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Synthetic studies towards the tetracyclic diterpenoids aphidicolin and stemodin Herbert, David John 1979

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SYNTHETIC STUDIES TOWARDS THE TETRACYCLIC DITERPENOIDS APHIDICOLIN AND STEMODIN by DAVID JOHN HERBERT B.Sc, University of British Columbia, 1971 M.Sc, University of British Columbia, 1974 A THESIS SUBMITTED IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY in THE FACULTY OF GRADUATE STUDIES (Department of Chemistry) We accept this thesis as conforming to the required standard THE UNIVERSITY OF BRITISH COLUMBIA September, 1979 © David John Herbert, 1979 In p r e s e n t i n g t h i s t h e s i s i n p a r t i a l f u l f i l m e n t o f the r e q u i r e m e n t s f o an advanced deg ree a t the U n i v e r s i t y o f B r i t i s h C o l u m b i a , I a g r e e tha t the L i b r a r y s h a l l make i t f r e e l y a v a i l a b l e f o r r e f e r e n c e and s t u d y . I f u r t h e r ag ree t h a t p e r m i s s i o n f o r e x t e n s i v e c o p y i n g o f t h i s t h e s i s f o r s c h o l a r l y p u r p o s e s may be g r a n t e d by the Head o f my Depar tment o r by h i s r e p r e s e n t a t i v e s . I t i s u n d e r s t o o d t h a t c o p y i n g o r p u b l i c a t i o n o f t h i s t h e s i s f o r f i n a n c i a l g a i n s h a l l not be a l l o w e d w i t h o u t my w r i t t e n p e r m i s s i o n . r Department o f The U n i v e r s i t y o f B r i t i s h C o l u m b i a 2075 Wesbrook Place Vancouver, Canada V6T 1W5 6 i i ABSTRACT The work described in this thesis i s concerned with the develop-ment of a general synthetic approach to the tetracyclic diterpenoids aphid-i c o l i n J} and stemodin j). This novel class of diterpenoids has to date been represented by aphidicolin and stemodin j). Although these materials contain different substituents, they do possess remarkably similar carbon skeletons. This work began with the transformation of the Wieland-Miescher ketone 4f>, using a six-step sequence, into the bicyclic ketal ketone 45. The conversion of this material into the next key intermediate, the t r i -cyclic ketal enone 44^was accomplished i n two manners. The f i r s t approach made use of, as the key reaction, the internal Wittig-Horner cyclization ©f the P,e-diketo phosphonate 108 to the desired enone 44 while the second proposal involved the aldol condensation of the bicyclic diketone 131 to the desired enone 44. This second pathway was i n i t i a l l y explored by means of a model system. The g,e-diketo phosphonate 108 was prepared in the following manner. Alkylation of the enolate of 45 with methyl iodoacetate gave the keto ester 105. Saponification of the ester 105 gave the acid 123 which was converted into the corresponding acyl chloride and treatment of this material with the anion of dimethyl methylphosphonate gave the desired 6 ,E-diketo phosphonate 108. The bicyclic diketone 131 was prepared as follows. Alkylation of the enolate of the bicyclic ketone 4_5 with methallyl iodide gave the keto olefin 130 and oxidative cleavage of the olefinic double bond in 130 using i i i osmium tetraoxide and sodium meta-periodate gave the bicyclic diketone 131. The next phase of this work dealt with the construction of the tetracyclic ketones j>5 and 6£, possessing the basic tetracyclic carbon skeletons of aphidicolin JB and stemodin 9_ respectively. The proposed syn-thetic pathway to these materials i s discussed but only partially realized during the scope of this work. The photochemically induced addition of allene to the enone 44_ gave the photoadducts 5j> and 57_. The keto olefins 56 and 57_ were transformed into the keto esters 5j) and 133, obvious pre-cursors to the tetracyclic ketones S5 and 60. iv TABLE OF CONTENTS Page TITLE PAGE i ABSTRACT i i TABLE OF CONTENTS iv LIST OF FIGURES v ACKNOWLEDGEMENTS v i INTRODUCTION I General 1 II Isolation and Structural Elucidation of Aphidicolin 5 and Stemodin III Previous Syntheses of Aphidicolin 8 DISCUSSION I The Development of the Basic Synthetic Strategy 16 II Synthesis of the Tricyclic Keto Esters ^ 1 and 62 25 A. Preparation of the Tricyclic Enone 63_ 26 B. Conversion of the Enone 63_ into the Tricyclic Keto Esters 61 and 62 40 III Synthesis Directed Toward the Aphidicolane Class of Tetracyclic Diterpenoids 48 A. Synthesis of the Ketal Ketone 45 49 B. Conversion of the Ketal Ketone 45_ into the Tricyclic Ketal Enone 44 50 C. Conversion of the Enone 44_ into the Tricyclic Keto Esters 59 and 133 78 EXPERIMENTAL 89 BIBLIOGRAPHY 131 V LIST OF FIGURES Page Figure 1 The ^nmr Spectrum of the Tricyclic Enone 63_ 37 2 The ^nmr Spectrum of the Tricyclic Enones 63 and 83_ 38 v i ACKNOWLEDGEMENTS I would like to express my sincere thanks to Dr. E. Piers for his guidance and aid during the course of this work. His a b i l i t y as a teacher and his kindness as a friend w i l l never be forgotten. I would also like to thank the many members of Dr. Piers' research group, past and present, for their understanding friendships. Special thanks must be extended to D. Shunamon for her prompt and efficient typing of this manuscript. I also wish to thank Mr. Howard Morton and Ms. Carol Montgomery for proof reading the thesis. 1 INTRODUCTION I. General The art of obtaining the e s s e n t i a l o i l s of many fragrant plants and flowers has been practised f o r centuries. Early i n v e s t i g a t o r s found that many of these o i l s contained one or more of a series of isomeric unsaturated hydrocarbons having the empirical formula C 1 0 H 1 6 . These hydrocarbons came to be known as terpenes from t h e i r association with o i l of turpentine. With the discovery of oxygenated derivatives of these terpenes, along with the ex-pansion of t h i s f i e l d of chemistry to embrace a wider variety of substances, many not of natural o r i g i n , the term terpenoids has come to be preferred. Terpenoids are pr i m a r i l y c l a s s i f i e d according to the number of s basic isopentane units i n the molecule. Thus, the monoterpenoids contain two uni t s , the sesquiterpenoids three units, the diterpenoids four units, the sesterpenoids f i v e u n i t s , the triterpenoids s i x un i t s , and the higher ana-logues, the polyterpenoids, contain more than s i x units. Secondary c l a s s i f i -cations of the terpenoids depend on the number and siz e of any rings i n the molecule and on the type of fu n c t i o n a l groups present. The t e t r a c y c l i c diterpenoids form a large group of plant and fungal products which are a l l derivable i n p r i n c i p l e from the c y c l i z a t i o n of geranyl-geraniol _1 (possibly as i t s pyrophosphonate 2^ ). The major pathway leading to 2 2 the various p o l y c y c l i c carbon skeletons appears to lead i n i t i a l l y to the b i c y c l i c diterpenoids. C y c l i z a t i o n of these b i c y c l i c systems leads to the t r i c y c l i c diterpenoids and further c y c l i z a t i o n of these materials leads to the t e t r a c y c l i c systems. The t e t r a c y c l i c diterpenoids, although widespread i n nature, have been shown to possess carbon skeletons that are quite s i m i l a r . The struc-t u r a l s i m i l a r i t y between the kaurane _3, beyerane b_ and atisane 5_ classes has been r a t i o n a l i z e d i n terms of t h e i r biosynthesis from a common t r i c y c l i c pre-cursor belonging to the primaradiene 6^  class of t r i c y c l i c diterpenoids."'" The gibbane ]_ class of t e t r a c y c l i c diterpenoids owes i t s s t r u c t u r a l s i m i l a r i t y to these other classes of diterpenoids through i t s formation v i a a rearrangement 3 of the basic kaurane 3_ skeleton." 3—6 Recently, several papers have appeared i n the l i t e r a t u r e des-c r i b i n g the i s o l a t i o n and s t r u c t u r a l e l u c i d a t i o n of a number of compounds possessing a novel t e t r a c y c l i c carbon skeleton. Two of these compounds, aphidi-3-4 5 c o l i n and stemodin 9_, represent a new class of t e t r a c y c l i c diterpenoids, 4 the aphidicolanes, whose basic carbon skeleton along with the proposed number-ing system, i s shown i n s t r u c t u r a l formula 10. 17 19 10 4 The i n t e r e s t i n these compounds stems not only from the synthetic challenge t h e i r novel and complex structures present to the organic chemist, 3 but also from the a n t i v i r a l a c t i v i t y displayed by a p h i d i c o l i n 8. For these reasons, the work described i n t h i s thesis was directed toward the development of a st e r e o s e l e c t i v e synthetic approach leading to the synthesis of these novel t e t r a c y c l i c diterpenoids. 5 II . Isolation and Structural Elucidiation of Aphidicolin and Stemodin Aphidicolin J5, a new antiviral diterpenoid, was isolated by Hesp 3 4 and co-workers ' from culture f i l t r a t e s of the fungus Cephalosporium aphidi- cola Petch. An examination of the infrared and 1Hnmr spectra of this material, along with the results of a series of chemical transformations on the parent compound, led these workers to propose the alternate structures 11^  and 12 for aphidicolin. CH2OH CH2OH CH2OH 11 12 In order to obtain an unambiguous structure for aphidicolin, an X-ray 3 study of the bis-acetonide derivative 1^3 was undertaken. The results of these investigations, coupled with collaborative chemical and physical evidence, led to structure 1_1 being assigned to aphidicolin. This study also allowed these workers to assign the relative stereochemistry of the various substituents and thus structure J5 fully represents aphidicolin. 6 13 8. Stemodin 9^, another diterpenoid containing an unusual tetracyclic carbon skeleton, was isolated by Manchand e_t al."* from leaf extracts of the rare l i t t o r a l plant Stemodia maritima L. (Scrophulariaceae) obtained from the Palisadoes peninsula of Jamaica. The structural elucidation of the novel stemodin ring structure was effected by means of a single-crystal X-ray analysis of the diterpenoid stemo-dinone 14 obtained from a less polar fraction of S. maritima L. 7 The r e l a t i o n s h i p between stemodinone and stemodin 9_ was c l e a r l y demonstrated by the oxidation of the l a t t e r to stemodinone. The stereo-chemistry of the C-2 hydroxyl group was assigned using ^nmr s p e c t r a l e v i -dence. 8 III. Previous Syntheses of Aphidicolin At the outset of this work, the literature contained no reports of previous work directed toward the syntheses of aphidicolin or stemodin. 7 8 Quite recently, however, Trost eit a_l. and McMurry et a l . have each pub-lished a total synthesis of aphidicolin and a brief discussion of each of these syntheses i s in order. Since the keto acetonide _15 (obtained by degradation of aphidi-3 colin ) had already been reconverted into aphidicolin, both research groups chose this material as their target molecule. The similarity between their approaches extended not only to their choice of target molecule but also to their choice of starting material, compound 16_. Furthermore, both groups chose a very similar synthetic route for the preparation of the AB ring system of aphidicolin. 15 16 This synthetic work, involving the conversion of the diketone _16 into the bicyclic keto acetonide _21, was accomplished in the following manner. 9 Selective ketalization of the diketone 16^ at the saturated ketone functionality gave the bicyclic ketal 1_7_ which, when reductively 9 hydroxymethylated using the procedure developed by Stork, gave compound 1_8 (eq. 1). 1) L i , NH3 2) H2C0 4 (1) 16 17 CH 2OH 18 The stereoselective reduction of the keto group of _18 to afford the ketal diol 19 (eq. 2) was accomplished by Trost^ using the "ate" complex generated In situ from freshly prepared tert-butyllithium and diisobutyl-10 8 aluminium hydride while McMurry used lithium tri-sec-butylborohydride TM (L-Selectride ) to reduce the keto group. i H CH 2OH L-Selectride HO' CH 2 OH (2) 18 19 10 The keto acetonide 21 was prepared by McMurry" in a one step procedure by treatment of the ketal diol _19 with acetone in methylene chloride containing a catalytic amount of p_-toluenesulfonic acid (eq. 3) . The same material was obtained by Trost^ who chose to hydrolize the ketal group in a separate step and then form the acetonide derivative via a subsequent trans-formation. It was in the construction of the CD ring system of aphidicolin that these two groups of workers differed dramatically in their synthetic approaches. Trost and co-workers^ chose to form the C ring via their cyclo-pentanone annulation procedure. x x Thus, condensation of the keto acetonide 21 with phenylsulfonium cyclopropylide A i under reversible ylide generation conditions gave the oxaspiropentane 22_ which upon treatment with sodium 12 phenylselenide gave the alkylidenecyclopropanol 23_ (eq. 4). Flash vacuum 11 21 22 23 (4) pyrolysis of the trimethylsilyl ether of this material (compound 24, eq. 5) gave a 2:1 mixture of the t r i c y c l i c s i l y l enol ethers 2_5 and 26^ , with the major isomer _25 having the undesired stereochemistry at C-8. To circumvent this problem, the mixture of 25 and 26 was oxidized [Pd(0Ac)2, CH3CN] to the enone 26a. Reduction of the material with lithium in ammonia, followed by quenching the intermediate enolate anion with chlorotrimethylsilane gave the single s i l y l enol ether 2_6 (eq. 6). Generation of the enolate, by treatment of the s i l y l enol ether 2b_ with n-butyllithium and subsequent quenching of 12 TMSO 25,26 26(a) 26 (6) this enolate 26b with a l l y l iodide gave as the major product, in 35% yield, the keto olefin 27 (eq. 7). The remaining steps in the synthesis, involving TMSO 26 • H 26(b) H (7) 27 the formation of the D ring, were rather straightforward. Hydroboration of the keto olefin 2_7 using monothexylborane gave, after oxidation of the intermediate alkylborane, the keto alcohol 28. Oxidation of this material, using pyridinium 13 chlorochromate gave the keto aldehyde 29^ (eq. 8) which was directly c y c l i -zed to give a 3:7 mixture of the tetracyclic keto alcohols 30 and 31. 13 (8) This mixture of alcohols was converted into their corresponding tetrahydro-pyranyl ether derivatives _32 and 3_3 prior to reduction of the carbonyl moiety under Wolff-Kishner conditions. Removal of the tetrahydropyranyl blocking 13 group and oxidation of the resulting mixture of alcohols 3_4 and _3_5 gave the keto acetonide 15_ (eq. 9). 29 30 + 31 R = H 32+33 R = THP 34 + 35 (9) 14 McMurry approached the formation of the CD ring system of aphi-dicolin in a very different manner. The C ring system was again formed f i r s t but in this case i t was accomplished via an aldol type condensation of the diketone 3_7. This material was prepared in two steps. Treatment of the enolate anion generated from (lithium diisopropylamide) the keto acetonide 21^  with methallyl iodide gave the keto olefin 3_6. Oxidative cleavage of the olefinic bond of 3_6_ using a trace of osmium tetroxide and sodium meta-periodate furnished the diketone _3_7. This material was smoothly cyclized to the t r i -cyclic enone 3_8 using sodium hydride in refluxing benzene containing a trace of tert-amyl alcohol (eq. 10). 38 The construction of the D ring proved to be more challenging. Stereoselective reduction of the keto group of 3_8, using lithium aluminium 15 hydride, gave a single alcohol 39^ which was converted into i t s corresponding vinyl ether 40_ using mercuric acetate and ethyl vinyl ether (eq. 11). 38 39 40 Pyrolysis of this material gave the Claisen rearrangement product, the ole-fi n i c aldehyde 41, but only in low yield (20%). In order to knit the D ring together, the olefinic aldehyde kl_ was f i r s t reduced with lithium aluminium hydride and the resulting alcohol 42 was converted into the corresponding tosylate 4_3. Treatment of this tosylate with disodium tetracarbonylferrate"*" produced the desired keto acetonide 15 (eq. 12) but once again, the reaction gave only a low yield (30%) Q f product. (12) 15 16 DISCUSSION I. The Development of the Basic Synthetic Strategy In the construction of complex diterpenoids such as aphidicolin j5 or stemodin _9, a number of synthetic approaches are possible. Usually, two factors are involved in the formulation of a synthetic route. These factors are the sequence in which the various substituents or functional groups are introduced and the order in which the rings forming the basic carbon skeleton are constructed. In many cases, the best approach to take when considering these factors is to formulate a synthetic route which allows for the forma-tion of the basic carbon skeleton to take precedence. The synthetic plan obtained in this manner i s then modified to allow for the introduction of the various substituents and functional groups. 8 9 44 An analysis of the carbon skeletons of these two diterpenoids, bearing in mind that the object of this work was the development of a general synthetic route to both these complex structures, suggested that a t r i c y c l i c intermediate such as 44^  best suited our requirements. Such an intermediate 17 contains a masked ketone suitably located to allow for the elaboration of the A ring of aphidicolin j5 or stemodin 9_ and an a,B-unsaturated ketone in the C ring which we f e l t could be manipulated to allow for the introduc-tion of the remaining carbocyclic ring. Thus, from the choice of a single key intermediate, a basic syn-thetic plan was formulated. The i n i t i a l phase of this plan involved the preparation of the key intermediate 44. The next phase of the plan dealt with the completion of the basic tetracyclic carbon skeletons while the f i n a l phase of the plan was concerned with the elaboration of the functional groups on the A and D rings of aphidicolin and stemodinRespectively. 1) Proposed Synthesis of the T r i c y c l i c Enone A4_ The synthesis of the t r i c y c l i c enone 44_ could be accomplished in a number of different ways. Recently, Ellison"''"' has surveyed the numerous available methods for the preparation of 3-oxocyclopentenes. This survey contained a number of basic approaches, including the cyclization of 1,4-diketones, the modification of dioxocyclopentanes and the direct introduction of oxygen into cyclopentadienes. Heathcock"^ has also reported the prepara-tion of a number of 3-oxocyclopentenes via the cyclization of various sub-stituted 3,e-diketo phosphonates. With this wealth of information available, i t was f e l t that the enone 44_ could be formed from the bicyclic ketone 45 (eq. 13) using one or another of the above procedures. 18 45 (13) The synthetic planning involved in the preparation of the ketone 45 was greatly facilitated by a search of the available chemical literature. 17-19 Considerable work, by a number of research groups, had been published on the overall transformation of the well-known and commercially available 20 19 Wieland-Miescher ketone 46_ into the keto alcohol 4^ 5. One such method is outlined below (eq. 14). Once the keto alcohol 4j$ was obtained, one can readily envisage i t s conversion into the desired ketone 45 by a two step 46 Li;NH3 47 48 (14) procedure. Protection of the carbonyl functionality as i t s corresponding ketal would give compound 49 which after oxidation with some suitable reagent should afford the desired ketone 45_ (eq. 15). 19 48 49 45 (15) 2) Proposed Synthesis of the Desired Tetracyclic Carbon Skeletons With the i n i t i a l phase of the basic synthetic strategy outlined, we then turned our attention toward the second phase of the plan, the comple-tion of the basic tetracyclic carbon skeletons. It was our intention to stereoselectively introduce a vinyl side chain at the B carbon of the a,j3-unsaturated carbonyl functionality present in compound 44_. With the intro-duction of the vinyl side chain accomplished, i t was then proposed to form 21-22 the D ring by the insertion of an "acyl anion equivalent" between the terminal carbon of the vinyl side chain and the carbon of the C ring bearing the carbonyl group. Such an insertion reaction would, of course, require the necessary functionalization of the vinyl side chain and the conversion of the carbonyl functionality into a suitable leaving group. One possible method of stereoselectively introducting a vinyl side chain into compound hh_ would be the conjugate addition of lithium divinyl-cuprate to the a,B-unsaturated ketone functionality present in 44_. An exami-nation of molecular models of 44^ along the assumption that the "cuprate" 20 reagent should attack the enone system from the less hindered side suggested that treatment of compound 44^  with lithium divinylcuprate would give the olefinic ketone 50_ (eq. 16) having an a oriented vinyl side chain. Hydro-(16) 44 50 boration of the olefinic linkage present in compound _50, followed by the stereoselective reduction of the carbonyl group in the resultant product _5_1 would give the diol 52_ (eq. 17). Treatment of the corresponding dimesylate 5 3 (or ditosylate ^ 4) derivative with methyl methylthiomethyl sulfoxide ' in the presence of a suitable base should afford, after appropriate hydrolysis of the resultant product, the desired tetracyclic system 55. 21 (18) 53 R=OMs 55_ 54 R=OTs If such a proposal were successful, then the same basic strategy could be adopted for the construction of an intermediate similar to compound 55 but possessing a D ring system of opposite relative stereochemistry at the bridgehead carbons C-9 and C-12. Such a proposal would be initiated by the introduction of a vinyl side chain (or some other suitable alternative) into compound 44_ to give a material possessing a g oriented side chain. While we were considering how to stereoselectively introduce a substituent at C-9 of the enone ^4 in either an a or a 8 sense, we were 23—26 intrigued by the reports in the literature concerning the photochemical addition of allene across a,6-unsaturated carbonyl systems. Although much of the published material was not concerned with the photochemical addition of allene to a,g-unsaturated carbonyl systems that were incorporated into a five membered carbocyclic ring, there was enough information available to suggest the f e a s i b i l i t y of such an approach. 22 I n i t i a l l y any prediction of the stereochemical outcome of such a reaction, with respect to the orientation of the newly formed cyclobutane ring, was hampered by the absence of any definitive guide in the literature. 23 It should be noted, however, that at least one author has proposed a general 25 rule which allowed him and some other authors to rationalize some of their results. In any event, the photochemical addition of allene to the t r i -cyclic enone 44^  would, i f successful, give tetracyclic products having the basic structure of either compound 56_ or 5_7, assuming that only head-to-head products are formed (eq. 19). (19) 44 56 57 This alternative proposal has several advantages over the previous one. For instance, i f only one photoadduct was obtained, for example, com-pound 56, this material could be transformed into compound 5_2 and then this material could be converted into the tetracyclic material _55 using the method-ology previously discussed. The transformation of compound 5_6_ into compound 5^  could be accom-plished in the following manner. Oxidative cleavage of the exocyclic double bond present in 5_6 with ozone and treatment of the resulting dione 5J3 with 23 sodium methoxide in methanol should provide the keto ester 59_ via opening of the cyclobutanone ring system. Reduction of the ester moiety to the corresponding primary alcohol functionality, along with the stereoselective reduction of the ketone carbonyl group, would result in the formation of the diol 52 (eq. 20). (20) 52 11 On the other hand, i f the only photoadduct obtained was compound 57, then use of a sequence very similar to that just described would result in the conversion of 5_7 into the tetracyclic compound 6_0 (eq. 21), an obvious synthetic precursor for stemodin. 2 4 (21) 57 60 One of the most important potential advantages of this synthetic proposal lay in the possibility of obtaining a mixture of photoadducts 56_ and 57. Such an occurrence, i f 5_6_ and 5_7 could be easily separated, would allow immediate entry in both the aphidicolin and stemodin ring systems (via 55 and 60, respectively). 3) Elaboration of the A and D Rings of Ketones 55 and .6J2 The f i n a l stage of the basic synthetic strategy, the elaboration of the functionality in the A and D rings, could be accomplished in a step-wise manner. The carbonyl group present in the D rings of 5_5 and 6>0, would serve as a handle to introduce the necessary functional groups. Indeed, for the aphidicolin system 5_5 such a series of transformations has already been reported. The construction of the A ring systems could be considered in the same light since hydrolysis of the ketal group present in the A ring would give a carbonyl group which once again could be used as a handle for the introduction of the required functionalities. 25 II . Synthesis of the Tricyclic Keto Esters 6_1 and 62 At the outset of this work, the preparation of the i n i t i a l key intermediate 44^  was anticipated to present no experimental problems. However, the key transformations in the proposed synthetic strategy, the conversion of this material into the tetracyclic ketal ketones j>5_ and 60_, were considered to be of a more challenging nature (eq. 22). 55 60 In view of these considerations, a suitable model, the t r i c y c l i c enone 6_3 was prepared and used to investigate the construction of the basic tetracyclic carbon skeletons possessed by 5_5 and 60. The t r i c y c l i c enone 6_3 was chosen as the model system for two reasons. F i r s t l y , such a system was very similar to the parent system 44 and thus would be expected to behave chemically in an analogous manner. Secondly, i t was f e l t that the methodology used in constructing such a model system would be readily adaptable for use in constructing the t r i c y c l i c ketal enone 44. 26 A. Preparation of the Tricyclic Enone 63 The description of the preparation of the t r i c y c l i c enone 63_ can be conveniently divided into two sections. The f i r s t section is concerned with the formation of the bicy c l i c ketone 6_4 and the second section deals with the transformation of this material into the enone 63. 27 1. Preparation of the Bicyclic Ketone 6_4_ The synthetic pathway leading to the ketone 64*"' was greatly fac i l i t a t e d by a search of the chemical literature. A large number of work-17 19 28 29 ers ' ' ' have reported the preparation of the bicyclic ketol 48^  and 17 this material has been reduced to give the bicyclic alcohol 65_. This alco-hol could then be oxidized to the desired ketone 6_4. Using this approach and 17 19 28-31 drawing upon the chemical literature ' ' the following plan for the synthesis of the ketone 6_4 was formulated (Scheme I) . OTHP OTHP 48 NH2NH2,KOH 65 C5H5NCr03-HCl, 64 SCHEME I 27 Reduction of the enone 66_ (prepared from the Wieland-Miescher 20 30 31 ketone 6^_ using published procedures ' ) was accomplished with lithium in liquid ammonia using ether as a cosolvent and dry ethanol as a proton source. The crude reaction product was oxidized with pyridinium chloro-13 * chromate and after suitable work-up, the bicyclic ketone 67_ was isolated 28 29 in 83% yield. The physical and spectral properties of this material were in accord with i t s proposed structure and were similar to those reported in the literature. 31 Acid catalyzed methanolysis of this material removed the tetra-hydropyranyl ether protecting group and gave the bic y c l i c ketol 48^  in 88% yield. The physical and spectral properties of this material were in accord with i t s proposed structure and were similar to those reported in the l i t e r -ature. 32 The bicyclic ketol 4*8 was reduced using the Huang-Minion modifi-cation of the Wolff-Kishner procedure to give the desired alcohol 65_ in 94% yield. The physical and spectral properties of this material were similar to those reported in the l i t e r a t u r e . ^ Oxidation of the alcohol 6_5 using a suspension of pyridinium 13 chlorochromate and sodium acetate in methylene chloride gave the desired 27 bicyclic ketone 64^  in 84% yield. The i r spectrum of this material showed a strong absorption at 1710 cm 1, characteristic of a six-membered ring ketone, while the JHnmr spectrum showed a three-proton singlet at 6 1.08 which was assigned to the tertiary bridgehead methyl. For the sake of simplicity, mixtures of isomers resulting from the asymmetry of the tetrahydropyranyl group w i l l be referred to as one compound. 28 Since i t was anticipated that substantial quantities of the bicyclic ketone 6_4 would be required to complete the synthesis of the model system 6_3, a shorter and more productive route to this material from the Wieland-Miescher ketone 46_ was investigated. It i s clear that in the sequence described above, several of the steps used in our i n i t i a l approach dealt with the "protection" of the saturated carbonyl group prior to reduction of the enone system. A shorter route might therefore be found i f a better system for the protection of this carbonyl group were found. This problem was solved by the use of the corres-ponding ketal derivative 6_8 of the enone 46_ and a four-step sequence leading to the ketone bk_ was developed (Scheme II) . 1*1 K SCHEME II 29 The f i r s t step in this alternate route was the preparation of * the monoketal 6_8. This was accomplished in 89% yield by treatment of the dione 46 with 2,2-dimethyl-l,3-propanediol and p_-toluenesulfonic acid in refluxing benzene. The structure of the monoketal 6_8, a crystalline solid (mp 100-102° C) , was confirmed by i t s spectral data. A strong absorption band at 241 nm (e = 18,200) in the uv spectrum and two strong bands at 1680 and 1610 cm-1 in the i r spectrum of this material indicated the presence of an a,B-unsaturated carbonyl functionality. The single olefinic proton a to the carbonyl group gave rise to a doublet (J = 2 Hz) at 6 5.89 in the xHnmr spectrum, while the three tertiary methyl groups gave rise to three three-proton singlets at 6 0.82, 1.17 and 1.27. The lithium-ammonia reduction of the a,B-unsaturated carbonyl group present in compound 6j5 gave as expected, the ketal ketone 6_9 in 79% yield. The i r spectrum of this material indicated that i t contained a six-membered ring ketone (Y 1710 cm-1) while the presence of the ketal moiety ° max was confirmed by the JHnmr spectrum. The three tertiary methyl groups present in the molecule gave rise to two signals i n the 1Hnmr spectrum, a three-proton singlet at <5 0. 70 and a six-proton singlet at 6 1.13. The bicyclic ketal 70. was obtained in 77% yield from the ketal ketone 69^ by reduction of the carbonyl group using a solution of potassium 32 hydroxide and hydrazine in refluxing diethylene glycol. The i r spectrum of the product showed no absorptions in the region characteristic of a car-bonyl group while the H^nmr spectrum exhibited three three-proton singlets * The saturated carbonyl group of 46_ has been ketalized using ethylene glycol by Corey e_t a l . 3 30 at 6 0 . 6 8 , 0 .92 and 1.16 which were r e a d i l y assigned to the t e r t i a r y bridge-head methyl group and the two t e r t i a r y methyl groups present i n the keta l moiety of 70. The hydrolysis of the k e t a l group was effected by tr e a t i n g a s o l u t i o n of the k e t a l 7_1 i n tetrahydrofuran with d i l u t e aqueous hydrochloric acid. The ketone bk_ obtained i n t h i s manner was i d e n t i c a l i n a l l respects to the material reported e a r l i e r . Thus, the ketone 6J+ was now av a i l a b l e i n 43% o v e r a l l y i e l d i n four steps from the Wieland-Miescher ketone 46 . Although the o v e r a l l y i e l d of t h i s second sequence was a l i t t l e lower than that of the f i r s t method, the reduction i n the t o t a l number of steps required resulted i n the saving of s u b s t a n t i a l amounts of both time and reagents. 2. Conversion of the B i c y c l i c Ketone 6_4_ i n t o the T r i c y c l i c Enone i i i With the b i c y c l i c ketone 6A_ i n hand, the conversion of t h i s mater-i a l i nto the t r i c y c l i c enone J53 was investigated. Of the many possible ways of e f f e c t i n g t h i s o v e r a l l transformation, "^ those employing as the key step the a l d o l condensation of a 1 , 4-dicarbonyl system to i t s corresponding conjugated cyclopentenone d e r i v a t i v e seemed to be the most d i r e c t . Two exam-34 35 pies ' of the many to be found i n the l i t e r a t u r e are shown i n equations 23 and 24 . 31 (23) (24) 73 74 In order to pursue this approach, the ketone 64^  would f i r s t have to be converted into a suitable material containing a 1,4-dicarbonyl system. The means of accomplishing this task are outlined in equation 25. 64 75 76 Alkylation of the lithium enolate anion of (>4_ in tetrahydrofuran with methallyl chloride resulted in the formation of a mixture of products. The desired keto olefin _75 could be isolated (in yields from 36% to 60%) along with some dialkylated material (2% to 20%) and some starting material. 36 3 7 In an effort to improve this situation, the use of methallyl iodide ' as alkylating agent was investigated. Treatment of the lithium enolate anion of 6_4 in tetrahydrof uran at 0° C with methallyl iodide gave, after suitable work-up, the keto olefin 7_5 32 in 80% yield. This material, after d i s t i l l a t i o n , was not contaminated with any dialkylation product or with any starting material. The structure of the keto olefin 7_5 was confirmed by i t s spectral properties. The i r spec-trum of this material exhibited absorptions at 3110, 1705 and 1635 cm--*- which were attributed to the stretching vibrations of the olefinic C-H bonds, the six-membered ring carbonyl group and the disubstituted olefinic double bond, respectively. The 1Hnmr spectrum showed the presence of a tertiary bridge-head methyl group and a vinyl methyl group which gave rise to three-proton singlets at 6 1.13 and 1.72 respectively. The two protons on the terminus of the unsaturated linkage resonated as one-proton multiplets centered at 6 4.64 and 4.72. The stereochemistry of the side chain (at C-8) was assigned the a configuration because, under the conditions the reaction was performed, this center would be epimerizable and thus the thermodynamically more stable product would be expected. If the keto olefin 7_5 were to contain a 8 oriented side chain, then this configuration would introduce a 1,3 diaxial interaction between the tertiary bridgehead methyl group and the newly introduced side chain. The diketone 7_6 was prepared by subjecting a solution of the keto olefin 7_5 in methylene chloride at -78° C to a stream of ozone, followed by reduction of the intermediate ozonide with dimethyl sulfide. The resulting dione 7_6_, obtained in 79% yield, exhibited the appropriate spectroscopic properties. The i r spectrum showed two strong carbonyl absorptions ( Y m a x 1714 and 1721 cm •'-) . The 1Hnmr spectrum of this material confirmed the pre-sence of two methyl groups. The bridgehead methyl group produced a three-proton singlet at 6 1.30 while the methyl group adjacent to the side chain 33 carbonyl group gave rise to a three-proton singlet at 6 2.32. The two methylene protons located at C - l ' of the diketone 76_ gave rise to a pair of doublets centered at 6 2.07 (J = 17 Hz, 4 Hz) and 6 2.91 (J = 17 Hz, 6 Hz). With the diketone 76_ in hand, the fi n a l steps in the preparation of the model systems, the cyclization of the diketone 76_ to the t r i c y c l i c enone 6_3, could be investigated. The base catalyzed aldol condensation of the diketone 7_6 followed by dehydration of the intermediate ketol 7_7_ should lead to the formation of the enone 6_3 (eq. 26). However, i t is possible that a number of other products could be formed in this reaction. These secondary T ^ 76 77 63 H (26) products would result from the base-catalyzed rearrangement of the enone 6_3 (see Scheme III). Since a l l these proposed products 6_3, 79_, 80, 82 and 83_ could be in equilibrium with one another, the actual product mixture, i f equilibrium were to occur, should reflect the relative thermodynamic stabi-l i t i e s of these materials. That is to say, the higher the relative thermo-dynamic stability of an individual species, the greater the percentage of the product mixture i t should represent. H 81 SCHEME III 35 On this basis, then, several of these possible products would appear to be relatively unstable and could be dismissed as possible products. Thus, compound 80, containing an out of conjugation olefinic double bond and compounds _79_ and 82_, the configuration of which would require the B ring of these materials to adopt a boat-like conformation would clearly be ther-modynamically less favourable than the enones 6J3 and 83. Thus, the aldol condensation of the diketone 7_6 might have been expected to give enone 83_ as well as enone 6^ 3. In order to reduce the possible equilibration df the i n i t i a l l y formed enone 63^ into enone 83_ (or any other material) the reaction was f i r s t carried out at low temperatures and in an aprotic solvent (to remove an obvious proton source). Treatment of an ether solution of the diketone _76_ at 0° C with 1.2 equivalents of potassium tert-butoxide for 45 min (optimum conditions for the best mass balance) gave a 30% yield of a 1:2 mixture of the diketone 7_6_ and the desired enone 6_3. The remaining portion of the reaction product was an unidentified yellow gum. In the hope of improving the mass balance of this reaction and of obtaining a product free of starting material, another series of experi-ments was carried out using a solvent system containing a small amount of a proton source (tert-butanol) and employing higher reaction temperatures. Using these new conditions (2 equivalents of base, a mixture of tert-butanol and ether, room temperature) the mass balance of the reaction was increased to 70%. However, the product of this reaction was shown to contain a mixture of the enones 6_3 and 83_ with the major product being the undesired isomer 83. Not only was the desired enone 63_ the minor product of this reaction, but i t also proved impossible, in our hands, to separate this mixture of enones. 36 The structures of enones 63_ and 83_, as well as the relative ratio of these materials in the product mixtures obtained from the above experiments, were based on their spectral properties. Two strong absorption bands at 1 6 9 0 and 1 6 0 6 cm--'- in the i r spectrum and a strong absorption band at 2 2 9 nm (e = 1 6 , 4 0 0 ) in the uv spectrum of the crystalline enone 63_ (mp 7 5 - 7 7 ° C) indicated the presence of an a,3-unsaturated carbonyl functionality. The single olefinic proton a to the carbonyl group gave rise to a one-proton multiplet centered at S 5 . 8 0 (Wj = 3 . 5 Hz) in the -^Hnmr spectrum (Figure 1 ) , while the tertiary bridgehead methyl group gave rise to a three-proton singlet at 6 1 . 0 8 . Although a pure sample of the enone 83_ was not available, the i r spectrum of a mixture of the enones 6_3 and 83^ clearly demonstrated that an a,3-unsaturated ketone moiety was present in both of these compounds. The %nmr spectrum of this mixture (Figure 2 ) exhibited the appropriate signals assigned to compound 6_3 as well as a singlet at <5 0 . 5 6 which was assigned to the tertiary bridgehead methyl group present in 83_ and a multiplet centered at 6 5 . 8 4 (Wi.^ = 6 Hz) which was assigned to the olefinic proton also present in 83. The 1Hnmr spectra of these materials provided a convenient method for differentiating between the two isomers. It is well known that the chemical shift of a proton or a group of protons is frequently modified by neighbouring functional groups. In the case of a carbonyl functionality, this modification takes the form of an upfield shift for protons lying in a cone extending above and below the plane of the carbonyl group, while protons lying outside this cone generally experience a downfield shift. It is per-tinent to the following discussion to remember that these f i e l d effects operate through space as opposed to inductive effects which operate through 39 the chemical bonds present in the molecule. With these considerations in mind, an examination of molecular models of the enones 6_3 and j$_3 suggested that there should be an observable difference in the chemical shift of the bridgehead methyl groups present in these materials. This conclusion was reached by considering the relative environments experienced by the tertiary methyl groups present in each isomer. In the case of the enone 6_3, molecular models show that the r i g i d i t y of the entire system makes i t impossible for the carbonyl group of the cyclopenta-none ring to interact "through space" with the bridgehead methyl group. Therefore, any effect that the enone system has on the chemical shift of the methyl group would be due to an inductive effect and would thus be expected to be quite small. However, in certain conformations of the isomeric enone 83 the tertiary bridgehead methyl group lie s at least partially in the shield-ing cone of the carbonyl group of the cyclopentenone ring. Therefore, i t would be expected that the protons of this methyl group should resonate upfield relative to the protons of the bridgehead methyl group present in 63. Indeed, the xHnmr spectrum (Figure 2) of the mixture of these two isomeric enones exhibited two distinct singlets, located at 6 1.08 and 0.56. Since these resonances must have been due to the bridgehead methyl groups, the material having the high fie l d methyl group was assigned structure jS_3 and the material isolated in crystalline form, exhibiting a three-proton singlet at 6 1.08 was assigned structure 63. In addition to the relative chemical shifts of the bridgehead methyl groups, the widths of the signals arising from the olefinic protons present 40 i n enones 63 and 83 supply a clue to the structures of 6^ 3 and 83^. The o l e f i n i c proton present i n compound 6_3 could, i n theory, be a l l y l i c a l l y coupled to j u s t one proton whereas the o l e f i n i c proton present i n 83_ could be a l l y l i c a l l y coupled to three protons. Although the s i z e of a l l y l i c coupl-ings are generally small, one might expect that the width of the s i g n a l a r i s i n g from the o l e f i n i c proton present i n fr3 to be greater than the width of the corresponding s i g n a l i n 63. Indeed, an examination of the 1Hnmr spectrum (Fig. 1) of the material assigned structure 63^ showed that the s i g n a l at 6 5.80 which was att r i b u t e d to the o l e f i n i c proton had a width at half-height of 3.5 Hz whereas the ole-f i n i c proton present i n the material assigned structure j33_ (1Hnmr Fi g . 2) gave r i s e to a s i g n a l at 6 5.84 whose width at half-height was 6 Hz. Thus, the assignment of the structures to compounds 6_3 and 83_ using the widths of the s i g n a l a t t r i b u t e d to the o l e f i n i c protons present i n these compounds i s f u l l y consistent with the e a r l i e r method based on the r e l a t i v e chemical s h i f t s of the bridgehead methyl groups present i n and 83. A l l attempts to optimize the conditions necessary to e f f e c t the a l d o l condensation of J76_ to a s i n g l e enone 63_ i n high y i e l d proved f r u i t l e s s . How-ever, s u f f i c i e n t q uantities of the enone j63_ could be recovered from these reactions to allow f o r the continuation of the model study. B. Conversion of the Enone 63. into the T r i c y c l i c Keto Esters 6_1 and jj2_ With s u f f i c i e n t quantities of the t r i c y c l i c enone 6_3 a v a i l a b l e , i t was possible to proceed with an i n v e s t i g a t i o n of the construction of the D ring system (eq. 27). As mentioned e a r l i e r i n th i s d iscussion, i t was planned 41 i H 63 61 H + r^ySC (27) 62 to begin the construction of the D ring by effecting the conjugate addition of an organocopper reagent, lithium divinylcuprate, to the a,^-unsaturated ketone group present in our model system. The 1,4-addition of lithium divinylcuprate to enone systems has found frequent application in the chemical literature"^ ^ and the overall scope of this reaction is too large a subject to be reviewed here. The lithium divinylcuprate used in this work was generated in situ 40 41 from the dimethyl sulfide complex of cuprous bromide and vinyllithium 40 using the procedure of House et. a l . However, when the enone 63_ was treated 40 with 1 equivalent of this organocopper reagent under the usual conditions, the only material recovered (mass balance 74%) from the reaction (eq. 28) mix-ture was unchanged starting material. H "vinyl cuprate" (28) 63 84,85 42 In order to further test the overall fea s i b i l i t y of this approach, the conjugate addition of lithium dimethylcuprate"^'^ to the enone system in compound 63 was attempted (eq. 29). Thus, treatment of a cold (0° C) solution of the enone 6_3 in ether with 4 equivalents of lithium dimethyl-cuprate gave, af ter work-up, a mixture of the t r i c y c l i c enones 6_3 and 83. 42 Although i t is not clear where equilibration of the enone 63_ took place, either during the reaction or during the work-up, i t is clear that addition had not taken place. H "methyl cuprate"^ (29) 63 86,87 In view of the failures mentioned above, i t was decided to investi-gate an alternate method of functionalizing the enone system, involving the photochemical addition of allene to the a,B-unsaturated carbonyl group present in our model system. The chemical literature contains a large number of examples of this type of reaction and two representative examples are shown in equations 30^ and 31 44 enone In most of the known examples of the photoaddition of allene to an system, the orientation of the cyclobutane olefinic double bond is as shown in the following examples. The stereochemistry of the addition of 23 allene i s , however, usually more d i f f i c u l t to predict, although Wiesner has proposed one method of doing so. 43 (30) (31) 90 91 Irradiation of a cold (-72° C) solution of the t r i c y c l i c enone (±3 and allene in tetrahydrofuran resulted in the formation of two major photo-adducts (eq. 32). This product mixture proved to be resistant to separation by glc analysis (columns A, B and C) or by chromatography on s i l i c a gel. However, recrystallization of the product mixture from pentanes did afford a small amount of one pure isomer 92. 63 92 93 The structures assigned to compounds 9J2_ and 93_ were based on their 4 4 spectral properties. The crystalline isomer 92_ (mp 92-94° C) gave the following spectral data. The i r spectrum showed a strong absorption at 1735 cm-1 and a weaker absorption at 1665 cm-1. This information was con-sistent with the presence of a five-membered ring ketone group and an olefinic linkage in 92_. The 1Hnmr spectrum of 92_ exhibited a three-proton singlet at 6 0.87 which was assigned to the tertiary bridgehead methyl group and a pair of one-proton multiplets centered at 6 4.79 and 4.94 which were attributed to the protons on the terminus of the exocyclic double bond. The ^ nmr spectrum of this material also exhibited a broad one-proton signal at 6 3.12 and a two-proton multiplet at 6 2.81 which were assigned to the C - l l methine proton and the C-14 methylene protons present in 9_2. The determination of the stereochemistry of the cyclobutane ring system of this photoadduct w i l l be discussed in a later section of this thesis (see page 83 ). The assignment of structure 9_3 to the second photoadduct obtained in this reaction w i l l also be discussed in greater detail at a later stage in this thesis. Although attempted separations of the mixture of photoadducts 92 and 9j3_ were not successful, the 'Hnmr spectrum of this mixture showed that the ratio of these two photoadducts was approximately 1:1. Usually, the formation of a mixture of products in a synthesis of this type is a phenomenon to be avoided. However, in this case, such an event had i t s advantages. In this instance, separation of compounds 92_ and 9j3 and subsequent transfor-mation of these materials would allow entry into both the aphidicolin (from 92) and stemodin (from 93) ring systems. With the successful functionalization of the enone system in 6_3 to give the tetracyclic materials 92_ and 93^  i t was f e l t that this model study 45 had served i t s purpose. Rather than converting these photoadducts into tetracyclic materials having the basic carbon skeletons possessed by the tetracyclic ketones 5_5_ and 6JD, i t was decided to investigate only the con-version of 9_2 and 93_ into the corresponding esters 6_1 and (>2_, respectively. The synthetic plan for the preparation of the keto esters 6_1 and bl_ was to make use of a two step procedure. I n i t i a l l y , oxidative cleavage of the exocyclic double bond present in the photoadducts 9_2 and 9_3 would give the corresponding tetracyclic diketones 9j4 and 95_. Secondly, base promoted opening of the cyclobutanone ring system present in 9h_ and 95_ would lead to the formation of the desired keto esters 6_1 and 6_2 (eq. 33). 92,93 94,95 61,62 The cleavage of the olefinic double bond present in 92_ was accom-plished by subjecting a cold (-78° C) solution of _92_ in a mixture of methylene chloride and methanol to a stream of ozone unt i l the solution remained blue. The cooling bath was removed and the reaction mixture was allowed to warm to room temperature while a stream of oxygen was passed through the solution. When the blue color had discharged, the solution was recooled to -78° C and dimethyl sulfide was added to reduce the intermediate a-methoxyalkyl hydro-46 peroxide m a t e r i a l . H J T h e resulting solution was once again allowed to warm to room temperature and then stirred at that temperature for 18 h. Removal of the solvents and recrystallization of the residue from pentanes gave a 76% yield of the crystalline (mp 83-84° C) t r i c y c l i c keto ester 61. The structure assigned to the product of this reaction was confirmed by i t s spectral data. The i r spectrum of 61^ showed a strong absorption at 1740 cm-1 due to the presence of a five-membered ring ketone group and an ester carbonyl functionality. The i r spectrum was devoid of any absorption characteristic of a four-membered ring ketone (1780 cm - 1). The 'Hnmr spectrum displayed a pair of three-proton singlets at 6 0.97 and 3.57 which were readily assigned to the tertiary bridgehead methyl group and the carbomethoxy group, respectively. Since the keto ester 6JL was isolated from the- reaction mixture rather than the expected diketone 9k_, this result eliminated the need for performing the second step of the synthetic plan. Since separation of the mixture of photoadducts _9_2_ and SK3 could not be accomplished, this mixture (rather than pure 93) was subjected to the ozonolysis conditions identical with those used for the preparation of the keto ester 6^ . The products of this reaction were, as expected, a mixture of the t r i c y c l i c keto esters 6_1 and 6_2. This mixture also proved d i f f i c u l t to separate but the spectral data obtained from this mixture fully confirmed the structural assignments. The 1Hnmr spectrum of the mixture exhibited two signals at <5 0.97 and 0.99 which were assigned to the bridgehead methyl groups present in esters 6_1 and 6^ 2, respectively, and another pair of three-47 proton singlets at 6 3.57 and 3.55 which were assigned to the carbomethoxy groups present in (rl and 62^ , respectively. 48 III. Synthesis Directed Toward the Aphidicolane Class of Tetracyclic  Diterpenoids As outlined in the section of this discussion dealing with the development of the basic synthetic strategy, i t had been planned to prepare the tetracyclic ketal ketones 55_ and 6_0 from the t r i c y c l i c ketal enone 44 which in turn would be prepared from the bicyclic ketal ketone 45_. Thus, for the purpose of the present discussion, the subject matter can be divided into three main areas: the construction of the key intermediate 4_5, i t s subsequent transformation into the second key intermediate 44 and the con-version of this material into the tetracyclic ketal ketones j>5_ and 60 (eq. 34). (34) 55 60 49 A. Synthesis of the Ketal Ketone A i The preparation of the bicyclic ketal ketone 45 was achieved using a straighforward sequence of reactions (eq. 15). Thus, treatment of the (15) 17-19 ketal 48^  in refluxing benzene with 3 equivalents of 2,2-dimethyl-l,3-propanediol and a small amount of _g-toluenesulfonic acid gave, after work-up, an 89% yield of the ketal alcohol 4_9. The i r spectrum of this crystalline material (mp 80-81.5° C) exhibited a strong absorption at 3480 cm~x due to the hydroxyl functionality. The ^nmr spectrum of this material clearly demon-strated that ketalization had occurred. The two tertiary methyl groups of the ketal moiety, along with the bridgehead methyl group, gave rise to three-proton singlets at 6 0.85, 0.93 and 0.99. Oxidation of the ketal alcohol ^ 9_ to the ketone 5^_ was accomplished 13 using 2.1 equivalents of pyridinium chlorochromate and a small amount of sodium acetate as a buffer. The crystalline ketone 5^_ (mp 68-72° C) was ob-tained in good yield (88%) and i t s spectral properties were in accord with the proposed structure. The i r spectrum showed a strong carbonyl absorption at 1704 cm_x indicating the presence of a six-membered ring ketone, while the *Hnmr spectrum of this material exhibited the expected three three-proton singlets (6 0.90, 1.02, 1.12) for the tertiary methyl groups. 50 B. Conversion of the Ketal Ketone A5_ into the Tr i c y c l i c Ketal Enone AA. 1) Via the Bicyclic Diketo Phosphonate 208, With the ketal ketone 4_5 in hand, i t s conversion into the t r i c y c l i c enone 44 came under consideration. It should be pointed out that at the time this transformation was to be attempted, the methodology to be used was in doubt. The reason for this quandary lay in the unsatisfactory results obtained during the course of the work performed during the model study (see pages 35-36 ). Thus, although i t had been possible to convert the bicyclic ketone 6_4 into the diketone 76_, i t s subsequent transformation via an aldol type intramolecular condensation into the t r i c y c l i c enone 6_3 had proven to be quite d i f f i c u l t (eq. 35). In view of these results, we decided to explore some other means of carrying out the overall annelation of the cyclopentenone ring system to the bicyclic ketal ketone 45. (35) Perhaps one of the most promising methods of accomplishing the desired transformation of the bicyclic ketone 4_5_ into the enone 6_3 lay in 47 effecting an intramolecular Wittig-Horner reaction using a suitable 6,e-diketo phosphonate. The appeal of this method lay in i t s a b i l i t y to avoid the double bond isomerization that had plagued the aldol condensation approach. 51 An excellent example of t h i s type of methodology was found i n the work of Heathcock e_t. al. These workers have prepared and c y c l i z e d a number of g,e-diketo phosphonates and two representative cases are diagrammed i n equa-tions 36 and 37. (36) (37) H 98 99 In order to obtain some f a m i l i a r i z a t i o n i n dealing with these types of compounds and i n order to develop the required experimental experience, i t was decided to undertake the preparation and c y c l i z a t i o n of a simple model system. The o v e r a l l set of reactions which were performed toward this end are outlined i n Scheme IV. 48 Thus, treatment of the keto ester 100 with 2,2-dimethyl-l,3-propanediol i n the presence of a small amount of p_-toluenesulfonic acid gave, a f t e r s u i t a b l e work-up, an 88% y i e l d of the k e t a l ester 101. The :Hnmr spectrum of t h i s material c l e a r l y showed the presence of a k e t a l group and 52 104 SCHEME IV of a carbomethoxy ester functionality. The two tertiary methyl groups gave rise to a pair of three-proton singlets at 6 0.75 and 1.15 whereas the car-bomethoxy group gave rise to a three-proton singlet at 6 3.67. The i r spectrum also confirmed the presence of an ester group since a strong absorp-tion at 1735 cm 1 was observed. 49 Following the procedure of Corey, the anion of dimethyl methyl-phosphonate was generated in tetrahydrofuran at -78° C using n-butyllithium. Treatment of the ketal ester 101 with 2.5 equivalents of this anion gave, 53 after suitable work-up, a 95% yield of the keto ketal 102. This material, purified by column chromatography on s i l i c a gel, exhibited spectral proper-ties in accord with i t s proposed structure. The i r spectrum showed a strong absorption at 1710 cm~l due to the aliphatic ketone and two broad absorptions at 1250 and 1030 cm-x which are characteristic of a phosphonate group (P=0 and P-OR respectively). The 'Hnmr spectrum of this material exhibited two three-proton singlets at 6 0.75 and 1.15 which were attributed to the ter-tiary methyl groups of the ketal moiety, and a six-proton doublet centered at <5 3.12 (Jy_p = 12 Hz) which was attributed to the methoxy groups of the phosphonate functionality. Removal of the ketal group was achieved by refluxing a solution of the ketal phosphonate 102 and a small amount of p_-toluenesulfonic acid in 2-butanone for 2 h. Chromatography of the product of this reaction on s i l i c a gel gave a 73% yield of the g,e-diketo phosphonate 103. This material exhi-bited the following spectral properties. The i r spectrum showed a broad ab-sorption from 1700 to 1710 cm - x due to the two keto carbonyl groups (C=0 stretch). There were also broad absorptions at 1250 and 1030 cm~l which are characteristic of a phosphonate group (P=0 and P-OR). The 'Hnmr spectrum exhibited a six-proton doublet centered at <5 3.80 ( J H _ p = 12 Hz) which was assigned to the methoxy groups of the phosphonate functionality. With the successful preparation of the model 3,e-diketo phosphonate 47 system, i t was possible to attempt the intramolecular Wittig-Horner reaction. Toward this end, a solution of the diketo phosphonate 103 in dry dimethoxy-methane was added to a cold (0° C) slurry of 1 equivalent of sodium hydride. The resulting solution was stirred at 0° C for 1/2 h and then overnight at 54 room temperature. After suitable work-up, the bicyclic enone 104 was iso-lated in 68% yield. The physical and spectral properties of this material were essentially the same as those previously reported"*^ for this substance. In view of this successful experience with a simple model system, attention was next given to the application of this procedure to the ketal ketone 4_5. The overall proposed synthetic route is outlined in Scheme V. Successive treatment of a cold (-78° C) solution of lithium d i -isopropylamide (1.5 equivalents) in tetrahydrof uran with the ketal ketone 4_5 (1.0 equivalents), hexamethylphosphoric triamide (2.0 equivalents) and methyl iodoacetate^''" (3 equivalents), gave, after the resulting solution had been allowed to warm to room temperature and stirred at that temperature overnight, a slightly colored o i l . This o i l was chromatographed on s i l i c a gel. Elution of the column with a 4:1 mixture of petroleum ether and ether gave a 96% yield of the crystalline (mp 133-135° C) bicyclic keto ester 105. The pro-posed structure of this material was supported by the following spectral data. The i r spectrum showed the presence of a saturated six-membered ring ketone (1705 cm-"'") and an ester group (1730 cm . The three tertiary methyl groups present in the molecule gave rise to three-proton singlets at 6 0.89, 1.02 and 1.18 in the %nmr spectrum. There was also present in the "'"Hnmr spectrum a fou r t h three-proton singlet at 6 3.64, which confirmed the presence of a carbomethoxy functionality. At this stage in the proposed synthetic pathway attempts were made to protect the saturated six-membered ring carbonyl group, as had been done in the model series, as i t s corresponding ketal derivative using 2,2-dimethyl-1,3-propanediol (see Scheme V). However, after several attempts to effect this 56 transformation, i t became evident that such a conversion, in our hands, seemed unattainable. In view of the failures mentioned above, i t was decided to investi-gate an alternate method of protecting the saturated carbonyl group present in 105. This alternate method involved the reduction of the ketone 105 to the alcohol 109 and the transformation of this material into the tetrahydro-pyranyl ether 110 (eq. 38). XT' ° J R ] OMe OH °THP (38) 105 H 109 H 110 The reduction of the saturated ketonic carbonyl group present in 105 could lead to the formation of either one or both of the epimeric alcohols 109 and 111 (eq. 39). OH OH NaBH OMe OMe OMe (39) 109 H 111 Obviously, from a synthetic point of view, i t would be more advan-tageous to obtain only one of these alcohols rather than a mixture of them. The prediction of the stereochemical outcome of the metal hydride reduction 52 of cyclic ketones has been shown to be somewhat d i f f i c u l t . However, the 57 reduction of hindered ketones by metal hydrides has been shown to occur 52 predominantly from the less hindered side of the carbonyl group. An examination of molecular models of the ketone 105 suggested that the a face of the carbonyl group present in this material was the more open face. This conclusion coupled with the above considerations led to the prediction that i f this reduction step were to lead to the formation of a single or a mixture of products, the major product should be the bicyclic alcohol 109. The reduction of the ketone 105 was effected using a solution of * o sodium borohydride in methanol at low temperature (0 C). The product mix-ture from this reaction was chromatographed on s i l i c a gel and elution of the column with an 8:2 mixture of benzene and ethyl acetate gave two compounds, in a ratio of approximately 2:1. The major product of this reaction, a crystalline alcohol (mp 143-145° C), was assigned structure 109 on the basis of the above considera-tions. The spectral data obtained from this material were in accord with the proposed structure. The i r spectrum of 109 showed the presence of a hydroxyl group (3600 cm--*-) and of an ester carbonyl functionality (1725 cm--'-) . The " 4 l n m r spectrum of this material exhibited three three-proton singlets at 6 0.82, 0.90 and 0.96 which were attributed to the presence of three tertiary methyl groups. There was also present in the "klnmr spectrum a fourth three-proton singlet at 6 3.62, which confirmed the presence of a carbomethoxy functionality. This metal hydride is well known to selectively reduce a ketone group in 53 the presence of an ester group 58 The minor product from this reaction, a crystalline lactone (mp 124-126° C), was assigned structure 112 on the following basis. The i r spectrum of this material showed a strong absorption at 1770 cm~l which was attributed to the carbonyl group situated in a five-membered ring lac-tone, and no major absorptions in the region characteristic of a hydroxyl group. The •LHnmr spectrum of 112 showed three-proton singlets at 6 0.87, 0.89 and 0.99 which were attributed to the three tertiary methyl groups present in the molecule. The ^ Hnmr spectrum also showed a one-proton doublet centered at 6 3.94 (J = 4 Hz) which was readily assigned to the C-9 methine proton. The small J value (4 Hz) observed for the coupling between the C-9 methine and the C-8 methine proton is in agreement with the observed values (2-5 Hz) for the coupling constants for vicinal protons that have an axial-equatorial orientation to one another. The isolation of the lactone 112 from the product mixture of this reaction rather than the bicyclic alcohol 111 can be explained i f at some time during the course of this reaction or during the work-up of this reac-tion, the intramolecular lactonization of the bicyclic alcohol 111 to the lactone 112 had taken place (eq. 40). Regardless of the reasons for the formation of the lactone 112, this result was not altogether disheartening 59 since this material might also be used to complete the synthesis of the bicyclic diketo phosphonate 108. The potential synthetic u t i l i t y of 112 stemmed from the obvious fact that the lactone functionality present in this molecule might accomplish the dual role of "protecting" the carbonyl group (to be regenerated at C-9 at a later stage) and providing an ester group (in the form of a lactone) for the attachment of the dimethyl phosphonate moiety. However, since the lactone 112 was formed as a minor product during the reduction of the keto ester 105 another possible pathway to the diketo phosphonate 108, the direct attachment of the dimethyl phosphonate moiety to the bicyclic alcohol 109, was explored. Toward this end, the compound 109 was treated with 3 equivalents of the anion of dimethyl methylphosphonate, at -78° C under argon (eq. 41), and the crude material obtained from the product r° O M e (41) 109 113 mixture was purified by preparative t i c . Unfortunately, the product obtained from this reaction proved to be a crystalline lactone (mp 138-140° C) whose proposed structure 113 was supported by i t s spectral data. The i r spectrum of this material showed a strong absorption at 1775 cm--*- clearly indicating the presence of a five-membered ring lactone. The ^ Hnmr spectrum of 113 60 exhibited three singlets at 6 0.90, 0.92 and 1.03 which were attributed to the three tertiary methyl groups, while the C-9 methine proton present in 113 gave rise to a one-proton doublet centered at 6 4.22 (J = 8 Hz). The assignment of a trans fusion between the five-membered lactone ring and the six-membered B ring of 113 was supported by the observed J value for the coupling constant between the C-9 methine proton and the C-8 methine proton. The size of this J value (8 Hz) indicated that these protons should be trans-diaxial to one another. It seemed apparent from these results that the use of the bicyclic alcohol 109 or the lactones 112 and 113 to complete the preparation of the diketo phosphonate 108 was at best uncertain. Therefore, the transformation of the alcohol 109 into the corresponding tetrahydropyranyl ether 110 was investigated (eq. 38, page 56). In general, the formation of the tetrahydropyranyl ethers of alcohols 28 30 31 has usually been accomplished using acid catalyses. ' ' In view of the possibility of cleaving the ketal moiety present in 109 under strongly acidic 54 conditions, the use of a weaker acid, pyridinium p_-toluenesulfonate, (PPTS) , to catalyze the desired transformation of the bicyclic alcohol 109 into the corresponding tetrahydropyranyl ether 110 was investigated (eq. 42). Follow-OH OTHP 109 (42) 61 ing the procedure of Yoshikoshi e_t. al."""* a solution of the ketal alcohol 109, pyridinium p_-toluenesulf onate and dihydropyran in methylene chloride was stirred at room temperature. The crude product obtained from this reac-tion was used without purification in the next step of this overall synthetic pathway. However, the crude ether 110 (95% yield) exhibited spectral data in accord with i t s proposed structure. With the preparation of the tetrahydropyranyl ether 110 accomplished, an alternate method of protecting the saturated carbonyl group present in compound 105 had been realized. Thus, the reaction between the ester 105 and the anion of dimethyl methylphosphonate could be attempted (eq. 43). of dimethyl methylphosphonate in tetrahydrofuran with 1 equivalent of the ketal ether 110 gave, after chromatography of the residue on s i l i c a gel, an 83% yield of the ketal phosphonate 114. The spectral data obtained from compound 114 were in accord with i t s proposed structure. The i r spectrum of this material showed a strong absorption at 1710 cm~l due to the aliphatic ketone present in the molecule. The three tertiary methyl groups present in 62 114 gave rise to five singlets (6 0.84, 0.86, 0.89, 0.90 and 0.93)* in the -^Hnmr spectrum of this material while the two methoxy groups gave rise to a six-proton doublet centered at <5 3.70 ( J u „ = 12 Hz). n—r Before proceeding with the f i n a l two steps in this present synthetic pathway, i t was decided to investigate the key transformation, the oxidation of an alcohol functionality to the corresponding ketone group in the presence of a phosphonate side chain, using a simple model system. Therefore, the preparation and oxidation of the phosphonate 115 was undertaken. The phosphonate 115 was prepared in 96% yield by treatment of cyclo-hexanecarboxaldehyde 116 with 2.1 equivalents of the anion of dimethyl methyl-phosphonate (eq. 44). The structure assigned to compound 115 was supported (44) by the following spectral data. The i r spectrum of this material showed a strong absorption at 3370 cnT^ due to the hydroxyl group. The presence of a phosphonate side chain in 115 was clearly shown by the H^nmr spectrum of this material. The two methoxy groups, of this phosphonate moiety gave rise to a six-proton doublet centered at 6 3.70 (J H_p = 12 Hz). It must be remembered that compound 114 is really a diasteromeric mixture of two epimers (see page 27). 63 The oxidation of the phosphonate 115 to the keto phosphonate 117 13 was smoothly done using pyridinium chlorochromate (PCC) as the oxidizing agent (eq. 45). Thus, stir r i n g a mixture of the alcohol 115 (1 equivalent), 13 pyridinium chlorochromate (1.5 equivalents) and sodium acetate (0.15 equi-valents) in methylene chloride at room temperature for 1.5 h gave, after work-up, an 82% yield of the keto phosphonate 117. The structure assigned (45) to compound 117 was in accord with the spectral data obtained from this mater-i a l . The i r spectrum of compound 117 showed a strong absorption at 1710 cm _l due to the saturated carbonyl group. The "^ Hnmr spectrum of this material showed a two-proton doublet centered at 6 3.13 (Jjj_p = 22 Hz) which was a t t r i -buted to the methylene protons of the carbon situated next to the phosphorus atom and a six-proton doublet centered at 6 3.78 O^-P = 12 Hz). Since the oxidation of our model system presented no d i f f i c u l t i e s , the f i n a l two steps in the proposed synthesis of bicyclic diketone phosphonate 108 were investigated. The f i r s t of these steps, the removal of the tetrahydropyranyl ether group was accomplished by s t i r r i n g a solution of the tetrahydropyranyl 64 ether 114 (1 equivalent) and pyridinium p_-toluenesulfonate"'n (.2 equivalents) in methanol at 50° C for 3 h. The crude product from this reaction, the alcohol 118 ( i r spectrum y 3425 and 1710 cm--*-) was oxidized using pyridi-r max 13 nium chlorochromate without further purification (eq. 46). The oxidation product, obtained in 65% yield, proved to be the desired diketo phosphonate 108. The i r spectrum of this material confirmed the presence of the carbonyl groups (1710-1730 cm--*-, C=0 stretch). The ^ nmr spectrum of 108 was most informative. The three tertiary methyl groups present in the molecule gave rise to three singlets at 6 0.82, 1.01 and 1.16. There also appeared a pair of three-proton doublets centered at 6 4.78 ( J H _ p = 12 Hz) and 4.80 (J H_p = 12 Hz) which were attributed to the methoxy groups of the phosphonate moiety. With the diketo phosphonate 108 in hand, i t s conversion via an 47 internal Wittig-Horner type of reaction into the desired t r i c y c l i c enone 4_4 could be attempted (eq. 47). Toward this end, a solution of the diketo phos-phonate 108 (1 equivalent) and sodium methoxide (1 equivalent) in methanol was refluxed under argon for 18 h. The crude product mixture was chromato-graphed on s i l i c a gel and elution of the column with a 2:1 mixture of hexanes and ether gave a 72% yield of the crystalline (mp 116-116.5° C) t r i c y c l i c ketal enone 44. 65 NaOCH. (OMe), 108 (47) The assignment of the structure of compound 44_ was based on the following spectral data. Two strong absorption bands at 1690 and 1604 cm 1 in the i r spectrum and a strong absorption band at 230 nm (e = 17,100) in the uv spectrum of this material confirmed the presence of an a,g-unsatura-ted carbonyl functionality. The 'Hrnnr spectrum of the enone 44_ provided the best evidence for the assignment of i t s structure. The single olefinic proton present in 44_ gave rise to a one-proton multiplet centered at 6 5.80 (Wj =3.5 Hz), while the three tertiary methyl groups gave rise to three singlets at 6 0.89, 0.94 and 1.08. A direct comparison between enones 44 and 63 (page 36) can be made on the basis of the above data. The olefinic protons present in 44_ and ^3 have identical widths at half-height and one of the tertiary methyl groups present in 44^  has the same chemical shift (6 1.08) as does the tertiary bridgehead methyl group present in 6_3. Thus, the assignments of the structures of 44_ and 63_ are consistent with one another. Although the preceding synthetic pathway did eventually lead to the formation of the ketal enone ji4, the overall yield of this sequence, from the keto ester 105 to the ketal enone 44_, was only 16%. This rather poor result initiated the search for a more productive means of accomplish-66 ing the same overall transformation. If the protection of the saturated carbonyl group present in the ketal ester 105 could be avoided, then the overall transformation of the ester 105 into the diketo phosphonate 108, could be done via a shorter (and perhaps a higher yielding) synthetic pathway. However, success of this possible route would require the selective reaction of the anion of dimethyl methylphosphonate with the ester group of the side chain in the presence of the ketone carbonyl group in ring B. This would appear to be unlikely. One possible means of avoiding this d i f f i c u l t y would be to modify the ester functionality, so that the carbonyl group of this moiety would become more reactive (more electrophilic). R e c e n t l y , a number of workers have made use of the high reac-t i v i t y of acyl imidazolides towards nucleophilic reagents. The reactivity of these acyl imidazolides has been reported to resemble that of the cor-responding acid chlorides,^ a very reactive species indeed. In point of fact, the conversion of a number of acyl imidazolides 119 into the corres-ponding alkanoylmethylenetriphenylphosphoranes 120, a process quite similar to the one we wished to accomplish, had been reported^'^ (eq. 48). N P h P P H r n 3 r u i RCHCOCHPPh- , / 5 n - 1 2 3 (48) 119 120 In order to test the f e a s i b i l i t y of adapting such a process to 55 58 the problem at hand, the simple acyl imidazolide 121 ' was prepared and used as a model compound. The acyl imidazolide 121 was obtained by treating 67 a solution of cyclohexanecarboxcylic acid 122 in dry methylene chloride with 59 1.1 equivalents of N,N -carbonyldiimidazole (eq. 49). The crystalline OH CD I (49) 122 121 (mp 90-91.5°C) product of this reaction was assigned structure 121 on the basis of i t s spectral data. The i r spectrum showed a strong absorption at 1735 cm 1 due to the carbonyl moiety present in 121. The 'Hrimr spectrum of this material exhibited three one-proton signals at 6 7.02, 7.42 and 8.13 which were attributed to the protons of the imidazole ring. 55 58 Treatment of the acyl imidazolide 121 ' with the anion of d i -methyl methylphosphonate (1 equivalent) resulted in the formation of the desired keto phosphonate 117 in 64% yield (eq. 50). This material was identical in a l l respects with the keto phosphonate 117 prepared earlier (see page 63). ° O O ^P(OMe)„ LiCH2PO(OMe)2 (50) 121 117 With the apparent success of this new methodology, i t was then applied to the preparation of the diketo phosphonate 108. The sequence of steps required for this proposed transformation i s outlined in Scheme VI. 68 124 108 SCHEME VI The bicyclic keto acid 123 was prepared in 84% yield from the keto ester 105 by treatment of the latter with potassium hydroxide in a warm (60° C) mixture of water and 2-propanol for 2 h. The proposed structure of the crystalline (mp 177-179° C) acid 123 was in accord with the spectral data obtained from this material. The presence of an acid functionality was confirmed by the i r spectrum of this compound (3400-2900 and 1705 cm 1 ) . The *Hnmr spectrum of 123 exhibited three three-proton singlets at 6 0.85, 0.90 and 1.13 which were attributed to the tertiary methyl groups present in 123. The acid hydroxyl proton present in 123 gave rise to a broad one-proton singlet between 6 9.10 and 9.70. 59 Treatment of the keto acid 123 with N,N-carbonyldiimidazole (1 equivalent) gave after recrystallization of the crude reaction product, a 69 91% yield of the bicyclic acyl imidazolide 124. The spectral data obtained from this material were in accord with i t s proposed structure. The i r spectrum of this crystalline [mp 184-186° C (with decomposition)] material showed two strong absorptions at 1710 and 1740 cm 1 which indicated the presence of a saturated six-membered ring ketone and an acyl imidazolide carbonyl functionality. The !Hnmr spectrum of 124 exhibited three three-proton singlets at 6 0.89, 1.03 and 1.23 which were attributed to the tert-iary methyl groups present in the molecule. Also present were three one-proton signals at 6 7.06, 7.24 and 8.16 which were readily assigned to the protons of the imidazolide ring. With the acyl imidazolide 124 in hand, i t s conversion into the diketo phosphonate 108 could be considered. However repeated attempts to effect this desired transformation were fruitless. Treatment of a cold (-78° C) solution of the anion of dimethyl methylphosphonate with the acyl imidazolide 124 repeatedly resulted in the formation of the t r i c y c l i c ketal lactone 125 (eq. 51) in good yield (70%). 124 (51) In an attempt to duplicate the results obtained by Miyano and Stealey 5 6 (see equation 48) the acyl imidazolide 124 was treated with 1 equivalent of a salt-free solution of methylenetriphenylphosphorane in ben-60 zene. However, the product of this reaction was again, the t r i c y c l i c ketal 70 lactone 125 (80% yield). The structure of the crystalline (mp 162-164°C) t r i c y c l i c ketal lactone 125 was proposed on the basis of i t s spectral data. Three strong absorption bands at 1750, 1730 and 1640 cm 1 in the i r spectrum and a strong absorption band at 213 nm ( e = 16,900) in the uv spectrum of this material confirmed the presence of a five-membered, a,g-unsaturated lactone ring possessing an a hydrogen. The ^ nmr spectrum of this material was most i n -formative. The three tertiary methyl groups gave rise to three-proton singlets at 6 0.60, 0.88 and 1.01 while the single olefinic proton present in 125 gave rise to a one-proton t r i p l e t centered at 6 5.72 ( J = 2Hz, W, = 6 Hz) and the C-9 proton gave rise to a one-proton singlet at 6 4.41. The assignment of the stereochemistry of the C-9 proton present in compound 125 was facilitated by comparing the spectral data obtained from this material with the spectral data obtained from the enone 63^. The struc-ture of enone J53_ was assigned on the basis of a combination of conformational arguments and supportive spectral data (see pages 36-40) and a similar line of reasoning would suggest that the C-9 proton of compound 125 has an a orientation. With the failure of these reactions to produce a desirable result, another means of selectively modifying the ester carbonyl functionality present in the keto ester 105 was sought. Since the acyl imidazalide group was f i r s t considered because i t mimics the reactivity of an acid chloride group, i t was decided to explore the possible use of the corresponding acid chloride derivative of 105. Due to the high reactivity of acid halides in general, a procedure for the direct use of the ketal acid chloride 126, without purification, was 71 followed.°X The ketal acid 123 was f i r s t converted into i t s sodium salt and subsequent treatment of this salt with oxalyl chloride (.98 equivalents) formed the required acid chloride 126. Treatment of this material with the anion of dimethyl methyl phosphonate (2 equivalents) led to the recovery of a substantial amount of the ketal acid 123, along with the desired diketo phosphonate 108 (eq. 52). This material was identical in a l l respects with 123 126 108 the compound 108 prepared earlier (see page 64). Since the diketo phosphonate 108 was available in 57% yield from the ketal acid 123 using the procedure just described, the yield of the overall conversion of the ketal ester 105 into the t r i c y c l i c enone 44_ using this alternate route was 31%, a considerable improvement over the 16% obtained by the previously employed pathway (see pages 56-64 ). 2. Via the Bicyclic Diketone 131 Although conversion of the bicyclic ketal ketone 4_5 into the t r i c y c l i c enone 44_ had been accomplished, the overall yield of the t r i c y c l i c enone 44_ using the better of the two synthetic pathways just described was only 31% In view of the importance of this key intermediate 44_, an altern-ate higher yielding synthetic pathway from the ketone 4_5 to the enone 44_ was sought. One possible alternate pathway that was considered was the use 72 of the methodology employed during the construction of the model enone system 63. However, one drawback to such a plan was the capricious nature of the key step, the aldol condensation of the diketone _7_6 to the enone 63_. O O (26) 76 11 §1 The solution to this problem was found when the work of Ragault 62 63 and Brown ' came to our attention. These workers have published a pro-cedure for the conversion of the diketone 127 into the t r i c y c l i c enone 128 62 (eq. 53) using a solution of sodium tert-butoxide in benzene. (53) 127 128 It was interesting to note that only one of the several possible isomeric enones that could be formed under these reaction conditions was isolated. However, these workers did report that i f a proton source was present during the reaction (tert-butanol) then a mixture of the two iso-meric enones 128 and 129 was formed (eq. 54). 73 127 128 129 63 In a related paper, Ragault and Brown reported some of the 'Hnmr data which they obtained for their two enones 128 and 129. The noteworthy signals reported were the chemical shifts of the bridgehead tertiary methyl groups. These values, 6 1.04 and 0.56, respectively were very similar to those which had been obtained from the 'Hnmr spectra of enones j>3_ and 83, thus providing additional evidence for the structural assignments made for these substances. Although f u l l experimental details were not given in the papers 62 63 of Ragault and Brown ' i t was possible to successfully apply their con-ditions to our work. Thus, treatment of the bicyclic diketone 76. with sodium tert-butoxide (2 equivalents) in refluxing benzene gave, after work-up, a 77% yield of the t r i c y c l i c enone 6r3 (eq. 26, page 3 3 ). The product obtained from this reaction was free of starting material and contained only a trace (as shown by ^ nmr analysis) of the isomeric enone 83. 74 With the success of this reaction, the application of the method-ology used to construct the model system, to the preparation of the t r i c y c l i c enone 4_4 now seemed most attractive. The synthetic pathway leading from the ketal ketone 45 to the t r i c y c l i c ketal enone 44^  using the methodology just mentioned is outlined in Scheme VII. 131 44 132 SCHEME VII 75 Alkylation of the lithium enolate anion of 4_5 in tetrahydrof uran 36 37 at 0° C with methallyl iodide ' gave, after suitable work-up, an 80% yield of the ketal keto olefin 130. The structure of this crystalline mat-er i a l (mp 74-76° C) was confirmed by i t s spectral data. The i r spectrum of 130 exhibited absorptions at 3080, 1704 and 1624 cm 1 which were attributed -to the stretching vibrations of the olefinic C-H bonds, the six-membered ring carbonyl group and the disubstituted olefinic linkage, respectively. The ^nmr spectrum showed the presence of three tertiary methyl groups and a vinyl methyl group which gave rise to three-proton singlets at 6 0.85, 0.98, 1.12 and 1.64 respectively. The two protons on the terminus of the unsaturated linkage resonated as one-proton multiplets centered at 6 4.59 and 4.71. The stereochemistry of the side chain (at C-8) was assigned the a configuration by direct analogy to the similar keto olefin 75 (see page The ketal dione 131 was prepared by treating a solution of the ketal olefin 130 in a mixture of water and tetrahydrofuran with a small 64 amount of osmium tetraoxide and an excess of sodium metaperiodate. Af 31). O 130 131 76 work-up of this reaction, the crystalline bicyclic ketal dione 131 (mp 77-78° C) was isolated in 93% yield and this material exhibited the appropriate spectroscopic properties. The i r spectrum showed a strong carbonyl absorp-tion at 1714 cm The ^nmr spectrum of this material confirmed the pres-ence of four methyl groups. The bridgehead methyl group and the two ketal methyl groups gave rise to three three-proton singlets at 6 0.84, 0.98 and 1.13 while the methyl group adjacent to the side chain carbonyl group gave rise to a three proton singlet at 62.14. The f i n a l step in this alternate route to the t r i c y c l i c ketal enone 44, the aldol condensation of the diketone 131, was carried out under the same conditions developed for the cyclization of the diketone 7_6. Thus, treatment of the diketone 131, with sodium tert-butoxide (2 equivalents) in refluxing benzene gave, after work-up, a 79% yield of the desired t r i c y c l i c ketal enone 44_. There was also isolated from the product mixture of this reaction, an 18% yield of the undesired isomer 132. Separation of these materials was easily accomplished using column chromatography on s i l i c a and eluting with a 2:1 mixture of cyclohexane and ethyl acetate. 132 7 7 The structures of the products from t h i s r e a ction, the enones 44_ and 132, were assigned on the basis of t h e i r s p e c t r a l data. The k e t a l enone 44 has been reported e a r l i e r i n t h i s work (see page 65). The i r spectrum of the c r y s t a l l i n e enone 132 (mp 136.5-137° C) showed two strong absorption bands at 1680 and 1630 cm 1 while the uv spectrum showed a strong absorption at 232 nm (e = 17,000). These r e s u l t s are consistent with compound 132 con-t a i n i n g an a,g-unsaturated carbonyl f u n c t i o n a l i t y . The three methyl groups present i n the molecule gave r i s e to three-proton s i n g l e t s at 6 0.60, 0.88 and 0.97 i n the ^nmr spectrum of t h i s material while the si n g l e o l e f i n i c proton present i n 132 gave r i s e to a one-proton t r i p l e t centered at 6 5.87 (J = 2 Hz, W, =5 Hz). The high f i e l d chemical s h i f t of the bridgehead t e r t i a r y methyl group (6 0.60) and the width at one-half height of the o l e -f i n i c proton (Wj = 5 Hz) strongly suggested that the assigned structure of compound 132 was correct since these p a r t i c u l a r ^nmr s i g n a l assignments 63 are consistent with those observed and one s i g n a l (6 0.56) reported for the s i m i l a r compounds 8^3 and 129 (see pages 36 and 7 3 ) . Using the synthetic pathway j u s t discussed, the t r i c y c l i c k e t a l enone 44 was prepared i n 59% o v e r a l l y i e l d from the b i c y c l i c ketone 45. This i s a notable improvement over the previous route whose o v e r a l l y i e l d was only 31%. With a short and high y i e l d i n g route to the key intermediate 44 a v a i l a b l e , the conversion of t h i s enone 44_ into material possessing the basic carbon skeletons of a p h i d i c o l i n and stemodin could be investigated. 78 C. Conversion of the Enone 44_ into the Tricyclic Keto Esters _59 and 133 Of the two proposed schemes for the conversion of the t r i c y c l i c enone 44 into the tetracyclic ketones and ^ 0 (eq. 22) that were outlined in Part I of this discussion section, the results obtained during the course of our work on the model system Q3_ clearly indicated that the photochemical approach would be the method of choice. This section of the thesis i s concerned with a description of the conversion of the enone 44 into the t r i c y c l i c keto esters _59_ and 133, which, hopefully, w i l l serve as suitable precursors to the tetracyclic ketones 5_5 and 60 respectively. The proposed synthetic pathway for such a set of transformations was based on the results obtained during the course of work performed on the model system 63_ and i s outlined in Scheme VIII. 79 SCHEME VIII Irradiation of a cold (-78° C) solution of the enone 44 and allene in tetrahydrofuran for 4.5 h resulted in the formation of two photoadducts (eq. 19). This product mixture was chromatographed on s i l i c a gel and elution of the column with a 10:5:2 mixture of cyclohexane, hexane and ethyl ace-tate gave a major component, the ketal ketone 5_6 (42% yield) and a minor com-ponent, the isomeric ketal ketone 5_7_ (39% yield). 80 (19) 44 56 57 The crystalline ketal ketone 57 (mp 134-135° C) exhibited the following spectroscopic data. The i r spectrum of this material showed a strong absorption at 1730 cm 1 and a weaker absorption at 1670 cm This information was consistent with the presence of a five-membered ring ketone group and an olefinic linkage in 5_7. The ^ nmr spectrum of _5_7 exhibited three-proton singlets at 6 0.87, 0.95 and 0.97 which were attributed to the three tertiary methyl groups present in the molecule. The ^ nmr spectrum also showed a one-proton singlet at & 3.29 which was assigned to the C - l l methine proton. The other crystalline photoadduct j>6 (mp 132-134° C) exhibited similar spectral properties. The i r spectrum of this material showed a strong absorption at 1730 cm 1 and a weaker absorption at 1670 cm 1 which indicated the presence of a five-membered ring ketone group and an olefinic double bond. The ^ nmr spectrum of this material exhibited three-proton singlets at 6 0.88, 0.95 and 0.99 which were attributed to the three tert-iary methyl groups present in _56_. The ^ nmr spectrum also exhibited a one-proton singlet at 6 3.11 which was assigned to the C - l l methine proton and a broad two-proton signal at 6 2.77. 81 Since i t was very important that the structures of compounds 56 and _5_7 were firmly established i t was pertinent at this point to obtain further evidence (in addition to the spectral evidence summarized above) concerning this point. The photochemical addition of allene to the enone system present in the t r i c y c l i c compound 44_ could, in theory, have led to the formation of one or more of the four photoadducts j>6_, _57_, 134 and 135 (Scheme IX). In practice, the reaction produced only two products. There-fore two of the possibilities outlined in Scheme IX had to be eliminated. SCHEME IX 82 This problem could, in theory, be solved on the basis of the different chem-istry expected from the photoadducts _56 and _5_7 as opposed to that of 134 and 135. That i s , i f the exocyclic double bonds of these possible adducts were to be subjected to oxidative cleavage then only two of the resultant diketone derivatives would be expected to undergo cleavage with sodium meth-oxide to give the corresponding keto ester analogs. Thus, treatment of the diketo derivatives of _56 and 57_ with a solution of sodium methoxide in methanol should give the keto ester counterparts, whereas 134 and 135 under similar conditions should not result in the formation of any ester containing materials. These considerations coincided with the direction of the synthetic plan of this work. Since both the photoadducts obtained from the addition of allene to the enone 4_4 were independently converted into the correspond-ing keto ester derivatives _59 and 133 (vide infra) these photoadducts could be assigned structures _56 and 57. 83 Although the above considerations, coupled with the pertinent spectral data, led to the assignment of structures 5_6 and 5_7_, i t was of great importance to be able to assign the relative stereochemistry of the cyclobutane ring system present in each photoadduct. Toward this end, one of these materials, the photoadduct with mp 134-135° C was submitted for X-ray crystallographic a n a l y s i s . T h e results of this investigation left no doubt that the structure of this material was as shown in 5_7. By i n -ference, the isomer with mp 132-134° C possessed the structure shown in 56. The establishment of the structures of compounds _56 and 5_7 could, in turn, be used to assign structures to the photoadducts 92^ and 93_ (eq.32) which had been obtained during the course of the model study described in an earlier section of this thesis (see page 43). (32) 63 92 93 * The crystals of this photoadduct were of the necessary size and quality suitable for X-ray crystallography while those of the second photoadduct were not. 1 84 The assignment of the structures to compounds 92_ and 93^ were based on the similarity of the ^nmr spectra obtained from pairs of the photoad-ducts _56, _57, 91_ and 93^. Since the ^nmr spectra of the photoadduct with mp 92-94° C and the photoadduct _56 were quite similar (the C - l l methine protons present in these materials gave rise to one-proton signals at 6 3.12 and 6 3.11 respectively) the structure of this photoadduct was assigned as shown in 92_. By inference then, the other photoadduct (obtained only as a mixture of 92 and 93) was assigned the structure as shown in 93^. The close simil i a r i t y between the chemical shifts of the C - l l methine protons present in 57_ and _93 (<S 3.29 and 3.27) led additional support to the assignment of the structure of 93. With the photoadducts 56^ and _57 in hand, the transformation of these materials into the corresponding t r i c y c l i c keto esters _59 and 133 was investigated. A cold (-78° C) solution of the photoadduct _56 in a mix-ture of methylene chloride and methanol was subjected to ozonolysis under conditions identical with those used for the preparation of the keto esters 61 and 6_2 (eq. 27, page 41). The products of this reaction were separated by column chromatography on s i l i c a gel. Elution of the column with a mixture of petroleum ether and ether gave a major component, the desired t r i c y c l i c keto ester _59, in 55% yield, and a minor component, the t r i c y c l i c diketal ester 136, in 20% yield. 85 The structures of these materials were assigned on the basis of spectral data. The crystalline ester _5J^  (mp 154-155° C) exhibited the following spectral properties. The i r spectrum of this material showed a strong absorption at 1740 cm 1 due to the presence of a five-membered ring ketone and an ester carbonyl functionality. The 'Hnmr spectrum displayed a three-proton singlet at 6 0.87 and a six-proton singlet at 6 0.98 which were assigned to the three tertiary methyl groups present in the molecule. A fourth three-proton singlet at 6 3.56 was attributed to the carbomethoxy group present in 59. The i r spectrum of the diketal ester 136 showed a broad absorption at 1740 cm 1 due to the presence of the ester carbonyl functionality. The ^mnr spectrum of this material exhibited six three-proton singlets. The singlets at 6 0.84, 0.94 and 1.00 were attributed to the three tertiary methyl groups present in 136. The two singlets at 6 3.06 and 3.10 were at-tributed to the methoxyl groups of the dimethyl ketal functionality, while the last singlet at 6 3.36 was attributed to the carbomethoxy group. Since the ozonolysis of the photoadduct 5_6 gave not only the 86 desired keto ester J39 but also the diketal ester 133, the ozonolysis of the isomeric photoadduct 57_ was carried out under conditions different from those used previously (vide supra). Thus, a cold (-78° C) solution of the keto olefin 5_7 in methanol was subjected to a stream of ozone u n t i l the solution turned blue. At that point, a stream of nitrogen was introduced into the reaction mixture and the flow of ozone was stopped. When the reaction mixture had once again become colourless, one equivalent of d i -methyl sulfide was added to the s t i l l cold (-78° C) reaction mixture. The resulting solution was warmed to -15° C and stirred at that temperature for 30 minutes. The reaction mixture was allowed to warm to 0° C, at which temperature the sti r r i n g was continued for 30 minutes, and then allowed to warm to room temperature and stirred for an additional hour (eq. 57). (57) The crystalline material (mp 141-143° C) obtained from this reaction in 91% yield was assigned structure 137 on the basis of i t s spec-t r a l data. The i r spectrum of this material showed strong absorptions at 1780 and 1730 cm 1 indicating the presence of a four-membered ring and a five-membered ring carbonyl functionality, respectively. The three tertiary 87 methyl groups present in 137 gave rise to three-proton singlets at 6 0.91, 1.01 and 1.03 in the 'Hnmr spectrum of this material. The ^ nmr spectrum of 137 also exhibited a broad one-proton singlet at 6 3.7 9 and a broad two-proton singlet at 6 3.26 which were assigned to the C - l l methine proton and the C-14 methylene protons respectively. A solution of the ketal dione 137 in dry methanol containing sodium methoxide (2 equivalents) was stirred at room temperature for 1 h. After suitable work-up, the ketal ester 133 was isolated in 80% yield (eq. 58). o (58) 137 133 The structure of the crystalline keto ester 133 (mp 183.5-184° C) was assigned on the basis of i t s spectral properties. The i r spectrum of this material showed a strong absorption at 1735 cm 1 due to the presence of a five-membered ring and an ester carbonyl functionality. The 'Hnmr spectrum of this material exhibited three-proton singlets at 6 0.91, 0.99 and 1.01 which were attributed to the three tertiary methyl groups present in the molecule. There also appeared a fourth three-proton singlet at 6 3.60, which was readily assigned to the carbomethoxy group present in 133. With the successful conversion of the t r i c y c l i c enone 44 into the 88 t r i c y c l i c keto esters 59 and 133, the overall approach to the synthesis of the tetracyclic diterpenoids aphidicolin and stemodin undertaken in this work seems a l i k e l y and viable enterprise. 89 EXPERIMENTAL General Information Melting points, which were determined with a Fisher-Johns melting point apparatus are uncorrected. D i s t i l l a t i o n temperatures are also uncor-rected and refer to the mean air bath temperature during a short path d i s t i l l a t i o n . Infrared spectra were recorded on a Perkin-Elmer model 710 infrared spectrophotometer. Ultraviolet spectra were obtained with a Cary 15 spectrophotometer using a solution of the sample in methanol. The proton magnetic resonance ^Hnmr) spectra were taken in deuterochloroform solution oh Varian Associates Spectrometers, models T-60, HA-100, and XL-100 and on an instrument made up from an Oxford Instruments 63.4 KG superconducting magnet, a Bruker TT-23 console with a Nicolet 16 K computer and a homemade transmitter-receiver system. Signal positions are given in parts per million (6) with tetramethylsilane as an internal reference; the multiplicity, inte-grated peak areas, and proton assignments are indicated in parentheses. Analytical gas liquid chromatography (glc) was performed on a Hewlett Packard HP 5832 A Gas Chromatography unit connected to a HP 18850 A GC terminal. The following columns were used: (A) 6 ft x 0.125 i n . , 5% OV-210 on Applied Science Laboratories Inc. Gas-Chrom Q (100/120 mesh); (B) 6 ft x 0.125 i n . , 5% OV-17 on Applied Science Laboratories Inc. Gas-Chrom Q (100/120 mesh); (C) 6 f t x 0.125 i n . , 5% Silar 1000 on Applied Science Laboratories Inc. Gas-Chrom Q (100/120 mesh). The specific column used along with column tempera-ture and carrier gas (helium) flow rate (in ml/min) are indicated in parenth-eses. 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 was carried out on 20 x 5 cm glass 90 plates coated with 0.5 mm of neutral s i l i c a gel (E. Merck, S i l i c a Gel 60). Preparative thin layer chromatography was carried out using 20 x 20 cm glass plates coated with 1 mm of neutral s i l i c a gel (E. Merck S i l i c a Gel 60). These plates were baked for 12-14 hours in an oven to activate them. Visualiza-tion was achieved by putting the plate into an iodine tank or by spraying the plate with a 5% solution of ammonium molybdate in 10% aqueous sulfuric acid. The alumina used in f i l t r a t i o n columns was neutral alumina Act I (Alumina Wolem B, Act I) or basic alumina Act I (Alumina Wolem B, Act I ) . Low resolution mass spectra were recorded with a Varian/MAT CH4B mass spec-trometer. High resolution mass spectra were recorded with a Kratos/AEI MS50 or a Kratos/AEI MS902 mass spectrometer. Microanalyses were performed by Mr. P. Borda, Microanalytical Laboratory, University of Brit i s h Columbia. Whenever dry solvents are referred to, they were dried in the following manner. Tetrahydrofuran and dimethoxyethane were d i s t i l l e d from a refluxing solution of sodium benzophenone ketyl in the appropriate solvent under argon. Hexamethylphosphoric triamide and benzene were d i s t i l l e d from lithium aluminum hydride. Dry methanol and ethanol were obtained by d i s t i l -lation from their respective magnesium alkoxides. Pyridine and diisopropyl-amine were d i s t i l l e d from calcium hydride. Dichloromethane was d i s t i l l e d from phosphorous pentoxide and tert-butyl alcohol was d i s t i l l e d from a solution of potassium tert-butoxide in the alcohol. Anhydrous ether was obtained commercially. Dry ammonia was d i s t i l l e d from metallic sodium. 91 Preparation of Bicyclic Ketone 67 OTHP The bicyclic ketone 67_ was prepared by the following procedure, 18 a modification of that reported by Spencer et. al. To a stirred solution of 1.00 g (71.9 mmol) of lithium in 250 ml of dry ammonia, cooled to -78°C, 30 31 was added a solution of 7.93 g (30.0 mmol) of the bicyclic enone 6^6_ ' in 100 ml of ether. The cooling bath was removed and the reaction mixture was stirred for 1 h. At the end of this time, sufficient ethanol was added to just discharge the blue colour and the ammonia was allowed to evaporate. The residue was diluted with water and the resulting mixture was thoroughly extracted with dichloromethane. The combined extract was dried (MgSO^ ) and concentrated to a volume of about 50 ml. To this solution was added 38.6 g 13 (180 mmol) of pyridinium chlorochromate and 3.07 g (37.4 mmol) of sodium acetate. The resulting mixture was stirred at room temperature for 3 h before being diluted with 150 ml of ether. The resulting mixture was passed through a short column of neutral alumina. The column was eluted with several portions of ether and the combined elutant was concentrated. The residue was recryst-allized from hexanes to give 6.60 g (83%) of the bicyclic ketone 67_: mp 93-97°C ( l i t . 2 8 mp 98-99°C); l r , _ . _ . N, v 1715 cm"1; ^nmr, 6 1.06 (s, 3H, v (CHC13)' max tertiary methyl), 4.75 (m, 1H, -0CH0-). Anal, calcd. for C 1 6H 2 603: C, 72.14; H, 9.84. Found: C, 71.96; H, 9.93. 92 Preparation of the B i c y c l i c Ketol 48^  OH i H A solution of 6.60 g (24.8 mmol) of the b i c y c l i c ketone 67_ and 250 mg of £-toluenesulfonic acid i n 200 ml of methanol was s t i r r e d at room temperature for 3 h. The solvent was removed and the residue was diluted with 200 ml of ether. The resulting solution was washed with an aqueous solution of sodium bicarbonate and brine before being dried (MgSO^). Removal of the solvent and r e c r y s t a l l i z a t i o n of the residue from ether gave 3.96 g (88%) of the b i c y c l i c ketol 48: mp 68-69°C ( l i t . 1 9 mp 68-70°C); i r( C H C l 3)» v 3450 and 1709 cm"1; ^nmr, 6 1.01 (s, 3H, t e r t i a r y methyl), 1.62 (s, max IH, hydroxyl proton), 3.26 (broad m, IH, -CH0H) . Anal, calcd. for CnHi 80: C, 72.49; H, 9.95. Found: C, 72.48; H, 10.00. Preparation of the B i c y c l i c Alcohol 65_ OH H The b i c y c l i c alcohol 6_5 was prepared following the procedure of Huang-Minion. To the mixture resulting from the careful addition of 9.84 g (0.43 mol) of sodium metal to 280 ml of diethylene g l y c o l , under nitrogen, 93 was added 10.6 ml of dry hydrazine and 10.5 g (57.8 mmol) of the bicyclic ketol 4_8. The resulting mixture was refluxed for 6 h before a mixture of hydrazine and water was d i s t i l l e d from the reaction flask u n t i l the internal temperature of the solution reached 210°C. The remaining solution was refluxed for 10 h and then allowed to cool to room temperature. The cool solution was combined with the d i s t i l l a t e obtained previously and this mix-ture was subjected to a petroleum ether-brine partition. The organic phase was washed with water and brine before being dried (MgSO^). Removal of the solvents and recrystallization of the residue from hexanes gave 7.00 g (94%) of the bicyclic alcohol 65: mp 49-51°C ( l i t . 1 7 mp 52-56°C); i r( C H C l 3)» v 3480 cm"1: ^nmr.S 0.78 (s, 3H, tertiary methyl), 1.72 (s, 1H, -CH0H), max — 3.18 (m, 1H, -CHOH). Anal, calcd. for CuH2oO: C, 78.51; H, 11.97. Found: C, 78.29; H, 12.00. Preparation of Bicyclic Ketal Enone _68 A solution of 2.90 g (16.3 mmol) of the Wieland-Miescher ketone 20 46, 5.08 g (48.8 mmol)of 2,2-dimethyl-l,3-propanediol and 50.0 mg (0.29 mmol) of p-toluenesulfonic acid in 50 ml of benzene was refluxed for 45 min under nitrogen using a Dean-Stark trap to remove the water. The cooled solution was diluted with 50 ml of ether and successively washed with satura-ted aqueous sodium bicarbonate, water and brine. The organic phase was 94 dried (MgSO^ ) and evaporated. The residue was chromatographed on 250 g of s i l i c a gel. Elution of the column with an 8:2 mixture of benzene and ethyl acetate gave 280 mg of starting material followed by 3.35 g (89%, based on unrecovered starting material) of the bicyclic ketal enone 68^ . Recrystal-lization of this material from a mixture of ether and pentanes gave an analytical sample: mp 100-102°C; uv, ^ m a x 241 nm (e = 18,200); i r(cHci3)' v 1680 and 1610 cm"1; ^nmr, 6 0.82, 1.17,1.27 (s, s, s, 9H, tertiary max methyls), 3.22-3.64 (m, 4H, ketal methylene protons), 5.80 (d, IH, olefinic proton, J = 2Hz). Anal, calcd. for C 1 6H2i+0 3: C, 72.69; H, 9.15. Found: C, 72.63; H, 9.15. Mol. Wt. calcd. for C 1 6H 2i40 3: 264.1725 . Found (high resolution mass spectrometry): 264.1722. Preparation of Bicyclic Ketal Ketone 69_ A solution of 1.32 g (5.00 mmol) of the bicyclic ketal enone 6f$_ and 1.5 ml of dry tert-butyl alcohol in 20 ml of dry ether was added dropwise to a solution of 1.39 mg (20.0 mmol) of lithium ribbon in 30 ml of dry ammonia cooled to -78°C under nitrogen. The cooling bath was removed and the reaction mixture was allowed to reflux for 1 h. The dry ice condenser was removed and a sufficient amount of ethanol to just discharge the blue colour was added. The ammonia was allowed to evaporate and the residue was 95 diluted with 50 ml of ether. The organic phase was washed with brine, dried (MgSO^), and concentrated. The residue was dissolved in 20 ml of dry d i -chloromethane and the resultant solution was added to a suspension of 1.61 g 13 (7.50 mmol) of pyridinium chlorochromate and 128 mg (1.56 mmol) of sodium acetate in 20 ml of dry dichloromethane. This mixture was stirred for 3 h at room temperature before 50 ml of ether was added. The entire volume of liquid was passed through a short column of neutral alumina. The column was eluted with several portions of ether and the combined elutants were concentrated. The residue was d i s t i l l e d (air bath temperature 133-135°C, 0.02 Torr) to give 1.04 g (79%) of the bicyclic ketal ketone 69: i r ( f n m ) » vmax 1 7 1 0 c m _ 1 ; l H m r» 6 °- 7 0 (s» 3H> tertiary methyl), 1.13 (s, 6H, tert-iary methyls), 3.20-3.80 (m, 4H, ketal methylene protons). Anal, calcd. for C 1 6H 2 603: C, 72.14; H, 9.84. Found: C, 71.86; H, 9.66. Preparation of Bicyclic Ketal _70_ To a stirred solution of 344 mg (1.29 mmol) of the bicyclic ketal ketone 6_9_ in 8 ml of diethylene glycol under nitrogen was added 224 mg (mmol) of potassium hydroxide, followed by 0.50 ml of 85% hydrazine. The resulting mixture was refluxed for 1.5 h and then sufficient liquid to raise the internal temperature of the reaction mixture to 210°C was removed by d i s t i l l a t i o n . The solution was refluxed for 2 h and then allowed to cool 96 to room temperature. The cool solution was combined with the d i s t i l l a t e obtained previously and this mixture was subjected to a petroleum ether-brine partition. The organic phase was washed with water and brine before being dried (MgSO^). Removal of the solvents followed by d i s t i l l a t i o n (air bath temperature 172-176°C, 14.0 Torr) gave 250 mg (77%) of the bicyclic ketal 70_: ^nmr, 6 0.68, 0.92, 1.16 (s, s, s, 9H, tertiary methyls), 3.18-3.80 (m, 4H, ketal methylene protons). Anal, calcd. for C15H28O2: C, 76.14; H, 11.18. Found: C, 76.54; H, 11.50. Mol. Wt. calcd. for C 1 6H 280 2: 252.2090. Found (high resolution mass spectrometry): 252.2099. Preparation of Bicyclic Ketone 64_ H (a) by Oxidation of Bicyclic Alcohol 65_ To a suspension of 19.3 g (90.0 mmol) of pyridinium chlorochrom-13 ate and 1.54 g (18.7 mmol) of sodium acetate in 225 ml of dichloromethane was added 7.00 g (41.7 mmol) of the bicyclic alcohol 65. After the result-ant mixture had been stirred for 3 h at room temperature, 400 ml of ether was added. The entire volume of liquid was passed through a short column of neutral alumina. The column was eluted with several portions of ether and the combined elutants were concentrated. The residue was d i s t i l l e d (air 27 bath temperature 105-107°C, 0.80 Torr; l i t . bp 119°C, 14-15 Torr) to give 5.84 g (84%) of the bicyclic ketone 64: i r , x v 1710 cm l; JHnmr 6 — (film)' max 6 1.08 (s, 3H, tertiary methyl). Anal, calcd. for C nH 1 80: C, 79.46; O 97 H, 10.91. Found: C, 79.49; H, 11.10. (b) by Hydrolysis of Bicyclic Ketal _70 To a stirred solution of 147 mg (0.58 mmol) of the bicyclic ketal J7J0 in 10 ml of tetrahydrof uran was added 10 ml of 0.10 M hydrochloric acid. The resulting solution was stirred at room temperature for 2 h, concentrated and the residue was diluted with 20 ml of a saturated aqueous solution of sodium bicarbonate. The aqueous phase was extracted thoroughly with dichloromethane and the combined extracts were washed with brine and dried (MgSO^). Removal of the solvent and d i s t i l l a t i o n of the residue gave 80 mg (83%) of the bicyclic ketone 64_. The physical and spectral properties of this material were identical with those reported earlier. Preparation of Methallyl iodide Methallyl iodide was prepared by the following procedure, essen-37 t i a l l y identical with that reported by Sarett e_t. a l . To a stirred solu-tion of 56.4 g (376 mmol) of sodium iodide in 250 ml of acetone was added 27.1 g (375 mmol) of methallyl chloride. The resulting mixture was refluxed for 1 h, allowed to cool to room temperature and diluted with 500 ml of a saturated aqueous solution of sodium thiosulphate. The organic phase was separated, dried (Na2S0i+) and concentrated (at atmospheric pressure) . The 36 residue was d i s t i l l e d (air bath temperature 68-70°C, 120 Torr; l i t . bp 37-40°C, 29 Torr) to give 54.0 g (99%) of a clear o i l . This material exhibited: i r , . . , x, v 3075, 1620 and 900 cm"1; ^nmr, S 1.84 (s, 3H, (film) max H2C=CRCH3), 3.87 (s, 2H, -CH 2I), 4.85 (m, IH, -OCH ), 5.14 (broad s, IH, -C=CHj>) . 98 Preparation of Bicyclic Keto Olefin 75 To a stirred solution of 5.87 g (39.0 mmol) of lithium diiso-propylamide in 50 ml of dry tetrahydrofuran cooled to -78°C under argon was added 4.32 g (26.0 mmol) of the bicyclic ketone _64. The cooling bath was removed and the reaction mixture was allowed to warm to 0°C. After 30 min, 14.2 g (78.0 mmol) of methallyl iodide was added and the cooling bath was removed. After 2 h at room temperature, 100 ml of water was added and the resulting mixture was concentrated. The residue was thoroughly extracted with ether and the combined extracts were washed with brine and dried (MgSO^), Removal of the solvent and d i s t i l l a t i o n (air bath temperature 79-82°C, 0.50 Torr) of the residue gave 4.59 g (80%) of the bicyclic keto olefin 75: ir/^., \ , v 3110, 1705 and 1635 cm"1; !Hnmr, 6 1.13 (s, 3H, tertiary (film) max * methyl), 1.72 (s, 3H, olefinic methyl), 4.64, 4.72 (m, m, 2H, -C=CH?). Anal, calcd. for C15H2t+0: C, 81.76; H, 10.98. Found: C, 81.50; H, 10.77. Preparation of the Bicyclic Diketone _76 O 99 A stirred solution of A.40 g (20.0 mmol) of the bicyclic keto olefin 7_5 in 200 ml of dry dichloromethane, cooled to -78°C, was subjected 'to a stream of ozone unt i l the solution remained blue. The cooling bath was removed and the solution was allowed to warm to room temperature. The stirring was continued u n t i l the blue color had disappeared. The solution was cooled again to -78°C and 20 ml of dimethylsulfide was added. The solution was allowed to warm to room temperature again and left overnight. Removal of the solvent, followed by d i s t i l l a t i o n (air bath temperature 110-114°C, 0.02 Torr) of the residue, gave 3.50 g (79%) of the bicyclic diketone 76: i r / £ J 1 v 1714 and 1721 cm-1; ^nmr, <5 1.30 (s, 3H, tertiary — (film)' max methyl), 2.07 (dd, IH, C-l' proton, J=17 Hz, J=4 Hz), 2.32 (s, 3H, -COCH^ )> 2.91 (dd, IH, C-l' proton, J=17 Hz, J=6 Hz), 3.31 (m, IH, C-8 proton). Anal, calcd. for 0 ^ 2 2 0 2 : C, 75.63; H, 9.97. Found: C, 75.38; H, 10.27. Preparation of Tricyclic Enones 63^ and 8_3 83 (a) using potassium tert-butoxide in ether To a stirred solution of 1.38 (12.3 mmol) of potassium tert-butoxide in 275 ml of dry ether under nitrogen and cooled to 0°C was added 2.22 g (10.0 mmol) of the bicyclic diketone 76. in 25 ml of dry ether. The resulting solution was stirred at 0°C for 3/4 h before 100 ml of brine was added. The reaction mixture was transferred to a separatory funnel and the 100 aqueous phase was removed. The aqueous phase was extracted with three portions of ether and the combined ether phases were washed with two portions of water followed by a single portion of brine. The organic phase was dried (MgSO^ ) and concentrated. The residue was chromatographed on 60 g of s i l i c a gel. Elution of the column with a 9:1 mixture of benzene and ethyl acetate gave 210 mg of starting material followed by 410 mg (22% based on recovered starting material) of the crystalline t r i c y c l i c enone J33: mp 75-77°C; uv, X 229 nm (e = 16,400); i r , m p 1 v 1690 and 1608 cm"1, ^ nmr, max » ' (CHCip' max ' 6 1.08 (s, 3H, tertiary methyl), 1.92 (dd, 1H, C-13 proton, J=19, 2 Hz), 2.54 (dd, IH, C-13 proton J=19, 6 Hz), 2.93 (m, IH, C-8 proton), 5.72 (m, IH, C - l l proton, 1^ = 3.5 Hz). Anal, calcd. for C 1i +H 2oO: C, 82.30; H, 9.87. Found: C, 82.06; H, 9.88. (b) using potassium tert-butoxide in a mixture of tert-butanol and ether To a stirred solution of 224 mg (2.00 mmol) of potassium tert-butoxide in a mixture of 2 ml of tert-butanol and 10 ml of dry ether under nitrogen was added a solution of 222 mg (1.00 mmol) of the bicyclic dione 76 in 5 ml of dry ether. The resulting solution was stirred at room temp-erature for 1.5 h before 10 ml of brine was added. The reaction mixture was transferred to a separatory funnel and the aqueous phase was removed and extracted with several portions of dichloromethane. The combined organic phases were washed with brine and dried (MgSO^). The solvents were removed and d i s t i l l a t i o n (air bath temperature 128-130°C, 0.04 Torr) of the residue gave 150 mg (74%) of a colorless o i l . This material was shown by ^ Hnmr spectroscopy to be about a 4:5 mixture of the desired enone 63 and i t s isomeric form £53. Although separation of this mixture proved 101 Impossible, from a comparison of the ^nmr spectrum of the pure isomer 63 and the 1Hnmr spectrum of the material obtained from this experiment, i t was possible to assign some of the signal positions for compound j53_: XH nmr, 6 0.56 (s, 3H, tertiary methyl), 5.84 (m, IH, C - l l proton, Wj^  = 6 Hz). (c) using sodium tert-butoxide and benzene To a stirred solution-suspension of 630 mg (6.60 mmol) of sodium tert-butoxide in 25 ml of dry benzene under argon was added 730 mg (3.30 mmol) of the bicyclic diketone 7JL- The resulting red solution was refluxed for 4 h and then allowed to cool to room temperature. The reaction mixture was washed with cold brine and the organic phase was dried (MgSO^). Re-moval of the solvent and recrystallization of the residue from pentanes gave 520 mg (77%) of the t r i c y c l i c enone j)3_. The physical and spectral properties of this material were identical in a l l respects to those reported earlier. Preparation of Tetracyclic Keto Olefins j^ 2 and _93_ 92 93 A pyrex test-tube (15 x 160 mm) containing a solution of 260 mg (1.17 mmol) of the t r i c y c l i c enone ^ 3 in 15 ml of dry tetrahydrofuran was cooled under nitrogen by means of an ethanol/dry ice bath. Allene gas was bubbled through the solution u n t i l the volume of the solution had increased 102 by 1 ml. The resulting solution was irradiated (450 Watt Hanovia Lamp) for 4.5 h. The solution was transferred to a 125 ml beaker and allowed to warm to room temperature. The solvents were removed and the residue was chroma-tographed on 50 g of s i l i c a gel. Elution of the column with benzene gave 200 mg (71%) of a mixture of the tetracyclic keto olefins 92^  and jK3. Re-peated attempts to separate this mixture by chromatography on s i l i c a gel failed. However, a small amount of crystalline tetracyclic keto olefin 92_ was obtained from this mixture by recrystallation from pentanes: mp 92-94°C; i r , v 1735 and 1665 cm"1; ^nmr, 6 0.87 (s, 3H, tertiary max methyl), 2.81 (m, 2H, unassigned ), 3.12 (broad s, IH, C - l l proton), 4.79, 4.94 (m, m, 2H, C-16 protons). Anal, calcd. for C17H2i+0: C, 83.55; H, 9.90. Found: C, 83.69; H, 10.02. Mol. Wt. calcd. for C17H24O: 244.1827. Found (high resolution mass spectrometry): 244.1818. From a comparison of the 'Hnmr spectrum of the tetracyclic keto olefin 92_and the ^nmr spectrum of the mixture of tetracyclic keto olefins 92_ and j?3_, i t was possible to assign some of the signal positions for compound 93_: ^nmr, 6 0.84 (s, 3H, tertiary methyl), 4.82, 4.98 (m, m, 2H, C-16 protons). Preparation of Tricyclic Keto Esters 94_ and 95_ 103 (a) Ozonolysis of Tetracyclic Keto Olefin 92_ A stirred solution of 42.0 mg (0.17 mmol) of the tetracyclic keto olefin 92_ in a mixture of 5 ml of dichloromethane and 10 ml of dry methanol, cooled to -78°C, was subjected to a stream of ozone u n t i l the solution remained blue. The resulting solution was allowed to warm to room temperature. When the blue color had disappeared, the solution was cooled to -78°C and 1 ml of dimethylsulfide was added. The reaction mixture was allowed to warm to room temperature where the stirring was continued for 18 h. The reaction mixture was concentrated and the residue was recrystal-lized from a mixture of ether and pentanes to give 37 mg (76%) of the t r i -cyclic keto ester 94: mp 83-84°C: i r . , v 1740 cm *; 'Hnmr. 6 — (CHCI3) max 0.97 (s, 3H, tertiary methyl), 2.81 (m, 2H, unassigned), 3.57 (s, 3H, -C02CH3). Anal, calcd. for C17H2603: C, 73.35; H, 9.41. Found: C, 73.15 H, 9.25. (b) Ozonolysis of a Mixture of Tetracyclic Keto Olefins 92_ and 93_ A mixture of 128 mg (0.49 mmol) of the tetracyclic keto olefins 92 and 93_ was treated with ozone under conditions identical with those reported above, to give 111 mg (82%) of a mixture of t r i c y c l i c keto esters 94 and 95_. From a comparison between the *Hnmr spectrum of the t r i c y c l i c keto ester 94_ and the ^nmr spectrum of the mixture of t r i c y c l i c keto esters 94 and _95_, i t was possible to assign some of the signal positions for com-pound 9_5: 2Hnmr, 6 0.99 (s, 3H, tertiary methyl), 3.27 (m, IH, C - l l proton), 3.55 (s, 3H, -C02CH3). 104 Preparation of the Bicyclic Ketal Alcohol 4j? OH A solution of 6.10 g (33.5 mmol) of the bicyclic ketol 4J3, 10.4 g (100 mmol) of 2,2-dimethyl-l,3-propanediol and 100 mg (0.58 mmol) of p.-toluenesulfonic acid in 200 ml of benzene was refluxed for 2 h under a nitrogen atmosphere using a Dean-Stark trap to remove the water. The cooled solution was diluted with 100 ml of ether and successively washed with sat-urated aqueous sodium bicarbonate, water and brine. The organic phase was dried (MgSOi,) and concentrated. The residue was d i s t i l l e d (air bath temp-erature 133-137°C, 0.15 Torr) to give 8.00 g (89%) of the bicyclic ketal alcohol 4_9. Recrystallization of this material from pentanes gave an analytical sample: mp 80-81.5°C; i r , v 3480 cm 1; iHnmr, 6 ^CriCX^./ TH3X 0.85, 0.93, 0.99 (s, s, s, 9H, tertiary methyls), 3.30 (broad m, IH, C-9 proton), 3.40-3.60 (m, 4H, ketal methylene protons). Anal, calcd. for C l 6 H 2 8 ° 3 : C, 71.60; H, 10.52. Found: C, 71.76; H, 10.44. 105 Preparation of the Bicyclic Keto Ketal 4_5 To a suspension of 11.8 g (55.0 mmol) of pyridinium chlorochrom-13 ate and 800 mg (10.7 mmol) of sodium acetate in 100 ml of dry dichloro-methane was added 7.20 g (26.8 mmol) of the bicyclic ketal alcohol 49. After the resulting mixture had been stirred for 3 h at room temperature, 100 ml of ether was added and the resulting mixture was passed through a short column of neutral alumina. The column was flushed with several portions of ether and the combined elutants were concentrated. The residue was re-crystallized from a mixture of ether and pentanes to give 6.30 g (88%) of the bicyclic keto ketal 45: mp 68-72°C; i r , - , . - , x, v 1704 cm"1; lU — VL.nL/X3y max nmr, 6 0.90, 1.02, 1.12 (s, s, s, 9H, tertiary methyls), 3.30-3.72 (m, 4H, ketal methylene protons). Anal, calcd. for C15H26O3: C, 72.14; H, 9.84. Found: C, 71.75; H, 10.11. Mol. Wt. calcd. for C16H26O3: 266.1881. Found (high resolution mass spectrometry): 266.1868. 106 Preparation of the Ketal Ester 101 A solu t i o n of 3.40 g (20.0 mmol) of the keto ester 100, 3.12 g (60.0 mmol) of 2,2-dimethyl-l,3-propanediol, and 500 mg (0.29 mmol) of p-toluenesulfonic a c i d i n 50 ml of dry benzene was refluxed f o r 2.5 h under a nitrogen atmosphere using a Dean-Stark trap to remove the water. The cooled s o l u t i o n was d i l u t e d with 50 ml of ether and successively washed with saturated aqueous sodium bicarbonate, water, and br i n e . The organic phase was dried (MgSO^) and evaporated. The residue was d i s t i l l e d ( a i r bath temperature 110-115°C, 0.10 Torr) to aff o r d 4.48 g (88%) of a c o l o r l e s s o i l : i r , , . . , . , v 1735 cm J; ^nmr, 6 0.75, 1.15 (s, s, 6H, t e r t i a r y ( f i l m ) ' max methyls), 3.16-3.64 (m, 4H, k e t a l methylene protons), 3.67 (s, 3 H , -C0CH3). Anal, calcd. f o r Cj^H^O^: C, 65.60; H, 9.44. Found: C, 64.50; H, 9.50. Mol. Wt. calcd. for Cml^O^: 256.1674. Found (high r e s o l u t i o n mass spec-trometry): 256.1671. Preparation of Ketal Phosphonate 102 107 To a stirred solution of 1.24 g (10.0 mmol) of dimethyl methyl-phosphonate in 8 ml of dry tetrahydrofuran, cooled to -78°C under nitrogen, was added 2.70 ml (10.0 mmol) of a 2.7 M solution of n-butyllithium in hexane. To the resulting solution was added a solution of 1.04 g (4.06 mmol) of the ketal ester 101 in 5 ml of dry tetrahydrofuran. The cooling bath was removed and the reaction mixture was stirred for 18 h. At the end of this time, the reaction mixture was acidified with acetic acid, concen-trated, and the residue was diluted with ether. The organic phase was washed with water and brine before being dried (MgSO^). Removal of the solvent gave 1.34 g (95%) of an o i l . A portion of this material (1.00 g) was chromatographed on 50 g of s i l i c a gel. Elution of the column with an 8:2:2 mixture of benzene, ethyl acetate and methanol gave 870 mg of the pure ketal phosphonate 102: i r v 1710, 1250 and 1030 cm"1; !Hnmr, (film)' max ' 6 0.75, 1.15 (s, s, 6H, tertiary methyls), 3.79 (d, 6H, PO(OCH3)2, J u = H—P 12 Hz). Moi. Wt. calcd. for C 1 6H 2 90P: 348.1701. Found (high resolution mass spectrometry): 348.1676. Preparation of Diketo Phosphonate 103 o 108 A solution of 780 mg (2.24 mmol) of the ketal phosphonate 102, 25.0 mg (0.14 mmol) of j>-toluenesulfonic acid in 60 ml of 2-butanone was refluxed under nitrogen for 2 h. The cooled solution was diluted with 200 ml of ether and successively washed with saturated aqueous sodium bicarbonate, water, and brine. The organic phase was dried (MgSO^ ) and concentrated. The residue was chromatographed on 40 g of s i l i c a gel. Elution of the column with an 8:2:5 mixture of benzene, ethyl acetate, and methanol gave 431 mg (73%) of the diketo phosphonate 103: i r ( f i i m ) > v m a x 1700-1710, 1250, and 1030 cm"1; ^nmr, 6 2.80 to 3.62 (m, 3H, C-2 H and C-3' methylene protons), 3.80 (d, 6H, PO(OCH3)2, J„ =12 Hz). Moi. Wt. calcd. for Cj jHjg H—r O5P: 262.0970. Found (high resolution mass spectrometry): 262.0966. Preparation of Bicyclic Enone 104 To a stirred suspension of 24.0 mg (1.00 mmol) of sodium hydride (50% dispersion in oil) in 2 ml of dry dimethoxymethane, cooled to 0°C and under nitrogen, was added a solution of 262 mg (1.00 mmol) of the diketo phosphonate 103 in 4 ml of dry dimethoxymethane. The resulting mixture was stirred at 0°C for 30 min and at room temperature for 18 h. The reaction mixture was diluted with 20 ml of water and then thoroughly extracted with ether. The combined extracts were washed successively with water and brine and dried (MgSO^). Removal of the solvent and d i s t i l l a t i o n (air bath temp-erature 48-50°C, 0.05 Torr; l i t . 5 0 bp 59-62°C, 0.05 Torr) of the residue 109 gave 89 mg (68%) of the bicyclic enone 104: i r , v. v 1705 and 1615 (film)' max cm"1; ^nmr, 6 5.86 (s, IH, C-6 proton). Anal, calcd. for C9H120: C, 79.37; H, 8.88. Found: C, 79.10; H, 9.06. Preparation of Methyl Iodoacetate ICH 2C0 2CH 3 To a stirred solution of 45.0 g (300)mmol of sodium iodide in 150 ml of acetone was added 21.6 g (200 mmol) of methyl chloroacetate. The resulting mixture was refluxed for 1 h before most of the solvent was re-moved by d i s t i l l a t i o n . The residue was diluted with 100 ml of water and thoroughly extracted with ether. The combined extracts were successively washed with an aqueous solution of sodium thiosulfate, water^and brine before being dried (MgSO^). The solvents were removed and d i s t i l l a t i o n (air bath temperature 70-77°C, 14 Torr; l i t . 5 1 bp 165-167°C, 1 atm) of the residue gave 29.2 g (81%) of methyl iodoacetate: i r . , . . , v 1720-1740 cm"1; (film) max ^nmr, 3.72 (s, 2H, -CH2I), 3.75 (s, 3H, -CO2CR3). Preparation of Bicyclic Keto Ester 105 O 110 To a stirred solution of 4.16 g (27.6 mmol) of lithium diiso-propylamide in 50 ml of dry tetrahydrofuran, cooled to -78°C and under nitrogen, was added 5.00 g (18.7 mmol) of the bicyclic keto ketal 4_5, f o l -lowed by 6.68 g (37.2 mmol) of hexamethylphosphoric triamide. The resulting solution was allowed to warm to 0°C and stirred for 30 min at this temper-ature. After 9.60 g (56.0 mmol) of methyl iodoacetate had been added, the cooling bath was removed and the solution was stirred at room temperature for 17 h. The reaction mixture was concentrated, diluted with 100 ml of water and thoroughly extracted with ether. The combined extracts were washed with water and brine before being dried (MgSO^ ) . The solvents were removed and the residue was chromatographed on 300 g of s i l i c a gel. Elution of the column with a 4:1 mixture of light petroleum ether and ether gave 6.18 g (96%) of the crystalline bicyclic keto ester 105. This material was recrystallized from a mixture of methanol, ether and hexanes to give an analytical sample: mp 133-135°C; ir,,,,,,,, N, v 1705 and 1730 cm 1: 'Hnmr, J r r (CHCI3) max 6 0.89, 1.02, 1.18 (s, s, s, 9H, tertiary methyls), 3.05-3.68 (m, 4H, ketal methylene protons), 3.64 (s, 3H, -CO2CH3). Anal, calcd. for C19H30O5: C, 67.43; H, 8.93. Found: C, 67.02; H, 8.90. Moi. Wt. calcd. for ClgH3o05: 338.2093. Found (high resolution mass spectrometry): 338.2102. I l l Reduction of the Bicyclic Keto Ester 105. Formation of Tricyclic Ketal Lactone 112 and Bicyclic Ketal Alcohol 109. keto ester 105 in 5 ml of methanol, cooled to 0°C, was added a solution of 56 mg (1.48 mmol) of sodium borohydride in 1 ml of methanol. After the solution had been stirred at 0°C for 4 h, i t was concentrated and the res-idue was diluted with water. The aqueous phase was carefully acidified with acetic acid and then thoroughly extracted with ether. The combined extracts were dried (MgSO^ ) and concentrated. The residue was chromatographed on 20 g of s i l i c a gel. Elution of the column with an 8:2 mixture of benzene and ethyl acetate gave 45 mg (25%) of the t r i c y c l i c ketal lactone 112. This material was recrystallized from a mixture of ether and hexanes to give an analytical sample: mp 124-126°C; ir,„u„.. <. , v 1770 cm"1; ^nmr, 6 0.87, 0.89, 0.99 (s, s, s, 9H, tertiary methyls), 3.38-3.66 (m, 4H, ketal methylene protons), 3.94 (d, IH, C-9 proton, J=4 Hz). Anal, calcd. for C i e ^ S ^ : C, 70.10; H, 9.15. Found: C, 70.21; H, 9.11. Further elution of the column gave 112 mg (56%) of the bicyclic ketal alcohol 109. This material was recrystallized from a mixture of ether and hexanes to give an analytical sample: mp 143-145°C; i r ^ ^ ^ ^ , v m a x 3600, 3420 and 1725 cm"1; ^nmr, 6 0.82, 0.90, 0.96 (s, s, s, 9H, tertiary To a stirred solution of 200 mg (0.59 mmol) of the bicyclic 112 methyls), 3.34-3.58 (m, 4H, ketal methylene protons), 3.62 (s, 3H, -CO2CH3) . Anal, calcd. for C19H3205: C, 67.03; H, 9.47. Found: C, 67.06; H, 9.54. Preparation of Tricyclic Ketal Lactone 113 To a stirred solution of 65.7 mg (0.53 mmol) of dimethyl methyl-phosphonate in 1 ml of dry tetrahydrofuran, cooled to -78°C under argon, was added 0.20 ml (0.53 mmol) of a 2.7 M solution of n-butyllithium in hexane. To the resulting solution was added 45.0 mg (0.13 mmol) of the bicyclic ketal alcohol 109. The cooling bath was removed and the reaction mixture was allowed to warm to room temperature. After 18 h, the reaction mixture was concentrated and the residue was purified by preparative t i c ( s i l i c a gel -9:1:1 benzene, ethyl acetate, methanol) to give 20 mg (49%) of the t r i c y c l i c ketal lactone 113. This material was recrystallized from a mixture of ether and hexanes to give an analytical sample: mp 138-140°C; ir/n„„. v 1775 cm"1; ]Hnmr, 6 0.90, 0.92, 1.03 (s, s, s, 9H, tertiary (CHCI3) max ' ' ' ' ' J methyls), 2.32-2.52 (m, 2H, AB part of ABM), 3.32-3.72 (m, 4H, ketal methy-lene protons), 4.22 (d, IH, C-9 proton, J=8 Hz). Moi. Wt. calcd. for C18H28 0k: 308.1993. Found (high resolution mass spectrometry): 308.2005. 113 Preparation of Bicyclic Ketal Phosphonate 114 OTHP To a solution of 210 mg (0.62 mmol) of the bicyclic ketal alco-hol 109 and 104 mg (1.24 mmol) of 2,3-dihydropyran in 10 ml of dichloro-methane was added 307 mg (1.24 mmol) of pyridinium p-toluenesulfonate. The resulting solution was l e f t at room temperature for 3 h before 20 ml of ether was added. The mixture was washed with two portions of water and then with brine before being dried (MgS04). Removal of the solvents gave 250 mg (95%) of an o i l . The i r spectrum of this material, the tetra-hydropyranyl ether 110, exhibited no absorption due to a hydroxy1 moiety. A solution of 250 mg (0.587 mmol) of this material in 5 ml of dry tetra-hydrofuran was added dropwise to a cold (-78°C) solution of the anion of dimethyl methylphosphonate [prepared from 186 mg (1.50 mmol) of dimethyl methyphosphonate and 0.56 ml of a 2.70 M solution of n-butyllithium in hexanes]. After 18 h at room temperature, the reaction mixture was concen-trated and the residue was dissolved in 50 ml of dichloromethane. The resulting solution was washed with water and then with brine before being dried (MgSO^). Removal of the solvent gave an oily residue which was chromatographed on 10 g of s i l i c a gel. Elution of the column with ethyl 114 acetate gave 250 mg (83%) of the bicyclic ketal phosphonate 114: ir(fixm)» v 1710 cm"1; 1Hnmr,0.84, 0.86, 0.89, 0.90, 0.93 (s, s, s, s, s, 9H total, IU3.X tertiary methyls), 3.04 (d, 2H, C-3 ' protons; J=22 Hz), 3.29-3.52 (m, 4H, ketal methylene protons), 3.70 (d, 6H, -PO(OCH3)2, J„ =12 Hz), 4.30 (broad singlet, IH, C-4 proton). Moi. Wt. calcd. for C26Hi+508P: 516.2852. Found (high resolution mass spectrometry): 516.2847. Preparation of the Keto Phosphonate 117 (a) by Oxidation of the Alcohol Phosphonate 115 Prepared by Treatment of Cyclohexanecarboxaldehyde 116 with the Anion of Dimethyl Methylphos-phonate (Lithium Counterion). OH 115 To a stirred solution of 1.24 g (10.0 mmol) of dimethyl methyl-phosphonate in 8 ml of dry tetrahydrofuran, cooled to -78°C under nitrogen, was added 3.7 ml of a 2.7 M solution of n-butyllithium in hexanes. To the resulting solution was added 525 mg (4.68 mmol) of cyclohexanecarboxaldehyde 116 and the resulting solution was allowed to warm to room temperature. The reaction mixture was stirred for 1 h before being concentrated. The residue 115 was acidified with acetic acid, diluted with water and the resulting mixture was thoroughly extracted with ether. The combined extracts were dried (MgSO^ ) before being concentrated. The residue was chromatographed on 50 g of s i l i c a gel. Elution of the column with ethyl acetate gave 1.11 g (96%) of the alcohol phosphonate 115: ± r / r j ^ v 3370 cm 1: ^ nmr. (film) max 6 3.45 (broad s, IH, -CHOH), 3.70 (d, 6H, -PO(OCH3)2, J u ,,=12 Hz). To a suspension of 324 mg (1.50 mmol) of pyridinium chloro-13 chromate and 12.0 mg (0.15 mmol) of sodium acetate in 20 ml of dry dich-loromethane was added 246 mg (1.00 mmol) of the alcohol phosphonate 115. After the reaction mixture had been stirred for 1.5 h at room temperature, 100 ml of ether was added and the entire volume of liquid was passed through a short column of neutral alumina. The column of alumina was eluted with a further 100 ml of ether and the combined elutants were concentrated. The residue was chromatographed on 2.50 g of s i l i c a gel. Elution of the column with ethyl acetate gave 200 mg (82%) of the keto phosphonate 117: •Lr(fiim)» v 1710 cm"1; ^nmr, 6 3.13 (d, 2H, C-2' protons , J=22 Hz), 3.78 (d, 6H, PO(OCH3)2, J„ =12 Hz). Mol. Wt. calcd. for CioHxgOi+P : 234.1021. Found (high resolution mass spectrometry): 234.1025. (b) From the Acyl Imidazolide 121 To a stirred solution of 496 mg (4.00 mmol) of dimethyl methyl-phosphonate in 5 ml of dry tetrahydrofuran, cooled to -78°C under argon, was added 1.48 ml (4.00 mmol) of a 2.70 M solution of n-butyllithium in hexanes. To the resulting solution was added 356 mg (2.00 mmol) of the acyl 55 58 imidazole 121. ' The cooling bath was removed and the solution was a l -lowed to warm to room temperature. After 18 h, the reaction mixture was 116 concentrated and the residue was chromatographed on 5 g of s i l i c a gel. Elution of the column with ethyl acetate gave 300 mg (64%) of the keto phosphonate 117. This material was identical in a l l respects to the mater-i a l reported earlier. Preparation of the Bicyclic Diketo Phosphonate 108 o (a) by Oxidation of the Bicyclic Alcohol Phosphonate 118, Prepared by Methanolysis of the Bicyclic Ketal Phosphonate 114. OH A solution of 240 mg (0.46 mmol) of the bicyclic ketal phosphon-54 ate 114 and 23.0 mg (0.09 mmol) of pyridinuim .p-toluenesulfonate in 10 ml of methanol was l e f t at 50°C for 3 h. At the end of this time, the solvent was removed and the residue was diluted with a mixture of 40 ml of dichloro-methane and 100 ml of ether. The resulting solution was washed with water and then with brine before being dried (MgSO^). Removal of the solvents gave 160 mg (80%) of an o i l whose infrared spectrum exhibited a hydroxyl absorption at 3425 cm 1 and a carbonyl absorption at 1710 cm This material 117 was dissolved in 10 ml of dry dichloromethane and to the resulting solution 13 was added 120 mg (0.56 mmol) of pyridinium chlorochromate and 5.0 mg (0.06 mmol) of sodium acetate. After the mixture had been stirred at room temperature for 3 h, 25 ml of ether was added. The entire volume of liquid was passed through a short column of neutral alumina. The column was eluted with a further 50 ml of ether and the combined elutants were concen-trated. The residue was purified by preparative t i c ( s i l i c a gel-ethyl ace-tate) to give 103 mg (65%) of the bicyclic diketo phosphonate 108: i r (film)' v 1710-1730 cm"1; ^nmr. 6 0.82, 1.01, 1.16 (s, s, s, 9H, tertiary meth-max yls) 2.31-2.45 (m, 2H, C-l' protons), 2.95-3.20 (m, 2H, C-3' protons), 3.25-3.66 (m, 5H, C-8 proton and ketal methylene protons), 4.78, 4.80 (d, d, 6H, P0(0CH3)2, J=12 Hz). Moi. Wt. calcd. for C21H37O7P: 430.2121. Found (high resolution mass spectrometry) 430.2106. (b) From the Bicyclic Ketal Acid 123 To a solution of 272 mg (0.84 mmol) of the bicyclic ketal acid 123 in 5 ml of tetrahydrofuran was added 2.0 ml of a 0.41 M solution of sodium hydroxide in water. The resulting mixture was concentrated and dried under reduced pressure (vacuum pump). The resulting solid was sus-pended in 5 ml of dry benzene and cooled to 0°C under argon. To this mix-ture was added, successively, 67.0 mg (0.84 mmol) of dry pyridine and 470 J*l (0.84 mmol) of oxalyl chloride. After the evolution of gas had ceased, the cooling bath was removed and the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was quickly fil t e r e d through a plug of glass wool and the f i l t r a t e was frozen (liquid nitrogen) and l e f t under reduced pressure (vacuum pump) for 2 h. The residual solid was 118 dissolved in 5 ml of dry tetrahydrofuran and the resulting solution was added to a cold (-78°C) solution of the anion of dimethyl methylphosphonate [prepared from 208 mg (1.68 mmol) of dimethyl methylphosphonate and 0.62 ml of a 2.70 M solution of n-butyllithium in hexanes J. The reaction mix-ture was allowed to warm to room temperature and the stirring was continued for 18 h. The reaction mixture was concentrated, carefully acidified with acetic acid, and the resulting solution was extracted thoroughly with ether. The combined extracts were dried (MgSO^ ) and concentrated. The residue was chromatographed on 20 g of s i l i c a gel. Elution of the column with an 8:2:1 mixture of benzene, ethyl acetate, and methanol gave 129 mg (57% based on recovered starting material) of the bicyclic diketo phosphonate 108. The physical and spectral properties of this material were identical in a l l respects to those reported earlier. Preparation of Tricyclic Ketal Enones 44_ and 132 (a) From the Bicyclic Diketo Phosphonate 108 A solution of 5.40 mg (0.10 mmol) of sodium methoxide and 43.0 mg (0.10 mmol) of the bicyclic diketo phosphonate 108 in 1 ml of dry d i -methoxymethane was refluxed for 18 h under argon. The cooled reaction mixture was diluted with water and the resulting mixture was extracted thoroughly with ether. The combined extracts were washed with water and 119 brine before being dried (MgSO^). The solvents were removed and the residue was chromatographed on 400 mg of s i l i c a gel. Elution of the column with a 2:1 mixture of hexanes and ether gave 27.0 mg (72%) of the t r i c y c l i c ketal enone 44^ Recrystallization of this material from a mixture of ether and hexanes gave an analytical sample: mp 116-116.5°C; uv, ^ m a x 230 nm (E = 17,100); ir,™... N, v 1710, 1690 and 1604 cm"1; ^nmr, <5 0.89, 0.94, 1.08 ' (CHCI3)' max ' ' ' ' ' (s, s, s, 9H, teitiary methyls), 1.89 (dd, IH, C-13 proton, J=17 Hz, j'=2 Hz ), 2.52 (dd, IH, C-13 proton, J=17 Hz, J=6 Hz), 2.92 (m, IH, C-8 proton), 3.30-3.64 (m, 4H, ketal methylene protons), 5.80 (m, IH, olefinic proton, Wj = 3.5 Hz). Anal, calcd. for C 1 9H 2 60 3: C, 74,96; H, 9.27. Found: C, 75.03; H, 9.10. Mol. Wt. calcd. for C 1 9H 260 3: 304.2038. Found (high resolution mass spectrometry): 304.2024. (b) From the Bicyclic Ketal Dione 131 To a stirred solution of 1.58 g (4.91 mmol) of the bi c y l i c ketal dione 131 in 250 ml of dry benzene was added 941 mg (9.81 mmol) of sodium tert-butoxide. The resulting solution was refluxed for 4 h under argon, and was then allowed to cool to room temperature. The reaction mixture was washed with 100 ml of brine and the organic phase was dried (MgSO^ ) and con-centrated. The residue was chromatographed on 200 g of s i l i c a gel. Elution of the column with a 2:1 mixture of cyclohexane and ethyl acetate gave 1.18 g (79%) of the t r i c y c l i c ketal enone 44_. The physical and spectral proper-ties of this material were identical to those reported earlier. Further elution of the column gave 275 mg (18%) of the t r i c y c l i c ketal enone 132. Recrystallization of this material from a mixture of ether and pentanes gave an analytical sample: mp 136.5-137°C; uv, ^ m a x 232 nm (e = 17,000); i r / P I i r 1 N, v 1710, 1680 and 1630 cm"1; ^nmr, 6 0.60, 0.88 (CHC13) max 120 0.97 (s, s, s, 9H, tertiary methyls), 3.34-3.66 (m, 4H, ketal methylene protons), 5.87 (t, IH, C-13 proton, 3=2 Hz, W, =5 Hz). Anal, calcd. for Ci9H 2 8 ° 3 : c» 74.96; H, 9.27. Found: C, 74.93; H, 9.40. Mol. Wt. calcd. for CxgH2803: 304.2038. Found (high resolution mass spectrometry): 304. 2024. Preparation of Acyl Imidazolide 121 The acyl imidazolide 121 was prepared following the general 5 8 procedure outlined by Staab. Thus, to a stirred solution of 128 mg (1.00 mmol) of cyclohexanecarboxylic acid 122 in 10 ml of dry dichloromethane 59 under argon was added 178 mg (1.10 mmol) of N,N -carbonyldiimidazole. The resulting solution was stirred at room temperature un t i l the evolution of gas had ceased. The entire reaction mixture was transferred to a separa-tory funnel and washed with brine. The organic phase was dried (MgSO^ ) and then concentrated. The residue was recrystallized from a mixture of ether and pentanes to give 165 mg (93%) of the acyl imidazolide 121; mp 90-91.5°C ( l i t . 5 8 bp 87-88°C, 0.3 Torr); i r , ^ . N, v 1735 cm"1; ^nmr, 6 7.02, VCHL13; max 7.42, 8.13 (m, m, s, 3H, imidazale protons). 121 Preparation of Bicyclic Keto Acid 12 3 O A solution of 4.00 g (11.7 mmol) of the bicyclic keto ester 105 and 1.40 g (25.0 mmol) of potassium hydroxide in a mixture of 100 ml of 2-propanol and 25 ml of water was stirred for 2 h at 60°C. The reaction mixture was concentrated and the residue was diluted with 100 ml of water. The aqueous phase was extracted with several portions of ether and cooled to 0°C. To the cold solution was added 250 ml of 0.10 M hydrochloric acid in small portions. The s t i l l cold solution was rapidly extracted with several portions of ether. The combined extracts were washed with water and brine before being dried (MgSO^). Removal of the solvent and recrystal-lization of the residue from ether gave 3.20 g (84%) of the bicyclic keto acid 123: mp 177-179°C; l x , m n . N, v 3400-2900 and 1705 cm"1; W , r (CHCI3) max 6 0.85, 0.90, 1.13 (s, s, s, 9H, tertiary methyls),3.05-3.70 (m, 4H, ketal methylene protons), 9.10-9.70 (broad singlet, IH, -CO2H). Anal, calcd. for C, 66.64; H, 8.70. Found: C, 66.47; H, 8.56. 122 Preparation of the Bicyclic Acyl Imidazolide 124 O To a stirred solution of 232 mg (0.72 mmol) of the bicyclic keto acid 123 in 20 ml of dry dichloromethane under argon was added 117 mg 59 (0.72 mmol) of N,N -carbonyldiimidazole. The resulting solution was stirred at room temperature u n t i l the evolution of gas had ceased. The entire reaction mixture was transferred to a separatory funnel and washed with brine. The organic phase was dried (MgSOi^ ) and concentrated. The residue was recrystallized from a mixture of ether and hexanes to give 245 mg (91%) of the bicyclic acyl imidazolide 124: mp 184-186°C (with decom-position); i r , _ , „ , x, v 1710 and 1740 cm"1; W , 6 0.89, 1.03, 1.23 r (CHCI3) max (s, s, s, 9H, tertiary methyls), 3.12-3.66 (m, 4H, ketal methylene protons), 7.06, 7.24, 8.16 (m, m, m, 3H, imidazole protons). Anal, calcd. for C21H30 NzO^: C, 67.36; H, 8.07; N, 7.48. Found: C, 67.29; H, 8.04; N, 7.50. Preparation of the Tricyclic Ketal Lactone 125 123 (a) From the Reaction Between the Bicyclic Acyl Imidazole 124 and the Anion of Dimethyl Methyphosphonate (Lithium Counterion). To a stirred solution of 99.2 mg (0.80 mmol) of dimethyl methyl-phosphonate in 10 ml of dry tetrahydrofuran, under argon and cooled to -78°C, was added 0.30 ml of a 2.7 M solution of n-butyllithium in hexanes. To the resulting solution was added 150 mg (0.40 mmol) of the bicyclic acyl imidazolide 124. The reaction mixture was allowed to warm to room tempera-ture. After 18 h, the reaction mixture was concentrated and the residue was chromatographed on 7.0 g of s i l i c a gel. Elution of the column with an 8:2 mixture of benzene and ethyl acetate gave 86 mg (70%) of the t r i c y c l i c ketal lactone 125. This material was recrystallized from a mixture of ether and pentanes to give an analytical sample: mp 162-164°C; uv, ^ m a x 213 nm (e = 16,900); ir,„,01 s , v 1750, 1730 and 1640 cm"1; W n r , 6 ( . C H C I 3 } max 0.60, 0.88, 1.01 (s, s, s, 9H, tertiary methyls), 3.28-3.68 (m, 4H, ketal methylene protons), 4.41 (s, IH, C-9 proton), 5.72 (t, IH, C-12 proton, J= 2 Hz, Wj=6 Hz). Anal, calcd. for C^H^O^: C, 70.56; H, 8.55. Found: C, 69.88; H, 8.49. Mol. Wt. calcd. for C18H260i+: 306.1831. Found (high resolution mass spectrometry): 306.1838. (b) From the Reaction Between the Bicyclic Acyl Imidazolide 124 and a Solution of Salt-Free Methylenetriphenylphosphorane in Benzene. To a stirred solution of 75.0 mg (0.20 mmol) of the bicyclic acyl imidazolide 124 in 2 ml of dry tetrahydrofuran, cooled to 0°C under argon, was added 0.92 ml (0.20 mmol) of a salt-free solution of methylene-triphenylphosphorane ^ in benzene. After the reaction mixture had been stirred for 2 h at 0°C, the bath was removed and the reaction mixture was 124 allowed to warm to room temperature. After an additional 18 h, the solution was concentrated. The residue was diluted with 10 ml of a saturated aqueous solution of sodium bicarbonate. The resulting mixture was thoroughly ex-tracted with ether and the combined extracts were washed with brine before being dried (MgSOi^ ) . The solvent was removed and the residue was chromato-graphed on 5.0 g of s i l i c a gel. Elution of the column with an 8:2 mixture of benzene and ethyl acetate gave 50 mg (82%) of the t r i c y c l i c ketal lactone 125. The physical and spectral properties of this material were identical to those reported earlier. Preparation of the Bicyclic Ketal Olefin 130 O To a stirred solution of 1.93 g (12.8 mmol) of lithium diiso-propylamide in 50 ml of dry tetrahydrofuran, cooled to -78°C under argon, was added 2.62 g (9.85 mmol) of the bicyclic keto ketal 4_5. The resulting solution was allowed to warm to 0°C. After 30 min, 7.00 g (38.4 mmol) of methallyl iodide was added and the stirring was continued for another hour. The reaction mixture was concentrated, diluted with water and fi n a l l y ex-tracted thoroughly with ether. The combined extracts were washed with brine and dried (MgSOt,). Removal of the solvent and chromatography of the residue on s i l i c a gel, eluting the column with a 4:1 mixture of light petroleum ether and ether gave 2.52 g (80%) of the bicyclic ketal olefin 130. Recrys-125 ta l l i z a t i o n of this material from light petroleum ether gave an analytical sample: mp 74-76°C; i r . , v 3080, 1704 and 1624 cm"1; ^nmr, 6 v , L r l L l 3 ; max 0.85, 0.98, 1.12 (s, s, s, 9H, tertiary methyls), 1.64 (s, 3H, olefinic methyl), 3.24-3.64 (m, 4H, ketal methylene protons), 4.59, 4.71 (m, m, 2H, olefinic protons). Anal. calcd. for C2oH3203: C, 74.96; H, 10.06. Found: C, 74.94; H, 10.06. Preparation of Bicyclic Ketal Dione 131 To a stirred solution of 800 mg (2.50 mmol) of the bicyclic keto olefin 130 in a mixture of 25 ml of tetrahydrofuran and 25 ml of water, cooled to 0°C, was added a small crystal of osmium tetraoxide followed by 1.33 g (6.22 mmol) of sodium meta-periodate. The resulting mixture was allowed to warm to room temperature and was stirred at that temperature for 18 h. The reaction mixture was f i l t e r e d and the f i l t r a t e was concen-trated. The residue was extracted thoroughly with ether and the combined extracts were washed with an aqueous solution of sodium bisulphite and brine before being dried (MgSO^). The solvent was removed and recrystallization of the residue from hexanes gave 749 mg (93%) of the bicyclic ketal dione 131: mp 77-78°C; i r , m , v 1713 cm"1; ^nmr, 6 0.84, 0.98, 1.13 (s, (CHfjlo) » max s, s, 9H, tertiary methyls), 2.14 (s, 3H, -C0CH3), 2.89 (dd, IH, C - l ' proton, J=17 Hz, J=7 Hz), 3.1-3.7 (m, 5H, C-8 proton and ketal methylene protons). 126 Anal, calcd. for Cxgl^oHi,: C, 70.79; H, 9.38. Found: C, 70.66; H, 9.50 Preparation of T e t r a c y c l i c Keto Ole f i n s 56 and 57 A large pyrex tube containing a so l u t i o n of 1.00 g (3.29 mmol) of the t r i c y c l i c k e t a l enone 44_ and 10 ml of allene i n 60 ml of dry t e t r a -hydrofuran, cooled to -72°C under nitrogen, was i r r a d i a t e d (450 Watt Hanovia Lamp) for 4.5 h. The reaction mixture was transferred to a 250 ml beaker and allowed to warm to room temperature. The solvents were removed and the residue was chromatographed on 200 g of s i l i c a g e l . E l u t i o n of the column with a 10:5:2 mixture of cyclohexane, hexane, and ethyl acetate gave 4.40 mg (39%) of the t e t r a c y c l i c keto o l e f i n 57_. 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 gave an a n a l y t i c a l sample: mp 134-135°C; i r ( ^ C l 3 ) ' Vmax and 1670 cm"1; ^nmr, 6 0.87, 0.95, 0.97 (s, s, s, 9H, t e r t i a r y methyls), 3.29 (s, IH, C - l l proton), 3.43-3.62 (m, 4H, k e t a l methylene protons), 4.82, 4.97 (m, m, 2H, o l e f i n i c protons). Anal, calcd. f o r C 22 H32 03 : c . 76.70; H, 9.36. Found: C, 76.90; H, 9.47. Mol. Wt. calcd. for C22H3203= 344.2351. Found (high r e s o l u t i o n mass spectrometry): 344. 2351. Further e l u t i o n of the column gave 470 mg (42%) of the isomeric t e t r a c y c l i c keto o l e f i n 5_6. R e c r y s t a l l i z a t i o n of t h i s material from a mix-ture of ether and hexanes gave an a n a l y t i c a l sample: mp 132-134°C; *r(Qic±3)» v 1730 and 1670 cm"1; ^nmr, 6 0.88, 0.95, 0.99 (s, s, s, 9H, t e r t i a r y max 127 methyls), 2.77 (broad s, 2H, unassigned), 3.11 (m, IH, C - l l proton), 3.44-3.64 (m, 4H, ketal methylene protons), 4.78, 4.92 (m, m, 2H, C-16 protons). Anal, calcd. for C22H32O3: C, 76.70; H, 9.36. Found: C, 76.99; H, 9.63. Moi. Wt. calcd. for C22H32O3: 344.2351. Found (high resolution mass spec-tometry): 344.2343. Ozonolysis of Tetracyclic Keto Olefin 56_. Preparation of the Tricyclic Diketal Ester 136 and the Tricyclic Keto Ester 59 A stirred solution of 100 mg (0.29 mmol) of the tetracyclic keto olefin j[6 in a mixture of 15 ml of dry methanol and 5 ml of dry dichloro-methane, cooled to -78°C, was subjected to a stream of ozone u n t i l the sol-ution remained blue. The resulting solution was allowed to warm to room temperature. When the blue colour had disappeared, the solution was cooled to -78°C and 1 ml of dimethyl sulfide was added. The reaction mixture was allowed to warm to room temperature, and stirr i n g was continued for 18 h. The reaction mixture was concentrated and the residue was chromatographed on 8 g of s i l i c a gel. Elution of the column with a 3:1 mixture of light petroleum ether and ether gave 25 mg (20%) of the t r i c y c l i c diketal ester 136. A l l attempts to crystallize this material from a variety of solvents and solvent mixtures failed. When a small sample of this material was dis-t i l l e d under reduced pressure (0.02 Torr), decomposition occurred. However, 128 an analytical sample of this material was obtained by preparative t i c ( s i l i c a gel - 3:1 light petroleum ether and ether): i r (film), 1740 cm"1; ^nmr, 6 0.84, 0.94, 1.00 (s, s, s, 9H, tertiary methyls), 3.06, 3.10 (s, s, 6H, -C0(CH3)?), 3.36-3.44 (m, 4H, ketal methylene protons), 3.36 (s, 3H, -C00CH3). Mol. Wt. calcd. for 02^^006 : 424.2825. Found (high resolution mass spec-trometry): 424.2816. Further elution of the column gave 58 mg (55%) of the t r i c y c l i c keto ester 5J3. Recrystallization of this material from a mixture of ether and hexanes gave an analytical sample: mp 154-155°C; i r , _ , - - * , v 1740 (.01013} max cm"1; ^nmr, 6 0.87 (s, 3H, tertiary methyl), 0.98 (s, 6H, tertiary methyls), 3.32-3.66 (m, 4H, ketal methylene protons), 3.56 (s, 3H, -C0 2CH 3). Anal, calcd. for 022^1*05: C, 69.81; H, 9.05. Found: C, 69.86; H, 9.20. Mol. Wt. calcd. for 022^1*05: 378.2407. Found (high resolution mass spectro-metry): 378.2398. Preparation of the Tetracyclic Diketone 137 A stirred and cold (-78°C) solution of 70.0 mg (0.20 mmol) of the keto olefin 57_ in 8 ml of methanol was subjected to a stream of ozone un t i l the solution remained blue. The resulting solution vas flushed with nitrogen u n t i l the blue colour had disappeared and then 15 ul (0.20 mmol of 129 dimethyl sulfide was added. The reaction mixture was stirred at -15°C for h h, 0°C for h h and room temperature for 1 h. The solvent was removed and the residue was recrystallized from a mixture of ether and hexanes to give 64 mg (91%) of the diketone 137: mp 141-143°C; i r ( C H C 1 ), v m a x 1 7 8 0 a n d 1730 cm'1; W , 6 0.91, 1.01 1.03 (s, s, s, 9H, tertiary methyls), 3.26 (broad s, 2H, unassigned), 3.38-3.62 (m, 4H, ketal methylene protons), 3.79 (broad s, IH, C - l l methine proton). Moi. Wt. calcd. for C 2iH 3 20 6: 346.2144. Found (high resolution mass spectrometry): 346.2136 Preparation of the Tricyclic Ketal Ester 133 To a stirred solution of 9.36 mg (0.17 mmol) of sodium methoxide in 5 ml of dry methanol, under argon, was added 20.0 mg (57.8 umol) of the t r i c y c l i c diketone 137. The resulting solution was stirred at room tempera-ture for 1 h before being concentrated. The residue was diluted with 1.7 ml of a 0.10 molar solution of hydrochloric acid and the resulting solution was thoroughly extracted with ether. The combined extracts were washed with water and brine before being dried (MgS0i+) . Removal of the solvent and re-crystallization of the residue from a mixture of ether and hexanes gave 17.0 mg (80%) of the t r i c y c l i c ketal ester 133: mp 183.5-184° C; i r ( C H C l 3 ) , \ a x 1735 cm"1; ^mr, 6 0.91, 0.99, 1.01 (s, s, s, 9H, tertiary methyls), 3.38-3.59 (m, 4H, ketal methylene protons), 3.60 (s, 3H, -CO^CH^). Moi. Wt. calcd. 130 for 0221131+05: 378.2407. Found (high resolution mass spectrometry): 378. 2394. 131 BIBLIOGRAPHY 1. E. Wenkert, Chem. and Ind. t 282 (1955). 2. R. McCrindle and K.H. Averton, Advan. Org. Chem., 5_, 47 (1965). 3. K.M. Brundrett, W. Dalzlel, B. Hesp, J.A. Jarvis, and S. Meidle, J_. Chem. Soc. Chem. 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C, 501 (1966). 65. R. Pauptit and J. Trotter, unpublished results. 135 Every year is getting shorter, never seem to find the time Plans that either come to naught or half a page of scribbled lines Hanging on in quiet desperation i s the English way The time is gone the song i s over, thought I'd something more to say N. Mason, R. Waters, R. Wright, D. Gilmour 

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