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Synthetic studies directed towards the indole alkaloid (±)-aristoteline Jamieson, Patrick Robert 1979

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SYNTHETIC STUDIES DIRECTED TOWARDS THE INDOLE ALKALOID (±)-ARISTOTELINE by PATRICK ROBERT JAMIESON B.Sc. , University of Alberta, 1974 A THESIS SUBMITTED IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY i n THE FACULTY OF GRADUATE STUDIES (DEPARTMENT OF CHEMISTRY) We accept t h i s thesis as conforming to the required standard THE UNIVERSITY OF BRITISH COLUMBIA NOVEMBER 1979 ©PATRICK ROBERT JAMIESON, 1979 In present ing th is thes is in p a r t i a l fu l f i lment of the requirements for an advanced degree at the Un ivers i ty of B r i t i s h Columbia, I agree that the L ibrary sha l l make it f ree ly ava i lab le for reference and study. I fur ther agree that permission for extensive copying of th is thes is for scho la r ly purposes may be granted by the Head of my Department or by h is representa t ives . It is understood that copying or pub l ica t ion of th is thes is for f inanc ia l gain sha l l not be allowed without my wri t ten permission. Department of The Univers i ty of B r i t i s h Columbia 2075 Wesbrook P l a c e V a n c o u v e r , Canada V6T 1W5 Date 7 l V ^ - /0 , /f ?? 6 i i ABSTRACT This thesis describes some synthetic studies directed towards ( ± ) — a r i s t o t e l i n e (8), a natur a l l y occurring indole a l k a l o i d possessing a novel molecular structure. An e f f i c i e n t , stereoselective synthesis of the k e t a l carbamate (116) and attempts to transform t h i s material into (8) are reported. The synthesis of the intermediate d i k e t a l ether (35) was accom-plished as follows. Treatment of 9-methyl-5(10)-octalin-l,6-dione with 2,2-dimethyl-l,3-propanediol i n the presence of j p-toluenesulfonic a c i d (as c a t a l y s t ) produced the corresponding d i k e t a l compound. Subjection of the l a t t e r material to a hydroboration-oxidation sequence, using borane-dimethylsulfide complex and hydrogen peroxide, afforded two alcohols i n a r a t i o of approximately 9:1. The r e l a t i v e stereochemistry of these alcohols was determined by chemical c o r r e l a t i o n with compounds of known structure and stereochemistry. The preparation of the d i k e t a l ether (35) was completed by the e t h e r i f i c a t i o n of the major product from the hydroboration-oxidation sequence with /9-methoxyethoxymethyl c h l o r -ide. The elaboration of the d i k e t a l ether (35) into the «,/?-unsaturated ester (61) was accomplished i n two steps. Thus, treatment of compound (35) with 2-methylcyclohexanone i n the presence of a c a t a l y t i c amount of j>-toluenesulfonic acid produced a mixture of the corresponding monoketal compounds. This crude mixture was allowed to react with the potassium s a l t of t r i e t h y l phosphonoacetate giving the «,^-unsaturated ester (61) as a 1:1 mixture of geometric isomers. i i i Hydrogenation of compound (61) using platinum oxide c a t a l y s t pro-duced a mixture (64:36, r e s p e c t i v e l y ) of two saturated e s t e r s , the desired a-face epimer (72) and i t s diastereomer. The sterochemical d i s p o s i t i o n of these compounds was deduced by chemical c o r r e l a t i o n with compounds of known stereochemistry i n conjunction with nmr s p e c t r a l a n a l y s i s . The synthesis of the k e t a l carbamate (116) was completed i n three steps from the saturated ester (72). Treatment of the l a t t e r compound with l i t h i u m diisopropylamide and methyl iodide afforded the corres-ponding a , a-dimethylester. The ester f u n c t i o n a l i t y was then cleaved using a mixture of potassium tert-butoxide i n anhydrous dimethylsul-foxide. The r e s u l t i n g carboxylic a c i d was elaborated i n t o the k e t a l carbamate (116) through the use of a novel and e f f i c i e n t modification of the Curtius r e a c t i o n . Unfortunately, the conversion of the k e t a l carbamate (116) into (±)-aristoteline (8), v i a an intramolecular c y c l i z a t i o n , was unsuccess-f u l . A l l attempts to s e l e c t i v e l y remove the methoxyethoxymethyl (MEM) ether moiety from (116) met with f a i l u r e . In an attempt to circumvent t h i s problem a modified approach for the completion of the synthesis of (8) was i n i t i a t e d . The ketal car-bamate (116) was treated with excess titanium t e t r a c h l o r i d e r e s u l t i n g i n the removal of both the ketal group and the ether f u n c t i o n a l i t y . Oxi-dation of the r e s u l t i n g a l c o h o l , with a chromium t r i o x i d e - p y r i d i n e complex, afforded the carbamate dione (128). Unfortunately, attempts to deprotect the amino group of (128), and subsequently elaborate the desired product into (8), v i a a reductive amination, were unsuccessful. (72 ) (128 ) M E M = C H 20CH 2 C H 20CH 3 V TABLE OF CONTENTS Page TITLE PAGE i ABSTRACT i i TABLE OF CONTENTS v LIST OF TABLES v i ACKNOWLEDGEMENTS v i i INTRODUCTION 1 I. General Comments 1 II . The I s o l a t i o n and Structural E l u c i d a t i o n of (±)-Aristoteline 6 II I . The Objective 8 DISUCSSION 10 I. General Considerations 10 II . The Synthesis of the Dik e t a l Ether (35) 20 II I . The Synthesis of the a,0-Unsaturated Ester (61) 39 IV. The Introduction and Proof of Stereochemistry at C 3 . 53 V. Attempted Synthesis of the T r i c y c l i c Ketone (12) v i a Intramolecular C y c l i z a t i o n 79 VI. Attempted Synthesis of the T r i c y c l i c Ketone (12) v i a Reductive Amination 105 VII. *H nmr Assignments 114 EXPERIMENTAL 122 BIBLIOGRAPHY 175 LIST OF TABLES v i Page TABLE 1: Chemical S h i f t s (6) of Methyl Group Protons i n the B i c y c l i c Diketal Series 118 TABLE 2: Chemical S h i f t s (6) of Methyl Group Protons i n the B i c y c l i c Monoketal Series (/?~C3 Substituted) 119 TABLE 3: Chemical S h i f t s (6) of Methyl Group Protons i n the B i c y c l i c Monoketal Series (<*-C3 Substituted) 120 TABLE 4: Chemical S h i f t s (6) of Methyl Group Protons i n the B i c y c l i c Monoketal Series (sp^ - C^) 121 v i i ACKNOWLEDGEMENTS I wish to express my sincere appreciation to Professor Edward Piers for h i s encouragement and i n t e r e s t during the course of these studies and for a l l h i s many e f f o r t s on my behalf. It has been a p r i v i l e g e to work under h i s d i r e c t i o n . My thanks to Mr. Edward H. Ruediger for proofreading portions of t h i s thesis and to Mr. Stuart H. Stubbs for h i s very generous loan of o f f i c e equipment. F i n a n c i a l assistance i n the form of scholarships from the National Research Council of Canada and from the Killam Foundation i s g r a t e f u l l y acknowledged. I also wish to express my h e a r t f e l t appreciation to my parents for the i r unwaivering moral (and f i n a n c i a l ) support during the course of my un i v e r s i t y studies. Above a l l , I wish to thank my wife, Janice, for typing and i l l u s -t r a t i n g the e n t i r e manuscript and e s p e c i a l l y for her patience and under-standing while these studies were being conducted. 1. INTRODUCTION I. General Comments Perhaps one of the greatest demonstrations of the e f f i c a c y of modern organic chemistry i s expressed through i t s a p p l i c a t i o n i n the form of organic synthesis. A l l of us, i n our day to day existence, make use of a v i r t u a l l y countless number of synthetic items. Since modern society demands an ever increasing number of these novel and diverse synthetic materials, often the impetus for the development of new syn-t h e t i c methods i s provided through t h i s challenge. Thus, the rapid development of t h i s branch of the f i e l d of chemical science i s witnessed by the overwhelming number of publications d e t a i l i n g new synthetic procedures. Most of these new methods for accomplishing a given chemical trans-formation are i n i t i a l l y applied to a seri e s of organic molecules which are r e l a t i v e l y simple i n structure. In t h i s way, the u t i l i t y of a given procedure i s demonstrated and a general idea of i t s e f f i c i e n c y and l i m i t a t i o n s i s documented. Before any of these methods may be regarded as generally a p p l i c a b l e , however, they should be f i r s t tested i n the synthesis of a v a r i e t y of complex organic compounds. In these more elaborate and highly f u n c t i o n a l i z e d molecules, an appreciation of the compatability of a new synthetic method, i t s r e a c t i o n conditions and the necessary reagents, with the a d d i t i o n a l complications of molecular 2. complexity may be evaluated more r e a l i s t i c a l l y . In a broader sense, i n f a c t , many of the most fundamental concepts which underlie organic chemistry as a whole meet with th e i r most c r u c i a l t r i a l s when they are applied during the course of the synthesis of i n t r i c a t e organic molecules. These complex chemical systems are omni-present i n nature and many of these n a t u r a l l y occurring substances have proven to be useful i n a wide v a r i e t y of ways. The use of natural products as medicinals, for example, dates back to man's e a r l i e s t r e -cords.* Frequently, however, the p h y s i o l o g i c a l l y active substances i s o l a t e d from nature are present i n only very small quantities and their i s o l a t i o n u s u a l l y requires rather elaborate and time consuming tech-niques. Thus, i t i s often through th e i r t o t a l syntheses that many of these compounds eventually become available i n useful quantities. Of the large number of known p h y s i o l o g i c a l l y active natural pro-ducts, a great many belong to the family of the indole a l k a l o i d s . These compounds comprise a very large family of natural products (approx-imately 700 are now known) and they have been a c t i v e l y investigated for 2 3 A decades. ' ' Some t y p i c a l examples are reserpine (1), i s o l a t e d from the Indian snake root plant Rauwolfia serpentina and used for the t r e a t -ment of mental disorders and strychnine (2), the cardiac stimulant i s o l a t e d from Strychnos nux vomica. The f i r s t t o t a l syntheses of both reserpine ( a n d strychnine (2)^ were completed by the l a t e R.B. Woodward's group i n 1958 and 1954, r e s p e c t i v e l y . 3. Synthet ic approaches to the indole a l k a l o i d fami ly of compounds, not s u r p r i s i n g l y , have been numerous and most of the major s t r u c t u r a l types of t h i s c l a s s of na tu ra l products have been s u c c e s s f u l l y p r e -pared s y n t h e t i c a l l y . For example, the recent synthes is of v i n b l a s t i n e (3) , a complex b i s i n d o l e a l k a l o i d which i s cu r rent l y f i n d i n g use c l i n i -c a l l y as an antitumor agent, serves as an i n t e r e s t i n g i l l u s t r a t i o n of the syn thet i c chal lenges being met i n t h i s a r e a . ^ C0 2Me 4. Naturally occurring indole a l k a l o i d s are found i n a large number of flowering plants and they display a multiformity of s t r u c t u r a l types. For the most part, though, they may be c l a s s i f i e d into four major groups based on t h e i r carbon skeletons. These four c l a s s i f i c a t i o n s are i l l u s -t rated by corynantheine (4) (corynanthe type), tabersonine (5) (aspido-sperma type), geissoschizoline (6) (strychnos type) and coronaridine (7) (iboga type). In 1975 the s t r u c t u r a l e l u c i d a t i o n of a novel indole a l k a l o i d , q a r i s t o t e l i n e (8), was reported. A r i s t o t e l i n e was found to possess an as yet unknown type of carbon skeleton which had not been observed 5. i n any previously i s o l a t e d indole a l k a l o i d s . Thus, t h i s compound repre-sented the f i r s t member of a new class of indole a l k a l o i d and, i n the short time since i t s structure was determined, three other a l k a l o i d s belonging to t h i s group have been i s o l a t e d . A ristotelone (9) has been found i n A r i s t o t e l i a c h i l e n s i s which also contains a r i s t o t e l i n e ( 8 ) . ^ Aristone (10) and a r i s t o t e l i n i n e (11), both belonging to t h i s new c l a s s , are also present i n A r i s t o t e l i a c h i l e n s i s . * * (11) 6. Although this c l a s s of indole a l k a l o i d s provides an i n t e r e s t i n g synthetic challenge, as yet there have been no reported synthetic approaches to t h i s family of compounds. II . The I s o l a t i o n and Structural E l u c i d a t i o n of A r i s t o t e l i n e A r i s t o t e l i n e (8) was f i r s t i s o l a t e d from the New Zealand wineberry plant A r i s t o t e l i a serrata and, l a t e r , i t was also found to occur i n A r i s t o t e l i a c h i l e n s i s . This a l k a l o i d , which was extracted from the roots and stems of the wineberry plant i n a y i e l d of approximately 0.07% (from d r i e d plant m a t e r i a l ) , was the main a l k a l o i d present, making up approximately 40% of the t o t a l a l k a l o i d s . Microanalysis of c r y s t a l l i n e a r i s t o t e l i n e (8), c r y s t a l l i z e d from 20 methanol (mp 164 °C, [ a ] n + 16 °), indicated a molecular formula of ^20^26^2' a S t* l e k*-6h r e s o l u t i o n mass spectrum. The compound gave a negative E h r l i c h t e s t , yet i t s uv spectrum resembled that of an i n -13 1 dole. Since both the C nmr and H nmr spectra were consistent with the presence of a 2,3-disubstituted indole system, and since both showed the absence of o l e f i n i c f u n c t i o n a l i t y , a r i s t o t e l i n e (8) had to have three r i n g s i n a d d i t i o n to the indole nucleus. The i r spectrum of the a l k a -l o i d displayed a d i s t i n c t NH stretching absorption and, since e q u i l i -bration of the compound with D^O removed two broad one-proton reson-ances i n the *H nmr spectrum ( 8 7.59 and 0.96), both of the nitrogen atoms i n the molecule were secondary. This f i n d i n g was further sup-ported by the f a c t that the e q u i l i b r a t e d material produced a molecular 7. ion of the pure a l k a l o i d . In addition, treatment of the a l k a l o i d under mild a c e t y l a t i o n conditions gave a c r y s t a l l i n e N-acetyl derivative which exhibited mp 268-270 °C. The acetylated derivative retained the i n d o l i c NH f u n c t i o n a l i t y as judged from i t s *H nmr and uv spectra. The *H nmr spectrum of a r i s t o t e l i n e (8) showed three 3-proton sing-l e t s (methyl groups) at high f i e l d . Two of these were s h i f t e d down-f i e l d to a s i m i l a r extent upon the add i t i o n of e i t h e r t r i f l u o r o a c e t i c a c i d or a europium s h i f t reagent. The chemical s h i f t of the t h i r d methyl s i n g l e t , however, was affe c t e d to a far lesser extent under both conditions. This f i n d i n g suggested that a r i s t o t e l i n e (8) probably had geminal methyl groups attached to a carbon atom adjacent to the non-i n d o l i c nitrogen atom. According to these observations, the t h i r d methyl group appeared to be remote from t h i s nitrogen atom. Since the mass spectrum of the molecule displayed an intense M-CH^ ion at m/e = 279 mass u n i t s , a methyl group attached to a carbon atom a to a n i t r o -gen atom was indeed l i k e l y . The mass spectrum of (8) also showed a strong i on corresponding to the l o s s of C^H^N from the molecular ion, along with the appearance of the appropriate metastable ion. These f a c t s , when considered i n conjunction with the *H nmr data, d e f i n i t e l y supported the presence of geminal methyl groups a to the non-indolic nitrogen atom. A broad, one-proton absorption i n the *H nmr spectrum of (8) at S 3.6 was assigned to a proton attached to another carbon atom a to the non-indolic nitrogen atom. This proton s h i f t e d downfield on N-acetyl-a t i o n and was coupled to two other protons resonating at 82.58 and 3.05. 8. The l a t t e r two protons were assigned as being due to a methylene group attached to the indole nucleus. The aforementioned data supported the p a r t i a l structure shown below. H Treatment of a methanolic s o l u t i o n of a r i s t o t e l i n e (8) with hydro-gen bromide gave the hydrobromide s a l t of the a l k a l o i d as large c o l o r -l e s s prisms. Subjection of t h i s material to a sing l e c r y s t a l , x-ray c r y s t a l l o g r a p h i c a n a l y s i s produced the complete structure and absolute stereochemistry of a r i s t o t e l i n e (8). II I . The Objective A r i s t o t e l i n e (8) represents the f i r s t member of a new class of indole a l k a l o i d s . Since t h i s c l a s s of a l k a l o i d s presents a new and i n t e r e s t i n g synthetic challenge, the objective of the research described 9 . i n t h i s t h e s i s was to explore and develop synthet ic routes which would hopefu l l y lead to the eventual t o t a l synthes is of a r i s t o t e l i n e ( 8 ) . Thus, the work descr ibed here in shou ld , i n the f u t u r e , lay the ground-work lead ing to the synthes is of t h i s h i t h e r t o unexplored c l a s s of i n -dole a l k a l o i d s . 10. DISCUSSION I. General Considerations One of the most fundamental approaches employed i n the develop-ment of a viable t o t a l synthesis of a complex organic compound involves a methodology which has recently been given the name "retero-synthetic 12 13 an a l y s i s " . ' The l a t t e r term r e f e r s to the commonly used practice of reducing the synthesis of a complex molecule into a serie s of succes-s i v e l y l e s s complex intermediates. Each of these has the c a p a b i l i t y ( i n theory, i f not always i n practice) of being converted into the next more complex intermediate i n the s e r i e s , usually through the use of care-f u l l y selected synthetic procedures which have been developed and r e -f i n e d previously. In t h i s way, one eventually a r r i v e s at a s t a r t i n g material for the synthesis which i s both r e l a t i v e l y simple i n structure and r e a d i l y a v a i l a b l e , and one which, i n theory, can ultimately be converted into the desired product by the aforementioned s e r i e s of transformations. Although t h i s type of analysis i s not without i t s 14 c r i t i c s , the technique has proven i t s ge n e r a l i t y many times i n the past. The a p p l i c a t i o n of a retero-synthetic analysis to ( + ) - a r i s t o t e l i n e (8) led to the se r i e s of intermediates i l l u s t r a t e d i n Scheme I. The following discussion describes how t h i s scheme was developed and the progress which has been made toward i t s completion. On examining the structure of the natural product, i t can r e a d i l y be r e a l i z e d that t h i s material should be d i r e c t l y a v a i l a b l e from the 11. 12. (19) 13. t r i c y c l i c ketone (12) v i a a Fischer indole synthesis . The prepara-t i o n of indole a l k a l o i d s through the use of the Fischer indole synthe-s i s , performed on appropriately f u n c t i o n a l i z e d ketones, has been ex-p l o i t e d i n the past. For example, Stork et a l published the f i r s t t o t a l synthesis of quebrachamine (19) [via (23b)] and aspidospermine (20) [via 1 f\ 17 (23a) ] from the t r i c y c l i c ketone (22). Ban e_t £l and Stevens et 18 a l have also reported syntheses of the ketone (22) employing quite d i f f e r e n t synthetic routes from that used by Stork. Ban's group has also published an elegant synthesis of epiibogamine 19 (26) from the isoquinuclidine (25) v i a a Fischer indole synthesis. (26) Thus, with this i n i t i a l reduction i n the complexity of the task, 14. the target molecule of our synthetic e f f o r t s became the t r i c y c l i c ketone (12) . An examination of a molecular model of t h i s substance l e d to the idea that perhaps one e f f i c i e n t method of producing the desired t r i -c y c l i c system would involve an Intramolecular c y c l i z a t i o n of compound (13) (R' = Ts or Ms) to produce the t r i c y c l i c k e t a l (27). The l a t t e r would be expected to y i e l d the t r i c y c l i c ketone (12) by a c i d catalyzed cleavage of the k e t a l . (13a) (13b) 15. Ring closures i n v o l v i n g the i n t e r a c t i o n of a n u c l e o p h i l i c nitrogen atom with a carbon atom substituted with a suitable leaving group are well known. In addition, i t was expected that compound (13) could a t t a i n a conformation [resembling (13a)] i n which a process of t h i s type should be f a c i l i t a t e d by v i r t u e of the proximity of the two centers i n question. Thus, i t was f e l t that the construction of compound (13), fu n c t i o n a l i z e d with a r e l i a b l e leaving group (e.g. tosylate, R1 = Ts) a f f i x e d at C, i n the required stereochemical o r i e n t a t i o n , would provide o the t r i c y c l i c k e t a l (27) v i a a base-promoted c y c l i z a t i o n . Obviously, i f the r i n g closure to produce the desired t r i c y c l i c system was to be successful, the stereochemical o r i e n t a t i o n of the nitrogen containing appendage, attached at C^, was c r u c i a l . The syn-t h e t i c scheme c a l l e d for the introduction of the desired stereochemistry at through the hydrogenation of the a,j8- unsaturated ester (14). Again, c a r e f u l examination of a molecular model of t h i s compound sug-gested that the hydrogenation re a c t i o n should give predominantly the desired epimer, since the convex side (/8 face) of the molecule i s , for s t e r i c reasons, far more accessible to a heterogeneous c a t a l y s t than the concave side ( a fa c e ) . (14) (28) 16. The elaboration of the predicted product, the saturated ester (28), into compound (13), was envisaged as a p o t e n t i a l l y straightforward process. D i a l k y l a t i o n of the saturated ester (28) to give a gem-di-methyl system a to the ester f u n c t i o n a l i t y , followed by the s a p o n i f i -cation of the r e s u l t i n g product (29), should produce the carboxylic a c i d (30). The l a t t e r compound, i t was hoped, could then be converted into the desired nitrogen containing system by way of the well known Curtius r e a c t i o n . N C O 2 R ; R , (28) Of the wide v a r i e t y of procedures which may be employed to generate a,/?-unsaturated e s t e r s , perhaps the most widely used i s the W i t t i g reac-21 22 t i o n or one of the many modifications thereof. ' This type of reac-t i o n i s both very general and, more of t e n than not, proceeds to a f f o r d high y i e l d s of unsaturated carbonyl compounds. Therefore, i t was f e l t that the a,/?-unsaturated ester (14) would be most e f f i c i e n t l y obtained from the corresponding ketone (15), u t i l i z i n g a Wittig-type procedure. 17. (15) (14) The synthesis of the monoketone (15) was to be completed by the s e l e c t i v e deprotection of the A r i n g ketone of the d i k e t a l compound (16), where R' i s a suitable alcohol protecting group (vide i n f r a ) . This scheme rested on the observation that the A r i n g k e t a l was c o n s i -derably l e s s s t e r i c a l l y encumbered than the k e t a l at i n the B r i n g and, for t h i s reason, i t was considered l i k e l y that the less-hindered k e t a l group could be hydrolyzed s e l e c t i v e l y . (16) (15) F i n a l l y , the synthetic plan for the synthesis of the d i k e t a l com-pound (16) began from the r e a d i l y a v a i l a b l e 9-methyl-5(10)-octalin-l,6— 18. dione ( 1 8 ) ^ J . D i k e t a l i z a t i o n of t h i s dione should produce the corres-ponding d i k e t a l o l e f i n (17). Hydroboration of t h i s material would be expected to occur from the /? face of the molecule, since the approach of a borane complex from the a side of the molecule would be s t e r i c a l l y more hindered, mainly due to the a x i a l l y orientated oxygen atoms of the two k e t a l f u n c t i o n a l i t i e s . (18) (17) (31) The hydroboration-oxidation of s i m i l a r l y situated o l e f i n s i n other b i c y c l i c systems has been used i n the past to r e g i o s e l e c t i v e l y introduce an oxygen f u n c t i o n a l i t y at C^.^ For example, compound (32) was con-25 verted into a mixture of the alcohols (33) and (34) i n a y i e l d of 62%. (32) (33) (34) 19. In the case of the d i k e t a l o l e f i n (17), i t was expected that the hydroboration reaction would proceed both r e g i o - and s t e r e o s e l e c t i v e l y to produce the d i k e t a l alcohol (31) as the predominant product. This expectation was based on the observation that the d i k e t a l o l e f i n (17) was subject to hind ranee provided by both the a x i a l l y orientated oxygen atoms at and C^. A borane reagent was therefore expected to approach the o l e f i n from the side of the molecule ( fH face) c i s to the angular methyl group. The preparation of the d i k e t a l compound (16) could then be com-pleted by the protection of the alcohol f u n c t i o n a l i t y i n the d i k e t a l alcohol (31) with a suitable protecting group. A wide v a r i e t y of pro-26 t e c t i n g groups are available for the protection of hydroxyl groups. ( 3 1 ) ( 1 6 ) The recently introduced MEM (/8-methoxyethoxymethyl) ether was selected since t h i s protecting group was both devoid of c h i r a l i t y and was r e p o r t -27 edly formed and removed i n high y i e l d . In addition, the MEM ether was expected to be stable to the r e a c t i o n conditions that were anticipated during the course of the synthesis. Armed with the synthetic scheme outlined above, we began our empir-20. i c a l studies directed toward the preparation of the target molecule, the t r i c y c l i c ketone (12). I I . The Synthesis of the Diketal Ether (35) The s t a r t i n g material used for the preparation of the d i k e t a l ether (35), 9-methyl-5(10)-octalin-l,6-dione (18), was prepared according to a 23 l i t e r a t u r e procedure from 2-methyl-l,3-cyclohexanedione, i n a y i e l d of 51-55%^. The dione (18) was r e c r y s t a l l i z e d , dried under reduced pres-sure and subjected to standard k e t a l i z a t i o n conditions using dry benzene as the solvent, a c a t a l y t i c amount of j)-toluenesulf onic a c i d , and approx-imately ten equivalents of 2,2-dimethyl-l,3-propanediol producing the d i k e t a l o l e f i n (17) i n 72% y i e l d . This material underwent su b s t a n t i a l decomposition when subjected to column chromatography ( s i l i c a gel) i f 28 i t s duration on the column was lengthy (large scale p u r i f i c a t i o n s ) . (18) (17) (35) In our hands, the y i e l d of 9-methyl-5(10)-octalin-l,6-dione was con-s i s t e n t l y between 51% and 55%. Marshall e_t a l have reported a y i e l d of 76%. 2 3 The H nmr spectrum of t h i s material showed f i v e t e r t i a r y methyl groups ( 8 0.71, 0.86, 1.02, 1.16 and 1.18), a complex eight-proton m u l t i p l e t ^ between 8 3.24 and 3.88, due to the k e t a l methylenes, and a one-proton, broad s i n g l e t at 8 5.26-5.40 for the o l e f i n i c proton. In 13 the C nmr spectrum, the o l e f i n i c carbons, C,. and Cg, appeared at 8138.21 and 120.41, r e s p e c t i v e l y . The d i k e t a l o l e f i n (17) was hydroborated with excess borane-di-29 methyl s u l f i d e complex i n hexane (room temperature, 20 h) and, a f t e r the oxidation of the intermediate organoborane s p e c i e s ^ with a l k a l i n e hydrogen peroxide, a mixture of two alcohols was obtained i n a r a t i o of approximately 9:1. On s t e r i c grounds, i t was expected that the major product i s o l a t e d from the hydroboration re a c t i o n would be the desired c i s - f u s e d a lcohol (31). Therefore, i t seemed reasonable to propose that the minor product was the trans-fused alcohol (36), r e s u l t i n g from the A d e t a i l e d a n a l y s i s of the complex H nmr pattern produced by the methylene protons of t h i s type of k e t a l has been described. ^ A white s o l i d was i s o l a t e d from the hydroboration reaction, before oxidation, as a p r e c i p i t a t e d , amorphous material which proved to be the organoboronic a c i d (37); mp 160-161 °C. (37) 22. attack of the hydroborating reagent from the more hindered (yffface) side of the o l e f i n . However, since the hydroboration step determined the stereochemistry at both C,. and and, since the stereochemical o r i e n t a -t i o n at both these centres was c r u c i a l to the successful development of our synthetic plan, i t was decided to a s c e r t a i n whether or not these assignments were indeed correct. 0. 0 CD H = OH (36) There has been a considerable amount of research i n the s t e r o i d f i e l d d irected toward the c o r r e l a t i o n of the chemical s h i f t s of angular methyl protons with the stereochemistry of the AB r i n g junction i n both 31-33 the c i s and trans-fused systems. In a l l the cases studied, the c i s - f u s e d system exhibited an angular methyl resonance at lower f i e l d than the coresponding trans-fused case. For example, the angular methyl group on the AB r i n g junction of 5/8,14a-androstane (38) resonates at SO.925 whereas the s i g n a l due to the angular methyl group of 5a,14a-androstane (39) appears at 8 0.792. 23. Generally speaking, the same tendency i s found i n b i c y c l i c systems as w e l l . For example, i n the cis-fused ketone (40), the angular methyl group gives r i s e to a s i n g l e t at 8 0.95 i n the *H nmr spectrum, whereas i n the trans-fused system (41), the corresponding resonance i s found at 8 0.80. 3 4 (40) (41) The major product (mp 162-163 °C) i s o l a t e d (84%) from the hydrobora-t i o n of the d i k e t a l o l e f i n (17) exhibited a three-proton s i n g l e t at 81.21 i n the *H nmr spectrum. This s i g n a l was a t t r i b u t e d to the angular methyl group. The minor product (mp 189-191 °C), i s o l a t e d i n 9% y i e l d , displayed a three-proton s i n g l e t at 8 0.94, also assigned to the angular methyl group. 24. Although the preceding *H nmr data, as well as the expected course of the hydroboration r e a c t i o n based on s t e r i c arguments, supported the i n i t i a l assignments, i t was decided to seek d i r e c t chemical evidence confirming our assignments. This was done for three reasons. F i r s t l y , the s t e r o i d studies alluded to e a r l i e r were not s t r i c t l y applicable to b i c y c l i c systems. Secondly, although we were quite confident of the assignments for the angular methyl resonances i n the *H nmr spectra (see Section VII), the molecules i n question each possessed f i v e t e r -t i a r y methyl groups, a l l resonating between 8 0.68 and 1.21. C l e a r l y , the s p e c i f i c angular methyl group assignments would have to be c o n s i -dered somewhat te n t a t i v e . F i n a l l y , at the time that our work was being c a r r i e d out, the l i t e r a t u r e contained an apparent exception to general observation that, i n cis-fused b i c y c l i c systems, the angular methyl group resonates at lower f i e l d than i n the corresponding trans-fused 35 system. Thus, J.E. McMurry reported that the angular methyl group i n the c i s - f u s e d compound (42) exhibited a three-proton s i n g l e t at 8 1.08 i n i t s *H nmr spectrum. The coresponding trans-fused system (43) showed a t e r t i a r y methyl group at 8 1.23.^ (42) (43) Later, a f t e r our studies i n t h i s area were complete, D.L. Boger at Har-vard University conclusively demonstrated that these assignments were i n e r r o r . 25. It appeared that a rather straightforward chemical means of proving the stereochemistry of the products r e s u l t i n g from the hydroboration of (17) could be achieved as follows. Oxidation of the major product, t e n t a t i v e l y assigned as the cis - f u s e d compound (31), under non-epimer-i z i n g conditions, should a f f o r d the cis-fused ketone (44) i f t h i s assign-ment was c o r r e c t . The l a t t e r material should epimerize, under basic conditions, to f u r n i s h the thermodynamically more stable trans-fused ketone (45). (31) (44) (45) The C o l l i n s oxidation (treatment of an alcohol with a chromium tr i o x i d e - p y r i d i n e complex i n methylene chloride) i s a well known method used for the oxidation of secondary alcohols to the corresponding ketone 37 under e s s e n t i a l l y neutral conditions. Grieco, for example, oxidized the alcohol (46) with C o l l i n s reagent, furnishing the ketone (47), i n 38 96% y i e l d . The l a t t e r compound i s thermodynamically le s s stable than the corresponding trans-fused system. (46) _-0CH3 ^ O C H 3 (47) 26. Accordingly, the major product i s o l a t e d from the hydr o b o r a t i o n — oxidation of (17) was oxidized with chromium t r i o x i d e - p y r i d i n e complex i n methylene chloride to a f f o r d a single product i n 77% y i e l d . This material showed a saturated carbonyl absorption at 1705 cm * i n the i r spectrum. The *H nmr spectrum of t h i s compound exhibited a two-proton m u l t i p l e t between 8 2.72 and 3.06, for the protons on C^, and the signal due to the angular methyl group appeared at 8 0.86. Surp r i s i n g l y , the ketone i s o l a t e d from the C o l l i n s oxidation of (31 ) was recovered unchanged when treated with base (sodium methoxide), even after prolonged periods of time. In addition, when the minor product from the hydroboration-oxidation of (17) was oxidized under conditions i d e n t i c a l with those employed for the major alcohol, the same ketone (91%) was obtained as the sole product. For reasons which were not r e a d i l y apparent, one of the ketonic products obtained from the oxidations described above was epimerizing, under the reaction condi-tions or during work-up, to the trans-fused ketone (45). In an attempt to circumvent t h i s problem, the pyruvate ester (48) was prepared (pyridine, pyruvoyl chloride) from the d i k e t a l alcohol which had t e n t a t i v e l y been assigned the cis-fused stereochemistry as 00 (31) (48) 27. 39 shown i n (31). A recent a r t i c l e by Binkley had reported that the photolysis of pyruvate esters provided the corresponding ketone i n high y i e l d , under conditions which were completely n e u t r a l . For example, Binkley reported that menthol (49) was converted (88% y i e l d ) into men-thone (50) using t h i s method. (49) (50) The pyruvate ester (48) showed a carbonyl absorption at 1728 cm * i n the i r spectrum and, i n the *H nmr spectrum, the methyl group of the pyruvate ester moiety gave r i s e to a s i n g l e t at 8 2.43. Unfortunately, when t h i s material was subjected to photolysis (benzene, 1.1 h, ambient temperature) a complex mixture ( t i c ) of products was formed and t h i s oxidation approach was abandoned. Since these attempts to a s c e r t a i n the stereochemistry of the two compounds i s o l a t e d from the hydroboration of the d i k e t a l o l e f i n (17) had not been su c c e s s f u l , i t was decided to co r r e l a t e these compounds with the known octalones (51)^° and (52)* > 1. Thus, i t was f e l t that the (51) (52) 28. corresponding tosylate (53) of the desired c i s - f u s e d d i k e t a l alcohol (31) could be converted, by hydride reduction, into the b i c y c l i c d i k e t a l (54)« The l a t t e r material would a f f o r d , v i a a c i d i c hydrolysis of the k e t a l groups, the known octalone (51) (see Scheme 2). (53) (54) S C H E M E 2 42 43 H.C. Brown ' has demonstrated that the displacement of c e r t a i n "leaving groups", notably ch l o r i d e , bromide, mesylate and tos y l a t e , may be achieved very e f f i c i e n t l y with l i t h i u m triethylborohydride ("super-hydride"). For example, the tosylate (55) was converted into c y c l o -octane (56) i n 81% y i e l d using the reagent. 29. OTs (55) (56) Therefore, the preparation of the d i k e t a l tosylate (53) was under-taken. Reaction of the d i k e t a l a l cohol (31) with excess £-toluenesul-fo n y l chloride i n pyridine (ambient temperature, 24 h) provided the tosylate (53) i n 88% y i e l d . Treatment of the l a t t e r substance with l i t h i u m triethylborohydride i n tetrahydrofuran gave a mixture of two compounds, i n a r a t i o of 5:2 ( g l c ) . The major product was i d e n t i f i e d as the o l e f i n (57), mp 134.5-135.5 °C. The *H nmr spectrum of t h i s material showed f i v e t e r t i a r y methyl groups ( 8 1.18, 1.12, 1.00, 0.90, 0.70), an eight-proton m u l t i p l e t (8 3.20-3.88) for the k e t a l methylenes, and a two-proton m u l t i p l e t ( o l e f i n i c protons) between 8 5.28 and 5.68. (57) The minor product (mp 128-130 °C) i n i t i a l l y created some confusion. 30. Thus, although i t s molecular weight (352 mass units) was i d e n t i c a l with that of the desired b i c y c l i c d i k e t a l (54), the *H nmr spectrum of t h i s compound was anomalous and could not be r e c o n c i l e d with that expected of the desired material (54). Furthermore, t h i s material proved to be very d i f f i c u l t to obtain i n pure form since i t c o n s i s t e n t l y c o - c r y s t a l l i z e d with the major product (57). P u r i f i c a t i o n of t h i s compound could be e f f e c t e d by preparative t i c but the e f f i c i e n c y of t h i s method was low due to the s i m i l a r i t y of the a f f i n i t i e s of t h i s material and the o l e f i n (57) to s i l i c a g e l . For these reasons, as well as for the f a c t a more e f f e c t i v e preparation of (57) was found (vide i n f r a ) , t h i s compound was not investigated further. These r e s u l t s suggested that an type of e l i m i n a t i o n of the tosylate anion was occurring i n preference to i t s d i r e c t displacement. The displacement of the t o s y l a t e , i n an S N2 fashion, required that the attacking species (hydride ion) approach from the concave side ( a face) of the molecule. Molecular models of the tosylate (53) c l e a r l y showed that s t e r i c hindrance would make such a process quite d i f f i c u l t [cf. (53a), (53b)]. On the other hand, the e l i m i n a t i o n pathway, involving n 31. the a b s t r a c t i o n of a proton from C^, would presumably be les s s t e r i c a l l y encumbered. Since the d i r e c t displacement of the tosylate did not appear to be a f a c i l e mode of r e a c t i o n for (53), a more e f f i c i e n t preparation of the o l e f i n (57) was sought. It was expected that the conversion of (57) into the desired b i c y c l i c d i k e t a l (54) could be accomplished v i a the hydrogenation of the double bond i n (57). (57) (54) It was found that the treatment of a s o l u t i o n (dimethyl s u l f o x i d e — benzene) of (53) with potassium tert-butoxide i n the presence of 1 8 — Crown-6 (1,4,7,10,13,16-hexaoxacyclooctadecane) at 55 °C (0.5 h) pro-duced the o l e f i n (57) i n good y i e l d . 4 4 » 4 " ' The l a t t e r compound was further characterized by the hydrolysis of the two k e t a l moieties (hy-dr o c h l o r i c acid-acetone), thus aff o r d i n g the diketo o l e f i n (58). The o l e f i n i c protons of (58) appeared as a two-proton m u l t i p l e t at S 5.84 i n 32. (57) (58) the H nmr spectrum and the i r spectrum of t h i s material showed a car-bonyl absorption at 1710 cm *. Hydrogenation of the o l e f i n (57) over 10% palladium-on-carbon i n e t h y l acetate produced the b i c y c l i c d i k e t a l (54) i n 88% y i e l d . The *H nmr spectrum of t h i s material (mp 123.5-125 °C) showed an absence of any o l e f i n i c protons. The k e t a l methylenes of (54) gave r i s e to an eight-proton m u l t i p l e t between 8 3.16 and 3.80, and the f i v e t e r t i a r y methyl groups resonated at 8 1.18, 1.11, 0.98, 0.90 and 0.68. 33. 0 0 0 0 ft CO (57) (54) (17) Compound (54) was also d i r e c t l y a v a i l a b l e from the d i k e t a l o l e f i n (17) by hydrogenation over palladium (96% y i e l d ) . As discussed pre-v i o u s l y (vide supra), the /3 face of the d i k e t a l o l e f i n (17) was thought to be considerably more hindered than the a side. Since hydrogenation of (17) gave the b i c y c l i c d i k e t a l (54) as the sole product, t h i s pro-posal was c e r t a i n l y consistent with the above r e s u l t . Hydrolysis of (54) i n acetone containing IN hydrochloric acid afforded the dione (51) (88% y i e l d ) , which exhibited mp 62-65 °C ( l i t . 4 0 mp 64.5-65.5 °C). This material was i d e n t i c a l i n a l l respects with an authentic sample of the dione (51) which was prepared by the hydrogen-a t i o n of 9-methyl-5(10)-octalin-l,6-dione (18) (93%) at room temperature for 16 h. The o v e r a l l s e r i e s of transformations i s summarized i n Scheme 3. For the purpose of d i r e c t comparison (*H nmr, i r ) of the cis-fused dione (51) with the corresponding trans isomer (52), an authentic sample of the l a t t e r substance was prepared. Hydrolysis of the monoketal ketone (59)^ with aqueous hydrochloric acid-acetone gave the dione (52) This material was kin d l y supplied by Dr. D.J. Herbert, Department of Chemistry, Un i v e r s i t y of B r i t i s h Columbia. SCHEME 3 35. i n 83% y i e l d . This material, which was c l e a r l y d i f f e r e n t from the c i s - f u s e d dione (51) as judged by g l c , *H nmr and i r analyses, exhibited mp 55-56 °C ( l i t . 4 1 mp 56-57 °C). (59) (52) The r e s u l t s summarized above f u l l y substantiated our tentative assignment of the major product from the hydroboration of the d i k e t a l o l e f i n (17) as the c i s - f u s e d a l c o h o l (31). The l a t t e r compound was characterized further by i t s conversion into the dione alcohol (60). This material was i s o l a t e d (97% y i e l d ) from the a c i d catalyzed hydrol-y s i s (2U hydrochloric acid-acetone) of (31). Compound (60), e x h i b i t i n g mp 108-109 °C, showed a hydroxyl absorption at 3430 cm - 1 and a sat-urated carbonyl absorption at 1706 cm 1 i n i t s i r spectrum. The *H nmr (31) (60) spectrum of t h i s material exhibited a three-proton s i n g l e t at 8 1.47 36. (angular methyl group), a one-proton doublet (J = 4 Hz) at 8 3.00, due to the hydroxyl proton, and a one-proton, seven-line s i g n a l (dddd, J = 8,8,4 and 4 Hz) at 8 3.89 due to the proton at C^. When the hydroxyl proton was replaced by deuterium (D^O exchange), the *H nmr resonance for the hydroxyl proton disappeared and the s i g n a l at 8 3.89, due to C^H, collapsed to a symmetrical s i x - l i n e s i g n a l (ddd, J = 8,8 and 4 Hz). Since the i n i t i a l stereochemical assignment regarding the c i s -fused alcohol (31) proved to be corr e c t , an epimerization (of the ketone product) must have occurred when (31) had been subjected to oxidation with C o l l i n s reagent (vide supra). This anomalous r e s u l t seemed worthy of r e - i n v e s t i g a t i o n . When the oxidation of the alcohol (31) was r e -peated under conditions s i m i l a r to those used previously (chromium t r i o x i d e - p y r i d i n e complex), the cis-fused ketone (44) was i s o l a t e d (93%) as the sole product! This material showed a saturated carbonyl absorp-t i o n at 1705 cm i n the i r spectrum and, i n the H nmr spectrum, the angular methyl group produced a three-proton s i n g l e t at 8 1.22. The only difference between the two procedures used for the oxida-(31) (44) 37. t i o n of (31) involved the work-up of the reactions. In the experiment i n which the trans-fused ketone (45) was i s o l a t e d , the work-up procedure involved f l u s h i n g the crude r e a c t i o n mixture through a short column of neutral alumina. E l u t i o n of the column with e t h y l acetate, followed by the evaporation of the solvents from the eluent, afforded the trans-fused ketone (45) (77%). In the experiment which res u l t e d i n the i s o l a -t i o n of the ci s - f u s e d ketone (44), the work-up of the re a c t i o n involved simple f i l t r a t i o n of the crude r e a c t i o n mixture, followed by an aqueous work-up of the r e s u l t i n g f i l t r a t e . The cis - f u s e d ketone (44) thus i s o l a t e d was unaffected when passed through a column of basic alumina (eth y l acetate eluent) and was only p a r t i a l l y epimerized upon treatment with sodium methoxide i n methanol at 70 °C (3 h). The reason(s) for these apparently contradictory r e s u l t s remain a mystery. Since the only experimental differences i n the oxidations described above involved the respective work-up procedures, i t i s prob-able the epimerlzation of (44) occurred at t h i s point. The mechanism of th i s transformation, however, i s obscure and any r a t i o n a l i z a t i o n s toward t h i s end would be i d l e speculation. Treatment of the d i k e t a l ketone (44) with sodium methoxide i n methanol at room temperature for four days, gave the epimerized com-pound (45) i n e s s e n t i a l l y quantitative y i e l d . This material (mp 146-148 °C) was i d e n t i c a l (*H nmr, i r ) with the previously prepared ketone 1451 . 38. (44) (45) The synthesis of the d i k e t a l ether (35) was completed by protection of the alcohol (31) as the /?-methoxyethoxymethyl ether (MEM ethe r ) . The alcohol (31) was f i r s t treated with potassium hydride i n tetrahy-drofuran containing approximately 10% hexamethylphosphoramide. The r e s u l t i n g alkoxide was allowed to react with ft-methoxyethoxymethyl chloride (MEM chloride) a f f o r d i n g the desired ether (35) i n 89% y i e l d . The *H nmr spectrum of compound (35) displayed a three-proton s i n g l e t at 8 3.40 (due to the methoxy methyl group of the MEM moiety) and a two-13 proton AB quartet at 8 4.85 (-0CH20-). The C nmr spectrum of (35) showed a t r i p l e t ( J = 162 Hz) at 8 95.69 (-0CH20-). (31) (35) 39. I I I . Synthesis of the a,/?-Unsaturated Ester (61) In accord with our synthetic plans, i t was envisaged that the d i k e t a l ether (35) could be transformed into the «,^-unsaturated ester (61) v i a the monoketone (62). The l a t t e r , p o t e n t i a l l y a v a i l a b l e from the ether (35) by s e l e c t i v e A r i n g ketal cleavage, would then be con-verted into the a,^-unsaturated ester (61) by means of a Horner-Emmons 46 r e a c t i o n . (35) (62) (61) Unfortunately, the i n i t i a l attempts to s e l e c t i v e l y remove the A r i n g k e t a l i n (35) met with only moderate success. Treatment of the d i k e t a l ether (35) with 5% a c e t i c a c i d i n acetone (ambient temperature, 5 h) afforded a mixture of the monoke tones (63) and (62), i n a r a t i o of approximately 2:1, r e s p e c t i v e l y . These compounds were almost i n d i s -tinguishable by t i c , but the *H nmr spectrum of the mixture c l e a r l y indicated that the major component was the undesired material (63). Thus, the *H nmr spectrum of t h i s material showed s i x s i n g l e t s i n the h i g h - f i e l d region ( t e r t i a r y methyl groups), three of which were c o n s i -derably more intense than the other three. The more intense signals 40. appeared at 8 1.31, 1.00 and 0.88, while the three l e s s intense signals appeared at 8 1.40, 1.20 and 0.72. On the basis of the observation that the methyl groups of the B r i n g ketal f u n c t i o n a l i t y c o n s i s t e n t l y gave r i s e to s i n g l e t s at 8 1.18 + 0.02 and 8 0.70 + 0.02 (see section VII), the minor isomer was assigned structure (62), the desired keto k e t a l . (63) (62) Other a c i d i c cleavage conditions, including d i l u t e aqueous hydro-c h l o r i c acid-acetone and 0.05 _N p e r c h l o r i c acid-tetrahydrofuran mix-tures, gave r e s u l t s e s s e n t i a l l y i d e n t i c a l with those obtained p r e v i -ously. These r e s u l t s demonstrated that the acid catalyzed hydrolysis of the B r i n g k e t a l i n (35) was a more f a c i l e process than the correspond-ing A r i n g k e t a l cleavage. In add i t i o n , based on the poor r e s o l u t i o n of the two monoketones (62) and (63) by t i c , i t appeared that the separa-t i o n of these two compounds by column chromatography would also prove to be problematic. For these reasons, the exploration of a p o t e n t i a l l y more e f f i c i e n t route to the a,^-unsaturated ester (61) was i n i t i a t e d . It was envisaged that exposure of the d i k e t a l ether (35) to mildly a c i d i c hydrolysis conditions would produce the dione (64), s t i l l r e -t a i n i n g the somewhat acid s e n s i t i v e MEM protecting group. This material 41. should a f f o r d the a ,/J-unsaturated ester (65) when subjected to a 46 47 Horner-Emmons r e a c t i o n . ' It was expected that the B r i n g ketone (35) (64) (65) would be considerably less r e a c t i v e than the A r i n g carbonyl since the intro d u c t i o n of an «,/? -unsaturated ester at t h i s p o s i t i o n would be retarded by s t r a i n ( A 1 , 3 ) i n the t r a n s i t i o n s t a t e . 4 8 The synthesis of (61) could then be completed by the r e - k e t a l i z a t i o n of the B r i n g ketone i n (65) as depicted below. C02E» O M E M C0 2Et O M E M (65) (61) Accordingly, the d i k e t a l ether (35) was treated with IN hydrochlor-i c a c i d i n acetone at ambient temperature, thus affording the dione 42. (64) i n 92% y i e l d . This material exhibited a saturated carbonyl absorp-t i o n at 1705 cm * i n the i r spectrum. The *H nmr spectrum of (64) displayed a three-proton s i g n l e t at 8 3.38 (methoxy methyl) and a two-proton s i n g l e t AB quartet (J = 6 Hz) at 8 4.83 (-0CH20-), i n d i c a t i n g that the MEM protecting group had survived the hydrolysis conditions. The dione (64) reacted smoothly with three equivalents of the potassium s a l t of t r i e t h y l phosphonoacetate i n 1,2-dimethoxyethane (6 h, ambient temperature) giving the atB -unsaturated ester (65) i n good y i e l d . Compound (65) was obtained as a 1:1 mixture of geometric isomers (64) (65) which were separable by preparative t i c . One of the geometric isomers of (65) showed a strong absorption at 221 nm ( e = 15,200) i n the uv spectrum and absorptions at 1708 and 1646 cm * i n the i r spectrum. The *H nmr spectrum of t h i s material exhibited a three-proton t r i p l e t ( J = 7 Hz) at 6 1.29, a two-proton quartet (J «= 7 Hz) at 6 4.16 and a one-proton s i n g l e t ( o l e f i n i c proton) at 6 5.66, i n d i c a t i n g the presence of an a,^-unsaturated e t h y l ester. The other isomer of (65) showed resonances i n the *H nmr spectrum at 6 1.29 (a three-proton t r i p l e t , J = 7 Hz), 6 4.18 (a two-proton quartet, J = 7 Hz) and at 6 5.69 (a one-proton s i n g l e t ) . The angular 43. methyl group and the methoxy methyl group appeared at i d e n t i c a l chemical s h i f t s (6 1.34 and 3.38, r e s p e c t i v e l y ) i n both isomers. When the a,/?-unsaturated ester (65) was exposed to "standard" k e t a l i z a t i o n conditions (2,2-dimethyl-l,3-propanediol and £-toluenesul-f o n i c a c i d i n benzene), the desired substance (61) was, unfortunately, not obtained. Instead, the ether cleaved compound (66), as a mixture of geometric isomers, was i s o l a t e d i n 89% y i e l d . C 0 2 E t O M E M . C 0 2 E t O H (65) (66) The two isomers of compound (66) were c l e a r l y distinguishable by t i c . Separation of the mixture by preparative t i c (50% e t h y l acetate i n cyclohexane) gave a pure sample of each isomer. One of the isomers (mp 110-112 °C) showed an absorption at 222 nm ( e = 12,900) i n the uv spec-trum. The i r spectrum of t h i s material exhibited absorptions at 3500 cm 1 (hydroxyl group) and at 1695 and 1648 cm 1 (unsaturated e s t e r ) . The *H nmr spectrum substantiated the loss of the MEM group and the presence of the k e t a l moiety (two three-proton s i n g l e t s at $ 0.70 and 1.18). :) The other isomer of compound (66) also displayed a hydroxyl group absorption (3450 cm *) and absorptions c h a r a c t e r i s t i c of an «,/8-unsatur-ated ester (1710 and 1642 cm - 1) i n i t s i r spectrum. The *H nmr spectrum 44. of t h i s material showed three h i g h - f i e l d s i n g l e t s (methyl groups) at 60.72, 1.21 and 1.28, and a broad, one-proton s i n g l e t at 6 5.70 ( o l e f i n i c proton). Since the MEM protecting group was obviously not stable to the k e t a l i z a t i o n conditions described above, a milder method for repla c i n g the k e t a l group was sought. One a l t e r n a t i v e would be to treat the a,B— unsaturated ester (65) with ethylene g l y c o l (as solvent) containing a c a t a l y t i c amount of j)-toluenesulfonic a c i d . This r e a c t i o n could be performed at room temperature, thereby avoiding the elevated temperature (80 °C) used i n the "standard" k e t a l i z a t i o n conditions. Unfortunately, compound (65) afforded only the MEM cleaved ethylene k e t a l (67) under the rea c t i o n conditions described above (24 h). The C0 2 E t O M E M C 0 2 E » 0 H (65) (67) two isomers of compound (67) were separated by preparative t i c (25% e t h y l acetate i n cyclohexane). One of the isomers (mp 163-167 °C) exhibited an absorption at 3600 cm * (hydroxyl group) and absorptions at 1703 and 1641 cm * (unsaturated ester) i n the i r spectrum. The protons of the ethylene k e t a l group gave r i s e to a four-proton s i n g l e t at 6 3.96 i n the *H nmr spectrum. The uv spectrum of t h i s substance showed an absorp-45. t i o n at 223 nm ( e= 11,300). The other geometric isomer of (67) (mp 177-178 °C) showed an absorption at 224 nm ( e= 11,060) i n i t s uv spectrum and absorptions at 3500 cm - 1 (broad, :hydroxyl group) and at 1687 and 1642 cm - 1 (unsaturated ester) i n i t s i r spectrum. The *H nmr spectrum of t h i s substance showed a three-proton s i n g l e t at 6 1.14 (angular methyl group), a broad, one-proton resonance between 6 3.91 and 4.28 (hydroxyl proton) and a broad, one-proton s i n g l e t at 6 5.80 ( o l e f i n i c proton). Results very s i m i l a r to those described above were obtained when other a c i d c a t a l y s t s were used i n conjunction with ethylene g l y c o l i n attempts to k e t a l i z e (65). For example, the use of a c a t a l y t i c amount 49 of e i t h e r hydrochloric a c i d or boron t r i f l u o r i d e - e t h e r a t e r e s u l t e d i n the cleavage of the MEM ether during the course of the k e t a l i z a t i o n r e a c t i o n . Another procedure used for the k e t a l i z a t i o n of ketones involves a t r a n s - k e t a l i z a t i o n procedure, i n which the ketone i s treated with a large excess of another k e t a l i n the presence of an acid c a t a l y s t . This type of procedure has been used advantageously by S i r Derek Barton to e f f e c t the k e t a l i z a t i o n of a c i d s e n s i t i v e molecules which proved to be unstable under the usual k e t a l i z a t i o n c o n d i t i o n s . ^ For example, com-pound (68) was converted into the a c e t a l (69) using diethylene ortho-carbonate."' 1 46. (68) (69) In an analogous fashion, (65) was treated with 2-ethyl-2,5,5-tri-methyl-1,3-dioxane (70) (as solvent) containing a c a t a l y t i c amount of £-toluenesulfonic acid (60 °C, 4 days) to produce a rather complex mixture of products. This mixture was separated by preparative t i c , a f f o r d i n g the desired a,/?-unsaturated ester (61) (27%), as w e l l as the a,^-unsaturated ester (66) (34%) and recovered s t a r t i n g material (23%). 4- (65) (65) (61) (66) The desired material, compound (61), was i s o l a t e d as a mixture of geometric isomers which were indistinguishable by t i c and g l c analyses. One of these isomers could be obtained i n pure form by f r a c t i o n a l c r y s -47. t a l l i z a t i o n of the mixture from ether-hexane. This material exhibited mp 57-58.5 °C, and gave an absorption at 223 nm ( «= 7700) i n the uv spectrum and absorptions at 1705 and 1645 cm 1 i n the i r spectrum, c h a r a c t e r i s t i c of an a,^-unsaturated ester f u n c t i o n a l i t y . The *H nmr spectrum of t h i s substance showed signals due to three t e r t i a r y methyl groups ( 6 1.30, 1.18 and 0.70) and the a ,3-unsaturated e t h y l ester moiety was evidenced by resonances at 6 1.26 (three-proton t r i p l e t , J = 7 Hz), 6 4.11 (two-proton quartet, J = 7 Hz) and 6 5.58 (one-proton s i n g l e t , o l e f i n i c proton). The MEM protecting group gave c h a r a c t e r i s t i c *H nmr resonances at 6 3.40 (methoxy methyl) and at 6 4.78, for the two protons a to two oxygen atoms, as an AB quartet (J = 7 Hz). The k e t a l methylenes, C^H, and the remaining protons of the MEM group appeared as a broad m u l t i p l e t , i n t e g r a t i n g for nine protons, between 6 3.12 and 3.94. Although the procedure discussed above did provide the desired a,/?— unsaturated ester (61), the r e a c t i o n was not clean and the y i e l d (27%) of the desired material was f a r too low to be considered s y n t h e t i c a l l y u s e f u l . For these reasons, i t was decided to r e - i n v e s t i g a t e the s e l e c -t i v e cleavage of the A r i n g k e t a l i n (35) i n the hopes of discovering a more e f f i c i e n t route to the a,/?-unsaturated ester (61). Since a mole-cular model of (35) suggested that the A r i n g k e t a l group of t h i s mater-i a l was considerably more open ( l e s s hindered) than the B r i n g k e t a l , a method for s e l e c t i v e l y removing the A r i n g k e t a l e x p l o i t i n g t h i s d i f f e r -48. (35) ence i n s t e r i c encumberance seemed an a t t r a c t i v e p o s s i b i l i t y . With t h i s consideration i n mind, the d i k e t a l ether (35) was s t i r r e d with dry methyl e t h y l ketone containing p-toluenesulfonic a c i d to e f f e c t t r a n s - k e t a l i z a t i o n to the solvent. Under these conditions (0 °C, 18 h), a 2:1 r a t i o of the monoketones (62) and (63), r e s p e c t i v e l y , was obtained i n 91% y i e l d . This r a t i o was the reverse of that obtained v i a the a c i d catalyzed h y d r o l y s i s of the d i k e t a l ether (35) (vide supra). (35) (62) (63) The r a t i o of the ketones (62) and (63) was based on an *H nmr spectrum of a pure mixture of these compounds. As discussed previously, the t e r t i a r y methyl signals at 6 1.40, 1.20 and 0.72 were assigned to the monoketone (62). In order to a s c e r t a i n whether or not t h i s assign-49. ment was correct, a pure sample of one of the monoketones was necessary. By e q u i l i b r a t i o n of a pure sample of one of the monoke tones (62) or (63) with methanol-d^, i n the presence of sodium methoxide, i t would be possible to d i f f e r e n t i a t e between these two materials by determining the number of deuterium atoms incorporated into the given monoketone. A pure sample of compound (63) (mp 64-65 °C) was obtained by sub-j e c t i o n of the mixture of compounds (62) and (63) to preparative t i c . This substance exhibited a saturated carbonyl absorption at 1703 cm * i n the i r spectrum. The *H nmr spectrum of (63) showed signals due to three t e r t i a r y methyl groups at 6 1.31, 1.00 and 0.88. The MEM ether group exhibited c h a r a c t e r i s t i c absorptions at 6 3.40 (methoxy methyl) and at <5 4.87 (two protons, -0CH 20-), an AB quartet (J = 8 Hz). The deuteration of (63) was accomplished by treatment of t h i s material with methanol-d^ containing a small amount of sodium methoxide. The r e s u l t i n g s o l u t i o n was refluxed gently for 30 h, thus a f f o r d i n g (71) as the sole product. This material exhibited a molecular ion peak at m/e 372 (low r e s o l u t i o n ms) i n d i c a t i n g the incorporation of two deuterium atoms. There was no i n d i c a t i o n of any material corresponding to the introduction of four deuterium atoms, which would have been the expected r e s u l t i f compound (62) were to be treated under si m i l a r con-d i t i o n s . 52 0 0 D (63) (71) 50. Since the exchange d i k e t a l i z a t i o n of the d i k e t a l ether (35) with methyl e t h y l ketone had produced the desired monoketone (62) and the undesired isomer (63) i n a r a t i o of 2:1, r e s p e c t i v e l y , i t was hoped that a more s t e r i c a l l y demanding ketone (as solvent) would produce the de-s i r e d material i n a s t i l l more s e l e c t i v e fashion. Accordingly, a s o l -ution of the d i k e t a l ether (35) i n f r e s h l y d i s t i l l e d 2-methylcyclo-hexanone, containing a small amount of £-toluenesulfonic a c i d as cata-l y s t , was s t i r r e d for 17 h at ambient temperature. Under these condi-t i o n s , the monoketones (62) and (63) were i s o l a t e d (82%) i n a r a t i o of approximately 3.5:1, r e s p e c t i v e l y . The solvent, 2-methylcyclohexanone, was recovered from the crude product by d i s t i l l a t i o n under reduced pressure. The use of 2,6-dimethylcyclohexanone as the solvent, under re a c t i o n conditions s i m i l a r to those described above, produced approximately the same r a t i o of the monoketones (62) and (63). Under these conditions, however, the r e a c t i o n was considerably slower, re q u i r i n g approximately 120 h at ambient temperature to proceed to completion ( t i c ) . Since a reasonably e f f i c i e n t method for the preparation of the desired monoketone (62) was now i n hand, i t was envisaged that the a,B— unsaturated ester (61) could be produced i n good y i e l d v i a the r e a c t i o n of the monoketone mixture [(62) and (63)] with an appropriate Horner-Emmons reagent. In p r a c t i c e , the monoketone mixture was not p u r i f i e d . Instead, the crude product r e s u l t i n g from the r e a c t i o n of the d i k e t a l ether (35) with 2-methylcyclohexanone as described above, was treated d i r e c t l y with three equivalents of the potassium s a l t of t r i e t h y l phos-51. phonoacetate (19 h, ambient temperature). Under these conditons, the desired material (61) was i s o l a t e d i n a 73% o v e r a l l y i e l d from the d i k e t a l ether (35), a f t e r column chromatography. (35) (61) The undesired monoketone (63), containing a small amount of r e -covered (62), was also i s o l a t e d from the r e a c t i o n described above i n a y i e l d of approximately 20%. This mixture could be recycled through i t s conversion (92% y i e l d ) into the d i k e t a l a l c o h o l (31) using "standard" k e t a l i z a t i o n conditions. The o v e r a l l s e r i e s of transformations described i n t h i s section are summarized i n Scheme 4, shown below. 53. IV. The Introduction and Proof of the Stereochemistry at With a s a t i s f a c t o r y synthetic route to the a,/?-unsaturated ester (61) i n hand, the next step of the synthetic scheme c a l l e d for the introduction of the required stereochemistry at C^. It was envisaged that t h i s objective could be accomplished through the hydrogenation of the double bond i n compound (61). An examination of a molecular model of (61) suggested that the convex side (/?face) of the molecule was con-siderably more open ( l e s s hindered) to a heterogeneous c a t a l y s t than the concave side of the molecule. It was expected, therefore, that the hydrogenation of (61) would a f f o r d the desired saturated ester (72) i n a st e r e o s e l e c t i v e fashion. The i n i t i a l attempts to hydrogenate compound (61) (10% p a l l a d i u m — on-carbon, ethanol), at atmospheric pressure and room temperature, produced several products (as judged by t i c ) , a l l of which were con-siderably more polar than the s t a r t i n g material. The *H nmr spectrum of the crude mixtures i s o l a t e d from these reactions indicated that, i n addi t i o n to the hydrogenation of the double bond, the k e t a l f unction-a l i t y had been removed under the r e a c t i o n conditions. When platinum oxide was used as the c a t a l y s t , however, the hydro-genation of compound (61) (et h y l acetate as solvent) afforded two com-pounds (91% y i e l d ) i n a r a t i o of 6:4 ( g l c ) . This mixture was separated by column chromatography ( s i l i c a g e l , 33% e t h y l acetate i n benzene as eluent) a f f o r d i n g a pure sample of each compound. The major product, t e n t a t i v e l y assigned as the desired saturated ester (72), exhibited an absorption at 1737 cm~* i n i t s i r spectrum due 54. to the saturated ester moiety. The iH nmr spectrum of t h i s material showed three 3-proton s i n g l e t s (6 0.68, 1.04 and 1.16) due to the t e r -t i a r y methyl groups, a three-proton t r i p l e t (J = 7.5 Hz, 6 1.24) and a two-proton quartet (J = 7.5 Hz, 64.09) due to the e t h y l ester, and a 13 two-proton AB quartet centred at 64.70 (-OCH^O-). The C nmr spectrum of t h i s compound exhibited a t r i p l e t (J = 162 Hz) at 6 93.61 (-0CH20-) and two s i n g l e t s at 6 102.48 (C q) and 173.06 (ester carbonyl). (61) (72) (76) The minor product, t e n t a t i v e l y assigned structure (76), displayed an absorption at 1730 cm * i n i t s i r spectrum i n d i c a t i v e of a saturated ester f u n c t i o n a l i t y . In the *H nmr spectrum t h i s substance exhibited two h i g h - f i e l d s i n g l e t s at 6 0.68 (three protons) and at 61.13 (six protons) accounting for the three t e r t i a r y methyl groups. Resonances appearing at 61.21 (three-proton t r i p l e t , J = 7 Hz) and at 6 4.06 (two-proton quartet, J = 7 Hz) indicated the presence of an e t h y l ester moiety. Signals c h a r a c t e r i s t i c of the MEM ether group appeared at 6 3.33 (methoxy methyl, three-proton s i n g l e t ) and at <S 4.74 (-OCH^O- > two-proton AB quartet, J = 7 Hz). Although the sp e c t r a l data of the two compounds described above was i n accord with that expected for the saturated esters (72) and (76), re s p e c t i v e l y , i t was not possible to d e f i n i t i v e l y assign the structures 55. of e i t h e r of these materials s o l e l y on the basis of th e i r respective s p e c t r a l data. In order to secure these assignments, the following scheme was devised. It was envisaged that the corresponding tosylate (73) of the desired ester (72) would undergo an intramolecular c y c l i z -a t i o n [cf. (73a)], upon treatment with a suitable base, to provide the t r i c y c l i c system (74). On the other hand, i t was expected that the (73) (74) (73a) corresponding tosylate (75) of the undesired epimer, saturated ester 56. (76) , would not undergo intramolecular a l k y l a t i o n upon treatment with an appropriate base, since compound (75) could not a t t a i n a conformation i n which an i n t e r n a l c y c l i z a t i o n was possible. Both of the tosylates (73) and (75) were p o t e n t i a l l y a v a i l a b l e from the corresponding saturated esters (72) and (76), r e s p e c t i v e l y , v i a removal of the MEM ether pro-t e c t i n g group, followed by the t o s y l a t i o n of the r e s u l t i n g alcohols (77) and (78). (72) ; R=/?-H (77) (73) (76) ; R = « - H (78) (75) Unfortunately, treatment of the minor product (76), r e s u l t i n g from the hydrogenation of (61), with titanium t e t r a c h l o r i d e i n methyl-ene chloride (0 °C, 45 min) did not produce the desired k e t a i alcohol (78). The *H nmr spectrum of the i s o l a t e d crude product c l e a r l y showed that both the MEM ether f u n c t i o n a l i t y and the k e t a l group had been cleaved under the reaction conditions. This problem was eventually circumvented by t r e a t i n g compound (76) with j>-toluenesulfonic acid under "standard" (2,2-dimethyl-l,3-propanediol, benzene) k e t a l i z a t i o n condi-t i o n s . Under these reaction conditions ( r e f l u x , 45 min) two products were formed ( t i c ) . P u r i f i c a t i o n of the crude product by preparative t i c (40% e t h y l acetate i n benzene) gave a major product (higher Rp) and a 57. minor product (lower R^), i n a r a t i o of approximately 3:1, r e s p e c t i v e l y . The major product (75%) exhibited absorptions at 3480 (hydroxyl group) and 1735 cm * (saturated ester) i n i t s i r spectrum. In i t s *H nmr spectrum, t h i s compound showed s i n g l e t s at 6 0.70 (three protons) and 1.18 ( s i x protons), a broad, one-proton s i n g l e t at 6 1.68 (hydroxyl proton), and a one-proton, s i x - l i n e s i g n a l (ddd, J = 10,10 and 5.5 Hz) centred at 6 3.78 (C 6H). A l l of the signals c h a r a c t e r i s t i c of a MEM ether were absent. The s p e c t r a l data summarized above indicated that t h i s compound was the desired k e t a l alcohol (78). The minor product (22%) showed absorptions at 3452 (hydroxyl group), 1720 (shoulder, ester carbonyl) and 1702 cm * (ketone carbonyl) i n the i r spectrum. In the mass spectrum of t h i s substance, the molecular ion (m/e = 268) appeared as an extremely weak si g n a l while the signal corresponding to a loss of water from the molecular ion (m/e = 250) was the base peak. The *H nmr spectrum of t h i s compound exhibited only one h i g h - f i e l d s i n g l e t at 6 1.21 (three protons, angular methyl) and a o n e — proton s i n g l e t at 6 1.77 (hydroxyl proton). This material evidently was the keto alcohol (79), obtained from compound (76) by cleavage of both the MEM ether group and the k e t a l f u n c t i o n a l i t y . Treatment of the k e t a l alcohol (78) with ja-toluenesulfonyl chloride i n pyridine (ambient temperature, 13 h) afforded the corresponding tosylate (75) (81%). This compound [mp 148-149 °C (dec.)] exhibited a saturated ester absorption at 1720 cm * i n i t s i r spectrum. In i t s *H nmr spectrum t h i s material showed two s i n g l e t s due to the t e r t i a r y methyl groups at 6 0.68 (three protons) and 1.13 ( s i x protons), a t h r e e — 58. proton t r i p l e t at 6 1.26 (J = 7 Hz, ester methyl), and a two-proton quartet at 64.11 (J = 7 Hz, ester methylene). The k e t a l methylenes appeared as a four-proton m u l t i p l e t between 6 3.14 and 3.70, and the proton at C & appeared as a s i x - l i n e s i g n a l (ddd, J = 11,11 and 5.5 Hz) at 6 4.78. The tosylate group gave r i s e to signals at 6 2.40 (three-proton s i n g l e t , aromatic methyl) and at 6 7.31 and 7.80 (two 2-proton doublets, J = 8 Hz, aromatic protons). (75) (78) The major product i s o l a t e d from the hydrogenation of compound (61), t e n t a t i v e l y assigned as the desired saturated ester (72) (vide 59. supra), was converted into the corresponding tosylate (73) under condi-tions similar to those outlined above. Thus, treatment of compound (72) with jj-toluenesulfonic a c i d , under "standard" k e t a l i z a t i o n condi-t i o n s , afforded a mixture of the ke t a l alcohol (77) and the keto alcohol (80).^ Separation of t h i s mixture was effected by preparative t i c using 33% e t h y l acetate i n benzene as the developing solvent. The k e t a l a l c ohol (77) (54%) exhibited absorptions at 3495 (hy-droxyl group) and 1728 cm * (ester carbonyl) i n the i r spectrum. The nmr spectrum of t h i s material showed three t e r t i a r y methyl s i n g l e t s (60.68, 1.12 and 1.15), a three-proton t r i p l e t (6 1.22, J = 7 Hz) due to the methyl group of the eth y l ester, and a two-proton quartet (6 4.09, J = 7 Hz), assigned to the methylene group of the e t h y l ester function-a l i t y . The hydroxyl proton appeared as a one-proton s i n g l e t at 6 3.68. The minor product, keto a l c o h o l (80) (30%), displayed absorptions at 3605 (hydroxyl group), 1723 (shoulder, ester carbonyl), and 1708 cm * (ketone carbonyl) i n i t s i r spectrum. The ''"H nmr spectrum of compound (80) exhibited a three-proton t r i p l e t (J = 7 Hz) at 6 1.20 and a two— proton quartet (J = 7 Hz) at 6 4.07 due to the e t h y l ester function-a l i t y . The angular methyl group appeared as a three-proton s i n g l e t at 61.38. The product d i s t r i b u t i o n obtained from t h i s r e a c t i o n v a r i e d s i g n i f i -cantly even when attempts were made to duplicate the conditions des-cribed herein. Often, a larger proportion of the keto alcohol (80) was i s o l a t e d accompanied by several side products. 60. The hydroxyl group proton exhibited a one-proton s i n g l e t at <5 1.82 and the proton attached to appeared as a broad, one-proton s i n g l e t at 6 3.87. The tosylate (73) was prepared from the k e t a l a lcohol (77) v i a treatment of the l a t t e r substance with j>-toluenesulfonyl chloride i n pyridine (17 h, ambient temperature). Compound (73), i s o l a t e d i n 80% y i e l d a f t e r preparative t i c , showed an absorption at 1722 cm * i n i t s i r spectrum (ester carbonyl). In i t s *H nmr spectrum, t h i s material ex-h i b i t e d a three-proton s i n g l e t (6 1.01) due to the angular methyl group and two a d d i t i o n a l three-proton s i n g l e t s (6 0.68, 1.13) due to the ke t a l methyls. The e t h y l ester moiety gave r i s e to signals at <S 1.24 (methyl group, three-proton t r i p l e t , J = 7 Hz) and at 6 4.07 (methylene group, two-proton quartet, J = 7 Hz). Resonances at 6 2.42, 7.31 and 7.56, a three-proton s i n g l e t and two 2-proton doublets ( J = 8 Hz), r e s p e c t i v e l y , substantiated the presence of the tosylate f u n c t i o n a l i t y . The k e t a l methylene groups appeared as a four-proton mu l t i p l e t between 6 3.12-3.80 and the proton attached to exhibited a broad, one-proton s i n g l e t at 6 4.49. 61. 0 0 0 (73) (77) In order to demonstrate that the major product r e s u l t i n g from the hydrogenation of the a,^-unsaturated ester (61) was, i n f a c t , the de-s i r e d ester (72), the intramolecular c y c l i z a t i o n (vide supra) of the tosylate (73) was attempted. Accordingly, compound (73) was added to a cold (-78 °C) s o l u t i o n containing excess l i t h i u m diisopropylamide i n tetrahydrofuran. The r e s u l t i n g s o l u t i o n was warmed to room temperature and s t i r r e d for several hours. Unfortunately, only the s t a r t i n g mater-i a l (73) (>90%) was recovered from the reaction mixture ( t i c , *H nmr 62. analyses). Attempts to c y c l i z e compound (73) at elevated temperature (50 °C), using l i t h i u m diisopropylamide as the base, also r e s u l t e d only i n the recovery of the s t a r t i n g material. At t h i s stage, i t appeared possible that the (tentative) s t r u c t u r a l assignments made with respect to the hydrogenation products (72) and (76) were i n c o r r e c t . However, s u r p r i s i n g l y , treatment of the epimeric tosylate (75) with l i t h i u m diisopropylamide under conditions i d e n t i c a l with those described above also f a i l e d to produce the t r i c y c l i c system (74). Here again, the s t a r t i n g material was recovered unchanged. In a synthesis of the triterpene lupeol (81), Stork et a l c y c l i z e d the ester (82) producing the r i n g closed material (83).''"' The e x p e r i -mental conditions used i n t h i s transformation involved the treatment of compound (82) with sodium b i s ( t r i m e t h y l s i l y l ) a m i d e i n benzene s o l u t i o n . (81) 63. Piers and co-workers had also used s i m i l a r conditions to e f f e c t the intramolecular c y c l i z a t i o n of compound (85)."^ Thus, treatment of compound (85) with sodium b i s ( t r i m e t h y l s i l y l ) a m i d e (room temperature, 40 min) furnished (-)-ylangocamphor (84), i n 84% y i e l d . MsO (85) (84) Accordingly, the tosylates (73) and (75) were each treated with excess sodium b i s ( t r i m e t h y l s i l y l ) a m i d e i n benzene at room temperature. Both tosylates f a i l e d to undergo the desired r e a c t i o n ( t i c ) at t h i s temperature (2 h) and, unfortunately, when the re a c t i o n mixtures were heated to r e f l u x (1 h) none of the desired t r i c y c l i c compound (74) was i s o l a t e d from either of the tosylates (73) or (75). Under these condi-tions the s t a r t i n g materials were not recovered, however, and these reactions l e d only to i n t r a c t a b l e material. 64. It was not clear why the desired tosylate (73) had f a i l e d to under-go the expected c y c l i z a t i o n r e a c t i o n to form compound (74). It appeared a^  p r i o r i that t h i s system was, i n f a c t , quite well suited to c y c l i z e as proposed. An examination of a molecular model of (73), as well as 57 geometric considerations , both f a i l e d to suggest any reason for our lack of success. Examination of the *H nmr spectra of the tosylates (73) and (75) suggested that the tentative s t r u c t u r a l assignments were indeed correct. Thus, the spectra of these two compounds exhibited a p o t e n t i a l l y meaning-f u l difference i n the appearance of the resonances due to the protons attached at C^. In compound (75), t e n t a t i v e l y assigned as the undesired epimer, the proton at gave r i s e to a symmetrical s i x - l i n e s i g n a l (ddd, J = 11, 11 and 5.5 Hz) at 6 4.78. This i s a coupling pattern 58 which i s t y p i c a l of an a x i a l l y orientated proton on a cyclohexane r i n g which i s coupled to two adjacent a x i a l protons (usually equally, as i s the case here) and to one adjacent equ a t o r i a l proton ( i n t h i s instance at C^). The d i a x i a l couplings gave r i s e to two large s p l i t t i n g s (approx-imately 11 Hz) and the a x i a l - e q u a t o r i a l coupling produced a smaller s p l i t t i n g of 5.5 Hz. The *H nmr spectrum of (75) was thus consistent with the conformation of t h i s material [cf. (75a)] which was predicted, on the basis of conformational a n a l y s i s , to be the most stable c h a i r -chair arrangement.^ 65. The epimeric material, compound (73), on the other hand, exhibited a broad ( w j y 2 = ^ Hz), one-proton s i n g l e t at 6 4.49 due to the proton at Cg. The lac k of s i m i l a r i t y of t h i s resonance with that of the corres-ponding proton i n compound (75) strongly suggested that the conforma-tions of these two materials were quite d i s s i m i l a r . However, on the basis of conformational a n a l y s i s , i t was predicted that t h i s material would e x i s t p r e f e r e n t i a l l y i n a conformation [cf. (73a)] that was very s i m i l a r to that proposed for the isomeric material, compound (75). In th i s conformation one 1,3-diaxial i n t e r a c t i o n was present as opposed to three s i m i l a r i n t e r a c t i o n s i n conformation (73b). (73a) (73b) To complicate matters further, i f compound (73) did, i n f a c t , e x i s t p r e f e r e n t i a l l y i n a conformation resembling (73b), as the above data suggested, then i t would be expected that the proton (which i s equa-t o r i a l i n t h i s case) would resonate at lower f i e l d than the correspond-58 ing proton ( a x i a l l y orientated) i n compound (75). In point of f a c t , the opposite was the case. The 1H nmr spectrum (270 MHz) of the k e t a l alcohol (78), tenta-t i v e l y assigned as possessing a /?-oriented carboethoxymethyl group at 66. C^, exhibited a resonance at 6 3.78 due to the proton. This s i g n a l also appeared as a s i x - l i n e m u l t i p l e t (ddd, J = 10, 10 and 5.5 Hz) consistent with the resonance i n the corresponding tosylate (75). In the epimeric alcohol (77), however, the proton (resonating at approx-imately 6 3.50) was not separated (even at 270 MHz) from the resonances due to the k e t a l methylenes. Thus, although the shape of t h i s resonance could not be observed, i t did appear, as before, at higher f i e l d than the resonance due to the corresponding proton i n the epimeric material (78). C0 2 E t O H C0 2 E t OH (78) (77) During the period of time that the attempted intramolecular c y c l i z -a t i o n reactions were being studied, another study of the tosylates (73) and (75) was being conducted. This i n v e s t i g a t i o n involved the study of the s p i n - l a t t i c e r e l a x a t i o n ^ ' * ' * rates of some selected protons i n both the tosylates (73) and (75) conducted with the hope of gaining some ins i g h t concerning the conformational preferences of these materials, and of obtaining information regarding the tentative assignment of the stereochemistry at Cy At th i s juncture a b r i e f explanation of the phenomenon of s p i n - l a t t i c e r e l a x a t i o n i s i n order. A more d e t a i l e d 67. discussion of this process, including the experimental procedure i n -volved, has been p u b l i s h e d ^ 0 and i s beyond the scope of the present discussion. The study of s p i n - l a t t i c e r e l a x a t i o n Involves the e x c i t a t i o n and subsequent transfer of energy (magnetic) between a given proton (or set of protons) which i s being observed and the surrounding molecular l a t -t i c e . The mechanism responsible for t h i s r e l a x a t i o n (a "dipole-dipole" i n t e r a c t i o n ) i s such that i t i s dominated by interproton i n t e r a c t i o n s . Thus, i t i s the nearest neighbour protons which are by far the largest contributors to the r e l a x a t i o n of a given proton. Since t h i s e f f e c t i s distance dependent, varying as the inverse s i x t h power of the distance between the n u c l e i , the protons which are i n the c l o s e s t proximity to each other r e l a x most r a p i d l y . The experiment consists of the a c q u i s i t i o n and subsequent analysis of a s e r i e s of p a r t i a l l y relaxed spectra from which the s p i n - l a t t i c e r e l a x a t i o n time (T^-value) of a proton of i n t e r e s t may be measured. The values obtained from such measurements, proton T^-values, r e f l e c t the environment and the o r i e n t a t i o n of a given proton with respect to i t s surrounding neighbours. These r e l a x a t i o n times have been shown to be s e n s i t i v e to "through-space" i n t e r a c t i o n s ( i n disaccharides) between protons of a given molecule which are separated from each other by several carbon atoms but are held i n proximity to each other by v i r t u e of molecular geometry. Therefore, i t i s sometimes possible to obtain a d i r e c t measure of the r e l a t i v e s p a t i a l d i s p o s i t i o n s of protons on a given molecule and hence to deduce the geometry of the molecule i n question. A rather simple example which demonstrates the use of t h i s 68. technique i s provided by the r e l a x a t i o n measurements performed on v i n y l t o acetate (86). The geminal protons (E^ and R3) , which have the small-est internuclear separation, were found to r e l a x much more r a p i d l y than the v i n y l i c proton H^. In a d d i t i o n , 1^ relaxes more quickly than does due to the proximity of the former to ( c i s r e l a t i o n s h i p ) . (26.9 s e c ) (86.2 s e c ) H 2 . / H l : c H 7' " O C C H o II (35.8 s e c ) 0 (86) In the context of the work described i n t h i s t h e s i s , i t was f e l t that this technique could provide pertinent insight r e l a t i n g to the molecules which were t e n t a t i v e l y assigned as the tosylates (73) and (75). In the expected preferred conformation of compound (75) [cf. (75a) ], the rate of r e l a x a t i o n of the proton was expected to be influenced p r i m a r i l y by only the e q u a t o r i a l l y orientated (gauche r e l a -t ionship) proton at C^. In the epimeric material (73), a quite d i f -ferent s i t u a t i o n prevailed regardless of whether t h i s compound existed p r e f e r e n t i a l l y i n a conformation resembling (73a) or (73b). If t h i s substance preferred a conformation l i k e (73a), the proton would be held i n close proximity to the methylene group a to the ester function-a l i t y . The l a t t e r protons would thus be expected to contribute substan-t i a l l y to the rate of r e l a x a t i o n experienced by C,H. In the diastereo-meric material (75) t h i s mode of r e l a x a t i o n would not be a v a i l a b l e since the ester containing side chain (at C^) would be positioned such that i t 69. was a considerable distance from the enti r e B-ring. If compound (73) preferred a conformation resembling (73b), on the other hand, the proton at would s t i l l be ant i c i p a t e d to undergo a more rapid rate of r e l a x a t i o n than the corresponding proton i n (75). In t h i s conformation the r e l a x a t i o n of the proton would be affe c t e d by three neighbouring protons (at C,. and C^), a l l of which are held i n a gauche r e l a t i o n s h i p to C^H. Thus, regardless of the conformational d i s p o s i t i o n of compound (73), i t was envisaged that the T^-value mea-sured for C,H would be considerably smaller than that determined for the o proton at i n compound (75). As a r e s u l t of these considerations, i t was hoped that i t would be possible to e s t a b l i s h whether or not our tentative stereochemical as-signments for these compounds were i n f a c t correct. The *H nmr spectrum (270 MHz) of each of the tosylates (73) and (75) exhibited a c l e a r l y d i s t i n g u i s h a b l e resonance f o r the proton at C^. Thus, i n each case, observation of t h i s proton during the r e l a x a t i o n experiment^ was s t r a i g h t -forward. Unfortunately, the T^-values determined for the protons i n compounds (73) and (75) were, within the l i m i t s of experimental e r r o r , i d e n t i c a l . The f a i l u r e of t h i s technique to provide evidence which could a i d i n the d i f f e r e n t i a t i o n between the epimers (73) and (75) was rather disappointing. However, while s p i n - l a t t i c e r e l a x a t i o n phenomena are usually interpretable i n most r e l a t i v e l y simple systems, often, i n more complex compounds, there are many poorly understood interconnecting These experiments were conducted by Dr. L.D. Colebrook, Concordia Uni-ve r s i t y , o n sabbatical leave at the University of B r i t i s h Columbia. 70. r e l a x a t i o n pathways which can make a simple evaluation of the r e s u l t s quite d i f f i c u l t . Since the studies discussed above d i d not r e s u l t i n the confirm-a t i o n of the tentative assignments regarding the stereochemistry at C.j, another approach of a d i f f e r e n t tenor was developed to solve t h i s quandary. It i s well known that a l k a l i metal-ammonia reductions of unsaturated carbonyl compounds produce, as a r u l e , the thermodynami-c a l l y more stable product i n those cases where two epimeric products are possible. Although there are known e x c e p t i o n s ^ t o t h i s gen-e r a l i z a t i o n , a l b e i t very few, the vast majority of a,^-unsaturated carbonyl compounds which have been reduced with a l k a l i metals i n ammonia adhere to i t . On the basis of the foregoing information, i t was anticipated that 68 lithium-ammonia reduction of the a,^-unsaturated ester (61) would produce the alcohol (89). C l e a r l y , compound (89) [cf. (89a)] would be expected to be thermodynamically more stable than the epimeric material (90) [ cf. (90a)] on the basis of conformational a n a l y s i s . Compound OMEM ^ £ ^ 7 OMEM (89a) (90a) 71. (89) should also be the product r e s u l t i n g from the reduction of the undesired saturated ester (76) with a suitable metal hydride reducing agent (e.g. l i t h i u m aluminum hydride). (61) (89) (76) Conversely, the desired saturated ester (72) was expected to f u r -n i s h the epimeric alcohol (90) upon reduction with a suitable metal hydride reagent. These conversions were thus expected to provide tan-g i b l e evidence as to the tentative stereochemical assignments made for the epimeric saturated esters (72) and (76). (72) (90) Reduction of compound (61) was accomplished by the treatment of a s o l u t i o n of this material (ammonia, ether and ethanol) with l i t h i u m 72. metal at -78 °C. A single product, alcohol (89), was obtained from the r e a c t i o n mixture i n 84% y i e l d . This substance showed a broad hydroxyl group absorption at 3480 cm * i n i t s i r spectrum. The *H nmr spectrum of t h i s material exhibited a broad, one-proton singlet- at 6 2.12 (hy-droxyl proton) and demonstrated the absence of o l e f i n i c protons and of a l l the resonances due to the e t h y l ester moiety. The three t e r t i a r y methyl groups gave r i s e to signals at 6 0.68 (three-proton s i n g l e t ) and at <5 1.15 (six-proton s i n g l e t ) . Treatment of the saturated ester (76) with l i t h i u m aluminum hydride i n anhydrous ether (-78 °C, 1 h) afforded the alcohol (89) as the sole product of the reduction (99%). This material was i d e n t i c a l i n a l l respects with the compound i s o l a t e d (as described above) from the l i t h -ium-ammonia-ethanol reduction of the a,^-unsaturated ester (61). Reduction of the saturated ester (72), under conditions s i m i l a r to those ou t l i n e d above ( l i t h i u m aluminum hydride, ether, -78 °C), gave the epimeric alcohol (90) as a c o l o r l e s s gum (100%). The s p e c t r a l data obtained from t h i s substance c l e a r l y showed that t h i s material was d i f f e r e n t from the alcohol (89). Infrared a n a l y s i s of t h i s material showed a broad hydroxyl group absorption at 3490 cm * and, i n the *H nmr spectrum, the angular methyl group gave r i s e to a three-proton s i n g l e t at 6 1.04. The r e s u l t s described above provided ample evidence for the f a c t that the tentative assignments made for the structure of the saturated esters (72) and (76) (vide supra) were, i n f a c t , correct. These com-pounds were further characterized by t h e i r conversion into the keto ethers (92) and (91), whose preparations are outlined below. 73. Acid-catalyzed hydrolysis of the saturated ester (72) with IN hydrochloric a c i d i n acetone (ambient temperature, 1 h) afforded the keto ether (92) (77%). The i r spectrum of t h i s material ( p u r i f i e d by preparative t i c ) showed the presence of both an ester group and a keto f u n c t i o n a l i t y (1732 and 1705 cm r e s p e c t i v e l y ) . As expected, the *H nmr spectrum of compound (92) revealed only one t e r t i a r y methyl reson-ance, a three-proton s i n g l e t at 6 1.35 (angular methyl group). The MEM ether protons (-OCIL^CH^O-) and C^H gave r i s e to a complex mul t i p l e t between 6 3.48 and 3.86. (72) (92) Hydrolysis of the saturated ester (76), under conditions i d e n t i c a l with those described above (IN hydrochloric acid-acetone, room temper-ature, 1 h), yielded the keto ether (91) (82%) as the sole product. The i r spectrum of the l a t t e r compound showed absorptions at 1730 (ester carbonyl group) and at 1708 cm * (keto f u n c t i o n a l i t y ) . In i t s *H nmr spectrum, compound (91) exhibited a resonance due to the angular methyl group at 6 1.21 (a three-proton s i n g l e t ) . The proton attached to produced a si g n a l at 6 4.16 which was coincident with the two-proton 74. quartet ( J = 7 Hz) due to the methylene group of the et h y l ester func-t i o n a l i t y . C0 2Et OMEM C0 2Et OMEM (76) (91) At t h i s point, the focus of our atte n t i o n was directed once again toward the hydrogenation of the a,^-unsaturated ester (61). As men-tioned previously, the hydrogenation of (61) using platinum oxide as cat a l y s t i n e t h y l acetate afforded a disappointingly low r a t i o of the desired saturated ester (72) to the epimeric compound (76) (6:4, respec-t i v e l y ) . Somewhat unexpectedly, v a r i a t i o n of the re a c t i o n conditions ( c a t a l y s t , solvent, hydrogen pressure and temperature) f a i l e d to improve t h i s r a t i o by more than approximately 10%. A f a i r l y wide v a r i e t y of combinations of c a t a l y s t s (10% palladium-on-carbon, platinum oxide, 5% palladium-on-barium s u l f a t e , tris(triphenylphosphine)rhodium c h l o r i d e , 5% ruthenium-on-alumina) and solvents (ethyl acetate, hexane, ethanol, 5% potassium hydroxide i n ethanol, cyclohexane, benzene, tetrahydro-furan and 8% triethylamine i n tetrahydrofuran) were evaluated. V a r i a -tions of both the r a t i o of c a t a l y s t to substrate, as well as substrate concentration, f a i l e d to a l t e r the product d i s t r i b u t i o n s i g n i f i c a n t l y . 75. (61) (72) (76) The conditions which were found to be the most s e l e c t i v e (deter-mined by g l c ) were 5% palladium-on-barium su l f a t e i n hexane (atmospheric pressure, ambient temperature) which provided (72) and (76) i n a r a t i o of 34:66, r e s p e c t i v e l y , and 5% ruthenium-on-alumina i n ethanol contain-ing 5% potassium hydroxide (atmospheric pressure, ambient temperature) which afforded (72) and (76) i n a r a t i o of 69:31, r e s p e c t i v e l y . In p r a c t i c e , however, the conditions which were used r o u t i n e l y were p l a t -inum oxide i n tetrahydrofuran (50 p s i , ambient temperature), since these conditions provided a r a t i o [(72):(76) = 66:34] sim i l a r to that obtained i n the ruthenium catalyzed case and the c a t a l y s t was more r e a d i l y a v a i l -able. I n t e r e s t i n g l y , i t was found that under the f i n a l l y chosen condi-tions (platinum oxide, tetrahydrofuran, 50 p s i ) , one of the geometric isomers of (61), obtained as a pure s o l i d by f r a c t i o n a l c r y s t a l l i z a t i o n of the mixture of isomers (vide supra), afforded the saturated esters (72) and (76) i n a r a t i o of 85:15, r e s p e c t i v e l y . Thus, for some obscure 76. reason(s), one geometric isomer of (61) was more accessible to hetero-geneously catalyzed hydrogenation from the a face than was the other geometric isomer. By inference, the l a t t e r material displayed v i r t u a l l y no s e l e c t i v i t y when hydrogenated under the aforementioned conditions. During the course of these studies a major complication became evident. It was found that only selected batches of ca t a l y s t (platinum oxide) gave r i s e to reproducible hydrogenation of compound (61). With other l o t s , varying degrees of side product formation occurred. The major side product formed i n these reactions was the keto ether (92) which appeared to r e s u l t from keta l cleavage of the desired saturated ester (72) under the hydrogenation conditions. The epimeric (and un-desired) saturated ester (76), seldom underwent noticeable decomposition even under reaction conditions i n which the desired saturated ester (72) was almost e n t i r e l y converted into compound (92). A s a t i s f a c t o r y explanation for t h i s rather unusual behavior was not found. Another attempt to increase the e f f i c i e n c y of the production of the desired saturated ester (72) was c a r r i e d out as follows. It was hoped that the preparation and subsequent hydrogenation of the endocyclic o l e f i n s (93) and (94) might give r i s e to a greater proportion of the desired material (72) than that obtained from compound (61). Thus, a mixture of these compounds, which were inseparable by glc and t i c , was prepared by the treatment of the a,/?-unsaturated ester (61) (a 1:1 mixture of isomers) with a 1:1 complex of l i t h i u m d i i s o p r o -pylamide and hexamethylphosphoramide (-78 °C, 1.25 h) i n tetrahydro-69 furan , followed by protonation of the resultant mixture of enolate anions. P u r i f i c a t i o n of the r e s u l t i n g crude product by preparative t i c 77. gave (62% y i e l d ) the o l e f i n s (93) and (94), i n a r a t i o of approximately 3:1, r e s p e c t i v e l y . The major product was t e n t a t i v e l y assigned structure (93). This assignment was based on l i t e r a t u r e precedent^ 0'^*'^ 2 and also on the observation that the protons on would be k i n e t i c a l l y more a c i d i c than those on C.. This was believed to be the case since the 4 l a t t e r protons were judged to be considerably more hindered than those attached to C„. (61) (93) (94) In t e r e s t i n g l y , treatment of one of the geometric isomers of (61) (vide supra) with l i t h i u m diisopropylamide-hexamethylphosphoramide, under conditions i d e n t i c a l with those outlined above, afforded the o l e f i n (93) as the sole product (80% y i e l d ) . The i r spectrum of t h i s material showed an absorption due to a saturated ester group at 1730 cm In the *H nmr spectrum the protons a to the ester f u n c t i o n a l i t y appeared as a two-proton s i n g l e t ( 6 2.94) and the o l e f i n i c proton pro-duced a broad, one-proton resonance at 6 5.49. The hydrogenation (platinum oxide, tetrahydrofuran) of either the mixture of o l e f i n s (93) and (94), or compound (93) alone, was substan-t i a l l y slower than the hydrogenation of compound (61) under s i m i l a r 78. conditions. Analysis of the crude material i s o l a t e d from these reac-tions ( g l c , t i c ) showed that the saturated esters (72) and (76) were formed i n a r a t i o of approximately 1:1. These products were accompanied by several, more polar side products. The l a c k of pronounced s t e r e o s e l e c t i v i t y encountered i n the hydro-genation reactions described i n t h i s s ection was rather disappointing. These r e s u l t s tended to suggest that the /3 face (convex side) of the a,0-unsaturated ester (61), as w e l l as the o l e f i n s (93) and (94), were somewhat more hindered than was a n t i c i p a t e d a_ p r i o r i . An a l t e r n a t i v e r a t i o n a l i z a t i o n , however, i s perhaps worthy of consideration. It i s 73 conceivable that an a t t r a c t i v e ("haptophilic") i n t e r a c t i o n between the MEM ether moiety^ and the surface of the c a t a l y s t may have a l t e r e d the expected course of the hydrogenation r e a c t i o n . Thus, i f the MEM ether group was "held" on the c a t a l y s t s surface i n such a fashion so as to allow hydrogen (adsorbed on the surface of the c a t a l y s t ) to attack the o l e f i n from the concave side ( o face) of the molecule, then the unde-s i r e d saturated ester (76) would be produced. This type of i n t e r a c t i o n has previously been proposed as a r a t i o n -a l i z a t i o n for anomalous ("contra-steric") hydrogenation r e s u l t s i n other systems. ^ For example, McMurry^ found that while the hydrogenation It i s of passing i n t e r e s t to note that the MEM ether moiety has been found to exert powerful (and unusual) d i r e c t i n g e f f e c t s on the stereo-chemistry of some carbonyl reductions. 79. (platinum oxide) of compound (87) occurred e x c l u s i v e l y from the l e s s hindered side of the molecule, the corresponding alcohol (88) produced a mixture of products (55:45) favoring the addi t i o n of hydrogen from the more hindered side of the molecule. (88) (87) V. Attempted Synthesis of the T r i c y c l i c Ketone (12) v i a  Intramolecular C y c l i z a t i o n The synthetic scheme envisaged for the conversion of the saturated ester (72) into the t r i c y c l i c ketone (12) i s i l l u s t r a t e d i n Scheme 5. D i a l k y l a t i o n of compound (72) should a f f o r d the o,a-dimethyl ester (95) which, i n turn, was to be transformed into the amino compound (13) (R' = MEM) by the sa p o n i f i c a t i o n of (95), followed by subjection of the 20 r e s u l t a n t acid to a Curtius r e a c t i o n . Compound (13) would then be converted into the corresponding t o s y l a t e , a f t e r cleaving the MEM ether moiety, and subsequently c y c l i z e d and deprotected to a f f o r d the t r i -c y c l i c system (12). (12) (13) S C H E M E 5 However, at t h i s stage another possible synthetic approach to the d i a l k y l a t e d ester (95), employing the a,/?-unsaturated ester (61) as s t a r t i n g m a t e r i a l , was considered. Schlessinger et a l had demonstrated that the deconjugative a l k y l a t i o n of a,/?-unsaturated e s t e r s , producing «,a-dialkyl-/3,Y-unsaturated est e r s , often proceeds i n e x c e l l e n t y i e l d s . ^ For example, e t h y l crotonate (96) afforded (94% o v e r a l l ) the d i a l k y l a t e d material (97) employing t h i s methodology. (96) (97) 81. Thus, i t was ant i c i p a t e d that the a,/?-unsaturated ester (61) could be transformed into the a,a -dimethyl-/3,y-unsaturated compound (98) [and/or (99)]. This substance, i t was hoped, could then be hydrogenated to produce the desired d i a l k y l a t e d ester (95). This methodology poten-t i a l l y provided both s i m p l i c i t y as well as an opportunity to attempt to increase the s t e r e o s e l e c t i v i t y of the production of the desired epimer ( a face at C^) i n the hydrogenation step. Accordingly, the a,/3-unsaturated ester (61) was treated successive-l y with two equivalents of l i t h i u m diisopropylamide-hexamethylphosphor-amide complex and excess methyl iodide (tetrahydrofuran, -78 °C to 0 °C). The crude product was p u r i f i e d by preparative t i c g i v i n g , i n low y i e l d , what appeared to be a mixture of the monoalkylated compounds (100) and (101). This mixture was treated under conditions s i m i l a r to those C0 2Et OMEM (95) 82. described above affo r d i n g (62% y i e l d ) the desired d i a l k y l a t e d system as a mixture of compounds (98) and (99) (approximately 5:1 r a t i o ) . These compounds were Indistinguishable on the basis of t h e i r respective spec-t r a l data. (100) (101) Unfortunately, i n our hands a l l attempts to hydrogenate t h i s mix-ture r e s u l t e d only i n the recovery of the s t a r t i n g material. Presum-ably, with the a d d i t i o n a l s t e r i c encumbrance due to the geminal dimethyl groups on the side chain, the endocyclic double bond was e f f e c t i v e l y i n e r t to hydrogenation under the conditions employed. This possible route toward the d i a l k y l a t e d ester (95) was not investigated f u r t h e r , i n part because the o v e r a l l y i e l d of the alky-l a t i o n procedure was low. In a d d i t i o n , the f a i l u r e of these compounds to undergo hydrogenation precluded further studies i n t h i s d i r e c t i o n . At t h i s juncture, i t was decided to return to the o r i g i n a l plan for the synthesis of the d i a l k y l a t e d material (95). This transformation was accomplished as follows. Treatment of the saturated ester (72) with excess l i t h i u m diisopropylamide (tetrahydrofuran, -78 °C, 1 h), followed by methyl iodide i n hexamethylphosphoramide (-20 °C, 30 min; 0 °C, 30 min), afforded the d i a l k y l a t e d ester (95) i n e s s e n t i a l l y quantitative 83. y i e l d . The i r spectrum of t h i s substance showed an absorption at 1725 cm * due to the ester carbonyl group. Five t e r t i a r y methyl groups were evident i n the *H nmr spectrum, three as three-proton s i n g l e t s (<5 0.70, 1.05 and 1.18) and the remaining two as a six-proton s i n g l e t at 6 1.07. Attempts to saponify the d i a l k y l a t e d ester (95) with IN potassium hydroxide i n methanol (52 h, r e f l u x ) were unsuccessful and the s t a r t i n g material was recovered q u a n t i t a t i v e l y . Several other methods aimed at producing the d i a l k y l a t e d a c i d (102) were also investigated. These 78 included the use of potassium tert-butoxide i n ether-water s o l u t i o n (ambient temperature, 15 h) and treatment of (95) with l i t h i u m t h i o -79 methoxide i n hexamethylphosphoramide (80 °C, 2 h), both of which have been used i n the past to cleave hindered e s t e r s . In our hands neither of these methods produced the desired product (102) i n any appreciable quantity. C0 2 H OMEM (102) When the d i a l k y l a t e d ester (95) was treated with potassium t e r t -80 butoxide i n dry dimethyl sulfoxide (ambient temperature, 1.75 h), however, a l l the s t a r t i n g material disappeared with the concomitant formation of a very polar product (baseline by t i c ) . N e u t r a l i z a t i o n of the reaction mixture (0.25 _N hydrochloric a c i d ) , followed by routine aqueous work-up, afforded only the keto a c i d (103), i n moderate y i e l d . 84. This material displayed a broad absorption (3400-2450 cm"1) i n i t s i r spectrum due to the carboxylic a c i d f u n c t i o n a l i t y . That the k e t a l group had been removed under these conditions was substantiated by the *H nmr spectrum of (103) which showed only three t e r t i a r y methyl signals at <5 1.08, 1.11 and 1.35 (angular methyl). (95) (103) C l e a r l y , the k e t a l cleavage must have occurred during the n e u t r a l -i z a t i o n step since the hydrolysis conditions used were quite basic i n nature. After considerable experimentation, i t was found that i f the n e u t r a l i z a t i o n was performed under d i f f e r e n t conditions than those described above, the desired carboxylic a c i d (102), mp 124-125 °C, was obtained i n a y i e l d of 88%. These conditions e n t a i l e d cooling (0 °C) the r e a c t i o n mixture, followed by the n e u t r a l i z a t i o n of the excess base through the portion-wise addition of a c i d i c ion exchange r e s i n . The r e s u l t i n g c o l d suspension was then immediately f i l t e r e d to remove the a c i d i c exchange r e s i n . Under these conditions, there was no detectable k e t a l cleavage. In the Ir spectrum of the carboxylic a c i d (102), the carboxylic a c i d f u n c t i o n a l i t y gave r i s e to absorptions at 3450-2400 (broad) and at 1695 cm *. The *H nmr spectrum of t h i s material displayed signals accounting for f i v e t e r t i a r y methyl groups as three 3-proton s i n g l e t s 85. (6 0.70, 1.06 and 1.18) and one six-proton s i n g l e t at 6 1.11. The elaboration of the carboxylic a c i d (102) into the nitrogen containing material (13) (see Scheme 5) was to be attempted through the 20 use of a Curtius degradation sequence or a r e l a t e d modification 81 82 thereof. ' Thus, the plan involved the conversion of the carboxylic a c i d (102) into the corresponding isocyanate (106), v i a the intermed-iacy of the ac i d chloride (104) and the ac y l azide (105), as indicated i n the accompanying equation. (104) NCO OMEM CN, OMEM II 3 0 (106) (105) The f i r s t step of t h i s proposed sequence involved the formation of 86. the a c i d chloride (104). Acid chlorides may be prepared from the parent 83 a c i d i n a v a r i e t y of ways. Reagents such as t h i o n y l chloride and 84 phosphorus pentachloride have l a r g e l y been replaced by reagents r e -q u i r i n g less vigorous r e a c t i o n conditions such as triphenylphosphine-85 86 87 carbon t e t r a c h l o r i d e , phosgene , and o x a l y l chloride . The l a t t e r reagent was chosen for our purposes since the y i e l d of a c i d chloride produced using the reagent i s often very good and, since the gaseous biproducts formed (carbon monoxide and carbon dioxide) leave the reac-t i o n mixture, the equilibrium i s driven to the side of the desired a c y l c h l o r i d e . Oxalyl chloride may be used to form a c i d chlorides i n a number of 88 89 d i f f e r e n t ways. These involve the use of the reagent alone ' i n a s o l u t i o n (usually benzene) containing the given a c i d or i n the presence 89 90 of pyridine i n a s o l u t i o n containing either the parent acid ' or i t s 91 92 93 sodium ' or potassium s a l t . In the case of the carboxylic a c i d (102), the use of o x a l y l c h l o r -ide alone was avoided due to the inherently a c i d i c nature of t h i s method and the i n c o m p a t i b i l i t y of compound (102) with even traces of a c i d . However, even the r e a c t i o n of t h i s reagent with the l a t t e r compound i n the presence of pyridine (ambient temperature, 3 h), afforded the desired a c y l chloride (104) i n only moderate y i e l d . Infrared analysis of the crude product demonstrated the presence of unreacted s t a r t i n g material (102) (3300-2450 and 1700 cm - 1), as well as the desired a c i d chloride (1785 cm"*). This material was subsequently allowed to react with sodium azide (0 °C, 1.5 h) i n acetone-water and the r e s u l t i n g product, which showed an a c y l azide absorption at 2155 cm * i n the i r 87. spectrum, was then refluxed (2 h) i n benzene. The crude material thus obtained was a mixture of several products ( t i c ) . This mixture con-tained some material possessing an isocyanate f u n c t i o n a l i t y (Ir absorp-t i o n at 2280 cm * ) . However, the presence of carbonyl containing mater-i a l was also indicated (broad i r band at 1700-1780 cm-'''). Attempts to trap the isocyanate (106), assumed to be present i n the mixture ( i r 94 95 a n a l y s i s ) , by reaction with methyl l i t h i u m ' (0 °C, 10 min) l e d only to i n t r a c t a b l e material. The sodium s a l t of compound (102) [obtained from aqueous sodium hydroxide (1 equivalent) by l y o p h i l i z a t i o n ] was treated with o x a l y l chloride (benzene) containing a small amount of pyridine and the mater-i a l thus obtained was allowed to react with sodium azide (as above). A s o l u t i o n of the r e s u l t a n t crude product i n benzene was refluxed (3 h), producing a mixture quite s i m i l a r to that described above ( t i c , i r ) . Since the preparation of the a c i d chloride (104), and subsequently the isocyanate (106), was not being accomplished e f f i c i e n t l y under the conditions o u t l i n e d above, some a l t e r n a t i v e procedures were i n v e s t i -gated. The f i r s t of these involved the attempted conversion of the s i l y l ester (107) into the desired a c y l chloride (104). Wissner e_t a l 96 had r e c e n t l y reported the synthesis of a c i d chlorides from the cor-responding t e r t - b u t y l d i m e t h y l s i l y l e s t e r s , i n e x c e l l e n t y i e l d s , using a complex of o x a l y l chloride and dimethylformamide. Accordingly, the s i l y l ester (107) was prepared (99% y i e l d ) from the carboxylic a c i d (102) v i a treatment of the l a t t e r compound with t e r t - b u t y l d i m e t h y l s i l y l chloride i n dry dimethylformamide containing 88. imidazole (60 °C, 17 h). Compound (107) displayed a carboxyl group absorption at 1715 cm * i n i t s i r spectrum. In the *H nmr spectrum, t h i s substance exhibited resonances at 6 0.26 (six-proton s i n g l e t ) and at 6 0.95 (nine-proton s i n g l e t ) due to the methyl groups and the t e r t — butyl group, r e s p e c t i v e l y , attached to the s i l i c o n atom. This material was allowed to react with dimethylformamide-oxalyl chloride (room temperature, 3 h) i n methylene chloride and the resultant material was treated with excess sodium azide (ambient temperature, 3.5 h) i n acetone. The crude product i s o l a t e d from t h i s r e a c t i o n showed a weak azide absorption at 2150 cm * i n the i r spectrum. Unfortunately, when t h i s material was refluxed i n xylene (2.5 h) several products were formed ( t i c ) . The i r spectrum of the crude material showed the d i s -appearance of the azide band and the appearance of a weak isocyanate absorption (2275 cm *) but also exhibited a strong carbonyl absorption at 1710 cm - 1. Since the synthesis of the acyl chloride (104), by any of the methods o u t l i n e d above, was not being accomplished e f f i c i e n t l y , the preparation of the hydrazide (108) was attempted. It i s well known that hydrazides may be converted i n t o the corresponding a c y l azides by the treatment of the former substances with sodium n i t r i t e (or an organic C O S i ; — f OMEM (107) II 0 89. 97 n i t r i t e ) i n a c i d i c s o lutions. A l t e r n a t i v e l y , azides may be prepared from hydrazides through the treatment of the l a t t e r materials with 98 n i t r o s y l chloride at low temperature. In the context of these syn-t h e t i c studies, i t was clear that due to the s e n s i t i v i t y of the i n t e r -mediate compounds to a c i d i c conditions, only the l a t t e r methodology was 99 appropriate. This type of sequence has re c e n t l y been used to advan-tage i n preparing azides i n other a c i d s e n s i t i v e molecules. CNHNH 2 OMEM o (108) Thus, i t was f e l t that the preparation of the hydrazide (108), p o t e n t i a l l y a v a i l a b l e from the d i a l k y l a t e d ester (95), would provide an a l t e r n a t i v e route to the desired azide (105). Unfortunately, subjection of the d i a l k y l a t e d ester (95) to hydrazinolysis conditions (excess anhydrous hydrazine i n methanol, ambient temperature, 90 h) r e s u l t e d only i n the recovery of the s t a r t i n g material. Even at elevated temp-eratures (65 °C, 24 h) compound (95) f a i l e d to undergo the desired transformation. Although the preparation of hydrazides i s usually an uncomplicated process, i n t h i s case, perhaps due to the hindered nature of the ester carbonyl (vide supra), the s t a r t i n g material was i n e r t under the given r e a c t i o n conditions. Another approach which was b r i e f l y investigated involved the attempted preparation of the isocyanate (106) from the mixed anhydride 90. (109). W e i n s t o c k i U U developed t h i s modification of the Curtius r e a c t i o n e x p l i c i t l y for use with acid s e n s i t i v e substrates. In a recent modi-f i c a t i o n of t h i s method, Overman e_t a l * ^ * prepared a seri e s of s e n s i t i v e N-acylamino-l,3-dienes i n good o v e r a l l y i e l d . (102) 0 0 (109) (106) Thus, the carboxylic a c i d (102) was treated with e t h y l c hloro-formate and N,N-diisopropylamine i n acetone (0 °C, 5 h) and the r e s u l -tant material was treated with excess sodium azide i n acetone-water (ambient temperature, 20 h). The crude mixture thus obtained was d i s -solved i n dry j>-xylene and the s o l u t i o n was refluxed (3 h). Examin-a t i o n of the crude product by i r s p e c t r a l analysis showed that i t con-tained both an isocyanate moiety ( i r absorption at 2280 cm *) and a carbonyl group ( i r absorption at approximately 1705 cm * ) . By t i c , t h i s m a t erial was found to contain a considerable amount of the s t a r t i n g material (102). Although the presence of recovered s t a r t i n g material (102) i n the crude product could be due simply to i t s incomplete r e a c t i o n , i t was suspected that t h i s material r e s u l t e d from the attack of azide ion at the "wrong" carbonyl of the mixed anhydride (109). Mixed anhydrides of t h i s type predominantly react with nucleophiles (e.g. azide ion) at the more rea c t i v e carbonyl group ( l a b e l l e d a) o r i g i n a t i n g from the parent 91. ac i d . In the case of compound (109), however, t h i s centre was s t e r -i c a l l y very hindered due to the presence of the adjacent geminal methyl groups. It was f e l t that t h i s arrangement could tend to discourage n u c l e o p h i l i c attack at t h i s carbonyl group. Attack of azide ion at the other carbonyl group (/?) would generate the carboxylate of (102) which would be expected to protonate during work-up regenerating the s t a r t i n g material (102). 0 0 I I I I R C O C 0 R1 « fi Another modification of the Curtius r e a c t i o n , reported by Yamada 102 and co-workers i n 1972, made use of a novel reagent, diphenylphos-phoryl azide. Yamada demonstrated that, with t h i s reagent, the d i r e c t C 6H 50 C 6 H 5 ° - N . transformation of a carboxylic acid to a carbamate (urethane) was possible. For example, benzoic a c i d (110) was converted into the corresponding t e r t - b u t y l carbamate (111) i n a y i e l d of 74%. 92. (110) (111) This method was experimentally far l e s s complex than the standard Curtius r e a c t i o n and i t provided the given amine as the carbamate deriva-103 t i v e . For the purposes of the synthetic scheme under i n v e s t i g a t i o n here, the l a t t e r a t t r i b u t e of t h i s technique was of considerable impor-tance. According to the synthetic plan (see Scheme 5), the tosylate d e r i v a t i v e (13) (R' = Ts) was to be prepared from the corresponding MEM ether (R* = MEM) v i a cleavage of the ether protecting group followed by the t o s y l a t i o n of the r e s u l t i n g alcohol (R 1 = H). Obviously, the s e l e c -t i v e t o s y l a t i o n of the a l c o h o l , i n the presence of a free amine (R = H), could prove to be quite d i f f i c u l t i f not impossible. It i s also per-tinent to note that Yamada's procedure was conducted under e s s e n t i a l l y neutral conditions and thus i t was expected that both the ac i d s e n s i t i v e MEM ether group and the extremely a c i d l a b i l e k e t a l f u n c t i o n a l i t y of compound (102) would survive these r e a c t i o n conditions. (13) 93. In order to determine whether or not t h i s was the case, i t was decided to tre a t the carboxylic a c i d (112) with Yamada's reagent. In t h i s way, the compa t i b i l i t y of the r e a c t i o n conditions with the k e t a l group and the MEM ether f u n c t i o n a l i t y could be evaluated on an expend-able compound which was formally a v a i l a b l e ( v i a saponification) from the "undesired" saturated ester (76). C0 2 Et O M E M C0 2 H OMEM NHC0 2Bo t OMEM (76) (112) (113) Accordingly, the saturated ester (76) was treated with IN potassium hydroxide i n methanol ( r e f l u x , 2 h) furnishing the carboxylic acid (112) i n 54% y i e l d . That t h i s material contained, a carboxylic a c i d f u n c t i o n a l i t y was shown by a broad absorption between 3500 and 2390 cm * (hydroxyl group) and by a sharp signal at 1713 cm * (carbonyl group) i n the i r spectrum. The *H nmr spectrum of t h i s substance demonstrated the absence of an ester f u n c t i o n a l i t y and exhibited a broad, one-proton s i n g l e t ( 6 8.78-9.20) for the carboxylic a c i d proton. The carboxylic a c i d (112) was allowed to react with f r e s h l y d i s -t i l l e d diphenylphosphoryl azide^ and triethylamine i n dry t e r t - b u t y l alcohol (relux, 18 h). P u r i f i c a t i o n of the crude product by preparative Prepared from diphenyl phosphorochloridate and sodium azide, bp 170 °C (0.8 mm) [ l i t . 1 0 2 bp 157 °C (0.17 mm)]. This material slowly d i s c o l o r s when stored at ambient temperature. 94. tic gave the tert-butyl ester (114) (19%) and an Inseparable mixture , (approximately 40%) which appeared to contain the desired carbamate (113) as well as a small amount of an unidentified side product. The ir spectrum of this mixture showed a distinct NH absorption at 3350 cm 1 and the 1H nmr spectrum exhibited resonances at 6 6.13 (broad, one— proton singlet, -NH-) and between 6 3.0 and 4.0, indicating the MEM ether and the ketal group were present. The mass spectrum of this material showed a strong signal at m/e = 485, consistent with compound (113). The side product, compound (114), showed an ester carbonyl absorp-tion at 1722 cm-1 in the ir spectrum. In the *H nmr spectrum, this material exhibited resonances attributed to three tertiary methyl groups at 6 0.70 (three-proton singlet) and at 6 1.18 (six-proton singlet). The tert-butyl group gave rise to a nine-proton singlet at 6 1.43. The MEM ether group displayed characteristic resonances at 6 3.37 (three— proton singlet, methoxy methyl group) and at 6 4.72 and 4.78 (two 2— proton doublets, J = 8 Hz, AB quartet, -OCH^ O-). + C 0 2 H OMEM I „ „ t O M E M NHCOjBo 1 C0 2 B u OMEM (112) (113) (114) The results outlined above suggested that both the MEM ether func-tionality and the ketal moiety were stable to the reaction conditions involved with the use of Yamada's reagent 1 0 2. However, the yield of the 95. r e a c t i o n employing compound (112) as the substrate was quite low and the appearance of the t e r t - b u t y l ester side product (presumably a r i s i n g from the reaction of t e r t - b u t y l a l c ohol with the intermediate acyl azide species) was somewhat discouraging. With the carboxylic a c i d (102), however, the formation of the corresponding t e r t - b u t y l e ster, as a side r e a c t i o n , was u n l i k e l y . If the intermediate a c y l azide (105) was formed as expected, t h i s material was a n t i c i p a t e d to be too hindered (based on the r e s u l t s obtained from both the attempted hydrazide formation and the formation of the a c y l azide v i a the Weinstock modification**^) to react with the solvent ( t e r t - b u t y l alcohol) to any appreciable degree. Thus, the carboxylic a c i d (102) was treated with f r e s h l y d i s t i l l e d diphenylphosphoryl azide and triethylamine i n dry t e r t - b u t y l alcohol ( r e f l u x , 27 h). S u r p r i s i n g l y , when the r e s u l t i n g crude product was p u r i f i e d by preparative t i c , the isocyanate (106) was i s o l a t e d i n 45% y i e l d . This material, which was a sta b l e , c o l o r l e s s gum, exhibited a c h a r a c t e r i s t i c absorption for an isocyanate moiety (2265 cm *) i n the i r spectrum. The *H nmr spectrum showed three t e r t i a r y methyl groups at 6 0.70 and 1.20 (two three-proton s i n g l e t s , k e t a l methyl groups) and at 6 1.07 (three-proton s i n g l e t , angular methyl group). The geminal methyl groups, a to the isocyanate moiety, were c h a r a c t e r i s t i c a l l y (105) 96. s h i f t e d downfield with respect to the s t a r t i n g material (102), giving r i s e to a six-proton s i n g l e t at 6 1.28. (102) (106) (116) Treatment of the isocyanate (106) with dry methanol ( r e f l u x , 24 h) afforded the k e t a l carbamate (115) i n quantitative y i e l d . This sub-stance showed absorbances due to the carbamate mo i e t y at 3440 cm"1 (NH) and at 1722 cm 1 (carbonyl group) i n the i r spectrum. The *H nmr spectrum of t h i s compound exhibited two low f i e l d , three-proton s i n g l e t s at 6 3.41 (methoxy methyl of the MEM ether group) and at 6 3.62 (carbo-rne thoxy group). The proton on the nitrogen atom of the carbamate func-t i o n a l i t y appeared as a broad, one-proton s i n g l e t at 6 4.60. These r e s u l t s suggested that the isocyanate group i n compound (106) was s t e r i c a l l y too encumbered to react with the solvent ( t e r t — b utyl alcohol) to produce the expected t e r t - b u t y l urethane. As men-tioned previously, i t seemed l i k e l y that the geminal dimethyl groups a to the isocyanate f u n c t i o n a l i t y were e f f e c t i v e l y s h i e l d i n g t h i s group from r e a c t i n g . Even with the use of a s t e r i c a l l y l e s s demanding alcohol (e.g. methanol), the r e a c t i o n of t h i s material to form the corresponding carbamate was quite slow. This data i s i n accord with published reports i n d i c a t i n g that primary alcohols react with isocyanates approximately 97. 200 times faster than t e r t i a r y alcohols. The successful preparation of the k e t a l carbamate (116), a l b e i t an encouraging r e s u l t , was tempered by the f a c t that the y i e l d (45%) of 102 t h i s material was low. In Yamada's communication on the use of diphenylphosphoryl azide, i t was suggested that the formation of the carbamate product proceeds v i a the intermediacy of the corresponding a c y l azide. Furthermore, the formation of the l a t t e r was proposed as occurring through an intermediate such as that depicted below [cf. ( I ) ] . It seemed a t t r a c t i v e to question whether or not the predominant i n t e r -mediate might not a c t u a l l y be the mixed phosphate anhydride ( I I ) . II I II t R - C - O - P - (OPh) R - C - O - P - (OP H,.) | ^ 6 5 2 3 (II) (I) This general type of anhydride was not unknown*^"* and i t was f e l t that t h i s type of compound might meet our synthetic needs from two points of view. F i r s t l y , the formation of t h i s type of derivative from compound (102) could be effected under basic conditions. It was f e l t that, considering the demonstrated l a b i l i t y of t h i s system [cf. (102)] to a c i d , these conditions might well give r i s e to superior y i e l d s of a de r i v a t i z e d a c i d as compared to those involving the p o s s i b i l i t y of the presence of even trace amounts of a c i d i c materials (e.g. a c y l chloride preparations). Secondly, i t was hoped that t h i s type of mixed anhy-dride, as opposed to that produced using Weinstocks' m o d i f i c a t i o n * ^ , 98. would react with a nucleophile (e.g. azide ion) p r e f e r e n t i a l l y at carbon rather than phosphorus. In t h i s regard, i t i s of i n t e r e s t to note that the c y c l i c system (117) was found to react with primary amines predominantly at carbon but, with alcoh o l s , almost e x c l u s i v e l y at p h o s p h o r u s . O n the other (117) hand, Masamune e_t a l * ^ had reported that the r e a c t i o n of t h i s type of mixed anhydride, with T l (I) t h i o l a t e s , afforded the corresponding t h i o l e s ters i n exc e l l e n t y i e l d . For example, c h o l i c a c i d (118) gave the 2-methylpropane-2-thiol ester (119) i n an o v e r a l l y i e l d of 86%. (118) (119) Thus, i n the hopes of increasing the y i e l d of the k e t a l carbamate (116), the following ser i e s of transformations were c a r r i e d out. A s o l u t i o n of the carboxylic a c i d (102) i n dry tetrahydrofuran was treated 99. with dry triethylamine (2.3 equivalents), followed by two equivalents of d i e t h y l phosphorochloridate (ambient temperature, 4 h). The crude product was dissolved i n hexamethylphosphoramide and the r e s u l t i n g s o l u t i o n was added to a solution-suspension of excess sodium azide i n hexamethylphosphoramide (ambient temperature, 15 h). A so l u t i o n of. the r e s u l t i n g a c y l azide ( i r absorption at 2155 cm *) i n dry toluene was refluxed for 3 h. F i n a l l y , the crude material obtained from the toluene s o l u t i o n was dissolved i n methanol containing a small amount of DBN^ (l,5-diazabicyclo[4.3.0]non-5-ene), and the r e s u l t i n g s o l u t i o n was refl u x e d for 90 min. The i s o l a t e d crude product (97%) was pure by t i c , *H nmr, and g l c , and proved to be the desired ket a l carbamate (116). In order to complete the synthesis of the t r i c y c l i c ketone (12), the removal of the MEM ether protecting group, followed by the conver-sion of the r e s u l t i n g alcohol (120) into a suitable leaving group (e.g. t o s y l a t e ) , was necessary. With the molecule thus f u n c t i o n a l i z e d , a base promoted intramolecular c y c l i z a t i o n should form the t r i c y c l i c compound (122). Hydrolysis of both the k e t a l group and the carbamate function-a l i t y should then f u r n i s h the desired ketone (12) (Scheme 6). Following t h i s plan, studies aimed at s e l e c t i v e l y removing the MEM ether were i n i t i a t e d . This task was anticipated to be problematic since the k e t a l group present i n several of the intermediates leading to compound (116) had been found to be very l a b i l e i n a c i d . Indeed, t h i s Without a c a t a l y t i c amount of DBN, the r e a c t i o n of the crude i s o c y a -nate (106) ( i r absorption at 2280 cm" ) with methanol was very slow (incomplete a f t e r 22 h at room temperature). 100. (120) (121) N H (12) S C H E M E 6 101. concern proved j u s t i f i e d , for when the k e t a l carbamate (116) was treated under a wide v a r i e t y of a c i d i c conditions, the desired alcohol (120) was not obtained. Exposure of the k e t a l carbamate (116) to titanium t e t r a c h l o r -27 53 ide ' (-20 °C, 0.5 h), for example, afforded the keto carbamate (123) and the carbamate alcohol (124), i n a r a t i o of 4:1, r e s p e c t i v e l y . There was no evidence to indicate that any of the desired material (120) had been produced. (116) (123) (124) The keto carbamate (123) exhibited absorptions i n i t s i r spectrum at 3447 and 1723 cm 1 (NH and the carbonyl group of the carbamate func-t i o n a l i t y , r e s p e c t i v e l y ) and at 1701 cm 1 (keto group). In the *H nmr spectrum the gem-dimethyl group gave r i s e to two three-proton s i n g l e t s (6 1.17 and 1.20). A l l of the resonances c h a r a c t e r i s t i c of the k e t a l group were absent. The i r spectrum of the carbamate alcohol (124) showed absorptions due to the hydroxyl group (3620 cm - 1), the carbamate f u n c t i o n a l i t y (3450 and 1720 cm * ) , and the keto group (1706 cm * ) . The *H nmr spectrum of t h i s material exhibited signals due to the carbamate f u n c t i o n a l i t y at 6" 3.60 (three-proton s i n g l e t , methoxy methyl group) and at 6 4.53 (a broad, one-proton s i n g l e t , -NH-). The lack of any resonances character-102. i s t i c of the MEM ether group or the k e t a l f u n c t i o n a l i t y was c l e a r l y evident. The use of other a c i d i c reagents were a l l uniformly unsuccessful i n s e l e c t i v e l y removing the MEM ether group from compound (116). The use 27 of anhydrous stannic chloride (0 °C, 1.2 h) i n methylene chl o r i d e , for example, s e l e c t i v e l y removed the k e t a l f u n c t i o n a l i t y a f f o r d i n g the keto carbamate (123) as the only detectable product i n high y i e l d . In the hopes of maintaining a protected ketone f u n c t i o n a l i t y at C g , during the acid catalyzed cleavage of the MEM ether moiety, a t r a n s - k e t a l i z a t i o n r e a c t i o n on the k e t a l carbamate (116) was attempted. 99 This type of strategy had been employed by K i s h i during the course of the t o t a l synthesis of saxitoxln (127). K i s h i found that the repl a c e -ment of the a c i d l a b i l e k e t a l group (63%) (by t r a n s - k e t a l i z a t i o n using propanedithiol) i n compound (125), forming the th i o k e t a l compound (126), allowed the use of a c i d i c r e a c t i o n conditions employed i n subsequent steps which otherwise had cleaved the k e t a l f u n c t i o n a l i t y . C H 2 0 C H 2 C 6 H 5 0 II C H 2 O C N H 2 R NH (125) (126) (127) R= NHC0NH 2 Accordingly, the k e t a l carbamate (116) was treated with excess 103. propanedithiol i n dry a c e t o n i t r i l e containing a c a t a l y t i c amount of boron t r i f l u o r i d e etherate (ambient temperature, 41 h). Unfortunately, the only compound i s o l a t e d (85%) from the crude product (which was pure by t i c and g l c analyses) was the keto carbamate (123). (116) (123) O v e r a l l , these r e s u l t s suggested, i n no uncertain terms, that the f e a s i b i l i t y of s e l e c t i v e l y removing the MEM ether moiety i n compound (116) was very doubtful. In a l l the re a c t i o n procedures which were studied, the k e t a l moiety was removed q u a n t i t a t i v e l y whereas the MEM ether group was usually maintained. In those cases where the ether protecting group was s u c c e s s f u l l y removed, the concomitant loss of the k e t a l f u n c t i o n a l i t y appeared to be unavoidable. Thus, we were forced to attempt to complete the synthesis of the t r i c y c l i c ketone (12) u t i l i z i n g a d i f f e r e n t methodology (vide i n f r a ) . The seri e s of transformations described i n t h i s section, leading to the k e t a l carbamate (116), are i l l u s t r a t e d i n Scheme 7. SCHEME 7 105. VI. Attempted Synthesis of the T r i c y c l i c Ketone (12) v i a  Reductive Amination An a l t e r n a t i v e synthetic pathway which was envisaged for the com-p l e t i o n of the synthesis of the t r i c y c l i c ketone (12) i s shown schemat-i c a l l y below (Scheme 8). On the basis of the r e s u l t s obtained during the attempted removal of the MEM ether group of the k e t a l carbamate (116), i t was anticipated that the treatment of t h i s material under a c i d i c conditions more vigorous than those used previously would a f f o r d the carbamate alcohol (124) as the predominant product. The carbamate al c o h o l (124), i t was hoped, could then be oxidized to f u r n i s h the carbamate dione (128). Treatment of t h i s material under conditions necessary to cleave the urethane f u n c t i o n a l i t y would provide the amino dione (129). It was f e l t that t h i s substance could then be transformed d i r e c t l y i n t o the desired t r i c y c l i c ketone (12) by way of a reductive amination. It i s pertinent to note that the ( t h e o r e t i c a l l y ) possible epimer-i z a t i o n of the carbamate (128), to form the undesired trans r i n g fused system (131), was not expected to be a complication. An examination of a molecular model of each of the molecules i n question c l e a r l y indicated that the cis-fused system, compound (128), was the thermodynamically more stable of the two compounds. On the basis of conformational analy-s i s , one would expect the dione (128), containing an e q u a t o r i a l l y o r i -ented substituent at [cf. (128a) ], to be more stable than the dione (131), possessing a bulky side chain (at C 3) i n an a x i a l o r i e n t a t i o n [c f . (131a)]. 106. SCHEME 8 107. The conversion of compound (129) into the t r i c y c l i c ketone (12) was v i s u a l i z e d as occurring through a reductive amination [via (130)] using sodium cyanoborohydride. *^'r» This transformation, i t was hoped, would occur i n a r e g i o - and stereoselective fashion. Thus, although both the keto f u n c t i o n a l i t i e s of the amino dione (129) were t h e o r e t i -c a l l y capable of r e a c t i n g (intramolecularly) with the amino group, i t was a n t i c i p a t e d that the keto group at Cfi would react p r e f e r e n t i a l l y . 108. This expectation was based on the f a c t that, geometrically, the f o r -mation of an intermediate Iminium species at could occur only with d i f f i c u l t y . A molecular model of t h i s intermediate species suggested that t h i s material was indeed severely strained. That t h i s transformation would occur s t e r e o s e l e c t i v e l y was based on an examination of a molecular model of compound (130), the expected intermediate iminium species, which suggested that approach of the reducing agent (e.g. cyanohydridoborate anion) would, for s t e r i c r e a -sons, be from the convex side (/? face) of the molecule. Furthermore, the reduction of ketones at pH 6-7 with sodium cyanoborohydride has been shown*^ to be very slow whereas iminium species are reduced r a p i d l y under these conditions. Thus, the keto group at i n compound (129) was not expected to be reduced using t h i s methodology. Intramolecular reductive aminations have been used s u c c e s s f u l l y i n the past during the course of various t o t a l syntheses. ' For example, i n a synthesis of the a l k a l o i d n i c o t i n e (134), Borch et a l * ^ ^ converted the ketoaldehyde (132) into compound (133) (47%) u t i l i z i n g t h i s technique. And, more recent l y , Kende and co-workers**^ used a reductive amination procedure as the key step [cf. (135) to (136)] i n an elegant t o t a l synthesis of dendrobine (137). (132) (133) (134) 109. 0 0 35% (136) The scheme outlined above (Scheme 8) was thus a t t r a c t i v e from two points of view. F i r s t l y , the proposed conversion of the k e t a l carbamate (116) into the t r i c y c l i c ketone (12) was envisaged as a p o t e n t i a l l y straightforward sequence of events involving r e l a t i v e l y simple exper-imental conditions and reagents. Secondly, the o v e r a l l number of steps involved i n the transformation was not increased i n number from that of the o r i g i n a l plan (see Scheme 6). Accordingly, the k e t a l carbamate (116) was treated with excess titanium t e t r a c h l o r i d e (1.5 h, 0 °C) i n methylene chloride affording (80%) the carbamate alcohol (124), which was i d e n t i c a l i n a l l respects to the material prepared previously. Oxidation of t h i s material with 37 C o l l i n s reagent (a chromium t r i o x i d e - p y r i d i n e complex i n methylene chloride) for 30 min at ambient temperature furnished the carbamate dione (128) i n 81% y i e l d . In the i r spectrum of the carbamate dione (128), the carbonyl 110. groups gave r i s e to a strong absorption at 1715 cm x and the carbamate group displayed an absorption at 3450 cm *. The *H nmr spectrum of t h i s substance exhibited resonances at 6 1.14, 1.18, and 1.21 ( t h r e e -proton s i n g l e t s , t e r t i a r y methyl groups), at 6 3.59 (three-proton sing-l e t , methoxy methyl group), and at <S 4.65 (a broad, one-proton s i n g l e t , NH proton). Unfortunately, i n our hands, a l l attempts to deprotect the amino group i n compound (128) were unsuccessful. Treatment of the carbamate dione (128) under a v a r i e t y of conditions f a i l e d to f u r n i s h the desired amino dione (129). Compound (128) proved to be exceptionally stable and was recovered even af t e r treatment with 6N hydrochloric acid i n dioxane (2 h, 100 °C). The use of reagents such as t r i m e t h y l s i l y l i o d i d e * * * ' * * ^ (22 h, ambient temperature), t r i c h l o r o s i l a n e - t r i e t h y l a m i n e 1 1 3 ' 1 1 4 (46 h, room temperature), and excess l i t h i u m iodide-dimethylformamide**^ (18 h, r e f l u x ) , a l l of which have been used to cleave carbamates, were also i n e f f e c t i v e . Treatment of compound (128) under conditions (30% hydrogen bromide i n a c e t i c a c i d , 3 h, r e f l u x ) which were recently used by Overman et a l * * * ' to e f f e c t the cleavage of an unusually stable carbamate, led only to i n t r a c t a b l e material. These r e s u l t s were rather discouraging and prompted the consider-a t i o n of an a l t e r n a t i v e route to the amino dione (129), as shown i n the equations below. Thus, i t was envisaged that the carboxylic acid (102) could be converted into the desired amino dione (129) using a method-ology s i m i l a r to that used to prepare the k e t a l carbamate (116) (vide 111. supra). That i s , successive treatment of the acid (102) with d i e t h y l phosphorochloridate, sodium azide, and r e f l u x i n g toluene, would produce the intermediate isocyanate (106). This material, i t was hoped, could be converted, without i s o l a t i o n , into the keto amine (139) by exposure of the crude isocyanate (106) to aqueous a c i d i c conditions. (102) (106) (139) A l t e r n a t i v e l y , the isocyanate (106) p o t e n t i a l l y could be trans-formed into the amino dione (129) i n two steps v i a the k e t a l amine (138) and the keto amine (139). S p e c i f i c a l l y , treatment of the i s o -cyanate (106) under aqueous basic conditions was expected to a f f o r d the k e t a l amine (138) which could then be converted into the keto amine (139) through the removal of both the MEM ether group and the k e t a l f u n c t i o n a l i t y under conditions s i m i l a r to those used previously. (106) (138) (139) 112. Although these proposed conversions have not been examined i n d e t a i l , some preliminary r e s u l t s have been obtained. For example, i t was found that the treatment of the crude isocyanate (106) (see p. 98) under a c i d i c hydrolysis conditions (IN hydrochloric a c i d i n tetrahydro-furan, 2 h, r e f l u x ) gave r i s e to a considerable number of products, as judged by t i c . However, subjection of the isocyanate (106) to basic hydrolysis conditions (21tf sodium hydroxide i n £-dioxane, 3 h, r e f l u x ) afforded the ket a l amine (138) i n 83% y i e l d . The mass spectrum of (138) showed c h a r a c t e r i s t i c ions at m/e 398 (M® - CH3) a t l d at m/e 58 (C^HgN®, base peak), both r e s u l t i n g from a— cleavage adjacent to the nitrogen atom. The i r spectrum of t h i s sub-stance displayed an absorption at 3450 cm * due to the amino group. In the *H nmr spectrum the geminal methyl groups a to the nitrogen atom and the angular methyl group gave r i s e to a nine-proton s i n g l e t at 6 1.04. The protons attached to the nitrogen atom appeared as a two-proton s i n g l e t at <5 1.95. It was anticipated that treatment of t h i s material (138) with titanium t e t r a c h l o r i d e , under conditions s i m i l a r to those used for the conversion of the ket a l carbamate (116) into the carbamate alcohol (124), would f u r n i s h the keto amine (139). However, treatment of t h i s substance with titanium t e t r a c h l o r i d e i n methylene chloride ( f i v e equiv-a l e n t s , 1 h, 0 °C) gave r i s e only to i n t r a c t a b l e material. Although no further experimental studies have been performed d i -rected toward the completion of the synthesis of the t r i c y c l i c ketone (12), i t i s appropriate at t h i s juncture to comment on the d i r e c t i o n that further studies i n t h i s area might take. One possible so l u t i o n to 1 1 3 . N H 2 0 ( 1 2 9 ) NHC0 2R O M E M ( 1 4 0 ) , R = C H 2 C 6 H 5 ( 1 4 1 ) , R = C ( C H 3 ) 3 1) T i C l 4 2 ) C r O , - 2 C c H [ : N = C ( C H 0 ) ( 1 2 ) S C H E M E 9 114. the d i f f i c u l t i e s encountered i n the preparation of the amino dione (129), for example, would involve the preparation of compound (140) or (141) (see Scheme 9). These substances would be expected to be con-v e r t i b l e to the amino dione (129) i n two steps. Thus, treatment of either (140) or (141) under a c i d i c conditions (e.g. titanium t e t r a c h l o r -i d e ) , followed by the oxidation of the r e s u l t i n g crude product (cf. C o l l i n s o x i d a t i o n ) , would be a n t i c i p a t e d to produce compounds (142) or (143), r e s p e c t i v e l y . The l a t t e r compounds, due to the r e l a t i v e ease of removal of the amino protecting groups* 1^, would be expected to produce the desired amino dione (129) under quite mild conditions. Assuming that the transformation of compound (129) into the t r i c y c l i c ketone (12) would proceed uneventfully, t h i s route would provide a convenient completion of the synthesis of (12). VII. *H nmr Assignments This section of the discussion i s included to provide an explana-t i o n of the basis on which some of the *H nmr resonances were assigned. As mentioned previously (section I I ) , on several occasions during the course of the research described herein, i t was important to be able to d i s t i n g u i s h the resonance due to the angular methyl group from those of the k e t a l moiety(ies). It was found that t h i s objective could be accomplished through the comparison of several d i f f e r e n t molecules of a given s t r u c t u r a l s e r i e s . For example, a comparison of the t e r t i a r y methyl group s h i f t s i n a series of compounds a l l bearing two ketal func-t i o n a l i t i e s (at C^ and Cq), but possessing d i f f e r e n t substituents at 115. C,., and C^, showed that the these resonances were subject to only small changes i n p o s i t i o n (see Table 1). In t h i s group of compounds the angular methyl group resonated at 6 1.16 + 0.05 and the A-ring ketal methyl groups at 6 0.85 + 0.05 and 6 1.00 + 0.08. The B-ring ket a l methyl groups gave r i s e to signals at 6 0.71 + 0.06 and 6 1.17 + 0.02. In t h i s series of compounds, the three-proton s i n g l e t due to the angular methyl group usually appeared as an appreciably more intense signal than those due to the ketal methyl groups. It seemed l i k e l y that t h i s phenomenon was a r e s u l t of a lesser degree of long range coupling experienced by the angular methyl group as opposed to that f e l t by the 30 k e t a l methyl groups . Thus, the angular methyl resonances were i n i -t i a l l y assigned on t h i s basis. However, further support for these assignments was l a t e r obtained from the examination of the *H nmr spec-trum of the monoketone (62). The angular methyl group of t h i s material gave r i s e to a three-proton s i n g l e t at 6 1.40 and the ketal methyl groups produced resonances at 6 0.72 and 1.20. It seemed clear that the absence of the A-ring ke t a l i n t h i s compound might well a f f e c t the s h i f t of the angular methyl group but was extremely u n l i k e l y to a f f e c t the k e t a l methyl groups which are remote from C„. OMEM (62) In addition to the considerations discussed above, an examination 116. of the chemical s h i f t s of the compounds l i s t e d i n Table 2 supports the angular methyl group and B-ring ket a l methyl assignments. The compounds which are considered i n Table 2 lack an A-ring ketal f u n c t i o n a l i t y (at Cg) and, instead, possess /? face substitutents at t h i s p o s i t i o n . It i s clear that both t h i s series of compounds and the d i k e t a l series (Table 1) also share a common conformation (see Section IV). Thus, i t was expected that the angular methyl group s h i f t s and the s h i f t s of the t e r t i a r y methyl groups of the B-ring ket a l moiety would be very s i m i l a r . This i s i n fact the case. It should also be noted that, i n the remaining two series of com-pounds tabluated (Tables 3 and 4), the B-ring ket a l methyl group s h i f t s are e s s e n t i a l l y i n v a r i a n t and are i n f u l l accord with the assignments discussed above. S p e c i f i c a l l y , the compounds i n Table 3 ( a substituted at C^) exhibit the expected s h i f t s due to the ketal methyls (6 0.70 + 0.02, 1.18 + 0.03) and show angular methyl s h i f t s consistently at lower f i e l d than those i n Tables 1 and 2. The series of compounds i n Table 4 2 (sp at C^) also display predictable s h i f t s for the B-ring ketal methyls and e x h i b i t angular methyl group s h i f t s c o n s i s t e n t l y at higher f i e l d (6 1.35 + 0.05) than those tabulated i n Tables 1 and 2. In those cases where, by coincidence, other t e r t i a r y methyl groups resonate i n close proximity to e i t h e r one of the ketal methyls or the angular methyl group, no s p e c i f i c assignment has been made. For ex-ample, compound (95) [entry 5, Table 3] e x h i b i t s resonances at 6 1.05 (a three-proton s i n g l e t ) and at 6 1.07 (a six-proton s i n g l e t ) which are too si m i l a r i n p o s i t i o n to assign and are thus denoted as " t e r t i a r y methyls". Thus, on the basis of the s h i f t s tabulated i n Tables 1 through 4, 117. the assignments of many of the t e r t i a r y methyl signals i n the *H nmr spectra of the compounds discussed i n t h i s d i s s e r t a t i o n have been made. Since t h i s deductive form of resonance assignment does not constitute a proof, the assignments herein must be considered tentative. TABLE 1; Chemical S h i f t s (5) of Methyl Group Protons i n the B i c y c l i c D i k e t a l Series o o A B & 6 Entry C 5 Substituents C6 C7 Angular Methyl Group Ketal Methyl Groups A Ring B Ring Compound Number 1. H, 1.18* 0.86 1.02 0.71 1.16 (17) 2. B-H B-OH H2 1.21* 0.85 1.02 0.69 1.17 (31) 3. B-H 0-OMEM H2 1.18* 0.88 0.96 0.70 1.16 (35) 4. B-H H, 1.22 0.80 1.08 0.74 1.18 (44) 5. B-H ^8-OCOCOCH2 H2 1.22* 0.84 0.92 0.70 1.18 (48) 6. B-H H2 H2 1.11 0.90 0.98 0.68 1.18 (54) 7. B-H 1X3 1.12* 0.90 1.00 0.70 1.18 (57) Oo *Signal i n t e n s i t y stronger than remaining signals. 119. TABLE 2: Chemical S h i f t s (<S) of Methyl Groups Protons i n the B i c y c l i c  Monoketal Series (B-C0 Substituted) Entry Substituents C3 C6 Angular Methyl Group Ketal Methyl Groups Compound Number 1. /?-CH2C02Et y3-0Ts 1.13 0.68 1.13 (75) 2. /3-CH2C02Et /3-OMEM 1.13 0.68 1.13 (76) 3. /?-CH2C02Et B-OH 1.18 0.70 1.18 (78) 4. /3-CH2CH2OH /8-OMEM 1.15 0.68 1.15 (89) 5. /8-CH2C02H )3-0MEM 1.18 0.70 1.18 (112) 6. /3-CH2C02But /3-OMEM 1.18 0.70 1.18 (114) 120. TABLE 3; Chemical S h i f t s (6) of Methyl Group Protons i n the B i c y c l i c  Monoketal Series ( g~C 3 Substituted) f) 6 Entry S ubstituents C3 C6 Angular Methyl Group Ketal Methyl Groups Additional T e r t i a r y Methyl Groups Compound Number 1. a-CH 2C0 2Et j8-OMEM 1.04 0.68 1.16 (72) 2. <*-CH2C02Et /3-OTs 1.01 0.68 1.13 (73) 3. a-CH 2C0 2Et P-OK 1.12 0.68 1.15 (77) 4. «-CH 2CH 2OH /8-0MEM 1.04* 0.68 1.16 (90) 5. «-C(CH 3) 2C0 2Et /3-OMEM 1.05T 0.70 1.18 1.07T (95) 6. <*-C(CH3)2C02H P-OHEH 1.06tt 0.70 1.18 l . l l t t (102) 7. «-C(CH 3) 2NCO P-OKEH 1.07 0.70 1.20 1.28 (106) 8. «-C(CH 3) 2C0 2Si p-onm 1.07 0.71 1.19 1.07 (107) 9. a-C(CH 3) 2NHC0 2-CH 3 /3-OMEM 1.06 0.72 1.20 1.24 (116) 10. a-C(CH 3) 2NH 2 0-OMEM 1.04 0.70 1.19 1.04 (138) *Signal i n t e n s i t y stronger than remaining s i g n a l s . t , t t These assignments may be exchanged. 121. TABLE 4: Chemical S h i f t s (6) of Methyl Group Protons i n the B i c y c l i c 2 Monoketal Series (sp -C 0) Entry Substituents C3 C6 Angular Methyl Group Ketal Methyl Groups Compound Number 1. = 0 B-OMEM 1.40 0.72 1.20 (62) 2. ^ C 0 2 E t B-OK 1.32 0.70 1.18 (66) * 3. ' ^ C O ^ t B-OR 1.34 0.72 1.21 (66) * 4. ^ C 0 2 E t /?-0MEM 1.30 0.70 1.18 (61) *These compounds are geometric isomers. EXPERIMENTAL 122. General Information Melting points, determined with a Fisher-Johns melting point appar-atus, and b o i l i n g points are uncorrected. U l t r a v i o l e t (uv) spectra were obtained with a Cary 15 spectrophotometer using methanol as solvent. Infrared spectra were recorded on Perkin-Elmer model 710 and model 710B i n f r a r e d spectrophotometers. The proton magnetic resonance (*H nmr) spectra were taken i n deuterochloroform s o l u t i o n on Varian Associates Spectrometers, models T-60, HA-100 and XL-100 and on a 270 MHz unit composed of an Oxford Instruments 63.4 KG superconducting magnet and a N i c o l e t 16K computer attached to a Bruker TT-23 console. Signal p o s i -tions are given i n parts per m i l l i o n (8) with tetramethylsilane as an i n t e r n a l reference; the m u l t i p l i c i t y , integrated peak areas and proton assignments are indicated i n parentheses. Protons attached to a b i c y c -l i c system are assigned by carbon number according to the diagram below. The methyl group attached to the b i c y c l i c system at C i n i s denoted "angular". The carbon magnetic resonance ( i JC nmr) spectra were taken i n deuterochloroform so l u t i o n on a Varian CFT-20 Spectrometer. Signal p o s i t i o n s are given i n parts per m i l l i o n (8) with tetramethylsilane as an i n t e r n a l reference; where available the m u l t i p l i c i t y and carbon assignments are indicated i n parentheses. Gas-liquid chromatography 4 6 123. (glc) was c a r r i e d out on a Hewlett Packard HP 5832 A gas chromatograph. The following columns were used: (A) 6 f t x 0.125 i n , 5% OV-210 on Gas-Chrom Q (100/120 mesh); (B) 6 f t x 0.125 i n , 5% OV-17 on Gas-Chrom Q (100/120 mesh). The column used and the column temperature are i n d i -cated i n parentheses. A flow rate of 30 ml/min of helium gas was em-ployed for a l l analyses. Column chromatography was performed using neutral s i l i c a gel (E. Merck, S i l i c a Gel 60). Thin layer chromatography ( t i c ) was c a r r i e d out on 20 x 5 cm glass plates coated with 0.7 mm of neutral s i l i c a g e l (E. Merck, s i l i c a g e l 60) or with commercial s i l i c a gel' plates (Eastman Chromatogram Sheet Type 13181). Preparative t h i n layer chromatograpy was c a r r i e d out with 20 x 20 cm glass plates coated with 0.7 mm of neutral s i l i c a g e l (E. Merck, s i l i c a g e l 60). The high r e s o l u t i o n mass spectra were recorded with a Kratos/AEI MS50 or a Kra-tos/AEI MS902 mass spectrometer. Microanalyses were performed by Mr. P. Borda, M i c r o a n a l y t i c a l Laboratory, University of B r i t i s h Columbia. A l l the reactions described herein were performed under an atmos-phere of dry argon (or, i n some instances, nitrogen) unless otherwise s p e c i f i e d . The solvents used were dried and p u r i f i e d as described below. Tetrahydrofuran and dimethoxyethane were d i s t i l l e d from sodium benzo-118 phenone k e t y l i n the appropriate solvent under argon. Methanol and ethanol were d i s t i l l e d from their respective magnesium alkoxides. o Benzene was d i s t i l l e d from calcium hydride and stored over 4A molecular sieves. Dichloromethane was d i s t i l l e d from phosphorous pentoxide and o stored over 3A molecular sieves. Hexamethylphosphoramide was d i s t i l l e d from barium oxide and stored over 13X molecular sieves. Anhydrous ether was obtained commercially. 124. Preparation of the Diketal O l e f i n (17) To 175 ml of f r e s h l y d i s t i l l e d benzene was added 5.0 g (48 mmol) of 2,2-dimethyl-l,3-propanediol and the r e s u l t i n g s o l u t i o n was heated to r e f l u x f or 0.5 h with azeotropic removal of water u t i l i z i n g a Dean-Stark trap. The s o l u t i o n was then cooled to room temperature and 865 mg (4.8 23 mmol) of r e c r y s t a l l i z e d 9-methyl-5(10)-octalin-l,6-dione was added, followed by 91 mg (0.48 mmol) of j>-toluenesulfonic a c i d monohydrate. After the r e a c t i o n mixture had been refluxed for 5 h (Dean-Stark t r a p ) , i t was cooled to room temperature, poured into saturated aqueous sodium bicarbonate (150 ml) and d i l u t e d with ether (250 ml). The layers were separated, the aqueous layer was extracted with ether (100 ml) and the combined ether s o l u t i o n was washed successively with f i v e portions of water and one portion of brine. Removal of the solvents ^n vacuo, a f t e r drying over anhydrous sodium s u l f a t e , gave the crude product as a yellow gum. When t h i s material was dissol v e d i n a small amount of methanol (approximately 10 ml) and the r e s u l t i n g s o l u t i o n was cooled i n a f r e e -zer, 1.6 g of a pale yellow amorphous s o l i d was i s o l a t e d . R e c r y s t a l -l i z a t i o n of th i s s o l i d (methanol) gave 1.03 g (61%) of water white prisms which proved to be the desired d i k e t a l o l e f i n (17), pure by nmr, t i c and g l c (column A, 160 °C). Chromatography of the residue on 50 g 125. of s i l i c a g el (e l u t i o n of the column with 17% ethyl acetate i n benzene) gave a further 187 mg (11%) of the d i k e t a l o l e f i n (17). The r e c r y s t a l -l i z e d d i k e t a l o l e f i n (17), mp 137-139 °C, exhibited the following spec-t r a l data: i r (CHC1-) v 1092 cm"1; XH nmr 8 0.71, 1.16 (2s, 3H each, 3 max B r i n g k e t a l methyls),0.86, 1.02 (2s, 3H each, A r i n g ketal methyls), 1.18 (s, 3H, angular methyl), 3.24-3.88 (m, 8H, ke t a l methylenes), 5.26-5.40 (broad s, IH, C 6H); 1 3 C nmr 8 98.26 ( C 3 ) , 99.93 (Cg), 120.41 ( C 6 ) , 138.21 ( C 5 ) . Anal, calcd. f o r C 2 1 H 3 4 0 A : C 71.96, H 9.78; found: C 71.78, H 9.94. Hydroboration of the Diketal O l e f i n (17):  Preparation of the Diketal Alcohols (31) & (36) (31) To a s t i r r e d i c e - c o l d s o l u t i o n of 1.21 g (3.3 mmol) of the d i k e t a l o l e f i n (17) i n 75 ml of n-hexane was added, dropwise, 3 ml (29 mmol) of borane-methyl s u l f i d e complex. The so l u t i o n was allowed to warm to room temperature and was s t i r r e d for 20 h. The re a c t i o n mixture was cooled i n an ice-water bath and absolute ethanol (10 ml), followed by 3N sodium hydroxide (10 ml), was added slowly. Aqueous hydrogen peroxide (30%, 2.6 ml) was added to the mixture, the cooling bath was removed, and the re a c t i o n mixture was warmed to a gentle r e f l u x i n a fume hood (approxi-126. mately 10 minutes). After the s o l u t i o n had been cooled to room temper-ature, i t was poured into water (100 ml) and the r e s u l t a n t mixture was d i l u t e d with ether (150 ml). The aqueous layer was then i s o l a t e d , extracted with ether (50 ml), and the combined organic phases were washed successively with water and brine and dried over anhydrous sodium s u l f a t e . Concentration of the dried s o l u t i o n to 20 ml i n volume f o l -lowed by cooling i n a freezer gave 818 mg (64%) of the desired alcohol (31) as an amorphous s o l i d which was homogeneous by glc (column A, 175 °C) and t i c analyses. The r e s i d u a l crude product obtained from the mother l i q u o r was p u r i f i e d by column chromatography on 60 g of s i l i c a g e l . E l u t i o n of the column with 33% e t h y l acetate i n benzene afforded 88 mg of the s t a r t i n g material (17), a further 250 mg (20%) of the desired a l c o h o l (31) and 91 mg (9%) of the trans-fused alcohol (36). An a n a l y t i c a l sample of the desired alcohol (31), mp 162-163 °C, was obtained by r e c r y s t a l l i z a t i o n from methylene chloride-hexane and gave the following s p e c t r a l data: i r (CHC1 ) v 3450 cm - 1; 1H nmr8 0.69, 1.17 (2s, 3H each.B r i n g k e t a l methyls), 0.85, 1.02 (2s, 3H each, A r i n g k e t a l methyls), 1.21 (s, 3H, angular methyl), 3.20-3.86 (m, 8H, k e t a l methylenes), 3.90-4.23 (broad m, IH, C 6H); 1 3 C nmr 8 97.86 (C-j), 100.21 ( C q ) . Anal, calcd. for C 2 1 H 3 6 0 5 : C 68.45, H 9.85; found: C 68.21, H 9.72. The minor product, the trans-fused alcohol (36), was r e c r y s t a l l i z e d from e t h y l ether and exhibited mp 189-191 °C; i r (CHC1-) v 3620, 3 * ' 3' max ' 1105 cm"1; XH nmr 8 0.68, 1.13 (2s, 3H each, B r i n g k e t a l methyls), 0.90, 1.00 (2s, 3H each, A r i n g k e t a l methyls), 0.94 (s, 3H, angular 127. methyl), 3.18-3.78 (m, 9H, ke t a l methylenes, -OCH2CH20-, & C 6H); A J C nmr « 97.88 (C^), 99.4A (Cg). Anal, calcd. for C 2 1 H 3 6 Q 5 : c 68.45., H 9.85; found: C 68.19, H 10.02. Preparation of the Dike to Alcohol (60) 0 OH To a s i t r r e d mixture of 2 ml of acetone and 2 ml of 2N^  hydrochloric a c i d was added 200 mg (0.54 mmol) of the d i k e t a l alcohol (31) at room temperature. The re a c t i o n mixture was s t i r r e d for 2 h and poured into aqueous sodium bicarbonate. The r e s u l t i n g mixture was thoroughly ex-tracted with methylene chloride and the combined organic extracts were washed successively with water and brine and dried over anhydrous sodium s u l f a t e . Removal of the solvent under reduced pressure gave a yellow gum which c r y s t a l l i z e d on standing, mp 103-106 °C. The crude s o l i d was r e c r y s t a l l i z e d from chloroform-hexane y i e l d i n g 104 mg (97%) of the diketo a l c o h o l (60) as a white s o l i d which exhibited mp 108.5-109 °C: i r (CHC1-) v 3430, 1706 cm"1; XH nmr S 1.47 (s, 3H, angular methyl), 3 max 3.00 (d, IH, J = 4 Hz, -OH), 3.89 (dddd, IH, J = 8,8,4 & 4 Hz, C 6H). Anal, calcd. for C 1 1 H 1 6 0 ; } : C 67.32, H 8.22; found: C 67.16, H 8.09. 128. Preparation of the Diketal Ketone (45) A) By Oxidation-Epimerization of the cis-Fused Diketal Alcohol (31) To a s o l u t i o n of 0.13 ml (1.6 mmol) of dry pyridine i n 4 ml of dry methylene chloride was added 82 mg (0.82 mmol) of chromium t r i o x i d e . The r e s u l t i n g mixture was s t i r r e d for 15 min and a s o l u t i o n of 49 mg (0.135 mmol) of the dry d i k e t a l alcohol (31) i n 5 ml of methylene c h l o r -ide was added i n one portion. The reac t i o n mixture was s t i r r e d at room temperature f o r 15 min and poured onto a short column of a c t i v i t y I, neutral alumina (approx. 10 g). E l u t i o n of the column with e t h y l ace-tate, followed by evaporation of the solvent i j i vacuo, gave 53 mg of a c l e a r , viscous o i l . T r i t u r a t i o n of the o i l with hexane gave 38 mg (77%) of the d i k e t a l ketone (45), as a pure ( t i c , *H nmr) white s o l i d . R e c r y s t a l l i z a t i o n of the i s o l a t e d s o l i d from hexane gave an a n a l y t i c a l sample e x h i b i t i n g mp 147-148 °C: i r (CHCl.) v 1705, 1097 cm"1; XH 3 max ' nmr 8 0.72, 1.16 (2s, 3H each, B r i n g k e t a l methyls), 0.83, 0.98 (2s, 3H each, A r i n g k e t a l methyls), 0.86 (s, 3H, angular methyl), 2.72-3.06 (m, 2H), 3.20-3.82 (m, 8H, ke t a l methylenes). Exact mass calcd. for C ^ H ^ O ^ 366.2406; found: 366.2410. B) By Oxidation of the trans-Fused Diketal Alcohol (36) To a s t i r r e d , ice cold s o l u t i o n of 0.32 ml (4.0 mmol) of pyridine 129. and 15 ml of methylene chloride was added 198 mg (2.0 mmol) of dry chromium t r i o x i d e . After aproximately 15 min the so l u t i o n was warmed to room temperature and the mixture was s t i r r e d for 45 min y i e l d i n g a dark red, homogeneous s o l u t i o n . A solu t i o n of the trans-fused alcohol (36) (121 mg, 0.33 mmol), i n 10 ml of methylene c h l o r i d e , was added and, af t e r 25 min, the reac t i o n mixture was f i l t e r e d . The r e s i d u a l s o l i d was washed with ether, dissolved i n 5% aqueous sodium hydroxide and the r e s u l t i n g s o l u t i o n was extracted with ether. The f i l t r a t e was combined with the ether extracts and the r e s u l t i n g s o l u t i o n was washed with 5% aqueous sodium hydroxide, water and brine. Evaporation of the solvent from the dried (anhydrous sodium su l f a t e ) s o l u t i o n , followed by t r i -t u r a t i o n of the r e s i d u a l material with hexane, gave 110 mg (91%) of the d i k e t a l ketone (45) as a pure ( t i c , g l c , *H nmr) s o l i d . This material (mp 146-147 °C) was i d e n t i c a l with the d i k e t a l ketone (45) prepared according to the procedure above ( i r , *H nmr). Preparation of the Pyruvate Ester (48) To a cold (0 °C) so l u t i o n of 0.2 ml (2.5 mmol) of pyridine and 356 mg (0.97 mmol) of the c i s - f used d i k e t a l a l c o h o l (31) i n 30 ml of dry benzene was added a s o l u t i o n of 145 mg (1.4 mmol) of pyruvoyl chloride^ TThis. material was prepared according to the procedure of Ottenheijm et a l from pyruvic a c i d and dichloromethyl methyl ether. 130. i n 2 ml of benzene. S t i r r i n g was continued for 25 min, the reaction mixture was f i l t e r e d and the f i l t r a t e was evaporated y i e l d i n g a c o l o r -l e s s o i l . D i s s o l u t i o n of t h i s crude o i l i n ether, followed by cooling, gave 83 mg (19%) of the desired ester (48) as a white amorphous s o l i d , mp 148-151 °C. Chromatography (45 g s i l i c a g e l , 20% e t h y l acetate i n benzene used as e l u t i n g solvent) gave a further 174 mg (41%) of the pyruvate ester (48), as well as 100 mg of recovered s t a r t i n g material (31). R e c r y s t a l l i z e d (ether-chloroform) pyruvate ester (48), mp 156-157 °C, gave the following spectral data: i r (CHC1«) v 1728, 1110, 1085 cm - 1; XH nmr 8 0.70, 1. 18 (2s, 3H each, B r i n g ketal methyls), 0.84, 0.92 (2s, 3H each, A r i n g ketal methyls), 1.22 (s, 3H, angular methyl), 2.43 (s, 3H, -0C0C0CH 3), 3.20-3.84 (m, 8H, k e t a l methylenes), 5.20-5.52 (m, IH, C 6H). Exact mass calcd. for C 2 4 H 3 8 ° 7 : 438.2617; found: 438.2612. Preparation of the Diketal Tosylate (53) The d i k e t a l alcohol (31) (818 mg, 2.2 mmol) was dissolved i n 20 ml of pyridine and the s o l u t i o n was cooled i n an ice-water bath. Recrys-t a l l i z e d j>-toluenesulfonyl chloride, 4.24 g (22 mmol), was added, i n portions with s t i r r i n g , and the reaction mixture was warmed to room temperature. After 24 h the mixture was cooled i n an ice-water bath, 131. ice was added and the resultant mixture was s t i r r e d for t h i r t y minutes. The s o l u t i o n was poured i n t o ether (50 ml) and the organic phase was washed successively with saturated aqueous sodium bicarbonate, water and brine. The d r i e d (sodium sulfate) ethereal s o l u t i o n was evaporated to y i e l d a crude s o l i d which, when r e c r y s t a l l i z e d from acetone, gave 700 mg (61%) of pure ( t i c , *H nmr) d i k e t a l tosylate (53) as a white amorphous s o l i d . The material obtained from the mother liquor was chromatographed on 50 g of s i l i c a g e l . E l u t i o n of the column with 25% e t h y l acetate i n benzene gave a further 317 mg (27%) of the desired product (53). An a n a l y t i c a l sample of the d i k e t a l tosylate (53), prepared by r e c r y s t a l -l i z a t i o n from acetone, exhibited mp 123-125 °C (dec); i r (CHC1„) v r 3' max 1170, 1085 cm"1; XH nmr 8 0.68 (s, 3H, k e t a l methyl), 0.93 (s, 6H, k e t a l methyls), 1.15 (s, 6H, k e t a l methyl and angular methyl), 2.42 (s, 3H, aromatic methyl), 3.20-3.74 (m, 8H, k e t a l methylenes), 5.02-5.30 (broad m, IH, C,H), 7.32, 7.84 (2d, 2H each, J = 8 Hz, aromatic protons), o Anal, calcd. for C o oH / o0,S: C 64.34, H 8.10; found: C 64.29, H 8.20. 28 42 7 Preparation of the Diketal O l e f i n (57) To a s o l u t i o n of 143 mg (0.27 mmol) of the d i k e t a l tosylate (53) i n 5 ml of dry dimethyl sulfoxide and 1 ml of dry benzene was added 217 mg 132. (0.82 mmol) of 18-Crown-6 (1,4,7,10,13,16-hexaoxacyclooctadecane) and 82 mg (0.73 mmol) of potassium tert-butoxide. This mixture was warmed, with s t i r r i n g , to 55 °C and s t i r r e d for 30 min. The r e s u l t i n g dark brown s o l u t i o n was poured into water, the aqueous layer was thoroughly extracted with ether and the combined ether extracts were washed suc-c e s s i v e l y with d i l u t e aqueous hydrochloric a c i d , water and brine. Evaporation of the solvent from the dried (sodium s u l f a t e ) extracts under reduced pressure, followed by c r y s t a l l i z a t i o n of the crude product from hexane, gave 58 mg (60%) of the desired d i k e t a l o l e f i n (57) as an amorphous s o l i d , mp 123-129 °C. The mother liquor (33 mg) consisted of two compounds ( g l c , t i c ) , the desired o l e f i n (57) and an u n i d e n t i f i e d side product i n a r a t i o of 6:4, r e s p e c t i v e l y . An a n a l y t i c a l sample of the o l e f i n (57), prepared by r e c r y s t a l -l i z a t i o n of a portion the crude material from hexane, exhibited mp 134.5-135.5 °C; i r (CHC1_) v 1087 cm"1; JH nmr 8 0.70, 1.18 (2s, 3H 3 max each, B r i n g k e t a l methyls), 0.90, 1.00 (2s, 3H each, A ring k e t a l methyls), 1.12 (s, 3H, angular methyl), 3.20-3.88 (m, 8H, ketal methyl-enes), 5.28-5.68 (m, 2H, C 6H & C 7H). Anal, calcd. for C 2 1 H 3 4 0 4 : C 71.96, H 9.78; found: C 72.08, H 9.70. 133. Preparation of the Diketo O l e f i n (58) 0 0 The d i k e t a l o l e f i n (57) (46 mg, 0.26 mmol) was dissolved i n 2 ml of acetone and 2 ml of 2 N hydrochloric acid was added dropwise with s t i r -r i n g at room temperature. The s t i r r i n g was continued for 2 h and the rea c t i o n mixture was poured into aqueous sodium bicarbonate and the r e s u l t i n g s o l u t i o n was thoroughly extracted with ether. The combined ethereal extracts were washed (water and brine) and dried over anhydrous sodium s u l f a t e . Removal of the solvents i n vacuo gave 15 mg (64%) of a pale yellow o i l which was pure by t i c and *H nmr analyses. The diketo o l e f i n (58) gave the following spectral data: i r (CHCl^) v m a x 1710 cm"'1; lE nmr 8 1.30 (s, 3H, angular methyl), 3.02 (unresolved d, 2H, J = 4 Hz, C gHs), 5.84 (m, 2H, C &H & CyH). Exact mass calcd. for C n H 1 A 0 2 : 178.0994; found: 178.0996. Preparation of the B i c y c l i c Diketal (54) 134. A) By C a t a l y t i c Hydrogenation of the Diketal O l e f i n (57) To a s o l u t i o n of the d i k e t a l o l e f i n (57) (25 mg, 0.07 mmol) i n 7 ml of e t h y l acetate was added 10 mg of 10% palladium-on-carbon. The mix-ture was hydrogenated at atmospheric pressure and room temperature for 1.75 h. The r e s u l t i n g mixture was f i l t e r e d through c e l i t e and the f i l t r a t e was evaporated i n vacuo y i e l d i n g a c o l o r l e s s o i l which c r y s t a l -l i z e d on standing. This material was r e c r y s t a l l i z e d from ether giving 22 mg (88%) of pure b i c y c l i c d i k e t a l (54), which exhibited mp 123.5-125 °C; i r (CHC1 0) v 1095 cm"1; *H nmr 8 0.68, 1.18 (2s, 3H each, B r i n g 3 max ket a l methyls), 0.90, 0.98 (2s, 3H each, A r i n g k e t a l methyls), 1.11 (s, 3H, angular methyl), 3.16-3.80 (m, 8H, ke t a l methylenes). Anal, calcd. for C 2 1 H 3 6 0 4 : C 71.55, H 10.29; found: C 71.70, H 10.15. B) By C a t a l y t i c Hydrogenation of the Diketal O l e f i n (17) A so l u t i o n of 165 mg (0.47 mmol) of the d i k e t a l o l e f i n (17) i n 10 ml of e t h y l acetate containing 50 mg of 10% palladium-on-carbon, was hydrogenated at atmospheric pressure and room temperature for 16 h. The r e s u l t i n g suspension was f i l t e r e d through c e l i t e and the f i l t r a t e was evaporated under reduced pressure g i v i n g 160 mg (96%) of a pure ( t i c , g l c ) , c o l o r l e s s o i l which c r y s t a l l i z e d on standing (mp 113-117 °C). Re c r y s t a l l a t i o n of the i s o l a t e d s o l i d from ether gave an a n a l y t i c a l sample of the b i c y c l i c d i k e t a l (54), mp 122.5-125 °C, which was i d e n t i c -a l ( t i c , g l c , *H nmr, mp, mixture mp) with the material previously pre-pared (see part A). 135. Preparation of the Dione (51) 0 A) By Hydrolysis of the B i c y c l i c Diketal (54) To a s t i r r e d s o l u t i o n of the b i c y c l i c d i k e t a l (54) (87 mg, 0.25 mmol) i n 5 ml of acetone was added 5 ml of IN hydrochloric a c i d . The r e a c t i o n mixture was warmed to 50 °C and maintained at t h i s temperature for 5 h. The s o l u t i o n was cooled to room temperature, poured into water and the r e s u l t i n g s o l u t i o n was extracted with two portions of ether. The combined organic phase was washed with water and brine and d r i e d over anhydrous sodium s u l f a t e . Evaporation of the solvents gave a pale yellow o i l which c r y s t a l l i z e d when t r i t u r a t e d with hexane, y i e l d i n g 39 mg (88%) of pure ( t i c , g l c , column B, 150 °C) dione (51), as a white s o l i d , mp 62-65 °C ( l i t 4 0 mp 64.5-65.5 °C); i r (CHC1-) v 1703 cm - 1; ' r * 3 max *H nmr 8 1.36 (s, 3H, angular methyl). B) By Hydrogenation of 9-Methyl-5(10)-0ctalin-l,6-Dione To a s o l u t i o n of 343 mg (1.9 mmol) of 9-methyl-5( 1 0 ) - o c t a l i n - l , 6 -d i o n e 2 3 i n 20 ml of e t h y l acetate was added 32 mg of 10% palladium-on-carbon. The mixture was hydrogenated at room temperature and atmos-pheric pressure for 16 h. The r e s u l t i n g mixture was f i l t e r e d through c e l i t e and the f i l t r a t e was evaporated y i e l d i n g a yellow o i l which c r y s t a l l i z e d upon standing (mp 51-57 °C). R e c r y s t a l l i z a t i o n of the 136. crude s o l i d from ether-hexane gave 320 mg (93%) of a water-white s o l i d , mp 63-65.5 °C ( l i t . 4 0 m p 64.5-65.5 °C), which was pure by t i c and g l c (column B, 150 °C). This material was i d e n t i c a l ( t i c , *H nmr) with the previously prepared dione (51) (see part A). A mixed melting point of the i s o l a t e d s o l i d with the previously prepared material was not de-pressed. Preparation of the trans-fused Dione (52) The monoketal ketone (59) 1 (143 mg, 0.54 mmol) was dissolved i n 3 ml of acetone and 3 ml of IN hydrochloric a c i d was addea with s t i r r i n g at room temperature. After 2 h had elapsed, the rea c t i o n mixture was d i l u t e d with water and the resultant s o l u t i o n was extracted with two portions of ether. The combined ethereal extracts were washed succes-s i v e l y with three portions of water and one portion of brine and dried over anhydrous sodium s u l f a t e . Removal of the solvents i n vacuo gave a c o l o r l e s s o i l which c r y s t a l l i z e d when cooled i n an i c e bath. The i s o -l a t e d s o l i d , the trans-fused dione (52), weighed 81 mg (83%). R e c r y s t a l -l i z a t i o n of t h i s material from ether-hexane gave a white s o l i d , exhi-0 This compound was kindly supplied by Dr. D.J. Herbert, Department of Chemistry, University of B r i t i s h Columbia. 137. b i t i n g mp 55-56 °C ( l i t . 4 1 m p 56-57 °C), which was c l e a r l y d i f f e r e n t from the dione (51) as judged by glc (column B, 150 °C), t i c and *H nmr analyses. *H nmr S 1.30 (s, 3H, angular methyl). Preparation of the cis-Fused Diketal Ketone (44) To a s t i r r e d , cold (0 °C) s o l u t i o n of 0.34 ml (4.17 mmol) of p y r i -dine i n 10 ml of methylene chloride was added 210 mg (2.1 mmol) of dry chromium t r i o x i d e . After 15 min the so l u t i o n was warmed to room temper-ature and the s t i r r i n g was continued for 45 min. To the r e s u l t i n g dark red s o l u t i o n was added a s o l u t i o n of 128 mg (0.35 mmol) of the d i k e t a l alcohol (31) i n 10 ml of methylene chl o r i d e . After 25 min the re a c t i o n mixture was f i l t e r e d and the s o l i d residue was washed with two portions of ether and dissolved i n 5% aqueous sodium hydroxide. The resultant s o l u t i o n was extracted with ether and the combined ether s o l u t i o n was added to the f i l t r a t e . This s o l u t i o n was washed successively with three portions of 5% aqueous sodium hydroxide, two portions of water and brine and dried over anhydrous sodium s u l f a t e . Evaporation of the solvent gave 145 mg of a pale yellow s o l i d (mp 138-148 °C) which was r e c r y s t a l -l i z e d from methylene chloride-hexane giving 118 mg (93%) of pure c i s -fused d i k e t a l ketone (44), mp 150.5-151.5 °C; i r (CHC1,) v 1705, 1100 3 max 138. cm - 1; AH nmr 8 0.74, 1. 18 (2s, 3H each, B r i n g k e t a l methyls), 0.80, 1.08 (2s, 3H each, A r i n g k e t a l methyls), 1.22 (s, 3H, angular methyl), 2.88 (ddd, IH, J = 13.5,6.5 & 1.5 Hz), 3.14-3.84 (m, 9H, k e t a l meth-ylenes and C 5H). Anal, calcd. for C ^ H ^ O y C 68.82, H 9.35; found: C 68.82, H 9.30. Epimerization of the cis-Fused Diketal Ketone (44) Approximately 5 mg of m e t a l l i c sodium was added to 8 ml of anhy-drous methanol and the r e s u l t i n g suspension was s t i r r e d u n t i l a l l the sodium had reacted. A so l u t i o n of the cis-fused d i k e t a l ketone (44) (11 mg, 0.03 mmol) i n 4 ml of anhydrous methanol was added and the mixture was s t i r r e d at room temperature for four days. The reac t i o n mixture was poured into water and the r e s u l t i n g s o l u t i o n was thoroughly extracted with ether. The combined ether extracts were washed successively with water and brine and dried with anhydrous sodium s u l f a t e . Removal of the solvent under reduced pressure gave a pale yellow gum which was c r y s t a l -l i z e d from hexane, y i e l d i n g 10 mg (91%) of the desired trans-fused ketone (45), as a pure s o l i d e x h i b i t i n g mp 146-148 °C. This material was i d e n t i c a l i n a l l respects with the trans-fused ketone (45) which had been prepared previously (see page 128). Preparation of the Diketal Ether (35) 139. A s o l u t i o n of 7.02 g (15.4 mmol) of the d i k e t a l alcohol (31) i n 300 ml of tetrahydrofuran and 40 ml of hexamethylphosphoramide was cooled i n an ice-water bath. Two equivalents of potassium hydride (23% suspen-sion, 6.6 ml) were added and the r e a c t i o n mixture was s t i r r e d for f i f -teen minutes. The mixture was then warmed to a gentle r e f l u x (steam bath) over ten minutes, allowed to r e f l u x for f i f t e e n minutes, then cooled i n an ice-water bath. An opaque, milky s o l u t i o n r e s u l t e d when MEM-chloride (/?-methoxyethoxymethyl chloride) (2.6 ml, 23 mmol) was added dropwise. The r e s u l t i n g mixture was s t i r r e d at room temperature u n t i l no s t a r t i n g material was i n evidence by t i c (approximately 1.5 h). Neutral alumina (50 g, a c t i v i t y IV) and water (25 ml) were added slowly and successively. After the resultant mixture had been s t i r r e d v i g o r -ously for ten minutes, i t was f i l t e r e d . The f i l t r a t e was d i l u t e d with 50 ml of saturated aqueous sodium bicarbonate and the r e s u l t i n g s o l u t i o n was extracted with ether. The combined ether extracts were washed with water and brine and dried over anhydrous sodium s u l f a t e . Removal of the solvent gave a clear gum which was dissolved i n hot n-hexane. When the resultant s o l u t i o n was cooled, 6.0 g (69%) of the desired d i k e t a l ether (35) was obtained as a pure [ t i c , g l c (column A, 175 °C)] white amor-phous s o l i d . Chromatography of the material obtained f r om the mo ther l i q u o r on 200 g of s i l i c a g e l ( e l u t i o n of the column with 25% e t h y l acetate in benzene) gave an a d d i t i o n a l 1.71 g (20%) of the desired product (35). An a n a l y t i c a l sample, prepared by r e c r y s t a l l i z a t i o n of a small amount of this material from n-hexane, exhibited mp 101.5-103 °C; i r (CHC1,) v 1110 cm - 1; *H nmr 8 0.70, 1.16 (2s, 3H each, B r i n g 3 max ' » & 140. k e t a l methyls), 0.88, 0.96 (2s, 3H each, A r i n g k e t a l methyls), 1.18 (s, 3H, angular methyl), 3.40 (s, 3H, -0CH 3), 3.98 (broad s, IH, C 6H), 4.80, 4.91 (2d, 2H, J = 7 Hz, -0CH20-, AB quartet); 1 3 C nmr 8 95.69 ( t , J -162 Hz, -0C_H20-), 97.98 (C-j), 100.13 (Cg). Anal, calcd. for C 2 5 H 4 4 ° 7 : C 68.45, H 9.85; found: C 68.19, H 10.02. Preparation of the Dione Ether (64) 0 OMEM To a s o l u t i o n of 95 mg (0.21 mmol) of the d i k e t a l ether (35) i n 7 ml of acetone was added 7 ml of 1 JN hydrochloric acid with s t i r r i n g at room temperature. After 2.4 h had elapsed, the r e a c t i o n mixture was poured into cold, saturated aqueous sodium bicarbonate and the r e s u l t a n t mixture was extracted with ether. The combined ether extracts were washed, successively, with water and brine and dried over anhydrous magnesium s u l f a t e . Evaporation of the solvent gave 54 mg (92%) of a c o l o r l e s s gum which was pure by t i c , *H nmr and g l c (columns A & B, 190 0 analyses. This material exhibited i r ( f i l m ) v 1705, 1100, 1030 3 max ' ' cm - 1; XH nmr 8 1.43 (s, 3H, angular methyl), 3.38 (s, 3H, -OCRj), 3.50-3.92 (m, 5H, -0CH 2CH 20- & C f iH), 4.79, 4.87 (2d, 2H, J = 6 Hz, -0CH20-, AB quartet). Exact mass calcd. for C.,.H,,0,: 284.1624; found: 284. 1645. 141. Preparation of the a ^ -Unsaturated Ester (65) 0 To a so l u t i o n of 925 mg (2.0 mmol) of the d i k e t a l ether (35) i n 15 ml of acetone was added 15 ml of IN aqueous hydrochloric a c i d . The sol u t i o n was s t i r r e d at room temperature for 2.25 h and then poured into cold saturated aqueous sodium bicarbonate (60 ml). The r e s u l t i n g s o l u -t i o n was extracted thoroughly with methylene chloride and the combined organic extracts were washed with water and brine and dried over sodium s u l f a t e . The solvent was then evaporated in vacuo giving 545 mg of a c o l o r l e s s o i l which was dried overnight under high vacuum. This material was dissolved i n 20 ml of dry 1,2-dimethoxyethane and the r e s u l t i n g s o l u t i o n was cooled i n an ice-water bath. A cold (0 °C) solu t i o n ^ (10 ml, 3.0 mmol) of the potassium s a l t of t r i e t h y l phosphono-acetate i n 1,2-dimethoxyethane was added dropwise. The cooling bath was removed and the reaction mixture was s t i r r e d for 6 h at room tempera-ture. The s o l u t i o n was poured into water and thoroughly extracted with The potassium s a l t of t r i e t h y l phosphonoacetate was prepared as f o l -lows: 17 ml of 1,2-dimethoxyethane and 1 ml of a 21% suspension of potas-sium hydride i n mineral o i l was cooled to 0 °C and 1.15 ml (5.8 mmol) of t r i e t h y l phosphonoacetate was added dropwise and the mixture was s t i r r e d for 15 min giving a c l e a r , pale yellow s o l u t i o n . 142. ether. The combined ethereal extracts were washed with water and brine and dried over anhydrous sodium s u l f a t e . Evaporation of the solvent gave a pale yellow o i l which was dissolved i n e t h y l acetate and passed through a short column of s i l i c a g e l (appoximately 20 g) giving 646 mg of crude product. P u r i f i c a t i o n of t h i s material by preparative t i c , using 25% cyclohexane i n e t h y l acetate as e l u t i n g solvent, yielded 580 mg (81%) of the desired a,/3-unsaturated ester (65), a 1:1 mixture [nmr, g l c (column A, 200 °C)] of geometric isomers, as a c o l o r l e s s gum. A pure sample of one of the geometric isomers of the a,^-unsaturated ester (65) was obtained by preparative t i c (35% cyclohexane i n e t h y l acetate eluent; t r i p l e development) and exhibited: uv A x 221 nm (e=15,212); i r ( f i l m ) v 1708, 1646, 1050 cm"1; XH nmr 8 1.29 ( t , 3H, J = 7 Hz, -max ' ' ' 0CH 2CH 3), 1.34 (s, 3H, angular methyl), 3.38 (s, 3H, -0CH 3), 4.16 (q, 2H, J = 7 Hz, -0CH 2CH 3), 4.84 (s, 2H, -0CH 20-), 5.66 (s, IH, o l e f i n i c proton). Exact mass calcd. for c 1 9 H 3 Q 0 6 : 354.2043; found: 354.2050. By comparing the *H nmr spectra of the pure geometric isomer with that of the pure mixture, the *H nmr resonances due to the other isomer could be assigned as follows: XH nmr 8 1.29 ( t , 3H, J = 7 Hz, -OCH 2CH 3), 1.34 (s, 3H, angular methyl), 3.38 (s, 3H, -0CH 3), 4.18 (q, 2H, J = 7 Hz, -OCH 2CH 3), 4.80 (s, 2H, -0CH 20-), 5.69 (s, IH, o l e f i n i c proton). Preparation of the a,^-Unsaturated Ester (66) 143. A s o l u t i o n c o n s i s t i n g of 60 mg (0.17 mmol) of a, B-unsaturated ester (65), 100 mg (0.96 mmol) of 2,2-dimethyl-l,3-propanediol, approxi-mately 4 mg (0.02 mmol) of p_-toluenesulfonic acid monohydrate and, 25 ml of f r e s h l y d i s t i l l e d benzene was refluxed for 5.5 h with azeotropic removal of water u t i l i z i n g a Dean-Stark trap. The r e a c t i o n mixture was cooled to room temperature and poured into aqueous sodium bicarbonate. The r e s u l t i n g s o l u t i o n was extracted thoroughly with ether and the combined organic extracts were washed (water, brine) and dried over anhydrous sodium s u l f a t e . Removal of the solvents under reduced pres-sure gave a yellow gum which was p u r i f i e d by preparative t i c (50% e t h y l acetate i n cyclohexane e l u e n t ) . Two compounds, both of the geometric isomers of the a ,/3-unsaturated ester (66), were thus i s o l a t e d . The f i r s t , which s o l i d i f i e d on standing (26 mg, 44%), was r e c r y s t a l -l i z e d from carbon tetrachloride-hexane and exhibited mp 110-112 °C; uv A „ 222 nm (e= 12,893); i r (CHC1,) v 3500 (broad), 1695, 1648 cm - 1; nia.x j nicix lE nmr 8 0.70, 1.18 (2s, 3H each, ket a l methyls), 1.25 ( t , 3H, J = 7 Hz, -0CH 2CH 3), 1.32 (s, 3H, angular methyl), 4.12 (q, 2H, J = 7Hz, -OCH 2CH 3), 4.14 (s, IH, -OH), 5.74 (broad s, IH, o l e f i n i c proton). Anal, calcd. for C 2 Q H 3 2 0 5 : C 68.15, H 9.15; found: C 68.23, H 9.18. The second geometric isomer (27 mg, 45%) gave the following spec-t r a l data: i r ( f i l m ) v 3450 (broad), 1710, 1642 cm"1; XH nmr 8 0.72, max ' ' 1.21 (2s, 3H each, k e t a l methyls), 1.28 ( t , 3H, J = 8 Hz, -OCH 2CH 3), 1.34 (s, 3H, angular methyl), 4.16 (q, 2H, J = 8 Hz, -OCH 2CH 3), 5.70 (broad s, IH, o l e f i n i c proton). Exact mass calcd. for C 2o H32°5 : 352.2250; found: 352.2262. 144. Preparation of the g,/MJnsaturated Ester (67) The a,/3-unsaturated ester (67) (62 mg, 0.18 mmol) was dissolved i n 3 ml of ethylene g l y c o l and 0.02 ml (0.16 mmol) of f r e s h l y d i s t i l l e d boron t r i f l o r i d e etherate was added with s t i r r i n g . The mixture was s t i r r e d at room temperature for 24 h, poured into aqueous sodium b i c a r -bonate and the r e s u l t i n g s o l u t i o n was thoroughly extracted with ether. The combined ether extracts were washed successively with water and brine and dried over anydrous sodium s u l f a t e . Evaporation of the s o l -vents under reduced pressure gave a brown o i l which was p u r i f i e d by preparative t i c (25% eth y l acetate i n cyclohexane) giving both the geometric isomers of the a,^-unsaturated ester (67). One of these isomers (R f = 0.3, 42%), which s o l i d i f i e d on stand-ing, mp 163-167 °C, gave the following a n a l y t i c a l data: uv A. 223 max (E= 11,324); i r (CHC1,) v 3600, 1703, 1641 cm - 1; *H nmr S 1.13 (s, 3H, 3 max angular methyl), 1.28 ( t , 3H, J = 8 Hz, -OCH 2CH 3), 3.96 (s, 4H, ke t a l protons), 4.16 (q, 2H, J = 8 Hz, -OCH 2CH 3), 5.71 (broad s, IH, o l e f i n i c proton). Exact mass calcd. for C 1 7 H 2 6 0 5 : 310.1780; found: 310.1773. The other geometric isomer (R f = 0.2, 48%) exhibited mp 177-178 °C; uv A 224 ( e = 11,064); i r (CHC1-) v 3500 (broad), 1687, 1642 max 3 max ' ' cm"1; XH nmr 8 1.14 (s, 3H, angular methyl), 1.28 ( t , 3H, J = 7 Hz, -OCH 2CH 3), 3.91-4.28 (broad s, IH, -OH), 3.95 (s, 4H, ke t a l protons), 145. 4.18 (q, 2H, J = 7 Hz, -0CH 2CH 3), 5.80 (broad s, IH, o l e f i n i c proton). Exact mass calcd. for C, 7H„,0 q: 310.1780; found: 310.1786. Preparation of the a,^-Unsaturated Ester (61) A) From the Diketal Ether (35) To 75 ml of dry 2-methylcyclohexanone was added 5.54 g (12.1 mmol) of the d i k e t a l ether (35) followed by 210 mg (1.1 mmol) of p-toluenesul-f o n i c a c i d monohydrate. This s o l u t i o n was s t i r r e d at room temperature for three days, at which time only a trace of the s t a r t i n g material was present by t i c . The reac t i o n mixture was poured into aqueous sodium bicarbonate and the resultant mixture was extracted with two portions ether. The combined ethereal extracts were washed with water and brine and dried over anhydrous sodium s u l f a t e . The solvent was removed i n vacuo to a f f o r d a pale yellow o i l which consisted p r i m a r i l y of the monoketal ethers (62) and (63) i n a r a t i o of 3.5:1, r e s p e c t i v e l y ( g l c ) . A s o l u t i o n of t h i s o i l i n 50 ml of 1,2-dimethoxye thane was added to a cold (0 °C) so l u t i o n of the potassium s a l t of t r i e t h y l phosphonoacetate (32 mmol).* 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 for 0.5 h at 0 °C. The The potassium s a l t of t r i e t h y l phosphonoacetate was prepared as f o l -lows: to a c o l d (0 °C) s o l u t i o n of 6.6 ml (32 mmol) of a 21% suspension of potassium hydride i n mineral o i l and 200 ml of dry 1,2-dimethoxy-ethane was added 7.2 ml (36 mmol) of t r i e t h y l phosphonoacetate and the r e s u l t i n g s o l u t i o n was s t i r r e d for 15 min. 146. ice-water bath was removed and the re a c t i o n mixture was s t i r r e d for 19 h at room temperature. The s o l u t i o n was poured into cold water and d i -lu t e d with ether. The aqueous layer was extracted with a further por-t i o n of ether, the combined organic extracts were washed (water, brine) and the dri e d (sodium sulfate) s o l u t i o n was evaporated giving 11.0 g of crude product. Chromatography (400 g s i l i c a g e l , 33% e t h y l acetate i n benzene as e l u t i n g solvent) of t h i s material gave 3.91 g (73%) of the a,/3 -unsaturated ester (61), a 1:1 mixture of geometric isomers (nmr), as a viscous, c o l o r l e s s gum and 0.9 g (20%) of the monoketal ether (63), containing a small amount of recovered (62). Selective c r y s t a l l i z a t i o n of a portion of the a ./^-unsaturated ester (61) from ether-hexane afforded a pure sample of one of the geometric isomers as c o l o r l e s s prisms, mp 57-58 °C; uv A 223 nm ( e = 7684): i r max ' (CHC1,) v 1705, 1645, 1147, 1105, 1040 cm - 1; *H nmr 8 0.70, 1.18 (2s, 3 max » » » » » 3H each, k e t a l methyls), 1.26 ( t , 3H, J = 7 Hz, -0CH 2CH 3), 1.30 (s, 3H, angular methyl), 3.40 (s, 3H, -OCH-j), 4.11 (q, 2H, J = 7 Hz, -OCH 2CH 3), 4.73, 4.82 (2d, 2H, J = 7 Hz, -0CH20-, AB quartet), 5.58 (s, IH, o l e -f i n i c proton). Anal, calcd. for c 24 H 4 o°7 : c 6 5 » 4 3 , H 9.15; found: C 65.56, H 9.19. By comparing the *H nmr spectrum of the isomer i s o l a t e d as a pure s o l i d with that of the pure mixture of geometric isomers, the spectral data due to the geometric isomer not i s o l a t e d i n pure form could be assigned as as follows: *H nmr 8 0.70, 1. 18 (2s, 3H each, keta l meth-y l s ) , 1.24 ( t , 3H, J = 7 Hz, -OCH 2CH 3), 1.30 (s, 3H, angular methyl), 3.36 (s, 3H, -0CH 3), 3.91 (q, 2H, J - 7 Hz, -OCH 2CH 3), 4.62, 4.74 (2d, J « 8 Hz, -0CH20-, AB quartet), 5.70 (broad s, IH, o l e f i n i c proton). 147. B) From the a,/?-Unsaturated Ester (65) A s o l u t i o n of the a,/J-unsaturated ester (65) (202 mg, 0.57 mmol) i n 12 ml of f r e s h l y d i s t i l l e d 2-ethyl-2,5,5-trimethyl-l,3-dioxane (70)* was treated with 32 mg (0.17 mmol) of js-toluenesulfonic a c i d monohydrate. The mixture was heated to 60 °C and s t i r r e d at t h i s temperature for 4 days. The rea c t i o n mixture was cooled to room temperature, d i l u t e d with ether and the r e s u l t i n g s o l u t i o n was washed successively with two por-tions of aqueous sodium bicarbonate, two portions of water and one portion of brine. The ether was removed under reduced pressure and the r e s i d u a l s o l u t i o n , containing the crude product and (70), was passed through a short column of neutral alumina ( a c t i v i t y IV) using petroleum ether (bp 30-60 °C) as e l u t i n g solvent. After a l l the solvent (70) had been eluted (glc) from the column, e t h y l acetate, i n gradually increasing proportions, was added to the e l u t i n g solvent. The column was flushed with solvent u n t i l a l l the crude product ( t i c ) had been eluted and the combined product containing f r a c t i o n s were concentrated i n vacuo. The crude product contained four compounds ( t i c ) which were separated by preparative t i c (40% e t h y l acetate i n cyclohexane as devel-This material was prepared as follows: to a s o l u t i o n of dry butanone (40 g, 0.56 mol) i n 400 ml of dry benzene was added 2,2-dimethyl-l,3— propanediol (125 g, 1.2 mol) and a c a t a l y t i c amount of j>-toluene-s u l f o n i c a c i d . The r e s u l t i n g s o l u t i o n was refluxed under a Dean-Stark trap for four hours, cooled to room temperature and poured into aqueous sodium bicarbonate. The r e s u l t i n g mixture was thoroughly extracted with ether and the combined organic extracts were washed (water, brine) and dri e d (sodium s u l f a t e ) . Evaporation of the solvents under reduced pres-sure, followed by f r a c t i o n a l d i s t i l l a t i o n of the residue (74°C/56 mm), gave 2-ethyl-2,5,5-trimethyl-l,3-dioxane (70)as a pure [glc (column A, 70 °C), H nmr], c o l o r l e s s l i q u i d . 148. oping solvent) y i e l d i n g 46 mg (23%) of recovered s t a r t i n g material (65) > 36 mg (34% t o t a l ) of each of the geometric isomers of the «,j8-unsaturated ester (66) (both of which were i d e n t i a l i n a l l respects with previously prepared material, see p. 142) and 68 mg (27%) of the desired o,/?-unsaturated ester (61). The l a t t e r proved to be i d e n t i c a l ( i r , nmr) with the material prepared previously (see Part A). Preparation of the Monoketones (62) and (63) (62) OMEM (63) OMEM To a s o l u t i o n of 19 mg (0.04 mmol) of the d i k e t a l ether (35) i n 10 ml of dry methyl e t h y l ketone was added 4 mg (0.02 mmol) of £-toluene-sulphonic a c i d . The s o l u t i o n was cooled to 0 °C and s t i r r e d for 18 h. The reaction mixture was poured into d i l u t e aqueous sodium bicarbonate and the r e s u l t i n g s o l u t i o n was thoroughly extracted with ether. The combined ether extracts were washed successively with water and brine and dried over anhydrous sodium s u l f a t e . Removal of the solvents gave a viscous o i l which was subjected to preparative t i c (33% eth y l acetate i n cyclohexane) giving 14 mg (91%) of a 2:1 mixture ( g l c , *H nmr) of the monoketones (62) and (63), r e s p e c t i v e l y . A pure sample of monoketone (63) was obtained by preparative t i c ( t r i p l e development using 25% eth y l acetate i n cyclohexane). This material c r y s t a l l i z e d a f t e r prolonged 149. storage at -6 UC; r e c r y s t a l l i z a t i o n from chloroform-hexane gave the monoketone (63) as white needles, mp 64-65 °C; i r (CHC1„) v 1703, 3 max 1090, 1035 cm"1; XH nmr 8 0.88, 1.00 (2s, 3H each, keta l methyls), 1.31 (s, 3H, angular methyl), 2.58-3.02 (m, IH, C gH), 3.40 (s , 3H, -OCUj), 4.83, 4.91 (2d, 2H, J = 8 Hz, -OCH^O-, AB quartet). Anal, calcd. for C 2 0 H 3 4 ° 6 : C 6 4 , 8 4 > H 9' 2 5> f o u n < i : C 65.05, H 9.35. The *H nmr spectral data of the major component, monoketone (62), obtained v i a a comparison of the *H nmr spectra of the pure mixture with that of the pure monoketone (63), i s as follows: *H nmr 8 0.72, 1.20 (2s, 3H each, k e t a l methyls), 1.40 (s, 3H, angular methyl), 3.34 (s, 3H, -0CH 3), 4.63, 4.78 (2d, 2H, J = 7 Hz, -OCH^O-, AB quartet). Deuteration of the Monoketone (63) The monoketone (63) (32 mg, 0.08 mmol) was dissolved i n 4 ml of methanol-d^ and a small amount of sodium methoxide was added. The r e -s u l t i n g s o l u t i o n was gently refluxed for 30 h, cooled to room tempera-ture and poured into water. The r e s u l t i n g mixture was extracted with two portions of ether and the combined ether s o l u t i o n was washed with water and brine and dried over anhydrous sodium s u l f a t e . Evaporation of the solvents gave 30 mg of the deuterated ketone (71), which exhibited a molecular i o n peak at m/e 372 (low r e s o l u t i o n mass spectrometry) cor-responding to the introduction of 2 deuterium atoms. The *H nmr spe c t r a l data of t h i s material was as follows: *H nmr 8 0.88, 1.00 (2s, 3H each, k e t a l methyls), 1.31 (s, 3H, angular methyl), 3.40 (s, 3H, -0CH 3), 4.83, 4.91 (2d, 2H, J = 8 Hz, -0CH20-, AB quartet). 150. K e t a l i z a t i o n of the Monoketals (63) and (62) To a s o l u t i o n of 190 mg (0.51 mmol) of a 65:35 mixture ( g l c , nmr) of the monoketals (63) and (62), r e s p e c t i v e l y , and 530 mg (5.0 mmol) of 2,2-dimethyl-l,3-propanediol i n 30 ml of benzene was added 10 mg (0.05 mmol) of £-toluenesulfonic acid monohydrate. The so l u t i o n was refluxed under a Dean-Stark trap for 4 h and subsequently cooled to room temper-ature. D i l u t i o n of the mixture with ether, followed by washing the r e s u l t i n g s o l u t i o n with aqueous sodium bicarbonate, water and brine, gave a c l e a r , yellow s o l u t i o n which was dried over anhydrous sodium s u l f a t e . Removal of the solvents under reduced pressure yielded a pale yellow gum. C r y s t a l l i z a t i o n of t h i s material from methylene c h l o r i d e -hexane afforded 95 mg (48%) of the d i k e t a l alcohol (31) as a pure s o l i d . Concentration of the mother l i q u o r followed by the p u r i f i c a t i o n of the r e s u l t i n g residue by preparative t i c (30% e t h y l acetate i n benzene), gave a further 88 mg (44%) of the d i k e t a l alcohol (31). This material (mp 161-163 °C) was i d e n t i c a l i n a l l respects with the d i k e t a l alcohol (31) which was prepared previously (see page 125 )• Hydrogenation of the a,/?-Unsaturated Ester (61) To a s o l u t i o n of 525 mg (1.2 mmol) of the a ,/?-unsaturated ester (61) i n tetrahydrofuran was added 50 mg of platinum oxide. The mixture was hydrogenated at 50 p s i and room temperature. After the reaction was complete ( t i c , 2 h), the mixture was f i l t e r e d through c e l i t e . Evapor-ati o n of the solvent from the f i l t r a t e gave a viscous c o l o r l e s s gum which was composed of two compounds ( t i c ) i n a r a t i o of 66:34 [glc 151. column A, 220 °C)]. The crude product was subjected to column chroma-tography on 40 g of s i l i c a g e l using 25% e t h y l acetate i n cyclohexane as e l u t i n g solvent, y i e l d i n g 176 mg (34%) of the saturated ester (76) and 332 mg (63%) of the desired product, saturated ester (72). The undesired epimer, saturated ester (76), gave the following a n a l y t i c a l data: i r (film) v 1730, 1100, 1032 cm"1; lH nmr 8 0.68 max (s, 3H, k e t a l methyl), 1.13 (s, 6H, ketal methyl & angular methyl), 1.21 ( t , 3H, J = 7 Hz, -0CH 2CH 3), 3.33 (s, 3H, -OCH-j), 4.06 (q, 2H, J = 7 Hz, -0CH 2CH 3), 4.69, 4.79 (2d, 2H, J = 7 Hz, -0CH20-, AB quartet); 1 3 C nmr8 94.70 (-0CH20-), 99.85 (Cg), 172.71 ( - C O ^ ^ ) . Exact mass calcd. for C 2 4 H 4 2 ° 7 : 4 4 2 « 2 9 3 ° ; found: 442.2946. The desired epimer, saturated ester (72), gave the following analy-t i c a l data: i r (film) v 1737, 1118, 1045 cm - 1, XH nmr 8 0.68, 1. 16 max (2s, 3H each, k e t a l methyls), 1.04 (s, 3H, angular methyl), 1.24 ( t , 3H, J = 7.5 Hz, -OCH 2CH 3), 2.06-2.52 (m, 4H, -CH 2C0 2C 2H 5, CgH and C 5H), 3.35 (s, 3H, -0CH 3), 4.09 (q, 2H, J = 7.5 Hz, -0CH 2CH 3), 4.64, 4.77 (2d, 2H, J = 7.5 Hz, -0CH20-, AB quartet); 1 3 C nmr 8 93.61 ( t , J = 162 Hz, -0CH 20-), 102.48 ( C g ) , 173.06 (-C_02C2H5). Exact mass calcd. for C„,H._0,: 442.2930; found: 442.2948. 24 42 7 152. Deprotection of the Saturated Ester (76): Preparation of the Ketal Alcohol (78) and the Keto Alcohol (79) (78) (79) To a s o l u t i o n of 155 mg (0.35 mmol) of the saturated ester (76) i n 20 ml of dry benzene was added 182 mg (1.75 mmol) of r e c r y s t a l l i z e d 2,2— dimethyl-l,3-propanediol followed by 25 mg (0.13 mmol) of p-toluene-s u l f o n i c a c i d . The s o l u t i o n was ref l u x e d i n an apparatus f i t t e d with a Dean-Stark separator for 45 min. The mixture was cooled to room temper-ature, poured into aqueous sodium bicarbonate and thoroughly extracted with ether. The combined organic extracts were washed with water (3 portions) and brine and dried over anhydrous sodium s u l f a t e . Evapor-a t i o n of the solvents i n vacuo, followed by p u r i f i c a t ion of the crude product by preparative t i c (40% eth y l acetate i n benzene developer), afforded 93 mg (75%) of the ke t a l alcohol (78), as well as 21 mg (22%) of the ke t a l cleaved product, the keto alcohol (79). The k e t a l a l c ohol (78) displayed the following s p e c t r a l character-i s t i c s : i r ( f i l m ) v 3480 (broad), 1735, 1103 cm"1; XH nmr 8 0.70 (s, max ' 3H, k e t a l methyl), 1.18 (s, 6H, ketal methyl & angular methyl), 1.24 ( t , 3H, J = 7 Hz, ~OCH 2CH 3), 1.68 (broad s, IH, -OH), 3.18-3.78 (m, 4H, k e t a l methylenes), 3.78 (ddd, IH, J = 10, 10 & 5.5 Hz, C &H), 4.14 (q, 2H, J = 7 Hz, -0CH 2CH 3). Exact mass calcd. for C 2 ( )H 3 40 5: 354.2406; 153. found: 354.2391. The keto alcohol (79) gave the following s p e c t r a l data: i r (CHCl^) v 3452 (broad), 1720 (shoulder), 1702 cm - 1; lE nmr 8 1.21 (s, 3H, max \ f t \ *» angular methyl), 1.28 ( t , 3H, J = 7 Hz, -OCH 2CH 3), 1.77 (s, IH, -OH), 4.08-4.40 (m, IH, C 6H), 4.16 (q, 2H, J = 7 Hz, -0CH 2CH 3). Exact mass cal c d . for C ^ H ^ O ^ 268.1674; found: 268.1676. Preparation of the Ketal Tosylate (75) To a cold s o l u t i o n (0 °C) of 62 mg (0.18 mmol) of the k e t a l alcohol (78) i n 5 ml of dry pyridine was added 300 mg (1.6 mmol) of r e c r y s t a l -l i z e d £-toluenesulfonyl chloride with s t i r r i n g . The reaction mixture was warmed to room temperature and s t i r r e d for 13 h. The mixture was d i l u t e d with ether and the r e s u l t i n g s o l u t i o n was washed with aqueous sodium bicarbonate, water and brine. After the s o l u t i o n had been dried over anhydrous sodium s u l f a t e , the solvents were removed i n vacuo. The crude product (98 mg) thus obtained was p u r i f i e d by preparative t i c (25% e t h y l acetate i n cyclohexane) affording 72 mg (81%) of the k e t a l tosy-l a t e (75) as a cream colored s o l i d (mp 142-143 °C). R e c r y s t a l l i z a t i o n of this material from acetone gave pure white needles of the k e t a l tosylate (75), which exhibited mp 148-149 °C (dec); i r (CHC1.) v 1720 ' - — - r 3 max cm"1; *H nmr 8 0.68 (s, 3H, k e t a l methyl), 1.13 (s, 6H, k e t a l methyl & 154. angular methyl), 1.26 ( t , 3H, J = 7 Hz, -0CH 2CH 3), 2.40 (s, 3H, aromatic methyl), 3.14-3.70 (m, 4H, k e t a l methylenes), 4.11 (q, 2H, J = 7 Hz, -OCH 2CH 3), 4.78 (ddd, IH, J = 11,11 & 5.5 Hz, CgH), 7.31, 7.80 (2d, 2H each, J = 8 Hz, aromatic protons). Exact mass calcd. for C^H^QO^S: 508.2494; found: 508.2501. Deprotection of the Saturated Ester (72): Preparation of the Ketal Alcohol (77) and the Keto Alcohol (80) <77> XXJ \c0 2 Et L ^ O D ^ E ^ (80) OH OH A solution c o n s i s t i n g of 200 mg (0.45 mmol) of the saturated ester (72), 235 mg (2.3 mmol) of dry, r e c r y s t a l l i z e d 2,2-dimethyl-l,3-propan-e d i o l , 25 mg (0.13 mmol) of j)-toluenesulfonic a c i d and 30 ml of dry benzene was refluxed for 45 min using an apparatus f i t t e d with a Dean-Stark trap. After the re a c t i o n mixture had been cooled to room temper-ature, i t was d i l u t e d with ether. The r e s u l t i n g s o l u t i o n was washed with aqueous sodium bicarbonate (two portions). The ether layer was is o l a t e d and washed with water and brine and dried over anhydrous sodium s u l f a t e . P u r i f i c a t i o n of the crude product by preparative t i c (33% ethy l acetate i n benzene as developing solvent) gave 86 mg (54%) of the ke t a l alcohol (77) as a pale yellow gum and 36 mg (30%) of the keto alcohol (80). The k e t a l alcohol (77) gave the following spectral data: i r (film) 155. v 3495 (broad), 1728, 1095 cm"1; XH nmr 8 0.68, 1.15 (2s, 3H each, max k e t a l methyls), 1.12 (s, 3H, angular methyl), 1.22 ( t , 3H, J = 7 Hz, -0CH 2CH 3), 3.11-3.83 (m, 5H, keta l methylenes & C f eH), 3.68 (s, IH, -OH), 4.09 (q, 2H, J = 7 Hz, -OCH 2CH 3). Exact mass calcd. for C^H^O^. 354.2406; found: 354.2408. The keto alcohol (80) had the following s p e c t r a l c h a r a c t e r i s t i c s : i r (CHC1.) v 3605, 1723 (shoulder), 1708 cm - 1; XH nmr 8 1.20 ( t , 3H, 3 max ' ' J = 7 Hz, -OCH 2CH 3), 1.38 (s, 3H, angular methyl), 1.82 (s, IH, -OH), 2.72-3.18 (m, IH, C gH), 3.87 (broad s, IH, C^H), 4.07 (q, 2H, J = 7 Hz, -0CH„CH,). Exact mass calcd. for C 1 (-H 9,0 A: 268.1675; found: 268. 1674. Preparation of the Ketal Tosylate (73) To a s o l u t i o n of 85 mg (0.24 mmol) of the k e t a l alcohol (77) i n 5 ml of dry pyridine was added, at 0 °C with s t i r r i n g , 460 mg (2.4 mmol) of r e c r y s t a l l i z e d j)-toluenesulfonyl c h l o r i d e . The re a c t i o n mixture was warmed to room temperature and s t i r r e d at t h i s temperature for 17 h. The mixture was cooled to 0 °C and i c e was added to the re a c t i o n mix-ture. After the resultant mixture had been s t i r r e d u n t i l a l l the ice had melted, the s o l u t i o n was d i l u t e d with ether and the organic layer was i s o l a t e d and washed with aqueous sodium bicarbonate, water and brine. The dried (sodium s u l f a t e ) s o l u t i o n was evaporated under reduced 156. pressure to give a pale yellow gum (one component by t i c ) . P u r i f i -cation of t h i s material by preparative t i c (25% e t h y l acetate i n ben-zene) gave 98 mg (80%) of the ket a l tosylate (73). The l a t t e r gave the following spectral data: i r (film) v 1722 cm - 1; *H nmr 8 0.68, 1.13 (2s, 3H each, k e t a l methyls), 1.01 (s, 3H, angular methyl), 1.24 ( t , 3H, J = 7 Hz, -0CH 2CH 3), 2.42 (s, 3H, aromatic methyl), 3.12-3.80 (m, 4H, keta l methylenes), 4.09 (q, 2H, J = 7 Hz, -0CH 2CH 3), 4.49 (broad s, IH, C^H), 7.31, 7.56 (2d, 2H each, J = 8 Hz, aromatic protons). Exact mass calcd. for C„ 7H,„0 7S: 508.2494; found: 508.2455. Preparation of the Keto Ether (92) 0 C0 2Et OMEM The saturated ester (72), 32 mg (0.07 mmol), was dissolved i n 5 ml of acetone and 5 ml of IN hydrochloric a c i d was added with s t i r r i n g . The s o l u t i o n was s t i r r e d at room temperature for 1 h, poured into satur-ated aqueous sodium bicarbonate and the r e s u l t i n g mixture was thoroughly extracted with ether. The combined organic phase was washed with three portions of water and one portion of brine and dried over anhydrous sodium s u l f a t e . Removal of the solvents In vacuo afforded 20 mg (77%) of the keto ether (92) as a c o l o r l e s s o i l which was pure by t i c , *H nmr and g l c (column A, 190 °C) analyses. This material exhibited the f o l -lowing a n a l y t i c a l data: i r (film) v 1732, 1705, 1115, 1050 cm"1; 157. H nmr 8 1.25 ( t , 3H, J = 7 Hz, -0CH 2CH 3), 1.35 (s, 3H, angular methyl), 3.42 (s, 3H, -OCH 3), 3.48-3.86 (m, 5H, C 6H & -Oq^CjL/)-) , 4.14 (q, 2H, J = 7 Hz, -OCH 2CH 3), 4.82, 4.88 (2d, 2H, J = 7 Hz, -OCIL/)-, AB quartet). Exact mass calcd. for C 1 9 H 3 2 0 6 : 356.2199; found: 356.2191. Preparation of the Keto Ether (91) C0 2Et OMEM To a so l u t i o n of 48 mg (0.11 mmol) of the saturated ester (76) i n 5 ml of acetone was added, with s t i r r i n g at room temperature, 5 ml of IN hydrochloric a c i d . The s o l u t i o n was s t i r r e d for 1 h and poured into saturated aqueous sodium bicarbonate. Thorough ex t r a c t i o n of the r e -s u l t i n g mixture with ether, followed by washing (water, brine) and drying (sodium sulfate) of the combined organic phase, gave 32 mg (82%) of the keto ether (91) a f t e r the solvents had been removed under reduced pressure. The product, a c o l o r l e s s o i l , was pure by t i c , *H nmr and g l c (column A, 190 °C) analyses. The following spectral data was obtained from t h i s material: i r (film) v 1730, 1708, 1108, 1048 cm"1; ^ nmr8 max 1.21 (s, 3H, angular methyl), 1.25 ( t , 3H, J = 7 Hz, -0CH 2CH 3), 3.42 (s, 3H, -0CH 3), 3.48-3.86 (m, 4H, -OCJ^CIL/)-) , 4.12 (m,lH, C 6H), 4.16 (q, 3H, J = 7 Hz, -0CH 2CH 3), 4.85, 4.91 (2d, 2H, J = 7 Hz, -0CH20-, AB quartet). Exact mass calcd. for C.qH,,90,: 356.2199; found: 356.2187. 158. Preparation of the Alcohol (89) H 0 ' OMEM A) By Reduction of the Saturated Ester (76) A suspension containing 20 mg (0.5 mmol) of 95% l i t h i u m aluminum hydride i n 10 ml of anhydrous ether was cooled to -78 °C. To t h i s cold s o l u t i o n was added, dropwise with s t i r r i n g , 105 mg (0.24 mmol) of the saturated ester (76) dissolved i n 8 ml of anhydrous ether. After 1 h the r e a c t i o n mixture was warmed to 0 °C and 4 ml of e t h y l acetate was added followed by 5 ml of water. The mixture was warmed to room tempera-ture, f i l t e r e d through c e l i t e and the f i l t r a t e was d i l u t e d with water and ether. The layers were separated and the organic phase was washed successively with two portions of water and one portion of brine. The dried (sodium s u l f a t e ) organic extracts were evaporated i n vacuo a f f o r d -ing 94 mg (99%) of the alcohol (89) which was pure by t i c and glc ( c o l -umn A, 220 °C) analyses. This material exhibited the following s p e c t r a l properties: i r ( f i l m ) v 3480 (broad), 1105, 1035 cm"1; XH nmr 8 0.68 max ' ' (s, 3H, k e t a l methyl), 1.15 (s, 6H, angular methyl & k e t a l methyl), 2.12 (broad s, IH, -OH), 2.54 (dd, IH, J = 3 & 11 Hz, C 5H), 3.12-3.81 (m, 9H, k e t a l methylenes, -OCH2CH20-, & C 6H), 3.34 (s, 3H, -OCUj), 3.87 (ddd, IH, J - 11, 11 & 5 Hz, C 6H), 4.66, 4.80 (2d, 2H, J - 7 Hz, -0CH20-, AB quartet). Exact mass calcd. for C 2 2 H A Q 0 6 : 400.2825; found: 400.2855. 159. B) By Birch-type Reduction of the g,/?-Unsatur ated Ester (61) Freshly d i s t i l l e d ammonia (from l i t h i u m metal), 30 ml, was added to a cold s o l u t i o n (-78 °C) consisting of 78 mg (0.18 mmol) of the a,/?— unsaturated ester (61), 15 ml of anhydrous ether and 10 ml of absolute ethanol. Lithium wire was added, i n f i n e l y cut portions, u n t i l a blue color remained i n s o l u t i o n between additions for 10-15 min. The reac-t i o n was quenched by the portion-wise addition of ammonium chloride. The ammonia was allowed to evaporate and the residue was d i l u t e d with water and ether. The ether layer was i s o l a t e d and subsequently washed with water and brine and dried over anhydrous sodium s u l f a t e . Removal of the solvents under reduced pressure afforded 60 mg (84%) of the alcohol (89) as a c o l o r l e s s gum which was pure by *H nmr, t i c and g l c (column A, 220 °C) analyses. This material was i d e n t i c a l i n a l l respects with the material prepared previously (see Part A). Preparation of the Alcohol (90) To a cold (-78 °C) suspension of 20 mg (0.5 mmol) of 95% lithium aluminum hydride i n 10 ml of anhydrous ether was added, dropwise with s t i r r i n g , 60 mg (0.14 mmol) of the saturated ester (72) dissolved i n 5 ml of anhydrous ether. The temperature was maintained at -78 °C for one 160. hour then the s o l u t i o n was warmed to 0 °C. Ethyl acetate (5 ml), f o l -lowed by water (4 ml), was added to the re a c t i o n mixture and the so l u -t i o n was warmed to room temperature. The mixture was f i l t e r e d through c e l i t e , the f i l t r a t e was d i l u t e d with water, and thoroughly extracted with ether. The combined organic extracts were washed with water and brine, dried over anhydrous sodium s u l f a t e and evaporated y i e l d i n g 57 mg (100%) of the alcohol (90) as a pure [ t i c , glc (column A, 220 °C)], c o l o r l e s s gum; i r (film) v 3490 (broad), 1100, 1035 cm"1; lE nmr8 0.68, 1.16 (2s, 3H each, k e t a l methyls), 1.04 (s, 3H, angular methyl), 2.33 (m, 2H, C 3H & C 5H), 3.12-3.80 (m, 11H, -CH^OH, -OCH2CH20-, k e t a l methylenes & C 6H), 3.35 (s, 3H, -OCH-j), 4.68, 4.78 (2d, 2H, J = 7 Hz, -OCH^O-, AB quartet). Exact mass calcd. for C 2 2 H 4 0 ° 6 : 400.2825; found: 400.2859. Preparation of the /?,y-Unsaturated Ester (93) To a cold (-78 °C) so l u t i o n containing 150 mg (0.34 mmol) of the a ,/^-unsaturated ester (61) ( c r y s t a l l i n e isomer) i n 5 ml of dry t e t r a -hydrofuran was added 1.03 ml (1.75 M, 0.85 mmol) of a cold (0 °C) so l u -t i o n of l i t h i u m diisopropylamide-hexamethylphosphoramide (1:1) in t e t r a -hydrofuran. The r e s u l t i n g s o l u t i o n was s t i r r e d at -78 °C for 3 h. Water (approximately 1 ml) was added to the reaction mixture and the 161. mixture was warmed to room temperature. The s o l u t i o n was poured into ether and the resultant s o l u t i o n was d i l u t e d with water. The aqueous layer was thoroughly extracted with ether and the combined organic phase was washed with brine and dried over anhydrous sodium s u l f a t e . Evapora-t i o n of the solvents i n vacuo gave 129 mg of a yellow gum [100% by glc (column A, 180 °C)]. P u r i f i c a t i o n of t h i s material by preparative t i c (25% e t h y l acetate i n cyclohexane) afforded 120 mg (80%) of the B,y— unsaturated ester (93) as a pale yellow gum; i r (film) v 1730, 1100, 1038 cm"1; *H nmr 8 0.70, 1. 19 (2s, 3H each, k e t a l methyls), 1.10 (s, 3H, angular methyl), 1.24 ( t , 3H, J = 7 Hz, -OCH^Ej), 2.94 (s, 2H, -CH 2C0 2C 2H 5), 3.18-3.90 (m, 9H, k e t a l methylenes, -0CH2CH20-, & C 6H), 3.38 (s, 3H, -0CH 3), 4.13 (q, 2H, J = 7 Hz, -0CH 2CH 3), 4.70, 4.81 (2d, 2H, J = 7 Hz, -0CH20-, AB quartet), 5.49 (broad s, IH, C 2H). Exact mass calcd. for C 9,H, n0 7: 440.2774; found: 440.2769. Preparation of the Dialkylated Ester (95) A s o l u t i o n containing 251 mg (0.57 mmol) of the saturated ester (72) i n 3 ml of dry tetrahydrofuran was cooled to -78 °C and 2.0 ml (1.1 mmol) of a cold (0 °C), 0.54 M s o l u t i o n of l i t h i u m diisopropylamide i n tetrahydrofuran was added dropwise. The r e s u l t i n g s o l u t i o n was s t i r r e d at -78 °C for one hour and 0.07 ml (1.1 mmol) of methyl iodide i n 0.5 ml 162. of hexamethylphosphoramide was added dropwise. The rea c t i o n mixture was warmed to -20 °C (0.5 h) and subsequently warmed to 0 °C and s t i r r e d at th i s temperature for 0.5 h. Lithium diisopropylamide (2.6 ml, 0.54 M, 1.4 mmol) was added to the reac t i o n mixture at -78 °C and, aft e r the res u l t a n t s o l u t i o n had been s t i r r e d for 1 h, i t was warmed to -20 °C (30 min). A s o l u t i o n of 0.14 ml (2.3 mmol) of methyl iodide i n 5 ml of hexamethylphosphoramide was added to the reaction mixture at -78 °C, the mixture was warmed to -20 °C (30 min) and then warmed to 0 °C for 1.5 h. The r e a c t i o n mixture was poured into water and the r e s u l t i n g s o l u t i o n was thoroughly extracted with ether. The combined ether extracts were washed successively with water and brine and dried over anhydrous sodium s u l f a t e . Evaporation of the solvents gave 307 mg of a pale brown gum. Preparative t i c (25% e t h y l acetate i n benzene) p u r i f i c a t i o n of the crude product gave 264 mg (99%) of the pure d i a l k y l a t e d ester (95) as a c o l o r -l e s s gum; i r (f i l m ) v 1725, 1105, 1035 cm"1; JH nmr 8 0.70, 1.18 ° max ' ' (2s, 3H each, k e t a l methyls), 1.05 (s, 3H, t e r t i a r y methyl), 1.07 (s, 6H, t e r t i a r y methyls), 1.24 ( t , 3H, J = 8 Hz, -OCH ^ l l j ) , 2.26-2.48 (m, 2H, C 3H & C 5H), 3.10-3.78 (m, 9H, ketal methylenes, -0CH2CH20-, & C 6 H ) » 3.40 (s, 3H, -0CH 3), 4.12 (q, 2H, J - 8 Hz, -OCHjCH^, 4.72, 4.78 (2d, 2H, J = 7 Hz, -0CH20-, AB quartet). Exact mass calcd. for C 2 6 H 4 6 ° 7 : 470.3243; found: 470.3204. 163. Preparation of the Carboxylic Acid (102) C 0 2 H OMEM To a s o l u t i o n of 143 mg (0.3 mmol) of the di a l k y l a t e d ester (95) i n 1 ml of dry dimethyl sulfoxide was added 5 ml of a 1M solu t i o n of potassium tert-butoxide i n dry dimethyl sulfoxide, with s t i r r i n g at room temperature. The r e s u l t i n g dark brown sol u t i o n was s t i r r e d for 1.75 h, cooled to 0 °C and 2 ml each of methanol and water was added. A c i d i c ion exchange r e s i n (Amberlite IR-120) was added, i n portions with v i g o r -ous s t i r r i n g , u n t i l a neutral pH was reached (pH paper). The r e s u l t i n g cold mixture was immediately f i l t e r e d (sintered glass) and the r e s i n was washed with several portions of ether. The f i l t r a t e was d i l u t e d with water and the ether layer was i s o l a t e d and washed successively with water and brine. The dried (sodium s u l f a t e ) organic phase was evapora-ted y i e l d i n g 158 mg of a yellow gum. This material was p u r i f i e d by preparative t i c (ethyl acetate) affording 118 mg (88%) of a pale yellow gum which c r y s t a l l i z e d on standing. R e c r y s t a l l i z a t i o n of a portion of t h i s material from ether-hexane gave an a n a l y t i c a l sample of the carbox-y l i c a c i d (102), which exhibited mp 124-125 °C; i r (CHC1-) v 3450-' 3 max 2400 (broad), 1695, 1110, 1040 cm"1; JH nmr 8 0.70, 1.18 (2s, 3H each, k e t a l methyls), 1.06 (s, 3H, t e r t i a r y methyl), 1.11 (s, 6H, t e r t i a r y methyls), 2.20-2.54 (m, 2H, C 3H & C 5H), 3.10-3.84 (m, 9H, k e t a l methy-lenes, -OCH2CH20-, & C 6H), 3.40 (s, 3H, -OCHLj), 4.73, 4.78 (2d, 2H, J = 7 164. Hz, -OCH^O-, AB quartet). Anal, calcd. for C^^O^: C 65.13, H 9.57; found: C 65.19, H 9.64. Preparation of the S l l y l Ester (107) To a s o l u t i o n of the carboxylic acid (102) (150 mg, 0.27 mmol) i n 3 ml of dry dimethylformamide was added 102 mg (0.67 mmol) of t e r t - b u t y l — d i m e t h y l s i l y l chloride i n 1 ml of dry dimethylf ormamide. To t h i s s o l u -t i o n was added 92 mg (1.4 mmol) of imidazole with s t i r r i n g . The r e s u l t -ing s o l u t i o n was warmed to 60 °C and s t i r r e d for 17 h at t h i s tempera-ture. The re a c t i o n mixture was cooled to room temperature, poured into water and the resultant s o l u t i o n was thoroughly extracted with ether. The combined ether extracts were washed with aqueous sodium bicarbonate, water and brine and dried over anhydrous sodium s u l f a t e . Evaporation of the solvent under reduced pressure, followed by subjection of the r e s u l -tant o i l to high vacuum at 50 °C (24 h), afforded 187 mg (99%) of a pure [ t i c , *H nmr, g l c (column A, 180 °C)], c o l o r l e s s gum; i r (film) v 1113. X . 1715, 1105, 1041 cm"1; XH nmr 8 0.26 (s, 6H, - S i ( C H 3 ) 2 - ) , 0.71, 1.19 (2s, 3H each, k e t a l methyls), 0.95 (s, 9H, - S i C ( C H 3 ) 3 ) , 1.07 (s, 9H, angular methyl & -C(CH 3) 2CO-), 3.00-3.86 (m, 9H, ke t a l methylenes, -OCH2CH20-, & C 6H), 3.42 (s, 3H, -OCH-j), 4.76 (s, 2H, -0CH 20-). Exact  mass calcd. for C„ nH,- A0 7Si: 556.3795; found: 556.3756. 165. Preparation of the Acid (112) To a s o l u t i o n of 130 mg (0.29 mmol) of the saturated ester (76) i n 1 ml of methanol was added 6 ml of a IM s o l u t i o n of potassium hydroxide i n methanol. The r e s u l t i n g s o l u t i o n was refluxed for 2 h, cooled to room temperature and poured into water. This mixture was cooled to 0 °C and neutralized (pH paper) with a c i d i c ion exchange r e s i n (Amberlite IR-120). The mixture was f i l t e r e d and the exchange r e s i n was washed with ether. The aqueous layer of the f i l t r a t e was extracted with ether and the combined organic phase was washed with water and brine. Evaporation of the dried (anhydrous sodium sulfate) solvents under reduced pressure gave 66 mg (54%) of a pale yellow gum which was pure by t i c and *H nmr. This material exhibited the following s p e c t r a l data: i r (film) v max 3500-2390 (broad), 1713, 1110, 1042 cm - 1; 1H nmr 8 0.70 (s, 3H, k e t a l methyl), 1.18 (s, 6H, k e t a l & angular methyls), 3.16-4.02 (m, 9H, k e t a l methylenes, -OCj^CH^O-, & C 6H), 3.39 (s, 3H, -OCH-j), 4.75, 4.85 (2d, 2H, J = 7 Hz, -0CH20-, AB quartet), 8.78-9.20 (broad s, IH, -C0 2H). Exact  mass calcd. for C 2 2 H 3 8 ° 7 : 414.2618; found: 414.2621. 166. Reaction of the Acid (112) with Diphenylphosphoryl Azide:  Preparation of the Ester (114) To a s o l u t i o n of 66 mg (0.16 mmol) of the acid (112) i n 1.5 ml of dry t e r t - b u t y l a l cohol was added 0.038 ml (0.17 mmol) of f r e s h l y d i s -t i l l e d diphenylphosphoryl azide and 0.024 ml (0.17 mmol) of dry t r i -ethylamine. The r e s u l t i n g s o l u t i o n was refluxed for 18 h, cooled to room temperature and poured into water. This s o l u t i o n was thoroughly extracted with ether and the combined organic phase was washed with water and brine. The ether extracts were dried over anhydrous sodium su l f a t e and evaporated i n vacuo y i e l d i n g the crude product as a brown gum. This material was p u r i f i e d by preparative t i c (25% e t h y l acetate i n benzene) affording 14 mg (19%) of the ester (114) as a pure [ t i c , *H nmr, g l c (column A, 175 °C)], c o l o r l e s s gum and 31 mg of a mixture which contained some of the desired carbamate (113) as judged by i r , ms and *H nmr analyses. The ester (114) gave the following s p e c t r a l data: i r (film) v 1722, 1100, 1042 cm"1; JH nmr 8 0.70 (s, 3H, keta l methyl), 1.18 max ' ' ' ' J ' y (s, 6H, k e t a l & angular methyls), 1.43 (s, 9H, -C(CH 3) 3>, 3.12-3.98 (m, 9H, k e t a l methylenes, -OCjL^CH^O-, & C^H), 3.37 (s, 3H, -OCH-j), 4.72, 4.78 (2d, 2H, J = 8 Hz, -0CH20-, AB quartet). Exact mass calcd. for C ,H,,07: 470.3243; found: 470.3211. 167. Preparation of the Isocyanate (106) NCO O M E M To a s o l u t i o n of 29 mg (0.066 mmol) of the carboxylic a c i d (102) dissolved i n 1 ml of dry t e r t - b u t y l alcohol was added 0.5 ml (0.074 mmol, 0.15 M) of a s o l u t i o n of f r e s h l y d i s t i l l e d diphenylphosphoryl azide i n dry t e r t - b u t y l a l c o h o l . The r e s u l t i n g s o l u t i o n was refluxed for 27 h. The mixture was cooled to room temperature and the solvent was evaporated y i e l d i n g a l i g h t brown s o l i d . This material was d i s -solved i n chloroform, f i l t e r e d and the solvent evaporated from the f i l t r a t e y i e l d i n g 40 mg of a c o l o r l e s s gum. P u r i f i c a t i o n of t h i s mat-e r i a l by preparative t i c (17% e t h y l acetate i n benzene) gave 13 mg (45%) of the isocyanate (106) as as c o l o r l e s s gum. The l a t t e r exhibited i r ( f i l m ) v 2265, 1105, 1035 cm"1; *H nmr 8 0.70, 1.20 (2s, 3H each, max k e t a l methyls), 1.07 (s, 3H, angular methyl), 1.28 (s, 6H, -C(CH 3) 2NC0), 2.26-2.64 (m, 2H, C 3H & C 5H), 3.20-3.86 (m, 9H, ketal methylenes, -0CH2CH20-, & C 6H), 3.41 (s, 3H, -OCH-j), 4.75, 4.81 (2d, 2H, J = 7 Hz, -0CH20-, AB quartet). Exact mass calcd. for C^H^NO^ 439.2933; found: 439.2933. 168. Preparation of the Ketal Carbamate (116) To a s o l u t i o n containing 525 mg (1.19 mmol) of the carboxylic acid (102), 0.39 ml (2.8 mmol) of dry triethylamine and 15 ml of dry t e t r a -hydrof uran was added two equivalents (0.33 ml) of d i e t h y l phosphoro-c h l o r i d a t e , dropwise at room temperature. The r e s u l t i n g cloudy solution was s t i r r e d for 4 h, f i l t e r e d r a p i d l y through c e l i t e and the f i l t r a t e was concentrated i n vacuo. The r e s i d u a l material was dissolved i n dry hexamethylphosphoramide (10 ml) and the res u l t a n t s o l u t i o n was added to a solution-suspension comprised of 1.1 g (16.9 mmol) of dry, r e c r y s t a l -l i z e d sodium azide i n 20 ml of dry hexamethylphosphoramide. The r e s u l t -ing mixture was s t i r r e d for 15 h at room temperature and poured into cold, d i l u t e aqueous sodium bicarbonate. This mixture was thoroughly extracted with ether and the combined ethereal extracts were washed with water and brine and dried over sodium s u l f a t e . Evaporation of the solvents, followed by subjection of the residue to high vacuum for approximately 1 h, gave a pale yellow o i l . This material displayed c h a r a c t e r i s t i c a c y l azide absorptions i n the i r spectrum at 1712 and 2155 cm"1. The o i l was dissolved i n 20 ml of dry toluene and the resultant s o l u t i o n was heated at r e f l u x for 3 h. The solution was cooled to room temperature and the solvent was removed jLn vacuo y i e l d i n g a viscous, 169. pale yellow o i l . This material exhibited an intense absorption (2280 cm i n i t s i r spectrum c h a r a c t e r i s t i c of an isocyanate f u n c t i o n a l i t y and showed a complete absence of any absorptions c h a r a c t e r i s t i c of an ac y l azide. Dry methanol (20 ml), containing one drop of 1,5-diazabicyclo-[4.3.0]non-5-ene (DBN), was added to the o i l and the r e s u l t i n g s o l u t i o n was s t i r r e d at room temperature for 1.75 h, followed by 1.5 h at r e f l u x . Evaporation of the solvent gave 611 mg of an almost c o l o r l e s s , viscous gum. This material was placed under high vacuum for 24 h affording 545 mg (97%) of the ke t a l carbamate (116) which was pure by *H nmr, t i c and gl c (column A, 180 °C; column B, 190 °C) analyses. The l a t t e r compound exhibited the following s p e c t r a l data: i r (CHC1 3) v m a x 3440, 1722, 1110, 1040 cm"1; *H nmr 8 0.72, 1.20 (2s, 3H each, ket a l methyls), 1.06 (s, 3H, angular methyl), 1.24 (s, 6H, -C(CH 3) 2NHC0 2CH 3), 2.24-2.56 (m, 2H, C 3H & C 5H), 3.12-4.00 (m, 9H, ketal methylenes, -OCH2CH20-, & CgH), 3.41 (s, 3H, -0CH 2CH 20CH 3), 3.62 (s, 3H, -C0 2CH 3), 4.60 (broad s, IH, -NHC0 2CH 3), 4.74, 4.80 (2d, 2H, J = 7 Hz, -0CH20-, AB quartet). Exact mass calcd. for C„ CH.-NO-: 471.3196: found: 471.3213. 25 45 7 Preparation of the Carbamate Alcohol (124) A s o l u t i o n of 263 mg (0.56 mmol) of the ketal carbamate (116) i n 10 170. ml of dry methylene chloride was cooled to 0 UC. A solution of titanium t e t r a c h l o r i d e i n methylene chloride (0.37 ml, 1.5 1^) was added and the r e s u l t i n g mixture was s t i r r e d for 1.5 h. Concentrated ammonium hydrox-ide (10 drops) was added and the re a c t i o n mixture was poured into aque-ous sodium bicarbonate. This s o l u t i o n was extracted with f i v e portions of methylene chloride and the combined organic extracts were washed suc-ce s s i v e l y with water and brine. The dried (sodium sulfate) s o l u t i o n was concentrated under reduced pressure giving a pale yellow gum. Subjec-t i o n of t h i s material to high vacuum for 16 h at ambient temperature, afforded 172 mg (80%) of the carbamate alcohol (124) as an off-white foam which was pure by t i c , 1H nmr and g l c (column A, 190 °C) analyses. The carbamate alcohol (124) gave the following spectral data: i r (CHCl^) v 3620, 3450, 1720, 1706, 1509 cm"1; ltt nmr 8 1.16, 1.21 (2s, 3H max ' each, -C(CH 3) 2NH-), 1.41 (s, 3H, angular methyl), 3.60 (s, 3H, -0CH 3), 3.96 (broad s, IH, C 6H), 4.53 (broad s, IH, -NH-). Exact mass calcd. for C.,H„-,N0.: 297. 1940; found: 297. 1938. 16 27 4 Attempted trans-Ketalization of the Ketal Carbamate (116):  Preparation of the Keto Carbamate (123) To a s o l u t i o n of 23 mg (0.049 mmol) of the keta l carbamate (116) i n 4 ml of dry a c e t o n i t r i l e was added 0.073 ml (0.73 mmol) of 1,3—propane— 171. d i t h i o l followed by 0.1 equivalents of f r e s h l y d i s t i l l e d boron t r i f l u o r -ide etherate i n dry a c e t o n i t r i l e (0.1 ml, 0.07 M). The reaction mixture was s t i r r e d at ambient temperature i n a fume cupboard for 41 h. The s o l u t i o n was poured into 2% aqueous sodium hydroxide and the r e s u l t i n g s o l u t i o n was thoroughly extracted with ether. The combined ethereal extracts were washed successively with 2% aqueous sodium hydroxide, water and brine and dried over anhydrous sodium s u l f a t e . Evaporation of the solvents under reduced pressure afforded 16 mg (85%) of the keto carbamate (123) as the sole product [glc (column A, 190 °C) t i c , *H nmr]. This substance exhibited the following spectral data: i r (CHCl^) v 3447, 1723, 1701, 1505, 1100, 1045 cm - 1 ; *H nmr S 1.17, 1.20 (2s, max 3H each, -C(CH_3) 2NH-), 1.33 (s, 3H, angular methyl), 3.42 (s, 3H, -0CH 2CH 20CH 3), 3.50-3.98 (m, 5H, -OCH^jL/)- & C 6H), 3.62 (s, 3H, -NHC02CH_3), 4.51 (broad s, IH, -NH-), 4.81, 4.88 (2d, 2H, J = 7 Hz, -OCH^O-, AB quartet). Exact mass calcd. for c 2 o H 3 5 N 0 6 : 385.2464; found: 385.2449. Preparation of the Carbamate Dione (128) To a cold (0 °C) s o l u t i o n containing 10 ml of dry methylene c h l o r -ide and 0.26 ml (3.2 mmol) of dry pyridine was added 160 mg (1.6 mmol) of chromium t r i o x i d e . The r e s u l t i n g red s o l u t i o n was s t i r r e d at 0 °C for 15 min and subsequently warmed to room temperature and s t i r r e d for a 172. further 45 min. A solution of the carbamate alcohol (128) (79 mg, 0.26 mmol) in 4 ml of methylene chloride was added i n one portion and the rea c t i o n mixture was s t i r r e d at room temperature for 30 min. The sol u -t i o n was f i l t e r e d through glass wool and the s o l i d residue was washed with two portions of ether. The residue was dissolved i n 5% aqueous sodium hydroxide and the r e s u l t i n g s o l u t i o n was thoroughly extracted with ether. The ethereal extracts were then combined with the f i l t r a t e and the resultant s o l u t i o n was washed successively with 5% aqueous sodium hydroxide, water and brine. The dried (sodium sulfate) organic phase was evaporated under reduced pressure y i e l d i n g 64 mg (81%) of the desired dione (128) as a pure [ t i c , g l c (columns A & B, 190 °C)], c o l o r -l e s s gum; i r (CHC1.) v 3450, 1715 cm - 1; *H nmr S 1.14, 1.18, 1.21 J in sx (3s, 3H each, t e r t i a r y methyls), 3.59 (s, 3H, -0CH_3), 4.65 (broad s, IH, -NHCO-CH,). Exact mass calcd. for C,,Ho,N0.: 295.1781; found: 295.1761. — 2 3 16 25 4 Preparation of the Ketal Amine ( 1 3 8 ) /NX N H 2 O M E M To a s t i r r e d s o l u t i o n of the carboxylic a c i d (102) (125 mg, 0.28 mmol) i n dry tetrahydrofuran (8 ml) at room temperature, was added dry triethylamine (0.086 ml, 0.62 mmol) followed by a so l u t i o n of d i e t h y l chlorophosphate (0.073 ml, 0.48 mmol) i n 1 ml of tetrahydrof uran. The so l u t i o n was s t i r r e d at room temperature for 4 h and then r a p i d l y f i l -173. tered through c e l i t e . The f i l t r a t e was concentrated i n vacuo and the r e s u l t i n g o i l was dissolved i n dry hexamethylphosphoramide (4 ml). This s o l u t i o n was immediately added to a s l u r r y of dry sodium azide (0.26 g, 3.9 mmol) i n 10 ml of hexamethylphosphoramide and the reaction mixture was s t i r r e d at room temperature for 16 h. Cold (0 °C), d i l u t e aqueous sodium bicarbonate was then added and the r e s u l t i n g mixture was thorough-l y extracted with ether. The combined extracts were washed with brine and dried over anhydrous sodium s u l f a t e . Removal of the solvent gave the acyl azide (105) as a pale yellow o i l [ i r (film) v 2155, 1712, 1116, 1040 cm" 1]. A sol u t i o n of the crude a c y l azide (105) i n 10 ml of dry toluene was heated at r e f l u x for 3 h. The reac t i o n mixture was cooled and the solvent was removed af f o r d i n g 115 mg of the isocyanate (106) as a v i s -cous, pale yellow o i l [ i r (f i l m ) v m a x 2264, 1108, 1040 cm" 1]. A portion of the crude isocyanate (106) (47 mg, 0.11 mmol) was dissolved i n 2 ml of p-dioxane and 3 ml of 2N aqueous sodium hydroxide was added. The r e s u l t i n g s o l u t i o n was heated at r e f l u x for 3 h and then cooled to room temperature. The reaction mixture was poured into water and the r e s u l t i n g mixture was thoroughly extracted with ether. The combined ether layers were washed with water, with brine and dried over anhydrous sodium s u l f a t e . Removal of the solvent afforded 34 mg (83%) of the ke t a l amine (138) as a c o l o r l e s s gum. An a n a l y t i c a l sam-ple of th i s material, obtained by preparative t i c (30% cyclohexane i n et h y l acetate), exhibited i r (film) v 3450, 1116, 1040 cm"1; *H nmr max ' S 0.70 (s, 3H, ketal methyl), 1.04 (s, 9H, angular methyl & -C(CH 3) 2NH 2), 1.19 (s, 3H, k e t a l methyl), 1.95 (s, 2H, -NH_2), 3.08-3.86 (m, 9H, ketal 174. methylenes, -0CH2CH20-, & CgH), 3.40 (s, 3H, -0CH 3), 4.74, 4.80 (2d, 2H, J = 7 Hz, -0CH20-, AB quartet). Exact mass calcd. for C^H^NO^ 413.3141; found: 413.3164. 175. BIBLIOGRAPHY 1. L. Aikman, "Nature's G i f t s to Medicine", Journal of the National Geographic Society, 420, 1974. 2. S. Ito, i n "Natural Products Chemistry", ed. K. Nakanishi, T. Goto, S. Ito, S. Natori, and S. Nozoe, Academic Press, New York, 1975, Vol. 2, p. 255. 3. J.E. Saxton, i n "The A l k a l o i d s " , ed. M.F. Grundon, ( S p e c i a l i s t P e r i o d i c a l Reports), The Chemical Society, London, 1978, Vol. 8. 4. "The Total Synthesis of Natural Products", ed. J. 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It has been said that 99% pure by glc means: "when the substance was introduced into a c e r t a i n glc column, i n c e r t a i n conditions of gas flow and temperature, 99% of the integrated response of a recorder to that portion of the substance or i t s impurities or decomposition products that reached and affected the detecting device i n the time available was exhibited as a single peak." J.W. Cornforth i n a Robert Robinson lecture e n t i t l e d "The Logic of Working with Enzymes", [Quart. Rev., 1, 1973]. 

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