e i s o l a t i o n o f a n o t h e r s e s q u i t e r p e n e b e l o n g i n g t o the i shwarane f a m i l y was r e p o r t e d . From the f r e s h r o o t s o f A r i s t o l o c h i a 16 d e b i t i s S i e b . e t Zucc. , t h r e e s e s q u i t e r p e n i c k e t o n e s were o b t a i n e d . One o f t h e s e compounds e x h i b i t e d an i . r . s t r e t c h i n g band a t 3030 cm ^ and a m u l t i p l e t s i g n a l a t 60.6 i n t h e p.m.r. spectrum. These s p e c t r a l d a t a i n d i c a t e d t h e p r e s e n c e o f a c y c l o p r o p y l m o i e t y . F o r b i o g e n e t i c r e a s o n s , i t was s u s p e c t e d t o be a p o s i t i o n a l isomer o f i s h w a r o n e . Indeed, t h i s a s s u m p t i o n was p r o v e d by r e d u c i n g t h e k e t o n e t o t h e c o r r e s p o n d i n g h y d r o c a r b o n , w h i c h was i d e n t i f i e d by s p e c t r o s c o p i c d a t a as ishwarane 13. When r e f l u x e d i n D^O-dioxane i n t h e p r e s e n c e of sodium b i c a r b o n a t e , t h i s new s e s q u i t e r p e n e a f f o r d e d a t r i d e u t e r i o d e r i v a t i v e . A l t h o u g h t h e p.m.r. sp e c t r u m o f t h e p a r e n t s e s q u i t e r p e n e showed a 3 - p r o t o n d o u b l e t a t 60.89 ( s e c o n d a r y m e t h y l g r o u p ) , the c o r r e s p o n d i n g s i g n a l o f t h e t r i d e u t e r i o d e r i v a t i v e a p p e a red as a 3 - p r o t o n s i n g l e t . Based on t h e s e -17-data, as well as on the optical rotation dispersion curve of the natural product (from which i t was concluded that the conformation of the cyclohexanone ring was i n a chair form with the secondary methyl group i n an equatorial orientation), this new compound was formulated as 3-oxoishwarone 47 . 47 13 III. Synthesis of <Lis,-4,10-Dimethyl. Octalones and Related Systems The cis-relationship of the v i c i n a l dimethyl groups in ishwarone and ishwarane represents one of the interesting structural features of 2.7 this class of compounds. Furthermore, the 7-methyl-tricyclo[3.2.1.0 " ]— octane system present in these compounds represents a structurally novel moiety not found in many natural products. It i s therefore pertinent to discuss how each of these structural features has been obtained previously by synthesis. Procedures leading to c i s - v i c i n a l dimethyl groups in octalone systems are relatively well documented in the literature, mainly due to considerable efforts which have been directed towards the synthesis of eremophilane and valencane-type sesquiterpenoids. The construction of appropriate synthetic precursors containing the necessary c i s - v i c i n a l dimethyl groups has been attempted in various ways. -18-The well-known R o b i n s o n a n n u l a t i o n p r o c e d u r e has been w i d e l y adapted. In a s y n t h e t i c sequence l e a d i n g t o t h e p r e p a r a t i o n o f (±)-isonootkatone ( a - v e t i v o n e ) 5 1 ^ , t h e f i r s t e r e m o p h i l a n e s e s q u i t e r p e n e o b t a i n e d by t o t a l s y n t h e s i s , the fci-keto e s t e r underwent M i c h a e l a d d i t i o n w i t h t r a n s - p e n t - 3 - e n - 2 - o n e i n th e p r e s e n c e o f a s m a l l amount o f sodium e t h o x i d e . Subsequent t r e a t m e n t o f t h e r e s u l t i n g i n t e r m e d i a t e w i t h e x c e s s m e t h o x i d e , a f f o r d e d t h e c r y s t a l l i n e b i c y c l i c k e t o - e s t e r 50_ as the main p r o d u c t . The s t e r e o c h e m i c a l outcome o f the o v e r a l l a n n u l a t i o n r e a c t i o n , r e s u l t i n g i n a c i s - o r i e n t a t i o n o f the m e t h y l and t h e a n g u l a r -19-carbomethoxy groups, was rationalized by proposing that steric and electronic factors i n the Michael addition step would favour the transition state 49_. The latter would result in the observed con-figuration in the product. After protecting the ketone functionality in _50_ as the corresponding ethylene ketal, the carbomethoxy moiety was transformed into a methyl group via metal hydride reduction, mesylation of the alcohol and lithium-ammonia reduction of the primary mesylate. (±)-Isonootkatone 5_1 was then readily isolated after acid hydrolysis of the ketal. Even though Marshall and co-workers'^ found that the Robinson annulation of the cyclic keto ester 48 with trans-pent-3-en-2-one gave ketone 50_ with the required cis-stereochemical relationship between 18 the methyl and carbomethoxy groups, related studies with 2-methyl-cyclohexan-l,3-dione 52_ provided different results. Condensation of the dione with trans-pent-3-en-2-one in the presence of potassium hydroxide and pyrrolidine gave the trans isomer _5_3 as the predominant annulation product. The stereochemistry of the latter was firmly established by comparing the optical rotatory dispersion measurement of the optically resolved decalone _5_5 (obtained from the dione _53 via selective protection of the enone moiety, Wolff-Kishner reduction, regeneration of the enone functionality and lithium-ammonia reduction) with that of i t s optically pure epimer _56 , -20-H H 56 55 I n s t e a d o f d i r e c t c o n d e n s a t i o n o f 2 - m e t h y l c y c l o h e x a n - l , 3 - d i o n e _5_2 w i t h t r a n s - p e n t - 3 - e n - 2 - o n e , Coates and Shaw"""^  used the p y r r o l i d i n e enamine _57 of t h e d i o n e i n the a n n u l a t i o n p r o c e s s . These workers found t h a t t h i s p r o c e d u r e a l s o l e d to a m i x t u r e of t r a n s - and c i s -i s o m e r s 5_3_ and _54. However, i t was found t h a t the r a t i o of t h e s e i s o m e r s v a r i e d s i g n i f i c a n t l y w i t h t h e p o l a r i t y o f the s o l v e n t employed as the r e a c t i o n medium. Thus, when benzene was used as s o l v e n t , the 57_ 53 R e a c t i o n T o t a l R a t i o o f C o n d i t i o n % Y i e l d Two Isomers <j>H/HOAc/NaOAc 64 10 : 1 DMF/HOAc/NaOAc 27 1 : 1 t r a n s - i s o m e r 53 was the major component i n the crud e p r o d u c t ( t r a n s / c i s -21-10/1). However, the ratio was changed to approximately 1 to 1 by replacing benzene with N,N-dimethylformamide. Several eremophilane 20 20 sesquiterpenes, such as (±)-valencene , (±J-valerinol 3_0 , 20 20 21 (±)-eremopnilene _58_ , (±)-eremoligenol _59 and (±)-calarene 60_ , have been synthesized from the cis-dimethyl octalone 54. OH 10 30 58 The use of 2-methylcyclohexanone derivatives in the construction of cis-4,10-dimethyloctalone systems has also been investigated. In-22 23 dependently, Piers et a l and Ourisson et a l have found that 2,3-dimethylcyclohexanone 61_ underwent Robinson annulation with methyl vinyl ketone and/or i t s equivalent such as 4-diethylamino-2-butanone methiodide O + OR 61 The octalone isolated from the reaction consisted of a mixture of two epimers 6_2 and 63_ in the ratio of approximately 3:2, respectively. However, the total yield of the product was very low (ca. 15%). Although -22-Ourisson's group converted the cis-isomer 62 into (±)-aristolone 64, the inefficiency associated with the annulation step made this a rather impractical approach to the total synthesis of eremophilane sesquiterpenoids. 64 While the use of 2,3-dimethylcyclohexanone in Kobinson annulation appeared to be rather unsuccessful, certain other 2-methylcyclohexanone derivatives do find use in constructing the eremophilane skeleton. For 24 example, McGuire, Odom and Pinder obtain the ketal enone 66 i n 56% yield (based on unrecovered starting material) by condensing the monoketal 65 with trans-pent-3-en-2-one i n the presence of sodium hydride. Evidence for the cis-relationship between the methyl groups was obtained by comparing 8_ R=0 10 R=H2 the p.m.r. spectrum of the product 66_ with that of authentic nootkatone 27 8_. The intermediate 66_ was converted into (±)-valencene 10 and (±)-nootkatone 8..^ Van der Gen and co-workers have reported tne synthesis of optically -23-active eremophilane-type sesquiterpenoids using as starting materials optically active cyclohexanones derived from monoterpenes such as 6-pinene and sabinene. 8-Pinene 6_7 was converted into 2-methyl-4-isopropylidenecyclohexanone 70_ or 2-methyl-4-isopropenylcyclohexanone 25 71 via the chloride 68 or the acetate of the alcohol 69. 69 X=OH The sodium enolate of each of these ketones was condensed with trans-pent-3-en-2-one. In the case of the isopropylidene isomer _70_, a mixture of b i c y c l i c ketones was obtained in 50% yield. From these crude products, (±)-isonootkatone (a-vetivone) 51 was isolated in 21% yield while the rest of the product consisted of compounds which arose from condensation on the less substituted position of the 2-methylcyclohexanone. On the other 71 72 72 hand, a similar condensation involving the isopropenyl isomer 71 gave the ketol 72 which, upon refluxing with potassium hydroxide in methanol, -24-generated a 29% yield of (±)-7-epi nootkatone 73. Sabinene 7_4_ was transformed e f f i c i e n t l y into 3-methylsabinaketone 26 75. Treatment of this ketone with trans-pent-3-en-2-one in the presence of sodium amide gave an optically pure t r i c y c l i c enone 7_7 in good yield (ca. 67%). The assignment of product stereochemistry was based on the assumption that a transition state represented by 76, in which steric effects were the main factors to govern the reaction, was involved. The enone 7_7 was subsequently treated with hydrogen chloride and from the resultant monochloride 7_8, (-)-isonootkatone (a-vetivone) 51 and (-)-nootkatone j3 were synthesized. Recently, McMurry and his co-workers^' have modified Van der Gen's 25 procedure to obtain 7-epinootkatone 73 in higher yield. Furthermore, the former workers subsequently transformed compound 73 into eremophilone 6_, the f i r s t non-isoprene sesquiterpene isolated from nature. Keto alcohol 69, obtained from g-pinene 67, was acylated with acetic anhydride in the -25-p r e s e n c e o f t r i e t h y l a m i n e and 4 - ( N , N - d i m e t h y l a m i n o ) - p y r i d i n e . P y r o l y s i s o f t h e r e s u l t a n t a c e t a t e , a f f o r d e d , i n good o v e r a l l y i e l d from B-pinene 2 - m e t h y l - 4 - i s o p r o p e n y l c y c l o h e x a n o n e 71_. The l a t t e r was s u b j e c t e d t o R o b i n s o n a n n u l a t i o n w i t h trans-pent-3-en-2-one i n t h e p r e s e n c e o f sodium amide as base. The p r o d u c t , 7 - e p i n o o t k a t o n e 7_3 was i s o l a t e d by column chromatography i n s t e a d o f m o l e c u l a r d i s t i l l a t i o n . I n t h i s 25 manner, the y i e l d o f t h e d e s i r e d o c t a l o n e was improved from 29% to 50% (basedon r e c o v e r e d s t a r t i n g m a t e r i a l ) . The d i e n e o n e 73 was t h e n c o n v e r t e d i n t o t r i e n e 79_ which upon e p o x i d a t i o n and subsequent t r e a t m e n t w i t h l i t h i u m p e r c h l o r a t e , y i e l d e d two e p i m e r i c 3 , Y ~ u n s a t u r a t e d k e t o n e s . Both k e t o n e s p r o v i d e d (±)-eremophilone 6_ by b r i n g i n g t h e d o u b l e bond i n t o c o n j u g a t i o n w i t h s t r o n g base. I t has been p o i n t e d out t h a t , w i t h o r d i n a r y u n a c t i v a t e d c y c l o h e x a n o n e d e r i v a t i v e s , t h e R o b i n s o n a n n u l a t i o n p r o c e s s o f t e n p r o v i d e s u n s a t i s f a c t o r y -26-results because of competing polymerization of the vinyl ketones and, in the case of unsymmetrical cyclohexanones, because of the d i f f i c u l t y of controlling the site of condensation. Many modifications, such as the u t i l i z a t i o n of Mannich bases, S-haloketones, enamines, a - s i l y l enones etc., have been developed in order to overcome these problems. 28 Some of these methods have achieved a certain degree of success. Another entirely different approach to solve these d i f f i c u l t i e s involves the use of highly reactive alkylating reagents (halo ethers, halo ketals, a l l y l i c halides, etc.) which contain a latent ketone group. Indeed, Piers 22 and co-workers have demonstrated that cis-5,10-dimethyl octalone 6_2 could be e f f i c i e n t l y obtained from 2,3-dimethylcyclhexanone by this approach. 62 64 In their total synthesis of (±)-aristolone 6_4_, Piers et al_ observed that alkylation of the n-butylthiomethylene derivative of 2,3-dimethyl-cyclohexahone 80_ with methallyl halide gave, in f a i r l y good yield, a mixture of the cis and _trans_-isomers £^ 1 and 82_ (ca. 4:1, respectively). This result encouraged them to investigate the u t i l i z a t i o n of other potentially useful alkylating reagents in the stereoselective synthesis of octalone 6_2_ 61 80 81 4 : 1 82 -27-Alkylation of the n-butylthiomethylene derivative 80 with ethyl 3-bromopropionate gave a mixture of keto esters 83. in excellent yield. Removal of the blocking group and enol-lactonization of the resultant keto acids furnished two crystalline epimers 84 and 8_5 in high overall yield. The major isomer 85_, favoured by a 9:1 ratio, was eventually 30 > k ^ o Br 84 85 62 converted into octalone 62 via addition of methyllithium, acid hydrolysis, and base promoted cyclization. From this important intermediate, several 30 31 sesquiterpenes, such as (±)-fukinone 86 , (±)-eremophilenlide 87 , 31 31 (±)-tetrahydroligularenolide 8_8 , (i)-aristolochene 89. , (±)-isoishwarane 34 32-34 90 and (±)-ishwarane 13 have been synthesized. 86 87 88 89 90 13 -28-Although the Robinson annulation and related processes seem to be the most commonly used methods to obtain octalones with c i s - v i c i n a l methyl groups at and C^o' compounds of this type are also available 35 by acid ini t i a t e d T r-cyclization of polyenes. Brown and co-workers have used this type of reaction as the key step in their synthesis of (±)-tetrahydroeremophilone 96. The keto ester 91 was f i r s t transformed into a mixture of trienes 9_3 by standard reactions. 94 95 93 94 + 95 Cyclization proceeded smoothly in anhydrous formic acid to yield two esters 9_4_ and 95_, epimeric at the isopropyl side chain. The stereo-selectivity involved in the formation of only c i s - v i c i n a l dimethyl products has been explained by proposing the chair-like character of the incipient ring in the transition state 9_7. On the other hand, the trans-relationship could be obtained only through the less favourable boat-like transition state 98. The Diels-Alder reaction is one of the most powerful tools in modern synthetic organic chemistry. Its v e r s a t i l i t y has been demonstrated in 36 37 many areas. Dastur ' , in applying this reaction to the formation of (±)-nootkatone 8_, achieved high stereoselectivity with respect to the introduction of the c i s - v i c i n a l methyl groups at C^. and C,.. The diene 99, obtained by Birch reduction of 3,4,5-trimethylanisole, underwent in situ -30-8 Diels-Alder reaction with methyl acrylate in good yield. Due to steric factors, the methyl acrylate was expected to approach the diene from the side of the molecule opposite to the secondary methyl group (c.f. 100) , thus affording a product with the methyl groups in a cis-relationship. Indeed, one major adduct 101 was obtained. The latter was subsequently transformed into the tertiary alcohol 102, which upon solvolysis in formic acid yielded the octalone ester 103. Upon subjection to hydrolysis and dehydration, the latt e r gave (±)-nootkatone 8^. Not a trace of the corresponding trans-4,5-dimethyl compound could be detected in the reaction product. 38 Kitahara et a l used the Diels-Alder reaction to provide the simple cis-octalone 104. Addition of methylithium to this ketone gave the trans-and c_is_-isomers 105 and 106 as 1:1 mixture. Intramolecular oxymercuration, followed by reduction, furnished the internal ether 107. Cleavage of the ether linkage resulted in the formation of the unsaturated alcohol 108. After O 105 106 107 -31-conversion of this alcohol into the ketone ketal 109 via standard pro-cedures, the latter compound could readily be transformed (sodium methoxide in methanol or chromatography on alumina) into the thermo-dynamically more stable isomer 110, possessing a cis-relationship between the two methyl groups. The keto group of 110 was then removed by sodium borohydride reduction of the corresponding tosylhydrazone. The ketal 111 was later used in the total synthesis of (±)-eremophilenolide 87' 39 39 and (i)-furanoeremophilane 112 H H H 112 40 Sims and Selman have reported the stereoselective introduction of an angular methyl group into polycyclic systems via regioselective opening of a cyclopropane ring. This method offers promise as an alternative solution for the introduction of c i s - v i c i n a l methyl groups into an inter-mediate suitable for the synthesis of eremophilane sesquiterpenes. Sims and Selman found that Birch reduction converted 4-methyl-l-naphthoic acid 113 into two epimeric acids, 114 and 115, in the ratio of approximately 2:1, respectively. Separation of the isomers could be effected by fractional -32-r e c r y s t a l l i z a t i o n . C o n v e r s i o n o f t h e c i s - i s o m e r 114 i n t o t h e c o r r e s p o n d i n g e s t e r , f o l l o w e d by h y d r o g e n a t i o n o f t h e l a t t e r a f f o r d e d t h e o c t a l i n 116. C y c l o p r o p a n a t i o n o f 116 by t h e Simmon-Smith r e a c t i o n r e s u l t e d i n t h e f o r m a t i o n - 3 3 -o f a s i n g l e isomer 117. Thermal d e c a r b o x y l a t i o n o f the a c i d o b t a i n e d by s a p o n i f i c a t i o n o f 117 a f f o r d e d t h e o c t a l i n 118 v i a a r e g i o s p e c i f i c r i n g o p e n i n g o f t h e c y c l o p r o p y l m o i e t y . A s i m i l a r s e t o f r e a c t i o n s , i n v o l v i n g t h e i n t e r m e d i a t e s 119 and 120, r e s u l t e d i n the c o n v e r s i o n o f the _trans_-isomer 115 i n t o t h e o c t a l i n 121. 41 42 M a r s h a l l and Ruden ' a l s o i n v e s t i g a t e d the p o s s i b i l i t y o f r e g i o -s e l e c t i v e l y c l e a v i n g c y c l o p r o p y l systems by a c i d . These workers found t h a t t h e c y c l o p r o p y l enone 122 r e a c t e d smoothly w i t h l i t h i u m d i m e t h y l -c u p r a t e i n d i o x a n e t o g i v e a r e a c t i o n p r o d u c t w h i c h appeared t o be homo-geneous. However, upon s u b j e c t i o n t o a c i d c l e a v a g e , t h i s m a t e r i a l p r o v i d e d a m i x t u r e o f p r o d u c t s c o n s i s t i n g m a i n l y o f compound 126, w i t h l e s s e r amounts o f t h e c i s - and t r a n s - o c t a l o n e s 125 and 127 a l s o b e i n g p r e s e n t . I t thus appeared t h a t t h e c o n j u g a t e a d d i t i o n o f l i t h i u m d i m e t h y l -c u p r a t e t o enone 122 r e s u l t e d i n a m i x t u r e o f the c i s - and _ t r a n s - i s o m e r s 124 126 127 -34-123 and 124. In o r d e r t o g a i n more i n f o r m a t i o n c o n c e r n i n g the r e g i o -s e l e c t i v i t y o f the a c i d c l e a v a g e of the c y c l o p r o p y l r i n g , M a r s h a l l and Ruden e x p l o r e d t h e r e a c t i o n f u r t h e r w i t h a m i x t u r e o f k e t o n e s 123 and 124 i n a r a t i o o f a p p r o x i m a t e l y 1:3, r e s p e c t i v e l y . I t t u r n e d out t h a t t h e r e a c t i o n p r o d u c t c o n t a i n e d 25% o f the c i s - o c t a l o n e 125. T h e r e f o r e , i t was p r o p o s e d t h a t the c i s - i s o m e r 123 must be opened up u n i d i r e c t i o n a l l y t o g i v e the c i s - o c t a l o n e 125 whereas the _trans_-isomer 124 was c l e a v e d by a c i d i n t h e o p p o s i t e sense t o p r o v i d e the r e a r r a n g e d enone 126. C o n j u g a t e a d d i t i o n o f l i t h i u m d i a l k y l c u p r a t e s t o enones has been s u c c e s s f u l l y a p p l i e d i n many t o t a l s y n t h e s i s . From s t u d i e s o f t h i s t y p e of r e a c t i o n u s i n g s i m p l e c o n j u g a t e d enones as s u b s t r a t e s , i t has been c o n c l u d e d t h a t the s t e r e o c h e m i c a l outcome of the r e a c t i o n i s h i g h l y 43 s u b j e c t t o e l e c t r o n i c and s t e r i c c o n t r o l s . F o r example, S c h u d e l e t a l . found t h a t r e d u c t i v e m e t h y l a t i o n o f d i e n o n e 128 w i t h l i t h i u m d i m e t h y l c u p r a t e , gave a l m o s t e x c l u s i v e l y 4 - e p i n o o t k a t o n e 129 i n e x c e l l e n t y i e l d . S i m i l a r l y , Warne'*'* o b s e r v e d t h a t 1 , 4 - a d d i t i o n o c c u r r e d from the a-f a c e s o f the d i e n o n e 130 and the o c t a l o n e 132 to g i v e e x c l u s i v e l y t h e p r o d u c t s 131 and 133, r e s p e c t i v e l y , each p o s s e s s i n g v i c i n a l m e t h y l groups i n a t r a n s - r e l a t i o n s h i p . However, t h e c i s - f u s e d o c t a l o n e 134 a f f o r d e d 45 p r o d u c t 135 w i t h c o m p l e t e l y d i f f e r e n t s t e r e o c h e m i s t r y . -35-M a r s h a l l and Cohen employed t h i s t y p e o f c h e m i s t r y t o advantage i n t h e i r s t e r e o s e l e c t i v e s y n t h e s i s o f (±)-fukinone 8_6. The c r y s t a l l i n e c i s - f u s e d o c t a l o n e 137, o b t a i n e d from t h e b e n z y l i c a l c o h o l 136 v i a s t a n d a r d t r a n s f o r m a t i o n s , r e a c t e d w i t h l i t h i u m d i m e t h y l c u p r a t e t o p r o v i d e a s i n g l e s t e r e o i s o m e r 138 i n f a i r l y good y i e l d . T h i s k e t o a c e t a t e 138 was t h e n c o n v e r t e d i n t o f u k i n o n e J56_ by s t a n d a r d r e a c t i o n s . 138 86 47 48 On t h e o t h e r hand, P i e r s and K e z i e r e ' g e n e r a t e d t h e c h a r a c t e r i s t i c e r e m o p h i l a n e s k e l e t o n e i n a s l i g h t l y d i f f e r e n t manner. 3 - I s o p r o p e n y l c y c l o --36-hexanone was converted into the octalone 1 3 9 via several steps. The stereoselective introduction of the angular methyl group was achieved by 1 , 4 - a d d i t i o n of lithium dimethylcuprate to the enone 1 3 9 . Borohydride reduction of the tosylhydrazone derivative of the resultant product 1 4 0 , followed by catalytic hydrogenation, afforded ( ± ) - 7 B-eremophilane 1 4 1 . H LiMe2Cu 140 141 49 50 More recently, Ziegler and co-workers ' have reported two different approaches to the total synthesis of eremophilone 6_. In each case, the intermediate 142 served as the starting material. This compound could be conveniently prepared by the addition of lithium divinylcuprate to 3,4-dimethylcyclohexenone. This reaction proceeded stereoselectively, as expected, to give only 3,4-cis-dimethyl-3-vinylcyclohexanone 142. The stereochemistry of the product was determined by i t s conversion into cis-1,2-dimethylcyclohexylnitrile 143, a known compound with established stereochemistry. The assignment of the stereochemistry was further confirmed by converting the unsaturated ketone 142 into (±)-eremophilone 6_. (<^\)2CuLi 142 -37-142 143 IV. Synthesis of Tricyclo[3.2.1.0 * joctane Systems and the Total  Synthesis of Ishwarane In connection with the poss i b i l i t y of synthesizing ishwarane-type compounds with carbon skeleton 11, i t is clear from the above discussion 11 that the stereochemical problems associated with the synthesis of c i s -v i c i n a l methyl groups on decalin-type systems can be solved i n a variety 2 7 of ways. However, the formation of the 7-methyltricyclo[3.2.1.0 * ]octane system present in ishwaranes 11 and the inherent stereochemical problems associated with this moiety impose a challenge in designing the synthesis of ishwarane-type sesquiterpenes. 2.7 In recent years, several tricyclo[3.2.1.0 " ]octane-6-one systems have been synthesized and used as convenient precusors for bicyclo[3.2.l]octane or bicyclo[2.2.2]octane systems. Most of these investigations have u t i l i z e d the copper-catalyzed intramolecular addition of a carbenoid to a carbon-2.7 carbon double bond. For example, tricyclo[3.2.1.0 * ]octan-6-one 145 was obtained by LeBel and Hubbler in 1963 from thermal decomposition of the cyclohexenyl diazomethyl ketone 144 in the presence of copper bronze. 52 Similarly, House, Boots and Jones applied this type of reaction to the -38-b i c y c l i c d i a z o ketone 146 and i s o l a t e d t h e t e t r a c y c l i c k e t o n e 147 i n moderate y i e l d . H H 146 „ 147 C h a k r a b o r t t y et_ a l . have used s i m i l a r t r i c y c l i c systems to g e n e r a t e t h e b i c y c l o [ 3 . 2 . 1 ] o c t a n e m o i e t y i n t h e i r model s t u d y f o r t h e s y n t h e s i s o f g i b b e r e l l a n e and k a u r a n e - p h y l l o c l a d e n e t y p e d i t e r p e n o i d s . The k e t o n e s 149 and 152, o b t a i n e d from t h e d i a z o k e t o n e s 148 and 151 MeO-153 -39-respectively, were rearranged with acid to the bicyclooctanones 150 and 153, respectively, in excellent yield. However, the yields of the carbenoid reactions (formation of 149 and 152) varied from poor to moderate. In a report concerning the synthesis of (+)-kaurene 160 and (+)-phyllocladene 161 from (-)-abietic acid 154, Tahara, Shimagaki, Ohara and 54 2 7 Nakata employed the formation of the tricyclo[3.2.1.0 ' joctanone system as a key reaction. In their sequence, the diazoketone 155 (mixture of epimers) derived from (-)-abietic acid 154, was converted by thermolysis i n the presence of copper, into a 1:1 mixture of the pentacyclic keto esters 156 and 157. The yield of this reaction was not specified. The keto esters 156 and 157 were subsequently transformed into intermediates 158 and 159, respectively, v ia reductive cleavage of the cyclopropane ring and modification of the carbomethoxy functionality into a methyl group. From these intermediates 158 and 159, (+)-kaurene 160 and (+)-phyllocladene 161 were obtained, respectively, via standard reactions. 156 157 -40-C 0 2 M e 156 158 R=0 160 R=CH„ C0 2 Me 157 159 R=0 161 R=CH, A p p l i c a t i o n of t h i s t y p e o f methodology to the s y n t h e s i s of ishwarone 12 and ishwarane 13 would, a t f i r s t s i g h t , seemed t o be 12 13 p o s s i b l e . In t h e s e c a s e s , however, i t would be n e c e s s a r y to use a p p r o -p r i a t e l y s u b s t i t u t e d d i a z o e t h y l c y c l o h e x e n y l k e t o n e s . S c a n i o and L i c k e i ^ ^ , u s i n g a s i m p l e model system, have i n v e s t i g a t e d t h e f e a s i b i l i t y o f t h i s a p p r o a c h . The d i a z o k e t o n e 163, r e s u l t i n g from the r e a c t i o n o f d i a z o e t h a n e w i t h t h e a c y l c h l o r i d e 162, underwent i n t r a m o l e c u l a r c a r b e n e a d d i t i o n t o a f f o r d t h e d e s i r e d t e t r a c y c l i c k e t o n e 164 i n u n s p e c i f i e d y i e l d . However, e x t e n s i o n of t h i s methodology t o the attempted t o t a l s y n t h e s i s of ishwarone 12 and ishwarane 13 has so f a r been u n s u c c e s s f u l . " ^ -41-I CH CHN2 Cu/V N, 162 163 164 The f i r s t t o t a l synthesis of ishwarane was reported by K e l l y , 32-34 Zamecnik and Beckett i n the e a r l y seventies. Instead of using carbene a d d i t i o n as the key r e a c t i o n , these workers employed the more t r a d i t i o n a l intramolecular a l k y l a t i o n to form the t r i c y c l o -2 7 [3.2.1.0 ' ]octanone system from a bicyclo[2.2.2]octanone precusor. Thus, octalone 62_ with defined stereochemistry, underwent photoaddition 34 with a l l e n e to give the 1:1 adduct 165 stereo- and r e g i o s e l e c t i v e l y . Successive subjection of 165 to k e t a l i z a t i o n and epoxidation gave the two isomeric epoxides 166 and 167, which were obtained i n approximately equal amounts. Fortunately, the lack of s t e r e o s e l e c t i v i t y at t h i s stage di d not a f f e c t the e f f i c i e n c y of the synthesis, since both epoxides were =-=/hv 62 0 Ph -~U--- 00H 165 r-OH ^ ° LOH p-TSA/<j>H 166 LAH 1 : 1 167 LAH O H -42-23 c o n v e r t e d t o t h e same m i x t u r e o f e p i m e r i c k e t o a l c o h o l s 168. Thus t r e a t m e n t of t h e m i x t u r e of 166 and 167 w i t h l i t h i u m a luminium h y d r i d e , f o l l o w e d by a c i d - p r o m o t e d rearrangement o f t h e r e s u l t i n g k e t a l a l c o h o l s , a f f o r d e d 168 i n good y i e l d . T h i s l a t t e r m i x t u r e o f k e t o l s was d e h y d r a t e d t o t h e t r i c y c l i c u n s a t u r a t e d ketone 169. T h i s i m p o r t a n t enone underwent Huang-Minion r e d u c t i o n t o g i v e a h y d r o c a r b o n i d e n t i c a l w i t h i s o i s h w a r a n e 9_0_ p r e p a r e d from i s o i s h w a r o n e 23. When t h e k e t o n e 169 was r e d u c e d w i t h l i t h i u m aluminium h y d r i d e , e q u a l amounts o f the e p i m e r i c a l c o h o l s 170(R=H) and 171(R=H) were o b t a i n e d . The e x o - a l c o h o l 170(R=H), a f t e r b e i n g p r o t e c t e d as t h e c o r r e s p o n d i n g b e n z y l e t h e r 170(R=PhCH o), was s u b j e c t e d t o h y d r o b o r a t i o n and t h e r e s u l t a n t p r o d u c t -43-13 174 was o x i d i z e d w i t h J o n e s ' r e a g e n t . The k e t o b e n z y l e t h e r 172 (R=PhCH 2, Y=0) thus o b t a i n e d was smoothly h y d r o g e n o l i z e d t o t h e c o r r e s p o n d i n g k e t o a l c o h o l 172(R=H, Y=0). I n t r a m o l e c u l a r a l k y l a t i o n o f t h e c o r r e s p o n d i n g k e t o t o s y l a t e 172(R=Ts, Y=0) i n t o t h e c y c l o p r o p y l k e t o n e 174 was a c h i e v e d i n h i g h y i e l d -44-by heating the former with excess methylsulfinyl carbanion in dimethyl sulfoxide. Similarly, the endo-alcohol 171 was transformed into the same cyclopropyl ketone 174 in a somewhat lower yield. Finally, ishwarane 13_ was obtained from ketone 174 by subjection of the latter to a modified Wolff-Kishner reaction. Direct intramolecular nucleophilic displacement of the tosylate functionality of compound 173 would be mechanistically unfavourable. Therefore, Kelly proposed that the overall conversion of 173 into 174 involved a double displacement mechanism, in which the tosylate group of 173 was f i r s t replaced by the methylsulfinyl carbanion (or a molecule of solvent) and the resultant intermediate then underwent "normal" 34 intramolecular displacement by the enolate. This proposal was supported by further investigations which resulted in the total synthesis of 57 trachylobane 175 using the same basic approach. 175 Solvolytic cyclization of a homoallyic mesylate has been u t i l i z e d 58 successfully by Kelly to synthesize (±)-trachylobane 175. Upon heating in dimethylsulfoxide, the mesylate 176 was converted into a mixture of an alcohol 177 and the cyclopropyl ketone 178 in the ratio of approxi-mately 3:1, respectively. Direct oxidation of the crude product mixture with Jones' reagent allowed the isolation of ketone 178, the immediate precusor of trachylobane, in high yield. -45-This encouraging result, however, was not applied to the synthesis of ishwarane u n t i l very recently. Based on this methodology, Kelly and Alward found that ishwarane 13_ could be obtained from the homoallyic alcohol 170 (R=H) by refluxing i t s corresponding mesylate 170 (R=Ms) in ether in the presence of lithium aluminium hydride. This process improved the overall yield of ishwarane L3 from the alcohol 170 (R=H) to 65%, as compared with the 23% overall yield obtained from the cl a s s i c a l stepwise - u • 3 3 > 3 4 synthesis. 170 In 1975, Cory and Chan reported that the tricyclo[3.2.1.0 " ]octan-6-one system could be obtained in a one step synthesis. The success of this "bicycloannulation process" was based on the assumption that the kinetic enolate of an a,3-unsaturated cyclohexanone would react with a suitable Michael acceptor. The stabilized anion, thus formed, would undergo internal 1,4-cohjugate addition to give another enolate. If -46-the a c t i v a t i n g group o f t h e M i c h a e l a c c e p t o r i s a l s o a good l e a v i n g group, subsequent i n t r a m o l e c u l a r d i s p l a c e m e n t by the e n o l a t e would g e n e r a t e t h e d e s i r e d t r i c y c l i c o c t a n o n e system (see scheme 2 ) . Scheme 2 Indeed, each o f t h e c y c l o h e x e n o n e s 179, 180 and 181, a f t e r b r i e f t r e a t m e n t w i t h l i t h i u m d i i s o p r o p y l a m i d e , r e a c t e d w i t h v i n y l t r i p h e n y l -phosphonium bromide t o g i v e t h e c o r r e s p o n d i n g t r i c y c l i c k e t o n e s 182, 183 and 184 i n y i e l d s o f about 10, 22 and 18% r e s p e c t i v e l y . 181 184 -47-I n t r a m o l e c u l a r carbene i n s e r t i o n i n t o a c a r b o n hydrogen bond i s 61 a w e l l known r e a c t i o n . Moore and co-workers d i s c o v e r e d t h a t t h e b i c y c l o -b utane 186 c o u l d be o b t a i n e d as t h e predominant p r o d u c t when t h e dibromo-c y c l o p r o p a n e 185 was t r e a t e d w i t h an e x c e s s o f m e t h y l l i t h i u m . M e L i 185 186 62 63 2 7 R e c e n t l y , P a q u e t t e and h i s a s s o c i a t e s ' found t h a t t r i c y c l o [ 3 . 2 . 1 . 0 " ]-o c t a n e 189 c o u l d be o b t a i n e d e f f i c i e n t l y from the 7,7-dibromonorcarane 187 c o n t a i n i n g a syn m e t h y l group a t t h e p o s i t i o n . On the o t h e r hand, t h e c o r r e s p o n d i n g a n t i - i s o m e r 188 gave, under the same c o n d i t i o n s the b i c y c l o -b utane d e r i v a t i v e s 190 and 191. However, t h e s i t e s e l e c t i v i t y d e c r e a s e d B r \ ^ - B r Br-^_^Br M e L i 57 : 43 60 187 188 189 63 190 191 when more s u b s t i t u e n t groups were p r e s e n t . " " F o r example, t h e t r i c y c l o -o c t a n e 194 became t h e minor p r o d u c t when t h e d i s u b s t i t u t e d d i b r o m o n o r c a r a n e 192 and i t s epimer 193 were used i n the r e a c t i o n . B r .Br Br^ ^Br -48-64 Independently, Cory, Burton and McLaren observed that the dibromonorcarane 195, when treated with methyllithium, gave two products, 196 and 197, in the ratio of about 2:3, respectively. Br B MeLi 195 2 : 3 196 197 In 1977, Cory and McLaren^ reported a new, short synthesis of (i)-ishwarane 13 based on the type of methodology just described. In this sequence, octalone 62_ was treated with lithium dimethylcuprate in order to obtain the cis-decalone 198. 200 201 202 13 -49-The saturated ketone was allowed to react with methyl Grignard reagent to form the tertiary alcohol 199. The b i c y c l i c o l e f i n 200 was isolated in good overall yield by brief exposure of alcohol 199 to mineral acid. Reaction of 200 with dibromocarbene generated from carbon tetrabromide and one equivalent of methyllithium at low temperature gave the adduct 201. The latter was not isolated but was treated immediately with another equivalent of methyllithium to form the cyclopropylidene carbene inter-mediate 202. This reactive intermediate underwent the expected insertion reaction to form (i)-ishwarane 13_, which was isolated from the reaction products in 26% yield. V. The Problem Since the structures of ishwarone and ishwarane were proposed as 12 and L3 respectively, studies concerning the total synthesis of this class of sesquiterpenoids have been actively pursued. However, up to the present time, the efforts reported in the literature have been successful in achieving only the total synthesis of ishwarane 13. Therefore, the objective of the work described in this thesis was to carry out a stereo-selective total synthesis of ishwarone 12. Apart from the fact that ishwarone 12 has not yet been obtained by total synthesis, one of the major advantages in choosing ishwarone (rather 12 13 -50-than ishwarane 13) as the primary synthetic target has to do with the pos s i b i l i t y of transforming 1_2_ into other members of this class of sesquiterpenoids. For example, ishwarane 13_ can be obtained by Wolff-Kishner reduction of the ketone functionality in ishwarone. Also, ishwarone 12_ can be transformed at least in theory into 3-oxoishwarane 47 by a 1,3-transposition of carbonyl functionality via standard reactions. 47 12 13 -51-DISCUSSION I. General In planning a prospective pathway for the total synthesis of a complex natural product such as a polycyclic sesquiterpene, i t is advantageous to study carefully a molecular model of the compound and reduce the complex framework to simpler possible precursors. The theoretical cleavage of a bond in a polycyclic skeleton w i l l often yield an intermediate having a less complex ring structure. The cyclization of this appropriately functionalized intermediate would give back the desirable polycyclic compound. The usefulness of this approach has been demonstrated by many successful total syntheses of natural products. For example, in the synthesis of (i)-seychellene 66 203 reported by Piers, de Waal and Britton , theoretical cleavage (see 203) of the bicyclo[2.2.2]octane moiety produced a simplified b i c y c l i c system 204. The appropriately functionalized intermediate 205 having the skeleton of 204 underwent base-promoted intramolecular 203 204 cyclization to generate the t r i c y c l i c ketone 206, which was then elaborated into (t)-seychellene by standard reactions. -52-205 206 203 F o l l o w i n g t h i s g e n e r a l a p p r o a c h , v a r i o u s t h e o r e t i c a l c a r b o n -c a r b o n bond c l e a v a g e s i n ishwarone 12_ were c o n s i d e r e d . S i n c e we w i s h e d t o r e g e n e r a t e t h e t e t r a c y c l i c s k e l e t o n by i n t r a m o l e c u l a r a l k y l a t i o n , o n l y bonds i n c l o s e p r o x i m i t y t o t h e k e t o n e group were t a k e n i n t o c o n s i d e r a t i o n ( s e e Scheme 3 ) . Scheme 3 o 9 210 -53-Of the four possible intermediates 207, 208, 209 and 210 obtained by theoretical breakage of bonds a, b, c and d, respectively, those with obvious structural complexity were not considered further. It was quite clear that the stereoselective syntheses of compounds of the type depicted in 207 and 208 would be quite d i f f i c u l t , and hence, the possible use of these intermediates in the synthesis of (i)-ishwarone X2 was not investigated. The intramolecular cyclization of 209 seemed, at f i r s t sight, to be an attractive p o s s i b i l i t y . However, a synthetic pathway to ishwarone 12  via this intermediate was eventually excluded, mainly because the endo stereochemistry of the C^X group (see 209) would not be easily obtained. For example, the skeleton of 209 might be derived from the intermolecular carbenoid addition of diazoacetate to the o l e f i n 211 (Y=0 or protecting group), but the desired endo-isomer of 212 would be expected to be the minor product. For instance, cyclohexene reacted with diazoacetate to give the exo-isomer 213 as the major product.^ Furthermore, in order 213 1 ' 6 : 1 -54-to obtain the required cis-stereochemistry between the cyclopropyl moiety and the angular methyl group, i t would be necessary for the olefin 211 (Y=0 or protecting group) to have a cis-ring junction. Clearly, this stereochemical arrangement would be thermodynamically less stable than the corresponding trans-isomer. Hence, great care would have to be taken to prevent epimerization to the trans-fused isomer. On the other hand, intermediate 210 seemed to be a better choice. Carbenoid addition to the thermodynamically favoured trans-fused olefin 214 (Y=0 or protecting group) would be expected to give the required trans-stereochemistry between the cyclopropane ring and the angular methyl group (see 215). This type of stereoselectivity has been demons-trated by the reaction between diazoacetate and 173-hydroxyandrost-2-ene acetate 216. Only one isomer, 2a,3a-exo_-carboethoxymethano-5a-androstan-68 176-ol acetate 217, was isolated in about 45% yield. 210 -55-OAc 216 217 Obviously, the stereochemistry on the cyclopropane ring in 215 would be d i f f i c u l t to control i f an unsymmetrical carbenoid (Z=f=Z^ ) was employed. This problem could be avoided by using a symmetrical carbenoid (Z=Z') precursor. Assuming that steric hindrance between the endo and exo-faces of the adduct 215 would be sufficiently different to allow for selective transformation of the Z functional groups, an intermediate of the type depicted i n 210 might be obtained from the adduct 215 (Z=Z'). Indeed, this assumption has been validated in closely related cases. For example, the two ester groups in 7,7-dicarboethoxynorcarane 218 exhibit quite different 69 re a c t i v i t i e s . Hydrolysis of the diester with a limited amount of base at room temperature afforded only the endo half ester 219. Complete hydrolysis required much more drastic conditions, such as a large excess 220 -56-of base and high temperatures. The dicarboxylic acid 220 derived from 218 reacted with diazoethane to provide only the exo half ester 221. Recently, Kitatani, Hiyama and N o z a k i ^ ' ^ demonstrated that 7,7-dibromonorcarane 185 could be metalated selectively with n-butyllithium under thermodynamically controlled conditions to give the endo lit h o compound 222. Subsequent alkylation with reactive alkyl halides provided 185 222 223 predominately or exclusively the 7-endo-alkyl-7-bromonorcarane 223. If the carbene adduct 215 (Z=Z') could not be elaborated selectively into 210, i t s t i l l might be possible to transform the adduct into an intermediate of general structure 224. Intramolecular cyclization of the X 225 210 latter would provide the compound 225 with the skeleton of the ishwaranes. -57-Further elaboration of functional groups would give ishwarone 12_ and ishwarane 13 from this tetracyclic intermediate. This alternative would eleminate the d i f f i c u l t i e s which could arise in attempting to differentiate between the exo and endo functional groups on the cyclo-propane ring. After considering the potential v e r s a t i l i t y and a v a i l a b i l i t y of a l l of the possible precursors, intermediate 215 (Z=Z') seemed to be the best choice for our purpose. This proposal required the stereo-selective synthesis of the keto ole f i n 226 as the f i r s t key intermediate and the stereoselective transformation of this olefin into 210 or 225 via the carbenoid adduct 215. Indeed, the f e a s i b i l i t y of this synthetic proposal has been demonstrated by the stereoselective total synthesis 13 -58-II. Attempted Synthesis of the Keto Olefin 226 via a Diels-Alder  Reaction Having considered some of the possible approaches to the synthesis of ishwarane-type sesquiterpenes, we chose to use the intramolecular cyclization of an intermediate such as 210 or 224 as the key step to 2.7 form the tricyclo[3.2.1.0 * ]octane moiety present i n these natural products. The stereoselective synthesis of these intermediates would require the selective addition of a suitable carbenoid to the keto o l e f i n 226. Therefore, our f i r s t objective was the synthesis of the bi c y c l i c keto olefin 226. 210 224 226 At the outset of our work, there was no report in the literature concerning the synthesis of the keto ol e f i n 226 or of a closely analogous compound. The synthesis of this intermediate 226 would require unambiguous formation of the c i s - v i c i n a l dimethyl groups. From a perusal of the structural formula of this compound, one might expect that the formation of the b i c y c l i c o l e f i n 226 could be economically achieved by a Diels-Alder reaction between 3,4-dimethyl-2-cyclohexen-l-one 227 and 1,3-butadiene followed by epimerization of the resultant adduct 228 (cis- to trans-ring junction). -59-227 228 226 3,4-Dimethyl-2-cyclohexen-l-one 227 was obtained by Birch reduction (lithium-liquid ammonia-alcohol) of 3,4-dimethylanisole 229, 73 followed by acid hydrolysis of the resultant intermediate 230. In our hands, this enone 227 did not react with 1,3-butadiene to give the expected 1:1 adduct under different sets of conditions (various temperatures and various reaction times). From the various experiments, either recovery of the dienophile (under less drastic conditions) or extensive polymerization of starting materials (at higher temperatures and longer reaction times) was observed. The unsuccessful attempts were probably due to the low reactivity of the cyclohexenone 227 in the Diels-Alder reaction. It has been reported that the reactivity of unsaturated ketones in Diels-Alder reactions decreased significantly when alkyl or 74 aryl substituents were present at the 3-position. For example, methyl vinyl ketone 231 reacted readily with 1,3-butadiene to afford the adduct 228 -60-232 in 75-80% yield while trans-3-hexene-2-one 233 gave the adduct 234 in only 30% yield even at higher reaction temperatures and longer reaction times.^ Furthermore, 5-methyl-l,4-hexadien-3-one 235 reacted regioselectively with 1,3-butadiene at the non-substituted vinyl moiety 74 to produce the 1:1 adduct 236 in 70% yield. It should also be noted that the dienophilic properties of cyclic a,3-unsaturated ketones have been reported to be less significant than those of acyclic v i n y l ketones. This has been illustrated by the fact that reaction of 2-cyclohexen-l-one 237 with 1,3-butadiene gave the octalone 238 in only 11% y i e l d . ^ 78 In 1973, Cookson and his colleagues reported that 3-bromo-4--61-methyl-3-penten-2-one 239 and 4-methyl-3-penten-2-one 240 reacted with 1,3-pentadiene in methylene chloride containing aluminium chloride to give the corresponding 1:1 adduct 241 and 242, respectively, as mixtures of stereoisomers. These results led us to investigate the 240 242 (ca.trans/cis=13/87) po s s i b i l i t y of using Lewis acids to catalyse the reaction between 3,4-dimethyl-2-cyclohexen-l-one 227 and 1,3-butadiene. In preliminary studies, i t was found that 4-methyl-3-penten-2-one 240 and excess 1,3-butadiene in methylene chloride in the presence of a catalytic amount of aluminium chloride (approximately 20-30 mole %) proceeded smoothly when the mixture was heated at 50-60° for 15-20 hours. Under these conditions, the 1:1 adduct 243 was isolated in f a i r l y good yield. However, when the reaction was carried out at lower temperatures, only the starting material, the enone 240, was recovered. -62-240 243 The r e a c t i o n p r o d u c t 243 was i d e n t i f i e d by s p e c t r a l d a t a . The i . r . s p e c t r u m showed t h e p r e s e n c e o f an o l e f i n i c c a r b o n - h y d r o g e n s t r e t c h i n g a b s o r p t i o n a t 3060 cm ^ and a c a r b o n y l s t r e t c h i n g a b s o r p t i o n a t 1710 cm \ I n t h e p.m.r. s p e c t r u m , t h e two o l e f i n i c p r o t o n s o f t h e p r o d u c t a p p e a r e d as an u n r e s o l v e d m u l t i p l e t a t 65.60 w h i l e t h e ^em-d i m e t h y l g r o u p s and t h e a c e t y l m e t h y l group were o b s e r v e d as s i n g l e t s a t 60.93, 61.00 and 62.10 r e s p e c t i v e l y . These r e s u l t s i n d i c a t e d t h a t a t l e a s t a s i m p l e g , 8 - d i s u b s t i t u t e d enone c o u l d r e a c t w i t h 1 , 3 - b u t a d i e n e u n d e r f a v o u r a b l e c o n d i t i o n s t o g i v e t h e e x p e c t e d D i e l s - A l d e r a d d u c t i n p r a c t i c a l y i e l d . However, a l l a t t e m p t s t o c a r r y out a s i m i l a r r e a c t i o n between 3 , 4 - d i m e t h y l - 2 - c y c l o h e x e n - l - o n e 227 and 1 , 3 - b u t a d i e n e were u n s u c c e s s f u l . Under most o f t h e r e a c t i o n c o n -d i t i o n s w h i c h were t r i e d , t h e s t a r t i n g enone 277 was r e c o v e r e d . When f o r c i n g c o n d i t i o n s ( h i g h e r t e m p e r a t u r e s , i n c r e a s e d amounts o f c a t a l y s t ) were u s e d , e x t e n s i v e p o l y m e r i z a t i o n o f s t a r t i n g m a t e r i a l s was o b s e r v e d . 227 228 -63-The poss i b i l i t y of using 2-bromo-3,4-dimethyl-2-cyclohexen-l-one 244 as a dienophile was also explored b r i e f l y . The synthesis of the bromo enone 244 could not be achieved satisfactorily by the sequence used in the formation of 3-bromo-4-methylpent-3-en-2-one 239 from 4-methylpent-3-en-2-one 240 (bromination of the double bond and dehydro-bromination of the resulting a,3-dibromo ketone with alcoholic potassium 79 hydroxide ) due to the i n s t a b i l i t y and complexity of products formed in this reaction sequence. However, the desired compound was obtained in about 20% overall yield from the enone 227 via epoxidation, followed by treatment of the resultant epoxide 245 with hydrobromic acid. 227 245 244 246 By means of a standard procedure , the enone 227 was converted into the epoxy ketone 245 in good yield. The p.m.r. spectrum of the d i s t i l l e d product indicated that one isomer was obtained predominantly (ca. 9:1 by p.m.r.). The epoxy proton of the major isomer was observed as a singlet at 62.93 while the tertiary methyl group and the secondary methyl group appeared as a singlet (61.42) and a doublet (61.08, J=7.0 Hz), respectively. On the basis of the mechanism of the reaction and the steric 1.2 effect between the methyl groups (A ' strain) in enone 227, the predominant epoxy ketone 245 was tentatively predicted to possess a cis-relationship -64-between the two methyl groups. The mixture of the epoxy ketones was stirred with 30% hydrobromic 81 acid in acetone to give a complex mixture of products. The i . r . spectrum of this material indicated the presence of an a,3-unsaturated ketone and a saturated ketol. By means of careful column chromatography of the mixture on s i l i c a gel (elution with gradually increasing amounts of ether in benzene), the desired 2-bromo-3,4-dimethyl-2-cyclohexen-l-one 244 was obtained as a pale yellow o i l . The i . r . spectrum of this material exhibited a strong a,3-unsaturated carbonyl absorption at 1680 cm and a strong stretching band for the conjugated carbon-carbon double bond at 1600 cm \ The tetrasubstituted pattern of the double bond was established from the p.m.r. spectrum, which exhibited no signal which could be attributed to an ol e f i n i c proton. The vinyl methyl group appeared as a singlet at 62.13. The secondary methyl group gave rise to a doublet (61.27) with a coupling constant of 7.0 Hz. The i . r . spectrum of a more polar minor component eluted from the chromatography column showed a broad band at 3500 cm (0-H stretching frequency) and strong absorptions at 1730 and 1710 cm \ The position of the absorption due to the carbonyl stretch (ca. 1730 cm "*") indicated the presence of an a-bromo ketone moiety. Although i t seemed reasonable to propose that the minor component was 2-bromo-3,4-dimethyl-3-hydroxycyclo-hexanone 246, the lack of success in attempted cycloadditions between bromo enone 244 and 1,3-butadiene (see below), precluded attempts to convert this material into the bromo enone 244. Cycloaddition of 2-bromo-3,4-dimethyl-2-cyclohexen-l-one 244 with 1,3-butadiene was attempted in the presence of aluminum chloride with -65-methylene chloride or benzene as solvent at different temperatures (from room temperature to 60°). However, no 1:1 adduct 247 was obtained under any of the reaction conditions used. The i n a b i l i t y of this bromo enone -r A1C1, Br 244 247 239 244 to undergo cycloaddition with the conjugated diene in comparison with 3-bromo-4-methyl-3-penten-2-one 239 was probably a reflection of the decreasing dienophilic properties of cyclic a,B-unsaturated ketones as 74 compared with acyclic analogues. Due to the i n a b i l i t y of 8-alkyl substituted cyclic ct,B-unsaturated ketones to participate in the Diels-Alder reaction with unactivated dienes, i t was decided to replace this type of dienophile with a more active one. Since i t had been reported that aliphatic a,B-unsaturated esters such as 82 83 methyl methacrylate 248 , ethyl B-acetylacrylate 249 , and even the cyclic 84 85 86 analogues 250 , 251 and 252 readily reacted with 1,3-butadiene to give the corresponding adducts 253, 254, 255, 256 and 257, respectively, i t was f e l t that 3-carbomethoxy-4-methyl-2-cyclohexen-l-one 258 might react with 1,3-butadiene to give the desired adduct 259 which could then be transformed 160c 5-12 hr 248 C02Me -66-In 1956, P e t r o v and R a i l r e p o r t e d t h a t m e t h y l p r o p i o l a t e 260 condensed w i t h 1,3-pentadiene t o g i v e the u n c o n j u g a t e d c y c l i c d i e n e 261. F o l l o w i n g t h e i r p r o c e d u r e , a c o l o r l e s s o i l was o b t a i n e d . The i . r . s pectrum -67-C0 2Me 140-145e C 6H 5CH 3 COgMe 260 261 of this material exhibited a carbonyl absorption for an a,8-unsaturated ester at 1720 cm ^. The unconjugated diene system was evidenced by the p.m.r. spectrum. The ol e f i n i c protons of the disubstituted carbon-carbon double bond appeared as a two-protonmultiplet at 65.82, while the vinyl proton on the double bond conjugated with the ester group gave rise to a multiplet at 67.08. The chemical shift of this proton indicated that i t was at the B-carbon of the unsaturated ester moiety. A three-proton singlet at 63.86 was attributed to the methyl group of the methyl ester moiety, while signals at 62.98 and 63.32 were assigned to the a l l y l i c methylene and a l l y l i c methine protons respectively. The downfield shift of these protons as compared with the chemical shifts of ordinary a l l y l i c methylene and methine protons (at approximately 62.3 and 62.6 respectively) indicated that these protons were located between two unconjugated double bonds. The secondary methyl group was evidenced by a doublet at 61.26 with a coupling constant of 7.0 Hz. The less substituted double bond in the diene ester 261 was selectively hydrogenated with tris(triphenyl)rhodium chloride as catalyst to afford the a,8-unsaturated ester 262. The presence of the unsaturated ester functionality in compound 262 was evidenced by a carbonyl absorption at 1710 cm and a carbon-carbon double bond stretching absorption at 1640 cm in i t s i . r . spectrum. In the p.m.r. spectrum, the multiplets due to the a l l y l i c methylene and a l l y l i c methine protons of this ester had shifted upfield (62.18 and 62.68, -68-respectively) in comparison with the analogus signals in the diene ester 261. These upfield shifts were expected since the additive effect of the second double bond had been eliminated. The only signal in the o l e f i n i c region of the p.m.r. spectrum (a one-proton t r i p l e t at 57.06 with J=4.0 Hz) could be assigned to the 8-proton of the a, 8-unsaturated ester moiety. The methyl group of the methyl ester functionality appeared as a singlet at 63.84, while the secondary methyl group exhibited a doublet at 51.20 with a coupling constant of 7.0 Hz. 261 262 258 A l l y l i c oxidation of the unsaturated ester 262 was attempted with a number of different oxidizing agents, such as chromium trioxide-pyridine 88 89 90 complex , tert-butyl chromate , N-bromosuccinimide in moist dioxane and 91 chromic acid. In most of the cases, the results were unsatisfactory. However, the keto ester 258 could be obtained in acceptable yield by addition of excess chromium trioxide (about three equivalents) in portions to a solution of the unsaturated ester 262 in g l a c i a l acetic acid containing small amounts of water. It was advantageous to stop the reaction when the ratio of the starting ester 262 to the keto ester 258 had reached about 1:1. Addition of further amounts of chromium trioxide to force the reaction toward completion generally resulted in the generation of complex product mixtures and low recovery of material. The keto ester 258, a pale yellow o i l , -69-could be isolated in approximately 50% yield (based on unrecovered starting material) by subjection of the crude product mixture to molecular d i s t i l l a t i o n and column chromatography on s i l i c a gel, with a 4:1 mixture of petroleum ether-ether being used as the eluting solvent. The presence of the y-oxo-a,g-unsaturated ester functionality i n compound 258 was evidenced by the strong carbonyl absorptions at 1685 and 1720 cm ^ in the i . r . spectrum. In the p.m.r. spectrum, the o l e f i n i c proton appeared as a singlet at 66.58. The sharp singlet at 63.78 was associated with the methyl ester while the multiplet at 62.96 could be assigned to the a l l y l i c methine proton. The three-proton doublet at 61.24 with coupling constant of 7.0 Hz was attributed to the secondary methyl group. With the keto ester 258 i n hand, the next step involved the Diels-Alder reaction between this compound and 1,3-butadiene. It was hoped that the diene would, for steric reasons, attack 258 from the face opposite to the secondary methyl group to produce the b i c y c l i c keto ester 259 in which the methyl group and the carbomethoxy moiety would be cis to one another. 258 259 To the best of our knowledge at the time when we began this investi-gation, there was no previous report regarding the attempted use of the cyclic keto ester 258 or a closely related analog in Diels-Alder reaction. However, during the time that our study was underway, T o r i i , Kumitomi and 92 Okamoto reported that the keto ester 263 underwent a Diels-Alder reaction -70-with 1,3-butadiene at 130-140° to afford exclusively the cis-adduct 264. When the reaction was carried out at temperatures above 150°, a 263 264 265 temperature ratio of 264/265 130-140° 100:0 >150° 3:1 mixture of the cis and trans products 264 and 265 (ca. 3:1) was isolated. These workers also demonstrated that the cis-adduct 264, upon hydrolysis with wet alcoholic potassium hydroxide, provided a mixture of the cis and trans keto acids 266 and 267 in which the trans-isomer 267 predominated (266:267=1:4). 264 266 267 This result clearly implied that the trans-isomer 267 was thermodynamically more stable than the cis-isomer 266. In our hands, the thermal cycloaddition of the keto ester 258 with 1,3-butadiene proved to be very sluggish. Treatment of the dienophile 258 with excess 1,3-butadiene in the presence of a catalytic amount of hydroquinone -71-in a sealed tube for three to four days at temperatures up to approxi-mately 160° resulted only in recovery of the keto ester 258 and/or excessive polymerization of starting materials. The use of s t i l l more forcing conditions (e.g. heating a mixture of 258 and 1,3-butadiene at 180-200° in a sealed bomb with a glass lining for four days) also failed to produce any of the desired Diels-Alder product. 93 In the si x t i e s , Inukai and his colleagues showed that methyl acrylate reacted with 1,3-butadiene very rapidly in the presence of anhydrous aluminum chloride to give the corresponding Diels-Alder product. They reported that when the reaction was carried out for three hours at 10-20°, methyl 3-cyclohexene-l-carboxylate 268 could be obtained in 65% yield. However, without aluminum chloride as catalyst, not a trace of the product was detected after 96 hours at room temperature. With regards to 268 reaction mechanism, Inukai and Kojima^'^ postulated that the catalyst f i r s t coordinated with the electron withdrawing group of the dienophile and that this complex then reacted with the diene in a stepwise ring formation involving a very short-lived zwitterionic intermediate (see Scheme 4). This type of stepwise mechanism was further supported by the -72-Scheme 4 -b observations of Thompson and Melillo in a study of the catalyzed reaction between 1,3-butadiene and 2-phenyl-2-cyclo-hexen-l-one 269. Along with the expected adduct 270 (mixture of cis and trans-isomers), 269 270 271 these workers also isolated the t r i c y c l i c ketone 271 (mixture of isomers). The latt e r was proposed to arise from the internal trapping of the zwitterionic intermediate by electrophilic attack on the phenyl moiety. Encouraged by the results observed by Inukai's group on the catalytic 93 Diels-Alder reaction , we chose to explore the effect of a Lewis acid on the reaction between the keto ester 258 and 1,3-butadiene. Unfortunately, i t was found that no reaction occurred when butadiene was bubbled into a methylene chloride solution of the keto ester-aluminium chloride complex for three to four hours at room temperature. Similarly, when a methylene - 7 3 -chloride solution of the dienophile-aluminum chloride complex was saturated with 1,3-butadiene, and then kept at room temperature for three to four days, no Diels-Alder product was produced. However, when a solution of the keto ester 258 in methylene chloride was heated at 95-100° with excess 1,3-butadiene in the presence of aluminum chloride in a sealed tube for one day, a mixture of 1:1 Diels-Alder adducts was isolated from other polymeric products. On the basis of a g.l.c. analysis, the Diels-Alder adduct mixture consisted of two major products (1:1 ratio ) , which were later shown to be 272 and 273. The yield of this mixture was found to vary significantly (from 20-50% yield) with the amount of Lewis acid as well as the purity of the catalyst. The best results were obtained by using an approximately 2:1 ratio of the keto ester 258 to freshly 272 273 sublimed aluminum chloride. Other Lewis acids such as boron t r i f l u o r i d e etherate and copper tetrafluoroborate were also tried, but the results were unsatisfactory. Boron t r i f l u o r i d e etherate gave the same major products (also in a ratio of approximately 1:1), but with more side products and lower yields. Although copper tetrafluoroborate was 97 reported by Corey to be an effective catalyst for Diels-Alder reactions, i t seemed to be ineffective in our case. At room temperature, no reaction was observed after one day, while at 60-70°, excessive polymerization of -74-starting materials was observed. The physical and spectral properties of the 1:1 Diels-Alder adduct mixture were in agreement with structures 272 and 273. Thus the i . r . spectrum showed a strong o l e f i n i c carbon-hydrogen stretching absorption at 3080 cm and a broad carbonyl absorption (^1720 cm ^) for the ester and cyclohexanone-type carbonyl groups. This mixture of isomers was p a r t i a l l y separated by a careful gradient column chromato-graphy over s i l i c a gel, with mixtures of petroleum ether and ether being used as eluting solvent. The keto ester 272 was obtained as a colorless o i l which crystallized upon standing. Recrystallization from petroleum ether gave pure white needles (m.p. 96-97°). In the p.m.r. spectrum of this material, the o l e f i n i c protons appeared as a multiplet at 65.68 while the methyl group of the ester functionality gave ri s e to a singlet at 63.62. The bridgehead proton was observed as an unresolved multiplet at 62.88-3.06. A doublet at 60.99 with a coupling constant of 6.0 Hz was attributed to the secondary methyl group. Isomer 273 was very d i f f i c u l t to purify. It was eventually obtained from the above-mentioned column chromatography as colorless o i l containing a small amount of the isomer 272 as an impurity. By comparing the p.m.r. spectrum of the keto ester 272 with that derived from this material, i t was possible to assign the proton resonances of the isomer 273. Although the spectrum of the latter was very similar to that of compound 272, there were small differences. The vinyl protons of 274 gave ri s e to a signal at 65.60 (broad doublet) and the secondary methyl group produced a doublet (J=6.0 Hz) at 60.89. The methyl group of the ester functionality gave rise to a three-proton singlet at 63.74 and the bridgehead proton produced an unresolved doublet of doublets at 63.17. -75-At t h i s p o i n t , t h e s t e r e o c h e m i s t r y of b o t h of the D i e l s - A l d e r a d d u c t s 272 and 273 remained unknown. I t had been e x p e c t e d , on t h e b a s i s of the mechanism of the D i e l s - A l d e r r e a c t i o n and of s t e r i c e f f e c t s a s s o c i a t e d w i t h the s e c o n d a r y m e t h y l group, t h a t 1 , 3 - b u t a d i e n e would a t t a c k t h e k e t o e s t e r 258 from the l e s s h i n d e r e d f a c e (away from the s e c o n d a r y m e t h y l group) to g i v e the a l l c i s compound 259 as t h e i n i t i a l p r o d u c t . P e r h a p s , under the r e a c t i o n c o n d i t i o n s , t h i s p r i m a r y p r o d u c t c o u l d undergo p a r t i a l ( o r complete) e p i m e r i z a t i o n t o a f f o r d t h e t r a n s k e t o e s t e r 272 as a n o t h e r p o s s i b l e major component i n t h e m i x t u r e . 259 272 On t h e b a s i s o f c o n f o r m a t i o n a l a n a l y s e s of s t r u c t u r e s 272 and 259 (see Scheme 5 ) , i t was e x p e c t e d t h a t t h e t r a n s - i s o m e r 272 s h o u l d be -76-259a Scheme 5 M e 0 2 C 259b 1 gauche COOMe-CH3 1 gauche CH 2-CH 3 1 s y n - a x i a l COOMe-H 1 , 3 - d i a x i a l COOMe-sp 2( >=0) 2 s y n - a x i a l CH~-H 2 2 1 , 3 - d i a x i a l C H - s p ( > = < ) C 0 2 M e 272 1 gauche COOMe-CH3 1 gauche CH 2-CH 3 2 s y n - a x i a l COOMe-H 1 , 3 - d i a x i a l COOMe-sp 2( >=0) 1 , 3 - d i a x i a l COOMe-sp 2(>=< ) 1 gauche COOMe-CH3 2 s y n - a x i a l CH 3~H 1 s y n - a x i a l CH„-H 1 , 3 - d i a x i a l CH 2-sp ( >=0) 1 s y n - a x i a l COOMe-H 1 , 3 - d i a x i a l COOMe-Sp 2(>=< ) 2 2 1 , 3 - d i a x i a l sp (^>=0)-sp ( 259b-259a" = (2 s y n - a x i a l CH 3~H + 1 , 3 - d i a x i a l s p 2 ( > = 0 ) - s p ( > = < ) -(1 gauche CH 2-CH 3 + 1 s y n - a x i a l CH 2-H) = [1.8-(0.8+0.9)]Kcal/mole = 0.1 Kcal/mole 259b-272 = (2 s y n - a x i a l CH 2~H) - ( 1 s y n - a x i a l COOMe-H) = (1.8 - 0.55)Kcal/mole =1.25 Kcal/mole The c o n f o r m a t i o n a l energy a s s o c i a t e d w i t h a 1 , 3 - d i a x i a l i n t e r a c t i o n between two S p 2 c e n t e r s ( ^ C=0 and ^ C = C ^ ) was assumed to be s m a l l and n e g l i g i b l e . -77-theraodynamically more stable than the cis-isomer 259 and should therefore be the predominant isomer under epimerization conditions. Therefore the crystalline isomer 272 was subjected to equilibriation by treatment with sodium methoxide in dry methanol. After five hours at reflux, only the starting material was recovered. This indicated that the compound probably possessed a trans-ring junction. However, due to the ambiguity associated with estimating the effect of the double bond in the conformational analysis, i t was f e l t to be advantageous to remove the double bond in order to simplify the analysis. Upon hydrogenation of compound 272 i n the presence of palladium-on-carbon, the decalone 274 was obtained as white needles, after recry-s t a l l i z a t i o n from petroleum ether. This crystalline product exhibited physical properties in accord with the structure proposed. In the i . r . spectrum, the carbonyl stretching absorptions of the ester group and the ketone functionality appeared at 1720 and 1710 cm \ respectively. The p.m.r. spectrum of 274 showed no signals due to ol e f i n i c protons. The sharp singlet at 63.60 was attributed to the methyl group of the ester moiety, while the doublet (J=6.0 Hz) at 0.93 was assigned to the secondary methyl group. 272 274 -78-The decalone ester 274 was subjected to epimerization conditions by treatment with sodium methoxide in hot methanol. After the solution had been refluxed for five hours, the only compound isolated possessed a g.l.c. retention time identical with that of the starting material. Indeed, the i . r . and p.m.r. spectra of this component were identical with those of the starting material, decalone 274. On the basis of conformational analyses (see Scheme 6), i t could be seen that the trans-decalone 274 should be considerably more stable than the cis-decalone 275, and equilibration should thus favour the former compound. On this basis, i t was concluded that the decalone 274 and, in turn, the unsaturated keto ester 272, must possess trans-fused ring systems. -79-Scheme 6 O aMe 1 gauche COOMe-CH3 1 gauche CH 2~CH 3 1 s y n - a x i a l COOMe-H 1 , 3 - d i a x i a l COOMe-sp 2(>=0) 2 s y n - a x i a l CH 2~H 1 s y n - a x i a l CH-H MeQ2C 1 gauche COOMe-CH3 2 s y n - a x i a l CH 3~H 2 s y n - a x i a l COOMe-H 1 s y n - a x i a l CH 2~H 2 1 , 3 - d i a x i a l C H 2 - s p 2 ( > = 0 ) 275b-275a = (1 s y n - a x i a l COOMe-H + 1 , 3 - d i a x i a l C H 2 ~ s p 2 ( >=0) - (1 gauche CH 3"CH 2) = (0.55 + 0.35 - 0.8) Kc a l / m o l e = 0 . 1 K c a l / m o l e 274 1 gauche COOMe-CH3 1 gauche CH 2"CH 3 3 s y n - a x i a l COOMe-H 1 1 , 3 - d i a x i a l COOMe-sp 2(;>=0) 275a - 274_ = (2 s y n - a x i a l CH 2~H +1 s y n - a x i a l CH-H) -(2 , s y n - a x i a l COOMe-H) = (3 x 0.9 - 1.1) Kcal/mole = 1.6 Kcal/mole -80-At this point, the stereochemical relationship between the secondary methyl group and the angular ester group in compound 272 and 275 was not yet defined. However, in previous studies in our laboratory, the decalins 276 and 277 had been prepared unambiguously 98 from the octalone 62 (see Scheme 7). Therefore, correlation Scheme 7 277 of the keto ester 274 with the decalin 276 would provide unambiguous evidence regarding the relative stereochemistry of the methyl group and the ester functionality in 274. I n i t i a l l y , we chose to reduce the keto ester 274 to the diol(s) 278, which, hopefully, could be transformed into the decalin 276 by 99 Ireland's reductive deoxygenation procedure employing N,N,N',N'-tetramethylphosphorodiamidates 279 as intermediate(s). Although reduction of 274 to the diol(s) 278 proceeded smoothly with excess lithium aluminum hydride in refluxing ether, the attempted conversion of 278 into -81-the corresponding phosphorodiamidates 279 was unsuccessful. Therefore, this approach to the transformation of 274 into the decalin 276 was abandoned. In another approach, the ketone functionality of the decalone ester 274 was f i r s t converted into the corresponding dithioketal 280 by allowing the former to react with ethanedithiol in the presence of boron t r i f l u o r i d e etherate. The dithioketal ester 280 was then reduced smoothly with excess lithium aluminium hydride to afford the corresponding alcohol 281 in excellent yield. The spectral properties of this compound were in f u l l agreement with the assigned structure. Thus, the hydroxy group produced a broad absorption at 3467 cm ^ in the i . r . spectrum. The presence of the dithioketal moiety and the primary alcohol group was evidenced by the p.m.r. spectrum which exhibited a four-proton multiplet at 63.20 and a two-proton sharp singlet at 63.90. 274 280 ' 281 - 8 2 -s. s 282 276 277 Oxidation of 281 with chromium trioxide-pyridine complex"^^ produced a crystalline product 282 in good yield. A strong absorption at 1720 cm \ in association with an absorption at 2710 cm in the i . r . spectrum, indicated that the primary alcohol group had been oxidized to the corresponding aldehyde. The tertiary nature of the aldehyde functionality was shown by the p.m.r. spectrum of 282 which showed the aldehyde proton as a sharp singlet at 610.23. Interestingly, the doublet for the secondary methyl group in 282 had shifted up-field to 60.88 in comparison to the corresponding doublet in the dithioketal alcohol 281 (60.97). When the pure dithioketal aldehyde was subjected to Wolff-Kishner reduction, desulfurization also occurred."'"^ "'" The product appeared to be homogeneous by g.l.c. analysis and i t s retention time was identical with that of the hydrocarbon 276 as well as that of the decalin 277. The i . r . spectrum of this product indicated that the aldehyde functionality had been reduced to the corresponding methyl group. However, a careful comparison of the p.m.r. spectrum of the reduction product with those of authentic samples of the decalins 276 and 277 clearly showed that this material was actually a mixture of 276 and 277. The tertiary methyl group of pure 276 appeared as singlet at 60.70 while the secondary methyl group gave rise to a poorly resolved doublet at 60.74 (J=5.0 Hz). On the other hand, the signal due to the tertiary methyl group of the decalin 277 -83-appeared as a sharp singlet at 60.83 and the secondary methyl group produced a doublet at 60.75 (J=6.2 Hz). In the p.m.r. spectrum of the Wolff-Kishner reduction product, there was a strong singlet at 60.68 which could be attributed to the tertiary methyl group of the decalin 277. The characteristic pattern for the secondary methyl group of the decalin 277, however, could not be observed clearly due to interference by the signal attributed to the secondary methyl group of the decalin 276 which appeared at 60.72 as a doublet with a coupling constant of 6.0 Hz. The tertiary methyl group of decalin 277 appeared as a sharp signal at 60.80. From this spectrum, the ratio of the decalins 276 and 277 in the Wolff-Kishner reduction product was estimated to be approximately 60:40, respectively. The formation of the epimeric decalins 276 and 277 from the Wolff-Kishner reduction of the dithioketal aldehyde 282 can be rationalized by assuming that the dithioketal moiety f i r s t underwent base-promoted frag-mentation to generate a bicyclic ketone (see Scheme 8). Base-catalyzed epimerization of the ketone, followed by Wolff-Kishner reduction of the ° 102 carbonyl group could lead to a mixture of hydrocarbons. Indeed, 103 Heathcock and colleagues have reported that ethylene ketals are subjected to fragmentation (to afford the corresponding ketones which then undergo 1,2-addition with the excess alkyllithium) when treated with very strong bases such as n-butyllithium. Since protons adjacent to sulfur atoms are more acidic than those adjacent to oxygen atoms, i t appears that dithioketals might be even more susceptible to this kind of fragmentation than the corresponding ketals. -84-Scheme 8 NH 2NH 2/OH R=CHO o r CH=NNH, The p r o d u c t o b t a i n e d from t h e W o l f f - K i s h n e r r e d u c t i o n o f the d i t h i o k e t a l a l d e h y d e 282 was, u n f o r t u n a t e l y , a m i x t u r e o f t h e e p i m e r i c d e c a l i n s 276 and 277. However, t h e p r e s e n c e o f v i c i n a l c i s - d i m e t h y l groups i n b o t h components c l e a r l y d e f i n e d t h e r e l a t i v e s t e r e o c h e m i s t r y o f the se c o n d a r y m e t h y l group and t h e a n g u l a r e s t e r f u n c t i o n a l i t y i n t h e k e t o e s t e r 272. These r e s u l t s , i n c o n j u n c t i o n w i t h t h e p r e v i o u s l y d e s c r i b e d f a i l u r e o f th e c r y s t a l l i n e e s t e r 272 and i t s d i h y d r o d e r i v a t i v e 274 to e p i m e r i z e under b a s i c c o n d i t i o n s , c l e a r l y showed t h a t t h e s e compound p o s s e s s e d a c i s - r e l a t i o n s h i p between t h e m e t h y l group and t h e e s t e r f u n c t i o n a l i t y and a t r a n s - r e l a t i o n s h i p between t h e b r i d g e h e a d p r o t o n and t h e a n g u l a r c a r b o -methoxy m o i e t y . -85-272 274 259 275 As pointed out previously, conformational analyses had indicated that the i n i t i a l expected product 259 from the Diels-Alder reaction should be thermodynamically less stable than the trans-epimer 272 (see Scheme 5). In the case of the dihydro derivatives 274 and 275, i t was expected that the trans-isomer 274 would be the predominant isomer under equilibration conditions (see Scheme 6). Therefore, i f the other component isolated from the Diels-Alder reaction had possessed the a l l cis-stereo-chemistry (259), i t , and/or i t s dihydro derivative 275, would be expected to epimerize under basic conditions to the thermodynamically more stable isomers 272 and 274, respectively. When the o i l y component obtained from the Diels-Alder reaction was treated with sodium methoxide in methanol, a mixture of the starting keto ester and a new isomer 283 (ratio ~ 7:1), was obtained. By comparing the p.m.r. spectrum of this mixture with that of the starting keto ester, i t was possible to assign some of the proton resonances of the new isomer. Of particular interest were the signals due to the secondary methyl groups and the methyl groups of ester functionalities. The doublet (J=6.0 Hz) due to the secondary methyl group of the starting material appeared at 60.89, while the corresponding signal for the new isomer appeared at 61.23 (J=6.0 Hz). The three-proton singlets for the methyl group of the carbo-methoxy moieties appeared at 63.74 (starting material) and 63.64 (new isomer). -86-When these data were compared with those obtained from the f i r s t Diels-Alder product 272 (secondary methyl doublet at 60.99, J=6.0 Hz, and the singlet due to the carbomethoxy functionality at 63.62), i t was clear that the second Diels-Alder product must have possessed a trans stereo-chemical relationship between the secondary methyl group and the angular methyl ester moiety. Hence, this compound was assigned structure 273. Upon hydrogenation, the unsaturated keto ester 273 was converted into the dihydro derivative 284. The i . r . spectrum of the latter compound -1 -1 showed carbonyl stretching absorptions at 1720 cm (ester) and 1700 cm (ketone). The p.m.r. spectrum, which contained no signals due to ol e f i n i c protons, exhibited a three-proton singlet at 63.70 (methyl ester) and a three-proton doublet (J=6.0 Hz) at 60.86 (secondary methyl group). H ° H H2/Pd-C 284 COjMe NaOMe MeOH 285 COjM' When the keto ester 284 was subjected to equilibration conditions (sodium methoxide in methanol), a mixture of two major components, in a ratio of approximately 55:45, was obtained. A g.l.c. analysis indicated that the predominant component was the starting material, keto ester 284. These epimeric keto esters were separated by means of preparative t . l . c . (with a mixture of 3:7 ether-hexane being employed as the developing solvent) The p.m.r. spectrum of the new isomer showed that the secondary methyl group of this keto ester 285 gave rise to a doublet (J=6.5 Hz) at 61.20. Thus, -87-epimerization had caused a significant downfield shift of this signal, since the corresponding absorption in the starting material 284 was at 60.86. On the other hand, epimerization had caused an upfield shift of the signal due to the carbomethoxy group (63.70 in 284 and 63.62 in 285). When the p.m.r. spectrum of keto ester 285 was compared with that of decaione 274, i t was quite clear that the two compounds were different. The p.m.r. spectrum of 274 showed a singlet at 63.60 (methyl ester) and a doublet (J=6.0 Hz) at 60.73 (secondary methyl group). Conformational analyses involving the isomeric keto esters 284 and 285 indicated that the isomer with a cis-ring junction (284) should be sli g h t l y more stable than the trans-isomer (see Scheme 9). The calculated conformational energy difference between the more stable conformer 284b of the cis-isomer and the r i g i d conformation 285 of the trans-isomer was roughly 0.4 kcal/mole. This small difference in free energy indicated that the more stable isomer at equilibrium should be only sl i g h t l y favoured (in the ratio of approximately 65:35). Indeed, the ratio of the two products obtained from the epimerization experiment was approximately 55:45, Although the saturated keto ester 284 and. in turn, the unsaturated keto ester 273 isolated from the Diels-Alder reaction, could now be assigned to have cis-ring junctions and a trans-relationship between the secondary methyl group and the tertiary ester functionality, i t was f e l t desirable to obtain further unambiguous evidence to support these conclusions. To this end, i t was decided to convert the saturated keto ester 284 into the decalin(s) 286 and/or 287, which were available from a previous study in -88-Scheme 9 MeOzC 284a 1 s y n - a x i a l COOMe-H 1 1 , 3 - d i a x i a l COOMe-sp 2(>=0) 1 s y n - a x i a l CH^-H 2 1 , 3 - d i a x i a l CH 2-CH 3 1 s y n - a x i a l CH 9-H 284a-284b = (1 s y n - a x i a l CH 3"H + 2 1 , 3 - d i a x i a l CH 2-CH 3)-(1 gauche COOMe-CH3 + 1 gauche CH 3~CH 2 + 1 s y n - a x i a l COOMe-H) = (0.9 + 2x3.7)-(2x0.8+0.55) = 6.15 Kcal/mole 1 gauche C00Me-CH 3 1 gauche CH 3"CH 2 2 s y n - a x i a l COOMe-H 2 2 s y n - a x i a l sp ( >=0)-H 1 s y n - a x i a l CH 2~H CQ2Me 285-284b = (1 s y n - a x i a l COOMe-H + 2 s y n - a x i a l CH 3~H)-(1 gauche COOMe-CH3 + 1 gauche CH 3"CH 2 + 1 s y n - a x i a l sp 2(^>=0)-H) = (0.55 + 1.8)-(2 x 0.8 + 0.35) =0.4 Kca l / m o l e 285 1 1 , 3 - d i a x i a l COOMe-sp 2(>=0) 3 s y n - a x i a l COOMe-H 3 s y n - a x i a l CH 3~H -89-our laboratory. The authentic samples of 286 and 287 were prepared 97 from the octalone 63, the stereochemistry of which was known (see Scheme 10). Scheme 10 287 In the conversion of the saturated keto ester 284 into the corresponding decalin, the ketone group was f i r s t protected as the corresponding dithioketal. Treatment of the keto ester 284 with ethanedithiol in the presence of boron t r i f l u o r i d e afforded the dithioketal ester 288 in excellent yield. The spectral properties of 228 were in agreement with the assigned structure. The presence of the carbonyl group of the ester was shown by an absorption at 1720 cm ^ in the i . r . spectrum. The p.m.r. spectrum showed an unresolved doublet centered at 60.83 for the secondary methyl group while the protons due to the dithioketal moiety and the methyl group of the carbomethoxy functionality appeared as a multiplet at 63.30 and a singlet at 63.72, respectively. -90-290 286 287 Reduction of the ester 288 to give the alcohol 289 was achieved smoothly by treatment of the former with lithium aluminium hydride in refluxing tetrahydrofuran. The i . r . spectrum of the product 289 indicated the presence of the hydroxyl functionality by a broad absorption at 3450 cm \ In the p.m.r. spectrum, the methylene protons adjacent to the hydroxyl. group appeared as a pair of doublets (AB system) at 63.69 and 3.58, with a coupling constant of 11.0 Hz. A multiplet at 53.25 was attributed to the dithioketal protons. The hydroxyl proton gave rise to a singlet at 62.62. Finally, an unresolved upfield doublet at 60.83 was assigned to the secondary methyl group. The alcohol 289 was oxidized with chromium trioxide-pyridine complex"*"^ to afford the corresponding aldehyde 290 in 76% yield. The • presence of aldehyde functionality was supported by absorptions at 2717 and 1720 cm ^ in the i . r . spectrum. A downfield singlet at 69.35 in the p.m.r. spectrum also confirmed the presence of a tertiary aldehyde group. The signal attributed to the dithioketal protons appeared as a multiplet at 63.28, while the secondary methyl group produced an unresolved doublet -91-at 60.78. Reduction of the dithioketal aldehyde under Wolff-Kishner reduction conditions afforded a colorless o i l which appeared to be homogeneous by analysis on several different g.l.c. columns. The retention time of this material was identical with those of the authentic decalins 286 and/or 287. However, a careful study of the p.m.r. spectrum of this material showed that i t was actually a mixture of the decalins 286 and 287. In the p.m.r. spectrum of the pure authentic decalin 286, the tertiary methyl group appeared at 50.92 while the secondary methyl group was located as a doublet (J=4.5 Hz) centered at 0.97. On the other hand, the tertiary methyl group of the pure authentic decalin 287 gave rise to a sharp singlet at 51.02. The pattern of the secondary methyl group was very distinctive. It appeared as a broad unresolved signal at 60.82. The p.m.r. spectrum of the mixture of hydrocarbons obtained from the Wolff-Kishner reduction of the dithioketal aldehyde 290 contained a l l of the signals which would be expected from a mixture of 286 and 287. Two sharp singlets at 60.93 and 61.02 could be assigned to the tertiary methyl groups of the decalins 286 and 287, respectively. The doublet signal due to the secondary methyl group of 286 could not be identified easily due to interference from the tertiary methyl signal of the hydro-carbon 287. However, the characteristic unresolved signal for the secondary methyl group of 287 was observed at 60.82. From the integration of this p.m.r. spectrum, the ratio of the decalins 286 and 287 in the Wolff-Kishner reduction product was estimated to be approximately 1:1. The formation of -92-these hydrocarbons from the pure dithioketal aldehyde 290 could be explained by the postulation described previously (see Scheme 8). On the basis of this correlation, i t could be concluded that the o i l y Diels-Alder product 273 possessed a trans stereochemical relationship between the secondary methyl group and the ester functionality. The established relationship between the keto ester 272 and the decalins 276 and 277, as well as the conversion of the keto ester 273 into the decalins 286 and 287, clearly indicated that the Diels-Alder reaction between the keto ester 258 and 1,3-butadiene had not taken place with the hoped-for (and expected) stereoselectivity. Although the desired b i c y c l i c keto ester 272 had been obtained in four steps from the commerci-al l y available methyl propiolate 260, the formation of equal amounts of the isomer 273, along with the necessity for a tedious separation of 226 286 287 -93-isomers, and the capricious nature of the Diels-Alder reaction made this overall synthetic approach experimentally unsatisfactory. Therefore i t was decided to attempt the synthesis of the keto ole f i n 226 by another synthetic sequence. III. Synthesis of the Keto Olefin 226. xia Intramolecular Alkylation The d i f f i c u l t i e s encountered in the attempted synthesis of the bic y c l i c keto o l e f i n 226 via a Diels-Alder reaction led us to investigate a synthetic sequence in which the construction of the c i s - v i c i n a l methyl groups could be unambiguously achieved at an early stage. Although many methods which had resulted in the formation of c i s - v i c i n a l methyl groups in octalone systems had been documented, the one reported by Ziegler and 49 50 his colleagues ' seemed to be the most suitable for our purposes. These workers had reported that 1,4-addition of lithium divinylcuprate to 3,4-dimethyl-2-cyclohexen-l-one 227 resulted in the efficient formation of cis-3,4-dimethyl-3-vinylcyclohexanone 142 as the sole product. This cyclohexanone not only possessed the desired stereochemistry with respect to the v i c i n a l methyl groups, but also contained the vinyl group as a "handle" to allow for further elaboration to the bic y c l i c keto olefin 226. 226 -94-We chose as our f i r s t synthetic objective, the a l l y l i c alcohol, which could then hopefully serve as a direct precusor for the synthesis of the b i c y c l i c keto ole f i n 226. When 3,4-dimethyl-2-cyclohexen-l-one 227 was treated with a large excess of lithium divinylcuprate in the 104 presence of tri-n-butylphosphine as a stabilizing agent , the cyclo-hexanone 142 was formed as the only product. The physical and spectral properties of this material were in agreement with those previously reported.^ Thus, the i . r . spectrum clearly showed the presence of the v i n y l group (band at 3030, 1630 and 920 cm 1) and the ketone carbonyl functionality (1710 cm ^ ) . In the p.m.r. spectrum of 142, the tertiary v i n y l group gave ri s e to three different pairs of doublets. The downfield pair of doublets (J=18.0 and 9.0 Hz) at 65.78 could be assigned to the internal viny l proton. The second pair of doublets at 64.99 with coupling constants of 9.0 and 1.5 Hz was attributed to the terminal vinyl proton which was cis with respect to the internal viny l proton. Finally, the pair of doublets at highest f i e l d (64.95, J=18.0 and 1.5 Hz) could readily be assigned to the terminal o l e f i n i c proton which was trans to the internal vinyl hydrogen. Other signals of note in the p.m.r. spectrum of 142 were those associated with the secondary methyl group, which gave rise to a doublet at 60.91 (J=6.0 Hz) and the tertiary methyl group which produced a sharp singlet at 60.90. Although the conjugate addition of lithium divinylcuprate to, the cyclohexenone 227 proceeded smoothly to give the adduct 142 in excellent yiel d , there were some drawbacks to the reaction. F i r s t of a l l , a f a i r l y large excess of lithium divinylcuprate was required for the reaction. In addition to being somewhat wasteful, this requirement led to the necessity, -95-in large-scale reactions, of handling large volumes of vinyllithium solution. Thirdly, in large scale reactions, the relatively copious amounts of insoluble copper salts made work up rather tedious. Finally, the fact that vinyllithium was no longer commercially available caused yet another obstacle. In view of these inconveniences, i t was decided to investigate the copper-catalyzed 1,4-addition of vinyl magnesium halide to the cyclohexenone 227 as an alternative method. The conjugate addition of alkyl magnesium halides to a,8-unsaturated enones in the presence of cuprous halides was well documented.However, the use of alkenyl magnesium halides, especially vinyl magnesium halide i t s e l f , was less familiar. Nevertheless, Alexandre and Rouessac''"^'"''^ had reported that in the presence of diisopropylsulfide and a catalytic amount of cuprous iodide, v i n y l magnesium halide reacted with various cyclic a,6-unsaturated ketones to afford the corresponding 1,4-adducts in good to excellent yields. Thus cyclohexanones 293, 295, and 297 were obtained from corresponding enones 292, 294 and 296, respectively. The enone 298, under the same conditions, gave rise to two cyclohexanones 299 and 300 in the ratio of approximately 4:1. MgBr CuI/Pr^S 292 293 294 295 -96-298 299 300 Addition of 3 >4-dimethyl-2-cyclohexen-l-one 227 to a cold solution (0°) of vinyl magnesium bromide (prepared according to the 108 procedure of Seyferth ) in tetrahydrofuran containing dimethyl-sulfide and a catalytic amount of cuprous iodide resulted in the formation of only small amounts (10-20%) of the desired 1,4-adduct. The i . r . spectrum of the crude product showed a strong absorption at 3450 cm ^ which could be attributed to a hydroxyl functionality. Presumably, 1,2-addition to the carbonyl group had competed with 1,4-addition. It was known that this type of competition reaction could sometimes be minimized by employing an inverse addition procedure in which the Grignard reagent was added to a solution of the enone. Indeed, when a solution of vinyl magnesium bromide was added dropwise to a tetrahydrofuran solution of 3,4-dimethyl-2-cyclohexen-l-one 227 in the presence pf cuprous iodide and dimethylsulfide, the formation of the 1,4-adduct was improved dramatically. Hence, homogeneous cis-3,4-dimethyl-3-vinylcyclohexanone 142 could be isolated i n approximately 65% yield by direct d i s t i l l a t i o n of the crude product. The physical and spectroscopic properties of this compound were identical in a l l respects with those of an authentic sample obtained as described previously. The presence of a minor alcoholic component (presumably 301, resulting from competitative 1,2-addition) was shown by a broad -97-hydroxyl stretching absorption at 3450 cm in the i . r . spectrum of the crude product. This compound seemed to be thermally unstable because, upon d i s t i l l a t i o n of the crude product, significant amounts of water were collected. In a l l probability, the tertiary alcohol 301 underwent catalytic thermal dehydration to give water and highly v o l a t i l e hydrocarbon products. 227 142 301 When a procedure for the formation of the cyclohexanone 142 via 1,4-addition of v i n y l magnesium bromide had been secured, an investi-gation aimed at the conversion of 142 into the a l l y l i c keto alcohol 49 50 291 was begun. Ziegler and coworkers ' had shown that the ketal aldehyde 304 could be obtained e f f i c i e n t l y in three steps from the ketone 142. We f e l t that the former intermediate 304 could serve as a useful intermediate in our synthesis of the keto ol e f i n 226. For example, i t was hoped that 304 could be transformed e f f i c i e n t l y into the dibromo ole f i n 305. Treatment of the latter with two equivalents of n-butyllithium, followed by trapping of the resulting lithium acetylide with formaldehyde, should afford the propargylic alcohol 306. Sequential subjection of 306 to hydrolysis and semi-hydrogenation would furnish the desired a l l y l i c keto alcohol 291, from which the keto o l e f i n 226 -98-would be obtained via intramolecular alkylation. n0 OH p-TSA P 2)NaOH/H202 Cr0 3.2Pyr 142 o o X -CHO Zn 302 CBr 4/Ph 3P Br - B r l ) B u n L i 2) HCHo' 303 H 0 - H 3 % 304 305 306 HO-^ H2/Pd-BaS04 C9H?N OH 307 291 226 The ethylene ketal 302 of cis-3,4-dimethyl-3-vinylcyclohexanone was obtained e f f i c i e n t l y by refluxing a benzene solution of the cyclo-hexanone 142 and ethylene glycol in the presence of a catalytic amount of _p_-toluenesulfonic acid (Dean-Stark apparatus). The spectral data obtained from the product 302 were in f u l l agreement with the assigned structure. Of particular interest was the absence of a carbonyl absorption in the i . r . spectrum. In the p.m.r. spectrum, the vinyl group gave rise to three pairs of doublets in a pattern very similar to that observed in the spectrum of the ketone 142. A four-proton multiplet at 63.90 could be attributed to the protons of the ethylene -99-ketal moiety. The secondary and tertiary methyl groups were evidenced by a doublet (J=6.0 Hz) at 50.79 and a sharp singlet at 61.00, respectively. Hydroboration of the ketal o l e f i n 302 with disiamylborane"^ (formed 109 by the reaction of dimethylsulfide-borane complex with 2-methyl-2-butene ) afforded the ketal alcohol 303 as colorless viscous o i l . The presence of a primary alcohol functionality in this compound was shown by a strong, broad absorption at 3450 cm ^ in i t s i . r . spectrum, and by a two-proton t r i p l e t (J=7.0 Hz) at 63.69 in i t s p.m.r. spectrum. The p.m.r. signals for the methyl groups and the ketal protons were found at positions very similar to those of the corresponding signals in the ketal o l e f i n 302. Oxidation of the primary alcohol 303^ was achieved by chromium trioxide-pyridine c o m p l e x . T h e i . r . spectrum of the product 304 exhibited no absorption due to a hydroxy group, but showed two absorptions (2755, 1715 cm "*") which were clearly indicative of the presence of an aldehyde functionality. In the p.m.r. spectrum, a downfield t r i p l e t at 69.87 with a coupling constant of 3.0 Hz was characteristic of an alde-hyde proton. The methylene protons adjacent to the aldehyde group appeared as a doublet at 62.35 with a coupling constant of 3.0 Hz. The signals due to the ketal protons (63.90, multiplet) and the secondary methyl group (60.85, doublet, J=6.0 Hz) were at the same positions as the corresponding signals i n the ketal alcohol 303. However, the singlet due to the tertiary methyl group had shifted downfield from 60.90 to 61.06 when the primary alcohol group was oxidized to the aldehyde. Addition of this aldehyde 304 to a solution of dibromomethylene-triphenylphosphorane (generated ±n situ by the reaction of carbon tetra-bromide with triphenylphosphine in the presence of zinc dust"*""^) resulted -100-in the smooth formation of the 1,1-dibromoolefin 305. The p.m.r. spectrum of this material did not exhibit any signals at chemical shift values higher than (56.43. This observation, in conjunction with the absence of a carbonyl stretching absorption in the i . r . spectrum, clearly indicated that the aldehyde group had undergone the Wittig reaction with dibromomethylenetriphenylphosphorane to give the expected olefin. The most interesting feature in the p.m.r. spectrum of 305 was that the vinyl proton and the a l l y l i c methylene protons formed an ABX system. The v i n y l proton, which constituted the X part of the system, appeared as a " t r i p l e t " (overlapped pair of doublets) instead of the more commonly observed four-line pattern, while the a l l y l i c methylene protons, the AB part of the system, gave rise to an eight-line multiplet. By means of calculation"'"'''"'", i t was determined that the chemical sh i f t positions of the methylene protons were 61.91 and 62.26 with the coupling constants being J A T J = 15.0 Hz and J. =J_ =7.0 Hz. On the other AB AX. OA hand, the position of the v i n y l proton was found to be 66.43, with a coupling constant J =J =7.0 Hz. The protons associated with the ketal AX. DA. functionality gave rise to a multiplet at 63.91, and the three-proton signals due to the tertiary and secondary methyl groups appeared at 60.92 (singlet) and 60.86 (doublet, J=6.0 Hz), respectively. In order to add the last necessary carbon atom to the side chain of 305, the latter was allowed to react with two equivalents of n_-butyllithium at -78° to form the corresponding lithium acetylide."''"'" ^ Attempted trapping of this anion at -78° by means of treatment with gaseous formaldehyde (obtained from the pyrolysis of paraformaldehyde) proved to be only mildly successful, since varying amounts of the corres-ponding acetylene 308 were obtained as a side product. However, i t was -101-found that when the acetylene was converted back to the lithium acetylide (treatment with n-butyllithium) and the acetylide was allowed to react with gaseous formaldehyde at 0°, the propargylic alcohol 306 was formed in excellent yield. Therefore, the tetrahydrofuran solution of the 308 306 lithium acetylide, obtained directly from the reaction between the 1,1-dibromoolefin 305 and n-butyllithium was warmed to ice-bath temperature before gaseous formaldehyde was bubbled into the solution. By means of this modified procedure, an excellent yield (98%) of the desired propargylic alcohol 306 was obtained directly from the 1,1-dibromoolefin 305 without formation of the acetylene 308. The spectral properties of the alcohol 306 were in agreement with the assigned structure. Thus, in the i . r . spectrum, the hydroxyl group produced a broad band at 3475 cm and a weak absorption due to the t r i p l e bond stretching was located at 2255 cm \ In the p.m.r. spectrum, the signal due to the methylene protons adjacent to the hydroxyl group appeared as a t r i p l e t at 64.19 (J=2.0 Hz). The formation of a t r i p l e t signal instead of the expected singlet was due to long range coupling with the other propargylic methylene protons transmitted 112 through the t r i p l e bond. This long range coupling also affected the multiplicity of the other propargylic methylene group. Thus, the propargylic -102-m ethylene p r o t o n s a d j a c e n t t o t h e q u a t e r n a r y c e n t e r produced an un-r e s o l v e d t r i p l e t a t 62.14. The p r e s e n c e o f t h e k e t a l f u n c t i o n a l i t y was e v i d e n c e d by a f o u r - p r o t o n m u l t i p l e t a t 63.87. At t h i s s t a g e o f t h e s y n t h e s i s , i t was deemed n e c e s s a r y t o remove the k e t a l p r o t e c t i n g group b e f o r e t h e p r o p a r g y l i c a l c o h o l was h y d r o g e n a t e d t o the a l l y l i c a l c o h o l . T h i s was a c h i e v e d by s u b j e c t i n g t h e k e t a l p r o p a r g y l i c a l c o h o l 306 to a c i d h y d r o l y s i s i n aqueous m e t h a n o l . The c o r r e s p o n d i n g k e t o p r o p a r g y l i c a l c o h o l 307 was o b t a i n e d i n 92% y i e l d . The r e g e n e r a t i o n o f t h e k e t o f u n c t i o n a l i t y was shown by the s t r o n g c a r b o n y l s t r e t c h i n g a b s o r p t i o n i n t h e i . r . s p ectrum a t 1700 cm ^ as w e l l as by t h e d i s a p p e a r a n c e o f t h e s i g n a l due to k e t a l p r o t o n s i n t h e p.m.r. spectrum. The o t h e r s p e c t r a l d a t a d e r i v e d from compound 307 were v e r y s i m i l a r t o t h o s e of t h e s y n t h e t i c p r e c u r s o r 306. The n e x t t r a n s f o r m a t i o n i n t h e s y n t h e t i c sequence i n v o l v e d t h e c i s h y d r o g e n a t i o n of t h e t r i p l e bond p r e s e n t i n t h e k e t o p r o p a r g y l i c a l c o h o l 307. A l t h o u g h a number o f d i f f e r e n t c a t a l y s t s have been employed 113 t o e f f e c t t h i s t y p e o f c o n v e r s i o n , t h e L i n d l a r c a t a l y s t has found t h e w i d e s t usage. Indeed, when the k e t o p r o p a r g y l i c a l c o h o l 307 was h y d r o -genated i n e t h a n o l i n t h e p r e s e n c e of t h e c a t a l y s t and a t r a c e o f q u i n o l i n e , the k e t o a l l y l i c a l c o h o l 291 was o b t a i n e d as t h e s o l e p r o d u c t i n e x c e l l e n t y i e l d . However, i t was s u b s e q u e n t l y found t h a t i t was more c o n v e n i e n t t o c a r r y out t h e h y d r o g e n a t i o n i n e t h a n o l i n t h e p r e s e n c e of c o m m e r c i a l l y a v a i l a b l e p a l l a d i u m - o n - b a r i u m s u l f a t e c a t a l y s t and few d r o p s o f p u r i f i e d *114 q u i n o l i n e . Under t h e s e c o n d i t i o n s , t h e a l l y l i c a l c o h o l 291 was i s o l a t e d * Cram and A l l i n g e r l l 4 s u g g e s t e d t h a t s a t i s f a c t o r y r e s u l t s c o u l d be o b t a i n e d o n l y by use o f s y n t h e t i c q u i n o l i n e . However, we found t h a t commercial q u i n o l i n e , c a r e f u l l y p u r i f i e d by V o g e l ' s p r o c e d u r e l l ^ , was s a t i s f a c t o r y . -103-in 95% yield as viscous colorless o i l . The i . r . spectrum of compound 291 showed absorption bands at 3450 cm - 1(0-H), 3050 cm"1 (olefinic C-H) and 1710 cm"1 (C=0). In the p.m.r. spectrum, a multiplet at 65.62 was attributed to the two vinyl protons. The methylene protons adjacent to the hydroxyl functionality appeared as a doublet at 64.12, with a coupling constant of 5.5 Hz. Three-proton signals at 60.80 (singlet) and 60.93 (doublet) could be assigned to the tertiary and secondary methyl groups, respectively. With the achievement of our f i r s t synthetic objective, the keto a l l y l i c alcohol 291, the next step was to convert the hydroxyl group of 291 into a good leaving group so that a subsequent intramolecular alkylation could be achieved. Hence, we chose to explore the po s s i b i l i t y of forming the corresponding tosylate or mesylate from the keto a l l y l i c alcohol 291, although i t was recognized that these derivatives might not be stable enough to be isolated and purified. Following the procedure of Crossland and S e r v i s 1 1 ^ , the crude keto mesylate 309 was obtained as an orange-yellow o i l in excellent yield (96%). The i . r . spectrum of this crude product exhibited no absorption due to hydroxyl stretching, but showed strong bands at 1350 and 1170 cm 1 for the sulfonate functionality, as well as a carbonyl absorption at 1710 cm In the p.m.r. spectrum, the vinyl protons gave rise to a multiplet at 65.80 and the methylene protons adjacent to the methanesulfonate group appeared as a doublet (J=6.0 Hz) at 64.78. The signal due to the methyl group of the OMs group was a sharp singlet at 63.08. Finally, high-field signals at 60.90 (singlet) and 61.03 (doublet, J=6.0 Hz) were assigned to the tertiary and secondary methyl groups respectively. Due to the fact that the mesylate 309 was -104-too unstable to allow for purification, i t was used directly in the next transformation. 228 226 In 1961, Conia and Ronessac"1"1-' had reported that 3-(oo-bromobutyl)-2-methylcyclohexanone 310 (R=H or CH^) underwent stereoselective intra-molecular alkylation to afford the corresponding cis-fused decalone 312 (R=H or CH^) as the sole product. The stereochemical outcome of this reaction was rationalized by postulating that the cyclization took place via the transition 311, in which the alkylation occurred from an axial direction. When the cyclohexanone 313 (R=H or CH^) was subjected to the 312 -105-same reaction conditions, a mixture of the cis and trans isomers 314 315 (R=H or CH3) and 315 (R=H or CH3) was obtained, in which the latter predominated. Presumably, the cis-decalone 314 (R=H or CH3) was i n i t i a l l y formed and was subsequently epimerized to the thermodynami-cally more stable trans-fused ketone 315 (R=H or CH 3). More recently, Posner and his colleagues'^"^'^""^ observed that the enolate 317, formed by conjugated addition of lithium dimethylcuprate to the enone 316, underwent intramolecular alkylation with a high degree of stereoselectivity. In this reaction, only the cis-fused decalone 318 was formed. The stereochemistry of the latter compound was proved by i t s conversion into (±)-valerane 319, a sesquiterpene with known configuration. 318 319 -106-On the basis of these precedents, i t was expected that the intra-molecular alkylation of the keto mesylate 309 would i n i t i a l l y give the cis-fused octalone 228. However, presence of excess base would f a c i l i t a t e epimerization and, in this manner, i t was hoped that the desired trans-isomer 226 would be obtained directly from the reaction mixture. Indeed, when the keto mesylate 309 was treated with four equivalents of potassium tert-butoxide in dry tert-butyl alcohol at room temperature, a homogeneous o i l y compound was obtained in 63% overall yield from the keto a l l y l i c alcohol 291. The product exhibited spectral properties in good agreement with those expected for the octalone 226. The i . r . spectrum showed absorptions at 3050 and 1660 cm ^ due to the cis disubstituted carbon-carbon double bond, and a carbonyl absorption at 1705 cm In the p.m.r. spectrum, the signal due to the tertiary methyl group was at extraordinarily high f i e l d (60.66). The secondary methyl group appeared as a doublet (J=6.0 Hz) at 60.95. Finally, a broad singlet at 65.58 could be attributed to the o l e f i n i c protons. Although i t seemed highly l i k e l y that the octalone thus obtained should have the desired trans-ring junction, this point could not be proven from the available data. Hence, i t was decided to convert this compound into the corresponding dihydro derivative and then treat the latter compound with strong base under equilibration conditions. On the basis of conformational analyses of the decalones 320 and 321 (see Scheme 11), i t seemed that the trans-isomer 320 would be considerably more stable than the corresponding cis-isomer 321. The octalone 226 obtained from intramolecular cyclization of the keto mesylate 309 was hydrogenated with palladium-on-carbon in methanol -107-to afford the dihydro derivative 320. Apart from the absence of appro-priate absorptions due to the presence of a disubstituted carbon-carbon double bond, the spectral data ( i . r . , p.m.r.) obtained from the dihydro Scheme 11 1 gauche CH3-CH3 4 syn-axial CH^-H 2 syn-axial sp2(>=0)-H 1 syn-axial CH2~H 1 gauche CH3-CH3 1 gauche CH3~CH2 1 syn-axial CH3~H 1 1,3-diaxial CH 3-s P 2(>=0) 3 syn-axial CH^-H 321b-321a=(l syn-axial CH^-H + 1 syn-axial sp2(>=0)-H)-(l gauche CH3-CH2) = (0.85 + 0.35) - (0.8) = 0.4 Kcal/mole 321a-320 = 1 syn-axial CH3"H =0.85 Kcal/mole 320 1 gauche CH3~CH3 1 gauche CH3-CH2 3 syn-axial CH3~H 1 1,3-diaxial CH 3-sp 2(>=0) -108-d e r i v a t i v e 320 were v e r y s i m i l a r t o t h o s e of t h e s t a r t i n g m a t e r i a l 226. The d e c a l o n e 320 was s u b j e c t e d t o e q u i l i b r a t i o n c o n d i t i o n s by t r e a t m e n t w i t h p o t a s s i u m t e r t - b u t o x i d e i n d r y t e r t - b u t y l a l c o h o l f o r 2 ho u r s a t room t e m p e r a t u r e . The i s o l a t e d m a t e r i a l was shown t o be i d e n t i c a l w i t h t h e s t a r t i n g b i c y c l i c k e t o n e i n a l l r e s p e c t s . T h e r e f o r e , i t c o u l d be c o n c l u d e d t h a t t h e d e c a l o n e had a t r a n s - f u s e d r i n g j u n c t i o n (as r e p r e s e n t e d by s t r u c t u r e 320), and, i n t u r n , t h a t t h e o c t a l o n e o b t a i n e d from t h e i n t r a m o l e c u l a r c y c l i z a t i o n o f 309 p o s s e s s e d t h e d e s i r e d s t e r e o -c h e m i s t r y as shown by s t r u c t u r e 226. IV. Attempted S y n t h e s i s o f (±)-Ishwarone V J A D i b r o m o c y c l o p r o p a n e D e r i v a t i v e s I n a c c o r d w i t h our s y n t h e t i c p l a n s , i t was e n v i s a g e d t h a t the un-s a t u r a t e d k e t o o l e f i n 226 would be t r a n s f o r m e d by r e a c t i o n w i t h a s u i t a b l e c arbene ( o r c a r b e n o i d ) i n t o an a p p r o p r i a t e c y c l o p r o p a n e d e r i v a t i v e s u c h as 215 o r 224. I n t e r m e d i a t e 215 seemed to be an a t t r a c t i v e p o s s i b i l i t y b e c a u s e , p o t e n t i a l l y , t h e exo and the endo p o s i t i o n s on t h e c y c l o p r o p a n e r i n g (Z) c o u l d be m o d i f i e d s e p a r a t e l y t o a f f o r d a compound w i t h g e n e r a l s t r u c t u r e 210, which c o u l d t h e n s e r v e as a d i r e c t p r e c u r s o r f o r our f i n a l t a r g e t compound, ishwarone 12. 210 12 -109-+ :C 226 224 R e c e n t l y , K i t a t a n i , Hiyama and N o z a k i 7 0 ' 7 1 reported that 7,7-dibromonorcarane 185 underwent h a l o g e n - l i t h i u m exchange s t e r e o s e l e c t i v e l y when t r e a t e d w i t h an a l k y l l i t h i u m . The r e s u l t i n g carbenoid reacted w i t h v a r i o u s a l k y l a t i n g agents to g i v e 7-alkyl-7-bromonorcaranes 223 i n good to e x c e l l e n t y i e l d s . I t a l s o had been observed independently by 121 122 Hiyama et_ a l and Seebach et_ a l th a t l i t h i u m carbenoids of t h i s type reacted w i t h aldehydes and/or ketones to g i v e the corresponding bromohydrins 321. I n t e r e s t i n g l y , when the dibromide 185 was allowed to RX R L i Br 18 5 222 O 321 r e a c t w i t h two e q u i v a l e n t s of an a l k y l l i t h i u m i n the presence of d i e t h y l carbonate, 7,7-dicarboethoxynorcarane 218 could be obtained i n 72% y i e l d . * A species c o n t a i n i n g a carbanion on the same carbon as a good l e a v i n g group (such as bromide) has been named a carbenoid because such a species can r e a d i l y decompose to a carbene.120 -110-This type of reaction could possibly be extended to allow for the 185 218 conversion of an intermediate l i k e 215 (Z=Br) into a compound with general structure 224, another possible intermediate in our projected synthetic routes. 123 Hiyama and coworkers also found that gem-dihalocyclopropanes could be dialkylated stereoselectively by treatment with a lithium dialkylcuprate reagent, followed by trapping of the resultant organo-copper intermediate with different alkylating agents. Thus, for example, the dichlorocyclopropane derivative 322 was transformed into the ketone 323 in good overall yield. -111-On the basis of these encouraging results documented in the literature, i t was decided to investigate the possibility of synthesizing (±)ishwarone L2 via the intermediacy of the dibromocyclopropane derivative 215 (Z=Br, Y=0 or protecting group). To this end, the carbonyl group of the keto ol e f i n 226 was f i r s t protected as the corresponding 5,5-dimethyl-1,3-dioxane derivative 324. Thus, treatment of 226 with 2,2-dimethyl-1,3-propanediol under standard ketalization conditions afforded the crystalline ketal olefin 324 in very good yield. The i . r . data obtained 326 from this compound was consistent with the formation of the ketal, since no carbonyl absorption could be observed. In the p.m.r. spectrum, the ol e f i n i c protons gave rise to a multiplet at 65.62. The bridgehead proton appeared as an unresolved doublet of doublets at 62.82. Signals due to the three tertiary methyl groups were observed at 60.69, 0.80 and 1.18, while the secondary methyl group gave rise to a doublet (J=6.0 Hz) at 60.84. Of particular interest in this spectrum was the pattern due to the four ketal protons, which gave rise to an eleven-line signal between -112-63.18 and 3.82 as d e p i c t e d below: On the b a s i s o f c o n f o r m a t i o n a l a n a l y s i s , i t was a n t i c i p a t e d t h a t c onformer 324b would be c o n s i d e r a b l y more s t a b l e t h a n conformer 324a, due t o t h e p r e s e n c e i n t h e l a t t e r o f s e v e r e s t e r i c i n t e r a c t i o n between the a l l y l i c m ethylene p r o t o n s and t h e a x i a l p r o t o n s of t h e d i o x a n e r i n g . On t h e b a s i s o f t h i s r i g i d c o n f o r m a t i o n t h e d o w n f i e l d r e s o n a n c e of t h e k e t a l s i g n a l , w hich appeared as a " t r i p l e t " ( o v e r l a p p i n g p a i r o f d o u b l e t s a t 63.64 and 63.74, w i t h c o u p l i n g c o n s t a n t s of 11.0 Hz -113-f o r b o t h d o u b l e t s ) c o u l d be a s s i g n e d t o t h e e q u a t o r i a l p r o t o n s (H^) of t h e dioxane m o i e t y i n 324b. On t h e o t h e r hand, the p a i r o f q u a r t e t s a t h i g h f i e l d (63.28, J=11.0 and 2.0 Hz) was a t t r i b u t e d t o t h e two a x i a l p r o t o n s (H ) o f the k e t a l f u n c t i o n a l i t y . The f o r m a t i o n of a p a i r o f q u a r t e t s i n s t e a d o f a d o u b l e t f o r t h e s e p r o t o n s c o u l d be r a t i o n a l i z e d by p o s t u l a t i n g l o n g range W-type c o u p l i n g w i t h one o f t h e gem-dimethyl groups. The g e n e r a t i o n o f d i h a l o c a r b e n e s can be c a r r i e d out v i a a v a r i e t y 124 o f methods, such as t h e p y r o l y s i s o f sodium t r i h a l o a c e t a t e s , t h e 125 t h e r m a l d e c o m p o s i t i o n o f p h e n y l ( t r i h a l o m e t h y l ) m e r c u r y , and t h e dehydro-126 h a l o g e n a t i o n o f h a l o f o r m s w i t h s t r o n g base. One o f t h e most s i m p l e p r o c e d u r e s was t h e d e h y d r o h a l o g e n a t i o n o f h a l o f o r m s w i t h aqueous sodium 127 (or p o t a s s i u m ) h y d r o x i d e i n t h e p r e s e n c e of a phase t r a n s f e r a g e n t . 128 F o l l o w i n g t h e p r o c e d u r e r e p o r t e d by Makosza and F e d o r y u s k i , the k e t a l o l e f i n 324 was t r a n s f o r m e d i n t o t h e dibromo k e t a l 325, u s i n g t r i e t h y l -benzylammonium c h l o r i d e as t h e phase t r a n s f e r a g e n t . A l t h o u g h , i n pure form, t h e dibromo k e t a l 325 was q u i t e s t a b l e , the c r u d e p r o d u c t o b t a i n e d from the dibromocarbene a d d i t i o n r e a c t i o n p r o v e d t o be s u b j e c t t o some d e c o m p o s i t i o n . F o r example, when the c r u d e m a t e r i a l was a l l o w e d t o s t a n d a t room te m p e r a t u r e , t h e k e t a l m o i e t y was p a r t i a l l y l o s t , as shown by the i n c r e a s e o f c a r b o n y l a b s o r p t i o n i n t h e i . r . spectrum. T h i s b e h a v i o u r became even more pronounced when vaccum d i s t i l l a t i o n o f the m a t e r i a l was attempted. R a p i d column chromatography d i d not e n t i r e l y s o l v e the problem e i t h e r , s i n c e f r a c t i o n s c o n t a i n i n g s u b s t a n t i a l amounts of c a r b o n y l compound were o b t a i n e d . Presumably, some i m p u r i t i e s i n t h e c r u d e p r o d u c t were c a t a l y z i n g t h e d e c o m p o s i t i o n o f t h e k e t a l f u n c t i o n a l i t y . -114-In order to avoid this problem, the crude product obtained from the dibromocarbene addition reaction was immediately hydrolysed with aqueous mineral acid, and the resultant material was purified by column chromatography over s i l i c a gel, with 4:1 petroleum ether-ether being used as eluting solvent. A white crystalline compound (ketone 326) was obtained in approximately 80% yield. On the basis of g.l.c. and spectral analysis, i t was clear that this compound was stereochemical^ homogeneous. The stereochemistry of compounds 325 and/or 326 was assigned as shown on the basis of steric considerations. That i s , i t was expected that the addition of dibromocarbene to the ol e f i n i c double bond of 324 would occur from the side opposite to the angular methyl group. 325 In the i . r . spectrum of the keto dibromide 326, a sharp, strong absorption at 1710 cm indicated the presence of the ketone group. In the region associated with carbon-hydrogen bond stretching, a shoulder was observed at 3100 cm \ This absorption was assigned to stretching of the carbon-hydrogen bonds of the cyclopropane ring. In the p.m.r. -115-spectrum, the signal due to the tertiary methyl group was found at unusually high f i e l d (60.57). This was thought to be due to the anisotropic effect of the ketone functionality. The secondary methyl group gave rise to a doublet at 60.93, with a coupling constant of 6.0 Hz. Finally, a one-proton multiplet at 61.14-1.32 was assumed to be due to one of the cyclopropyl protons. The purified keto dibromide 326 was ketalized by means of a standard procedure. The ketal dibromide 325 thus obtained was a very viscous pale yellow o i l . This material was purified further by column chromatography on s i l i c a gel. The viscous pale yellow o i l was clearly much more stable than the crude product isolated from the dibromocarbene addition reaction. The p.m.r. spectrum of this material showed singlets due to the tertiary methyl groups at 60.66, 0.72 and 1.16. The secondary methyl group produced a doublet (J=5.0 Hz) at 60.83. The bridgehead proton associated with the two six-membered rings gave rise to a broad pair of doublets at 62.65-2.81 with coupling constants of 13.0 and 4.0 Hz. In the region of 63.17-3.75, the four ketal protons formed a complex multiplet signal which could not be analysed easily. Thus, although the pure ketal dibromide 325 could not be isolated directly from the crude product of the carbehe addition reaction (324 to 325), i t could be obtained in about 70% overall yield by this indirect route (324 325 + 326 + 325). One of the possible planned synthetic sequences involved the projected subjection of the dibromide 325 to a stereoselective halogen-lithium exchange to produce an intermediate which upon alkylation with a suitably functionalized alkylating agent would give the endo-alkylated product 327. Subsequent halogen-lithium exchange of the exo-bromide, followed by methylation of -116-the r e s u l t a n t i n t e r m e d i a t e and d e p r o t e c t i o n of t h e a l c o h o l and ke t o n e f u n c t i o n a l i t i e s would p r o v i d e t h e d e s i r e d p r e c u r s o r 210 (X=0H) which, h o p e f u l l y , c o u l d be c o n v e r t e d i n t o (±)-ishwarone 12_. In o r d e r t o o b t a i n some e v i d e n c e r e g a r d i n g t h e f e a s i b i l i t y o f s u c h a s y n t h e t i c sequence, i t was d e c i d e d t o use 7,7-dibromonorcarane 185 as a model t o i n v e s t i g a t e some of t h e s e r e a c t i o n s . 12 A. Model S t u d i e s Employing N o r c a r a n e D e r i v a t i v e s An a l k y l c h l o r o m e t h y l e t h e r seemed t o be a good c h o i c e as an a l k y l a t i n g agent f o r a c o n v e r s i o n o f the t y p e 325 to 327.. However, -117-use of the commercially available chloromethyl methyl ether would impose possible d i f f i c u l t i e s because the sensitivity of the cyclopropane ring to acidic conditions would limit the choice of reagents which could be used to cleave the methyl ether to the corresponding primary alcohol (328 to 210, X=0H). A better choice appeared to be chloromethyl benzyl ether since the primary alcohol functionality could then be liberated from the benzyl ether by hydrogenolysis under neutral conditions. Fortunately, chloromethyl benzyl ether was readily available from the reaction of benzyl alcohol and formaldehyde with hydrogen chloride 129 according to a procedure reported by Graham and McQuillin. Addition of chloromethyl benzyl ether to a cold (-95°) tetra-hydrofuran solution of 7-endo-litho-7-exo-bromonorcarane 222 (formed by treatment of 7,7-dibromonorcarane with n-butyllithium as described by Hiyama et a l ^ > 7 ^ ) resulted in the formation of only small amounts of the desired 7-endo-benzyloxymethyl-7-exo-bromonorcarane 329. In attempts to f a c i l i t a t e the alkylation step, i t was decided to add anhydrous hexamethyl-phosphoramide (HMPA) as a co-solvent. However, i t was found that the sequence in which the hexamethylphosphoramide and the alkylating agent were added was very crucial. Introduction of the hexamethylphosphoramide before the alkylating reagent (PhCH 90CH 5C£) resulted in the formation of a 330 -118-major product which was clearly not the desired material 329. On the basis of the i . r . , p.m.r. and the mass spectra (m/e 230 and 232), this product was assigned the structure 330. Clearly, upon addition of the hexamethylphosphoramide, the carbenoid 222 had reacted rapidly with the n-butyl bromide which had been formed during the i n i t i a l halogen-lithium exchange reaction. In order to overcome this problem, hexamethylphosphoramide was added simultaneously with or after the introduction of chloromethyl benzyl ether. By means of this simple experimental modification, i t was possible to obtain the benzyl ether 329 as the predominant product. Column chromatography of the crude product gave the benzyl ether 329 in 35 to 49% yield, depending upon the amount of chloromethyl benzyl ether used. The i . r . spectrum of the product, a pale yellow o i l , exhibited bands at 3050, 730 and 690 cm 1 due to the aromatic ring and a weak shoulder at 3090 cm 1 indicative of the presence of cyclopropyl protons. In the p.m.r. spectrum, the aromatic protons of the benzyl group were evidenced by a multiplet at 67.37 which integrated for five protons. The methylene protons for the benzyl group were located at 64.62 as a sharp singlet. The methylene protons of the ether moiety were found as a singlet at 63.80. Hydrogenolysis of the benzyl ether 329 with palladium-on-carbon at room temperature and atmospheric pressure, smoothly afforded 7 -exo-bromo-7-endo-hydroxymethylnorcarane 331. After this material had been d i s t i l l e d and cooled, i t s o l i d i f i e d to form a wax l i k e substance. The presence of the primary alcohol functionality was supported by a broad absorption at 3403 cm 1 in the i . r . spectrum and by a sharp singlet at 63.95 for the methylene protons adjacent to the hydroxyl group in the p.m.r. spectrum. The bromohydrin 331 was e f f i c i e n t l y converted into the corresponding 116 mesylate 332 (97% yield) by the procedure reported by Crossland and Servis. -119-T h i s s o l i d m e s y l a t e seemed t o be f a i r l y s t a b l e a t low t e m p e r a t u r e , s i n c e no s u b s t a n t i a l d e c o m p o s i t i o n was o b s e r v e d a f t e r t h e compound had been kept a t low temperature(0°) f o r a l o n g p e r i o d o f time. The i . r . s p e c trum of 332 e x h i b i t e d s t r o n g a b s o r p t i o n s a t 1360 and 1170 cm ^ w h i c h c o u l d be a t t r i b u t e d t o t h e p r e s e n c e o f t h e s u l f o n a t e group. I n t h e p.m.r. spectrum, t h e m e t h y l group o f m e t h a n e s u l f o n a t e m o i e t y gave r i s e t o a s h a r p s i n g l e t a t 62.63 w h i l e t h e methylene p r o t o n s a d j a c e n t t o t h e s u l f o n a t e were l o c a t e d a t 64.63 as a s i n g l e t . Ph A^Nv H 2/Pd - c 329 a CH 3S0 2C1 E t 3 N 331 cf 332 121 122 S i n c e Hiyama e_t a l . and Seebach e t a l . had b o t h o b s e r v e d t h a t t h e l i t h i u m c a r b e n o i d 222 c o u l d be t r a p p e d w i t h a l d e h y d e s t o g i v e t h e c o r r e s p o n d i n g b r o m o h y d r i n s , i t was a t l e a s t t h e o r e t i c a l l y p o s s i b l e t h a t t h e b r o m o h y d r i n 331 c o u l d be o b t a i n e d d i r e c t l y by p a s s i n g gaseous formalde-hyde i n t o a s o l u t i o n o f t h e l i t h i u m c a r b e n o i d 222. However, t h i s p r o v e d B u ^ L i 1) HCHO 2) H 20 HO--~^_— Br 185 222 331 -120-to be unsuccessful in practice. When the reaction was attempted at the necessary low temperatures (-95°), gaseous formaldehyde seemed to condense and polymerize rapidly and thus was not e f f i c i e n t l y trapped. On the other hand, i t is now well known that at higher temperatures (at which gaseous formaldehyde can be trapped e f f i c i e n t l y by carbanions) carbenoids of the 120 type 222 are not thermally stable, but decompose rapidly to carbenes. Therefore, we were not able to obtain the bromohydrin 331 directly from 222 even though several attempts were made. In order to gain some insight into the pos s i b i l i t y of replacing the second bromo group i n a compound such as 327 to give a gem-dialkylated cyclopropane derivative such as 328, the benzyl ether 329 was treated with an alkyllithium reagent. It was hoped that the corresponding cyclopropyl-335 -121-lithium intermediate 333 would be formed, which could then be trapped by an electrophile such as methyl iodide to give the desired derivative 334. However, a l l attempts to accomplish this transformation were unsuccessful. In most of the attempts, a complex mixture of products was obtained, although g.I.e. analyses indicated that the same major product had been formed in each case. A sample of this major component, collected by preparative g . l . c , was identified as benzyl alcohol by comparison with an authentic sample. In hindsight, the lack of success in these attempts was not entirely unexpected, since i t is very reasonable to propose that the lithium compound 333, formed from 329 by metal exchange, could readily undergo 1,2-elimination to give the lithium alkoxide (PhCH2OLi) and the ol e f i n 335. In view of this fail u r e , i t was decided to continue this aspect of the study using the readily available 7-endo-methyl-7-exo- hydroxymethyl -norcarane 339 as a substrate. Although this compound did not possess stereochemistry directly analogus to that of intermediates (e.g. 210) which could eventually become part of a synthesis of (±)-ishwarone, i t was nevertheless f e l t that a study of the chemical behavior of 339 might supply some insight into the chemical properties of a compound such as 210 (X=OMs or halogen). 339 ~ 210 -12.2-When the monobromide 336^'^ was mixed with two equivalents of t-butyllithium in anhydrous ether at low temperature (-78°), lithium exchange proceeded smoothly. Successive addition of methyl chloro-formate and dry hexamethylphosphoramide to the solution of the resultant cyclopropyllithium derivative gave 7-endo-methyl-7-exo-carbomethoxynor-carane 338 in about 60% yield. The i . r . spectrum showed a strong carbonyl absorption for the ester functionality at 1720 cm \ The stretching band due to the cyclopropyl protons was located at 3040 cm In the p.m.r. spectrum, sharp singlet signals at 51.20 and 63.57 could readily be attributed to the tertiary methyl group on the cyclopropane ring and the methyl group of the ester functionality, respectively. This monoester 338 was reduced by treatment with lithium aluminum hydride in ether at room temperature. The resultant product, the alcohol 339, was isolated as a colorless viscous o i l . The spectral properties of this material were in good agreement with the structure assigned. Thus, the i . r . spectrum showed a broad, strong band at 3400 cm 1 for the hydroxyl group. The absorption due to cyclopropane hydrogen stretching was found at 3020 cm 1 . In the p.m.r. spectrum, a sharp singlet at 63.20 was due to the methylene protons adjacent to the hydroxyl group. A broad singlet at 62.05 was attributed to the hydroxyl proton, while a sharp three-proton singlet at 61.06 could be assigned to the tertiary methyl group. Finally, the two cyclopropyl protons gave rise to a multiplet at 60.72. When a mixture of the epimeric monobromides 336 and 340 (ca. 4:1) (obtained by the treatment of the dibromide 185 with alkyllithium i n the  presence of methyl i o d i d e ^ ' ^ ) was subjected to the same reaction sequence -123-( i . e . l i t h i a t i o n , a c y l a t i o n with methyl chloroformate, and reduction with l i t h i u m aluminium hydride), a mixture of alcohols 339 and 341, i n a r a t i o of approximately 7:3 was obtained. The i . r . and p.m.r. spectra of t h i s m a t e r i a l were very s i m i l a r to those of the a l c o h o l 339. However, i n the p.m.r. spectrum, there was another sharp s i n g l e t at 63.65 which could be assigned to the methylene protons adjacent to the hydroxyl group of epimeric 7-endo- hydroxylmethyl -7-exo-methylnorcarane 341. 185 1) Mel 2) Bu L i 336 340 1) Bu L i 2) CICOOMe LAH -s* 339 341 Mesylation of the primary a l c o h o l 339 was attempted with methane-s u l f o n y l c h l o r i d e and triethylamine i n methylene c h l o r i d e and/or t e t r a -hydrofuran s o l u t i o n at 0 ° . H o w e v e r , no mesylate corresponding to the stru c t u r e 342 could be i s o l a t e d . M o d i f i c a t i o n s i n v o l v i n g removal of the triethylammonium s a l t by f i l t r a t i o n and rapid evaporation of the solvent (instead of the normal aqueous work-up procedure) were t r i e d , but, again i s o l a t i o n of the mesylate 342 was unsuccessful. Although the mesylate 344 (R=Me) and t o s y l a t e 344 (R^-CH-^CgH^) of (1-methylcyclopropyl) c a r b i n o l 343, as w e l l as the mesylate or t o s y l a t e 346 of the parent c y c l o p r o p y l c a r b i n o l -124-345, have been isolated successfully, the thermal i n s t a b i l i t y of these 130-132 compound was well known. Furthermore, solvolysis studies have 345 346 shown that the presence of methyl substituents on the ring would enhance the rate of solvolysis significantly. For example, the rate of solvolysis of the mesylate 344 was approximately five times faster than the solvolysis rate of the mesylate 346. Of even more interest was the fact that the relative rate of solvolysis of the mesylate 347 was ninety-six times 132 faster. Assuming that the effect of substituents on the rate of solvolysis was additive, i t is possible to postulate that the mesylate 342 would solvolyze even faster than the mesylate 347. This inherent i n s t a b i l i t y would account for the fact that the mesylate 342 could not be isolated from the reaction mixture. Although (1-methylcyclopropyl)carbinol 343 has been converted into 131 the corresponding chloride 348 by treatment with thionyl chloride , the product was contaminated with significant amounts of the rearranged product 1-chloro-l-methylcyclobutane 349. Therefore, i t was f e l t that this type -125-o f p r o c e d u r e w o u l d be a p o o r c h o i c e f o r o u r p u r p o s e s . O t h e r r e a g e n t s w h i c h c o u l d be employed f o r t h e s y n t h e s i s o f h a l i d e s f r o m a l c o h o l s , S0C1, -CI 343 348 349 133 ( e . g . , N - h a l o s u c c i n i m d e and t r i p h e n y l p h o s p h i t e , c a r b o n t e t r a h a l i d e and t e r t i a r y p h o s p h i n e s , p h o s p h o r o u s t r i b r o m i d e , t r i p h e n y l p h o s p h i n e and h a l o g e n 1 " ^ , d i m e t h y l b r o m o s u l f o n i u m b r o m i d e 1 " ^ ) u s u a l l y p r o c e e d v i a a pathway i n v o l v i n g a c a t i o n i c - t y p e t r a n s i t i o n s t a t e ( c f . 350) w h i c h i n t h e c a s e o f o u r d e s i r e d t r a n s f o r m a t i o n c o u l d w e l l f a v o u r r e a r r a n g e m e n t t o 352 r a t h e r t h a n g i v e 351. O H R 3 P / X 2 339 350 351 1 138 * R e c e n t l y , H a r d i n g and T r o t t e r have r e p o r t e d t h a t t h e a l c o h o l jL was t r a n s f o r m e d i n t o t h e c o r r e s p o n d i n g c h l o r i d e i i by t r e a t m e n t w i t h c a r b o n t e t r a c h l o r i d e and h e x a m e t h y l p h o s p h o r a m i d e . i i i -126-Acyloxy groups (RCOO ) have received limited use as leaving groups in organic synthesis. However, i t would be expected that the presence of a strongly electron attracting moiety in the R portion of such a group would enhance the leaving-group a b i l i t y of the species. Indeed, this type of rationalization has been demonstrated by the reaction of the 2,6-dichlorobenzoate 353 with lithium diphenylphosphide 139 140 to give product 354. .' Since one might expect that a p_-nitro-benzoate anion might also be a f a i r l y good leaving group, i t was decided to investigate the poss i b i l i t y of preparing the p_-nitrobenzoate derivative of the alcohol 339. \ = / - P P h 2 353 354 Treatment of the alcohol 339 with recrystallized £-nitrobenzoyl chloride in the presence of pyridine afforded the p-nitrobenzoate 355. The spectral data obtained from the latter were in agreement with the -127-assigned structure. In the i . r . spectrum, the ester functionality gave rise to a strong absorption at 1725 cm \ The presence of an aromatic ring was confirmed by absorption bands at 3030 and 1610 cm \ while the presence of a nitro group in the molecule was evidenced by strong absorptions at 1530 and 1350 cm \ In the p.m.r. spectrum, the aromatic protons gave rise to a multiplet at 68.16 while the methylene protons adjacent to the ester moiety produced a singlet at 64.00. • Finally a sharp singlet and a multiplet located at 61.12 and 0.86, respectively, could be assigned to the tertiary methyl group and the two cyclopropyl protons. It was thus clear that a p_-nitrobenzoate of the type 355 could easily be prepared and that this type of substance was su f f i c i e n t l y stable to allow for isolation and characterization. 339 355 As was discussed previously, the epimer 341 of the alcohol 339 could not be prepared from the benzyl ether 329 by halogen-lithium exchang followed by methylation and deprotection of the primary alcohol. 329 341 -128-I t was t h e r e f o r e d e c i d e d t o a t t e m p t t h e p r e p a r a t i o n o f t h e moncbromo e s t e r 356 as an a l t e r n a t i v e s t a r t i n g m a t e r i a l f o r t h e s y n t h e s i s o f t h e a l c o h o l 341. S i n c e h a l o g e n - l i t h i u m exchange i s a v e r y f a s t r e a c t i o n , i t was f e l t t h a t t r e a t m e n t o f 356 w i t h an a l k y l l i t h i u m a t low t e m p e r a t u r e w o u l d a f f o r d t h e l i t h o e s t e r 357, w h i c h upon a l k y l a t i o n w i t h m e t h y l i o d i d e w o u l d g i v e 358 R e d u c t i o n o f t h e l a t t e r compound w o u l d t h e n a f f o r d t h e a l c o h o l 341 w h i c h w o u l d p o s s e s s s t e r o c h e m i s t r y s i m i l a r t o t h e p r o s p e c t i v e I n t e r m e d i a t e 210 (X=0H). 341 ~ 210 The a t t e m p t e d s y n t h e s i s o f t h e monobromo e s t e r 356 i n v o l v e d an e x p e r i m e n t a l p r o c e d u r e v e r y s i m i l a r t o t h a t employed f o r t h e s y n t h e s i s o f t h e b e n z y l e t h e r 329, e x c e p t t h a t t h e l i t h i u m c a r b e n o i d 222 was t r a p p e d w i t h m e t h y l c h l o r o f o r m a t e i n s t e a d o f w i t h c h l o r o m e t h y l b e n z y l e t h e r . Thus, t r e a t m e n t o f a t e t r a h y d r o f u r a n s o l u t i o n o f 222 ( p r e p a r e d 185 222 356 -129-from dibromlde 185 by exchange with one equivalent of nj-butyllithium^' / X) with a large excess of d i s t i l l e d methyl chloroformate followed by hexa-methylphosphoramide at -95° for 1 hour and then at -78° for 4 hours resulted in the isolation of a colorless o i l . A g.l.c. analysis of the reaction product indicated that i t consisted of two major components which differed very significantly in g.l.c. retention times. By means of a co-injection experiment, one of the major components was identified as the starting material, 7,7-dibromonorcarane 185. The other major component was later identified as 7,7-dicarbomethoxynorcarane 359, by comparison with an authentic sample prepared by treatment of 7,7-dibro-monorcarane 185 with two equivalents of an ii-butyllithium, followed by acylation of the resultant intermediate(s) with methyl chloroformate (see below). The yield of 7,7-dicarbomethoxynorcarane 359 from the above-described reaction was approximately 30%. A similar type of observation 122 had been made by Seebach and his colleagues. These workers found that when 7-bromo-7-lithionorcarane was allowed to react with methyl benzoate or benzoyl chloride, a 25 to 32% yield of the diketone 360 was formed. -130-I n o r d e r t o a c c o u n t f o r t h e s e t y p e s o f t r a n s f o r m a t i o n s (185 t o 359; 185 t o 3 6 0 ) , i t seems r e a s o n a b l e t o p r o p o s e t h a t t h e r a t e o f a c y l a t i o n _ n . Bu L i PhCOCl o r PhCOOMe 185 222 360 o f t h e l i t h i o d e r i v a t i v e 222 was much s l o w e r t h a n t h e r a t e o f b r o m i n e -l i t h i u m exchange i n v o l v i n g 222 and t h e i n i t i a l a c y l a t e d p r o d u c t 356. Thus, as soon as 356 was forme d , i t w o u l d r e a c t w i t h t h e l i t h i o d e r i v a t i v e 222 t o a f f o r d 7 , 7 - d i b r o m o n o r c a r a n e 185 ( t h e o r i g i n a l s t a r t i n g m a t e r i a l ) and t h e new l i t h i o d e r i v a t i v e 357, w h i c h w o u l d t h e n a c y l a t e t o g i v e t h e f i n a l p r o d u c t 359. I n any c a s e , i t was c l e a r t h a t t h i s t y p e o f r e a c t i o n c o u l d n o t be us e d t o e f f e c t t h e s y n t h e s i s o f t h e d e s i r e d monobromo e s t e r 356. B u n L i CICOOMe MeQ2C B r 185 222 356 A~^i CICOOMe + I | Me02C\r^C02Me 185 357 359 When a s o l u t i o n o f 7 , 7 - d i b r o m o n o r c a r a n e 185 was t r e a t e d s u c c e s s i v e l y w i t h two e q u i v a l e n t s o f n - b u t y l l i t h i u m and e x c e s s m e t h y l c h l o r o f o r m a t e , 7 , 7 - d i c a r b o m e t h o x y n o r c a r a n e 359 c o u l d be i s o l a t e d i n 55% y i e l d . The i . r . -131-spectrum of 359 showed a strong carbonyl absorption at 1720 cm , while, in the p.m.r. spectrum, the two methyl groups of the ester functionalities gave rise to three-proton singlets at 63.66 and 3.75. Reduction of the diester 359 with lithium aluminum hydride afforded the d i o l 361 in very good yield. This compound exhibited a broad, strong absorption at 3400 cm in the i . r . spectrum. In the p.m.r. spectrum, the cyclopropyl protons gave rise to a multiplet at 60.90. Two singlets at 63.46 and 63.90 were attributed to the two sets of methylene protons adjacent to the hydroxyl groups. Finally, the two hydroxyl protons were observed as a broad singlet at 63.46. 363 Conversion of the d i o l 361 into the dimesylate 362 was accomplished by means of a standard p r o c e d u r e . T h e spectroscopic data obtained from the crude product were in good agreement with the assigned structure. In the i . r . spectrum, strong absorptions at 1355 and 1165 cm ^ were assigned to the stretching bands of the sulfonate moiety. In the p.m.r. spectrum, a signal at 63.05, which integrated for six protons was attributed to the methyl groups of the two mesylate functionalities. The methylene protons adjacent to the two mesylate groups appeared as two singlets at 64.00 and -132-64.43. Due to the fact that the dimesylate 362 did not appear to be very stable, the crude product was immediately used in the next trans-formation. When the crude dimesylate 362 was stirred with anhydrous lithium chloride in hexamethylphosphoramide, the dichloride 363 was formed in excellent yi e l d . In the p.m.r. spectrum of 363, the methylene protons adjacent to the chlorine atoms gave rise to two singlets at 63.50 and 3.87. It was thus clear that a dimesylate of the type 362 could easily be prepared and was sufficiently stable to allow for isolation. Further-more, both of the neopentyl type mesylate groups could be readily displaced by chloride ion to produce the corresponding dichloride 363. B. Attempted Synthesis of (i)-Ishwarone from the Dibromocyclopropane  Derivative 325. On the basis of the results obtained from the model studies, i t was possible to propose a number of routes which could possibly be used in the transformation of the dibromide 325 into ishwarone 12_. F i r s t l y , subjection of 325 to bromine-lithium exchange, followed by alkylation of the resultant intermediate with chloromethyl benzyl ether might afford the ketal benzyl ether 327 (R^PhCH^)• Since model studies had shown that the mesylate 332 was quite stable, i t was thought that 327 (R^PhCH^) could be converted by standard methodology into the keto mesylate 364, which could then be subjected to intramolecular alkylation to provide 365. After protection of the ketone functionality (e.g. ketal), the last required methyl group could be introduced by bromine-lithium exchange, -133-f o l l o w e d by m e t h y l a t i o n o f t h e r e s u l t i n g c y c l o p r o p y l l i t h i u m d e r i v a t i v e . A l t e r n a t i v e l y , i t was t h o u g h t t h a t i t m i g h t be p o s s i b l e t o s u b j e c t 325 t o t h e m e t a l e x c h a n g e - m e t h y l a t i o n sequence u n d e r c o n d i t i o n s w h i c h w o u l d a f f o r d e d t h e e x o - m e t h y l d e r i v a t i v e 366 as t h e m a j o r p r o d u c t . T r a p p i n g t h e c a r b a n i o n g e n e r a t e d f r o m t h i s compound w i t h m e t h y l c h l o r o f o r m a t e , w o u l d t h e n g i v e t h e k e t a l e s t e r 367. C o n v e r s i o n o f t h e l a t t e r i n t e r m e d i a t e i n t o t h e k e t o a l c o h o l 368 w o u l d be s t r a i g h t -f o r w a r d . T h e o r e t i c a l l y , i s h w a r o n e 12 c o u l d be o b t a i n e d d i r e c t l y f r o m t h i s k e t o a l c o h o l 368 by i n t r a m o l e c u l a r a l k y l a t i o n a f t e r t h e a l c o h o l f u n c t i o n a l i t y had been c o n v e r t e d i n t o a s u i t a b l e l e a v i n g g r o u p . -134-A t h i r d p o s s i b l e r o u t e w h i c h was c o n s i d e r e d was bas e d on t h e o b s e r v a t i o n t h a t 7 , 7 - d i b r o m o n o r c a r a n e 185 c o u l d be c o n v e r t e d i n t o t h e c o r r e s p o n d i n g d i e s t e r 359. Thus, by means o f a s i m i l a r t r a n s -f o r m a t i o n , t h e d i b r o m i d e 325 w o u l d a f f o r d t h e d i e s t e r 369. S u b j e c t i o n o f t h e l a t t e r compound t o a s t r a i g h t f o r w a r d sequence o f r e a c t i o n s w o u l d p r o v i d e t h e d i m e s y l a t e 370 (X=OMs), w h i c h p r e s u m a b l y c o u l d be t r a n s f o r m e d i n t o t h e d i c h l o r i d e 370 (X=C£) i f n e c e s s a r y . I n t r a -m o l e c u l a r a l k y l a t i o n f o l l o w e d by r e d u c t i v e r e m o v a l o f t h e s e c o n d m e s y l a t e ( o r c h l o r i d e ) w o u l d g i v e i s h w a r o n e 12. -135-12 359 We c h o s e f i r s t t o e x p l o r e t h e p o s s i b i l i t y o f c o n v e r t i n g t h e d i b r o m i d e 325 i n t o t h e b e n z y l e t h e r 327 (R=PhCH 2). To t h i s end, a s o l u t i o n o f compound 325 i n t e t r a h y d r o f u r a n was t r e a t e d w i t h one e q u i v a l e n t o f n - b u t y l l i t h i u m a t -95° f o r a p p r o x i m a t e l y 30 m i n u t e s , and t o t h e r e s u l t a n t s o l u t i o n ( p r e s u m a b l y c o n t a i n i n g t h e c a r b e n o i d 371) was added e x c e s s c h l o r o m e t h y l b e n z y l e t h e r and h e x a m e t h y l p h o s p h o r -amide. However, t h e e x p e c t e d b e n z y l e t h e r 327 (R=PhCH 2) was n o t o b t a i n e d . I n s t e a d , g . l . c . and t . l . c . a n a l y s e s showed t h a t t h e p r o d u c t c o n s i s t e d o f a complex m i x t u r e o f many compounds. A t t e m p t s t o i m p r o v e t h i s r e a c t i o n by c h a n g i n g r e a c t i o n c o n d i t i o n s were u n s u c c e s s f u l . A p p a r e n t l y , * These c o n d i t i o n s were e s s e n t i a l l y i d e n t i c a l w i t h t h o s e u s e d t o c o n v e r t 7 , 7 - d i b r o m o n o r c a r a n e 185 i n t o t h e b e n z y l e t h e r o f 7 - e n d o - h y d r o x y m e t h y l -7-exo-bromonorcarane 329. Br. -Br Bu 1^] Br 1) P h CH 2OCH 2Cl 2) HMPA -cT 185 329 1 -136-t h e r e a c t i o n o f t h e c a r b e n o i d w i t h c h l o r o m e t h y l b e n z y l e t h e r a t -95° 327 was v e r y s l u g g i s h , w h i l e , a t h i g h e r t e m p e r a t u r e , t h e i n h e r e n t t h e r m a l i n s t a b i l i t y o f t h e l i t h i u m c a r b e n o i d c a u s e d i t t o decompose t o f o r m o t h e r s i d e p r o d u c t s . I n v i e w o f t h i s f a i l u r e , i t was d e c i d e d t o a t t e m p t t h e c o n v e r s i o n o f 325 i n t o t h e c o r r e s p o n d i n g d i e s t e r 369 u n d e r c o n d i t i o n s w h i c h had p r e v i o u s l y s u c c e s s f u l l y t r a n s f o r m e d 7 , 7 - d i b r o m o n o r c a r a n e 185 i n t o 7 , 7 - d i c a r b o m e t h o x y n o r c a r a n e 359. Thus, a s o l u t i o n o f compound 325 i n d r y t e t r a h y d r o f u r a n a t -95° was t r e a t e d w i t h two e q u i v a l e n t s o f n-b u t y l l i t h i u m , and t o t h e r e s u l t a n t s o l u t i o n was added e x c e s s m e t h y l c h l o r o f o r m a t e f o l l o w e d by d r y h e x a m e t h y l p h o s p h o r a m i d e . However, s p e c t r a l and g . l . c . a n a l y s i s o f t h e m i x t u r e o f p r o d u c t s showed t h a t l i t t l e , i f any, o f t h e d e s i r e d d i e s t e r 369 had been formed. A g a i n , a l t e r i n g r e a c t i o n c o n d i t i o n s f a i l e d t o have a p o s i t i v e e f f e c t on t h e r e a c t i o n . -137-325 371 369 A t t h i s s t a g e , i t was d e c i d e d t o a t t e m p t t h e c o n v e r s i o n o f t h e d i b r o m i d e 325 i n t o t h e e x o - m e t h y l d e r i v a t i v e 366. To t h i s end, a p e n t a n e s o l u t i o n o f two e q u i v a l e n t s o f _ t - b u t y l l i t h i u m was added t o a c o l d (-95°) s o l u t i o n o f one e q u i v a l e n t o f t h e d i b r o m i d e 325, c o n t a i n i n g 3.5 e q u i v a l e n t s o f m e t h y l i o d i d e and 10% by volume o f h e x a m e t h y l p h o s p h o r a m i d e . G . l . c . a n a l y s i s o f t h e p r o d u c t i n d i c a t e d t h e p r e s e n c e o f two m a j o r components i n a r a t i o o f a p p r o x i m a t e l y 3:2. These m a j o r p r o d u c t s were s e p a r a t e d by means o f column c h r o m a t o g r a p h y o v e r s i l i c a g e l . The f i r s t component w h i c h was e l u t e d f r o m t h e column was o b t a i n e d i n 58% y i e l d . On t h e b a s i s o f t h e r e a c t i o n c o n d i t i o n s employed, i t was e x p e c t e d t h a t t h e m a j o r m e t h y l a t e d p r o d u c t s h o u l d have t h e c y c l o p r o p y l m e t h y l group i n an exo o r i e n t a t i o n and t h e r e f o r e t h i s compound was t e n t a t i v e l y a s s i g n e d s t r u c t u r e 366. T h i s a s s i g n m e n t was s u b s e q u e n t l y s u b s t a n t i a t e d by p.m.r. d a t a d e r i v e d f r o m a number o f d e r i v a t i v e s i n t h i s s e r i e s o f compounds ( s e e l a t e r ) . -138-Br 1) Mel/HMPA 2) 2eq B u C L i 325 366 372 I n t h e p.m.r. s p e c t r u m o f compound 366, t h e k e t a l p r o t o n s were o b s e r v e d as a m u l t i - l i n e s i g n a l between 63.12 and 3*. 70, w i t h a p a t t e r n v e r y s i m i l a r t o t h a t o f 325 ( s e e p-112) e x c e p t t h a t t h e h i g h f i e l d s i g n a l a s s i g n e d t o t h e a x i a l k e t a l p r o t o n s gave r i s e t o as a p a i r o f u n r e s o l v e d q u a r t e t s . The c h e m i c a l s h i f t s f o r t h e e q u a t o r i a l p r o t o n s were f o u n d a t 63.63 and 3.55, w i t h a c o u p l i n g c o n s t a n t o f 11.0 Hz f o r b o t h s i g n a l s . On t h e o t h e r h and, b o t h a x i a l k e t a l p r o t o n s had a c h e m i c a l s h i f t a t 63.22 w i t h a c o u p l i n g c o n s t a n t o f 11.0 Hz. The c o u p l i n g c o n s t a n t f o r t h e l a r g e r a n g e W-type c o u p l i n g between t h e s e p r o t o n s and one o f t h e g e m - d i m e t h y l group i n t h e k e t a l m o i e t y c o u l d n o t be measured f r o m t h e s p e c t r u m due t o t h e p o o r r e s o l u t i o n o f t h e s i g n a l . A d o u b l e t o f d o u b l e t s a t 62.62-2.78, w i t h c o u p l i n g c o n s t a n t s o f 12.0 Hz and 3.0 Hz, was a t t r i b u t e d t o t h e b r i d g e h e a d p r o t o n a s s o c i a t e d w i t h t h e two six-membered r i n g s . A s h a r p t h r e e - p r o t o n s i n g l e t a t 61.74 was a s s i g n e d t o t h e t e r t i a r y m e t h y l g r oup on t h e c y c l o p r o p a n e r i n g . The o t h e r t h r e e t e r t i a r y m e t h y l g r o u p s gave r i s e t o s i n g l e t s a t 60.64, 0.72 and 1.13, w h i l e t h e s e c o n d a r y m e t h y l g r oup p r o d u c e d a d o u b l e t a t 60.79, w i t h a c o u p l i n g c o n s t a n t o f 6.0 Hz. The s e c o n d m a j o r component ( 3 8 % y i e l d ) o b t a i n e d f r o m t h e above-m e n t i o n e d column c h r o m a t o g r a p h y was c l e a r l y e p i m e r i c w i t h t h e f i r s t compound and was t h e r e f o r e a s s i g n e d s t r u c t u r e 372. I n t h e p.m.r. s p e c t r u m , t h e p a t t e r n f o r t h e s i g n a l o f t h e k e t a l p r o t o n s was e x a c t l y t h e same as t h a t o f -139-t h e c o r r e s p o n d i n g s i g n a l d e r i v e d f r o m compound 325 (see p - 1 1 2 ) . Hence, a p a i r o f d o u b l e t s a t 63.63 and 3.54 ( b o t h w i t h J=12.0 Hz) c o u l d be a s s i g n e d t o t h e e q u a t o r i a l k e t a l p r o t o n s , w h i l e a p a i r o f q u a r t e t s a t 63.21 (J=12.0 Hz and 3.0 Hz) was a s s i g n e d f o r t h e a x i a l k e t a l p r o t o n s . The b r i d g e h e a d p r o t o n a d j a c e n t t o t h e k e t a l f u n c t i o n a l i t y was f o u n d as an i l l - r e s o l v e d d o u b l e t o f d o u b l e t s a t 62.61-2.78, w i t h c o u p l i n g c o n s t a n t s o f about 14.0 Hz and 4.0 Hz. The t e r t i a r y m e t h y l group on t h e c y c l o p r o p y l r i n g gave r i s e t o a s i n g l e t a t 61.62. The o t h e r t e r t i a r y m e t h y l groups gave r i s e t o s i n g l e t s a t 60.64, 0.71 and 1.12. The s e c o n d a r y m e t h y l group was l o c a t e d a t 60.77 (J=6.0 H z ) . The f a c t t h a t t h e s i g n a l f o r t h e c y c l o p r o p y l m e t h y l g roup o f t h e m i n o r i s o m e r 372 a p p e a r e d a t h i g h e r f i e l d (61.62) t h a n t h e c o r r e s -p o n d i n g s i g n a l (61.74) f o r t h e e p i m e r i c compound 366 p r o v i d e d some e v i d e n c e f o r t h e s t e r e o c h e m i c a l a s s i g n m e n t s . On t h e b a s i s o f examples fo u n d i n t h e l i t e r a t u r e , i t was e x p e c t e d t h a t t h e more s t e r i c a l l y c o n g e s t e d c y c l o p r o p y l m e t h y l group ( i n 372) w o u l d r e s o n a t e a t h i g h e r f i e l d t h a n t h e l e s s c o n g e s t e d c y c l o p r o p y l m e t h y l g roup i n 366. F o r example, t h e c h e m i c a l s h i f t s f o r t h e s t e r i c a l l y c o n g e s t e d c y c l o p y l m e t h y l g r o u p s i n compounds 377 378 336 340 -140-373, 375, 377 and 336 were f o u n d a t h i g h e r f i e l d t h a n t h e c o r r e s p o n d i n g s i g n a l s f o r t h e e p i m e r i c compounds 374, 376, 378 and 340. T r e a t m e n t o f compound 366 w i t h two e q u i v a l e n t s o f J : - b u t y l l i t h i u m i n p e n t a n e a t -78°, f o l l o w e d by t r a p p i n g t h e r e s u l t a n t c y c l o p r o p y l l i t h i u m d e r i v a t i v e w i t h f r e s h l y d i s t i l l e d m e t h y l c h l o r o f o r m a t e a f f o r d e d t h e c o r r e s p o n d i n g e s t e r 367 i n 71% y i e l d . The i . r . s p e c t r u m o f 367 showed a s t r o n g c a r b o n y l a b s o r p t i o n a t 1720 cm \ i n d i c a t i n g t h e p r e s e n c e o f t h e e s t e r g r o u p . I n t h e p.m.r. s p e c t r u m , t h e k e t a l p r o t o n s gave r i s e t o a m u l t i p l e t a t 63.16-3.74. A l t h o u g h t h e p a t t e r n o f t h i s m u l t i p l e t a p p e a r e d t o be v e r y s i m i l a r t o t h e a n a l o g o u s s i g n a l s i n t h e bromo k e t a l , d e t a i l e d a n a l y s i s c o u l d n o t be a c h i e v e d due t o i n t e r f e r e n c e f r o m t h e s i g n a l due t o t h e m e t h y l group o f t h e e s t e r m o i e t y , w h i c h gave r i s e t o a s h a r p s i n g l e t a t 63.66. The b r i d g e h e a d p r o t o n a s s o c i a t e d w i t h t h e two six-membered r i n g s p r o d u c e d an u n r e s o l v e d d o u b l e t o f d o u b l e t s a t 62.64-2.81. The s i g n a l due t o t h e c y c l o p r o p y l m e t h y l group was f o u n d a t 61.24, w h i l e t h e o t h e r t h r e e t e r t i a r y m e t h y l g r o u p s a p p e a r e d as s h a r p s i n g l e t s a t 60.66, 0.78 and 1.16. F i n a l l y , t h e s e c o n d a r y m e t h y l group p r o d u c e d a d o u b l e t (J=5.0 Hz) a t 60.80. R e d u c t i o n o f t h e k e t a l e s t e r 367 w i t h l i t h i u m aluminum h y d r i d e p r o d u c e d t h e k e t a l a l c o h o l 379 i n good y i e l d . The p r e s e n c e o f a h y d r o x y l group i n 379 was r e v e a l e d by a s t r o n g b r o a d a b s o r p t i o n a t 3500 cm ^ i n i t s i . r . s p e c t r u m . F u r t h e r m o r e , t h e p.m.r. s p e c t r u m o f t h i s compound e x h i b i t e d a t w o - p r o t o n s i n g l e t a t 63.58, w h i c h c o u l d be a t t r i b u t e d t o t h e m e t h y l e n e p r o t o n s a d j a c e n t t o t h e h y d r o x y l g r o u p . The o t h e r s i g n a l s i n t h e p.m.r. s p e c t r u m were v e r y s i m i l a r t o t h o s e o f compound 367. H y d r o l y s i s o f t h e k e t a l m o i e t y i n compound 379 was a c c o m p l i s h e d e f f i c i e n t l y by t r e a t m e n t o f t h i s m a t e r i a l w i t h aqueous h y d r o c h l o r i c a c i d -141-i n a c e t o n e . The s p e c t r a l d a t a o b t a i n e d f r o m t h e p r o d u c t 368 were i n good agreement w i t h t h e a s s i g n e d s t r u c t u r e . I n t h e i . r . s p e c t r u m , s t r o n g a b s o r p t i o n s a t 3450 cm 1 and 1705 cm 1 c o u l d be a t t r i b u t e d t o t h e p r e s e n c e o f t h e h y d r o x y l group and t h e k e t o n e f u n c t i o n a l i t y , r e s p e c t i v e l y . The p.m.r. s p e c t r u m o f t h i s compound e x h i b i t e d a two-p r o t o n s i n g l e t a t 63.56* f o r t h e m e t h y l e n e p r o t o n s a d j a c e n t t o t h e h y d r o x y l g r o u p , and two t h r e e - p r o t o n s i n g l e t s a t 61.13 and 0.66 f o r t h e t e r t i a r y m e t h y l g r o u p s . The s e c o n d a r y m e t h y l group gave r i s e t o a d o u b l e t a t 0.86, w i t h c o u p l i n g c o n s t a n t o f 6.0 Hz. * A c o m p a r i s o n o f t h e c h e m i c a l s h i f t s o f t h e m e t h y l e n e p r o t o n s o f t h e h y d r o x y m e t h y l g r o u p s i n compounds 379 and 368 w i t h t h o s e o f t h e a n a l o g o u s p r o t o n s i n compounds 381 and 382 ( p r e p a r e d f r o m 372 v i a a r o u t e a n a l o g o u s t o t h a t employed f o r t h e c o n v e r s i o n o f 366->-367->379->-368) p r o v i d e d f u r t h e r c o r r o b o r a t i o n f o r t h e s t e r e o c h e m i c a l a s s i g n m e n t s made f o r t h i s s e r i e s o f compounds. Thus, i n compounds 379 and 368, t h i s s i g n a l a p p e a r e d as s i n g l e t s a t 63.58 and 3.56, r e s p e c t i v e l y , w h e r e a s , i n t h e compounds 381 and 382, t h e s i n g l e t s c o u l d be f o u n d a t 63.30 and 3.26 r e s p e c t i v e l y . I n t h e e p i m e r i c 7 - m e t h y l - 7 - h y d r o x y -m e t h y l n o r c a r a n e s 341 and 339 ( o f e s t a b l i s h e d s t e r e o c h e m i s t r y ) , t h e m e t h y l e n e p r o t o n s o f t h e h y d r o x y m e t h y l group a p p e a r e d as s i n g l e t s a t 63.65 and 3.20, r e s p e c t i v e l y ( s e e page 122 and 123 ) . 379 ^ 83.es 368 382 -142-380 As m i g h t have b e e n i n d i c a t e d by t h e model s t u d i e s o n n o r c a r a n e d e r i v a t i v e s , c o n v e r s i o n o f t h e h y d r o x y k e t o n e 368 i n t o a d e r i v a t i v e i n w h i c h t h e h y d r o x y l group had been t r a n s f o r m e d i n t o a good l e a v i n g group p r o v e d t o be p r o b l e m a t i c . F o r example, a t t e m p t s t o p r e p a r e and i s o l a t e t h e c o r r e s p o n d i n g m e s y l a t e were c o n s i s t e n t l y u n s u c c e s s f u l , p r e s u m a b l y due t o t h e i n s t a b i l i t y o f t h e c y c l o p r o p y l c a r b i n y l m e s y l a t e s y s t e m . I n v i e w o f t h e s e f a i l u r e s , i t was d e c i d e d t o p r e p a r e t h e £-nitrobenzoate 380 w i t h t h e hope t h a t t h e p _ - n i t r o b e n z o a t e a n i o n w o u l d s e r v e as a l e a v i n g group f o r an i n t r a m o l e c u l a r c y c l i z a t i o n s t e p . Thus, t h e k e t o a l c o h o l 368 -143-was t r e a t e d w i t h r e c r y s t a l l i z e d p _ - n i t r o b e n z o y l c h l o r i d e and p y r i d i n e a t 0° and t h e k e t o e s t e r 380 was i s o l a t e d f r o m t h e c r u d e p r o d u c t by means o f p r e p a r a t i v e t . l . c . The s p e c t r a l p r o p e r t i e s o f t h i s compound were i n agreement w i t h t h e s t r u c t u r e 380. Thus, i n t h e i . r . s p e c t r u m , a s t r o n g a b s o r p t i o n a t 1720 cm 1 i n d i c a t e d t h e p r e s e n c e o f t h e a r y l e s t e r f u n c t i o n -a l i t y and t h e n i t r o group was e v i d e n c e d by s t r o n g a b s o r p t i o n s a t 1525 and 1345 cm ^. The k e t o n e c a r b o n y l g roup gave r i s e t o a s t r o n g band a t 1705 cm I n t h e p.m.r. s p e c t r u m , a f o u r - p r o t o n m u l t i p l e t a t 68.28 was a t t r i b u t e d t o t h e a r o m a t i c p r o t o n s . The m e t h y l e n e p r o t o n s a d j a c e n t t o t h e e s t e r group gave r i s e t o a s h a r p s i n g l e t a t 64.38, w h i l e t h e two t e r t i a r y m e t h y l g r o u p s p r o d u c e d s i n g l e t s a t 61.20 and 0.66. The p r e s e n c e o f a s e c o n d a r y m e t h y l group was e v i d e n c e d by a p o o r l y r e s o l v e d d o u b l e t a t 60.90, w i t h a c o u p l i n g c o n s t a n t o f 6.0 Hz. A t t e m p t s t o e f f e c t t h e i n t r a m o l e c u l a r c y c l i z a t i o n o f t h e j j - n i t r o -b e n z o a t e 380 were c a r r i e d o u t w i t h d i f f e r e n t b a s e s ( e . q . p o t a s s i u m t e r t -b u t o x i d e , p o t a s s i u m h y d r i d e ) i n d i f f e r e n t s o l v e n t s ( e . g . t e r t - b u t y l a l c o h o l , t e t r a h y d r o f u r a n ) under a v a r i e t y o f c o n d i t i o n s . U n f o r t u n a t e l y , i n a l l c a s e s , e i t h e r t h e s t a r t i n g m a t e r i a l 380 was r e c o v e r e d , o r t h e k e t o a l c o h o l 368 was i s o l a t e d as t h e o n l y p r o d u c t . I n no c a s e was i t p o s s i b l e t o d e t e c t any o f t h e d e s i r e d p r o d u c t (±)-ishwarone 12. 380 368 12 -144-The p r o j e c t e d c o n v e r s i o n o f t h e k e t o a l c o h o l 368 i n t o (±)-i s h w a r o n e 1_2 r e m a i n s an a t t r a c t i v e p o s s i b i l i t y . I t seems q u i t e l i k e l y t h a t some method c o u l d be i n v e n t e d w h i c h w o u l d e f f e c t t h i s t r a n s f o r m a t i o n . However, a t t h e same t i m e a t w h i c h t h e above s t u d y was b e i n g c a r r i e d o u t , an a l t e r n a t i v e s y n t h e t i c r o u t e t o (±)-ishwarone 1_2 was a l s o b e i n g i n v e s t i g a t e d . T h i s a l t e r n a t i v e , w h i c h i s d e s c r i b e d i n t h e f o l l o w i n g s e c t i o n o f t h i s t h e s i s , p r o v e d t o be s u c c e s s f u l and, t h e r e f o r e , a t t e m p t s t o e f f e c t t h e c o n v e r s i o n o f 368 i n t o (±)-ishwarone 1J2 were d i s c o n t i n u e d . V. T o t a l S y n t h e s i s o f (±)-Ishwarone and (±)-Ishwarane The d i f f i c u l t i e s e n c o u n t e r e d i n t h e a t t e m p t e d s y n t h e s i s o f (±)-i s h w a r o n e 12_ v i a t h e k e t o a l c o h o l 368 ( o b t a i n e d f r o m compound 325) were r e l a t e d t o l a c k o f s u c c e s s i n f i n d i n g a s u i t a b l e l e a v i n g group f o r t h e i n t r a m o l e c u l a r c y c l i z a t i o n s t e p . I t was f e l t t h a t t h e u n s u c c e s s f u l a t t e m p t s t o p r e p a r e t h e c o r r e s p o n d i n g m e s y l a t e f r o m t h e k e t o a l c o h o l 368 was a t l e a s t p a r t i a l l y due t o t h e e l e c t r o n d o n a t i n g e f f e c t o f t h e m e t h y l g r o u p . T h i s e f f e c t w o u l d enhance t h e e a s e o f s o l v o l y s i s o f t h e m e s y l a t e d e r i v a t i v e . On t h i s b a s i s , one c o u l d a t l e a s t q u a l i t a t i v e l y 325 368 12 a c c o u n t f o r t h e f a c t t h a t t h e k e t o m e s y l a t e was a p p a r e n t l y t o o u n s t a b l e t o a l l o w f o r i s o l a t i o n . -145-I n t h e p r e v i o u s l y d e s c r i b e d model s t u d i e s w i t h n o r c a r a n e d e r i v a t i v e s , i t had been f o u n d t h a t t h e d i o l 361 c o u l d be c o n v e r t e d s u c c e s s f u l l y i n t o t h e d i m e s y l a t e 362, w h i c h i n t u r n c o u l d be t r a n s f o r m e d i n t o t h e d i c h l o r i d e 363. These e n c o u r a g i n g r e s u l t s l e d us t o i n v e s t i g a t e t h e s y n t h e s i s o f t h e k e t o d i o l 383 w h i c h , upon m e s y l a t i o n , s h o u l d a f f o r d t h e d i m e s y l a t e 384. 383 384 369 The most l o g i c a l p r e c u r s o r f o r t h e k e t o d i o l 383 w o u l d be t h e k e t a l d i e s t e r 369. A l t h o u g h , i n t h e model s t u d i e s , i t was shown t h a t 7,7-d i b r o m o n o r c a r a n e 185 c o u l d be t r a n s f o r m e d i n t o t h e d i e s t e r 359, t h e a t t e m p t e d c o n v e r s i o n o f t h e k e t a l d i b r o m i d e 325 i n t o t h e d i e s t e r 369 p r o v e d t o be u n s u c c e s s f u l . However, i t was a l s o p o s s i b l e t o c o n s i d e r 185 359 -146-1) Bu L i 2) CICOOMe/HMPA C 0 2 M e C 0 2 M e 325 369 t h e d i e s t e r 369 as t h e p r o d u c t o f a r e a c t i o n between t h e k e t a l o l e f i n 324 and a c a r b e n o i d d e r i v e d f r o m d i m e t h y l m a l o n a t e . C O z M e ' C 0 2 M e CQ 2 Me 324 369 D i m e t h y l d i a z o m a l o n a t e 386 was p r e p a r e d by t h e r e a c t i o n o f 141 d i m e t h y l m a l o n a t e w i t h t o s y l a z i d e 385 i n t h e p r e s e n c e o f t r i e t h y l a m i n e , 142 a c c o r d i n g t o t h e p r o c e d u r e o f P e a c e , Carman and Wulfman. OJVle CO z Me N 2 = C CO-Me 386 + S 0 2 N H 2 The r e a c t i o n o f d i a z o m a l o n a t e w i t h v a r i o u s a c y c l i c and m o n o c y c l i c 143 o l e f i n s had been r e p o r t e d . However, t o o u r know l e d g e , t h e o n l y r e p o r t o f an a n a l o g o u s r e a c t i o n between d i a z o m a l o n a t e and a b i c y c l i c o l e f i n -147-144 i n v o l v e d t h e s i m p l e o c t a l i n 387 as s u b s t r a t e . T h e r e f o r e , no l i t e r a t u r e p r e c e d e n t w h i c h w o u l d p r o v i d e t h e b a s i s f o r p r e d i c t i n g t h e s t e r e o -c h e m i c a l outcome o f t h e p r o j e c t e d r e a c t i o n between t h e k e t a l o l e f i n 324 387 386 388 and d i m e t h y l d i a z o m a l o n a t e 386 e x i s t e d . However, on t h e b a s i s o f s t e r i c c o n s i d e r a t i o n s , i t a p p e a r e d h i g h l y l i k e l y t h a t t h e c a r b e n o i d formed by t h e r m a l d e c o m p o s i t i o n o f d i a z o m a l o n a t e i n t h e p r e s e n c e o f c o p p e r b r o n z e ( o r a c o p p e r s a l t ) , w o u l d add t o t h e c a r b o n - c a r b o n d o u b l e bond o f 324 f r o m t h e s i d e o p p o s i t e t o t h e a n g u l a r m e t h y l g r o u p " ( s e e b e l o w ) . Thus, o n l y t h e t r a n s p r o d u c t 369 w o u l d be e x p e c t e d . 369 -148-R e a c t i o n between t h e k e t a l o l e f i n 324 and e x c e s s d i m e t h y l d i a z o m a l o n a t e 386 i n t h e p r e s e n c e o f copper b r o n z e a t 130-140° gave an 80% y i e l d o f a s i n g l e a d d u c t w h i c h was a s s i g n e d s t r u c t u r e 369. The s p e c t r a l p r o p e r t i e s o f t h i s compound were i n agreement w i t h t h e a s s i g n e d s t r u c t u r e . I n t h e i . r . s p e c t r u m , t h e p r e s e n c e o f t h e c y c l o p r o p a n e - t y p e p r o t o n s and o f t h e e s t e r g r o u p s was r e v e a l e d f r o m a b s o r p t i o n s a t 3105 and 1730 cm r e s p e c t i v e l y . I n t h e p.m.r. s p e c t r u m , t h e k e t a l p r o t o n s a p p e a r e d as a m u l t i - l i n e s i g n a l . The p a t t e r n was s i m i l a r t o t h a t o b t a i n e d f r o m t h e k e t a l o l e f i n 324 ( s e e p - 1 1 2 ) , b u t due t o t h e i n t e r f e r e n c e o f t h e s t r o n g s i n g l e t s due t o t h e m e t h y l g r o u p s o f t h e m e t h y l e s t e r f u n c t i o n a l i t i e s (63.68 and 3 . 7 4 ) , d e t a i l e d a n a l y s i s o f t h i s p a t t e r n c o u l d n o t be a c h i e v e d . The s e c o n d a r y m e t h y l group i n t h e m o l e c u l e gave r i s e t o a d o u b l e t ( J = 6 . 0 Hz) a t 60.80, w h i l e t h e t e r t i a r y m e t h y l g r o u p s p r o d u c e d s i n g l e t s a t 60.66, 0.82 and 1.15. R e d u c t i o n o f t h e k e t a l d i e s t e r 369 w i t h l i t h i u m aluminum h y d r i d e i n a n h ydrous e t h e r p r o v i d e d t h e k e t a l d i o l 389 as a w h i t e powder i n 94% y i e l d . The p r e s e n c e o f t h e h y d r o x y l g r o u p s i n t h i s m o l e c u l e was shown by a b r o a d a b s o r p t i o n a t 3300 cm 1 i n i t s i . r . s p e c t r u m . I n t h e p.m.r. s p e c t r u m , a b r o a d e i g h t - p r o t o n m u l t i p l e t between 63.60 and 3.90 c o u l d be a t t r i b u t e d t o t h e m e t h y l e n e p r o t o n s o f t h e k e t a l f u n c t i o n a l i t y and t o t h e two h y d r o x y m e t h y l g r o u p s . S i n g l e t s a t 60.63, 0.75 and 1.10 were a t t r i b u t e d t o t h e t e r t i a r y m e t h y l g r o u p s , w h i l e a d o u b l e t a t 60.63 w i t h a c o u p l i n g c o n s t a n t o f 6.0 Hz was a s s i g n e d t o t h e s e c o n d a r y m e t h y l group. -149-383 384 H y d r o l y s i s o f t h e k e t a l d i o l 389 t o t h e k e t o d i o l 383 was a c h i e v e d by t r e a t m e n t o f t h e f o r m e r w i t h h y d r o c h l o r i c a c i d i n aqueous a c e t o n e . I n t h e i . r . s p e c t r u m o f 383, a b s o r p t i o n s a t 3300 and 1700 cm ^ c o u l d be a t t r i b u t e d t o t h e p r e s e n c e o f h y d r o x y l g r o u p s and a k e t o n e c a r b o n y l g r o u p , r e s p e c t i v e l y . I n t h e p.m.r. s p e c t r u m , t h e m e t h y l e n e p r o t o n s o f t h e endo h y d r o x y m e t h y l group gave r i s e t o an AB p a i r o f d o u b l e t s a t 63.45 and 3.61, w i t h a c o u p l i n g c o n s t a n t o f 12.0 Hz. The c o r r e s p o n d i n g AB p a i r o f d o u b l e t s f o r t h e exo h y d r o x y m e t h y l group a p p e a r e d a t 53.70 and 3.90, w i t h a c o u p l i n g c o n s t a n t a l s o e q u a l t o 12.0 Hz. An u p f i e l d s i n g l e t a t 50.66 and a d o u b l e t a t 60.91, w i t h c o u p l i n g c o n s t a n t o f 6.0 Hz, were a t t r i b u t e d t o t h e t e r t i a r y and s e c o n d a r y m e t h y l g r o u p s , r e s p e c t i v e l y . T r e a t m e n t o f t h e k e t o d i o l 383 w i t h m e t h a n e s u l f o n y l c h l o r i d e i n t h e p r e s e n c e o f t r i e t h y l a m i n e a f f o r d e d t h e k e t o d i m e s y l a t e 384 as a p a l e y e l l o w v i s c o u s o i l . The i . r . s p e c t r u m o f t h e c r u d e p r o d u c t e x h i b i t e d s t r o n g a b s o r p t i o n s a t 1355 and 1170 cm ^ w h i c h were due t o t h e s t r e t c h i n g bands o f t h e s u l f o n a t e m o i e t y . The c a r b o n y l group gave r i s e t o a s t r o n g band a t 1700 cm ^. I n t h e p.m.r. s p e c t r u m , t h e m e t h y l e n e p r o t o n s o f -150-t h e exo CH^OMs group gave r i s e t o a s i n g l e t a t 64.30, w h i l e t h e c o r r e s -p o n d i n g s i g n a l f o r t h e endo CH^OMs group was an AB p a i r o f d o u b l e t s a t 63.96 and 4.04. O t h e r s i g n a l s o f p a r t i c u l a r i n t e r e s t were a s i n g l e t a t 60.66 and an u n r e s o l v e d d o u b l e t a t 0.90, w h i c h were a s s i g n e d t o t h e t e r t i a r y and s e c o n d a r y m e t h y l g r o u p s r e s p e c t i v e l y . The m e t h y l g r o u p s o f t h e m e t h a n e s u l f o n a t e m o i e t y gave r i s e t o t h e s i n g l e t s a t 63.03 and 3.06. Because i t a p p e a r e d t o be r a t h e r u n s t a b l e , t h e c r u d e k e t o d i m e s y l a t e 384 was n o t p u r i f i e d , b u t was us e d i m m e d i a t e l y f o r t h e n e x t s t e p . A l l a t t e m p t s t o e f f e c t c o n v e r s i o n o f t h e k e t o d i m e s y l a t e 384 i n t o t h e t e t r a -c y c l i c k e t o monomesylate 390 v i a a base-promoted i n t r a m o l e c u l a r a l k y l a t i o n r e a c t i o n f a i l e d . A l t h o u g h i t a p p e a r e d t o be h i g h l y p r o b a b l e t h a t t h e d e s i r e d t r a n s f o r m a t i o n had o c c u r r e d , t h e d e s i r e d p r o d u c t 390 was a p p a r e n t l y n o t s u f f i c i e n t l y s t a b l e u n d e r t h e r e a c t i o n c o n d i t i o n s t o a l l o w f o r i s o l a t i o n . T h e r e f o r e , i t was f e l t t h a t i f t h e m e s y l a t e group o f 384 were r e p l a c e d by a " p o o r e r " l e a v i n g group s u c h as c h l o r i d e , t h e n t h e c o r r e s p o n d i n g t e t r a -c y c l i c k e t o c h l o r i d e m i g h t be s t a b l e enough t o be i s o l a t e d . OMs Bu t0K/THF OMs 384 390 The k e t o d i c h l o r i d e 391 was p r e p a r e d s m o o t h l y by s t i r r i n g t h e c r u d e d i m e s y l a t e 384 w i t h a nhydrous l i t h i u m c h l o r i d e i n a m i x t u r e o f h e x a m e t h y l -phosphoramide and e t h e r . The p r o d u c t , o b t a i n e d i n 91% o v e r a l l y i e l d f r o m - 1 5 1 -k e t o d i o l 383, e x h i b i t e d s p e c t r a l p r o p e r t i e s i n agreement w i t h s t r u c t u r e 391. Thus, t h e i . r . s p e c t r u m showed a c a r b o n y l a b s o r p t i o n a t 1706 cm 1 . 384 391 I n t h e p.m.r. s p e c t r u m , t h e p r o t o n s o f t h e endo c h l o r o m e t h y l group gave r i s e t o an AB p a i r o f d o u b l e t s a t 63.36 and 3.66, w i t h a c o u p l i n g c o n s t a n t o f 11.0 Hz, w h i l e t h e c o r r e s p o n d i n g s i g n a l s f o r t h e exo c h l o r o m e t h y l group -152-were l o c a t e d a t 63.61 and 3.81, w i t h a c o u p l i n g c o n s t a n t o f 12.0 Hz. The t e r t i a r y and s e c o n d a r y m e t h y l g r o u p s e x h i b i t e d a s i n g l e t a t 60.62 and a d o u b l e t (J=6.5 Hz) a t 60.92, r e s p e c t i v e l y . When t h e k e t o d i c h l o r i d e 391 was t r e a t e d w i t h a s l i g h t e x c e s s o f f r e s h l y p r e p a r e d p o t a s s i u m t e r t - b u t o x i d e i n t e t r a h y d r o f u r a n , i n t r a -m o l e c u l a r a l k y l a t i o n p r o c e e d e d s m o o t h l y t o a f f o r d t h e t e t r a c y c l i c k e t o c h l o r i d e 392 i n e x c e l l e n t y i e l d . I n t h e p.m.r. s p e c t r u m o f t h e p r o d u c t 392, a s h a r p t w o - p r o t o n s i n g l e t a t 63.60 c o u l d be a t t r i b u t e d t o t h e p r o t o n s of t h e c h l o r o m e t h y l g r o u p . A s i n g l e t a t 50.73 and a d o u b l e t a t 60.87 (J=6.0 Hz) were a s s i g n e d t o t h e t e r t i a r y and s e c o n d a r y m e t h y l g r o u p s , r e s p e c t i v e l y . A l t h o u g h t h i s c y c l o p r o p y l c a r b i n y l c h l o r i d e c o u l d be i s o l a t e d , i t d i d n o t appear t o be v e r y s t a b l e and i t t h e r e f o r e was u s e d i m m e d i a t e l y f o r t h e n e x t r e a c t i o n . R e d u c t i o n o f h a l i d e s and m e s y l a t e s ( o r t o s y l a t e s ) t o h y d r o c a r b o n s c a n be a c h i e v e d by a v a r i e t y o f r e d u c i n g a g e n t s , f o r example, l i t h i u m 145-147 t r i e t h y l b o r o h y d r i d e ("super h y d r i d e " ) , p o t a s s i u m t r i - s - b u t y l -148 b o r o h y d r i d e - c u p r o u s i o d i d e complex , complex m e t a l h y d r i d e s o f c o p p e r 149 150 ( i . e . Li^CuH,.) and l i t h i u m a l k y l c o p p e r h y d r i d e (LiCuHR) . Due t o t h e c o m m e r c i a l a v a i l a b i l i t y o f l i t h i u m t r i e t h y l b o r o h y d r i d e , we chose t o 145 i n v e s t i g a t e t h e r e d u c t i o n o f t h e k e t o m o n o c h l o r i d e 392 w i t h t h i s r e a g e n t . When 392 was t r e a t e d w i t h f o u r e q u i v a l e n t s o f t h e r e d u c i n g a g e n t i n t e t r a -h y d r o f u r a n , i t was c o n v e r t e d s m o o t h l y i n t o t h e a l c o h o l 393. The i s o l a t e d p r o d u c t e x h i b i t e d a s t r o n g , b r o a d a b s o r p t i o n a t 3350 cm 1 i n i t s i . r . s p e c t r u m . I n t h e p.m.r. s p e c t r u m , t h e p r e s e n c e o f two t e r t i a r y m e t h y l g r o u p s was shown by two t h r e e - p r o t o n s i n g l e t s a t 51.03 and 1.13. The -153-s e c o n d a r y m e t h y l group gave r i s e t o a d o u b l e t a t 60.77, w i t h a c o u p l i n g c o n s t a n t o f 5.5 Hz. A h i g h f i e l d m u l t i p l e t a t 60.55 was a s s i g n e d t o one o f t h e c y c l o p r o p y l p r o t o n s . An u n r e s o l v e d m u l t i p l e t a t 63.42, w i t h w i d t h a t h a l f - h e i g h t o f 6.0 Hz, was a t t r i b u t e d t o t h e p r o t o n a d j a c e n t t o t h e h y d r o x y l g r o u p . J u d g i n g f r o m t h e p.m.r. s p e c t r u m and t a k i n g i n t o a c c o u n t t h e s t e r i c h i n d r a n c e e x e r t e d by t h e a n g u l a r m e t h y l g r o u p , t h e s t e r e o c h e m i s t r y o f t h e h y d r o x y l group was t e n t a t i v e l y a s s i g n e d t o be c i s t o t h e a n g u l a r m e t h y l g r o u p . O x i d a t i o n o f t h e a l c o h o l 393 w i t h p y r i d i n i u m chlorochromate"^''' i n m e t h y l e n e c h l o r i d e gave a k e t o n i c compound 12_ i n 69% o v e r a l l y i e l d f r o m t h e k e t o d i c h l o r i d e 391. The i . r . s p e c t r u m o f t h i s compound e x h i b i t e d a s t r o n g a b s o r p t i o n a t 1700 cm due t o t h e c a r b o n y l g roup and a weak band ( s h o u l d e r ) a t 3030 cm ^ due t o t h e p r e s e n c e o f c y c l o p r o p a n e - t y p e p r o t o n s . I n t h e p.m.r. s p e c t r u m , t h e t e r t i a r y m e t h y l g r o u p s gave r i s e t o s i n g l e t s a t 60.74 and 1.16. F i n a l l y , a d o u b l e t a t 60.87, w i t h a c o u p l i n g c o n s t a n t o f 6.5 Hz, was a s s i g n e d t o t h e s e c o n d a r y m e t h y l g r o u p . These s p e c t r a l d a t a were i n f u l l agreement w i t h t h o s e r e p o r t e d f o r t h e n a t u r a l 12 p r o d u c t ( + ) - i s h w a r o n e 12. I n o r d e r t o c o n f i r m t h e s t r u c t u r e o f t h e f i n a l p r o d u c t , t h e s y n t h e t i c (±)-ishwarone 12 was c o n v e r t e d i n t o (±)-ishwarane 13_ by W o l f f -12 K i s h n e r r e d u c t i o n as r e p o r t e d . The i . r . s p e c t r u m o f t h e p r o d u c t , w h i c h showed no c a r b o n y l a b s o r p t i o n , e x h i b i t e d a band a t 3040 cm ^ w h i c h was a t t r i b u t e d t o t h e p r e s e n c e o f c y c l o p r o p a n e - t y p e p r o t o n s . I n t h e p.m.r. s p e c t r u m , t h e c y c l o p r o p y l p r o t o n s a p p e a r e d as a m u l t i p l e t a t 60.52. The t e r t i a r y m e t h y l g r o u p s p r o d u c e d s i n g l e t s a t 60.78 and 1.14, w h i l e t h e s e c o n d a r y m e t h y l group gave r i s e t o a d o u b l e t a t 60.74, w i t h a c o u p l i n g -154-c o n s t a n t o f 6.5 Hz. The s p e c t r a l p r o p e r t i e s and g . l . c . r e t e n t i o n t i m e s o f t h i s p r o d u c t were i d e n t i c a l w i t h t h o s e o f a u t h e n t i c (±)-ishwarane * 57 13 . I n c o n c l u s i o n , a s t e r e o s e l e c t i v e t o t a l s y n t h e s i s o f (±)-ishwarone and (±)-ishwarane was c a r r i e d o u t . To o u r kno w l e d g e , t h e work d e s c r i b e d h e r e i n c o n s t i t u t e s t h e f i r s t t o t a l s y n t h e s i s o f (±)-ishwarone. P o t e n t i a l l y , t h e sequence c o u l d be e x t e n d e d f u r t h e r t o i n c l u d e t h e s y n t h e s i s o f 3-o x o i s h w a r a n e , and t h u s a l l p r e s e n t l y known members o f t h e i s h w a r a n e c l a s s o f s e s q u i t e r p e n o i d s c o u l d be o b t a i n e d f r o m t h i s s e q u ence. * We a r e g r a t e f u l t o P r o f e s s o r R. B. K e l l y f o r a sample o f a u t h e n t i c (±)-ishwarane. -155-EXPERIMENT M e l t i n g p o i n t s , w h i c h were d e t e r m i n e d w i t h a F i s h e r - J o h n s m e l t i n g p o i n t a p p a r a t u s , and b o i l i n g p o i n t s a r e u n c o r r e c t e d . I n f r a r e d s p e c t r a were r e c o r d e d on a P e r k i n - E l m e r model 710 s p e c t r o -p h o t o m e t e r . The p r o t o n m a g n e t i c r e s o n a n c e s p e c t r a were t a k e n i n d e u t e r o c h l o r o f o r m s o l u t i o n on V a r i a n A s s o c i a t e s S p e c t r o m e t e r s , models T-60 a nd/or HA-100 o r XL-100. S i g n a l p o s i t i o n s a r e g i v e n i n p a r t s p e r m i l l i o n (6) w i t h t e t r a m e t h y l s i l a n e as an i n t e r n a l r e f e r e n c e ; t h e m u l t i p l i c i t y , i n t e g r a t e d peak a r e a s , and p r o t o n a s s i g n m e n t s a r e i n d i c a t e d i n p a r e n t h e s e s . G a s - l i q u i d c h r o m a t o g r a p h y ( g . l . c . ) was c a r r i e d o u t w i t h a V a r i a n A e r o g r a p h model 90-P gas c h r o m a t o g r a p h , o r w i t h a H e w l e t t -P a c k a r d model 5832A gas c h r o m a t o g r a p h . The f o l l o w i n g columns were em-p l o y e d . Column L e n g t h S t a t i o n a r y Phase S u p p o r t Mesh A 10' x V 20% SE-30 Chromosorb W 60/80 B " 10% SE-30 " " C " 10% OV-210 D 5' x V 20% SE-30 E " 10% SE-30 F 6' x 1/8" 10% OV-210 " 110/120 The s p e c i f i c column u s e d a l o n g w i t h column t e m p e r a t u r e and c a r r i e r gas ( h e l i u m ) f l o w - r a t e ( i n ml/min) a r e i n d i c a t e d i n p a r e n t h e s e s . Column ch r o m a t o g r a p h y was p e r f o r m e d u s i n g f l o r i s i l ( F i s c h e r S c i e n t i f i c Co.) o r n e u t r a l s i l i c a g e l (Camag o r M a c h e r a y , N a g e l and Co., o r E. M e r c k, S i l i c a G e l 6 0 ) . The a l u m i n a A c t I I I u s e d i n f i l t r a t i o n columns was o b t a i n e d by d e a c t i v a t i n g n e u t r a l a l u m i n a A c t I ( A l u m i n a Woelm B, A c t I ) w i t h 6% o f -156-w a t e r . T h i n l a y e r c hromatography was c a r r i e d o ut w i t h c o m m e r c i a l s i l i c a g e l p l a t e s (Eastman Chromagram Sheet Type 13181) o r w i t h 20 x 5 cm g l a s s p l a t e s c o a t e d w i t h 0.5 mm o f n e u t r a l s i l i c a g e l ( s i l i c a g e l GF 254, E. Merck) and a c t i v a t e d by h e a t i n g i n an oven f o r 12-24 h o u r s . P r e p a r a t i v e t h i n l a y e r c h r o m a t o g r a p h y was c a r r i e d o u t w i t h 20 x 20 cm g l a s s p l a t e s c o a t e d w i t h 1 mm o f n e u t r a l s i l i c a g e l ( s i l i c a g e l GF 254, E. Merck) and a c t i v a t e d by h e a t i n g i n an oven f o r 12-24 h o u r s . The h i g h r e s o l u t i o n mass s p e c t r a were r e c o r d e d on an AEI MS-902 mass s p e c t r o m e t e r . M i c r o a n a l y s e s were p e r f o r m e d by Mr. P. B o r d a , M i c r o a n a l y t i c a l L a b o r a t o r y , U n i v e r s i t y o f B r i t i s h C o l u m b i a . D r i e d s o l v e n t s were used i n a l l r e a c t i o n s . Dry t e t r a h y d r o f u r a n and h e x a m e t h y l p h o s p h o r a m i d e were d i s t i l l e d f r o m l i t h i u m aluminum h y d r i d e . M e t h y l e n e c h l o r i d e was d i s t i l l e d f r o m phosphorous p e n t o x i d e and m e t h a n o l was o b t a i n e d by d i s t i l l a t i o n o v e r magnesium m e t h o x i d e . t e r t - B u t y l a l c o h o l was d i s t i l l e d f r o m a s o l u t i o n o f p o t a s s i u m t - b u t o x i d e i n t h e a l c o h o l . Benzene was d i s t i l l e d f r o m m e t a l l i c p o t a s s i u m . P e t r o l e u m - e t h e r was o b t a i n e d by d i s t i l l a t i o n f r o m p o t a s s i u m permangenate. Anhydrous e t h e r was o b t a i n e d c o m m e r c i a l l y . P r e p a r a t i o n o f 2 - C a r b o m e t h o x y - l - m e t h y l - l , 4 - d i h y d r o b e n z e n e 2fiL A m i x t u r e o f 3.2 g o f m e t h y l p r o p i o l a t e (38.1 mmole), 6.4 g o f d i s t i l l e d 1 , 3 - p e n t a d i e n e (94.1 mmole) and 0.1 g o f h y d r o q u i n o n e i n 20 ml of t o l u e n e was h e a t e d i n two s e a l e d t u b e s a t 140-145° f o r a p p r o x i m a t e l y 10 h r s . A f t e r c o o l i n g , t h e r e a c t i o n m i x t u r e s o b t a i n e d f r o m t h e t u b e s were combined. The s o l v e n t and e x c e s s p e n t a d i e n e were e v a p o r a t e d t o g i v e 4.1 g o f a c o l o r l e s s o i l . D i s t i l l a t i o n o f t h e c r u d e p r o d u c t gave 3.8 g (66%) o f a c o l o r l e s s o i l , b.p., 92-98° a t 16-20 mm ( l i t . b.p.88-90° -157-87 — 1 a t 20 mm ) ; i . r . ( f i l m ) , v 3050, 1720, 1670, 1640 cm ; p.m.r., max 1.26 (d, 3H, secondary m e t h y l , J=7.0 Hz), 2.98 (m, 2H, a l l y l i c m e t h y l e n e ) , 3.32 (m, IH, a l l y l i c m e t h i n e ) , 3.86 ( s , 3H, -COOMe), 5.82 (m, 2H, v i n y l p r o t o n ) , 7.08 (m, IH, -CH=CC00Me). P r e p a r a t i o n of M e t h y l 6 - m e t h y l c y c l o h e x e n e c a r b o x y l a t e 262 To a s o l u t i o n o f 2-c a r b o m e t h o x y - l - m e t h y l - l , 4 - d i h y d r o b e n z e n e 261 (12.Og, 78.95 mmoles) i n 100 ml o f benzene was added 800 mg of t r i s -( t r i p h e n y l p h o s p h i n e ) r h o d i u m c h l o r i d e . The r e s u l t i n g s o l u t i o n was hydro-genated a t atmos p h e r i c p r e s s u r e and room temperature. A f t e r one e q u i v a l e n t of hydrogen had been absorbed, the b r i c k r e d s o l u t i o n was f i l t e r e d through a s h o r t column o f alumina (Act I I I ) , and the column was e l u t e d w i t h a p p r o x i m a t e l y 1£ o f benzene. The s o l v e n t was e v a p o r a t e d under reduced p r e s s u r e t o g i v e a deep y e l l o w o i l . Short path d i s t i l l a t i o n gave 9.80 g (80%) o f a c o l o r l e s s o i l , b.p., 86-87° a t 24 mm; i . r . ( f i l m ) , v 1710, max 1640 cm" 1; p.m.r., 1.20 (d, 3H, secondary m e t h y l , J=7.0 H z ) , 2.18 (m, 2H, a l l y l i c m e t h y l e n e ) , 2.68 ( u n r e s o l v e d m, IH, a l l y l i c m e t h i n e ) , 3.84 ( s , 3H, -COOMe), 7.06 ( t , IH, -CH=CC00Me, J=4.0 H z ) . A n a l . C a l c d . f o r C Q H l A 0 9 : C, 70.10; H, 9.15. Found: C, 69.88; H, 8.99. P r e p a r a t i o n of 3-Carbomethoxy-4-methyl-2-cyclohexen-l-one 2J38 To a s t i r r e d s o l u t i o n o f 10.0 g of me t h y l 6 - m e t h y l c y c l o h e x e n c a r b o x y l a t e 262 (64.93 mmoles) i n 60 ml of g l a c i a l a c e t i c a c i d and 1 ml of water was added 10.0 g of chromium t r i o x i d e (100 mmoles) over a p e r i o d o f 30 minutes w h i l e the temperature o f the s o l u t i o n was kept below 40° w i t h a c o l d water b a t h . Then, a f t e r s t i r r i n g f o r 2 h r s . a t 40-50°, another 10.0 g of chromium t r i o x i d e was added i n p o r t i o n s and the m i x t u r e was s t i r r e d -158-f o r a n o t h e r 2 h r s . I t was c o o l e d w i t h an i c e - b a t h and n e u t r a l i z e d w i t h 10% so d i u m h y d r o x i d e s o l u t i o n . The m i x t u r e was e x t r a c t e d w i t h e t h e r and t h e combined e t h e r e a l s o l u t i o n was washed w i t h w a t e r , s a t u r a t e d sodium b i c a r b o n a t e s o l u t i o n , w a t e r and b r i n e . I t was t h e n d r i e d o v e r a n hydrous magnesium s u l f a t e . A f t e r f i l t r a t i o n , t h e s o l v e n t was e v a p o r a t e d t o g i v e a g o l d e n y e l l o w o i l . S h o r t p a t h d i s t i l l a t i o n o f t h e c r u d e p r o d u c t gave 7.0 g o f a p a l e y e l l o w o i l , b.p. 85-140° a t 16-20 mm. A n a l y s i s o f t h i s m a t e r i a l by g . l . c . (column A, 175°, 70 ml/min) showed t h a t t h i s d i s t i l l a t e was a m i x t u r e c o n t a i n i n g a p p r o x i m a t e l y 25% o f t h e s t a r t i n g m a t e r i a l 262 and 75% o f t h e p r o d u c t 258. T h i s m a t e r i a l was s u b j e c t e d t o column c h r o m a t o g r a p h y on s i l i c a g e l (350 g) w i t h a 4:1 p e t r o l e u m e t h e r (30-60°) - e t h e r m i x t u r e b e i n g u s e d as e l u t i n g s o l v e n t . Those f r a c t i o n s c o n t a i n i n g p u r e s t a r t i n g m a t e r i a l were combined t o g i v e a t o t a l o f 1.53 g o f c o l o r l e s s o i l a f t e r d i s t i l l a t i o n . C o m b i n i n g t h e o t h e r f r a c t i o n s gave 5.03 g ( 5 6 % , bas e d on u n r e c o v e r e d s t a r t i n g m a t e r i a l ) o f 3 - c a r b o m e t h o x y - 4 - m e t h y l - 2 - c y c l o h e x e n - l - o n e 258, i s o l a t e d as a d a r k y e l l o w o i l . D i s t i l l a t i o n gave 4.92 g o f a p a l e y e l l o w o i l , b.p., 114-120° a t 15-18 mm; i . r . ( f i l m ) , v 1720, 1685 cm" 1; p.m.r., 1.24 ( d , 3H, max s e c o n d a r y m e t h y l , J=7.0 H z ) , 2.96 (m, I H , a l l y l i c m e t h i n e ) , 3.78 ( s , 3H, COOMe), 6.58 ( s , I H , -CCH=C-C00Me), M o l . Wt. C a l c d . f o r CgH^O.^: 168.0788. Found ( h i g h r e s o l u t i o n mass s p e c t r o m e t r y ) : 168.0786. D i e l s - A l d e r R e a c t i o n o f 3 - C a r b o m e t h o x y - 4 - m e t h y l - 2 - c y c l o h e x e n - l - o n e 253.  w i t h 1 , 3 - B u t a d i e n e To a s u s p e n s i o n o f 1.20 g (8.98 mmoles) o f f r e s h l y s u b l i m e d a n h y d r o u s a l u m i n i u m t r i c h l o r i d e i n 20 m l o f anhydrous m e t h y l e n e c h l o r i d e was added -159-3.60 g (21.43 mmoles) o f 3 - c a r b o m e t h o x y - 4 - m e t h y l - 2 - c y c l o h e x e n - l - o n e 258. A deep y e l l o w homogeneous s o l u t i o n was formed. T h i s s o l u t i o n was t r a n s -f e r r e d t o two t h i c k w a l l g l a s s t u b e s . A n o t h e r 14 ml o f a n h y d r o u s m e t h y l e n e c h l o r i d e was added t o each t u b e . Then each t u b e was c h a r g e d w i t h a p p r o x i -m a t e l y 20 m l o f l i q u i d 1 , 3 - b u t a d i e n e . The s e a l e d t u b e s were h e a t e d a t about 95-100° f o r one day. A f t e r c o o l i n g t o room t e m p e r a t u r e , t h e r e a c t i o n m i x t u r e s were d i l u t e d w i t h c h l o r o f o r m and t h e combined s o l u t i o n was washed w i t h d i l u t e h y d r o c h l o r i c a c i d and t h e n w i t h w a t e r and b r i n e . A f t e r d r y i n g w i t h a n hydrous magnesium s u l f a t e , t h e s o l v e n t was e v a p o r a t e d t o g i v e a gummy y e l l o w o i l . The l a t t e r was e x t r a c t e d t w i c e w i t h 100 m l p o r t i o n s o f r e f l u x i n g m e t h a n o l . The combined m e t h a n o l i c e x t r a c t s were f i l t e r e d t h r o u g h a bed o f C e l i t e and t h e f i l t r a t e was c o n c e n t r a t e d on a r o t a r y e v a p o r a t o r . The r e s i d u e was d i l u t e d w i t h e t h e r and d r i e d o v e r a n h y d r o u s magnesium s u l f a t e . Removal o f s o l v e n t and d i s t i l l a t i o n o f t h e r e s i d u e ( a i r b a t h t e m p e r a t u r e up t o 140° a t 0.05 mm) gave 3.28 g o f a l i g h t y e l l o w o i l . R e d i s t i l l a t i o n o f t h e m i x t u r e , w i t h a i r b a t h t e m p e r a t u r e a t 90-109° and 0.08 mm, gave 2.84 g o f a s l i g h t l y y e l l o w o i l . G . l . c . a n a l y s i s (column C, 180°, 70 ml/min) showed t h a t t h i s m a t e r i a l c o n s i s t e d o f two m a j o r components i n a r a t i o o f a p p r o x i m a t e l y 1:1. The m i x t u r e was s u b j e c t e d t o column c h r o m a t o g r a p h y on 300 g o f s i l i c a g e l u s i n g p e t r o l e u m e t h e r w i t h i n -c r e a s i n g amounts o f e t h e r as e l u t i n g s o l v e n t . The f i r s t i s o m e r 272 (420 mg, 21%) w h i c h was e l u t e d f r o m t h e column was o b t a i n e d a s a c r y s t a l l i n e compound, m.p., 96-97° ( r e c r y s t a l l i z e d f r o m p e t r o l e u m e t h e r ) ; i . r . (CHCl^)> v , 3080, 1720 cm" 1; p.m.r., 0.99 ( d , 3H, s e c o n d a r y m e t h y l , J=6.0 H z ) , max 2.88-3.06 (m, I H , b r i d g e h e a d p r o t o n ) , 3.62 ( s , 3H, COOMe), 5.68 (m, 2H, -160-v i n y l p r o t o n s ) . A n a l . C a l c d . f o r C 1 o H l Q 0 „ : C, 70.24; H, 8.16. Found: C, 70.20; 1 j l o J H, 8.21. The second i s o m e r 273 (350 mg, 18%) w h i c h was e l u t e d f r o m t h e column was i s o l a t e d as a p a l e y e l l o w v i s c o u s o i l [b.p. 95-105° ( a i r b a t h t e m p e r a t u r e ) a t 0.1 mm)]; i . r . ( f i l m ) , v , 3080, 1720 cm ^; p.m.r., 0.89 ( d , 3H, s e c o n d a r y m e t h y l , J=6.0 H z ) , 3.17 ( u n r e s o l v e d d o f d, b r i d g e h e a d p r o t o n ) , 3.74 ( s , 3H, COOMe), 5.60 ( b r o a d d, 2H, v i n y l p r o t o n s , J=6.0 H z ) . M o l . Wt. C a l c d . f o r C , o H , o 0 o : 222.1257. Found ( h i g h r e s o l u t i o n l o l o o mass s p e c t r o m e t r y ) : 222.1256. A t t e m p t e d E p i m e r i z a t i o n o f t h e K e t o E s t e r 222. A p p r o x i m a t e l y 14 mg o f m e t a l l i c sodium was added t o 10 m l o f s t i r r e d a n h y d r o u s m e t h a n o l . A f t e r a l l o f t h e sodium had r e a c t e d , a s o l u t i o n o f 100 mg (0.45 mmole) o f t h e k e t o e s t e r 272 i n 10 m l o f a n h y d r o u s m e t h a n o l was i n t r o d u c e d d r o p w i s e . The r e s u l t i n g s o l u t i o n was r e f l u x e d u n d e r a n i t r o g e n atmosphere f o r 5 h r s . A f t e r c o o l i n g most o f t h e s o l v e n t was removed un d e r r e d u c e d p r e s s u r e and t h e r e s i d u e was d i l u t e d w i t h w a t e r and a c i d i f i e d w i t h d i l u t e h y d r o c h l o r i c a c i d . The m i x t u r e was t h e n e x t r a c t e d w i t h e t h e r . The combined e t h e r e x t r a c t s were washed w i t h w a t e r , s a t u r a t e d aqueous s o d i u m b i c a r b o n a t e , w a t e r and t h e n b r i n e . A f t e r d r y i n g w i t h a n hydrous magnesium s u l f a t e and e v a p o r a t i n g o f f t h e s o l v e n t , a l i g h t y e l l o w o i l was o b t a i n e d . D i s t i l l a t i o n o f t h i s m a t e r i a l a t 110-117° ( a i r b a t h t e m p e r a t u r e ) and 0.35 mm gave 73 mg (73%) o f c o l o r l e s s o i l w h i c h s o l i d i f i e d upon c o o l i n g (m.p., 95-96°). G . l . c . r e t e n t i o n t i m e s (columns A and C, 150°, 100 ml/min) and i . r . and p.m.r. s p e c t r a o f 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 t h o s e o f t h e s t a r t i n g -161-m a t e r i a l ( k e t o e s t e r 2 7 2 ) . H y d r o g e n a t l o n o f t h e K e t o E s t e r 222. To a s o l u t i o n o f 0.20 g (0.90 mmole) o f t h e u n s a t u r a t e d k e t o e s t e r 272 i n 10 m l o f e t h a n o l , was added 15.2 mg o f 5% p a l l a d i u m - o n - c a r b o n . The m i x t u r e was h y d r o g e n a t e d a t a t m o s p h e r i c p r e s s u r e and room t e m p e r a t u r e . A f t e r a p p r o x i m a t e l y one e q u i v a l e n t o f h y d r o g e n had been a b s o r b e d , t h e m i x t u r e was f i l t e r e d t h r o u g h c e l i t e . E v a p o r a t i o n o f t h e s o l v e n t f r o m t h e f i l t r a t e g ave a v i s c o u s c o l o r l e s s o i l w h i c h c r y s t a l l i z e d upon s t a n d i n g . R e c r y s t a l l i z a t i o n f r o m hexanes gave 0.16 g (79%) o f compound 274 as w h i t e n e e d l e s , m.p., 63-65°; i . r . (CHC1-), v 1720, 1710 c m - 1 ; p.m.r., 0.93 ( d , 3H, s e c o n d a r y m e t h y l , J=6.0 H z ) , 2.39 (m, 3H, p r o t o n s a t o t h e k e t o c a r b o n y l g r o u p ) , 3.60 ( s , 3H, COOMe). A n a l . C a l c d . f o r C^^Oy. C, 69.61; H, 8.99. Found :C,69.79; H, 8.97. A t t e m p t e d E p i m e r i z a t i o n o f t h e K e t o E s t e r 22A A p p r o x i m a t e l y 46 mg o f m e t a l l i c sodium was added t o 10 m l o f s t i r r e d a n h y d r o u s m e t h a n o l . A f t e r a l l o f t h e sodium had r e a c t e d , a s o l u t i o n o f 76 mg (0.34 mmole) o f t h e s a t u r a t e d k e t o e s t e r 274 i n 3 m l o f a n h y d r o u s m e t h a n o l was i n t r o d u c e d . The m i x t u r e was r e f l u x e d under n i t r o g e n f o r 5 h r s . Most o f t h e s o l v e n t was removed and t h e r e s i d u e was d i l u t e d w i t h w a t e r . The aqueous s o l u t i o n was t h e n e x t r a c t e d w i t h e t h e r . The combined e t h e r e x t r a c t s were washed w i t h w a t e r and b r i n e . E v a p o r a t i o n o f t h e s o l v e n t a f t e r d r y i n g o v e r a n h y d r o u s magnesium s u l f a t e gave 60 mg (79%) o f a s l i g h t l y y e l l o w o i l w h i c h was shown by g . l . c . a n a l y s i s (column A and C, 150°, 100 ml/min) t o be one component w i t h a r e t e n t i o n t i m e i d e n t i c a l w i t h t h a t o f t h e s t a r t i n g k e t o e s t e r 274. The i . r . and p.m.r. s p e c t r a of t h e p r o d u c t were i d e n t i c a l w i t h t h o s e o f t h e s t a r t i n g m a t e r i a l . -162-P r e p a r a t i o n o f t h e D i t h i o k e t a l E s t e r 280 About 2 m l o f e t h a n e d i t h i o l was added t o a r o u n d bottomed f l a s k c o n t a i n i n g 366 mg (1.63 mmole) o f t h e s a t u r a t e d k e t o e s t e r 274 und e r a n i t r o g e n a t m o s p h e r e . The m i x t u r e was s t i r r e d u n t i l a l l o f t h e k e t o e s t e r had d i s s o l v e d . The s o l u t i o n was c o o l e d w i t h an i c e b a t h , and t h e n a p p r o x i m a t e l y 1 m l o f b o r o n t r i f l u o r i d e e t h e r a t e was added s l o w l y . The r e s u l t i n g m i x t u r e was s t i r r e d a t 0° f o r l % h o u r . The i c e b a t h was removed and t h e m i x t u r e was a l l o w e d t o warm t o room t e m p e r a t u r e . A f t e r h a v i n g been s t i r r e d a t room t e m p e r a t u r e f o r a n o t h e r 15 m i n u t e s , t h e m i x t u r e was p o u r e d i n t o 5% aqueous p o t a s s i u m h y d r o x i d e and t h e aqueous l a y e r was e x t r a c t e d w i t h e t h e r . The combined e t h e r , e x t r a c t s were washed t w i c e w i t h 5% aqueous p o t a s s i u m h y d r o x i d e and t h e n w i t h w a t e r u n t i l t h e e x t r a c t s were n o t a l k a l i n e . A f t e r a n o t h e r w a s h i n g w i t h b r i n e , t h e s o l u t i o n was d r i e d w i t h a n h y d r o u s magnesium s u l f a t e . E v a p o r a t i o n o f t h e s o l v e n t gave 561 mg o f a v i s c o u s o i l . D i s t i l l a t i o n ( a i r b a t h tem-p e r a t u r e 146-160° a t 0.6 mm) o f t h i s m a t e r i a l a f f o r d e d 495 mg (100%) o f a c o l o r l e s s v i s c o u s o i l ; i . r . ( f i l m ) , v 1720 cm "S p.m.r., 0.88 ( d , max 3H, s e c o n d a r y m e t h y l , J=6.0 H z ) , 2.95 (m, I H , b r i d g e h e a d p r o t o n ) , 3.18 (m, 4H, d i t h i o k e t a l p r o t o n s ) , 3.70 ( s , 3H, COOMe). M o l . Wt. C a l c d . f o r C 1 5 H 2 4 ° 2 S 2 : 3 0 0 • 1 2 2 4 • Found ( h i g h r e s o l u t i o n mass s p e c t r o m e t r y ) : 300.1218. P r e p a r a t i o n o f t h e D i t h i o k e t a l A l c o h o l 2BJL. A s o l u t i o n o f 495 mg (1.65 mmole) o f t h e d i t h i o k e t a l e s t e r 280 i n 6 m l o f an h y d r o u s t e t r a h y d r o f u r a n was added t o a s o l u t i o n o f 217 mg (5.71 mmole) o f l i t h i u m aluminum h y d r i d e i n 20 m l o f an h y d r o u s t e t r a -h y d r o f u r a n u n d e r a n i t r o g e n a tmosphere. The m i x t u r e was r e f l u x e d f o r 2 h r s . , and t h e n c o o l e d t o room t e m p e r a t u r e . Powdered sodium s u l f a t e -163-d e c a h y d r a t e was added c a u t i o u s l y . When a l l t h e e x c e s s l i t h i u m aluminum h y d r i d e had been d e s t r o y e d , t h e m i x t u r e was f i l t e r e d t h r o u g h C e l i t e and t h e s o l i d was washed w i t h e t h e r . The f i l t r a t e was c o n c e n t r a t e d u nder r e d u c e d p r e s s u r e and t h e r e s i d u e was d i l u t e d w i t h e t h e r . The r e s u l t a n t s o l u t i o n was d r i e d w i t h a n h y d r o u s magnesium s u l f a t e . Removal o f t h e s o l v e n t a f f o r d e d 467 mg o f c r u d e p r o d u c t . D i s t i l l a t i o n ( a i r b a t h t e m p e r a t u r e 145-160° a t 0.4 mm) o f t h i s m a t e r i a l gave 435 mg (97%) o f t h e d i t h i o k e t a l a l c o h o l 281 as a v i s c o u s c o l o r l e s s o i l ; i . r . ( f i l m ) , Vmax 3 4 ^ 7 ( b r o a d ) , 1024 cm "S p.m.r., 0.97 ( d , 3H, s e c o n d a r y m e t h y l , J=5.0 H z ) , 3.20 (m, 4H, d i t h i o k e t a l p r o t o n s ) , 3.93 ( s , 2H, -CH_ 20H). M o l . Wt. C a l c d . f o r C ^ H ^ O S ^ . 272.1286 Found ( h i g h r e s o l u t i o n mass s p e c t r o m e t r y ) : 272.1269 P r e p a r a t i o n o f t h e D i t h i o k e t a l A l d e h y d e 232. To a s o l u t i o n o f 1.10 g (13.92 mmoles) o f d r y p y r i d i n e i n 16 m l o f d r y m e t h y l e n e c h l o r i d e , was added c a r e f u l l y , w i t h v i g o r o u s s t i r r i n g , 660 mg (6.66 mmoles) o f d r y chromium t r i o x i d e . A f t e r t h e 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 f o r 15 m i n s . a t room t e m p e r a t u r e , a s o l u t i o n o f 300 mg (1.10 mmole) o f t h e d i t h i o k e t a l a l c o h o l 281 i n a minimum amount o f m e t h y l e n e c h l o r i d e was added. The r e a c t i o n m i x t u r e was s t i r r e d a t room t e m p e r a t u r e f o r 30 m i n s . , and was t h e n d e c a n t e d i n t o a s e p a r a t o r y f u n n e l . The r e s i d u e was washed twice, w i t h e t h e r . The combined o r g a n i c s o l u t i o n was washed s u c c e s s i v e l y w i t h 5% aqueous p o t a s s i u m h y d r o x i d e , w a t e r , d i l u t e h y d r o c h l o r i c a c i d , s a t u r a t e d aqueous sodium b i c a r b o n a t e , w a t e r , and b r i n e . A f t e r d r y i n g and e v a p o r a t i o n o f s o l v e n t , 251 mg (84%) o f a s l i g h t l y y e l l o w s o l i d was o b t a i n e d as t h e c r u d e p r o d u c t . R e c r y s t a l l i -z a t i o n o f t h e s o l i d f r o m e t h e r - p e t r o l e u m e t h e r gave 185 mg (62%) o f t h e -164-d i t h i o k e t a l a l d e h y d e 282 as c o l o r l e s s c r y s t a l s ; m.p., 83-85°; i . r . ( C H C 1 3 ) , v m a x 2710, 1720 cm" 1; p.m.r., 0.88 ( d , 3H, s e c o n d a r y m e t h y l , J=6.0 H z ) , 3.28 (m, 4H, d i t h i o k e t a l p r o t o n s ) , 10.23 ( s , I H , CHO). M o l . Wt. C a l c d . f o r 0 ^ ^ 2 0 8 2 : 270.1109. Found ( h i g h r e s o l u t i o n mass s p e c t r o m e t r y ) : 270.1120. W o l f f - K i s h n e r R e d u c t i o n o f t h e D i t h i o k e t a l A l d e h y d e 232, To 20 m l o f d i e t h y l e n e g l y c o l was added a p p r o x i m a t e l y 0.5 g o f m e t a l l i c sodium. The m i x t u r e was c a r e f u l l y h e a t e d by means o f a steam b a t h u n t i l a l l o f t h e sodium had r e a c t e d . To a two-necked f l a s k f i t t e d w i t h a thermometer and a s h o r t p a t h d i s t i l l a t i o n a p p a r a t u s , was added 18 m l (19.8 mmole) o f t h e sodium d i e t h y l e n e g l y c o l a t e s o l u t i o n ( p r e p a r e d as d e s c r i b e d a b o v e ) , 185 mg (0.685 mmole) o f t h e d i t h i o k e t a l a l d e h y d e 284 and 3 m l o f h y d r a z i n e h y d r a t e . The r e s u l t a n t m i x t u r e was h e a t e d s l o w l y and t h e l o w - b o i l i n g m a t e r i a l was a l l o w e d t o d i s t i l l u n t i l t h e i n t e r n a l t e m p e r a t u r e o f t h e m i x t u r e had r e a c h e d 180°. The m i x t u r e was t h e n r e f l u x e d f o r 21 h o u r s . D i s t i l l a t i o n was t h e n c o n t i n u e d u n t i l t h e i n t e r n a l t e m p e r a t u r e o f t h e r e a c t i o n m i x t u r e r e a c h e d 210° and r e f l u x i n g was c a r r i e d o u t a t t h i s t e m p e r a t u r e f o r a n o t h e r 25 h o u r s . A f t e r h a v i n g been c o o l e d t o room t e m p e r a t u r e , t h e r e a c t i o n m i x t u r e and t h e t o t a l d i s t i l l a t e w h i c h had been c o l l e c t e d were combined, d i l u t e d w i t h w a t e r , and t h o r o u g h l y e x t r a c t e d w i t h e t h e r . The combined e t h e r e x t r a c t s were washed w i t h w a t e r u n t i l t h e w a s h i n g s were no l o n g e r a l k a l i n e , and t h e n d r i e d w i t h a n h y d r o u s magnesium s u l f a t e . E v a p o r a t i o n o f t h e s o l v e n t u n d e r r e d u c e d p r e s s u r e a t low t e m p e r a t u r e ( c o l d w a t e r b a t h ) , gave 133 mg o f a p a l e y e l l o w o i l as t h e c r u d e p r o d u c t . . D i s t i l l a t i o n o f t h i s m a t e r i a l a t 110-120° ( a i r b a t h t e m p e r a t u r e ) and w a t e r a s p i r a t o r -165-p r e s s u r e gave 92.3 mg (81%) o f a c o l o r l e s s o i l ; i . r . ( f i l m ) , no c a r b o n y l a b s o r p t i o n . A n a l y s i s o f t h e d i s t i l l a t e by g . l . c . ( column A, 120°, 70 ml/min) showed o n l y one peak. However, t h e p.m.r. s p e c t r u m o f t h i s m a t e r i a l i n d i c a t e d t h a t i t was a m i x t u r e o f t h e e p i m e r i c h y d r o c a r b o n s 276 and 277 i n a r a t i o o f a p p r o x i m a t e l y 55:45 ( e s t i m a t e d f r o m t h e i n t e g r a t i o n o f t h e m e t h y l g r o u p s i n t h e p.m.r. s p e c t r u m ) ; p.m.r., 0.68 ( s , 3H, t e r t i a r y m e t h y l o f h y d r o c a r b o n 276),0.71 ( d , 3H, s e c o n d a r y m e t h y l o f h y d r o c a r b o n 277, J=6.5 H z ) , 0.78 ( s , 3H, t e r t i a r y m e t h y l o f h y d r o c a r b o n 2 7 7 ) . T h i s s p e c t r u m was i d e n t i c a l w i t h t h e c o m b i n a t i o n o f 98 t h e p.m.r. s p e c t r a o f a u t h e n t i c h y d r o c a r b o n s 276 and 277. A l s o , t h e g . l . c . r e t e n t i o n t i m e o f t h e p r o d u c t was i d e n t i c a l w i t h t h o s e o f t h e a u t h e n t i c s a m p l e s . E p i m e r i z a t i o n o f t h e K e t o E s t e r 273. A p p r o x i m a t e l y 14 mg o f m e t a l l i c sodium was added t o 10 m l o f a n h y d r o u s m e t h a n o l . A f t e r a l l t h e m e t a l had r e a c t e d , a s o l u t i o n o f 100 mg (0.450 mmole) o f t h e k e t o e s t e r 273 i n 10 m l o f anhydrous m e t h a n o l was added d r o p w i s e o v e r a p e r i o d o f 30 m i n u t e s . The s o l u t i o n was t h e n s t i r r e d a t room t e m p e r a t u r e u n d e r an i n e r t atmosphere ( n i t r o g e n ) f o r a n o t h e r 4 h o u r s . The s o l v e n t was removed und e r r e d u c e d p r e s s u r e and t h e r e s i d u e was d i l u t e d w i t h w a t e r , and a c i d i f i e d w i t h a few d r o p s o f d i l u t e h y d r o c h l o r i c a c i d . The m i x t u r e was e x t r a c t e d w i t h e t h e r . The combined e t h e r e x t r a c t s were washed t h o r o u g h l y w i t h w a t e r and b r i n e and t h e n d r i e d o v e r a n h y d r o u s magnesium s u l f a t e . E v a p o r a t i o n o f t h e e t h e r gave 87 mg (87%) o f a p a l e y e l l o w o i l . D i s t i l l a t i o n o f t h i s m a t e r i a l a t 100-115° ( a i r b a t h t e m p e r a t u r e ) and 0.35 mm gave 79 mg (79%) -166-o f a c o l o r l e s s o i l . G . l . c . a n a l y s i s (column D, 165°, 100 ml/min) showed t h a t t h e l a t t e r was a m i x t u r e o f s t a r t i n g m a t e r i a l 273 and a new p r o d u c t , p r e s u m a b l y 283 i n a r a t i o o f a p p r o x i m a t e l y 8:1 r e s p e c t i v e l y . T h i s new k e t o e s t e r 283 was n o t o b t a i n e d p u r e . However, by c o m p a r i n g t h e p.m.r. s p e c t r u m o f t h i s m a t e r i a l w i t h t h a t o f t h e k e t o e s t e r 273, i t was p o s s i b l e t o a s s i g n t h e f o l l o w i n g s i g n a l s t o 283: 1.23 ( d , 3H, s e c o n d a r y m e t h y l , J=6.0 H z ) , 3.64 ( s , 3H, COOMe), 5.60 ( b r o a d m, 2H, v i n y l p r o t o n s ) . H y d r o g e n a t i o n o f t h e K e t o E s t e r 2_7_3 To a s o l u t i o n o f t h e k e t o e s t e r 273 (462 mg, 2.08 mmoles) i n 25 m l o f e t h a n o l was added 26 mg o f 5% p a l l a d i u m - o n - c a r b o n . The m i x t u r e was h y d r o g e n a t e d a t a t m o s p h e r i c p r e s s u r e and room t e m p e r a t u r e t i l l t h e a b s o r p t i o n o f h y d r o g e n c e a s e d . The m i x t u r e was f i l t e r e d t h r o u g h C e l i t e . The s o l i d was washed w i t h e t h a n o l . The combined a l c o h o l i c s o l u t i o n was e v a p o r a t e d t o g i v e a s l i g h t l y y e l l o w o i l w h i c h upon d i s t i l l a t i o n ( a i r b a t h t e m p e r a t u r e 106-118° a t 0.3 mm) gave 457 mg (98%) o f t h e s a t u r a t e d k e t o e s t e r 284 as a c o l o r l e s s o i l ; i . r . ( f i l m ) , v 1720, 1700 cm "*"; ' ' max ' p.m.r., 0.86 ( d , 3H, s e c o n d a r y m e t h y l , J=6.0 H z ) , 2.96 (m, I H , b r i d g e h e a d p r o t o n ) , 3.70 ( s , 3H, COOMe). M o l . Wt. C a l c d . f o r c 1 3 H 2 o ° 3 : 2 2 4 - 1 3 9 0 - Found ( h i g h r e s o l u t i o n mass s p e c t r o m e t r y ) : 224.1413. E p i m e r i z a t i o n o f t h e K e t o E s t e r 28_4_ To 7 m l o f d r y m e t h a n o l was added 46 mg o f m e t a l l i c sodium. A f t e r t h e r e a c t i o n between t h e m e t h a n o l and sodium was c o m p l e t e , 152 mg (0.68 mmole) o f t h e k e t o e s t e r 284 i n 7 m l o f d r y m e t h a n o l was added t o t h e r e a c t i o n f l a s k . The m i x t u r e was t h e n g e n t l y s t i r r e d f o r a p p r o x i m a t e l y 5 h o u r s . A f t e r t h e m e t h a n o l had been removed, t h e r e s i d u e was d i l u t e d -167-w i t h w a t e r and a c i d i f i e d w i t h a few d r o p s o f d i l u t e h y d r o c h l o r i c a c i d . The aqueous s o l u t i o n was e x t r a c t e d t h o r o u g h l y w i t h e t h e r . The combined e t h e r e x t r a c t s were washed w i t h w a t e r , b r i n e and t h e n d r i e d w i t h a n h ydrous magnesium s u l f a t e . Removal o f s o l v e n t and d i s t i l l a t i o n o f t h e r e s u l t i n g y e l l o w o i l ( a i r b a t h t e m p e r a t u r e 110-120° a t 0.4 mm) gave 134 mg (88%) o f a c o l o r l e s s o i l . A n a l y s i s o f t h i s d i s t i l l a t e by g . l . c . (column E, 165°, 70 ml/min) showed t h a t i t c o n s i s t e d o f a m i x t u r e o f t h e s t a r t i n g k e t o e s t e r 285 and a new compound i n a r a t i o o f a p p r o x i m a t e l y 55:45, r e s p e c t i v e l y . These components were s e p a r a t e d by p r e p a r a t i v e t . l . c . ( u s i n g h e x a n e - e t h e r 7:3 as e l u t i n g s o l v e n t ) . The new e p i m e r i c k e t o e s t e r 285, a f t e r d i s t i l l a t i o n , e x h i b i t e d t h e f o l l o w i n g s p e c t r a l p r o p e r t i e s ; i . r . ( f i l m ) , v 1730, 1710 cm "*"; p.m.r., 1.20 ( d , 3H, s e c o n d a r y m e t h y l , J=6.5 H z ) , 3.62 ( s , 3H, COOMe). M o l . Wt. C a l c d . f o r c12B-20°3: 224.1395. Found ( h i g h r e s o l u t i o n mass s p e c t r o m e t r y ) : 224.1412. P r e p a r a t i o n o f t h e D i t h i o k e t a l E s t e r 288 To 457 mg (2.04 mmoles) o f t h e k e t o e s t e r 284 was added 2 m l o f e t h a n e d i t h i o l . The s o l u t i o n was c o o l e d w i t h an i c e b a t h and 1 m l o f b o r o n t r i f l u o r i d e e t h e r a t e was added. The r e a c t i o n m i x t u r e was l e f t a t 0° f o r 1% h o u r s ( w i t h o c c a s i o n a l s t i r r i n g ) , d i l u t e d w i t h 5% aqueous p o t a s s i u m h y d r o x i d e and t h o r o u g h l y e x t r a c t e d w i t h e t h e r . The combined e t h e r e a l e x t r a c t s were washed t w i c e w i t h 5% aqueous p o t a s s i u m h y d r o x i d e and t h e n w i t h w a t e r u n t i l t h e aqueous l a y e r was no l o n g e r a l k a l i n e . A f t e r t h e o r g a n i c l a y e r had been d r i e d o v e r a n hydrous magnesium s u l f a t e , t h e s o l v e n t was removed t o g i v e a v i s c o u s y e l l o w o i l as t h e c r u d e p r o d u c t . D i s t i l l a t i o n o f t h i s m a t e r i a l a t 132-150° ( a i r b a t h t e m p e r a t u r e ) and -168-0.15 mm gave 573 mg (94%) o f t h e d i t h i o k e t a l e s t e r 288 as a c o l o r l e s s v i s c o u s o i l ; i . r . ( f i l m ) , v 1720 cm \ p.m.r., 0.83 ( u n r e s o l v e d d, max 3H, s e c o n d a r y m e t h y l , J=5.0 H z ) , 3.30 (m, 4H, d i t h i o k e t a l p r o t o n s ) , 3.72 ( s , 3H, COOMe). M o l . Wt. C a l c d f o r C 1 5 H 2 4 0 2 S 2 : 3 0 0 - 1 2 3 6 - Found ( h i g h r e s o l u t i o n mass s p e c t r o m e t r y ) : 300.1217. P r e p a r a t i o n o f t h e D i t h i o k e t a l A l c o h o l 233. To a s u s p e n s i o n o f 670 mg (17.63 mmoles) o f l i t h i u m aluminum h y d r i d e i n 20 m l o f d r y t e t r a h y d r o f u r a n was added a s o l u t i o n o f 573 mg (1.91 mmoles) o f t h e d i t h i o k e t a l e s t e r 288 i n 10 m l o f d r y t e t r a h y d r o f u r a n . The m i x t u r e was r e f l u x e d g e n t l y f o r 3 h o u r s under an atmosphere o f n i t r o g e n . A f t e r t h e r e a c t i o n m i x t u r e had been c o o l e d t o room t e m p e r a t u r e , powdered sodium s u l f a t e d e c a h y d r a t e was added c a u t i o u s l y t o d e s t r o y t h e e x c e s s l i t h i u m aluminum h y d r i d e . The m i x t u r e was f i l t e r e d t h r o u g h C e l i t e and t h e s o l i d r e s i d u e was washed w i t h e t h e r . The combined o r g a n i c f i l t r a t e s w ere e v a p o r a t e d t o g i v e a y e l l o w v i s c o u s o i l w h i c h was d i l u t e d w i t h e t h e r and d r i e d w i t h magnesium s u l f a t e . Removal o f t h e s o l v e n t and d i s t i l l a t i o n [170-180° ( a i r b a t h t e m p e r a t u r e ) a t 0.35 mm] o f t h e r e s i d u e gave 430 mg (83%) o f t h e d i t h i o k e t a l a l c o h o l 289 as a c o l o r l e s s v i s c o u s o i l ; i . r . ( f i l m ) , v 3450 ( b r o a d ) , 1031 cm" 1; p.m.r., 0.83 ( u n r e s o l v e d d, 3H, max s e c o n d a r y m e t h y l ) , 2.62 ( s , I H , -OH), 3.25 (m, 4H, d i t h i o k e t a l p r o t o n s ) , 3.58 and 3.69 (AB p a i r o f d o u b l e t s , 2H, CH_20H, J=11.0 H z ) . M o l . Wt. C a l c d . f o r C-,H„,0S o: 272.1284. Found ( h i g h r e s o l u t i o n 14 24 I mass s p e c t r o m e t r y ) : 272.1268. -169-P r e p a r a t i o n o f t h e D i t h i o k e t a l A l d e h y d e 790 To a s o l u t i o n o f 1.50 g (18.99 mmoles) o f p y r i d i n e i n 20 m l o f d r y m e t h y l e n e c h l o r i d e was added 957 mg (9.57 mmoles) o f d r y chromium t r i -o x i d e . A f t e r t h e r e s u l t i n g m i x t u r e had been s t i r r e d f o r 15 m i n u t e s a t room t e m p e r a t u r e , a s o l u t i o n o f 430 mg (1.58 mmoles) o f t h e d i t h i o k e t a l a l c o h o l 289 i n 4 m l o f d r y m e t h y l e n e c h l o r i d e was added w i t h v i g o r o u s s t i r r i n g . The m i x t u r e was s t i r r e d f o r a n o t h e r 30 m i n u t e s and t h e n t h e s o l u t i o n was d e c a n t e d i n t o a s e p a r a t o r y f u n n e l . The r e s i d u e i n t h e r e a c t i o n f l a s k was washed w i t h e t h e r . The combined r e a c t i o n m i x t u r e and e t h e r w a s h i n g s were washed s u c c e s s i v e l y w i t h 5% aqueous p o t a s s i u m h y d r o x i d e , w a t e r , d i l u t e h y d r o c h l o r i c a c i d , s a t u r a t e d aqueous sodium b i c a r b o n a t e and b r i n e . A f t e r t h e o r g a n i c l a y e r had been d r i e d o v e r a n h y d r o u s magnesium s u l f a t e , t h e s o l v e n t was e v a p o r a t e d t o a f f o r d 354 mg o f a y e l l o w o i l . D i s t i l l a t i o n o f t h i s m a t e r i a l a t 155-170° ( a i r b a t h t e m p e r a t u r e ) and 0.4 mm gave 326 mg (76%) o f t h e d i t h i o k e t a l a l d e h y d e 290 as a c o l o r l e s s o i l ; i . r . ( f i l m ) , v m a x » 2717, 1720 cm "*"; p.m.r., 0.78 ( u n r e s o l v e d d, 3H, s e c o n d a r y m e t h y l , J=5.0 H z ) , 3.28 (m, 4H, d i t h i o k e t a l p r o t o n s ) , 9.35 ( s , I H , CHO). M o l . W t . C a l c d f o r c 1 4 H 2 2 O S 2 : 2 7 0 - 1 1 1 2 « Found ( h i g h r e s o l u t i o n mass s p e c t r o m e t r y ) : 270.1112. W o l f f - K i s h n e r R e d u c t i o n o f t h e D i t h i o k e t a l A l d e h y d e 2311 To 20 m l o f d i e t h y l e n e g l y c o l was added 500 mg o f sodium. The m i x t u r e was c a r e f u l l y warmed by a steam b a t h u n t i l a l l o f t h e sodium had r e a c t e d . To 274 mg (1.01 mmole) o f t h e d i t h i o k e t a l a l d e h y d e 290 was added 20 m l o f sodium d i e t h y l e n e g l y c o l a t e s o l u t i o n ( p r e p a r e d as d e s c r i b e d a b o v e ) . A f t e r -170-3 m l o f h y d r a z i n e h y d r a t e had been added, t h e m i x t u r e was h e a t e d s l o w l y and t h e l o w - b o i l i n g m a t e r i a l was a l l o w e d t o d i s t i l l u n t i l t h e i n t e r n a l t e m p e r a t u r e o f t h e r e a c t i o n s o l u t i o n r e a c h e d 180°. The m i x t u r e was t h e n r e f l u x e d f o r 18 h o u r s . S u b s e q u e n t l y , t h e d i s t i l l a t i o n was c o n -t i n u e d u n t i l t h e i n t e r n a l t e m p e r a t u r e r e a c h e d 210° and t h e n r e f l u x i n g was c o n t i n u e d f o r a n o t h e r 24 h o u r s . A l l o f t h e d i s t i l l e d m a t e r i a l was com-b i n e d w i t h t h e c o o l e d r e a c t i o n m i x t u r e . The combined m a t e r i a l was d i l u t e d w i t h w a t e r and t h e r e s u l t i n g m i x t u r e was e x t r a c t e d t h o r o u g h l y w i t h e t h e r . The combined e t h e r e x t r a c t s were washed w i t h w a t e r and b r i n e and t h e n d r i e d o v e r a n h y d r o u s magnesium s u l f a t e . E v a p o r a t i o n o f t h e s o l v e n t a f f o r d e d 173 mg o f a y e l l o w o i l as t h e c r u d e p r o d u c t . D i s t i l l a t i o n o f t h i s m a t e r i a l a t 120-125° ( a i r b a t h t e m p e r a t u r e ) and w a t e r - a s p i r a t o r p r e s s u r e f u r n i s h e d 118 mg (70%) o f a c o l o r l e s s o i l ; i . r . ( f i l m ) , no c a r b o n y l a b s o r p t i o n . G . l . c . a n a l y s i s (column A, 130°, 100 ml/min) o f t h i s o i l showed o n l y one m a j o r peak w i t h a r e t e n t i o n t i m e i d e n t i c a l w i t h t h o s e o f t h e a u t h e n t i c h y d r o c a r b o n s 286 and 287. However, t h e p.m.r. s p e c t r u m o f t h e p r o d u c t i n d i c a t e d t h a t i t was a m i x t u r e o f t h e e p i m e r i c h y d r o c a r b o n s 286 and 287, i n t h e r a t i o o f a p p r o x i m a t e l y 1:1 e s t i m a t e d f r o m t h e i n t e -g r a t i o n o f t h e s i g n a l s due t o t h e m e t h y l g r o u p s ; p.m.r., 0.93 ( s , 3H, t e r t i a r y m e t h y l o f h y d r o c a r b o n 2 8 6 ) , 0.98 ( d , 3H, s e c o n d a r y m e t h y l o f h y d r o c a r b o n 286, J=4.0 H z ) , 0.83 ( u n r e s o l v e d s i g n a l , 3H, s e c o n d a r y m e t h y l o f h y d r o c a r b o n 2 8 7 ) , 1.03 ( s , 3H, t e r t i a r y m e t h y l o f h y d r o c a r b o n 2 8 7 ) . T h i s s p e c t r u m was i d e n t i c a l w i t h t h e c o m b i n a t i o n o f t h e p.m.r. s p e c t r a 98 o f a u t h e n t i c samples o f 286 and 287. -171-P r e p a r a t i o n o f c _ i s _ - 3 , 4 - D i m e t h y l - 3 - V i n y l c y c l o h e x a n o n e 1A2. To a m i x t u r e o f 9.63 g (0.396 mole) o f magnesium, 100 m l o f d r y t e t r a h y d r o f u r a n and a few c r y s t a l s o f i o d i n e i n a 3-necked f l a s k f i t t e d w i t h a d r o p p i n g f u n n e l , a d r y - i c e c o n d e n s e r and a n i t r o g e n i n l e t , was added a s m a l l amount o f v i n y l b r o m i d e . When t h e f o r m a t i o n o f t h e v i n y l magnesium b r o m i d e had s t a r t e d , a s o l u t i o n o f 58.7 g (0.268 mole) o f v i n y l b r o m i d e i n 100 m l o f d r y t e t r a h y d r o f u r a n was added d r o p w i s e t o m a i n t a i n a g e n t l e r e f l u x . A f t e r t h e a d d i t i o n was c o m p l e t e , t h e m i x t u r e was h e a t e d t o r e f l u x f o r 30 m i n u t e s and t h e t e t r a h y d r o f u r a n s o l u t i o n was t h e n d e c a n t e d i n t o a f l a m e d r i e d d r o p p i n g f u n n e l . To a m i x t u r e o f 12.53 g (0.101 mole) o f 3 , 4 - d i m e t h y l - 2 - c y c l o h e x e n -73 1-one, p r e p a r e d a c c o r d i n g t o t h e p r o c e d u r e o f B i r c h and c o - w o r k e r s and 3.79 g (19.95 mmoles) o f c u p r o u s i o d i d e i n 300 m l o f d r y t e t r a h y d r o f u r a n a t i c e - b a t h t e m p e r a t u r e and u n d e r a n i t r o g e n a t m o s p h e r e , was added 20 m l o f d i m e t h y l s u l f i d e t o f o r m a b l a c k homogeneous s o l u t i o n . The f r e s h l y p r e p a r e d s o l u t i o n o f v i n y l magnesium b r o m i d e was added s l o w l y ( o v e r a p e r i o d o f 1 h o u r ) t o t h e r e a c t i o n f l a s k w i t h v i g o r o u s s t i r r i n g . A f t e r t h e a d d i t i o n was c o m p l e t e , t h e s o l u t i o n was s t i r r e d f o r a n o t h e r 2 h o u r s a t 0°. The m i x t u r e was p o u r e d i n t o 500 m l o f s a t u r a t e d aqueous ammonium c h l o r i d e and t h e r e s u l t a n t m i x t u r e was e x t r a c t e d w i t h e t h e r . The combined e t h e r '. e x t r a c t s were washed s u c c e s s i v e l y w i t h d i l u t e ammonium h y d r o x i d e , w a t e r and b r i n e , and t h e n d r i e d o v e r a n h y d r o u s magnesium s u l f a t e . Evapo-r a t i o n o f t h e s o l v e n t gave 22.6 g o f a y e l l o w o i l . F r a c t i o n a l d i s t i l l a t i o n o f t h i s m a t e r i a l gave 9.99 g (65%) o f c i s - 3 , 4 - d i m e t h y l - 3 - v i n y l c y c l o h e x a n o n e 142 as a v e r y p a l e y e l l o w o i l ; b.p. 115-120° a t 36-38 mm ( l i t . b.p., 51-54° a t 0.3 mm 5 0); i . r . ( f i l m ) , vmav 3030, 1710, 1630, 920 c m - 1 ; p.m.r., 0.90 -172-( s , 3H, t e r t i a r y m e t h y l ) , 0.91 ( d , 3H, s e c o n d a r y m e t h y l , J-6.0 H z ) , 4.95 (d o f d, I H , ^ =SH , J-18.0 and 1.5 H z ) , 4.99 (d o f d, I H , N = N U H J =9.0 and 1.5 H z ) , 5.78 (d o f d, I H , u > = , J=18.0 and 9.0 H z ) . H P r e p a r a t i o n o f t h e E t h y l e n e K e t a l o f c J 1 s _ - 3 , 4 - D i m e t h y l - 3 - v i n y l c y c l o h e x a n o n e 142 A s o l u t i o n o f 19.51 g (128.3 mmole) o f c i s - 3 , 4 - d i m e t h y l - 3 - v i n y l c y c l o -hexanone 142, 16.70 g (269.4 mmole) o f e t h y l e n e g l y c o l , and 405 mg (2.35 mmole) o f p - t o l u e n e s u l f o n i c a c i d i n 70 m l o f d r y benzene was r e f l u x e d f o r 18 h o u r s u n d e r a n i t r o g e n a t m o s p h e r e u s i n g a D e a n - S t a r k t r a p t o remove t h e w a t e r . The r e a c t i o n m i x t u r e was c o o l e d t o room t e m p e r a t u r e , d i l u t e d w i t h benzene and s u c c e s s i v e l y washed w i t h s a t u r a t e d aqueous sodium b i c a r -b o n a t e , w a t e r and b r i n e , and t h e n d r i e d o v e r a nhydrous magnesium s u l f a t e . Removal o f t h e s o l v e n t gave a y e l l o w o i l . D i s t i l l a t i o n o f t h i s m a t e r i a l a t 112-114° (14 mm) gave 21.10 g (84%) o f t h e o l e f i n i c k e t a l 302 as a v e r y p a l e y e l l o w o i l ( l i t . b.p., 71-73° a t 0.3 mm 5 0); i . r . ( f i l m ) , ^ m a x 3110, 1635, 905 c m - 1 ; p.m.r., 0.79 ( d , 3H, s e c o n d a r y . m e t h y l , J=6.0 H z ) , 1.00 ( s , 3H, t e r t i a r y m e t h y l ) , 3.90 (m, 4H, e t h y l e n e k e t a l ) , 4.92 (d o f d, I H , \===/H , J=18.0 and 1.5 H z ) , 4.95 (d o f d, I H , N = = = : \ H , J=10.0 and 1.5 H z ) , 5.72 (d o f d, 1 H , U > = J=18.0 and 10.0 H z ) . H P r e p a r a t i o n o f t h e K e t a l A l c o h o l 303 To a s o l u t i o n o f 61.5 g (0.879 mole) o f 2 - m e t h y l - 2 - b u t e n e i n 450 m l of d r y t e t r a h y d r o f u r a n a t 0° u n d e r n i t r o g e n was added 34 m l (0.354 mole) o f d i m e t h y l s u l f i d e - b o r a n e complex. A f t e r t h e r e s u l t i n g s o l u t i o n had been s t i r r e d f o r 30 m i n u t e s a t 0°, a s o l u t i o n o f 25.40 g (0.130 mole) o f t h e k e t a l o l e f i n 302 i n 200 m l o f d r y t e t r a h y d r o f u r a n was added d r o p w i s e . The i c e b a t h was removed a f t e r a l l t h e k e t a l o l e f i n 302 had been added and t h e -173-m i x t u r e was s t i r r e d a t room t e m p e r a t u r e f o r a n o t h e r 3 h o u r s . The s o l u t i o n was c o o l e d t o 0° and c a u t i o u s l y t r e a t e d w i t h 517 m l o f 3N sodium h y d r o x i d e f o l l o w e d by 517 m l o f 30% h y d r o g e n p e r o x i d e s o l u t i o n . The m i x t u r e was a l l o w e d t o warm t o room t e m p e r a t u r e , s t i r r e d f o r a n o t h e r 3 h o u r s , and t h e n p o u r e d i n t o a m i x t u r e o f i c e and w a t e r . The r e s u l t i n g m i x t u r e was t h o r o u g h l y e x t r a c t e d w i t h e t h e r . The combined e t h e r e x t r a c t s were washed w i t h s a t u r a t e d aqueous sodium b i c a r b o n a t e , w a t e r and b r i n e . The o r g a n i c l a y e r was d r i e d o v e r anhydrous magnesium s u l f a t e . E v a p o r a t i o n o f t h e s o l v e n t , f o l l o w e d by d i s t i l l a t i o n ( a i r b a t h t e m p e r a t u r e 115-120° a t 0.2 mm) o f t h e r e s i d u a l m a t e r i a l gave 21.87 g (79%) o f t h e k e t a l a l c o h o l 303 as a v i s c o u s c o l o r l e s s o i l ( l i t . b.p., 98-102° a t 0.05 mm^); i . r . ( f i l m ) , v 3450 cm p.m.r., 0.85 ( d , 3H, s e c o n d a r y H13X m e t h y l , J=6.0 H z ) , 0.90 ( s , 3H, t e r t i a r y m e t h y l ) , 2.05 ( b r o a d s, I H , OH), 3.69 ( t , 2H, CH 20H, J=7.0 H z ) , 3.90 (m, 4H, k e t a l p r o t o n s ) . P r e p a r a t i o n o f t h e K e t a l A l d e h y d e 2DA To a s o l u t i o n o f 38 g (0.481 mole) o f d r y p y r i d i n e i n 600 m l o f d r y m e t h y l e n e c h l o r i d e was added c a u t i o u s l y 24 g (0.24 mole) o f a n h y d r o u s chromium t r i o x i d e . The m i x t u r e was s t i r r e d f o r 30 m i n u t e s , and t h e n a s o l u t i o n o f t h e k e t a l a l c o h o l 303 (8.57 g, 0.04 mole) i n 30 m l o f d r y m e t h y l e n e c h l o r i d e was added i n one p o r t i o n . A f t e r t h e r e a c t i o n m i x t u r e had been s t i r r e d f o r a n o t h e r 30 m i n u t e s , t h e m e t h y l e n e c h l o r i d e s o l u t i o n was d e c a n t e d and t h e r e s i d u e was t r i t u r a t e d w i t h e t h e r . A f t e r t h e combined o r g a n i c s o l u t i o n had been washed s u c c e s s i v e l y w i t h 5% aqueous p o t a s s i u m h y d r o x i d e , s a t u r a t e d aqueous sodium b i c a r b o n a t e , w a t e r , and b r i n e , i t was d r i e d o v e r anhydrous magnesium s u l f a t e . Removal o f t h e s o l v e n t , f o l l o w e d by d i s -t i l l a t i o n ( a i r b a t h t e m p e r a t u r e 95-106°, 0.25 mm) o f t h e r e s i d u e gave -174-7.17 g (85%) o f t h e k e t a l a l d e h y d e 304 as a c o l o r l e s s o i l ( l i t . b.p., 83-85° a t 0.05 mm 5 0); i . r . ( f i l m ) , v 2755, 1715 cm" 1; p.m.r., 0.85 max ( d , 3H, s e c o n d a r y m e t h y l , J=6.0 H z ) , 1.06 ( s , 3H, t e r t i a r y m e t h y l ) , 2.35 ( d , 2H, CH_2CH0, J=3.0 H z ) , 3.90 (m, 4H, e t h y l e n e k e t a l ) , 9.87 ( t , I H , CHO, J=3.0 H z ) . P r e p a r a t i o n o f t h e K e t a l D i b r o m i d e 305 To a s u s p e n s i o n o f 5.35 g (0.0821 g/atom) o f z i n c d u s t and 21.0 g (80.15 mmoles) o f t r i p h e n y l p h o s p h i n e i n 280 m l o f d r y m e t h y l e n e c h l o r i d e was added 26.57 g (80.03 mmoles) o f c a r b o n t e t r a b r o m i d e . The m i x t u r e was s t i r r e d a t room t e m p e r a t u r e u n d e r n i t r o g e n f o r 27 h o u r s . 1 1 0 To t h i s p a l e brown m x i t u r e was added a s o l u t i o n o f 8.51 g (40.14 mmoles) o f t h e k e t a l a l d e h y d e 304 d i s s o l v e d i n a minimum amount o f d r y m e t h y l e n e c h l o r i d e . A f t e r t h e r e a c t i o n m i x t u r e had been s t i r r e d a t room t e m p e r a t u r e f o r a n o t h e r l % - 2 h o u r s , a p p r o x i m a t e l y 200 m l o f p e t r o l e u m e t h e r (30-60°) was added and t h e r e s u l t i n g m i x t u r e was f i l t e r e d . The s o l i d r e s i d u e was r e d i s s o l v e d i n 60 m l o f m e t h y l e n e c h l o r i d e , t h e r e s u l t i n g s o l u t i o n was d i l u t e d a g a i n w i t h 200 m l o f p e t r o l e u m e t h e r , and t h e n f i l t e r e d . T h i s p r o c e s s was r e p e a t e d t w i c e and a l l o f t h e f i l t r a t e s w e re combined. Removal o f t h e s o l v e n t gave a m i x t u r e o f a l i g h t y e l l o w o i l and a w h i t e s o l i d . The c r u d e p r o d u c t was d i l u t e d w i t h a s m a l l amount o f e t h e r and f i l t e r e d . The s o l i d r e s i d u e was washed w i t h e t h e r . The r e m o v a l o f t h e s o l v e n t f r o m t h e f i l t r a t e , f o l l o w e d by f l a s h d i s t i l l a t i o n o f t h e r e s i d u e a t 114-124° ( a i r b a t h t e m p e r a t u r e ) and 0.25-0.3 mm gave 11.33 g (77%) o f t h e k e t a l d i b r o m i d e 305 as a v e r y p a l e y e l l o w o i l ; i . r . ( f i l m ) , v 1615 cm "S p.m.r., 0.86 ( d , 3H, s e c o n d a r y m e t h y l , J=6.0 H z ) , 0.92 ( s , 3H, t e r t i a r y m e t h y l ) , 1.91 and 2.26 ( 8 - l i n e m u l t i p l e t , -175-t h e AB p r o t o n s o f t h e ABX s y s t e m , 2H, a l l y l i c m e t h y l e n e , J =J =7.0 Hz, J =15.0 H z ) , 3.91 (m, 4H, e t h y l e n e k e t a l p r o t o n s ) , 6.43 ( t , t h e X -AD p r o t o n o f t h e ABX s y s t e m , I H , v i n y l p r o t o n , J ^ X = J B X = ^ * ° H Z ) • M o l . Wt. C a l c d . f o r C ^ H ^ B r ^ : 367.9840. Found ( h i g h r e s o l u t i o n mass s p e c t r o m e t r y ) : 367:9810. P r e p a r a t i o n o f t h e K e t a l P r o p a r g y l A l c o h o l .306 To a c o l d (-78°) s t i r r e d s o l u t i o n o f 7.86 g (21.36 mmoles) o f t h e k e t a l d i b r o m i d e 305 i n 100 m l o f d r y t e t r a h y d r o f u r a n u n d e r an a tmosphere o f n i t r o g e n was added 21 m l (49.77 mmoles) o f a s o l u t i o n o f n - b u t y l l i t h i u m i n hexane (2.37M). The m i x t u r e was s t i r r e d a t -78° f o r 1% h o u r s and t h e n was a l l o w e d t o warm t o i c e b a t h t e m p e r a t u r e . Gaseous f o r m a l d e h y d e , o b t a i n e d by p y r o l y z i n g 8g o f p a r a f o r m a l d e h y d e a t 160-190° ( o i l b a t h t e m p e r a t u r e ) , was swept i n t o t h e r e a c t i o n f l a s k w i t h a s t r e a m o f n i t r o g e n . The r e s u l t i n g m i x t u r e was s t i r r e d v i g o r o u s l y f o r a n o t h e r 30 m i n u t e s and t h e n a bout 30 m l o f s a t u r a t e d aqueous ammonium c h l o r i d e was added. The r e s u l t i n g m i x t u r e was d i l u t e d f u r t h e r w i t h w a t e r and t h e aqueous l a y e r was e x t r a c t e d w i t h e t h e r . The s o l i d p a r a f o r m a l d e h y d e l e f t i n t h e r e a c t i o n f l a s k was washed t w i c e w i t h e t h e r . The combined e t h e r e x t r a c t s were washed w i t h w a t e r and b r i n e , and d r i e d o v e r a n h y d r o u s magnesium s u l -f a t e . E v a p o r a t i o n o f t h e s o l v e n t gave 5.106 g o f a v e r y p a l e y e l l o w v i s c o u s o i l . D i s t i l l a t i o n o f t h i s m a t e r i a l a t 135-145° ( a i r b a t h t e m p e r a t u r e ) and 0.4 mm a f f o r d e d 5.003 g (98%) o f t h e p r o p a r g y l a l c o h o l 306 as a c o l o r l e s s v i s c o u s o i l ; i . r . ( f i l m ) , v 3475 ( b r o a d , 2325, 2255 max cm "*"; p.m.r., 0.82 ( d , 3H, s e c o n d a r y m e t h y l , J=6.0 H z ) , 0.90 ( s , 3H, t e r -t i a r y m e t h y l ) , 2.14 ( u n r e s o l v e d t , 2H, CH_2C=C) , 3.09 ( b r o a d s, I H , -176-d i s a p p e a r e d upon a d d i t i o n o f D^O, OH), 3.87 (m, 4H, e t h y l e n e k e t a l p r o t o n s ) , 4.19 ( t , 2H, C=CCH_2OH, J=2.0 H z ) . M o l . Wt. C a l c d . f o r C 1 4 H 2 2 ° 3 : 238.1546. Found ( h i g h r e s o l u t i o n mass s p e c t r o m e t r y ) : 238.1569. H y d r o l y s i s o f t h e K e t a l P r o p a r g y l A l c o h o l 3_Q6_ A s o l u t i o n o f 5.37 g (22.14 mmoles) o f t h e k e t a l p r o p a r g y l a l c o h o l 306, 22 m l o f 3N h y d r o c h l o r i c a c i d and 22 m l o f w a t e r i n 300 m l o f m e t h a n o l was s t i r r e d a t room t e m p e r a t u r e f o r 3 h o u r s . Most o f t h e m e t h a n o l was removed under r e d u c e d p r e s s u r e . The r e s i d u e was d i l u t e d w i t h w a t e r and t h o r o u g h l y e x t r a c t e d w i t h e t h e r . The combined e t h e r e x t r a c t s were washed w i t h s a t u r a t e d aqueous sodium b i c a r b o n a t e , w a t e r and b r i n e , and t h e n d r i e d o v e r a n h y d r o u s magnesium s u l f a t e . Removal o f t h e s o l v e n t , f o l l o w e d by d i s t i l l a t i o n o f t h e r e s i d u e a t 130-140° ( a i r b a t h t e m p e r a t u r e ) and 0.5 mm a f f o r d e d 3.95 g (92%) o f a c o l o r l e s s v i s c o u s o i l w h i c h c r y s t a l l i z e d upon r e f r i g e r a t i o n . R e c r y s t a l l i z a t i o n f r o m e t h e r -p e t r o l e u m e t h e r gave t h e k e t o a l c o h o l 307 as w h i t e c r y s t a l s ; m.p., 43-45°: i . r . ( f i l m ) , v 3500 ( b r o a d , 2320, 2260, 1700 cm" 1; p.m.r., 0.80 ( s , 3H, t e r t i a r y m e t h y l ) , 0.93 ( d , 3H, s e c o n d a r y m e t h y l , J=6.0 H z ) , 3.03 ( b r o a d s, I H , d i s a p p e a r e d upon t h e a d d i t i o n o f D 20, OH), 4.29 ( b r o a d s, 2H, changed i n t o t upon t h e a d d i t i o n o f D 20, CH_20H, J=2.0 H z ) . A n a l . C a l c d . f o r C 1 2 H 1 8 0 2 : C ' 7 4 ' 1 9 ; H » 9 - 3 4 - Found: C,74.28; H, 9.30. H y d r o g e n a t i o n o f t h e K e t o P r o p a r g y l i c A l c o h o l 301. To a S o l u t i o n o f 2.73 g (14.07 mmoles) o f t h e k e t o p r o p a r g y l i c a l c o h o l 307 i n 50 m l o f e t h a n o l was added 548 mg o f 5% p a l l a d i u m - o n - b a r i u m s u l f a t e and f o u r d r o p s o f p u r i f i e d q u i n o l i n e . The m i x t u r e was h y d r o g e n a t e d -177-a t room t e m p e r a t u r e and a t m o s p h e r i c p r e s s u r e u n t i l a p p r o x i m a t e l y one e q u i v a l e n t o f h y d r o g e n had been a b s o r b e d . The i n s o l u b l e m a t e r i a l was f i l t e r e d t h r o u g h a bed of c e l i t e and t h e r e s i d u e was washed w i t h e t h a n o l . The combined e t h a n o l i c s o l u t i o n was e v a p o r a t e d u n d e r r e d u c e d p r e s s u r e t o g i v e a y e l l o w o i l w h i c h upon d i s t i l l a t i o n a t 132-140° ( a i r b a t h tem-p e r a t u r e ) and 0.4 mm gave 2.621 g (95%) o f t h e k e t o a l c o h o l 291 as a c o l o r l e s s v i s c o u s o i l : i . r . ( f i l m ) , v 3450 ( b r o a d ) , 3050, 1710 cm ^; max p.m.r., 0.80 ( s , 3H, t e r t i a r y m e t h y l ) , 0.93 ( d , 3H, s e c o n d a r y m e t h y l , J=6.0 H z ) , 3.58 ( b r o a d s, I H , OH), 4.12 ( d , 2H, CH_20H, J=5.5 H z ) , 5.62 (m, 2H, v i n y l p r o t o n s ) . M o l . Wt. C a l c d . f o r C 1 2 H 2 0 O 2 : 196.1457. Found: ( h i g h r e s o l u t i o n mass s p e c t r o m e t r y ) : 196.1463. P r e p a r a t i o n o f t h e K e t o M e s y l a t e _3_Q_9-To a c o l d (0°) s o l u t i o n o f 2.712 g (13.83 mmoles) o f t h e k e t o a l l y l i c a l c o h o l 291 and 2.103 g (20.82 mmoles) o f d r y t r i e t h y l a m i n e i n 50 m l o f d r y m e t h y l e n e c h l o r i d e was added s l o w l y 1.748 g (15.27 mmole) of m e t h a n e s u l f o n y l c h l o r i d e . The r e a c t i o n m i x t u r e was s t i r r e d a t 0° f o r 30 m i n u t e s under a n i t r o g e n atmosphere. The c l o u d y s u s p e n s i o n was p o u r e d i n t o i c e w a t e r and t h e o r g a n i c phase was s e p a r a t e d . The o r g a n i c l a y e r was washed t h r e e t i m e s w i t h i c e c o l d w a t e r and once w i t h b r i n e . A f t e r t h e s o l u t i o n had been d r i e d o v e r a n h y d r o u s magnesium s u l f a t e , t h e s o l v e n t was e v a p o r a t e d t o g i v e 3.64 g (96%) o f t h e c r u d e k e t o m e s y l a t e 309 as an o r a n g e y e l l o w o i l : i . r . ( f i l m ) , v m a x 3060, 1710, 1350, 1170 cm ^; p.m.r., 0.90 ( s , 3H, t e r t i a r y m e t h y l ) , 1.03 ( d , 3H, s e c o n d a r y m e t h y l , J=6.0 H z ) , 3.08 ( s , 3H, C H 3 S 0 3 ) , 4.78 ( d , 2H, CH_20Ms, J=6.0 H z ) , 5.80 (m, 2H, v i n y l p r o t o n s ) . -178-Due t o t h e f a c t t h a t t h e k e t o m e s y l a t e 309 was q u i t e u n s t a b l e , t h i s compound was n o t p u r i f i e d f u r t h e r , b u t was u s e d d i r e c t l y f o r t h e n e x t s y n t h e t i c t r a n s f o r m a t i o n . P r e p a r a t i o n o f t h e B i c y c l i c K e t o O l e f i n ,226 To 100 m l o f d r y t e r t - b u t y l a l c o h o l i n a t h r e e - n e c k e d f l a s k f i t t e d w i t h a c o n d e n s e r , a d r o p p i n g f u n n e l and a n i t r o g e n i n l e t t u b e was added 1.1 g o f m e t a l l i c p o t a s s i u m . The m i x t u r e was b r o u g h t t o r e f l u x u n t i l a l l o f t h e m e t a l l i c p o t a s s i u m had r e a c t e d w i t h t h e a l c o h o l , and was t h e n c o o l e d t o room t e m p e r a t u r e . A s o l u t i o n o f 3.644 g o f t h e c r u d e k e t o m e s y l a t e 309 i n 30 m l o f d r y t e r t - b u t y l a l c o h o l was added d r o p w i s e . When t h e a d d i t i o n was c o m p l e t e , t h e m i x t u r e was d i l u t e d w i t h a n o t h e r 75 m l o f d r y t e r t - b u t y l a l c o h o l t o f a c i l i t a t e t h e s t i r r i n g , and t h e o r a n g e r e d s u s p e n s i o n was s t i r r e d f o r 2% h o u r s a t room t e m p e r a t u r e . The r e a c t i o n m i x t u r e was t r e a t e d w i t h aqueous ammonium c h l o r i d e and t h e r e s u l t a n t m i x t u r e was t h o r o u g h l y e x t r a c t e d w i t h e t h e r . The combined e t h e r e x t r a c t s were washed w i t h w a t e r and d r i e d o v e r a n h y d r o u s magnesium s u l f a t e . Removal o f t h e s o l v e n t gave a r e d d i s h brown c r u d e p r o d u c t . D i s t i l l a t i o n o f t h i s m a t e r i a l a t 62-75° ( a i r b a t h t e m p e r a t u r e ) and 0.15 mm gave 1.558 g ( 6 3 % b a s e d on t h e k e t o a l l y l i c a l c o h o l 291) o f t h e b i c y c l i c k e t o o l e f i n 226 as a c o l o r l e s s o i l : i . r . ( f i l m ) , v 3050, 1705, 1660 cm \ p.m.r., max 0.66 ( s , 3H, t e r t i a r y m e t h y l ) , 0.95 ( d , 3H, s e c o n d a r y m e t h y l , J=6.0 H z ) , 5.58 ( b r o a d , . s , 2H, v i n y l p r o t o n s ) . A n a l . C a l c d . f o r C ^ H ^ O : C, 80.85; H, 10.18. Found: C, 80.51; H, 10.01. -179-H y d r o g e n a t i o n o f t h e B i c y c l i c K e t o O l e f i n 22£L A m i x t u r e o f 223 mg (1.253 mmole) o f t h e b i c y c l i c k e t o o l e f i n 226 and 52.6 mg o f 5% p a l l a d i u m - o n - c a r b o n i n 10 m l o f m e t h a n o l was h y d r o g e n a t e d a t room t e m p e r a t u r e and a t m o s p h e r i c p r e s s u r e u n t i l no more h y d r o g e n was a b s o r b e d . The m i x t u r e was f i l t e r e d t h r o u g h a c e l i t e bed and t h e r e s i d u e was washed w i t h m e t h a n o l . E v a p o r a t i o n o f t h e s o l v e n t f o l l o w e d by d i s t i l l a t i o n o f t h e r e s i d u e a t 160-172° ( a i r b a t h t e m p e r a t u r e ) and w a t e r a s p i r a t o r p r e s s u r e ( a p p r o x i m a t e l y 16-20 mm) gave 186 mg (83%) o f t h e d e c a l o n e 320 as a c o l o r l e s s o i l : i . r . ( f i l m ) , v 1710 cm ^; max p.m.r., 0.66 ( s , 3H, t e r t i a r y m e t h y l ) , 0.88 ( d , 3H, s e c o n d a r y m e t h y l , J=6.0 H z ) . M o l . Wt. C a l c d . f o r C ^ H ^ O : 180.1507. Found ( h i g h r e s o l u t i o n mass s p e c t r o m e t r y ) : 180.1514. A t t e m p t e d E p i m e r i z a t i o n o f t h e D e c a l o n e 320. To 10 m l o f d r y t e r t - b u t y l a l c o h o l was added 43 mg o f p o t a s s i u m m e t a l . A f t e r a l l t h e p o t a s s i u m had r e a c t e d , a s o l u t i o n o f 180 mg (1.0 mmole) o f t h e d e c a l o n e 320 i n 2 m l o f d r y t e r t - b u t y l a l c o h o l was added. The m i x t u r e was s t i r r e d under a n i t r o g e n atmosphere a t room t e m p e r a t u r e f o r 22 h o u r s , was t h e n d i l u t e d w i t h w a t e r and t h o r o u g h l y e x t r a c t e d w i t h e t h e r . The combined e t h e r e x t r a c t s were washed w i t h w a t e r and b r i n e , and d r i e d o v e r a n h y d r o u s magnesium s u l f a t e . E v a p o r a t i o n o f t h e s o l v e n t gave a s m a l l amount o f y e l l o w o i l . D i s t i l l a t i o n o f t h i s m a t e r i a l a t 165-176° ( a i r b a t h t e m p e r a t u r e ) and w a t e r a s p i r a t o r p r e s s u r e a f f o r d e d 129 mg (72%) o f a c o l o r l e s s o i l w h i c h was i d e n t i c a l w i t h t h e s t a r t i n g m a t e r i a l , d e c a l o n e 320 i n a l l r e s p e c t s : i . r . ( f i l m ) , v 1710 cm ^; max p.m.r., 0.68 ( s , 3H, t e r t i a r y m e t h y l ) , 0.86 ( d , 3H, s e c o n d a r y m e t h y l , -180-J=6.0 H z ) . P r e p a r a t i o n o f t h e B i c y c l i c K e t a l O l e f i n 3_24. A s o l u t i o n o f t h e o c t a l o n e 226 (5.20 g, 29.21 mmoles), 2,2-d i m e t h y l - l , 3 - p r o p a n e d i o l (4.50 g, 43.27 mmoles), and _ p _ - t o l u e n e s u l f o n i c a c i d (520 mg) i n 200 m l o f d r y benzene was r e f l u x e d f o r 20 h o u r s u n d e r a D e a n - S t a r k w a t e r s e p a r a t o r . The c o o l e d s o l u t i o n was d i l u t e d w i t h e t h e r and washed w i t h s a t u r a t e d aqueous s o d i u m b i c a r b o n a t e . The o r g a n i c l a y e r was washed w i t h w a t e r and b r i n e and t h e n d r i e d o v e r a n h y d r o u s magnesium s u l f a t e . E v a p o r a t i o n o f t h e s o l v e n t gave a p a l e y e l l o w v i s c o u s o i l w h i c h s o l i d i f i e d upon c o o l i n g i n t h e r e f r i g e r a t o r . R e c r y s t a l l i z a t i o n o f t h e s o l i d f r o m hexane f u r n i s h e d 6.52 g (85%) o f t h e k e t a l o l e f i n 324 a s w h i t e c r y s t a l s : ra.p., 100.5-102.5° i . r . ( C H C 1 3 ) , 3030, 1650 cm" 1; p.m.r., 0.69 ( s , 3H, t e r t i a r y m e t h y l ) , 0.80 ( s , 3H, t e r t i a r y m e t h y l ) , 0.84 ( d , 3H, s e c o n d a r y m e t h y l , J=6.0 H z ) , 1.18 ( s , 3H, t e r t i a r y m e t h y l ) , 2.82 ( u n r e s o l v e d d o f d , I H , b r i d g e h e a d p r o t o n ) , 3.28 ( p a i r o f q u a r t e t s , 2H, a x i a l p r o t o n s o f t h e k e t a l , J=11.0 Hz and 2.0 H z ) , 3.64 and 3.74 ( p a i r o f d o u b l e t s , 2H, e q u a t o r i a l p r o t o n s o f t h e k e t a l , J=11.0 H z ) , 5.62 (m, 2H, v i n y l p r o t o n s ) . A n a l . C a l c d . f o r C 1 7 H 2 g 0 2 : C, 77.22; H, 10.67. Found: C, 77.08; H, 10.55. P r e p a r a t i o n o f t h e K e t o D i b r o m i d e "326 To a m i x t u r e o f 358 mg (1.36 mmoles) o f t h e k e t a l o l e f i n 324, 82.3 mg (0.36 mmole) o f t r i e t h y l b e n z y l a m m o n i u m c h l o r i d e , a c a t a l y t i c amount o f e t h a n o l , and 5 g (19.76 mmoles) o f bromoform was added d r o p w i s e 10 m l o f 50% aqueous sodium h y d r o x i d e . The h e t e r o g e n e o u s m i x t u r e was warmed w i t h a sand b a t h a t 40-50° f o r 2-3 h o u r s . The m x i t u r e was p o u r e d i n t o -181-w a t e r and e x t r a c t e d t h o r o u g h l y w i t h m e t h y l e n e c h l o r i d e . The combined o r g a n i c e x t r a c t s were washed w i t h w a t e r and d r i e d w i t h anhydrous magnesium s u l f a t e . E v a p o r a t i o n o f t h e s o l v e n t gave a d a r k brown o i l , w h i c h was d i s s o l v e d i n 20 m l o f m e t h a n o l and 1 m l o f IN h y d r o c h l o r i c a c i d 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 a t room t e m p e r a t u r e f o r 4 h o u r s and t h e n c o n c e n t r a t e d . The r e s i d u a l m a t e r i a l was d i l u t e d w i t h s a t u r a t e d aqueous sodium b i c a r b o n a t e and t h e aqueous l a y e r was e x t r a c t e d w i t h e t h e r . Removal o f t h e s o l v e n t f r o m t h e combined e t h e r e x t r a c t s a f t e r d r y i n g o v e r a nhydrous magnesium s u l f a t e a f f o r d e d a d a r k brown o i l w h i c h was p u r i f i e d by column c h r o m a t o g r a p h y on 200 g o f s i l i c a g e l u s i n g 4:1 p e t r o l e u m e t h e r (30-60°)-ether as e l u t i n g s o l v e n t . C o m b i n i n g a l l o f t h e f r a c t i o n s c o n t a i n i n g t h e d e s i r e d k e t o d i b r o m i d e 326 f u r n i s h e d 378 mg (80%) o f t h i s compound as v e r y p a l e y e l l o w c r y s t a l s . An a n a l y t i c a l sample was o b t a i n e d by r e c r y s t a l l i z a t i o n f r o m e t h e r : m.p., 130-131.5°; i . r . (CHC1-), v 3100, 1710 c m - 1 ; p.m.r., 0.57 ( s , 3H, t e r t i a r y m e t h y l ) , 0.93 ( d , 3H, s e c o n d a r y m e t h y l , J=6.0 H z ) , 1.14-1.32 (m, I H , c y c l o p r o p y l p r o t o n ) . M o l . Wt. C a l c d . f o r C 1 3 H 1 8 B r 2 0 : 351.9693. Found ( h i g h r e s o l u t i o n mass s p e c t r o m e t r y ) : 351.9686. P r e p a r a t i o n o f t h e K e t a l D i b r o m i d e 325 A s o l u t i o n of t h e k e t o d i b r o m i d e 326 (351 mg, 1.00 mmole), 2,2-d i m e t h y l - 1 , 3 - p r o p a n e d i o l (1.5 g, 14.42 mmoles) and p _ - t o l u e n e s u l f o n i c a c i d (10 mg) i n 25 m l o f d r y benzene was r e f l u x e d under a D e a n - S t a r k w a t e r s e p a r a t o r f o r 20 h o u r s . The c o o l e d s o l u t i o n was d i l u t e d w i t h e t h e r and washed w i t h s a t u r a t e d aqueous sodium b i c a r b o n a t e . The o r g a n i c l a y e r was d r i e d o v e r a n h y d r o u s magnesium s u l f a t e and c o n c e n t r a t e d , a f f o r d i n g 463 mg -182-o f a v i s c o u s p a l e y e l l o w o i l . Column ch r o m a t o g r a p h y o f t h i s m a t e r i a l on 50 g o f s i l i c a g e l u s i n g 4:1 p e t r o l e u m e t h e r - e t h e r as t h e e l u t i n g s o l v e n t m i x t u r e y i e l d e d 405 mg (93%) o f t h e k e t a l d i b r o m i d e 317 as a v i s c o u s p a l e y e l l o w o i l : i . r . ( f i l m ) , no c a r b o n y l a b s o r p t i o n ; p.m.r., 0.66 ( s , 3H, t e r t i a r y m e t h y l ) , 0.72 ( s , 3H, t e r t i a r y m e t h y l ) , 0.83 ( d , 3H, s e c o n d a r y m e t h y l , J=5.0 H z ) , 1.16 ( s , 3H, t e r t i a r y m e t h y l ) , 2.65-2.81 (d o f d, I H , b r i d g e h e a d p r o t o n , J=13.0 and 4.0 H z ) , 3.17-3.75 (m, 4H, k e t a l p r o t o n s ) . M o l . Wt. C a l c d . f o r C ^ H ^ B r ^ : 438.0419, 436.0429 and 434.0475. Found ( h i g h r e s o l u t i o n mass s p e c t r o m e t r y ) : 438.0417, 436.0436 and 434.0456. P r e p a r a t i o n o f t h e B e n z y l E t h e r 32Q_ 128 To a s o l u t i o n o f 1.01 g (3.97 mmoles) o f 7 , 7 - d i b r o m o n o r c a r a n e i n 10 m l o f d r y t e t r a h y d r o f u r a n c o o l e d t o -95° w i t h a l i q u i d n i t r o g e n -t o l u e n e b a t h and k e p t under an atmosphere o f n i t r o g e n , was added 1.6 m l (4.13 mmoles) o f a s o l u t i o n o f n - b u t y l l i t h i u m i n hexane (2.58 M). A f t e r 20 m i n u t e s , a s o l u t i o n o f 1.26 g (8.05 mmoles) o f c h l o r o m e t h y l b e n z y l 129 e t h e r i n 2 m l o f d r y h e x a m e t h y l p h o s p h o r a m i d e was added, f o l l o w e d by a n o t h e r 2 m l o f d r y h e x a m e t h y l p h o s p h o r a m i d e . The m i x t u r e was s t i r r e d a t -95° f o r 30 m i n u t e s and t h e n a t -78° f o r 4 h o u r s . I t was t h e n p o u r e d i n t o v i g o r o u s l y s t i r r e d d i l u t e aqueous sodium h y d r o x i d e . The aqueous l a y e r was e x t r a c t e d w i t h p e n t a n e . The combined e x t r a c t s were washed w i t h w a t e r and b r i n e and d r i e d o v e r a n hydrous magnesium s u l f a t e . E v a p o r a t i o n o f t h e s o l v e n t a f f o r d e d 1.244 g o f a y e l l o w o i l w h i c h was s u b j e c t e d t o column c h r o m a t o g r a p h y o v e r 150 g o f s i l i c a g e l u s i n g 5% e t h e r i n p e t r o l e u m e t h e r as t h e e l u t i n g s o l v e n t . The d e s i r e d p r o d u c t , b e n z y l e t h e r 329, was o b t a i n e d as a p a l e y e l l o w o i l (0.583 g, 4 9 % ) . -183-D i s t i l l a t i o n a t 110-120° ( a i r b a t h t e m p e r a t u r e ) and 0.2 mm gave a c o l o r l e s s o i l : i . r . ( f i l m ) , v 3090, 3050, 730, 690 cm" 1; p.m.r., 3.80 ( s , 2H, max C=CH 20), 4.62 ( s , 2H, 0CH_ 2Ph), 7.37 (m, 5H, C g H 5 ) . However, an a n a l y t i c a l p u r e sample o f 329 c o u l d n o t be o b t a i n e d . The compound showed no p a r e n t peak i n t h e mass s p e c t r u m b u t gave a s t r o n g peak a t m/e 215 w h i c h c o r r e s p o n d e d t o M +-Br. H y d r o g e n o l y s i s o f t h e B e n z y l E t h e r 323. To a s o l u t i o n o f 301 mg (1.02 mmole) o f t h e b e n z y l e t h e r 329 i n 15 m l o f 95% e t h a n o l was added 61 mg o f 10% p a l l a d i u m - o n - c a r b o n and t h e r e s u l t i n g m i x t u r e was h y d r o g e n a t e d a t room t e m p e r a t u r e and a t m o s p h e r i c p r e s s u r e f o r 1 h o u r . By t h e n , a p p r o x i m a t e l y 1 e q u i v a l e n t o f h y d r o g e n had been consumed. The m i x t u r e was f i l t e r e d t h r o u g h C e l i t e and t h e r e s i d u e was washed w i t h e t h a n o l . Removal o f t h e s o l v e n t f r o m t h e f i l t r a t e gave a p a l e y e l l o w o i l . D i s t i l l a t i o n o f t h i s m a t e r i a l a t 75-80° ( a i r b a t h t e m p e r a t u r e ) and 0.2 mm a f f o r d e d 195 mg (93%) o f t h e a l c o h o l 331 as a c o l o r l e s s o i l w h i c h s o l i d i f i e d upon c o o l i n g : m.p., 36-37.5°; i . r . ( C H C 1 0 ) , v 3403 ( b r o a d ) cm" 1; p.m.r., 3.95 ( s , 2H, CH„0H). 3 max —2 A n a l . C a l c d . f o r C g H ^ B r O : C, 46.85; H, 6.39. Found: C, 46.56; H, 6.38. P r e p a r a t i o n o f t h e M e s y l a t e 332. To a s o l u t i o n o f 150 mg (0.732 mmole) o f t h e a l c o h o l 331 and 303 mg (3.00 mmoles) o f d r y t r i e t h y l a m i n e i n 6 m l o f d r y m e t h y l e n e c h l o r i d e a t 0° u n d e r a n i t r o g e n a tmosphere was added 218 mg (1.904 mmole) o f f r e s h l y d i s t i l l e d m e t h a n e s u l f o n y l c h l o r i d e . A f t e r t h e r e s u l t i n g m i x t u r e had been s t i r r e d a t 0° f o r 30 m i n u t e s , i t was p o u r e d i n t o i c e - c o l d w a t e r . The aqueous l a y e r was e x t r a c t e d t h o r o u g h l y w i t h m e t h y l e n e c h l o r i d e . The -184-combined m e t h y l e n e c h l o r i d e e x t r a c t s were d r i e d w i t h a n h y d r o u s magnesium s u l f a t e and t h e s o l v e n t was e v a p o r a t e d t o g i v e 200 mg (97%) o f t h e m e s y l a t e 332 as a p a l e y e l l o w o i l w h i c h s o l i d i f i e d upon c o o l i n g : m.p. 56-58.5°; i . r . ( f i l m ) , 3080, 1360, 1170 cm" 1; p.m.r., 2.63 ( s , 3H, C H 3 S 0 3 ) , 4.63 ( s , 2H, C H 2 0 H s ) . An a n a l y t i c a l sample o f 332 c o u l d n o t be o b t a i n e d due t o t h e i n s t a b i l i t y o f t h e compound i n t h e a t t e m p t e d r e c r y s t a l l i z a t i o n f r o m p e t r o l e u m e t h e r . The compound showed no p a r e n t peak i n t h e mass s p e c t r u m b u t e x h i b i t e d s t r o n g peaks a t m/e 203, 1 8 9 ( 1 8 7 ) , and 188(186) w h i c h + + + c o r r e s p o n d e d t o M - B r , M - C H 3 S 0 3 and M -CH 3S0 3H, r e s p e c t i v e l y . P r e p a r a t i o n o f 7-ead JQ.-methyl-7-e^Q.-carbomethoxynbrcarane 3_38 To a c o l d (-78°) s o l u t i o n o f 560 mg (2.96 mmoles) o f 7-exo-bromo-7 - e n d o - m e t h y l n o r c a r a n e ^ 0 ' ^ 1 i n 15 m l o f anhydrous e t h e r u n d e r a n i t r o g e n a t mosphere was added 3.3 m l (6.67 mmoles) o f a s o l u t i o n o f t e r t - b u t y l l i t h i u m i n p e n t a n e (2.02 M). The m i x t u r e was k e p t a t -78° f o r 30 m i n u t e s and 0.74 m l (9.50 mmoles) o f d i s t i l l e d m e t h y l c h l o r o f o r m a t e was added d r o p w i s e . A f t e r t h e a d d i t i o n was c o m p l e t e , 1.5 m l o f d r y h e x a m e t h y l p h o s p h o r a m i d e was i n t r o d u c e d by means o f a s y r i n g e . The m i x t u r e was k e p t a t -78° f o r a n o t h e r 4 h o u r s and t h e n p o u r e d i n t o w a t e r . The aqueous l a y e r was e x t r a c t e d w i t h p e t r o l e u m e t h e r (b.p. 35-65°). The combined o r g a n i c e x t r a c t s were washed w i t h w a t e r and d r i e d w i t h a n h y d r o u s magnesium s u l f a t e . Removal o f t h e s o l v e n t gave 357 mg o f a p a l e y e l l o w o i l . D i s t i l l a t i o n o f t h e l a t t e r a t 100-120° ( a i r b a t h t e m p e r a t u r e ) and w a t e r a s p i r a t o r p r e s s u r e gave 320 mg (64%) o f 7 - e n d o - m e t h y l - 7 - e x o - c a r b o m e t h o x y n o r c a r a n e 338 as a c o l o r l e s s o i l : i . r . ( f i l m ) , 3040, 1720 cm" 1; p.m.r., 1.20 ( s , 3H, t e r t i a r y m e t h y l ) , -185-3.57 ( s , 3H, COOMe). M o l . Wt. C a l c d . f o r C 1 0 H 1 6 0 2 : 168.1151. Found ( h i g h r e s o l u t i o n mass s p e c t r o m e t r y ) : 168.1151. P r e p a r a t i o n o f 7 - e n d o - m e t h y l - 7 - e x o - h y d r o x y m e t h y l n o r c a r a n e 339 A m i x t u r e o f 300 mg (7.89 mmoles) o f l i t h i u m aluminum h y d r i d e and 150 mg (0.89 mmole) o f t h e m o n o e s t e r 338 i n 30 m l o f a n hydrous e t h e r was s t i r r e d a t room t e m p e r a t u r e u n d e r an atmosphere o f n i t r o g e n f o r 20 h o u r s . The e x c e s s h y d r i d e was d e s t r o y e d by a d d i t i o n o f powdered sodium s u l f a t e d e c a h y d r a t e . The r e s u l t a n t m i x t u r e was f i l t e r e d and t h e c o l l e c t e d m a t e r i a l was washed w i t h e t h e r . The e t h e r e a l s o l u t i o n was d r i e d o v e r a n h y d r o u s magnesium s u l f a t e . E v a p o r a t i o n o f t h e s o l v e n t gave a v e r y p a l e y e l l o w v i s c o u s o i l . D i s t i l l a t i o n o f t h i s m a t e r i a l a t 100-110° and a s p i r a t o r p r e s s u r e gave 101 mg (81%) o f t h e p r i m a r y a l c o h o l 339 as a c o l o r l e s s v i s c o u s o i l : i . r . ( f i l m ) , v 3400 ( b r o a d ) , 3020 cm p.m.r., max 0.72 (m, 2H, c y c l o p r o p y l p r o t o n s ) , 1.06 ( s , 3H, t e r t i a r y m e t h y l ) , 2.05 ( b r o a d s, I H , OH), 3.20 ( s , 2H, CH 20H). M o l . Wt. C a l c d . f o r C_H.,,0: 140.1211. Found ( h i g h r e s o l u t i o n mass s p e c t r o m e t r y ) : 140.1201. P r e p a r a t i o n o f t h e . p - N i t r o b e n z o a t e 3JL5 A s o l u t i o n o f 100 mg (0.71 mmole) o f t h e a l c o h o l 339, 200 mg (1.08 mmole) o f r e c r y s t a l l i z e d p - n i t r o b e n z o y l c h l o r i d e and 200 mg (2.53 mmoles) o f d r y p y r i d i n e i n 10 m l o f d r y m e t h y l e n e c h l o r i d e was k e p t a t 0° f o r 24 h o u r s . The m i x t u r e was p o u r e d i n t o w a t e r and t h e aqueous l a y e r was e x t r a c t e d w i t h e t h e r . The combined e t h e r e x t r a c t s were d r i e d o v e r a n hydrous magnesium s u l f a t e and t h e n c o n c e n t r a t e d t o g i v e a b r i g h t y e l l o w -186-o i l w h i c h s o l i d i f i e d upon c o o l i n g . R e c r y s t a l l i z a t i o n f r o m p e t r o l e u m e t h e r gave y e l l o w c r y s t a l s : m.p., 70-73°; i . r . ( f i l m ) , v 3030, 1725, 1610, 1530, 1350 c m - 1 ; p.m.r., 0.86 (m, 2H, c y c l o p r o p y l p r o t o n s ) , 1.13 ( s , 3H, t e r t i a r y m e t h y l ) , 4.00 ( s , 2H, C H ^ O C A r ) , 8.16 (m, 4H, p_-N0 2C 6H 4C00). M o l . Wt. C a l c d . f o r C ^ I L - N O . : 289.1291. Found: ( h i g h r e s o l u t i o n 16 19 4 mass s p e c t r o m e t r y ) : 289.1314. P r e p a r a t i o n o f t h e D i e s t e r 3_59 128 To a s o l u t i o n o f 856 mg (3.37 mmoles) o f 7 , 7 - d i b r o m o n o r c a r a n e i n 10 m l o f d r y t e t r a h y d r o f u r a n u n d e r a n i t r o g e n atmosphere a t -95° was added a s o l u t i o n o f 3.8 m l (7.41 mmoles) o f n - b u t y l l i t h i u m i n hexane (1.95 M). A f t e r 30 m i n u t e s , 1.27 g (13.46 mmoles) o f m e t h y l c h l o r o -f o r m a t e was added, f o l l o w e d by 1 m l o f d r y h e x a m e t h y l p h o s p h o r a m i d e . A f t e r a n o t h e r 30 m i n u t e s a t -95°, t h e s o l u t i o n was warmed t o -78°, k e p t a t t h i s t e m p e r a t u r e f o r 3 h o u r s and t h e n p o u r e d i n t o w a t e r . The aqueous l a y e r was e x t r a c t e d w i t h p e n t a n e . The combined p e n t a n e e x t r a c t s were washed t h o r o u g h l y w i t h w a t e r and b r i n e , and t h e n d r i e d o v e r a n h y d r o u s magnesium s u l f a t e . Removal o f t h e s o l v e n t gave 852 mg o f a p a l e y e l l o w o i l . D i s t i l l a t i o n o f t h i s m a t e r i a l a t 80-105° ( a i r b a t h t e m p e r a t u r e ) and 0.3 mm gave 591 mg o f a c o l o r l e s s v i s c o u s o i l w h i c h was 80% p u r e by g . l . c . a n a l y s i s (column F, 90° f o r 10 m i n u t e s and t h e n column t e m p e r a t u r e r a i s e d t o 180° w i t h t h e r a t e o f 25°/min, 180 m l / m i n ) . The d i s t i l l a t e was s u b j e c t e d t o column c h r o m a t o g r a p h y on 60 g o f s i l i c a g e l . The f r a c t i o n s f r o m t h e column w h i c h were e l u t e d w i t h 1:9 e t h e r - p e t r o l e u m e t h e r gave 410 mg (57%) o f t h e c r y s t a l i n e d i e s t e r 359. R e c r y s t a l l i z a t i o n f r o m p e n t a n e gave c o l o r l e s s 142 -1 c r y s t a l s ; m.p., 92-95° ( l i t . m.p. 88.5-89° ) ; i . r . ( C H C 1 3 ) , v m a x 1720 cm ; p.m.r., 3.66 ( s , 3H, COOMe), 3.75 ( s , 3H, COOMe). -187-P r e p a r a t i o n o f t h e D i o l 3JJ1. To a s u s p e n s i o n - s o l u t i o n o f 200 mg (7.14 mmoles) o f l i t h i u m a l u m i n i u m h y d r i d e i n 20 m l o f anhydrous e t h e r was added a s o l u t i o n o f 200 mg (0.94 mmole) o f t h e d i e s t e r 359 i n 5 m l o f anhydrous e t h e r . The r e s u l t i n g m i x t u r e was s t i r r e d a t room t e m p e r a t u r e f o r 24 h o u r s u n d e r a n i t r o g e n atmosphere. The e x c e s s h y d r i d e was d e s t r o y e d by a d d i t i o n o f powdered sodium s u l f a t e d e c a h y d r a t e . The m i x t u r e was f i l t e r e d t h r o u g h C e l i t e and t h e c o l l e c t e d m a t e r i a l was washed w i t h more e t h e r . The combined e t h e r e a l s o l u t i o n was d r i e d o v e r anhydrous magnesium s u l f a t e . E v a p o r a t i o n o f t h e s o l v e n t f r o m t h e f i l t r a t e gave 125 mg (85%) o f t h e d i o l 354 as a c o l o r l e s s v i s c o u s o i l w h i c h c r y s t a l l i z e d upon c o o l i n g . R e c r y s t a l l i z a t i o n f r o m p e t r o l e u m e t h e r - e t h e r gave w h i t e c r y s t a l s , m.p., 71-72.5°; i . r . (CHC1„), v 3400 ( b r o a d ) cm" 1; p.m.r., 0.90 (m, 2H, J max c y c l o p r o p y l p r o t o n s ) , 3.46 ( s , 2H, CH^OH), 3.46 ( b r o a d , s, 2H, d i s a p p e a r e d upon a d d i t i o n o f D 20, OH), 3.90 ( s , 2H, CI^OH). A n a l . C a l c d . f o r C-H^O-: C, 69.19; H, 10.32. Found: C, 69.11; y l o 2. H, 10.50. P r e p a r a t i o n o f t h e D i m e s y l a t e Jj6_2. To a s o l u t i o n o f 100 mg (0.64 mmole) o f t h e d i o l 361 and 241 mg (2.39 mmoles) o f d r y t r i e t h y l a m i n e i n 7 m l o f d r y m e t h y l e n e c h l o r i d e a t 0° was added 183 mg (1.60 mmole) o f d i s t i l l e d m e t h a n e s u l f o n y l c h l o r i d e . The m i x t u r e was k e p t a t 0° f o r 30 m i n u t e s and t h e n p o u r e d i n t o i c e - c o l d w a t e r . The aqueous l a y e r was e x t r a c t e d w i t h e t h e r . The combined e t h e r e x t r a c t s were washed t h o r o u g h l y w i t h i c e - c o l d w a t e r and b r i n e and t h e n d r i e d o v e r anhydrous magnesium s u l f a t e . E v a p o r a t i o n o f t h e s o l v e n t gave -188-202 mg o f t h e d i m e s y l a t e 362 as a y e l l o w o i l ; i . r . ( f i l m ) , v m a x 3065, 1355, 1165 c m - 1 ; p.m.r., 3.05 ( s , 6H, C H 3 S 0 3 ) , 4.00 ( s , 2H, CH_2OMs), 4.43 ( s , 2H, CH 2OMs). Due t o t h e f a c t t h a t t h e d i m e s y l a t e 362 was q u i t e u n s t a b l e , t h i s compound was n o t p u r i f i e d f u r t h e r , b u t was u s e d d i r e c t l y f o r t h e n e x t t r a n s f o r m a t i o n . P r e p a r a t i o n o f t h e D i c h l o r i d e 363. To a s o l u t i o n o f 202 mg (0.64 mmole) o f t h e c r u d e d i m e s y l a t e 362 i n 5 m l o f d r y h e x a m e t h y l p h o s p h o r a m i d e was added 200 mg (4.71 mmoles) o f a nhydrous l i t h i u m c h l o r i d e . The m i x t u r e was s t i r r e d u nder a n i t r o g e n atmosphere a t room t e m p e r a t u r e f o r 20 h o u r s , and was t h e n p o u r e d i n t o w a t e r . The aqueous s o l u t i o n was e x t r a c t e d w i t h p e n t a n e . The combined p e n t a n e e x t r a c t s were washed t h o r o u g h l y w i t h w a t e r and d r i e d o v e r a nhydrous magnesium s u l f a t e . E v a p o r a t i o n o f t h e s o l v e n t gave 110 mg (89%) o f t h e d i c h l o r i d e 363 a s a p a l e y e l l o w o i l ; i . r . ( f i l m ) , v 3030 cm "S p.m.r., max 3.50 ( s , 2H, C H 2 C 1 ) , 3.87 ( s , 2H, CH_ 2C1). The a n a l y t i c a l sample was o b t a i n e d by p r e p a r a t i v e t . l . c . w i t h p e n t a n e b e i n g u s e d as t h e d e v e l o p i n g s o l v e n t . M o l . Wt. C a l c d . f o r C 9 H l 4 C l 2 : 192.0465 and 194.0432. Found ( h i g h r e s o l u t i o n mass s p e c t r o m e t r y ) : 192.0472 and 194.0443. P r e p a r a t i o n o f t h e K e t a l Monobromides 366, and 372, To a c o l d (-95°, l i q u i d n i t r o g e n - t o l u e n e b a t h ) s o l u t i o n o f 268 mg (0.61 mmole) o f t h e k e t a l d i b r o m i d e 325, 500 mg (3.52 mmoles) o f m e t h y l i o d i d e and 0.4 m l o f d r y h e x a m e t h y l p h o s p h o r a m i d e i n 4 m l o f d r y t e t r a -h y d r o f u r a n was added 0.7 m l (1.35 mmole) o f a s o l u t i o n o f t e r t - b u t y l l i t h i u m -189-i n p e n t a n e (1.93 M). The m i x t u r e was s t i r r e d a t -95° f o r 1 h o u r , was warmed t o -78° and t h e n s t i r r e d a t t h i s t e m p e r a t u r e f o r an a d d i t i o n a l 4 h o u r s . Water (10 ml) was added and t h e r e s u l t a n t m i x t u r e was e x t r a c t e d w i t h h exane. The combined hexane e x t r a c t s were washed w i t h w a t e r and b r i n e , and t h e n d r i e d o v e r a n h y d r o u s magnesium s u l f a t e . Removal o f t h e s o l v e n t gave 288 mg o f a v i s c o u s y e l l o w o i l . G . l . c . a n a l y s i s (column F, 150° f o r 5 m i n u t e s and t h e n r a i s e d t o 200° f o r 15 m i n u t e s w i t h t h e r a t e o f 25°/min, 180 ml/min) o f t h i s m a t e r i a l showed t h a t i t c o n s i s t e d m a i n l y o f two components i n a r a t i o o f a p p r o x i m a t e l y 3:2. The c r u d e p r o d u c t was s u b j e c t e d t o c h r o m a t o g r a p h y on 25 g o f s i l i c a g e l , w i t h 9:1 hexane-benzene b e i n g employed as t h e e l u t i n g s o l v e n t m i x t u r e . The m a j o r i s o m e r 366 (130 mg, 5 8 % ) , w h i c h was t h e f i r s t component t o be e l u t e d f r o m t h e column, was o b t a i n e d as a p a l e y e l l o w v i s c o u s o i l and e x h i b i t e d t h e f o l l o w i n g s p e c t r a l p r o p e r t i e s : i . r . ( f i l m ) , no c a r b o n y l a b s o r p t i o n ; p.m.r., 0.64 ( s , 3H, t e r t i a r y m e t h y l ) , 0.72 ( s , 3H, t e r t i a r y m e t h y l ) , 0.79 ( d , 3H, s e c o n d a r y m e t h y l , J=6.0 H z ) , 1.13 ( s , 3H, t e r t i a r y m e t h y l ) , 1.74 ( s , 3H, t e r t i a r y m e t h y l ) , 2.62-2.78 (d o f d, I H , b r i d g e h e a d p r o t o n , J=12.0 and 3.0 H z ) , 3.22 ( a p a i r o f u n r e s o l v e d q u a r t e t s , 2H, a x i a l p r o t o n s o f t h e k e t a l , J=11.0 H z ) , 3.55 and 3.64 ( a p a i r o f d o u b l e t s , 2H, e q u a t o r i a l p r o t o n s o f t h e k e t a l , J=11.0 H z ) . M o l . Wt. C a l c d . f o r C ^ H ^ B r O : 370.1522 and 372.1467. Found ( h i g h r e s o l u t i o n mass s p e c t r o m e t r y ) : 370.1537 and 372.1440. The m i n o r i s o m e r 372 (85 mg, 3 8 % ) , a l s o o b t a i n e d as a p a l e y e l l o w v i s c o u s o i l , e x h i b i t e d t h e f o l l o w i n g s p e c t r a l p r o p e r t i e s : i . r . ( f i l m ) , no c a r b o n y l a b s o r p t i o n ; p.m.r., 0.64 ( s , 3H, t e r t i a r y m e t h y l ) , 0.71 ( s , 3H, t e r t i a r y m e t h y l ) , 0.77 ( d , 3H, s e c o n d a r y m e t h y l , J=6.0 H z ) , -190-1.12 ( s , 3H, t e r t i a r y m e t h y l ) , 1.62 ( s , 3H, t e r t i a r y m e t h y l ) , 2.61-2.78 ( u n r e s o l v e d d o f d, I H , b r i d g e h e a d p r o t o n , J=14.0 and 4.0 H z ) , 3.20 ( p a i r o f q u a r t e t s , 2H, a x i a l p r o t o n s o f t h e k e t a l , J=12.0 and 3.0 H z ) , 3.54 and 3.63 ( p a i r o f d o u b l e t s , 2H, e q u a t o r i a l p r o t o n s o f t h e k e t a l , J=12.0 H z ) . M o l . Wt. C a l c d . f o r C ^ H ^ B r O : 370.1522 and 372.1467. Found ( h i g h r e s o l u t i o n mass s p e c t r o m e t r y ) : 370.1507 and 372.1488. P r e p a r a t i o n o f t h e K e t a l E s t e r 3_67 To a c o l d (-78°) s o l u t i o n o f 144 mg (0.39 mmole) o f t h e k e t a l b r o m i d e 366 i n 8 m l o f a n h y d r o u s e t h e r u n d e r a n i t r o g e n atmosphere was added s l o w l y 0.45 m l (0.87 mmole) of. a s o l u t i o n o f t e r t - b u t y l l i t h i u m i n p e n t a n e (1.93 M). A f t e r t h e 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 a t -78° f o r 1 h o u r , 0.25 m l (3.23 mmoles) o f m e t h y l c h l o r o f o r m a t e was added, f o l l o w e d by 0.8 m l o f d r y h e x a m e t h y l p h o s p h o r a m i d e . The m i x t u r e was m a i n t a i n e d a t -78° f o r a n o t h e r 4 h o u r s , and t h e n was d i l u t e d w i t h w a t e r . The r e s u l t a n t m i x t u r e was e x t r a c t e d w i t h p e t r o l e u m e t h e r , t h e combined e x t r a c t s were washed t h o r o u g h l y w i t h w a t e r and b r i n e , and t h e n d r i e d o v e r a n h y d r o u s magnesium s u l f a t e . E v a p o r a t i o n o f s o l v e n t gave 112 mg o f a p a l e y e l l o w o i l w h i c h was c h r o m a t o g r a p h e d o v e r 15 g o f s i l i c a g e l , w i t h 9:1 p e t r o l e u m e t h e r - e t h e r b e i n g u s e d as t h e e l u t i n g s o l v e n t m i x t u r e . The f r a c t i o n s c o n t a i n i n g t h e k e t a l e s t e r 367 were combined t o a f f o r d 97 mg (71%) o f t h e d e s i r e d m a t e r i a l as p a l e y e l l o w c r y s t a l s ; m.p., 120-123°; i . r . ( C H C 1 3 ) , 1720 cm" 1; p.m.r., 0.66 ( s , 3H, t e r t i a r y m e t h y l ) , 0.78 ( s , 3H, t e r t i a r y m e t h y l ) , 0.80 ( d , 3H, s e c o n d a r y m e t h y l , J=5.0 H z ) , 1.16 ( s , 3H, t e r t i a r y m e t h y l ) , 1.24 ( s , 3H, -191-t e r t i a r y m e t h y l ) , 2.64-2.81 ( u n r e s o l v e d d o f d, I H , b r i d g e h e a d p r o t o n ) , 3.16-3.74 (m, 4H, k e t a l p r o t o n s ) , 3.66 ( s , 3H, COOMe). M o l . Wt. C a l c d . f o r C o 1 H o / 0 . : 350.2432. Found ( h i g h r e s o l u t i o n 21 34 4 ° mass s p e c t r o m e t r y ) : 350.2457. P r e p a r a t i o n o f t h e K e t a l A l c o h o l 223, To a s u s p e n s i o n - s o l u t i o n o f 104 mg (2.73 mmoles) o f l i t h i u m aluminum h y d r i d e i n 5 m l o f a n hydrous e t h e r was added a s o l u t i o n o f 97 mg (0.277 mmole) o f t h e k e t a l e s t e r 367 i n 7 m l o f a n h y d r o u s e t h e r . The m i x t u r e was s t i r r e d f o r 20 h o u r s a t room t e m p e r a t u r e u n d e r a n i t r o g e n a t m o s p h e r e . The e x c e s s l i t h i u m aluminum h y d r i d e was d e s t r o y e d by a d d i t i o n o f powdered sodium s u l f a t e d e c a l h y d r a t e . The m i x t u r e was f i l t e r e d and t h e c o l l e c t e d m a t e r i a l was washed w i t h more e t h e r . The combined e t h e r e a l s o l u t i o n was d r i e d w i t h a n h y d r o u s magnesium s u l f a t e . Removal o f t h e s o l v e n t f r o m t h e f i l t r a t e a f f o r d e d 63 mg (71%) o f t h e k e t a l a l c o h o l 379 as a v e r y v i s o u s o i l w h i c h c o u l d n o t be d i s t i l l e d ; i.r.(CHC£~), v 3400 ( b r o a d ) cm" 1; p.m.r., 0.66 ( s , 3H, t e r t i a r y m e t h y l ) , -3 1113 X 0.78 ( s , 3H, t e r t i a r y m e t h y l ) , 0.80 ( d , 3H, s e c o n d a r y m e t h y l , J=4.0 H z ) , 1.10 ( s , 3H, t e r t i a r y m e t h y l ) , 1.15 ( s , 3H, t e r t i a r y m e t h y l ) , 2.56-2.83 ( u n r e s o l v e d d o f d, I H , b r i d g e h e a d p r o t o n ) , 3.06-3.75 (m, 4H, k e t a l p r o t o n s ) , 3.58 ( s , 2H, CH_ 20H). x M o l . Wt. C a l c d . f o r c 2 o H 3 4 ° 3 : 322.2506. Found ( h i g h r e s o l u t i o n mass s p e c t r o m e t r y ) : 322.2508. P r e p a r a t i o n o f t h e K e t o A l c o h o l 368 To a s o l u t i o n o f 63 mg (0.20 mmole) o f t h e k e t a l a l c o h o l 379 i n 3 m l o f r e a g e n t g r a d e a c e t o n e , 3 m l o f m e t h a n o l and 1 m l o f w a t e r was -192-added 6 d r o p s o f IN h y d r o c h l o r i c a c i d . The m i x t u r e was s t i r r e d u nder n i t r o g e n f o r 3 h o u r s . The s o l u t i o n was c o n c e n t r a t e d u n d e r r e d u c e d p r e s s u r e and t h e r e s i d u a l m a t e r i a l was d i l u t e d w i t h s a t u r a t e d aqueous sodium b i c a r b o n a t e . The r e s u l t i n g m i x t u r e was e x t r a c t e d w i t h e t h e r . C o n c e n t r a t i o n o f t h e combined e t h e r e a l s o l u t i o n , a f t e r i t had been washed w i t h w a t e r and b r i n e , and d r i e d o v e r a n h y d r o u s magnesium s u l f a t e , gave 56 mg o f t h e k e t o a l c o h o l as a v i s c o u s o i l . T h i s c r u d e m a t e r i a l was p u r i f i e d by means o f p r e p a r a t i v e t . l . c . u s i n g 2:1 m i x t u r e o f benzene and e t h y l a c e t a t e as e l u t i n g s o l v e n t m i x t u r e t o g i v e 46 mg (97%) o f t h e d e s i r e d k e t o a l c o h o l as a c o l o r l e s s v i s c o u s o i l : i . r . ( C H C & 0 ) , v 3500 v V ' max ( b r o a d ) , 1705 cm" 1; p.m.r., 0.66 ( S , 3H, t e r t i a r y m e t h y l ) , 0.86 ( d , 3H, s e c o n d a r y m e t h y l , J=6.0 H z ) , 1.13 ( s , 3H, t e r t i a r y m e t h y l ) , 3.56 ( s , 2H, CH_ 20H). M o l . Wt. C a l c d f o r C 1 5 H 2 4 ° 2 : 2 3 6 - 1 7 7 1 ' Found ( h i g h r e s o l u t i o n mass s p e c t r o m e t r y ) : 236.1776. P r e p a r a t i o n o f t h e K e t o n . - N i t r o b e n z o a t e 380 To a s o l u t i o n o f 45 mg (0.19 mmole) o f t h e k e t o a l c o h o l 368 i n 5 m l o f d r y m e t h y l e n e c h l o r i d e was added 100 mg (0.54 mmole) o f r e c r y s t a l l i z e d p _ - n i t r o b e n z o y l c h l o r i d e and 100 mg (1.27 mmole) o f d r y p y r i d i n e . The m i x t u r e was k e p t a t 0° f o r 24 h o u r s and t h e n d i l u t e d w i t h w a t e r . The p r o d u c t was e x t r a c t e d i n t o e t h e r . The combined e t h e r e x t r a c t s were d r i e d o v e r a n h y d r o u s magnesium s u l f a t e . Removal o f t h e s o l v e n t y i e l d e d 95 mg o f a y e l l o w v i s c o u s o i l as c r u d e p r o d u c t . The d e s i r e d k e t o _p_-n i t r o b e n z o a t e 371, i s o l a t e d f r o m t h i s c r u d e m a t e r i a l by means o f p r e p a r a t i v e t . l . c . w i t h 2:1 b e n z e n e - e t h y l a c e t a t e b e i n g u s e d as d e v e l o p i n g s o l v e n t , was o b t a i n e d as a p a l e y e l l o w v i s c o u s o i l (67 mg, 9 1 % ) ; i . r . ( f i l m ) , v -193-3100, 3070, 1720, 1705, 1609, 1525, 1345 cm~ x; p.m.r., 0.66 ( s , 3H, t e r -t i a r y m e t h y l ) , 0.90 ( u n r e s o l v e d d, 3H, s e c o n d a r y m e t h y l , J=6.0 H z ) , 1.20 ( s , 3H, t e r t i a r y m e t h y l ) , 4.38 ( s , 2H, CH_ 20C0Ar) , 8.28 (m, 4H, £ - N 0 2 C ^ C O O ) . M o l . Wt. C a l c d . f o r C 2 2 H 2 7 0 5 : 385.1889. Found ( h i g h r e s o l u t i o n mass s p e c t r o m e t r y ) : 385.1889. P r e p a r a t i o n o f t h e K e t a l D i e s t e r 2£9. To a m i x t u r e o f 786 mg (2.98 mmoles) o f t h e k e t a l o l e f i n 324 and 152 64 mg o f c o p p e r b r o n z e h e a t e d w i t h an e x t e r n a l o i l b a t h a t 130-140° u n d e r a n i t r o g e n a tmosphere was added, d r o p w i s e , 2.04 g (12.90 mmoles) 142 o f d i m e t h y l d i a z o m a l o n a t e . N i t r o g e n was e v o l v e d i m m e d i a t e l y . A f t e r t h e a d d i t i o n o f t h e d i a z o m a l o n a t e had been c o m p l e t e d , t h e m i x t u r e was s t i r r e d a t 130-140° f o r a n o t h e r lh h o u r . When t h e m i x t u r e was c o o l e d t o room t e m p e r a t u r e , i t s o l i d i f i e d . The s o l i d m i x t u r e was d i g e s t e d w i t h a s m a l l amount o f m e t h y l e n e c h l o r i d e , and t h e r e s u l t i n g s u s p e n s i o n was f i l t e r e d t h r o u g h a s h o r t f l o r i s i l column. The column was e l u t e d w i t h m e t h y l e n e c h l o r i d e . Removal o f t h e s o l v e n t f r o m t h e e l u a n t gave a c r u d e p r o d u c t w h i c h was d i g e s t e d w i t h e t h e r . The r e s u l t i n g s o l u t i o n -s u s p e n s i o n was f i l t e r e d . Removal o f t h e s o l v e n t f r o m t h e f i l t r a t e a f f o r d e d 2.29 g o f a y e l l o w s e m i - s o l i d v i s c o u s o i l . The l a t t e r m a t e r i a l was c h r o m a t o g r a p h e d on 230 g o f s i l i c a g e l w i t h a 1:3 m i x t u r e o f e t h y l a c e t a t e and p e t r o l e u m e t h e r b e i n g u s e d as t h e e l u t i n g s o l v e n t . E v a p o r a t i o n o f t h e s o l v e n t f r o m t h e f r a c t i o n s c o n t a i n i n g t h e d e s i r e d p r o d u c t gave 931 mg (80%) o f a n e a r l y c o l o r l e s s v i s c o u s o i l w h i c h c r y s t a l l i z e d upon s t a n d i n g . R e c r y s t a l l i z a t i o n f r o m hexane gave 599 mg -194-o f c o l o r l e s s c r y s t a l s . C o n c e n t r a t i o n o f t h e mother l i q u o r gave a n o t h e r 150 mg o f t h e k e t a l d i e s t e r 369 ( t o t a l y i e l d 64%) as c o l o r l e s s c r y s t a l s , m.p. 132-133.5°; i . r . (CHC1-), v 3105, 1730 cm" 1; p.m.r., 0.66 ( s , J max 3H, t e r t i a r y m e t h y l ) , 2.62-2.82 (m, I H , b r i d g e h e a d p r o t o n ) , 3.14-3.80 (m, 4H, k e t a l p r o t o n s ) , 3.68 ( s , 3H, COOMe), 3.74 ( s , 3H, COOMe). A n a l . C a l c d . f o r C ^ H ^ O g : C, 66.98; H, 8.69. Found: C, 67.09; H, 8.50. P r e p a r a t i o n o f t h e K e t a l D i o l 389_ To a s o l u t i o n - s u s p e n s i o n o f 500 mg (13.16 mmoles) o f l i t h i u m aluminum h y d r i d e i n 50 m l o f a n h y d r o u s e t h e r was added, o v e r a p e r i o d o f 30 m i n u t e s , a s o l u t i o n o f 532 mg (1.35 mmole) o f t h e k e t a l d i e s t e r 369 i n 50 m l o f a n h y d r o u s e t h e r . The m i x t u r e was s t i r r e d a t room t e m p e r a t u r e under a n i t r o g e n atmosphere f o r 20 h o u r s . A f t e r t h e r e a c t i o n m i x t u r e had been d i l u t e d w i t h m e t h y l e n e c h l o r i d e ( a p p r o x i m a t e l y 20 m l ) , t h e e x c e s s l i t h i u m aluminum h y d r i d e was d e s t r o y e d by a d d i t i o n o f e x c e s s powdered sodium s u l f a t e d e c a h y d r a t e . The r e s u l t a n t m i x t u r e was d i l u t e d w i t h more m e t h y l e n e c h l o r i d e and t h e n f i l t e r e d t h r o u g h a C e l i t e bed. The c o l l e c t e d m a t e r i a l was t r i t u r a t e d and washed w i t h m e t h y l e n e c h l o r i d e . Removal o f t h e s o l v e n t f r o m t h e combined f i l t r a t e , a f t e r d r y i n g o v e r a n hydrous magnesium s u l f a t e , gave a w h i t e s o l i d . T h i s s o l i d was washed t h r e e t i m e s w i t h s m a l l amounts o f e t h e r t o f u r n i s h 371 mg o f t h e k e t a l d i o l 389. C o n c e n t r a t i o n o f t h e e t h e r e a l w a s h i n g s gave a n o t h e r 58 mg o f t h e k e t a l d i o l 389 ( t o t a l y i e l d 429 mg, 94%) w i t h m.p. 170-172°. An a n a l y t i c a l s a m p l e , o b t a i n e d by r e c r y s t a l l i z a t i o n o f a s m a l l amount o f t h i s m a t e r i a l f r o m a c e t o n e , e x h i b i t e d m.p. 173-174.5°; i . r . ( n u j o l m u l l ) , v 3300 ( b r o a d ) cm 1 ; p.m.r., 0.63 ( s , 3H, t e r t i a r y m e t h y l ) , 0.75 ( s , in 3.x 3H, t e r t i a r y m e t h y l ) , 0.78 ( d , 3H, s e c o n d a r y m e t h y l , J=6.0 H z ) , 1.10 -195-( s , 3H, t e r t i a r y m e t h y l ) , 2.40 ( b r o a d s, 2H, OH), 3.60-3.96 (m, 8H, CH^OH and k e t a l p r o t o n s ) . A n a l . C a l c d . f o r C^E^O^: C, 70.97; H, 10.12. Found: C, 70.89; H, 10.00. H y d r o l y s i s o f t h e K e t a l D i o l 389 • To a s o l u t i o n o f t h e k e t a l d i o l 389 (371 mg, 1.10 mmole) i n 60 m l o f r e a g e n t g r a d e a c e t o n e and 5 m l o f w a t e r was added 5 d r o p s o f 4N h y d r o c h l o r i c a c i d . The s o l u t i o n was s t i r r e d u nder n i t r o g e n a t room t e m p e r a t u r e f o r 3 h o u r s . A f t e r a n hydrous sodium b i c a r b o n a t e had been added, most o f t h e s o l v e n t was removed under r e d u c e d p r e s s u r e . The r e s i d u e was d i l u t e d w i t h w a t e r and t h e aqueous l a y e r was e x t r a c t e d t h o r o u g h l y w i t h m e t h y l e n e c h l o r i d e . The combined e x t r a c t s were washed w i t h w a t e r and d r i e d o v e r a n h y d r o u s magnesium s u l f a t e . Removal o f t h e m e t h y l e n e c h l o r i d e gave 259 mg o f a p a l e y e l l o w o i l y s o l i d w h i c h was t r i t u r a t e d w i t h a s m a l l amount o f e t h e r . F i l t r a t i o n gave 147 mg o f t h e d e s i r e d k e t o d i o l 383 as a w h i t e powder. C o n c e n t r a t i o n o f t h e f i l t r a t e gave a n o t h e r 85 mg ( t o t a l y i e l d 232 mg, 84%) o f t h e d e s i r e d p r o d u c t , w h i c h e x h i b i t e d m.p. 138-139.5°; i . r . ( n u j o l m u l l ) , V m a x 3300 ( b r o a d ) , 1700 cm p.m.r., 0.66 ( s , 3H, t e r t i a r y m e t h y l ) , 0.91 ( d , 3H, s e c o n d a r y m e t h y l , J=6.0 H z ) , 1.00-1.15 (m, 2H, c y c l o p r o p y l p r o t o n s ) , 2.35 ( b r o a d s, 2H, d i s a p p e a r e d upon a d d i t i o n o f D 20, OH), 3.45, 3.61 (AB p a i r o f d o u b l e t s , 2H, CH_20H, J=12.0 H z ) , 3.70, 3.90 (AB p a i r o f d o u b l e t s , 2H, CH 20H, J=12.0 H z ) . A n a l . C a l c d . f o r C 1 5 H 2 4 0 3 : C, 71.39; H, 9.59. Found: C, 71.00; H, 9.52. -196-P r e p a r a t i o n o f t h e K e t o D i m e s y l a t e 3_8_4 To an i c e - c o l d s o l u t i o n o f t h e k e t o d i o l 383 (232 mg, 0.921 mmole) i n 20 m l o f m e t h y l e n e c h l o r i d e u n d e r an atmosphere o f n i t r o g e n was added 290 mg (2.87 mmoles) o f d r y t r i e t h y l a m i n e and 266 mg (2.32 mmoles) o f m e t h a n e s u l f o n y l c h l o r i d e . The m i x t u r e was s t i r r e d a t 0° f o r 30 m i n u t e s , was d i l u t e d w i t h e t h e r and t h e n washed f o u r t i m e s w i t h i c e - c o l d w a t e r . The o r g a n i c phase was wahsed w i t h b r i n e and d r i e d o v e r magnesium s u l f a t e . E v a p o r a t i o n o f t h e s o l v e n t gave 413 mg o f a s l i g h t l y y e l l o w v i s c o u s o i l as t h e c r u d e p r o d u c t ; i . r . ( f i l m ) , ^ m a x 1700, 1355, 1170 cm" 1; p.m.r., 0.66 ( s , 3H, t e r t i a r y m e t h y l ) , 0.90 ( u n r e s o l v e d d, 3H, s e c o n d a r y m e t h y l ) , 3.03 ( s , 3H, CH_ 3S0 3), 3.06 ( s , 3H, CH_ 3S0 3), 3.96, 4.04 (AB p a i r o f d o u b l e t s , 2H, CH^OMs, J=11.0 H z ) , 4.30 ( s , 2H, CH 2OMs). Due t o t h e f a c t t h a t t h i s d i m e s y l a t e 384 was q u i t e u n s t a b l e , t h i s c r u d e p r o d u c t was u s e d i m m e d i a t e l y i n t h e n e x t t r a n s f o r m a t i o n w i t h o u t f u r t h e r p u r i f i c a t i o n . P r e p a r a t i o n o f t h e K e t o D i c h l o r i d e 391 To a s o l u t i o n o f t h e c r u d e k e t o d i m e s y l a t e 384 (413 mg, o b t a i n e d f r o m m e s y l a t i o n o f 232 mg o f t h e k e t o d i o l 383) i n 15 m l o f a n hydrous e t h e r and 30 m l o f d r y h e x a m e t h y l p h o s p h o r a m i d e was added 2.1 g o f a n h y d r o u s l i t h i u m c h l o r i d e . The m i x t u r e was s t i r r e d o v e r n i g h t under an atmosphere o f n i t r o g e n , and t h e n p o u r e d i n t o a p p r o x i m a t e l y 150 m l o f w a t e r . The r e s u l t a n t m i x t u r e was e x t r a c t e d w i t h e t h e r . The combined e t h e r e x t r a c t s were washed t h o r o u g h l y w i t h w a t e r and d r i e d o v e r anhydr magnesium s u l f a t e . E v a p o r a t i o n o f t h e s o l v e n t gave 310 mg o f a s l i g h t l y -197-y e l l o w v i s c o u s o i l w h i c h s o l i d i f i e d upon c o o l i n g . The c r u d e p r o d u c t was r e c r y s t a l l i z e d f r o m hexane t o g i v e 242 mg (91%) o f t h e k e t o d i c h l o r i d e 391 as creamy c o l o r e d c r y s t a l s w h i c h e x h i b i t e d m.p. 133-135 ; i . r . ( C H C 1 0 ) , v 1706 c m - 1 ; p.m.r.!, 0.62 ( s , 3H, t e r t i a r y m e t h y l ) , 0.92 j max ( d , 3H, s e c o n d a r y m e t h y l , J=6.5 H z ) , 3.36, 3.66 (AB p a i r o f d o u b l e t s , 2H, CH 2C1, J=11.0 H z ) , 3.61, 3.81 (AB p a i r o f d o u b l e t s , 2H, CH_2C1, J-12.0 H z ) . A n a l . C a l c d . f o r C ^ H ^ C ^ O : C, 62.29; H, 7.67. Found: C, 62.27; H, 7.85. I n t r a m o l e c u l a r A l k y l a t i o n o f t h e K e t o D i c h l o r i d e 3JLL To a s m a l l amount o f d r y t e r t - b u t y l a l c o h o l was added 36 mg o f p o t a s s i u m m e t a l . The m i x t u r e was warmed b r i e f l y t o e n s u r e t h a t a l l t h e p o t a s s i u m had r e a c t e d . The e x c e s s t e r t - b u t y l a l c o h o l was removed un d e r r e d u c e d p r e s s u r e (vacuum pump). To t h e r e m a i n i n g p o t a s s i u m t e r t - b u t o x i d e ( w h i t e powder) was s u c c e s s i v e l y added 10 m l o f d r y t e t r a h y d r o f u r a n , and a s o l u t i o n o f 178 mg (0.615 mmole) o f t h e k e t o d i c h l o r i d e 391 i n 5 m l o f d r y t e t r a h y d r o f u r a n . The r e s u l t i n g o r a n g e y e l l o w s o l u t i o n was s t i r r e d under a n i t r o g e n atmosphere a t room t e m p e r a t u r e f o r lh h o u r . Aqueous ammonium c h l o r i d e was added and t h e r e s u l t i n g m i x t u r e was e x t r a c t e d w i t h p e n t a n e . The combined e x t r a c t s were washed w i t h w a t e r and b r i n e , and * A sample o f t h e k e t o d i c h l o r i d e 391 w h i c h was o b t a i n e d by means o f p r e p a r a t i v e t . l . c . u s i n g 7:3 h e x a n e - e t h e r as t h e d e v e l o p i n g s o l v e n t , and w h i c h was n o t r e c r y s t a l l i z e d , e x h i b i t e d m.p. 74-76°. -198-d r i e d o v e r anhydrous magnesium s u l f a t e . E v a p o r a t i o n o f t h e s o l v e n t gave 141 mg (91%) o f a p a l e y e l l o w o i l w h i c h was used i n t h e s u b s e q u e n t t r a n s f o r m a t i o n w i t h o u t f u r t h e r p u r i f i c a t i o n b e c a u s e o f i t s t h e r m a l i n s t a b i l i t y ; i . r . ( f i l m ) , v 1700 cm \ p.m.r., 0.73 ( s , 3H, t e r t i a r y m e t h y l ) , 0.87 ( d , 3H, s e c o n d a r y m e t h y l , d=6.0 H z ) , 3.60 ( s , 2H, CH_ 2C1). R e d u c t i o n o f t h e K e t o M o n o c h l o r i d e 3_9_2, To a c o l d (0°) s o l u t i o n o f 141 mg o f t h e c r u d e k e t o m o n o c h l o r i d e 392 i n 10 m l o f d r y t e t r a h y d r o f u r a n was added 2.8 m l (2.8 mmoles) o f a s o l u t i o n o f l i t h i u m t r i e t h y l b o r o h y d r i d e i n t e t r a h y d r o f u r a n ( I M ) . The m i x t u r e was s t i r r e d f o r 20 h o u r s a t room t e m p e r a t u r e under a n i t r o g e n a t m o s p h e r e . The e x c e s s r e d u c i n g a g e n t was d e s t r o y e d by a d d i t i o n o f 4 m l o f w a t e r . A p p r o x i m a t e l y 3 m l o f 3N sodium h y d r o x i d e and 3 m l o f 30% h y d r o g e n p e r o x i d e s o l u t i o n were c a r e f u l l y added t o t h e r e a c t i o n m i x t u r e . The m i x t u r e was s t i r r e d f o r a n o t h e r 4 h o u r s a t room t e m p e r a t u r e , was d i l u t e d w i t h w a t e r and t h e n t h o r o u g h l y e x t r a c t e d w i t h e t h e r . The combined e t h e r a l e x t r a c t s were washed w i t h w a t e r and b r i n e , and t h e n d r i e d o v e r a n h y d r o u s magnesium s u l f a t e . E v a p o r a t i o n o f t h e s o l v e n t gave 148 mg o f t h e a l c o h o l 393 a s a p a l e y e l l o w o i l . D i s t i l l a t i o n a t 100-110° ( a i r 12 b a t h t e m p e r a t u r e ) and 0.5 mm ( l i t . b . p . 114° a t 1 mm ) y i e l d e d 128 mg (94% b a s e d on t h e k e t o d i c h l o r i d e 391 used) o f a c o l o r l e s s v i s c o u s o i l ; i . r . ( f i l m ) , v 3350 ( b r o a d ) cm ^; p.m.r., 0.55 (m, I H , c y c l o p r o p y l in fix p r o t o n ) , 0.77 ( d , 3H, s e c o n d a r y m e t h y l , d=5.5 H z ) , 1.03 ( s , 3H, t e r t i a r y m e t h y l ) , 1.13 ( s , 3H, t e r t i a r y m e t h y l ) , 3.42 (m, I H , CHOH). P r e p a r a t i o n o f (±)-Ishwarone 12. To a s u s p e n s i o n o f chromium t r i o x i d e (282 mg, 2.82 mmoles) i n 20 m l -199-o f m e t h y l e n e c h l o r i d e was added 330 mg (2.86 mmoles) o f p y r i d i n i u m h y d r o c h l o r i d e . The m i x t u r e was s t i r r e d f o r 1 hour t o f o r m a b r i g h t y e l l o w - o r a n g e s u s p e n s i o n - s o l u t i o n . To t h i s s u s p e n s i o n - s o l u t i o n was added a s o l u t i o n o f 128 mg (0.58 mmole) o f a l c o h o l ( s ) 393 i n a minimum amount o f m e t h y l e n e c h l o r i d e . The r e a c t i o n m i x t u r e was s t i r r e d a t room t e m p e r a t u r e f o r 2 h o u r s , was d i l u t e d w i t h e t h e r and t h e n f i l t e r e d t h r o u g h a s h o r t f l o r i s i l column. The column was e l u t e d w i t h e t h e r . E v a p o r a t i o n o f t h e s o l v e n t f r o m t h e e l u a n t gave 115 mg o f a y e l l o w o i l . D i s t i l l a t i o n o f t h e c r u d e p r o d u c t a t 120-130° under w a t e r a s p i r a t o r p r e s s u r e gave 92 mg (73%) o f c o l o r l e s s o i l w h i c h s o l i d i f i e d upon c o o l i n g . R e c r y s t a l l i z a t i o n f r o m p e n t a n e gave (±)-ishwarone 12_ a s c o l o r l e s s c r y s t a l s w h i c h e x h i b i t e d m.p. 80-81°; i . r . ( f i l m ) , v 3030, 1700 cm "*"; 1 m a x » p.m.r., 0.56 (m, I H , c y c l o p r o p y l p r o t o n ) , 0.74 ( s , 3H, t e r t i a r y m e t h y l ) , 0.87 ( d , 3H, s e c o n d a r y m e t h y l , d=6.5 H z ) , 1.16 ( s , 3H, t e r t i a r y m e t h y l ) . The s p e c t r a l p r o p e r t i e s o f t h i s s y n t h e t i c ( i ) - i s h w a r o n e 12_ were i n f u l l 12 agreement w i t h t h o s e o f n a t u r a l i s h w a r o n e . M o l . Wt. C a l c d . f o r C ^ H ^ O : 218.1671. Found ( h i g h r e s o l u t i o n mass s p e c t r o m e t r y ) : 218.1679. W o l f f - K i s h n e r R e d u c t i o n o f (±)-Ishwarone JLZ t o (±)-Ishwarane 13. To 20 m l o f d i e t h y l e n e g l y c o l was added 0.5 g o f m e t a l l i c sodium. The m i x t u r e was warmed w i t h a steam b a t h u n t i l t h e r e a c t i o n between t h e sodium and d i e t h y l e n e g l y c o l was c o m p l e t e . To t h e r e s u l t a n t s o l u t i o n was added 31 mg (.0.14 mmole) o f i s h w a r o n e 1_2 and 3 m l o f h y d r a z i n e h y d r a t The s o l u t i o n was h e a t e d s l o w l y w i t h d i s t i l l a t i o n ( t h e d i s t i l l a t e was sa v e u n t i l t h e i n t e r n a l t e m p e r a t u r e r e a c h e d 180° and was t h e n r e f l u x e d a t t h i s -200-t e m p e r a t u r e f o r 18 h o u r s . The s o l u t i o n was a g a i n s l o w l y d i s t i l l e d ( t h e d i s t i l l a t e was saved) u n t i l t h e i n t e r n a l t e m p e r a t u r e had r e a c h e d 210°. A f t e r t h e r e a c t i o n m i x t u r e had been r e f l u x e d f o r 6 h o u r s , i t was c o o l e d , combined w i t h t h e two d i s t i l l a t e s o b t a i n e d as d e s c r i b e d a bove, and t h e n p o u r e d i n t o w a t e r . The r e s u l t a n t m i x t u r e was e x t r a c t e d w i t h e t h e r . The combined e t h e r e x t r a c t s were washed w i t h w a t e r and b r i n e and d r i e d o v e r a nhydrous magnesium s u l f a t e . E v a p o r a t i o n o f e t h e r and s u b s e q u e n t d i s t i l l a t i o n o f t h e c r u d e p r o d u c t a t 90-120° ( a i r b a t h t e m p e r a t u r e ) and w a t e r a s p i r a t o r p r e s s u r e gave 23.5 mg (81%) o f (±)-i s h w a r a n e L3 as a c o l o r l e s s o i l ; i . r . ( f i l m ) , no c a r b o n y l a b s o r p t i o n ; p.m.r., 0.52 (m, 2H, c y c l o p r o p y l p r o t o n s ) , 0.74 ( d , 3H, s e c o n d a r y m e t h y l , J=6.5 H z ) , 0.78 ( s , 3H, t e r t i a r y m e t h y l ) , 1.14 ( s , 3H, t e r t i a r y m e t h y l ) . T h i s 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 d a t a ( i . r . , p.m.r., and mass s p e c t r u m ) , and g . l . c . r e t e n t i o n t i m e (column F, 120° f o r 5 m i n u t e s and t h e n r a i s e d t o 200° f o r 10 m i n u t e s w i t h t h e r a t e o f 25°/min, 180 ml/min) 34 i d e n t i c a l w i t h t h o s e o f a u t h e n t i c (±)-ishwarane, M o l . Wt. C a l c d . f o r C 1 5 H 2 4 : 2°4.1898. Found ( h i g h r e s o l u t i o n mass s p e c t r o m e t r y ) : 204.1878. -201-BIBLIOGRAPHY 1. L. R u z i c k a , A. Eschenmoser, 0. J e g e r , and A. A r i g o n i , H e l v . Chem. A c t a , 38, 1890 ( 1 9 5 5 ) . 2. G. O u r i s s o n , S. M u n a v a l l i , and C. E h r e t , I n t e r n a t i o n a l t a b l e s o f  s e l e c t e d c o n s t a n t s , Volume 15, D a t a r e l a t i v e t o s e s q u i t e r p e n o i d s , Pergamon P r e s s , I n c . , New Y o r k , N.Y., ( 1 9 6 6 ) . 3. T. K. Devon and A. I . S c o t t , Handbook o f n a t u r a l l y o c c u r r i n g  compounds, Volume I I , T e r p e n e s , Academic P r e s s , New Y o r k , N.Y., ( 1 9 7 2 ) . 4. A. E. B r a d f i e l d , A. B. P e n f o l d , and J . L. Simonsen, J . Chem. S o c , 2744 ( 1 9 3 2 ) . 5. A. R. P e n f o l d and J . L. Simonsen, J . Chem. S o c , 87 ( 1 9 3 9 ) . 6. D. F. G r a n t , R. G. H o w e l l s , and D. R o g e r s , A c t a . C r y s t a l l o g r . , 10, 498 ( 1 9 5 7 ) . 7. W. D. MacLeod, J r . , T e t r a h e d r o n L e t t e r s , 4779 ( 1 9 6 5 ) . 8. D. F. MacSweeney, R. Ramage, and A. S a t t e r , T e t r a h e d r o n L e t t e r s , 557 ( 1 9 7 0 ) . 9. U. S. K. Rao, B. L. M a n j u n a t h , and K. N. Menon, J . I n d i a n Chem. S o c , 12, 494 ( 1 9 3 5 ) . 10. A. K. G a n g u l y , K. W. G o p i n a t h , T. R. G o v i n d a c h a r i , K. N a g a r a j a n , B. R. P a i , and P. C. P a r t h a s a r a t h y , T e t r a h e d r o n L e t t e r s , 133 ( 1 9 6 9 ) . •11. T. R. G o v i n d a c h a r i , K. N a g a r a j a n , and P. C. P a r t h a s a r a t h y . Chem. Commun., 823 ( 1 9 6 9 ) . 12. H. F u h r e r , A. K. G a n g u l y , K. W. G o p i n a t h , T. R. G o v i n d a c h a r i , K. N a g a r a j a n , B. R. P a i , and P. C. P a r t h a s a r a t h y , T e t r a h e d r o n , 26, 2371 ( 1 9 7 0 ) . -202-13. T. R. G o v i n d a c h a r i , P. A. Mohamed and P. C. P a r t h a s a r a t h y , T e t r a h e d r o n , 26, 615 ( 1 9 7 0 ) . 14. L. C. Teng and J . F. D e B a r d e l e b e n , E x p e r i e n t a , 27, 14 ( 1 9 7 1 ) . 15. S. Swaminathan and G. S r e e n i v a s a M u r t h y , C u r r . S c i . I n d i a , 38, 135 ( 1 9 6 9 ) . 16. R. N i s h i d a and Z. Kumazawa, A g r . B i o l . Chem., 37, 341 ( 1 9 7 3 ) . 17. J . A. M a r s h a l l , H. F a u b l , and T. M. Warne, Chem. COmmun., 753 ( 1 9 6 7 ) . 18. R. L. H a l e and L. H. Z a l k o w , Chem. Commun., 1249 ( 1 9 6 8 ) . 19. R. M. C o a t e s and J . M. Shaw, Chem. Commun., 47 ( 1 9 6 8 ) . 20. R. M. C o a t e s and J . M. Shaw, J . Org. Chem., 35, 2597 ( 1 9 7 0 ) . 21. R. M. C o a t e s and J . M. Shaw, J . Amer. Chem. S o c , 92, 5657 ( 1 9 7 0 ) . 22. E. P i e r s , R. W. B r i t t o n , and W. de Wa a l , Can. J . Chem., 47, 4307 (1969) 23. C. B e r g e r , M. Franck-Neumann, and G. O u r i s s o n , T e t r a h e d r o n L e t t e r s , 3451 ( 1 9 6 8 ) . 24. H. M. M c G u i r e , H. C. Odom, and A. R. P i n d e r , J . Chem. S o c , P e r k i n I , 1879 ( 1 9 7 4 ) . 25. A. Van d e r Gen, L. M. Van d e r L i n d e , J . G. W i t t e v e e n , and H. B o e l e n s , R e e l . T r a v . Chim. P a y s - B a s , 90, 1034 ( 1 9 7 1 ) . 26. A. Van d e r Gen, L. M. Van d e r L i n d e , J . G. W i t t e v e e n , and H. B o e l e n s , R e e l . T r a v . Chim. P a y s - B a s , 90, 1045 ( 1 9 7 1 ) . 27. J . E. McMurry, J . H. M u s s e r , M. S. Ahmad, and L. C. B l a s z c z a k , J . Org. Chem., 40, 1829 ( 1 9 7 5 ) . 28. M. E. J u n g , T e t r a h e d r o n , 33_, 3 ( 1 9 7 6 ) . 29. E. P i e r s , R. W. B r i t t o n , and W. de Wa a l , Can. J . Chem., 47, 831 ( 1 9 6 9 ) . 30. E. P i e r s and D. R. S m i l l i e , J . Org. Chem.,35, 3997 ( 1 9 7 0 ) . 31. E. P i e r s and M. B. G e r a g h t y , Can. J . Chem., 5 1, 2166 ( 1 9 7 1 ) . -203-32. R. B. K e l l y and J . Zamecnik, Chem. Commun., 1102 ( 1 9 7 0 ) . 33. R. B. K e l l y , J . Zamecnik, and B. A. B e c k e t t , Chem. Commun., 479 ( 1 9 7 1 ) . 34. R. B. K e l l y , J . Zamecnik, and B. A. B e c k e t t , Can. J . Chem., 50, 3455 ( 1 9 7 2 ) . 35. S. Murayama, D. Chan, and M. Brown, T e t r a h e d r o n L e t t e r s , 3715 ( 1 9 6 8 ) . 36. K. P. D a s t u r , J . Amer. Chem. S o c , 95, 6509 ( 1 9 7 3 ) . 37. K. P. D a s t u r , J . Amer. Chem. S o c , 96, 2605 ( 1 9 7 4 ) . 38. I . N a g a k u r a , H. O g a t a , M. Ueno, and Y. K i t a h a r a , B u l l . Chem. S o c , s ( J a p a n ) , 48, 2995 ( 1 9 7 5 ) . 39. I . N a g a k u r a , S. Maeda, M. Ueno, M. Fu m a n i z u , and Y. K i t a h a r a , C h e m i s t r y L e t t e r s , 1143 ( 1 9 7 5 ) . 40. J . J . Sims and L. H. Selman, T e t r a h e d r o n L e t t e r s , 561 ( 1 9 6 9 ) . 41. J . A. M a r s h a l l and R. A. Ruden, S y n t h . Commun., 1_, 227 ( 1 9 7 1 ) . 42. J . A. M a r s h a l l and R. A. Ruden, J . Org. Chem., 37, 659 ( 1 9 7 2 ) . 43. M. P e s a r o , G. B o z z a t o , and P. S c h u d e l , Chem. Commun., 1152 ( 1 9 6 8 ) . 44. T. M. Warne, J r . , Ph.D. T h e s i s , N o r t h w e s t e r n U n i v e r s i t y , 1971. 45. G. M. Cohen, U n p u b l i s h e d r e s u l t s ( c f . f o o t n o t e 4 o f R e f . 4 2 ) . 46. J . A. M a r s h a l l and G. M. Cohen, J . Org. Chem., 36, 877 ( 1 9 7 1 ) . 47. E. P i e r s and R. J . K e z i e r e , T e t r a h e d r o n L e t t e r s , 583 ( 1 9 6 8 ) . 48. E. P i e r s and R. J . K e z i e r e , Can. J . Chem., 4 7 , 137 ( 1 9 6 9 ) . 49. F. E. Z i e g l e r and P. A. Wender, T e t r a h e d r o n L e t t e r s , 449 ( 1 9 7 4 ) . 50. F. E. Z i e g l e r , G. R. R e i d , W. L. S t u d t , and P. A. Wender, J . Org. Chem., 42, 1991 ( 1 9 7 7 ) . 51. N. A. L e B e l and J . E. H u b l e r , J . Amer. Chem. S o c , 85, 3195 ( 1 9 6 3 ) . 52. H. 0. House, S. G. B o o t s , and V. K. J o n e s , J . Org. Chem., 30, 2519 ( 1 9 6 5 ) . -204-53. P. N. C h a k r a b o r t t y , R. D a s g u p t a , S. K. D a s g u p t a , S. R. Ghosh, and U. R. Ghat a k , T e t r a h e d r o n , 28, 4653 ( 1 9 7 2 ) . 54. A. T a h a r a , M. S h i m a g a k i , S. Oha r a , and T. N a k a t a , T e t r a h e d r o n  L e t t e r s , 1701 ( 1 9 7 3 ) . 55. C. J . V. S c a n i o and D. L. L i c k e i , T e t r a h e d r o n L e t t e r s , 1363 ( 1 9 7 2 ) . 56. D. L. L i c k e i , Ph.D. T h e s i s , Iowa S t a t e U n i v e r s i t y , 1973. 57. R. B. K e l l y , B. A. B e c k e t t , J . E b e r , H-K. Hung, and J . Zamecnik, Can. J . Chem., 53, 143 (1975) . 58. R. B. K e l l y , J . E b e r , and H-K. Hung, Chem. Commun., 689 ( 1 9 7 3 ) . 59. R. B. K e l l y and S. J . A l w a r d , Can. J . Chem., 55, 1786 ( 1 9 7 7 ) . 60. R. M. Cor y and D. M. T. Chan, T e t r a h e d r o n L e t t e r s , 4441 ( 1 9 7 5 ) . 61. W. R. Moore, H. R. Ward, and R. F. M e r r i t t , J . Amer. Chem. Soc., 83, 2019 ( 1 9 6 1 ) . 62. L. A. P a q u e t t e , G. Zon, and R. T. T a y l o r , J . Org. Chem., 39, 2677 ( 1 9 7 4 ) . 63. L. A. P a q u e t t e and R. T. T a y l o r , J . Amer. Chem. Soc., 99, 5708 ( 1 9 7 7 ) . 64. R. M. C o r y , L. P. J . B u r t o n , and F. R. M c L a r e n , A b s t r a c t s , 172nd N a t i o n a l M e e t i n g o f t h e A m e r i c a n C h e m i c a l S o c i e t y , San F r a n c i s c o , C a l i f o r n i a , Aug. 3 0 - S e p t . 3 , 1976, No. ORGN-11. 65. R. M. Cor y and F. R. M c L a r e n , Chem. Commun., 587 ( 1 9 7 7 ) . 66. E. P i e r s , W. de Waal and R. W. B r i t t o n , J . Amer. Chem. S o c , 9_3, 5113 ( 1 9 7 1 ) . 67. P. S. S k e l l and R. M. E t t e r , P r o c . Chem. S o c , ( L o n d o n ) , 443 ( 1 9 6 1 ) . 68. M. E. W o l f f , S-Y, Cheng, and W. Ho, J . Med. Chem., 1 1, 864 ( 1 9 6 8 ) . 69. H. Musso, Chem. B e r . , 101, 3710 ( 1 9 6 8 ) . 70. K. K i t a t a n i , T. Hiyama, and H. N o z a k i , J . Amer. Chem. S o c , 97, 949 ( 1 9 7 5 ) . -205-71. K. K i t a t a n i , T. Hiyama, and H. N o z a k i , B u l l . Chem. S o c . , (Japan) 50, 3288 ( 1 9 7 7 ) . 72. E. P i e r s and T. W. H a l l , Chem. Commun., 880 ( 1 9 7 7 ) . 73. A. J . B i r c h , E. M. A. S h o n k r y , and.F. S t a n s f i e l d , J . Chem. Soc., ( C ) , 5376 ( 1 9 6 1 ) . 74. A. S. O n i s h c h e n k o , D i e n e S y n t h e s i s , I s r a e l P rogram f o r S c i e n t i f i c T r a n s l a t i o n s , J e r u s a l e m , ( 1 9 6 4 ) . 75. R. J a c q u i e r and M. M o s s e r o n , B u l l . Soc. Chim. F r a n c e , 1653 ( 1 9 5 6 ) . 76. E. E. Van Tamelen, P. E. A l d r i c h , and T. J . K a t z , J . Amer. Chem. Soc., 79, 6427 ( 1 9 5 7 ) . 77. P. D. B a r t l e t t and G. F. Woods, J . Amer. Chem. S o c , 62_, 2933 ( 1 9 4 0 ) . 78. K. S. A y y a r , R. C. Cookson, and D. A. K a g i , Chem. Commun., 161 ( 1 9 7 3 ) . 79. H. P a u l y and H. L i e c k , Chem. B e r . , 33, 500 ( 1 9 0 0 ) . 80. R. L. Wasson and H. 0. House, Org. Syn. , C o l l . v o l . '_4, 552 ( 1 9 6 3 ) . 81. H. J . R i n g o l d , E. B a t r e s , 0. M a n c e r a , and G. R o s e n k r a n z , J . Org. Chem., 2 1 , 1432 ( 1 9 5 6 ) . 82. N. G r e e n and M. B e r o z a , J . Org. Chem., 24, 761 ( 1 9 5 9 ) . 83. S. D i x o n and L. F. W i g g i n s , J . Chem. S o c , 594 ( 1 9 5 4 ) . 84. R. L. K r o n e n t h a l and E. I . B e c k e r , J . Amer. Chem. S o c , 79, 1095 (1 9 5 7 ) . 85. G. S t o r k and P. L. S t o t t e r , J . Amer. Chem. S o c , 91, 7786 ( 1 9 6 9 ) . 86. L. L. D o l b y , S. E s f a n d i a r i , C. A. E l l i g e r and K. S. M a r s h a l l , J . Org. Chem., 36, 1277 ( 1 9 7 1 ) . 87. A. A. P e t r o v and K. B. R a i l , J . Gen. Chem., 26_, 1779 ( 1 9 5 6 ) . 88. W. G. Dauben, M. L o r b e r , and D. S. F u l l e r t o n , J . Org. Chem., 34, 3587 ( 1 9 6 9 ) . -206-89. S. L. M u k h e r j e e and P. C. D u t t a , J . Chem. S o c , 67 ( 1 9 6 0 ) . 90. B. W. F i n u c a n e and J . B. Thompson, Chem. Commun., 1220 ( 1 9 6 9 ) . 91. W. C. A g o s t a and W. W. Lawrance J r . , J . Org. Chem., 35, 3851 ( 1 9 7 0 ) . 92. S. T o r i i , T. K u n i t o m i , and T. Okamoto, B u l l . Chem. S o c , J a p a n , 47, 2349 ( 1 9 7 4 ) . 93. T. I n u k a i and T. K o j i m a , J . Org. Chem., 31, 3032 (1966) 94. T. I n u k a i and T. Ko j ima, J . Org. Chem., 32, 872 ( 1 9 6 7 ) . 95. T. I n u k a i and T. K o j i m a , J . Org. Chem., 31, 1121 (1966) 96. H. W. Thompson and D. G. M e l l i l o , J . Amer. Chem. S o c , 92, 3218 ( 1 9 7 0 ) . 97. E. J . C o r e y , U. K o e l l i k e r and J . N e u f f e r , J . Amer. Chem. S o c , 93, 1489 ( 1 9 7 1 ) . 98. P. W. W o r e s t e r , U n p u b l i s h e d r e s u l t s . 99. R. E. I r e l a n d , D. C. Muchmore, and U. H e n g a s t e r , J . Amer. Chem. Soc., 94, 5098 ( 1 9 7 2 ) . 100. R. R a t c l i f f e and R. R o d e h o r s t , J . Org. Chem., 35_, 4000 ( 1 9 7 0 ) . 101. V. G e o g i a n , R. H a r r i s o n , and N. G u b i s c h , J . Amer. Chem. Soc., 81, 5834 ( 1 9 5 9 ) . 102. R. L. C l a r k e , J . Amer. Chem. Soc., 83, 965 ( 1 9 6 1 ) . 103. C. H. H e a t h c o c k , J . E. E l l i s and R. A. Badger, J . H e t e r o c y c l i c  Chem., 6_, 139 ( 1 9 6 9 ) . 104. J . Hooz and R. B. L a y t o n , Can. J . Chem., 48, 1626 ( 1 9 7 0 ) . 105. G. H. P o s n e r , Org. R e a c t i o n s , v o l . 19_. J o h n W i l e y and Sons, I n c . , New Y o r k , New Y o r k ( 1 9 7 2 ) . 106. C. A l e x a n d r e and F. R o n e s s a c , B u l l . Soc. Chem. B e l g . , 83, 393 ( 1 9 7 4 ) . -207-107. C. A l e x a n d r e and F. R o n s s a c , Chem. Commun., 275 ( 1 9 7 5 ) . 108. D. S e y f e r t h , Org. Syn., C o l l . v o l . 4, 258 ( 1 9 6 3 ) . 109. H. C. Brown, A. K. Man d a l and S. U. K u l k a r n i , J . Org. Chem., 42, 1392 ( 1 9 7 7 ) . 110. E. J . C o r e y and P. L. F u c h s , T e t r a h e d r o n L e t t e r s , 3769 ( 1 9 7 2 ) . 111. E. W. G a r b i s c h J r . , J . Chem. Ed., 4 5 , 402 ( 1 9 6 8 ) . 112. L. M. Jackman and S. S t e r n h e l l , A p p l i c a t i o n s o f N u c l e a r M a g n e t i c  Resonance S p e c t r o s c o p y i n O r g a n i c C h e m i s t r y , 2nd Ed., Pergamon P r e s s , London ( 1 9 6 9 ) . 113. E. N. M a r v e l l and T. L i , S y n t h e s i s , 457 ( 1 9 7 3 ) . 114. D. J . Cram and N. L. A l l i n g e r , J . Amer. Chem. S o c , 78, 2518 ( 1 9 5 6 ) . 115. A. I . V o g e l , A T e x t b o o k o f P r a c t i c a l O r g a n i c C h e m i s t r y , Longmans, London ( 1 9 6 1 ) . 116. R. K. C r o s s l a n d and K. L. S e r v i s , J . Org. Chem., 35, 3195 ( 1 9 7 0 ) . 117. J-M. C o n i a and F. R o n e s s a c , T e t r a h e d r o n , 16, 45 ( 1 9 6 1 ) . 118. G. H. P o s n e r , C. E. W h i t t e n , J . J . S t e r l i n g , D. J . B r u n e l l e , T e t r a h e d r o n L e t t e r s , 2591 ( 1 9 7 4 ) . 119. G. H. P o s n e r , J . J . S t e r l i n g , C. E. W h i t t e n , C. M. L e n t z and D. J . B r u n e l l e , J . Amer. Chem. S o c , 97, 107 ( 1 9 7 5 ) . 120. G. K o b r i c h , Angew. Chem. I n t e r n a t . E d i t . , j6, 41 ( 1 9 6 7 ) . 121. T. Hiyama, S. T a k e h a r a , K. K i t a t a n i and H. N o z a k i , T e t r a h e d r o n  L e t t e r s , 3295 ( 1 9 7 4 ) . 122. M. B r a u n , R. Dammann and D. Seebach, Chem. B e r . , 2368 ( 1 9 7 5 ) . 123. K. K i t a t a n i , T. Hiyama and H. N o z a k i , J . Amer. Chem. S o c , 98, 2362 ( 1 9 7 6 ) . 124. S. W. Tobey and R. West, J . Amer. Chem. S o c , 88, 2481 ( 1 9 6 6 ) . -208-125. D. S e y f e r t h , J . M. B u r l i t c h , R. J . M i n a s z , J . Y.-P. M u i , H. D. Simmons, J r . , A. J . H. T r e i b e r , and S. R. Dowd, J . Amer. Chem. S o c , 87, 4259 ( 1 9 6 5 ) . 126. W. v o n E. D o e r i n g and A. K. Hoffman, J . Amer. Chem. S o c , 76, 6162 (1 9 5 4 ) . 127. E. V. Dehmlow, Angew. Chem. I n t e r n a t . E d i t . , 13, 170 ( 1 9 7 4 ) . 128. M. Makosza and M. F e d o r y n s k i , Syn. Commun. , 3_, 305 ( 1 9 7 3 ) . 129. C. L. Graham and F. J . M c Q u i l l i n , J . Chem. S o c , 4634 ( 1 9 6 3 ) . 130. D. D. R o b e r t s , J . Org. Chem., 3 1 , 2000 ( 1 9 6 6 ) . 131. M. N i k o l e t i c , S. B o r c i c and D. E. Sunko, T e t r a h e d r o n , 23, 649 ( 1 9 6 7 ) . 132. M. N i k o l e t i c , S. B o r c i c and D. E. Sunko, P r o c . N a t ' l . A c a d . S c i . , U.S. 5_2, 893 ( 1 9 6 4 ) . 133. A. K. Bose and B. L a i , T e t r a h e d r o n L e t t e r s , 3937 ( 1 9 7 3 ) . 134. R. A p p e l , Angew. Chem. I n t e r n a t . E d i t . , 14, 801 ( 1 9 7 5 ) . 135. L. H. S m i t h , Org. Syn., C o l l . v o l . 3, 793 ( 1 9 5 5 ) . 136. L. P. S c h a e f e r , J . G. H i g g i n s and P. K. Shenoy, Org. Syn., 48, 51 ( 1 9 6 8 ) . 137. N. Furukawa, T. I n o n e , T. A i d a and S. Oae, Chem. Commun., 212 ( 1 9 7 3 ) . 138. K. E. H a r d i n g and J . W. T r o t t e r , J . Org. Chem., 42, 4157 ( 1 9 7 7 ) . 139. B. L y t h g o e , T. A. Moran, M. E. N. Nambudiry, S. R u s t o n , J . T i d e s w e l l , and P. W. W r i g h t , T e t r a h e d r o n L e t t e r s , 3863 ( 1 9 7 5 ) . 140. B. L y t h g o e , T. A. Moran, M. E. N. Nambudiry and S. R u s t o n , J . Chem. S o c P e r k i n I , 2386 ( 1 9 7 6 ) . 141. W. v o n E. D o e r i n g and C. H. DePuy, J . Amer. Chem. S o c , 75, 5955 ( 1 9 5 3 ) . 142. B. W. P e a c e , F. Carman, D. S. Wulfman, S y n t h e s i s , 658 ( 1 9 7 1 ) . 143. B. W. Peace and D. S. Wulfman, S y n t h e s i s , 137 ( 1 9 7 3 ) . -209-144. R. K. S i n g h and S. D a n i s h e f s k y , J . Org. Chem., 41, 1668 ( 1 9 7 6 ) . 145. H. C. Brown and S. K r i s h m a m u r t h y , J . Amer. Chem. S o c , 95, 1669 ( 1 9 7 3 ) . 146. S. K r i s h n a m u r t h y , H. C. Brown, J . Org. Chem., 4 1 , 3064 ( 1 9 7 6 ) . 147. R. H. H o l d e r and M. G. M a t t u r r o , J . Org. Chem.,42, 2166 ( 1 9 7 7 ) . 148. E . - I . N e g i s h i , Chem. Commun., 762 ( 1 9 7 4 ) . 149. E. C. Ashby, A. B. G o e l and J . J . L i n , T e t r a h e d r o n L e t t e r s , 3695 ( 1 9 7 7 ) . 150. S. Masamune, G. S. B a t e s , P. E. G e o r g h i o u s , J . Amer. Chem. Soc., 96, 3686 ( 1 9 7 4 ) . 151. E. J . Corey and J . W. Suggs, T e t r a h e d r o n L e t t e r s , 2647 ( 1 9 7 5 ) . 152. J . E. H o d g k i n s and R. J . F l o r e s , J . Org. Chem., 28, 3356 ( 1 9 6 3 ) . 

Cite

Citation Scheme:

        

Citations by CSL (citeproc-js)

Usage Statistics

Share

Embed

Customize your widget with the following options, then copy and paste the code below into the HTML of your page to embed this item in your website.
                        
                            <div id="ubcOpenCollectionsWidgetDisplay">
                            <script id="ubcOpenCollectionsWidget"
                            src="{[{embed.src}]}"
                            data-item="{[{embed.item}]}"
                            data-collection="{[{embed.collection}]}"
                            data-metadata="{[{embed.showMetadata}]}"
                            data-width="{[{embed.width}]}"
                            async >
                            </script>
                            </div>
                        
                    
IIIF logo Our image viewer uses the IIIF 2.0 standard. To load this item in other compatible viewers, use this url:
http://iiif.library.ubc.ca/presentation/dsp.831.1-0060956/manifest

Comment

Related Items