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UBC Theses and Dissertations

Total synthesis of sesquiterpenoids (+)-eremophilenolide, (+)-Tetrahydroligularenolide,(+)-aristolochene,(-)-ylangocamphor,(-)-… Geraghty, M. Bert 1973

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/717* c TOTAL SYNTHESIS OF SESQUITERPENOIDS (+)-EREMOPHILENOLIDE, (+)-TETRAHYDROLIGULARENOLIDE, (+)-ARISTOLOCHENE, (-)-YLANGOCAMPHOR, (-)-YLANGOBORNEOL, (-)-YLANGOISOBORNEOL BY M. BERT GERAGHTY B . S c , University College, Galway, 1968. A THESIS SUBMITTED IN PARTIAL FULFILMENT OF THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY i n the Department of Chemistry We accept t h i s thesis as conforming to the required standard THE UNIVERSITY OF BRITISH COLUMBIA June, 1973 I n 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 r an advanced degree a t the U n i v e r s i t y o f B r i t i s h C olumbia, I agree t h a 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 agree t h a t p e r m i s s i o n f o r e x t e n s i v e c o p y i n g o f t h i s t h e s i s f o r s c h o l a r l y p urposes may be g r a n t e d by the Head o f my Department o r by h i s r e p r e s e n t a t i v e s . 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 n o t 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 . Department o f C^r g H I 5 1 ^ , The U n i v e r s i t y o f B r i t i s h Columbia Vancouver 8, Canada Date L h 7 3 d - i i -ABSTRACT The f i r s t part of t h i s thesis i s concerned with the successful development of a general synthetic approach to the eremophilane c l a s s of sesquiterpenoids, which culminated i n the t o t a l synthesis of (+)-eremophilenolide 6^ (+)-tetrahydroligularenolide 4_4 and (+)-aristolochene 34. The octalone 92_ was converted v i a an e f f i c i e n t , r e g i o s e l e c t i v e route into the keto ester 105, which served as a common synthetic intermediate f or the preparation of a l l three sesquiterpenoids. Successive subjection of 105 to a l k y l a t i o n , hydrolysis and decarboxylation afforded the keto a c i d 111. Hydrogenation of the l a t t e r provided both the cis-fused keto acid 113, which was r e a d i l y converted into (+)-eremophilen-oli d e J5, and the trans-fused keto acid 112, which was s i m i l a r l y transformed into (+)-tetrahydroligularenolide 44. Conversion of 105 i n t o the d i t h i o -k e t a l 127, followed by d e s u l f u r i z a t i o n and treatment of the resultant o l e f i n i c ester 124 with excess methyllithium, provided the o l e f i n i c alcohol 130. Dehydration of the l a t t e r yielded (+)-aristolochene 34. In the second part of t h i s t h e s i s , a s t e r e o s e l e c t i v e t o t a l synthesis of the ylango-type sesquiterpenoids, (-)-ylangocamphor 7_» (-)-ylango-borneol 2j} and (-)-ylangoisoborneol 143, i s described. The (+)-ketol 222, of known absolute stereochemistry, was converted by an e f f i c i e n t route into the keto ester 216. The l a t t e r was transformed into the bicyclo[3.2.l]octadione 203 by an intramolecular C l a i s e n condensation. Homologation of 203 to the keto aldehyde 245 was achieved by an e f f i c i e n t three-step sequence of reactions. Reaction of keto aldehyde 245 with methoxymethylenetriphenylphosphorane afforded the (+)-keto o l e f i n 204 - i i i -which could hopefully be used as a common intermediate i n the synthesis of the majority of known ylango sesquiterpenoids. Transformation of 204 into (-)-ylangocamphor _7_ was achieved by successive hydroboration, mesylation and intramolecular a l k y l a t i o n . Ylangocamphor was converted i n (-)-ylangoborneol 23 and (-)-ylangoisoborneol 143 by two completely st e r e o s e l e c t i v e reductions. - i v -TABLE OF CONTENTS Page TITLE PAGE 1 ABSTRACT 1 1 TABLE OF CONTENTS i v LIST OF FIGURES v i ACKNOWLEDGEMENTS v l ± INTRODUCTORY REMARKS 1 1. General ^ 2. Biosynthesis of Eremophilane- and Ylango-type sesquiterpenoids ^ PART I: TOTAL SYNTHESIS OF (+)-EREMOPHILENOLIDE, (+)-TETRAHYDROLIGULARENOLIDE AND (+)-ARISTOLOCHENE 10 INTRODUCTION PART I 11 1. Perspective 11 2. Or i g i n and St r u c t u r a l E l u c i d a t i o n of Eremophilenolide, Tetrahydroligularenolide and Aristolochene 17 3. Other Synthetic Approaches to Eremophilane-Type Sesquiterpenoids 26 DISCUSSION PART I 32 1. Total Synthesis of (+)-Eremophilenolide 6^  and (+)-Tetrahydroligularenolide 44 32 2. Stereochemical Proof of trans-Fused Keto Acid 112 .. 59 3. Total Synthesis of (+)-Aristolochene _34 62 EXPERIMENTAL PART I 73 - v -Page PART I I : STEREOSELECTIVE TOTAL SYNTHESIS OF (-)-YLANGOCAMPHOR, (-)-YLANGOBORNEOL AND (-)-YLANGOISOBORNEOL 93 INTRODUCTION PART II 9 4 1. Perspective 94 2. Other Synthetic Approaches to Copa and Ylango Sesquiterpenoids 99 DISCUSSION PART II 1 1 2 1. General 1 1 2 2. Synthesis of (+)-Keto O l e f i n 204 1 2 1 3. Synthesis of (-)-Ylangocamphor _7, (-)-Ylangoborneol 23, and (-)-Ylangoisoborneol 143 -^9 EXPERIMENTAL PART II 1 6 5 BIBLIOGRAPHY 1 8 9 - v i -LIST OF FIGURES Figure Page 1 Infrared Spectrum of Synthetic (+)-Eremophilenolide 6^  51 2 P.M.R. Spectrum of Synthetic (+)-Eremophilenolide 6^ . . 52 3 Infrared Spectrum of Authentic (+)-Eremophilenolide 6_ 53 4 P.M.R. Spectrum of Authentic (+)-Eremophilenolide 6^. 54 5 Infrared Spectrum of Synthetic (+)-Tetrahydroligular-enolide 44_ 57 6 P.M.R. Spectrum of Synthetic (+)-Tetrahydroligular-enolide 4_4_ 58 7 Infrared Spectrum of Synthetic (+)-Aristolochene 34_ . 68 8 P.M.R. Spectrum of Synthetic (+)-Aristolochene 34 ... 69 9 Infrared Spectrum of Authentic (-)-Aristolochene 34 . -JQ 10 P.M.R. Spectrum of Authentic (-)-Aristolpchene 34_ ... 71 11 Infrared Spectrum of (+)-Keto O l e f i n 204 1 4 5 12 P.M.R. Spectrum of (+)-Keto O l e f i n 204 1 4 6 13 Infrared Spectrum of (-)-Ylangocamphor 7_ 154 14 P.M.R. Spectrum of (-)-Ylangocamphor 1_ 155 15 Infrared Spectrum of (-)-Ylangoborneol 2_3 157 16 P.M.R. Spectrum ( i n CCl^) of (-)-Ylangoborneol 23 ... 158 17 Infrared Spectrum of (-)-Ylangoisoborneol 143 1*>1 18 P.M.R. Spectrum ( i n CC1.) of (-)-Ylangoisoborneol 143 1 6 2 - v i i -ACKNOWLEDGEMENTS I wish to thank Dr. Edward Piers f or h i s encouragement, thoughtful guidance and consistent i n t e r e s t during the course of t h i s research and the preparation of t h i s manuscript. I would also l i k e to thank Dr. Marcel Soucy, my coworker i n the research reported i n Part I I of t h i s t h e s i s , and the other members of Dr. P i e r s ' research group (past and present) f or h e l p f u l discussions and suggestions. Special thanks are due to Mr. Andrew Mar for proof reading t h i s thesis and to Miss Diane Johnson f o r her very capable typing. A s p e c i a l word of gratitude i s due to my wife f or her help i n drawing the many s t r u c t u r a l diagrams i n t h i s t h e s i s . Receipt of a f i n a n c i a l award from the B r i t i s h Columbia Sugar Refining Company and a University of B r i t i s h Columbia Graduate Fellowship are g r a t e f u l l y acknowledged. - 1 -INTRODUCTORY REMARKS 1 . General The sesquiterpenoids are a group of compounds within the b i o g e n e t i c a l l y r e l a t e d family of n a t u r a l products which are c o l l e c t i v e l y referred to as the terpenoids. The terpenoids are considered to be derived from two or more multiples of a basic b u i l d i n g u n i t , isoprene 1 2 1_. ' Thus mono terpenoids contain the equivalent of two isoprene u n i t s , sesquiterpenoids three u n i t s , diterpenoids four u n i t s , sesterterpenoids five u n i t s , t r i t e r p e n o i d s s i x units and carotenoids eight u n i t s . The sesquiterpenoids, normally containing f i f t e e n carbon atoms, have been known for a long time as constituents of the e s s e n t i a l o i l s . However, i t i s only i n r e l a t i v e l y recent times that the chemistry of these compounds has been extensively i n v e s t i g a t e d . This i s p a r t l y due to the fact that i n the e s s e n t i a l o i l s sesquiterpenoids often occur 1 - 2 -as very complex mixtures which could not be resolved by the c l a s s i c a l methods a v a i l a b l e . With the advent of modern separation techniques such as g a s - l i q u i d chromatography ( g . l . c ) , and modern spectroscopic methods such as proton magnetic resonance (p.m.r.), the structure and stereochemistry of a very large number of sesquiterpenoids have been established. Furthermore, p o l y f u n c t i o n a l sesquiterpenoids are r a r e l y found i n e s s e n t i a l o i l s because of t h e i r low v o l a t i l i t y . The s u b s t i t u t i o n of solvent extraction of plant materials f o r steam d i s t i l l a t i o n as the extraction process, has, i n recent years, been f r u i t f u l i n providing a large v a r i e t y of polyoxygenated sesquiterpenoids. As a r e s u l t of these i n v e s t i g a t i o n s , over f i f t y d i f f e r e n t sesqui-3 terpenoid s k e l e t a l types have been found to e x i s t i n nature. The d i v e r s i t y of sesquiterpenoid compounds i s m u l t i p l i e d further by stereochemical v a r i a t i o n s , the range of f u n c t i o n a l groups and by p o s i t i o n a l isomerism. Thus sesquiterpenoids may occur as a c y c l i c , monocyclic, b i c y c l i c , t r i c y c l i c or t e t r a c y c l i c hydrocarbons, a l c o h o l s , ketones, oxides or lactones, with structures as widely d i f f e r i n g as farnesene 2?* t u t i n _3,^'^ and ishwarane k? 2 3 4 - 3 -One large c l a s s of sesquiterpenoids i s the eremophilane c l a s s , which possesses the basic carbon skeleton _5, as exemplified by eremophilenolide g 6^ . For some years, the f i r s t i s o l a t e d members of t h i s class represented the only known exceptions to the "isoprene rule"^" i n the sesquiterpenoid f i e l d . Thus the carbon skeleton of the eremophilanes could not be r a t i o n a l i z e d i n terms of a simple linkage of isoprene u n i t s . Because of the existence of structures such as the eremophilanes, the 2 "isoprene r u l e " was revised to accommodate such s t r u c t u r e s , by allowing for s k e l e t a l rearrangements of the previously h e a d - t o - t a i l linked isoprene u n i t s . The eremophilane cla s s of sesquiterpenoids w i l l be the subject of discussion i n the f i r s t part of t h i s t h e s i s . The second part of t h i s thesis i s concerned with a small group of sesquiterpenoids, the ylango sesquiterpenoids. This group of compounds, 9 10 which includes structures such as ylangocamphor ]_, ' and sativene 8.,^ i s part of a larger class of s t r u c t u r a l l y r e l a t e d sesquiterpenoids which possess the bicyclo[2.2.l]heptane s k e l e t a l moiety or the r e l a t e d bicyclo[3.1.l]heptane moiety. Thus, other examples of t h i s c l a s s 12 13 of compounds are campherenone 9_ , cyclocopacamphene 10_ and a - l o n g i -pinene 1 1 . ^ The s t r u c t u r a l r e l a t i o n s h i p s within t h i s c l a s s of sesquiterpenoids w i l l be discussed l a t e r i n greater d e t a i l (see Introduction Part I I ) . - A -£ 10 11 2. Biosynthesis of Eremophilane- and Ylango-type Sesquiterpenoids The biosynthesis of sesquiterpenoids i s believed to a r i s e from the combination of the b i o l o g i c a l equivalent of three isoprene u n i t s , followed by subsequent c y c l i z a t i o n of the resultant f i f t e e n carbon unit i n a number of d i f f e r e n t ways.""""''^ The s p e c i f i c f i f t e e n carbon unit involved i n these transformations i s generally considered to be far n e s y l pyrophosphate 13_. The biosynthesis of the l a t t e r from a c e t y l CoA v i a the intermediacy of mevalonic acid 1_2 has been experimentally v e r i f i e d . " ^ On the other hand, the proposed biogenesis'^ of - 5 -0 SCoA 12 13 v i r t u a l l y a l l sesquiterpenoids from f a r n e s y l pyrophosphate 1_3_ has received r e l a t i v e l y l i t t l e experimental proof. Nevertheless, t h i s proposal o f f e r s an i n t e r e s t i n g r a t i o n a l i z a t i o n of the b i o l o g i c a l d e r i v a t i o n of the quite diverse s k e l e t a l structures found i n the sesquiterpenoid f i e l d . Since a recent comprehensive review'*"*' summarizes well the present state of th i s hypothesis, the proposed biosynthesis of the eremophilane and ylango sesquiterpenoids w i l l be discussed here i n o u t l i n e only. In order to accommodate the non-isoprenoid skeleton of the eremophilanes, trans-farnesyl pyrophosphate 1_3_ i s considered to undergo a s o l v o l y t f c c y c l i z a t i o n (or a related biogenetic process) to give a structure such as 14_. Further c y c l i z a t i o n of 1A_ gives a b i c y c l i c * intermediate 1_5_ which undergoes a 1,2-methyl s h i f t as shown, thus forming the intermediate 16_ which possesses the basic carbon skeleton of the eremophilanes. _ The representation of a formal cation i n t h i s discussion i s only a convenient symbolism, since the biosynthetic c y c l i z a t i o n s are undoubtedly enzymatically controlled and may occur v i a concerted processes. - 6 -16 15 An analogous c y c l i z e d form 18 (see Chart 1) of c i s - f a r n e s y l pyrophosphate 17 i s postulated as the precursor to the ylango sesquiterpenoids. By a 1,3-hydride s h i f t , cation 1_8 i s converted into 19_ which then c y c l i z e s to give the b i c y c l i c d e r i v a t i v e 20. The l a t t e r can c y c l i z e further i n two d i f f e r e n t ways. Thus Markownikoff c y c l i z a t i o n , followed by deprotonation affords ct-ylangene 21. On the other hand, anti-Markownikoff c y c l i z a t i o n of 20_ gives cation 22 9 which, by simple n e u t r a l i z a t i o n with water, affords ylangoborneol 23, 20 or by a 1,3-deprotonation produces cyclosativene 2k_. A l t e r n a t i v e l y , a Wagner-Meerwein rearrangement of 22_, followed by deprotonation, r e s u l t s i n sativene jS. - 8 -21 De Mayo and coworkers have postulated that a structure such as sativene might be the b i o l o g i c a l precursor to the sesquiterpenoid 22 t o x i n , helminthosporal 25^. Thus oxidative cleavage of sativene 8_ at the point i n d i c a t e d , followed by isomerization of the double bond, 21 would r e s u l t i n helminthosporal. Indeed, these workers have shown by 14 a tracer study using [2- C]-mevalonic acid that the unsaturated aldehyde carbon atom i n helminthosporal Z5 contained approximately one-t h i r d of the t o t a l incorporated a c t i v i t y . Thus i f the postulated de r i v a t i o n of helminthosporal from sativene i s c o r r e c t , t h i s r e s u l t supports the general o u t l i n e of the biogenetic scheme given above for sativene 8. CHO 25 An a l t e r n a t i v e hypothesis f o r the biogenesis of ylango s e s q u i t e r -penoids from a f i f t e e n carbon isoprenoid precursor has recently been 23 proposed. Thus, dihydrocryptomerion enol phosphate 2j6 i s envisaged as undergoing c y c l i z a t i o n to give campherenone 9_. The enol phosphate de r i v a t i v e of the l a t t e r could again c y c l i z e i n an analogous manner to give ylangocamphor _7_. Reduction of ylangocamphor to ylangoborneol 23 and s o l v o l y s i s of the l a t t e r gives the previously encountered cation 2^2 (see Chart 1). The formation of other ylango sesquiterpenoids from t h i s cation i s considered to occur by the mechanisms previously mentioned. PART I TOTAL SYNTHESIS OF (+)-EREMOPHILENOLIDE, (+)-TETRAHYDROLIGULARENOLIDE AND (+)-ARIS TOLOCHENE - 11 -PART I INTRODUCTION 1. Perspective The f i r s t n a t u r a l l y occurring sesquiterpenoids found to possess the eremophilane carbon skeleton _5, eremophilone 27, hydroxydihydro-eremophilone 28^  and hydroxyeremophilone 29_, were i s o l a t e d i n 1935 from the wood of Eremophila M i t c h e l l i by B r a d f i e l d , Penfold and 24 25 Simonsen. ' The work concerned with the s t r u c t u r a l e l u c i d a t i o n of these compounds extended over a number of years, leading eventually to 25 the formulation of the correct s k e l e t a l s t r u c t u r e s . Confirmation of the gross structures and a determination of the r e l a t i v e configuration of a l l three of the natural products was f i n a l l y secured i n the l a t e 26 27 1950's by the X-ray c r y s t a l l o g r a p h i c analysis ' of hydroxydihydro-28 eremophilone 2%_, and by the unambiguous c o r r e l a t i o n of 2]_ a n ^ 29. with j!8. At about that time, further examples of the presence i n plants of the b i o g e n e t i c a l l y anomalous eremophilanes began to emerge, 3 and the number of known n a t u r a l l y occurring eremophilanes has grown rapi d l y ever s i n c e . To date, approximately seventy d i f f e r e n t 3 eremophilanes have been i s o l a t e d and characterized. Because of space requirements, i t i s not f e a s i b l e to include a chart of a l l of these stru c t u r e s . However, i t does seem desirable to comment on the - 12 -28 29 v a r i a t i o n s on the b a s i c eremophilane s k e l e t o n which have given r i s e to such a l a r g e group of r e l a t e d compounds. The d i s t i n g u i s h i n g feature of the eremophilanes, apart from t h e i r non-isoprenoid carbon skeleton 5_, i s the c i s r e l a t e d v i c i n a l methyl groups. In a d d i t i o n , approximately one-half of the known n a t u r a l l y o c c u r r i n g eremophilanes possess the i n t e r e s t i n g c i s - f u s e d d e c a l i n 29 system as e x e m p l i f i e d by fukinone _30. (See Chart 2. S t r u c t u r e s shown do not n e c e s s a r i l y imply absolute c o n f i g u r a t i o n s ) . The occurrence of trans-fused and of C^-oxygenated eremophilane-type n a t u r a l products 30 31 i s r a r e . However, furanoligularenone J31 and euryopsol 32 provide, r e s p e c t i v e l y , an example of each type. The remainder of the - 13 -eremophilane-type sesquiterpenoids possess a double bond at the C ^ Q bridgehead p o s i t i o n . This double bond can occur i n e i t h e r r i n g , as 32 33 exemplified by the isomeric p a i r valencene 13 ' and aristolochene 34.3 4 Despite the r e s t r i c t i o n s imposed by the basic carbon skeleton, by the thus f a r i n v a r i a b l e presence of c i s v i c i n a l methyl groups and by the presence of mainly two types of r i n g f u s i o n , a great v a r i e t y of compounds e x i s t s within the eremophilane family of sesquiterpenoids. The isopropyl-type side-chain provides the basis for some of t h i s v a r i e t y . For example, t h i s three-carbon fragment i s 35 36 found as the saturated isopropyl group i n nardostachone 15 ' and 37 38 as the t e r t i a r y alcohol moiety i n v a l e r i a n o l 36. ' More often i t i s encountered i n the unsaturated forms, both as the isopropenyl group (see valencene 33) and as the isopropylidene moiety (see fukinone 30). In the former case, the question of stereochemistry at a r i s e s , and compounds possessing both alpha and beta substituents have been i s o l a t e d , including the epimeric p a i r valencene _33 and eremophilene 39 37. In approximately one-half of the known cases t h i s side-chain i s further o x i d i z e d , giving r i s e to ei t h e r the a,6-unsaturated 40 Y-lactone system as i n the p e t a s i t o l i d e s J38 or the c l o s e l y r e l a t e d 41 furan system as i n 9-hydroxyfuranoeremophilane 39_. The remaining s t r u c t u r a l v a r i a t i o n s i n the eremophilanes are based mainly on annular unsaturation and the presence of ketonic and hydroxyl fu n c t i o n a l groups at one or more of the secondary annular carbon atoms. The former can vary from the highly conjugated 42 warburgin 4_0, to aristolochene J34_ which possesses only a s i n g l e , - 15 -i s o l a t e d annular double bond. The hydroxyl-containing compounds are exemplified by 9-hydroxyfuranoeremophilane 39_ and the trihydroxy compound, euryopsol 32. Two small groups of recently i s o l a t e d sesquiterpenoids are considered within the eremophilane family, although they possess modified carbon skeletons. One group, the bakkanes, have the basic 43 44 structure of bakkenolide A 41, ' which i s f u n c t i o n a l l y the simplest known member. Approximately nine bakkanes are known to date, the others d i f f e r i n g from 41 i n the nature of the substituents at and Cg. The bakkanes can be regarded as eremophilanes which have undergone a r i n g contraction from a s i x - to a five-membered r i n g . The second 45 46 7 group, containing ishwarone A2_ (R = 0) ' and ishwarane 4_ (R = I^), as the only known members to date, possesses an i n t e r e s t i n g carbon skeleton whose r e l a t i o n s h i p to the eremophilanes i s evident. For the sake of completeness, i t i s appropriate to mention here the a r i s t o l a n e s , possessing the carbon skeleton 43, which are now generally regarded as a separate class of sesquiterpenes from the eremophilanes. 41 4, 42 43 Even though, as mentioned previ o u s l y , the number of known eremo-philane-type sesquiterpenoids i s large,and i n s p i t e of considerable t o t a l e f f o r t on the part of a number of research groups, only a few of - 16 -the s t r u c t u r a l l y f a i r l y simple members of t h i s c l a s s have y i e l d e d to * t o t a l synthesis. The work described i n the f i r s t part of t h i s thesis was aimed at the development of a general synthetic pathway to the eremophilanes. Since, as mentioned e a r l i e r , so many of the eremophilanes contain e i t h e r the a,g-unsaturated y-lactone or furan f u n c t i o n a l i t i e s and since a f a c i l e method of converting the former f u n c t i o n a l group into the l a t t e r was a v a i l a b l e , ^ i t was decided to synthesize two sesquiterpenoids containing the unsaturated lactone moiety. In a l l , three eremophilanes were t o t a l l y synthesized, eremophilenolide 6^ , tetrahydroligularenolide 4_4, and aristolochene 34_, each containing a 44 d i f f e r e n t l y fused decalin system. It seems appropriate to describe next the work which led to the establishment of the structure and stereo-chemistry of these three sesquiterpenoids. * To date, the following eremophilane-type and s t r u c t u r a l l y c l o s e l y r e l a t e d aristolane-type sesquiterpenoids have been t o t a l l y synthesized: ( + ) - a r i s t o l o n e ,4 7» 4 8 (+)-calarene,4^ (+)-dehydrofukinone,50 (+)-eremoligenol,51,52 (+)-eremophil-3,ll-diene,53 (+)-eremophilene,^'-'2 (+)-fukinone,54~58 (+)_hydroxyeremophilone,58 (+)-ishwarane,59 (+)-isonootkatone (a-vetivone)60>61 (-)-isonootkatone (a-vetivone),62 (+)~nootkatone,61,63-65 (-)-nootkatone,6^ (+)-7-epi-nootkatone,36,61 (+)-tetrahydroeremophilone,66 (+)-valencene,52 and (+)-valerianol.52 - 17 -2. O r i g i n and S t r u c t u r a l E l u c i d a t i o n of Eremophilenolide, Tetrahydro- l i g u l a r e n o l i d e and Aristolochene 68 (+)-Eremophilenolide was i s o l a t e d from Petasites o f f i c i n a l i s 8 Moench. by Sorm and coworkers i n 1961 and was subsequently shown to possess structure and absolute stereochemistry as depicted i n 6^ This s t r u c t u r a l determination w i l l be summarized i n the following paragraphs. H H 6 Absorption bands at 1760 and 1693 cm i n the i n f r a r e d spectrum of eremophilenolide (^..I^O) indicated the presence of an a, g-unsaturated y-lactone, while the u l t r a v i o l e t absorption maximum at 220-224 my (log e = 4.16) was consistent with t h i s chromophore. C a t a l y t i c hydrogenation (acetic acid-platinum oxide) gave dihydroeremophilenolide 45 (see Chart 3) which exhibited an i n f r a r e d absorption at 1780 cm ^ t y p i c a l of a saturated y l a c t o n e . Reduction of 45_ with l i t h i u m aluminum hydride afforded the d i o l 46. Further reduction of the d i t o s y l a t e d e r i v a t i v e of 4_6_ with l i t h i u m aluminum hydride gave a mixture of compounds from which the tetrahydrofuran d e r i v a t i v e 4_7 could be i s o l a t e d . This compound was i d e n t i c a l with the product of c a t a l y t i c hydrogenation of the n a t u r a l l y occurring furanoeremophilane 4 8 . ^ - 18 -In order to determine whether the termination point of the lactone i n eremophilenolide was C, or C o J dihydroeremophilenolide 45 was o o — reduced with l i t h i u m aluminum hydride under c o n t r o l l e d c o n d i t i o n s , thus y i e l d i n g the hydroxy aldehyde 49. The l a t t e r was subjected to Huang-Minion reduction, followed by Jones oxidation of the r e s u l t i n g alcohol 50 to give the ba s e - l a b i l e ketone 51_. Epimerization of the l a t t e r under basic conditions afforded the base-stable ketone 52. Ketone _52 was also obtained i n the following manner. C a t a l y t i c hydrogenation of the acetate of hydroxyeremophilone 29_> ° f known absolute s t e r e o c h e m i s t r y , ^ followed by successive reductive removal of the acetate groups In the r e s u l t i n g keto acetates f>3 with calcium i n l i q u i d ammonia and oxidation of the over-reduced keto group, produced a mixture of two ketones i n the r a t i o of 1:1. Since both of these ketones were base-stable, and since one was shown to be i d e n t i c a l with the known trans-fused decaLone _54,^ the remaining one had to be the cis-fused decalone d e r i v a t i v e 52_. In keeping with t h i s , 51_ exhibited a negative Cotton e f f e c t , superimposed on a p o s i t i v e background, which i s c h a r a c t e r i s t i c of A/B cis-fused 3-keto s t e r o i d s . Decalone 52, thus obtained, was i d e n t i c a l with the sample obtained from eremophileno-l i d e 6>. This conversion of eremophilenolide 6^  and hydroxyeremophilone 29 into a common intermediate, established Cg as the lactone terminus i n 6^ , and i t also proved the absolute configuration of (+)-eremophilenolide as that depicted i n structure j>. If the lactone terminus i n eremophilenolide 6^  i s a-oriented, the c a t a l y t i c hydrogenation of th i s compound should occur predominantly - 20 -from the beta face of the molecule (see 6a), thus giving r i s e eventually to the ketone 51_. Consideration of the conformational e q u i l i b r i a of 5_1_ and i t s C^ epimer 52_ shows that 52a, the preferred conformation of 52, i s thermodynamically more stable than 51a', the 52a 52a' favored conformation of _5_1. This i s due mainly to the fa c t that i n 51a', the secondary methyl group possesses an a x i a l o r i e n t a t i o n (with respect to r i n g A). Therefore decalone 51_ should be b a s e - l a b i l e as was a c t u a l l y observed. A p p l i c a t i o n of the modified Klyne-Hudson r u l e , ^ * using the molecular r o t a t i o n values of -12° f o r 45 and +42° for 47, 72 supported the 8a (R) stereochemical assignment. Although tetrahydroligularenolide 44^  has not yet been i s o l a t e d from 73 74 natural sources, i t has been obtained, ' i n high y i e l d , by palladium-catalyzed hydrogenation of the n a t u r a l l y occurring ( - ) - l i g u l a r e n o l i d e 73 55. The l a t t e r was i s o l a t e d i n 1968 from the herb "San-Shion", the root of a L i g u l a r i a species. The assignment of structure and absolute configura-73 74 t i o n to both compounds ' was based upon s p e c t r a l evidence and upon the c o r r e l a t i o n of 44 with a compound of known absolute stereochemistry. Ligularenolide 55 ( C 1 c H 1 o 0 „ ) exhibited absorption bands i n the i n f r a r e d spectrum c h a r a c t e r i s t i c of an a,6-unsaturated y-lactone (1764, 1648 and 1621 cm ^ ) , while the u l t r a v i o l e t spectrum indicated the presence of a conjugated system [ X m a x 261 and 331 my (e = 3560 and 20,700)]. The p.m.r. spectrum showed the presence of three methyl groups, primary, secondary and v i n y l at x 9.03, 9.00 and 8.09 r e s p e c t i v e l y ; of two v i n y l protons at T 4-21 and 4.08; and of an a l l y l i c methylene group which gave r i s e to a doublet ( J = 16.5 Hz) at T 7.15 and a broadened doublet ( J = 16,5 Hz) at T 7.78. - 22 -By extensive use of proton magnetic double and t r i p l e resonance experiments, i t was shown that long-range spin-couplings existed between the two v i n y l protons (J = 0.8 Hz), between the a l l y l i c proton ( T 7.78) and; the t e r t i a r y methyl group (J = 0.5 Hz), and between the same a l l y l i c proton and the v i n y l methyl group (J = 1.7 Hz). This suggested that the v i n y l methyl group was attached to the double bond i n the lactone r i n g and that the angular methyl group and the a l l y l i c proton ( T 7.78) were both a x i a l . These observations led to the p a r t i a l working structure 56^  which was extended to the f u l l structure 55_ from biogenetic considerations and on the basis of the observed features of long-range spin-couplings. C a t a l y t i c hydrogenation of (+)-ligularenolide 5_5 y i e l d e d the (-)-tetrahydro d e r i v a t i v e (0^^202) — which w a s named t e t r a h y d r o l i g u l a r -enolide. The u l t r a v i o l e t [X 222 my (e = 24,000)] and the i n f r a r e d max (v 1765,1745 and 1678 cm *") s p e c t r a l data indicated that the a, 8-max unsaturated y-lactone system was s t i l l i n t a c t . In the p.m.r. spectrum, the v i n y l proton signals were absent and a complex m u l t i p l e t (width at h a l f height = ca. 22 Hz) due to the proton at the lactone terminus (Cg) was evident. The large width at h a l f height of t h i s Cg proton s i g n a l , and the presence of long-range spin-couplings between i t and the o l e f i n i c methyl protons, implied that the C proton was a x i a l . o That tetrahydroligularenolide did indeed possess structure 44 was shown by the conversion of compound 5_7 into t e t r a h y d r o l i g u l a r e n o l i d e . 30 The former, a known compound prepared from n a t u r a l l y occurring (+)-30 furanoligularenone 31^ ° f known absolute stereochemistry, when treated with 2,3-dichloro-5,6^dicyanobenzoquinone (DDQ), afforded the enol - 23 -H H 31 57 58 lactone 58, contaminated with 44^ Hydrogenation of t h i s mixture over 5% palladium on charcoal gave pure 44_, the i n f r a r e d and p^m.r. spectra of which were i d e n t i c a l with those of t e t r a h y d r o l i g u l a r e n o l i d e . A molecular model indicates that hydrogenation of 58_ i s l e s s hindered from the alpha face and thus the expected product should have an a-oriented Cg hydrogen, as was implied also by the p.m.r. spectrum. The absolute configuration of (-)-tetrahydroligularenolide and the (+)-ligularenolide follow from the conversion of (+)-furanoligularenone 31 i n t o (-)-tetrahydroligularenolide and are those represented i n structure 4_4 and 5_5 r e s p e c t i v e l y . - 24 -The hydrocarbon (-)-aristolochene 4^_ was recently (1970) i s o l a t e d ^ from the roots of A r i s t o l o c h l a i n d l c a . The structure and absolute stereochemistry were determined^ from s p e c t r a l data of ^4 and der i v a t i v e s thereof, and by d i r e c t c o r r e l a t i o n of 34 with (+)-nootkatane, of known absolute stereochemistry. 34 33 The i n f r a r e d spectrum of aristolochene ( ^ 5 ^ 2 4 ^ — ' d i f f e r e n t 32 33 from that of the s t r u c t u r a l l y c l o s e l y r e l a t e d valencene 33_, ' showed the presence of a terminal methylene group with absorptions at 3080, 1648 and 886 cm- 1, and of a t r i s u b s t i t u t e d double bond with a band at 810 cm The u l t r a v i o l e t spectrum showed that the double bonds were not congjugated. In t;he p.m.r. spectrum, the presence of a primary, a secondary and a v i n y l methyl group was evident from the s i n g l e t at x 9.05, the doublet (J = 6 Hz) at T 9.17 and the broad s i g n a l at T 8.30 r e s p e c t i v e l y . The terminal o l e f i n i c protons and the v i n y l protons of the t r i s u b s t i t u t e d double bond gave r i s e to a broad s i n g l e t at x 5.33 and a broad mul t i p l e t at x 4.75 r e s p e c t i v e l y . Selenium-dehydrogenation of aristolochene 34_ afforded eudalene 59 (see Chart 4 ) , suggesting ei t h e r the eremophilane or the eudesmane carbon skeleton f o r the former compound. Hydrogenation of aristolochene, using deactivated Raney n i c k e l , afforded the dihydro d e r i v a t i v e (C^ 5H26^ - 25 -Chart 4 - 2 6 -6 0 , the p.m.r. spectrum of which indicated the s e l e c t i v e saturation of the terminal o l e f i n . The l a t t e r was subjected to successive hydro-boration with oxidative workup ( a l k a l i n e hydrogen peroxide), chromium t r i o x i d e oxidation of the r e s u l t i n g mixture of alcohols and homogenization of the product over basic alumina, to a f f o r d the trans-fused decalone 6 1 , This decalone was converted i n t o i t s ethylene d i t h i o k e t a l d e r i v a t i v e 6 2 , the mass spectrum of which showed an intense peak at m/e 1 7 3 due to the ion J 5 3 . ^ This suggested that the t r i s u b s t i t u t e d double bond was i n the r i n g to which the isopropyl side-chain was attached. C a t a l y t i c hydrogenation of aristolochene over platinum oxide afforded two hydrocarbons. One was 7-epi-eremophilane 6 4 . The other was (+)-nootkatane 6 5 , which was i d e n t i c a l i n a l l respects with an 4 5 authentic sample of (+)-nootkatane, prepared from (+)-valencene 3 3 . This c o r r e l a t i o n provided a d i r e c t chemical proof for the assignment of structure 3 4 to aristolochene, including absolute stereochemistry. 3 . Other Synthetic Approaches to Eremophilane-Type Sesquiterpenoids While i t i s not p o s s i b l e , i n the i n t e r e s t s of b r e v i t y , to discuss here each of the syntheses of eremophilane-type sesquiterpenoids reported to d a t e , ^ i t does seem pertinent to present a few representative examples. The f i r s t t o t a l synthesis of an eremophilane sesquiterpenoid, was that of isonootkatone (a-vetivone) 7_3, reported i n 1 9 6 7 by M a r s h a l l , Faubl and Warne.^ The key reaction i n t h e i r sequence was the condensation of 2-carbomethoxy-4-isopropylidenecyclohexanone 66_ with trans -3-penten -2-one 6 7 i n the presence of potassium t^-amylate i n _t-amyl - 27 -a l c o h o l . This afforded, a f t e r c y c l i z a t i o n and dehydration, the keto ester 68^ as a r e a d i l y p u r i f i a b l e c r y s t a l l i n e m a t e r i a l . K e t a l i z a t i o n of 68^ , and reduction of the carbomethoxy group i n the r e s u l t i n g k e t a l 69_ to the methyl group (69 -*• 7_0 J_l 72) gave, a f t e r k e t a l h y d r o l y s i s , isonootkatone 7_3. The l a t t e r showed s p e c t r a l properties i d e n t i c a l with those of the n a t u r a l l y occurring m a t e r i a l . 72 X=H Considerable e f f o r t has since been devoted to the synthesis of 76 63 nootkatanes, but each approach (excepting one ) has also involved a s i m i l a r Robinson annelation of a s u i t a b l y substituted cyclohexanone de r i v a t i v e with trans-3-pentene-2-one. Coates and Shaw also used t h i s technique to generate the cis-dimethyl system i n the dione _75_ (see - 28 -Chart; 5) which led to the synthesis of a number of eremophilane-type 49 51 52 sesquiterpenoids. ' ' Thus condensation of the p y r r o l i d i n e enamine 7_ of 2-methylcyclohexane~l,3-dione with trans-3-pentene-2-one gave a mixture of the c i s - and trans-dimethyloctalones 75, varying i n r a t i o from 1:1 to 1:10 r e s p e c t i v e l y depending on the reaction conditions employed. Selective t h i o k e t a l i z a t i o n of the 1:1 mixture, followed by d e s u l f u f i z a t i o n of the r e s u l t i n g t h i o k e t a l s with Raney n i c k e l , afforded a mixture of the c i s - and trans-dimethyloctalones 76 and 7_7, which were separated by f r a c t i o n a l d i s t i l l a t i o n of the mixture through a spinning-band column. Reaction of the cis-dimethyl octalone 76_ with d i e t h y l carbonate, i n the presence of sodium hydride, produced the corresponding 8-keto ester as a mixture of the keto and enol tautomers, formulated here as 78. The l a t t e r , when treated with methyllithium, followed by acid-catalyzed dehydration of the r e s u l t i n g 6-hydroxy ketone, gave r i s e to the a,g-unsaturated ketone 7_9. Treatment of t h i s ketone with hydrazine, followed by thermal decomposition of the r e s u l t i n g pyrazoline 80 over powdered potassium hydroxide, afforded racemic A ^ * ^ -a r i s t o l e n e 81, which was i d e n t i c a l i n a l l respects (except o p t i c a l a c t i v i t y ) w i t h an authentic sample from plant sources. Subjection of keto ester _78 to a l k y l a t i o n with chloromethyl methyl ether i n hexamethylphosphoramide afforded the enol ether d e r i v a t i v e 82. Reduction of the l a t t e r with l i t h i u m i n j l i q u i d ammonia, followed by appropriate work-up, produced the o c t a l i n ester 83_. The formation of the less stable a x i a l epimer was presumably the r e s u l t of k i n e t i c a l l y c o n t r o l l e d protonation (during work-up) of the ester enolate from the less hindered equatorial d i r e c t i o n . Reaction of t h i s ester with - 29 -Chart 5 - 30 -85 36 Chart 5 (cpnt.) methyllithium afforded eremoligenol 8A_ which, when dehydrated, y i e l d e d eremophilene 37_. Eremoligenol and eremophilene thus obtained exhibited s p e c t r a l properties i d e n t i c a l with those of the corresponding n a t u r a l l y occurring m a t e r i a l s . Because of the a x i a l nature of the carbethoxy group i n 83, t h i s compound was epimerizable to the more stable ester 85_. Subjection of the l a t t e r to methyllithium addition and subsequent dehydration produced v a l e r i a n o l J36 and valencene _33 r e s p e c t i v e l y . The s p e c t r a l data of 36_ and 33 were i d e n t i c a l with those obtained f or the n a t u r a l l y occurring m a t e r i a l s . A d i f f e r e n t approach to the introduction of the cis-dimethyl system 53 i n eremophilanes was explored by Piers and Keziere i n t h e i r synthesis of eremophil-3,11-diene 90_. Condensation of the hydroxymethylene derivative 86_ of 3-isopropenylcyclohexanone with l-diethylamino-3-pentanone methiodide 8_7 gave, a f t e r c y c l i z a t i o n , the octalone 88. Stereoselective introduction of the angular methyl group was accomplished by reaction of octalone 88 with l i t h i u m dimethylcuprate, thus y i e l d i n g the cis-dimethyl decalone de r i v a t i v e 89_. The tosylhydrazone d e r i v a t i v e of the l a t t e r was reacted with sodium ethylene glycolate i n r e f l u x i n g - 31 -90 89 ethylene g l y c o l , y i e l d i n g as major product racemic eremophila-3,11-diene £ 0 . Structure £ 0 was o r i g i n a l l y p r oposed^ for n a t u r a l l y occurring eremophilene but a comparison of the synthetic material with an authentic sample of eremophilene showed them to be d i f f e r e n t . The 3° structure of eremophilene was l a t e r revised to that of 37. - 32 -PART I DISCUSSION 1. Total Synthesis of (+)-Eremophilenolide 16 and Tetrahydroligularenolide 44 In an attempt to develop a r a t i o n a l , general, synthetic scheme for the synthesis of compounds of the eremophilane family of se s q u i t e r -penoids, the t o t a l synthesis of (+)-eremophilenolide 6^ , ( ^ - t e t r a -hydroligularenolide 4_4_ and (+)-aristolochene 34_ was undertaken. Taken together, these three compounds incorporate most of the problems posed H H H H 6 44 34 i n the synthesis of eremophilanes. Their common stereochemical feature, the only one common to a l l the eremophilane sesquiterpenoids, i s the presence of the d i s t i n c t i v e , v i c i n a l , c i s - r e l a t e d methyl substituents. The introduction of th i s system at an early stage of the synthesis would be of greatest use s y n t h e t i c a l l y , since at leas t a p a r t i a l common synthesis to the three compounds was de s i r e d . The common intermediacy - 33 -of a substituted octalin-type d e r i v a t i v e with the unsaturation at the bridgehead p o s i t i o n (A*) was also d e s i r a b l e . Such a compound could then be elaborated to give aristolochene 34, and hopefully could also be s e l e c t i v e l y hydrogenated to a f f o r d both the c i s and trans r i n g junctions required f or the synthesis of eremophilenolide 6_ and t e t r a -hydroligularenolide 44 r e s p e c t i v e l y . At the outset of t h i s work i n 1969, a number of approaches to the construction of the c i s dimethyl system of various eremophilanes had been attempted, but most had f a i l e d to provide a s t e r e o s e l e c t i v e method 78 of accomplishing t h i s . In connection with a synthetic proof of the stereochemistry of a r i s t o l o n e _91, an annelation of 2,3-dimethylcyclo-hexanone had been developed i n our laboratory, which resulted i n the 79 47 57 59 stereo s e l e c t i v e synthesis of the s y n t h e t i c a l l y e l u s i v e ' ' octalone 92. It was f e l t that t h i s octalone provided an i d e a l synthetic precursor to the eremophilanes and it . was thus adopted as an intermediate i n the present synthesis. Not only did t h i s compound s a t i s f y the requirement with regard to the c i s - r e l a t e d v i c i n a l methyl groups but i t also posses$ed the desired unsaturation at the r i n g junction which hopefully could be manipulated as mentioned above. In a d d i t i o n , the - 34 -ketone f u n c t i o n a l i t y was s t r a t e g i c a l l y placed for the i n t r o d u c t i o n of the remaining three-carbon unit required f o r the completion of the syntheses. This f u n c t i o n a l i t y would also provide the oxygen atom at C 0 which was necessary for the i n t r o d u c t i o n of the lactone f u n c t i o n a l i t y o present i n eremophilenolide 6^  and t e t r a h y d r o l i g u l a r e n o l i d e 44. The octalone 92^  was prepared from 2,3-dimethylcyclohexanone 9_3 79 by the method previously mentioned. Thus, the l a t t e r , r e a d i l y a v a i l a b l e s t a r t i n g material was converted i n 78% y i e l d into the 6-n-81 butylthiomethylene de r i v a t i v e 9_4 (see Chart 6) i n the usual manner. A l k y l a t i o n of the l a t t e r with e t h y l 3-bromopropionate i n the presence 81 of potassium _t-butoxide i n _t-butyl alcohol produced, i n 85% y i e l d , a mixture of the keto esters 95. Removal of the n-butylthiomethylene 81 blocking groups from 9_5_ was achieved i n the normal way (potassium hydroxide i n hot aqueous diethylene gl y c o l ) and was accompanied by hydrolysis of the ester group. The product, a mixture of the keto acids 96_, was obtained i n 90% y i e l d . When th i s mixture of keto acids was refluxed i n a c e t i c anhydride containing sodium a c e t a t e , ^ there was produced, i n 85% y i e l d , a c r y s t a l l i n e material which consisted of a mixture of the two epimeric enol lactones 97_ and j>8_ i n the approximate r a t i o of 9:1 r e s p e c t i v e l y (as judged by the p.m.r. spectrum). The major desired epimer 97 could r e a d i l y be separated from the mixture i n 80% y i e l d by c a r e f u l r e c r y s t a l l i z a t i o n of the l a t t e r from n-hexane. This enol lactone 97_ was converted, i n 70% y i e l d , into the desired octalone 92_ by reaction of the former with methyllithium i n dry ether at - 2 5 ° , followed by successive acid hydrolysis and base-catalyzed a l d o l c y c l i z a t i o n and dehydration. - 35 -6 34 Chart 6 - 36 -The octalone 9_2 could be s e l e c t i v e l y reduced to a f f o r d e i t h e r the 54 79 c i s - f used decalone 9_9 or the trans-fused decalone 100. Thus, t h i s octalone might be considered a s u i t a b l e branch-point f o r the synthesis of the three sesquiterpenoids under d i s c u s s i o n . However, while i t was an t i c i p a t e d that the octalone 9_2 and the decalone 100 could be r e g i o s e l e c t i v e l y alkylated at the desired p o s i t i o n s (and subsequently be transformed into aristolochene _3_4 and t e t r a h y d r o l i g u l a r -enolide 4_4 r e s p e c t i v e l y ) , i t was f e l t that the c i s - f used decalone 99_ (the corresponding precursor to eremophilenolide 6) would present a 82 major problem i n t h i s regard. Indeed, exploratory work performed i n our laboratory on the cis - f u s e d decalone 99, had indicated that a l k y l a t i o n at the p o s i t i o n was not a f e a s i b l e process. Thus, attempted a l k y l a t i o n of J39_ with e t h y l 2-bromopropionate or with methyl bromoacetate i n _t-butyl alcohol i n the presence of potassium b-butoxide, afforded a complex mixture of products. On changing the base and the solvent to triphenylmethylsodium (tritylsodium) and 1,2-dimethoxy-ethane r e s p e c t i v e l y , s i m i l a r r e s u l t s were obtained. Furthermore, i n an e f f o r t to at l e a s t avoid the problem of p o l y a l k y l a t i o n , 99_ was converted 83 by standard procedures into the mixture of enamine d e r i v a t i v e s 101 and 102, which were obtained i n a r a t i o of 2:3 r e s p e c t i v e l y . Attempted a l k y l a t i o n of t h i s mixture with ethyl 2-bromopropionate was also unsuccessful. Some alk y l a t e d product was obtained using methyl bromoacetate as a l k y l a t i n g agent, but the y i e l d was low, e s p e c i a l l y low i n the desired product because of the unfavorable r a t i o of the s t a r t i n g enamines. - 37 -102 104 A more favorable r a t i o was obtained of the corresponding enol acetates 103 and 104, formed from the decalone j?9_ and isopropenyl 84 acetate under e q u i l i b r a t i n g conditions. The r a t i o of 103 to 104 84 was 3:2 r e s p e c t i v e l y . When the mixture of li t h i u m enolates corresponding to 103 and 104 was reacted with e t h y l 2-bromopropionate, the spectra of the products obtained were not i n agreement with those predicted f or the desired compound. In view of these preliminary r e s u l t s , i t was f e l t that the elaboration of the cis-fused decalone 99_ to eremophilenolide 6_ would prove to be an i n e f f i c i e n t process, and hence t h i s transformation - 38 -was not attempted. Since the d i f f i c u l t y i n s e l e c t i v e l y a l k y l a t i n g decalone 99 at the p o s i t i o n stemmed at l e a s t p a r t i a l l y from the 85 c i s nature of the r i n g f u s i o n , i t was decided to introduce the side-chain at p r i o r to the generation of the cis-f u s e d r i n g j u n c t i o n . 86 On the basis of l i t e r a t u r e precedent, the d i r e c t a l k y l a t i o n of octalone 92_ would be expected to r e s u l t i n p r e f e r e n t i a l a l k y l a t i o n at the C^ p o s i t i o n , not at the desired p o s i t i o n . Therefore i n order to al k y l a t e r e g i o s e l e c t i v e l y at the p o s i t i o n , an a c t i v a t i n g group would f i r s t have to be introduced at this p o s i t i o n . Since a common synthetic precursor to the three sesquiterpenoids was d e s i r a b l e , the keto ester 105 was chosen as the activated form of octalone 92_. The d i r e c t a l k y l a t i o n of t h i s keto ester would hopefully r e s u l t i n an intermediate which could be s e l e c t i v e l y hydrogenated to a f f o r d both the ci s - f u s e d and 1 92 105 the trans-fused intermediates required for the synthesis of the two lactone-containing sesquiterpenoids. The elaboration of the carbomethoxy group i t s e l f ( i n 105) would a f f o r d the isopropenyl side-chain required for aristolochene 3^ synthesis. The keto ester 1Q5 was obtained from the octalone 9j2 by means of an e f f i c i e n t and completely r e g i o s e l e c t i v e synthetic route as outlined i n Chart 7. The octalone 92 was converted into the hydroxymethylene d e r i v a t i v e 106,"*4 i n quantitative y i e l d , by standard procedures^'*' (ethyl formate i n benzene i n the presence of sodium methoxide). 87 Dehydrogenation of the l a t t e r with 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ) i n dioxan afforded, i n 95% y i e l d , the c r y s t a l l i n e cross-conjugated keto aldehyde 107. The s p e c t r a l properties of t h i s material were consistent with structure 107. Of p a r t i c u l a r i n t e r e s t i n the i n f r a r e d spectrum were the four absorption bands at 1700, 1660, 1625 and 1600 cm "*" In the p.m.r. spectrum the aldehydic proton and the 8-vinyl proton were evident as sharp s i n g l e t s at x -0.33 and 2.17 r e s p e c t i v e l y , while the a-vinyl proton gave r i s e to a broadened s i n g l e t at x 3.80. The t e r t i a r y methyl group appeared as a s i n g l e t at x 8.76 and the secondary 88 methyl group as an unresolved m u l t i p l e t at x 8.87. 89 Oxidation of the keto aldehyde 107 with s i l v e r oxide afforded the c r y s t a l l i n e keto acid 108 i n 89% y i e l d . The presence of the carboxyl group was evidenced i n the i n f r a r e d spectrum by the broad absorption band at 3600-2280 cm ^ and i n the p.m.r. spectrum by the broad s i n g l e t at x -3.55. The s i n g l e t due to the aldehydic proton had disappeared. E s t e r i f i c a t i o n of the keto acid 108 was c a r r i e d out by reacting i t 90 with methyl ipdide i n the presence of s i l v e r oxide. The corresponding keto ester 109 was thus obtained i n 96% y i e l d . The conversion of compound 109 into the desired keto ester 105 required the s e l e c t i v e reduction of one of the t r i s u b s t i t u t e d o l e f i n i c double bonds i n 109. This was accomplished, i n 86% y i e l d , by reduction of 109 with sodium borohydride i n pyridine s o l u t i o n . I t has been 91 shown that such reaction conditions can be used to s e l e c t i v e l y reduce - 40 -an o l e f i n i c double bond which i s conjugated with two carbonyl groups as i n 109, without reducing e i t h e r of the carbonyl f u n c t i o n a l i t i e s themselves. The keto ester thus obtained, exhibited s p e c t r a l properties i n complete agreement with structure 105. The i n f r a r e d spectrum of 105 showed an absorption at 1740 cm ^ for the ester carbonyl group, and bands at 1670 and 1620 cm due to the a ,B-unsaturated ketone. That the desired reduction had indeed taken place was evident from the p.m.r. spectrum. Thus the s i g n a l due to the 6-vinyl proton had disappeared and a new s i g n a l , a doublet of doublets (J = 13.0 and 6.0 Hz), was evident at T 6.57. The l a t t e r s i g n a l was a t t r i b u t e d to the C_ proton. 1 105 109 108 Chart 7 - 41 -Since the work-up of the reduction r e a c t i o n j u s t described involved epimerizlng conditions, the keto ester 105 was expected to possess the thermodynamically more stable configuration at which i s that shown i n structure 105. The p.m.r. spectrum supported t h i s , since the observed proton coupling constants, J = 13.0 and 6.0 Hz, are i n agreement with those expected for the coupling of an a x i a l 92 proton to the a x i a l and equatorial protons r e s p e c t i v e l y . An a l t e r n a t i v e , d i r e c t conversion of the octalone 9_2 i n t o the keto esfer 105 inv o l v i n g base-promoted condensation of the former with dimethyl carbonate was also considered. However, on the basis of 86a l i t e r a t u r e precedent, i t was f e l t that a reaction of t h i s type would r e s u l t i n carbomefhoxylation of 92_ at as w e l l as at the desired p o s i t i o n (C^), and hence t h i s reaction was not attempted i n the present 58 synthesis. Indeed, t h i s d i r e c t conversion was l a t e r attempted and the product, although claimed to be 105, was not obtained c r y s t a l l i n e and no c r i t e r i o n of p u r i t y was given. Attempted a l k y l a t i o n of the sodium enolate of keto ester 105 with ethyl 2-bromopropionate i n r e f l u x i n g benzene, resulted i n an almost quantitative recovery of s t a r t i n g m a t e r i a l . On changing the a l k y l a t i n g reagent to methyl bromoacetate, however, there was obtained, under the same reaction conditions, a quantitative y i e l d of the keto d i e s t e r 110. The f a i l u r e to a l k y l a t e with ethyl 2-bromopropionate meant that the f i n a l carbon atom required to complete the syntheses, would have to be introduced at a l a t e r stage. The s p e c t r a l data obtained for the product of successful a l k y l a t i o n were i n agreement with structure 110. The i n f r a r e d spectrum c l e a r l y - 42 -showed the presence of the two ester carbonyl groups with absorptions at 1740 and 1720 cm Consistent with t h i s were the two s i n g l e t s at T 6.35 and T 6.41 i n the p.m.r. spectrum. The quartet a t t r i b u t e d to the C^ proton i n the s t a r t i n g material had disappeared, but the C^ v i n y l proton was s t i l l evident as a broad s i n g l e t at T 4.22. Thus the a l k y l a t i o n reaction had proceeded i n the desired r e g i o s e l e c t i v e manner. In a d d i t i o n , since the presence of only one diastereomeric product was in d i c a t e d , t h i s r e a c t i o n was also s t e r e o s e l e c t i v e . Although the stereochemistry of the product was not rig o r o u s l y proven, l i t e r a t u r e 93 precedent indicated that the newly alkylated center should possess the configuration shown i n 110. In any event, t h i s point was not c r u c i a l , since the next step of the synthesis involved h y d r o l y s i s and decarboxyla-t i v e removal of the t e r t i a r y carbomethoxy group. 1 105 110 111 Treatment of the die s t e r 110 with sodium hydroxide i n r e f l u x i n g ethanol-water f or t h i r t y minutes, provided the c r y s t a l l i n e keto acid 111 i n 82% y i e l d . This material exhibited the expected s p e c t r a l p r o p e r t i e s . Of p a r t i c u l a r pertinence i n the i n f r a r e d spectrum was the -1 -1 broad band at 3600-2400 cm and the absorption at 1710 cm due to the carboxyl group. The broad s i n g l e t at T -1.30 i n t^he p.m.r. spectrum was at t r i b u t e d to the exchangeable carboxylic acid proton. Since t h i s - 43 -keto acid was formed under epimerizlng conditions the stereochemistry at Cj i s undoubtedly that i n d i c a t e d . The epimeric compound would possess a 1,3-diaxial i n t e r a c t i o n between the angular methyl group and the a c e t i c acid side-chain. In order to obtain (from 111) a synthetic intermediate s u i t a b l e for elaboration into eremophilenolide, i t was necessary to reduce the double bond of 111 so as to produce the corresponding c i s - f u s e d decalone system. On the other hand, reduction to a trans-fused decalone was required f o r the production of a su i t a b l e precursor to tetrahydro-l i g u l a r e n o l i d e . Hydrogenation of 111 i n ethanol over palladium on charcoal afforded, i n q u antitative y i e l d , the c r y s t a l l i n e trans-fused keto acid 112. I t was subsequently shown by an independent synthesis that compound 112 ha4 the trans-fused configuration (vide i n f r a ) . This compound gave a strong absorption band at 1705 cm i n the i n f r a r e d spectrum, due to the two carbonyl groups and, i n the p.m.r. spectrum, showed no s i g n a l due to a v i n y l proton. The t e r t i a r y methyl group gave r i s e to a s i n g l e t 88 at x 9.00 and the secondary methyl group to an unresolved m u l t i p l e t at T 9.12. Subjection of keto acid 111 to hydrogenation with palladium on charcoal under basic conditions (ethanolic sodium hydroxide) afforded a quantitative y i e l d of a mixture of the cis-fused decalone 113 and the previously obtained trans-fused compound 112 i n a r a t i o of approximately 2:3 re s p e c t i v e l y (as determined by the p.m.r. spectrum). At t h i s stage, * Unless otherwise noted, eremophilane system numbering w i l l be hejiceforth employed. - 44 -considerable e f f o r t was expended i n order to f i n d conditions which would increase the proportion of the desired c i s - f u s e d keto a c i d 113. Eventually i t was found that hydrogenation of 111 i n ethanolic sodium hydroxide using rhodium on charcoal as c a t a l y s t , gave improved r e s u l t s . However, under these conditions the ketone carbonyl group was also reduced, and i t was therefore necessary to oxidize the i n i t i a l l y formed hydrogenation product. This was r e a d i l y accomplished by t r e a t i n g the crude product with ruthenium dioxide-sodium periodate under basic 94 conditions. There was thus obtained, i n quantitative y i e l d , a mixture of the cis-fused decalone 113 and the trans-fused decalone, 112 i n a r a t i o of approximately 3:2 r e s p e c t i v e l y . The two keto acids were - 45 i s o l a t e d i n pure form by c a r e f u l f r a c t i o n a l c r y s t a l l i z a t i o n of t h i s mixture from hexane-benzene. The s p e c t r a l properties of the c r y s t a l l i n e cis-fused decalone 113 were i n complete agreement with the structure shown. In the i n f r a r e d spectrum, the carbonyl groups gave r i s e to a common absorption at 1708 cm the carboxyl group e x h i b i t i n g a further broad band at 3600-2400 cm Of pertinence i n the p.m.r. spectrum was the s i n g l e t at 88 x 9.09 due to the t e r t i a r y methyl group, and the clean doublet (J = 7.0 Hz) at x 9.12 due to the secondary methyl group. Since bpth the hydrogenation and oxidation reactions were c a r r i e d out under b a s i c , epimerizing conditions, the stereochemistry (at C 7) of the 114a 114a 113a' 113a - 46 -cis-fused keto acid should be as indicated i n 113. The l a t t e r , on the basis of conformational a n a l y s i s , would be more stable than the corresponding epimeric (at C^) compound. Thus 113a, the preferred conformation of 113, i s thermodynamically more stable than 114a' the preferred conformation of the epimer of 113. This i s mainly due to the fact that the secondary methyl group i s i n an a x i a l o r i e n t a t i o n (with respect to r i n g A) i n 114a'. The stereochemical outcome of the hydrogenation reactions j u s t described merits further comment. The e f f e c t of increasing the r a t i o of cis-fused decalone products by employing basic conditions i n the c a t a l y t i c hydrogenation of octalone d e r i v a t i v e s had previously been 95 observed, i n p a r t i c u l a r instances. In our own laboratory, the c a t a l y t i c hydrogenation of octalone 92_ and i t s hydroxymethylene d e r i v a t i v e 106, when performed under basic c o n d i t i o n s , yielded only the correspond-54 ing c i s - f u s e d products. On the basis of these l a t t e r r e s u l t s , a higher r a t i o of the cis-fused decalone 113 was expected on hydrogenation of the s t r u c t u r a l l y related octalone 111 under s i m i l a r reaction c o n d i t i o n s . The low r a t i o a c t u a l l y obtained i n t h i s instance may r e f l e c t the 1,3-diax i a l - t y p e i n t e r a c t i o n generated (between -CH-C0„H and C,), as the - 47 -acet i c acid side-chain i s forced towards the unstable a x i a l p o s i t i o n i n the t r a n s i t i o n s t a t e , leading to the cis - f u s e d product. When the cis-fused keto acid 113 was subjected to standard l a c t o n i z a t i o n conditions ( r e f l u x i n g a c e t i c a c i d i n the presence of sodium a c e t a t e ^ ) , the expected unsaturated lactone 115 was produced i n very low y i e l d . The s p e c t r a l data of the crude reaction product mixture indicated that the major component was the mixed anhydride of the keto acid 113 and a c e t i c a c i d . Analogous r e s u l t s were obtained with the trans^fused keto acid 112. However, on tr e a t i n g the ci s - f u s e d keto acid 113 with p_-toluenesulfonic acid i n r e f l u x i n g toluene under a Dean-Stark water separator, there was obtained, i n 97% y i e l d , a c r y s t a l l i n e mixture of 11-demethyleremophilenolide 115 and 8 - e p i - l l -demethyleremophilenolide 116, i n a r a t i o of approximately 7:3 r e s p e c t i v e l y . R e c r y s t a l l i z a t i o n of th i s mixture afforded the desired (+)-11-demethyl-eremophilenolide 115 i n 55% y i e l d . The s p e c t r a l data supported the proposed structure for t h i s l a t t e r compound. Thus the u l t r a v i o l e t spectrum of 115 exhibited on absorption maximum at 216 my, while the in f r a r e d spectrum showed bands at 1780, 1745 and 1650 cm * c h a r a c t e r i s t i c of t h i s type of lactone f u n c t i o n a l i t y . The p.m.r. spectrum revealed a v i n y l proton as an unresolved m u l t i p l e t (width at h a l f height = 5.0 Hz) at x 4.31, while the very broad unresolved m u l t i p l e t at x 5.26 (width at h a l f height = 19 Hz) was assigned to the Cg proton. The doublet 74 (J = 14.0 Hz) at x 7.10 was a t t r i b u t e d to the C, equator i a l proton, o the s i n g l e t at T 8.99 to the t e r t i a r y methyl group and the doublet (J = 6.0 Hz) at x 9.23 to the secondary methyl group. - 48 -H H H H H 0 + 116 0 Attempts to obtain a pure sample of 8-epi-ll-demethyleremophilen-o l i d e 116 were not s u c c e s s f u l . However, the s p e c t r a l data obtained on the mother l i q u o r s (containing 115 and 116, r a t i o 1:2 respectively) of r e c r y s t a l l i z a t i o n of the l a c t o n i z a t i o n product supported the assigned s t r u c t u r e . Thus the i n f r a r e d spectrum exhibited absorption bands at 1785, 1750 and 1640 cm In the p.m.r. spectrum, the presence of a v i n y l proton was evident from the unresolved m u l t i p l e t (width at h a l f height =4.0 Hz) at T 4.24. The broad unresolved mul t i p l e t (width at h a l f height = 20 Hz) at x 5.07 was a t t r i b u t e d to the Cg proton, while the two doublets ( J = 14.0 Hz) at T 7.00 and 7.87 were assigned to the C^ protons. The secondary and t e r t i a r y methyl groups gave r i s e to a doublet (J = 6.6 Hz) at T 8.97 and a s i n g l e t at x 9.13 r e s p e c t i v e l y . That the major product of l a c t o n i z a t i o n was 11-demethyleremophilenolide 115 and not 8-epi-demethyleremophilenolide 116 was supported by the following evidence. As mentioned above, subjection of keto acid 113 to l a c t o n i z a t i o n conditions ( r e f l u x i n g toluene i n the presence of p_-toluenesulfonic acid) for 3 hours afforded 115 and 116, i n the r a t i o of approximately 70:30 r e s p e c t i v e l y . When the reaction was allowed to - 49 -proceed f o r 6 hours, the r a t i o of 115 to 116 increased to approximately 85:15 r e s p e c t i v e l y . Under the epimerizing conditions of the r e a c t i o n , the thermodynamically more stable product should predominate. On the basis of conformational a n a l y s i s , 11-demethyleremophilenolide 115 i s thermodynamically more stable than 8-epi-ll-demethyleremophilenolide 116. Thus a comparison of 115a, the preferred conformation of 11-demethyl-eremophilenolide, and 116a, the a l l - c h a i r conformation of 8 - e p i - l l -demethyleremophilenolide, shows that the l a t t e r i s thermodynamically less favored, mainly because of the a x i a l o r i e n t a t i o n (with respect to r i n g A) of the secondary methyl group. A s i m i l a r comparison of 115a with the 115a 115a' 0 0 116a 116a' H - 50 -a l t e r n a t i v e conformation 116a* of 8-epj-ll-demethyleremophilenolide, shows that the l a t t e r i s also l e s s favored thermodynamically, due to the presence i n the l a t t e r of the twist-boat conformation i n r i n g B. The f i n a l carbon required f o r completion of the synthesis of eremophilenolide 6. was introduced v i a an a l k y l a t i o n r e a c t i o n . Thus 11-demethyleremophilenolide 115 was treated with t r i t y l s o d i u m , and the r e s u l t i n g enolate was reacted with methyl iodide to give racemic eremophilenolide 6^ , i n 61% y i e l d . That the desired a l k y l a t i o n had occurred was evident from the s p e c t r a l data of the product. Thus, i n the u l t r a v i o l e t spectrum, an absorption maximum appeared at 220 my, while, i n the i n f r a r e d spectrum, the absorption band at 1780 cm ^ had now disappeared, i n d i c a t i n g the absence of the proton. This was confirmed" by the p.m.r. spectrum which, although s i m i l a r to that of the s t a r t i n g lactone, showed no s i g n a l due to a v i n y l proton. Instead, an unresolved m u l t i p l e t was evident at T 8.21, at t r i b u t e d to the newly introduced v i n y l methyl group. The i n f r a r e d (Figure 1) and p.m.r. (Figure 2) spectra of synthetic (+)-eremophilenolide thus prepared, were i d e n t i c a l with those of an authentic sample of natural (+)-eremophil-* enolide ( i n f r a r e d spectrum, Figure 3; p.m.r. spectrum, Figure 4 ) . The previously mentioned mother l i q u o r s of r e c r y s t a l l i z a t i o n , containing a 1:2 mixture of 11-rdemethyleremophilenolide 115 and 8-epl-11-demethyleremophilenolide 116, also proved to be s y n t h e t i c a l l y u s e f u l . Thus a l k y l a t i o n of t h i s mixture with methyl iodide under conditions We are very g r a t e f u l fo Professor V. Herout f o r a sample of (+)-eremophilenolide. o ce O UJ o oo 2 2 z> z IU J CM 0) •rt . - I O c CD a. o 0 CD U W I + 1 4 J .c c >. w <4-l O g u 4 J o w a) M u >4-l C <u u 3 60 •H 3 5 0 0 3 0 0 0 2 5 0 0 2 0 0 0 1800 1600 W A V E N U M B E R (CM"') 1400 1200 1 0 0 0 8 0 0 U1 Figure 3. Infrared Spectrum of Authentic (+)-Eremophilenolide J5. - 55 -H H H H 116 i d e n t i c a l with those used i n the a l k y l a t i o n of pure 11-demethyl-eremophilenolide, also afforded (+)-eremophilenolide, i n 52% y i e l d . The trans-fused keto acid 112 was converted i n t o ( ^ - t e t r a h y d r o -l i g u l a r e n o l i d e 44_ by a sequence of reactions i d e n t i c a l with that described above for the conversion of the cis-fused keto acid 113 i n t o (+)-eremophilenolide 6_. Lactonization of 112 y i e l d e d the c r y s t a l l i n e (+)-ll-demethyltetrahydroligularenolide 117 i n 94% y i e l d . This material exhibited s p e c t r a l properties s i m i l a r to those of (+)-H-demethyleremophilenolide 115. Thus, the u l t r a v i o l e t spectrum exhibited an absorption maximum at 216 my and the i n f r a r e d spectrum - 56 -the expected absorption bands at 1780, 1745 and 1645 cm ^ . The p.m.r. spectrum revealed an unresolved m u l t i p l e t (width at h a l f height = 4.0 Hz) at x 4.34 due to the v i n y l proton and a broad unresolved m u l t i p l e t (width at h a l f height =» 19.0 Hz) at T 5.33 due to the C g proton. The doublet ( J = 13.0 Hz) at T 7.25 was assigned to the equatorial protonJ4 the poorly resolved d o u b l e t ^ ( J = 5.5 Hz) at T 9.15 to the secondary methyl group and the s i n g l e t at T 9.36 to the t e r t i a r y methyl group. The assignment of configuration to the C 0 p o s i t i o n of the lactone o product 117 was based on the fact t h a t , as i n 11-demethyleremophilenolide 115, the thermodynamically more stable product was expected under the e q u i l i b r a t i n g conditions of the r e a c t i o n . Thus structure 117a i s thermodynamically favored over 118a, since r i n g B i n the l a t t e r possesses the twist-boat conformation. Methylation of 117 afforded racemic t e t r a h y d r o l i g u l a r e n o l i d e 44, i n 59% y i e l d . The expected changes i n the s p e c t r a l data were observed. Accordingly, there was a s h i f t i n the absorption maximum i n the u l t r a -v i o l e t spectrum to 220 my, and the absorption band at 1780 cm i n the in f r a r e d spectrum of the s t a r t i n g material disappeared. In the p.m.r. spectrum the s i g n a l due to the v i n y l proton had disappeared, and an unresolved m u l t i p l e t was now evident at T 8.21, at t r i b u t e d to the newly introduced v i n y l methyl group. Although an authentic sample of (-)-tetrahydroligularenolide was not obtained, the i n f r a r e d (Figure 5) and p.m.r. (Figure 6) spectra of the synthetic racemate thus prepared, 73 74 agree very well with the published data. ' 1 I I •• I • • i I -I i ' 1 1 ' 1 ' 1 1 1 1 ' 1 ' " 1 • 1 ' • ' I • • l - I I l • ' 1 I I i -I l -l 'I l I I I I I I I I I I I 00 Figure 6. P.M.R. Spectrum of S y n t h e t i c ( + ) - T e t r a h y d r o l i g u l a r e n o l i d e 44. 117a 118a 2. Stereochemical Proof of trans-Fused Keto Acid 112 Since one of the objectives of the synthesis of a natural product i s generally to provide unambiguous evidence f o r a s t r u c t u r a l proposal, i t was important to prove unequivocally the stereochemistry of the r i n g junqtion i n the two decalones, 112 and 113, obtained by hydrogenation of the corresponding octalone 111. The hydrogenation reactions which afforded a mixture of two products were performed under b a s i c , e q u i l i b r a t i n g conditions, and i t could therefore r e a d i l y be concluded that the two products were not merely epimers of one type of ring-fused product. Consequently, the c o n f i g u r a t i o n a l difference was at the C n - 60 -r i n g junction p o s i t i o n . Thus an unambiguous synthesis of one of the keto acids 112 or 113 would provide proof of the stereochemistry of the other keto acid a l s o . 100 99 In view of the previously mentioned (see p. 36 ) f a i l u r e to a l k y l a t e the cis-fused decalone 99, i t was decided to use the 79 corresponding, known, trans-fused decalone 100 f o r the present stereochemical proof. Decalone 100 was prepared from octalone 9_2 by successive B i r c h 79 reduction and oxidation. Treatment of t h i s trans-fused decalone 100 84 with isopropenyl acetate-p_-toluenesulfonic acid afforded a mixture of the corresponding enol acetates 119 and 120, i n a r a t i o of approximately - 61 -3:2 r e s p e c t i v e l y . Reaction of t h i s mixture with two equivalents of 84 methyllithium i n dimethoxyethane, followed by the addition of methyl bromoacetate, gave a mixture of compounds from which a sample of the keto ester 121 could be i s o l a t e d by column chromatography. A l k a l i n e hydrolysis of 121 yiel d e d the keto acid 112, which was i d e n t i c a l i n a l l respects (m.p., mixed m.p., i n f r a r e d and p.m.r. spectra) with the product obtained by hydrogenation of octalone 111 under neutral conditions (vide supra). 112 121 120 The above synthetic proof of the stereochemistry of the trans-fused keto acid 112 established the trans-nature of the r i n g fusion i n tetrahydroligularenolide 4_4. S i m i l a r l y , i t confirmed the c i s r e l a t i o n s h i p - 62 -of the r i n g fusion i n eremophilenolide 6_. The assignment of s t e r e o -chemistry to the asymmetric lactone terminal p o s i t i o n s (C Q) i n o eremophilenolide 6_ and t e t r a h y d r o l i g u l a r e n o l i d e 44_, was based on the generation of these centres under e q u i l i b r a t i n g c o n d i t i o n s , the structures 6^  and 44 being i n each case the thermodynamically more stable epimers (vide supra). H H H H 44 3. Total Synthesis of (+)-Aristolochene 34 Aristolochene 3h_ was also s u c c e s s f u l l y synthesized from the key intermediate keto ester 105. An i d e a l precursor to aristolochene was the o l e f i n i c ester 124 and hence the i n i t i a l objective was reduction of the C£ keto group i n 105 to the methylene group. It was f e l t that a convenient method of accomplishing t h i s was by reduction of 105 to the corresponding alcohol 122, a c e t y l a t i o n (or equivalent) of the l a t t e r , and, f i n a l l y , reductive cleavage of the r e s u l t i n g acetate 123 (or equivalent). - 63 -105 122 R - H 123 R = Ac I When the keto ester 105 was treated with excess sodium borohydride i n methanol at room temperature f o r one hour, the crude product obtained consisted of three compounds. These were the s t a r t i n g material 105, the desired alcohol 122 and a t h i r d component which appeared to be the d i o l 125. While such unwanted reductions of g-carbonyl esters 96 to the corresponding d i o l s are known to occur, sometimes the reaction conditions can be c o n t r o l l e d to give a good y i e l d of the monoalcohol 96 product. A l l e f f o r t s i n the present instance f a i l e d i n t h i s regard. Indeed, attempts to obtain the d i o l i n high y i e l d were also unsuccessful, so t h i s approach was not investigated f u r t h e r . - 64 -OH OH 105 122 125 An a l t e r n a t i v e method of reducing a keto group to the methylene group i s by successive t h i o k e t a l i z a t i o n and d e s u l f u r i z a t i o n . When the keto ester 105 was reacted neat with 1,2-ethanedithiol i n the presence of boron t r i f l u o r i d e - e t h e r a t e , a c r y s t a l l i n e product was obtained i n good y i e l d . This was not the desired t h i o k e t a l 127 however, rather i t appeared to be the i n t e r e s t i n g t h i o k e t a l lactone 126, as deduced from a preliminary a n a l y s i s . When the reaction conditions were modified by employing a c e t i c acid as solvent, there was produced, i n quantitative y i e l d , a c r y s t a l l i n e mixture of the desired t h i o k e t a l 127 and i t s epimer 128 i n a r a t i o of approximately 4:1 r e s p e c t i v e l y . The former could very r e a d i l y be i s o l a t e d i n pure form by r e c r y s t a l l i z a t i o n of the mixture from methanol. The s p e c t r a l properties of t h i s material were i n complete agreement with structure 127. Accordingly, the inf r a r e d spectrum showed one carbonyl absorption at 1728 cm ^ due to the ester f u n c t i o n a l i t y . The p.m.r. spectrum revealed a s i n g l e t at T 4.32 due to the v i n y l proton, and a mult i p l e t at x 6.52-6.99 which was assigned to the -SC^C^S- group and the proton. The three methyl groups gave r i s e to a s i n g l e t at T 6.32 (methoxy methyl), a 88 s i n g l e t at T 9.07 ( t e r t i a r y methyl) and an unresolved m u l t i p l e t at T 9.15 (secondary methyl). - 65 -De s u l f u r i z a t i o n of 127 with Raney n i c k e l i n r e f l u x i n g ethanol, followed by p u r i f i c a t i o n of the crude product by preparative g . l . c , afforded the desired o l e f i n i c ester 124 i n 63% y i e l d . In the p.m.r. spectrum of t h i s compound the expected broadening of the v i n y l proton si g n a l had occurred. It now appeared as a broad unresolved m u l t i p l e t at f 4.72. The signals due to the three methyl groups were also c l e a r l y evident. The mother l i q u o r s remaining from the r e c r y s t a l l i z a t i o n of t h i o k e t a l 127 were also found to be s y n t h e t i c a l l y u s e f u l . These mother l i q u o r s were composed of a mixture of 127 and 128 i n a r a t i o of approximately 1:2 r e s p e c t i v e l y . D e s u l f u r i z a t i o n of t h i s mixture yielded a mixture - 66 -of the o l e f i n i c esters 124 and 129 ( r a t i o 1:2 r e s p e c t i v e l y ) . E q u i l i b r a t i o n of the l a t t e r mixture with sodium methoxide i n methanol, followed by p u r i f i c a t i o n of the resultant material ( r a t i o of 124 to 129 = 9:1) by preparative g . l . c , also provided pure 124. 128 129 Because the o l e f i n i c ester 124 i s thermodynamically more stable than i t s epimer 129, the formation of the former i s favored under e q u i l i b r a t i o n conditions. Consequently, the e q u i l i b r a t i o n r e a c t i o n j u s t described f i r m l y established the configuration (at C^) of the keto ester derived from the major product of t h i o k e t a l i z a t i o n as that shown i n structure 124. Hence the major t h i o k e t a l product i t s e l f must possess the stereochemistry shown i n 127. - 67 -When the o l e f i n i c ester 124 was allowed to react with an excess of methyllithium i n r e f l u x i n g ether, the corresponding o l e f i n i c a lcohol 130 was obtained i n 95% y i e l d . The i n f r a r e d spectrum of t h i s material showed a strong hydroxyl absorption at 3380 cm while the p.m.r. spectrum exhibited two s i n g l e t s at T 8.84 and T 8.85, a t t r i b u t e d to the newly introduced methyl groups. Dehydration of 130 with t h i o n y l chloride i n pyri d i n e at 0 ° , followed by p u r i f i c a t i o n of the crude product by column chromatography on s i l v e r nitrate-impregnated s i l i c a g e l , gave pure racemic aristolochene 34, i n 43% y i e l d . The presence of the terminal o l e f i n was evidenced i n the i n f r a r e d spectrum by absorption bands at 3075, 1645 and 887 cm \ and i n the p.m.r. spectrum by the unresolved m u l t i p l e t at T 5.31. The in f r a r e d (Figure 7) and p.m.r. (Figure 8) spectra, and g . l . c . retention times of th i s synthetic product were i d e n t i c a l with those of authentic (-)-aristolochene ( i n f r a r e d spectrum, Figure 9; p.m.r. spectrum, Figure 10). We are indebted to Dr. T.R. Govindachari f or a sample of (-)-aristolochene. ON 00 — , , — _ _ _ — , 1 I — — — I 1 I 1— 3 0 0 0 2500 2 0 0 0 1800 1600 1400 1200 1000 8 0 0 WAVENUMBER (CM"') Figure 7. I n f r a r e d Spectrum of Synthetic (+)-Aristolochene 34_. - 69 \ 1 01 c X! O O U < I —. + 1 o •H 4 J O) •C 4-1 CO I M •W O QJ & CO P i a co 01 3 60 •H fa - 70 -- 71 -p->| c 0) CJ o CO •H M <: i a •H es 0) x: 4-> o % u 4-1 o <u p< C O PS S P-I 0) (-4 60 •H fa - 72 -In conclusion, a general synthetic approach to the eremophilane class of sesquiterpenoids has been developed. The construction of a large number of eremophilanes i s conceivable from an intermediate such as the s y n t h e t i c a l l y v e r s a t i l e keto ester 105. The f e a s i b i l i t y of t h i s approach i s demonstrated by the unambiguous t o t a l synthesis of (+)-eremophilenolide, (+)-tetrahydroligularenolide and (+)-aristolochene. This synthesis f u l l y corroborates the structures proposed for these three sesquiterpenoids. - 73 -PART I EXPERIMENTAL Melting p o i n t s , which were determined on a K o f l e r block, and b o i l i n g points are uncorrected. U l t r a v i o l e t spectra were measured i n methanol s o l u t i o n on a Unicam, model SP 800, spectrophotometer. O p t i c a l rotations were measured with a Perkin-Elmer, model 141, polarimeter. Routine i n f r a r e d spectra were recorded on e i t h e r a Perkin-Elmer model 137, 710 or 457 spectrophotometer. The l a t t e r instrument was employed for a l l comparison i n f r a r e d spectra. The p.m.r. spectra were taken i n deuterochloroform s o l u t i o n (unless otherwise noted) on Varian Associates spectrometers, models A-60, T-60 and/or HA-100 or XL-100. Signal positions are given i n the T i e r s T s c a l e , with t e t r a -methylsilane as an i n t e r n a l standard; the m u l t i p l i c i t y , integrated peak areas and proton assignments are indicated i n parentheses. Gas-liquid chromatography (g.l.c.) was c a r r i e d out on Aerograph g . l . c . u n i t s , models 700 or 90-P. The following columns were employed: Column Length Stationary Phase Support Mesh A 10 f t x 1/4 i n 20% SE 30 Chromosorb W 60/80 B 20% Carbowax I I I I C 5 f t x 1/4 i n 20% SE 30 I I II D 10 f t x 3/8 i n 30% SE 30 II - 74 -E 10 f t x 1/4 i n 10% FFAP Chromosorb W 60/80 F " 20% Apiezon J G 5 f t x 1/4 i n 3% SE 30 H 10 f t x 1/4 i n 10% OV-210 " " I " 8% FFAP Chromosorb G " The s p e c i f i c column used, along with column temperature and c a r r i e r gas (helium) flow-rate ( i n ml/min), are indicated i n parentheses. Column chromatography was performed using f l o r i s i l (Fisher S c i e n t i f i c Co.), neutral s i l i c a gel (Camag or Macherey, Nagel and Co.) or neutral alumina (Camag or Macherey, Nagel and Co.). The alumina was deactivated as required by addition of the correct amount of water. Microanalyses were performed by Mr. P. Borda, M i c r o a n a l y t i c a l Laboratory, Uni v e r s i t y of B r i t i s h Columbia, Vancouver. Preparation of the Hydroxymethylene Derivative 106 To an ice - c o o l e d , s t i r r e d suspension of powdered sodium methoxide (26.0 g, 0.50 mole) i n 700 ml of dry benzene and 25 g (0.338 mole) of ethyl formate, under an atmosphere of nitrogen, was added 40 g (0.222 mole) of octalone £ 2 . The ice-bath was removed and the rea c t i o n mixture was s t i r r e d overnight at room temperature. Water was added with external c o o l i n g , and the layers were separated. The organic layer was extracted with two portions of 10% aqueous sodium hydroxide. The combined aqueous layer and a l k a l i n e extracts were washed once with ether, a c i d i f i e d with 6 N hydrochloric a c i d and thoroughly extracted with ether. The combined ether extracts were washed with water, with b r i n e , and dried over anhydrous magnesium s u l f a t e . Removal of the solvent and d i s t i l l a t i o n of the r e s u l t i n g residue afforded 32.0 g (100%, based on unrecovered s t a r t i n g material) of the hydroxymethylene de r i v a t i v e 106 as yellow c r y s t a l s , b.p. 115-120° at 0.3 mm. An a n a l y t i c a l sample, obtained by vacuum sublimation, exhibited m.p. 6 8-71°; u l t r a v i o l e t , X 248 my (e = 9,280), 311 my (e = 3,860); i n f r a r e d IflcLX (CHC1 3), v m a x 1645, 1560 cm"1; p.m.r., T 0.0 (broad m u l t i p l e t , 1H, =CH0H), 2.61 (broad s i n g l e t , 1H, =CH0H), 4.21 (broad s i n g l e t , 1H, v i n y l H), 9.04 ( s i n g l e t , 3H, t e r t i a r y methyl),.9.08 (unresolved m u l t i p l e t 3H, secondary methyl). Anal. Calcd. for C 1 0H 1 00_: C, 75.69; H, 8.79. Found: C, 75.99; 1,3 l O Z H, 8.73. The combined benzene layer and ether wash were washed twice with brine and dried over anhydrous magnesium s u l f a t e . Removal of the solvents gave 11.84 g of the s t a r t i n g m a t e r i a l , octalone 92. In the p.m.r. spectrum of each of the compounds 34, 106-112, i n c l u s i v e 124, 127, and 130, the s i g n a l due to the secondary methyl group appeared as a broad band, with very l i t t l e r e s o l u t i o n , while i n compounds 44_ and 117 t h i s s i g n a l appeared as a poorly resolved ^ doublet. Presumably t h i s was, i n each case, due to v i r t u a l coupling. In contrast, the secondary methyl group of compounds J5, 113 and 115 gave r i s e , i n each case, to a clean, well-resolved doublet with the expected coupling constant (6-7 Hz). This observation was eventually used quite con s i s t e n t l y to d i s t i n g u i s h between those compounds of th i s s e r i e s possessing a trans (or t r a n s - l i k e ) r i n g fusion and those possessing a c i s ri n g f u s i o n . - 76 -Preparation of Keto Aldehyde 107 f " r-—" 1 ' To a s o l u t i o n of 5.0 g (24.2 mmoles) of the hydrpxymethylene de r i v a t i v e 106 i n 250 ml of dry dioxan was added a s o l u t i o n of 5.8 g (29.8 mmoles) of 2,3-dichloro-5,6-dicyanobenzoquinone (DEQ) i n 250 ml of dry dioxan. The reactipn mixture was s t i r r e d under an atmosphere of nitrogen at room temperature f o r 10 min and then d i l u t e d with 1150 ml of dichlorpmethane. The r e s u l t i n g mixture was f i l t e r e d and the f i l t r a t e was passed quickly through a short column of neutral alumina. The alumina was eluted with an a d d i t i o n a l 500 ml of dichlpromethane. Evaporation of the combined dichloromethane s o l u t i o n afforded 4.7 g (95%) of the c r y s t a l l i n e keto aldehyde 107. An a n a l y t i c a l sample, obtained by r e c r y s t a l l i z a t i o n of the crude product from hexane, exhibited m.p. 64.5r-66°; u l t r a v i o l e t , X 245 my (e = 12,600); r max i n f r a r e d (CHC1„), v 1700, 1660, 1625, 1600 cm- 1; p.m.r. T -0.33 3 max ( s i n g l e t , 1H, -CHO), 2.17 ( s i n g l e t , 1H, 6-vinyl H), 3.80 (broad s i n g l e t , 1H, a - v i n y l H), 8.76 ( s i n g l e t , 3H, t e r t i a r y methyl), 8.87 (unresolved m u l t i p l e t , 3H, secondary methyl). Anal. Calcd, for C ^ H ^ O ^ C, 76.44; H, 7.90. Found: C, 76.64; H, 7.70. Preparation of Keto Acid 108 To a s t i r r e d s o l u t i o n of s i l v e r n i t r a t e (19.1 g, 0.112 mole) and the keto aldehyde 107 (11.0 g, 0.054 mole) i n a mixture of ethanol (200 ml) and water (160 ml) was added dropwise, over a period of 1 h, a s o l u t i o n of sodium hydroxide (8.8 g, 0.22 mole) i n water (300 ml). After the, reaction mixture had been s t i r r e d f or an a d d i t i o n a l 2 h, I t was f i l t e r e d through c e l i t e . The f i l t r a t e was evaporated under reduced - 77 -pressure to a small volume. The residue was d i l u t e d with water, washed once with ether and a c i d i f i e d with 6 N hydrochloric a c i d . The r e s u l t i n g mixture was thoroughly extracted with ether. The combined extracts were washed with brine and then dried over anhydrous magnesium s u l f a t e . Removal of the solvent gave 10.7 g (89%) of the c r y s t a l l i n e keto acid 108. An a n a l y t i c a l sample was obtained by r e c r y s t a l l i z a t i o n from hexane-benzene and exhibited m.p. 1 0 5° : u l t r a v i o l e t , X 253 my max (s = 9,740); i n f r a r e d (CHC1-), v 3600-2280, 1745, 1650, 1600 cm"*1; , 3 in. 3 . x p.m.r.,x -3.55 (broad s i n g l e t , 1H, -COOH), 1.57 ( s i n g l e t , 1H, g-vinyl H), 3.67 (broad s i n g l e t , 1H, a - v i n y l H), 8.72 ( s i n g l e t , 3H, t e r t i a r y methyl), 8.84 (unresolved m u l t i p l e t , 3H, secondary methyl). Anal. Calcd. for C,,H,-,0„: C, 70.89; H, 7.32. Found: C, 70.88; I J lo 3 H, 7.30. Preparation of the Keto Ester 109 S i l v e r oxide (18.5 g, 0.080 mole) was added to a s o l u t i o n of the keto acid 108 (8.8 g, 0.040 mole) i n 240 ml of methanol. To the resultant mixture was added a s o l u t i o n of methyl iodide (11.3 g, 0.078 mole) i n 160 ml of methanol. The r e a c t i o n mixture was s t i r r e d at room temperature for 45 min, f i l t e r e d , and the f i l t r a t e was evaporated under reduced pressure. The residue was dissolved i n ether and the r e s u l t i n g s o l u t i o n was washed with aqueous sodium bicarbonate, with b r i n e , and then dried over anhydrous magnesium s u l f a t e . Removal of the solvent and d i s t i l l a t i o n of the residue under reduced pressure afforded 9.0 g (96%) of the keto ester 109, b.p. 147° at 0.1 mm; n*9'5 1.5388; u l t r a v i o l e t , X 245 my (e " 10,550); - 78 -i n f r a r e d ( f i l m ) , v m a x 1740, 1720 (shoulder 1660, 1640 (shoulder) cm ; p.m.r., x 2.25 ( s i n g l e t , 1H, g-vinyl H), 3.85 (broad s i n g l e t , 1H, ct-vinyl H), 6.12 ( s i n g l e t , 3H, -C00CH3), 8.79 ( s i n g l e t , 3H, t e r t i a r y methyl), 8.90 (unresolved m u l t i p l e t , 3H, secondary methyl). Anal. Calcd. f or C..Hlo0o; C, 71.77; H, 7.74. Found: C, 71.53; H, 7,84. Preparation of Keto Ester 105 To a s o l u t i o n of 7.02 g (0.030 mole) of the keto ester 109 i n 45 ml of pyridine was added 1.13 g (0.030 mole) of powdered sodium borohydride. External cooling (ice-bath) was required i n i t i a l l y to keep the temperature of the reaction mixture below 5 0 ° . A f t e r the so l u t i o n had been s t i r r e d for 30 min, i t was poured into r a p i d l y s t i r r i n g 2 N hydrochloric a c i d (360 ml). The r e s u l t i n g mixture was extracted thoroughly with ether. The combined extracts were washed with b r i n e , dried over anhydrous magnesium s u l f a t e and evaporated under reduced pressure. R e c r y s t a l l i z a t i o n of the r e s i d u a l crude c r y s t a l l i n e material from hexane-ethyl acetate gave 5.35 g (76%) of pure keto ester 105. Column chromatography ( s i l i c a gel) of the mother liq u o r s afforded an a d d i t i o n a l 0.7 g (10%) of the desired compound 105. An a n a l y t i c a l sample of keto ester 105 exhibited m.p. 108 - 1 0 8 . 5°; u l t r a v i o l e t , X 240 my (e =14,920); max in f r a r e d (CHC1„), v 1740, 1670, 1620 cm"1; p.m.r., T 4-31 (broad j max s i n g l e t , 1H, v i n y l H), 6.30 ( s i n g l e t , 3H, -C00CH3), 6.57 (doublet of i doublets, 1H, -CH-C00CH3, J = 13.0, 6.0 Hz), 8.88 ( s i n g l e t , 3H, t e r t i a r y methyl), 9.08 (unresolved m u l t i p l e t , 3H, secondary methyl). - 79 -Anal. Calcd. for C ^ H ^ O y C, 71.16; H, 8.53. Found: C, 71.02; H, 8.64. Preparation of the Keto Diester 110 To a s o l u t i o n of the keto ester 105 (5.29 g, 22.4 mmoles) i n dry benzene (180 ml), under an atmosphere of nitrogen, was added 1.04 g (24-6 mmoles) of sodium hydride (56% i n d i s p e r s i o n o i l ) . When the evolution of hydrogen had ceased (approximately 20 min), 7.5 g (49.0 mmoles) of methyl bromoacetate was added a l l at once, The reaction mixture was gradually heated to 8 0 ° , and was then refluxed for 2.5 h. The cooled reaction mixture was poured into d i l u t e hydrochloric a c i d , and the layers were separated. The aqueous layer was extracted further with ether. The combined benzene layer and ether extracts were washed twice with brine and dried over anhydrous magnesium s u l f a t e . Removal of the solvent and d i s t i l l a t i o n of the r e s i d u a l o i l under reduced pressure gave a quantitative y i e l d of the keto d i e s t e r 110 as a viscous o i l , b.p. 162-164° at 0.07 mm; u l t r a v i o l e t , A 242 my (e * 13,760); r max i n f r a r e d ( f i l m ) , v m a x 1740, 1720 (shoulder), 1665, 1640 (shoulder) cm"1; p.m.r., T 4.22 (broad s i n g l e t , 1H, v i n y l H), 6.35, 6.41 ( s i n g l e t s , 6H, methoxy methyls), 8.98 ( s i n g l e t , 3H, t e r t i a r y methyl), 9.12 (unresolved m u l t i p l e t , 3H, secondary methyl). Anal. Calcd. f o r C ^ H ^ O y C, 66.21; H, 7.84. Found: C, 66.29; H, 7.82. - 80 -Preparations of Keto Acid 111 The keto d i e s t e r 110 (6.5 g, 21.1 mmoles) was dissolved i n 210 ml of 5:1 ethanol-water containing 30 g (0.75 mole) of sodium hydroxide and the r e s u l t i n g s o l u t i o n was refluxed under an atmosphere of nitrogen for 30 min. Most of the ethanol was removed under reduced pressure. The residue was d i l u t e d with water, washed once with ether, and then a c i d i f i e d with 6 N hydrochloric a c i d . The r e s u l t i n g mixture was extracted with ether, the combined extracts were washed with brine and then dried over anhydrous magnesium s u l f a t e . Removal of the ether gave 5.0 g of a viscous o i l which c r y s t a l l i z e d on standing. R e c r y s t a l l i z a t i o n from benzene-hexane gave 3.1 g of pure keto acid 111. D i s t i l l a t i o n of the mother l i q u o r s [b.p. 190-205° (hot box) at 0.2 mm], followed by r e c r y s t a l l i z a t i o n of the d i s t i l l a t e afforded an a d d i t i o n a l 1.0 g of keto acid 111 ( t o t a l y i e l d = 82%). An a n a l y t i c a l sample exhibited m.p. 127. 5 - 1 2 8°; u l t r a v i o l e t , A 238 mu (e = 14,750); i n f r a r e d (CHC1.J, v „ max J max 3600-2400, 1710, 1665, 1620 cm- 1; p.m.r., x -1.30 (broad s i n g l e t , 1H, -C00H), 4.28 (broad s i n g l e t , 1H, v i n y l H), 8.85 ( s i n g l e t , 3H, t e r t i a r y methyl), 9.10 (unresolved m u l t i p l e t , 3H, secondary methyl). Anal. Calcd. for C ^ H ^ O ^ C, 71.16; H, 8.53. Found: C, 71.15; H, 8.47. Preparation of the trans-Fused Keto Acid 112 by Hydrogenation of 111 Under Neutral Conditions A s o l u t i o n of the keto acid 111 (21 mg, 0.089 mmole) i n 2 ml of ethanol was hydrpgenated at atmospheric pressure and room temperature over palladium on charcoal (11 mg) u n t i l uptake of hydrogen ceased. - 81 T F i l t r a t i o n of the reaction mixture, followed by evaporation of the f i l t r a t e under reduced pressure afforded a quantitative y i e l d of the trans-fused keto acid 112. An a n a l y t i c a l sample, obtained by r e c r y s t a l l i z a t i o n from hexane-benzene, exhibited m.p. 13 9 - 1 4 0°; i n f r a r e d (CHC1-), v 3600-2400, 1705 cm"1; p.m.r., T 0.04 (broad S i n g l e t , 1H, -C00H), 9.00 ( s i n g l e t , 3H, t e r t i a r y methyl), 9.12 (unresolved m u l t i p l e t , 3H, secondary methyl). Anal. Calcd. f o r C^H^O : C' 7 0*5 6 ; H» 9-3 0- Found: C, 70.80; H, 9.15. Preparation of the cis-Fused Keto Acid 113 and the trans-Fused Keto Acid 112 Hydrogenation of the keto acid 111 was c a r r i e d out at atmospheric pressure and room temperature. A s o l u t i o n of 111 (118 mg, 0.5 mmole) i n 3 ml of f r e s h l y prepared 0.2 N ethanolic sodium hydroxide containing 30 mg of 5% rhodium on charcoal was hydrogenated u n t i l two equivalents of hydrogen were taken up (approximately 5 h ) . The reaction mixture was f i l t e r e d and the f i l t r a t e was evaporated to dryness. The residue was dissolved i n d i s t i l l e d water (4 ml) and 6 mg of ruthenium dioxide was added. To the r e s u l t i n g s t i r r e d mixture was added, dropwise, a fr e s h l y prepared 5% so l u t i o n of sodium periodate i n d i s t i l l e d water, u n t i l the yellowish color of ruthenium tetroxide p e r s i s t e d . The reaction mixture was treated with a few drops of 2-propanol, and then f i l t e r e d . The f i l t r a t e was a c i d i f i e d with d i l u t e hydrochloric acid and then thoroughly extracted with ether. The combined ether extracts were washed with brine and dried over anhydrous magnesium s u l f a t e . - 82 -Removal cf the solvent gave 120 mg of c r y s t a l l i n e m a t e r i a l , which consisted of a mixture of the cis-fused keto acid 113 and the trans-fused keto a c i d 112 i n a r a t i o of approximately 3:2, r e s p e c t i v e l y (based on the p.m.r. spectrum). Both of the compounds could be obtained i n pure form by repeated f r a c t i o n a l c r y s t a l l i z a t i o n of the mixture from varying proportions of hexane-benzene. Although the actual amount of each isomer i s o l a t e d from the mixture varied somewhat from experiment to experiment, the les s soluble compound (trans-fused keto acid 112) was secured i n approximately 30% y i e l d , while the more soluble isomer (cis-fused keto acid 113) was obtained i n approximately 30-35% y i e l d . The trans-fused keto acid thus obtained was shown to be i d e n t i c a l (m.p., in f r a r e d and p.m.r. spectra) with the product obtained by hydrogenation of 111 under neutral conditions (vide supra). The cis- f u s e d keto acid 113 exhibited m.p. 11 4 . 5 - 1 1 5°; i n f r a r e d (CHC1-), v 3600-2400, 1708 cm"1; p.m.r., x -1.27 (broad s i n g l e t , 1H, •j H13.X -COOH), 9.09 ( s i n g l e t , 3H, t e r t i a r y methyl), 9.12 (doublet, 3H, secondary methyl, J = 7.0 Hz). Anal. Calcd. for C ^ H ^ O ^ C, 70.56; H, 9.30. Found: C, 70.42; H, 9.10. (+) -11-Demethyleremophilenolide 115 (a) C y c l i z a t i o n : 3-hour reaction A s o l u t i o n of the keto acid 113 (100 mg, 0.42 mmole) i n 24 ml of dry toluene containing 30 mg of p_-toluenesulfonic acid was refluxed gently under a Dean-Stark water separator i n a nitrogen atmosphere for 3 h. The cooled s o l u t i o n was washed with d i l u t e aqueous sodium bicarbonate, with b r i n e , and then dried over anhydrous magnesium s u l f a t e . - 83 -Removal of the solvent, followed by d i s t i l l a t i o n of the residue gave 90 mg of lactone material (97%) which c r y s t a l l i z e d on standing. R e c r y s t a l l i z a t i o n from hexane yiel d e d 51 mg (55%) of pure 11-demethyl-eremophilenolide 115, m.p. 112 - 1 1 2 . 5°; u l t r a v i o l e t , A 216 mu r r max (e = 14,830); i n f r a r e d (CHC1_), v 1780, 1745, 1650 cm"1; p.m.r., 3 max T 4.31 (unresolved m u l t i p l e t , 1H, v i n y l H, width at h a l f height = 4.0 Hz), 5.26 (broad, unresolved m u l t i p l e t , 1H, CQH, width at h a l f height = o 19.0 Hz), 7.10 (doublet, 1H, CgH-equatorial, J = 14.0 Hz), 8.99 ( s i n g l e t , 3H, t e r t i a r y methyl), 9.23 (doublet, 3H, secondary methyl, J = 6.0 Hz). Anal. Calcd. for c1 4H2 n02: C' 76'33> H» 9.15. Found: C, 76.30; H, 9.30. The mother liq u o r s from the above r e c r y s t a l l i z a t i o n consisted of an o i l y mixture of 11-demethyleremoph.ilenolide 115 and 8 - e p i - l l -demethyleremophilenolide 116 i n a r a t i o of approximately 1:2 r e s p e c t i v e l y , as judged by the p.m.r. spectrum. Column chromatography of t h i s mixture on s i l i c a gel yielded no separation of the two components. The mixture exhibited i n f r a r e d ( f i l m ) , v 1785, 1750, 1640 cm"1. By comparing max the p.m.r. spectrum of the 1:2 mixture of lactones with that of pure 11-demethyleremophilenolide, i t was possible to i d e n t i f y the sign a l s due to 8-epi-ll-demethyleremophilenolide. Thus the l a t t e r exhibited p.m.r., T 4.24 (unresolved m u l t i p l e t , 1H, v i n y l H, width at h a l f height = 4.0 Hz), 5.07 (broad, unresolved m u l t i p l e t , 1H, CgH, width at h a l f height = 20 Hz), 7.00 (broadened doublet, 1H, CgH, J = 14.0 Hz), 7.87 (doublet, 1H, CgH, J = 14.0 Hz), 8.97 (doublet, 3H, secondary methyl, J = 6.6 Hz), 9.13 ( s i n g l e t , 3H, t e r t i a r y methyl). - 84 -(b) C y c l i z a t i o n : 6-hour reaction A s o l u t i o n of the keto acid 113 (12.0 mg, 0.05 mmole) i n 4 ml of dry toluene containing 9 mg of p-toluenesulfonic a c i d , was refluxed under a Dean-Stark water separator i n a nitrogen atmosphere f o r 3 h. At t h i s p o i n t , a further 9 mg of p_-toluenesulfonic acid was added and r e f l u x i n g was continued for a further 3 h pe r i o d . The reaction mixture was worked up as above. D i s t i l l a t i o n (hot box) of the r e s u l t i n g crude product afforded 10.5 mg (95%) of c r y s t a l l i n e material which consisted mainly of a mixture of 11-demethyleremophilenolide 115 and 8-epi-ll-demethyleremophilenolide 116 i n the r a t i o of approximately 85:15 (as judged from the p.m.r. spectrum). (+)-Eremophilenolide j6 (a) From pure 11-demethyleremophilenolide 115 To a s t i r r e d s o l u t i o n of (+)-11-demethyleremophilenolide 115 (68 mg, 0.31 mmole) i n 3 ml of dry benzene under an atmosphere of nitrogen was added, dropwise, an ethereal s o l u t i o n of t r i t y l s o d i u m u n t i l the red color of the base p e r s i s t e d . A f t e r the r e s u l t i n g s o l u t i o n had been s t i r r e d at room temperature for 30 min, methyl iodide (142 p i , 2.28 mmoles) was added a l l at once. The s o l u t i o n was s t i r r e d f o r 6 h, d i l u t e d with ether, washed with cold water, with b r i n e , and then dried over anhydrous magnesium s u l f a t e . Removal of the solvents gave a crude product which was chromatographed over s i l i c a g e l . E l u t i o n with hexane afforded triphenylmethane. Further e l u t i o n with ether gave 73 mg of material which c r y s t a l l i z e d on standing. R e c r y s t a l l i z a t i o n from ether gave 31 mg of pure (+)-eremophilenolide 6_. Subjection of the - 8 5 -mother l i q u o r s to column chromatography on s i l i c a gel yiel d e d an ad d i t i o n a l 13 mg of b_ ( t o t a l y i e l d = 61%). An a n a l y t i c a l sample of (+)-eremophilenolide 6 exhibited m.p. 11 0 . 5 - 1 1 1 . 5°; u l t r a v i o l e t , X — r — max 220 my (e = 14,600); i n f r a r e d (CHC1 3), v m a x 1740, 1690 cm"1; p.m.r., T 5.37 (broad, unresolved m u l t i p l e t , 1H, CgH, width at h a l f heigth = 20.5 Hz), 7.11 (doublet, 1H, CgH-equatorial, J = 14.5 Hz), 8.21 (unresolved m u l t i p l e t , 3H, v i n y l methyl), 8.97 ( s i n g l e t , 3H, t e r t i a r y methyl), 9.20 (doublet, 3H, secondary methyl, J = 6.0 Hz). The i n f r a r e d and p.m.r. spectra of t h i s material were i d e n t i c a l with those of an authentic sample of natural (+)-eremophilenolide. Anal. Calcd. f or C1 5H2 2 ° 2: C' 7 6'8 85 H» 9-46. Found: C, 76.58; H, 9.60. (b) From the mixture of 115 and 116 A mixture of 11-demethyleremophilenolide 115 and 8-epi-ll-demethyl-eremophilenolide 116 (34 mg, 1:2, r e s p e c t i v e l y ) , the mother l i q u o r s of r e c r y s t a l l i z a t i o n of impure 115 (vide supra), was subjected to a l k y l a t i o n under conditions i d e n t i c a l with those described above. P u r i f i c a t i o n of the crude product, as above, afforded 19 mgs (52%) of (+)-eremophilenolide 6_. (+)-ll-Demethyltetrahydroligularenolide 117 A s o l u t i o n of the trans-fused keto acid 112 (44 mg, 0.19 mmole) i n 12 ml of dry toluene containing 15 mg of p_-toluenesulfonic acid was refluxed gently for 3 h i n an atmosphere of nitrogen under a Dean-Stark water separator. The cooled s o l u t i o n was washed with c o l d , - 86 -d i l u t e aqueous sodium bicarbonate, with brine and then dried over anhydrous magnesium s u l f a t e . Removal of the solvent and d i s t i l l a t i o n of the r e s i d u a l material afforded 38 mg (94%) of (+)-ll-demethyltetra-hydroligularenolide 117, m.p. 9 4 - 9 5° . An a n a l y t i c a l sample, obtained by r e c r y s t a l l i z a t i o n of th i s material from hexane, exhibited m.p. 9 8 - 9 9° ; u l t r a v i o l e t , A 216 my ( e = 14,870); i n f r a r e d (CHC1 0), v 1780, 1745, max 3 max 1645 cm •*"; p.m.r., T 4.34 (unresolved m u l t i p l e t , 1H, v i n y l H, width at ha l f height = 4.0 Hz), 5.33 (unresolved m u l t i p l e t , 1H, C gH, width at ha l f height = 19 Hz), 7.25 (doublet, 1H, CgH-equatorial, J = 13.0 Hz), 9.15 (poorly resolved doublet, 3H, secondary methyl, J » 5.5 Hz), 9.36 ( s i n g l e t , 3H, t e r t i a r y methyl). Anal. Calcd. for C ^ H ^ C y C, 76.33; H, 9.15. Found: C, 76.15; H, 9.03. (+)-Tetrahydroligularenolide 44^  To a s t i r r e d s o l u t i o n of the lactone 117 (85 mg, 0.39 mmole) i n 4 ml of dry benzene under an atmosphere of nitrogen was added, dropwise, an ethereal s o l u t i o n of t r i t y l s o d i u m u n t i l the red color of the base p e r s i s t e d . A f t e r the r e s u l t i n g s o l u t i o n had been s t i r r e d at room temperature f or 35 min, methyl ibdide (160 y l , 2.5 mmole) was added i n one p o r t i o n . The reaction mixture was s t i r r e d at room temperature f or 6 h, then d i l u t e d with ether and poured into ice-water. The organic layer was separated, washed with b r i n e , and dried over anhydrous magnesium s u l f a t e . Removal of the solvents gave 234 mg of r e s i d u a l material which was subjected to column chromatography on s i l i c a g e l . E l u t i o n of the column with hexane yiel d e d triphenylmethane, while - 87 -e l u t i o n with ether afforded 82 mg of crude c r y s t a l l i n e product. R e c r y s t a l l i z a t i o n from hexane-ether, followed by further p u r i f i c a t i o n (column chromatography) of the mother l i q u o r s , provided 53 mg (59%) of pure (+)-tetrahydroligularenolide 44, m.p. 9 1 . 5 - 9 2°; u l t r a v i o l e t , \ — max 220 my (e = 14,990); i n f r a r e d (CHC1 3), v m a x 1740, 1685 cm"1; p.m.r., T 5.38 (unresolved m u l t i p l e t , 1H, C0H, width at h a l f height = 21.0 Hz), o 7.24 (doublet, 1H, CgH-equatorial, J = 14.0 Hz), 8.21 (unresolved m u l t i p l e t , 3H, v i n y l methyl), 9.09 (poorly resolved doublet, 3H, secondary methyl, J = 5.5 Hz), 9.42 (doublet, 3H, t e r t i a r y methyl,J » 0.6 Hz). Although an authentic sample of (-)-tetrahydroligularenolide was not obtained, the i n f r a r e d and p.m.r. data given above agree very w e l l with 73 74 the published data. ' Anal. Calcd. f or C ^ H ^ O ^ C, 76.88; H, 9.46. Found: C, 76.65; H, 9.31. Preparation of the trans-Fused Keto Acid 112 by A l k y l a t i o n of the Decalone 100 A s o l u t i o n of the decalone 100 (180 mg, 1 mmole) i n 25 ml of isopropenyl acetate containing 100 mg of £ - t o l u e n e s u l f o n i c acid was slowly heated under a Dean-Stark water separator. The acetone-isopropenyl acetate mixture was slowly d i s t i l l e d u n t i l the r e s i d u a l volume was about 4 ml. The cooled reaction mixture was poured into aqueous sodium bicarbonate and the r e s u l t i n g mixture was extracted thoroughly with ether. The combined ether extracts were washed with brine and dried over anhydrous magnesium s u l f a t e . Removal of the ether, followed by d i s t i l l a t i o n of the r e s i d u a l o i l , afforded 220 mg of the mixture of - 88 -enol acetates 119 and 120 b.p. 80-90° (hot box) at 0.1 mm, i n a r a t i o of approximately 3:2. (On the basis of the p.m.r. spectrum, the major 2 compound was the A -isomer). This mixture exhibited i n f r a r e d ( f i l m ) , v 1750 cm p.m.r., x 4.75, 5.00 (unresolved m u l t i p l e t s , 1H, v i n y l IU3.X protons, width at h a l f height = 9 Hz and 5.5 Hz r e s p e c t i v e l y ) . A s o l u t i o n of the mixture of enol acetates 119 and 120 i n dry dimethoxyethane was added dropwise v i a a syringe to a s t i r r e d s o l u t i o n of methyllithium (2 mmoles) i n 1.5 ml of dimethoxyethane. To the r e s u l t i n g s o l u t i o n was added, a l l at once, 0.5 ml of methyl bromoacetate, s t i r r i n g was continued for 1 min, and the rea c t i o n mixture was then poured into cold d i l u t e hydrochloric a c i d . The r e s u l t i n g mixture was extracted with ether, the combined ether extracts were washed with water and dried over anhydrous magnesium s u l f a t e . Removal of the solvents gave 273 mg of crude m a t e r i a l . Subjection of the l a t t e r to column chromatography on s i l i c a g e l afforded the keto ester 121 which, upon hydrolysis at room temperature with potassium hydroxide i n methanol, provided the c r y s t a l l i n e keto acid 112. The l a t t e r was shown to be i d e n t i c a l (m.p., mixed m.p., i . r . and p.m.r. spectra) with the keto acid 112 prepared by hydrogenation of keto acid 111 under neutral conditions (vide supra). Preparation of the Thioketal Derivative 127 To a s o l u t i o n of the keto ester 105 (1.22 g, 5.2 mmoles) i n 30 ml of a c e t i c acid was added 2.5 ml of 1,2-ethanedithiol and 1.5 ml of boron t r i f l u o r i d e etherate. The mixture was s t i r r e d under nitrogen f or 26 h and then d i l u t e d with ether. Excess s o l i d sodium bicarbonate was added and the r e s u l t i n g mixture was c a r e f u l l y d i l u t e d with cold water. The - 89 -organic layer was separated, washed successively with aqueous sodium bicarbonate, water and b r i n e , and then dried over anhydrous magnesium s u l f a t e . Removal of the solvent afforded 1.67 g (100%) of crude c r y s t a l l i n e m a t e r i a l . The p.m.r. spectrum of t h i s material indicated that i t was an epimeric mixture of 127 and 128 i n a r a t i o of approximately 4:1, r e s p e c t i v e l y . One r e c r y s t a l l i z a t i o n of t h i s material from methanol yielded 1.16 g (72.5%) of the pure d i t h i o k e t a l 127, m.p. 1 1 0 . 5 - 1 1 1°; i n f r a r e d (CHC1„), v 1728 cm ^; p.m.r., T 4.52 (broad s i n g l e t , 1H, v i n y l H), 6.32 ( s i n g l e t , 3H, -CO0CH3), 6.52-6.99 ( m u l t i p l e t , 5H, -SCH2CH2S- and C 7H), 9.07 ( s i n g l e t , 3H, t e r t i a r y methyl), 9.15 (unresolved m u l t i p l e t , 3H, secondary methyl). Anal. Calcd. for C1£H..0_So: C, 61.50; H, 7.74; S, 20.52. Found: lo 2H 2 2 C, 61.64; H, 7.84; S, 20.35. The mother liq u o r s of the above r e c r y s t a l l i z a t i o n consisted of compounds 127 and 128 i n a r a t i o of approximately 1:2, r e s p e c t i v e l y . Attempts to i s o l a t e a pure sample of 128 by column chromatography of t h i s material were not s u c c e s s f u l . Preparation of the O l e f i n i c Ester 124 (a) From the d i t h i o k e t a l 127 To a s o l u t i o n of the d i t h i o k e t a l 127 (594 mg, 1.9 mmoles) i n 80 ml of ethanol was added about 20 g of W-2 Raney n i c k e l and the r e s u l t i n g mixture was refluxed with s t i r r i n g under nitrogen for 15 min. The reaction mixture was f i l t e r e d and the f i l t r a t e was evaporated under reduced pressure. D i s t i l l a t i o n of the r e s i d u a l material gave 373 mg of an o i l , b.p. 120° (hot box) at 0.15 mm, which was shown by g a s - l i q u i d chromatographic analysis (column F, 2 0 5° , 105) to consist mainly of one - 90 -compound, accompanied by two minor components. The desired, major component was isolated by preparative g.l.c. (column F, 200°, 90), 20 yielding 264 mg (63%) of pure olefinic ester 124, n D 1.4979; infrared (film), v 1735, 808 cm; p.m.r., x 4.72 (unresolved multiplet, 1H, max vinyl H), 6.36 (singlet, 3H, -COOCH3), 9.06 (singlet, 3H, tertiary methyl), 9.14 (unresolved multiplet, 3H, secondary methyl). Anal. Calcd. for c 1 i ^ 2 2 ° 2 ' C ' 7 5 - 6 3 ' H> 9-97. Found: C, 75.46; H, 10.04. (b) From a mixture of dithioketals 127 and 128 A mixture of compounds 127 and 128 (180 mg, 1:2, respectively), obtained from the mother liquors of recrystallization of impure 127 (vide supra), was subjected to desulfurization with Raney nickel under conditions identical with those described above. D i s t i l l a t i o n of the crude product gave 102 mg of material which was shown by g.l.c. analysis (column F, 205°, 105) to consist mainly (85%) of the epimeric olefinic esters 124 and 129 (approximately 1:2, respectively). A solution of this material in 10 ml of 0.82 M sodium methoxide in methanol was refluxed under nitrogen for 20 h. The cooled solution was poured into dilute aqueous acetic acid and the resulting mixture was extracted with ether. The combined extracts were washed with water, with brine, and then dried over anhydrous magnesium sulfate. Removal of the solvents, followed by d i s t i l l a t i o n of the residual material, afforded 65 mg of an o i l . Gas-liquid chromatographic analysis (column F, 205°, 105) of the latter revealed that the ratio of 124 and 129 was now approximately 9:1, respectively. The major component, isolated from the mixture by - 91 -preparative g . l . c . (column F, 2 0 5° , 105), was shown ( i . r . and p.m.r. spectra) to be i d e n t i c a l with 124 prepared as described above. Preparation of the O l e f i n i c Alcohol 130 An ethereal s o l u t i o n of methyllithium (6 mmoles) was added to a cold ( 0 ° ) s o l u t i o n of the o l e f i n i c ester 124 (222 mg, 1 mmole) i n 8 ml of anhydrous ether. The r e s u l t i n g s o l u t i o n was refluxed under nitrogen for 2.5 h, cooled, and poured into a mixture of dry i c e i n water. The ether layer was separated, successively washed with water and b r i n e , and dried over anhydrous magnesium s u l f a t e . Removal of the solvent gave an o i l which, upon d i s t i l l a t i o n under reduced pressure, afforded 212 mg (95%) of the o l e f i n i c alcohol 130, b.p. 125-130° (hot box) at 0.25 mm; rf?0 1.5075; i n f r a r e d ( f i l m ) , v 3380, 810 cm"1; p.m.r., x 4.71 u max (unresolved m u l t i p l e t , 1H, v i n y l H), 8.68 ( s i n g l e t , 1H, exchangeable, -OH), 8.84, 8.85 ( s i n g l e t s , -C(OH) ( C H ^ ) , 9.08 ( s i n g l e t , 3H, t e r t i a r y methyl), 9.14 (unresolved m u l t i p l e t , 3H, secondary methyl). Anal. Calcd. f o r C.cHo,0: C, 81.02; H, 11.79. Found: C, 80.93; 15 lb H, 11.67. (+)-Aristolochene 214 To a s o l u t i o n of the o l e f i n i c alcohol 130 (160 mg, 0.72 mmole) i n 5.2 ml of pyridine at 0° was added, dropwise, 520 y l of t h i o n y l c h l o r i d e . The r e s u l t i n g s o l u t i o n was s t i r r e d under a nitrogen atmosphere at 0° for 1 h and then poured i n t o c o l d , aqueous sodium bicarbonate. The r e s u l t i n g mixture was extracted with ether and the combined extracts were evaporated under reduced pressure. The residue was taken up i n - 92 -ether and the r e s u l t i n g s o l u t i o n was washed successively with water and b r i n e , and then dried over anhydrous magnesium s u l f a t e . Removal of the solvent gave 134 mg of crude m a t e r i a l . Subjection of the l a t t e r to column chromatography on s i l v e r nitrate-impregnated s i l i c a g e l (15%) gave, upon e l u t i o n with hexane-ether, 57 mg (43%) of pure (+)-aristolochene 34, i n f r a r e d ( f i l m ) , v 3075, 3030, 1645, 887, 810 cm"1; p.m.r. T 4.70 — max (unresolved m u l t i p l e t , 1H, v i n y l H, width at h a l f height = 9.0 Hz), 5.31 (unresolved m u l t i p l e t , 2H, =CH2» width at h a l f height =3.0 Hz), 8.29 (unresolved m u l t i p l e t , 3H, v i n y l methyl), 9.06 ( s i n g l e t , 3H, t e r t i a r y methyl), 9.17 (unresolved m u l t i p l e t , 3H, secondary methyl). This material exhibited i n f r a r e d and p.m.r. spectra i d e n t i c a l with authentic (-)-aristolochene. Anal. Calcd. f o r C ^ H ^ : C, 88.16; H, 11.84. Found: C, 88.40; H, 11.90. - 93 -PART II STEREOSELECTIVE TOTAL SYNTHESIS OF (-)-YLANGOCAMPHOR, (-)-YLANGOBORNEOL AND (-)-YLANGOISOBORNEOL - 9 4 -PART II INTRODUCTION 1. Perspective The ylango sesquiterpenoids belong to the i n t e r e s t i n g family of s t r u c t u r a l l y r e l a t e d sesquiterpenoids whose s k e l e t a l structures incorporate the bicyclo[2.2.1]heptane nucleus 131 or the related bicyclo[3.1.1]heptane nucleus 132. This group includes b i c y c l i c , t r i c y c l i c and t e t r a c y c l i c members as shown i n Chart 8. The sesquiterpenoids l i s t e d i n t h i s chart are arranged and drawn i n a manner which emphasizes t h e i r s t r u c t u r a l s i m i l a r i t y to known monoterpenoids which also possess e i t h e r the bicyclo[2.2.l]heptane or the bicyclo[3.1.1]heptane moieties. For example, the sesquiterpenoids l i s t e d i n the f i r s t v e r t i c a l column i n Chart 8, campherenone, copacamphor, ylangocamphor and longicamphor, a l l incorporate the s t r u c t u r a l features of the monoterpenoid camphor. Thus, these four sesquiterpenoids can be considered "isoprenologs" of camphor. 131 132 Row camphor (-)-campherenone boraeol isoborneol camphene tricyclene a-pinene I 134 9 / 133 12,97 (-)-campherenol 1 2'° 7 (+)-lsocampherenol 1 2'° 7 (-)-6-santalene~ ' ' 25.98.100 , x ^ .. 101-104 (+)-o-santalene ' ' (-)-o-trans-bergaffiotene ^ 1 3^8 [ 138 / 139* / 140 141 (+)-copacamphor 10,105-107 ,105-107 ,105-107 {+)-copaborneol i ," (+)-copalsoborneol ( _ ) _ c o p a c a m p h e n e 1 0 6 ' 1 0 8 ' 1 0 9 (+)-cyclocopacanphene 1 3 , 1 0 9 ( - ) - a - c o p a e a e 1 1 0 - 1 1 2 •i^ ef f^f ^ ^ ^ (-)-ylangocamphor''10 (-)-ylangoborneol9 <-)-ylangoisobomeol9 (-)-sativene 1 1 , 1 1 3 ( + ) - c y c l o s a t l v e n e 1 3 ' 2 0 ' 1 1 4 M-a-ylangene 1 1 2' 1 1 5' 1 1 7 \ 144 (+)-longicamphor 118.119 ( + ). L O N G L B O R N E O LU8-121 W-longllsoborneol 1 1 9' 1 2 0 W - l o n g i f o l e n e 2 5 ' 1 1 8 ' 1 2 2 " 1 2 5 O - l o n g i c y c l e n e 1 2 6 " 1 2 8 <+)-a-lonEipiner.e 14 „ . Chart 8 # # These compounds have been Isolated from naturally occurring sources. Absolute configurations are depicted by these structures. - 96 -S i m i l a r l y the sesquiterpenoids l i s t e d i n the other v e r t i c a l columns i n Chart 8 can be considered "isoprenologs" of the monoterpenes which head these columns. The sesquiterpenoids i n Chart 8 are also arranged i n h o r i z o n t a l rows i n a manner which emphasizes the s t r u c t u r a l s i m i l a r i t i e s among the sesquiterpenoids themselves. Thus longicamphor, longibomeol, l o n g i i s o b o r n e o l , l o n g i f o l e n e , longicyclene and a - l o n g i -pinene a l l possess a seven-membered r i n g containing geminal dimethyl groups. At the outset of the work described i n t h i s t h e s i s , the sesquiterpenoids ylangocamphor 7_, ylangoborneol 23, and ylangoiso-borneol 143 were unknown compounds. The names that have been proposed for these sesquiterpenoids are based on t h e i r s t r u c t u r a l r e l a t i o n s h i p both to the corresponding monoterpenoids (camphor, borneol, and i s o -borneol respectively) and to the sesquiterpenoid a-ylangene 21. a-Ylangene ( i s o l a t e d from ylang-ylang o i l ) was the f i r s t ylango-type sesquiterpenoid to be i s o l a t e d and named.11"' For convenience, throughout t h i s thesis a l l the sesquiterpenoids i n t h i s group (horizontal row 4) i n Chart 8 (ylangocamphor, ylangoborneol, ylangoisoborneol, sativene, cyclosativene and a-ylangene) w i l l be referred to c o l l e c t i v e l y as the ylango sesquiterpenoids. S i m i l a r l y the copa sesquiterpenoids w i l l r e f e r to the sesquiterpenoids i n row 3, and the l o n g i sesquiterpenoids to those i n row 5. Apart from the compounds l i s t e d i n Chart 8, other members of t h i s family of sesquiterpenoids are also known. Thus, a s e r i e s which bears an epimeric r e l a t i o n s h i p to the sesquiterpenoids i n row 2 i s known, 97 epicampherenone 149 being a representative example. Many of the other - 9 7 -known s t r u c t u r a l l y r e l a t e d sesquiterpenoids are merely oxygenated der i v a t i v e s of structures l i s t e d i n Chart 8 . Thus (+)-a-santalol 1 5 Q 2 5 , 1 2 9 , 1 3 0 ^ g r e i a t e ( j t o (+)-ct- s a ntalene i n row 2 of Chart 8 . 1 4 9 1 5 0 CH 2 0 H 1 5 1 1 5 2 1 3 1 The n a t u r a l l y occurring cyclocopacamphenols 1 5 1 are related to cyclo 1 3 2 1 3 3 copacamphene 10_ of the copa s e r i e s , while culmorin 1 5 2 ' is an oxidized form of longiborneol 1 4 5 of the lon g i s e r i e s . No n a t u r a l l y occurring ylango sesquiterpenoids are known which contain i n t a c t the b i c y c l o [ 2 . 2 . l ] h e p t a n e or b i c y c l o [ 3 . l . l ] h e p t a n e n u c l e i other than those shown i n Chart 8 . However, a group of sesquiterpenoids are known whose common carbon skeleton can be related to that of sativene. These n a t u r a l l y occurring compounds are - 98 -helminthosporal 25_, helminthosporol 153, prehelminthosporal 154 135 (R = H) and prehelminthosporol 155. Thus t h e o r e t i c a l cleavage of the satlvene carbon skeleton J3 at the point i n d i c a t e d , r e s u l t s i n the - 99 -formation of the s k e l e t a l structure 156, which i s common to the helmintho sesquiterpenoids. Indeed, de Mayo and co-workers have 21 obtained evidence which supports the biogenesis of these compounds from an intermediate such as sativene fi_ (see Introductory Remarks p. 8 ) . For convenience therefore, throughout the remainder of t h i s thesis the helmintho sesquiterpenoids w i l l also be included i n the term "ylango sesquiterpenoids". Because of the i n t e r e s t i n g t r i c y c l i c and t e t r a c y c l i c carbon skeletons of the copa, ylango and l o n g i sesquiterpenoids, a t t e n t i o n was directed i n our laboratory towards the development of synthetic approaches to these sesquiterpenoids. The i n i t i a l e f f o r t i n t h i s area was concentrated on synthetic access to the copa group of sesquiterpenoids. This e f f o r t has resulted i n the s t e r e o s e l e c t i v e t o t a l syntheses"*^'"""^ of (+)-copacamphor 138, (+)-copaborneol 139, (+)-copaisoborneol 140, (-)-copacamphene 141 and (-)-cyclocopacamphene 10. The work described i n the second part of t h i s thesis i s concerned with the development of a s i m i l a r general synthetic approach to the ylango group of sesquiterpenoids. This work has led to the 9 s t e r e o s e l e c t i v e t o t a l synthesis of (-)-ylangocamphor ]_, (-)-ylango-borneol _23 and (-)-ylangoisoborneol 143. 2. Other Synthetic Approaches to Copa and Ylango Sesquiterpenoids Because of the epimeric r e l a t i o n s h i p between the copa and ylango series of sesquiterpenoids, i t i s appropriate here to discuss synthetic approaches to compounds of both s e r i e s . - 1 0 0 -In connection with the s t r u c t u r a l e l u c i d a t i o n of copaborneol 1 3 9 , Kolbe-Haugwitz and W e s t f e l t1^ ' r e p o r t e d the conversion of (+)-a-s a n t a l o l 1 5 0 into (+)-copaborneol (see Chart 9 ) . The key step i n th i s conversion was the construction of the t h i r d r i n g i n copaborneol by a s t e r e o s e l e c t i v e intramolecular Michael-type add i t i o n r e a c t i o n . The s t a r t i n g material employed was a commercial mixture (ca. 7 : 3 ) of (+)-a-santalol 1 5 0 and (-)-g-santalol 1 5 7 . For convenience, the reactions of only the major component 1 5 0 w i l l be discussed here. Oxidation of 1 5 0 with selenium dioxide, followed by further oxidation of the r e s u l t i n g s a n t a l a l with s i l v e r oxide afforded the unsaturated keto acid 1 5 8 . The i n i t i a l oxidation reaction conditions also effected t o t a l isomerization of the o l e f i n i c double bond. Formolysis of 1 5 8 caused the cyclopropane r i n g to open i n two ways, thus g i v i n g r i s e to the syn and a n t i formates 1 5 9 and 1 6 0 r e s p e c t i v e l y . (The other component of the s t a r t i n g m a t e r i a l , (-)-B-santalol 1 5 7 , on subjection to the same series of reactions gave r i s e to only the syn formate 1 5 9 . ) Hydrolysis of t h i s mixture, followed by Jones oxidation and e s t e r i f i c a t i o n , produced a mixture of the corresponding keto esters 1 6 1 and 1 6 2 . Subjection of the keto. ester mixture to c y c l i z a t i o n conditions (potassium _t-butoxide i n dioxan), resulted i n the f a c i l e intramolecular a l k y l a t i o n of the syn isomer 1 6 1 , the a n t i isomer 1 6 2 remaining v i r t u a l l y unchanged. The c y c l i z e d product 1 6 3 was separated from the mixture by column chromatography on s i l i c a g e l . This product was stereochemically homogeneous with respect to the important C ^ Q p o s i t i o n (see structure 1 6 3 for numbering). Chart 9 - 102 -r The carbomethoxy group i n 163 was reduced to the desired methyl group by the following ser i e s of conversions: -CC^Me -*• -Cf^H -»• -C0C1 -»• -CH20H -CH2OMs -• -CRy The f i n a l r e a c t i o n , reductive removal of the mesylate group with l i t h i u m aluminum hydride, also e f f e c t e d reduction of the ketone f u n c t i o n a l i t y . Thus, the i s o l a t e d product was copaiso-borneol 140. Chromic acid oxidation of the l a t t e r afforded copacamphor 138. Reduction of copacamphor with sodium i n ethanol gave (+)-copaborneol 139, i d e n t i c a l i n a l l respects with the n a t u r a l l y occurring product. 130 Since a-santalol 150 has already been synthesized, t h i s represents a formal t o t a l synthesis of copaborneol, copacamphor and copaisoborneol. A s i m i l a r type of approach to the construction of the t h i r d r i n g i n copacamphor 138 and ylangocamphor 1_ was reported very recently by Hodgson, MacSweeney and Money.^ The s t a r t i n g material used i n t h i s instance was (+)-campherenone 9_ (see Chart 10). Reaction of 9_ with m-chloroperbenzoic acid gave r i s e to the diastereomeric mixture of keto epoxides 164. Subjection of 164 to c y c l i z a t i o n with potassium _t-butoxide i n _t-butanol, afforded a mixture of the t r i c y c l i c keto alcohols 165 and 166, which were separated by preparative g . l . c . Dehydration of 166 gave a mixture (7:3) of the keto o l e f i n s 167 and 168. This mixture of compounds was also separated by preparative g . l . c . C a t a l y t i c hydrogenation of keto o l e f i n 167 produced copacamphor 138, while hydrogenation of 168 gave r i s e to a mixture (5:1) of ylangocamphor J_ and copacamphor 138. The same sequence of reactions was applied to the epimeric keto alcohol 165, thus also y i e l d i n g ylangocamphor 7_ v i a the terminal o l e f i n 169. Copacamphor 138, thus synthesized, exhibited g a s - l i q u i d chromato-graphic and sp e c t r a l c h a r a c t e r i s t i c s i d e n t i c a l with those of an authentic - 104 -sample. The s p e c t r a l properties of ylangocamphor ]_ thus obtained, were i d e n t i c a l with those of (-)-ylangocamphor prepared as described i n t h i s 97 t h e s i s . Since Money and co-workers had previously t o t a l l y synthesized campherenone 9_, t h i s work represents a t o t a l synthesis of both copacamphor 138 and ylangocamphor 1_. De Mayo and Williams1"*" reported the conversion of (+)-longifolene 147 i n t o (-)-sativene J3 (see Chart 11) i n connection with t h e i r s t r u c t u r a l e l u c i d a t i o n of the l a t t e r . The o v e r - a l l r e s u l t of t h i s multi-step transformation was the contraction of the cycloheptane ri n g i n l o n g i -folene to the cyclohexane r i n g i n sativene. Thus lon g i f o l e n e 147 was reacted with bromotrichloromethane to give the halogenated d e r i v a t i v e 136 170 v i a a previously studied f r e e - r a d i c a l transannular hydrogen t r a n s f e r . Dehydrochlorination of 170 afforded the acetylene d e r i v a t i v e 171. Oxidation of the l a t t e r to the a c i d , followed by e s t e r i f I c a t i o n , yielded the bromo ester 172. D i s t i l l a t i o n of 172 from i r o n powder, under reduced pressure, produced the cyclohexene d e r i v a t i v e 173. Hydrogenation of the l a t t e r gave the ester 174. This p a r t i c u l a r product of hydrogenation was expected, since i t resulted from the approach of the c a t a l y s t from the le s s hindered side of the o l e f i n i c double bond i n 173. Reduction of the ester 174 with l i t h i u m aluminum hydride, and a c e t y l a t i p n of the r e s u l t i n g alcohol gave the acetate 175. P y r o l y s i s of t h i s acetate at 550° gave r i s e to sativene {?. (-)-Sativene, thus obtained, was i d e n t i c a l with the n a t u r a l l y occurring material except for the sign of i t s o p t i c a l r o t a t i o n . Since longifolene 125 147 has been t o t a l l y synthesized, t h i s represents a formal t o t a l synthesis of sativene j$. - 106 -Another approach to the synthesis of sativene j3 was reported by 113 McMurry. The s t a r t i n g material chosen f o r t h i s synthesis was the r e a d i l y a v a i l a b l e Wieland-Miescher ketone 176 (see Chart 12). S e l e c t i v e k e t a l i z a t i o n of the saturated ketone i n 176, followed by c a t a l y t i c hydrogenation of the r e s u l t i n g k e t a l , resulted i n the cis-fused decalone 177. Treatment of t h i s decalone with i s o p r o p y l l i t h i u m , followed by acid-catalyzed hydrolysis and dehydration of the r e s u l t i n g k e t a l a l c o h o l , afforded the keto o l e f i n 178. Since attempted hydroboration of 178 resulted i n p r e f e r e n t i a l reduction of the carbonyl group, the l a t t e r was f i r s t protected with a blocking group. Thus the keto o l e f i n 178 was converted into the 2,4-dinitrophenylhydrazone (2,4-DNP) d e r i v a t i v e 179. Subjection of the l a t t e r to hydroboration, followed by oxidative work-up and removal of the blocking group by ozonolysis, gave the desired keto alcohol 180. Intramolecular a l k y l a t i o n of the tosylate d e r i v a t i v e 181 of 180 was accomplished by reaction with m e t h y l s u l f i n y l carbanion i n dimethylsulfoxide, thus producing the t r i c y c l i c ketone 182. Reaction of the l a t t e r with methyllithium, and dehydration of the r e s u l t i n g t e r t i a r y a l c o h o l , afforded racemic sativene <8. The i n f r a r e d and p.m.r. spectra of t h i s material were i d e n t i c a l with those of the n a t u r a l l y occurring compound. 108 McMurry also succeeded i n synthesizing copacamphene 141 (see Chart 13), the epimer of sativene, from an intermediate used i n h i s sativene synthesis. Thus keto o l e f i n 178 was transformed i n t o the keto epoxide 183. Reaction of the l a t t e r with methylsulfInyl carbanion i n dimethyl sulfoxide at 60° for four days, effected the required c y c l i z a t i o n . Acid-catalyzed dehydration of the r e s u l t i n g keto alcohol - 108 -184 gave r i s e to a mixture (7:3) of two keto o l e f i n s . The major product was the endo-cyclic o l e f i n 185, the minor product being the corresponding exo-cyclic o l e f i n . C a t a l y t i c hydrogenation of keto o l e f i n 185 gave a product which possessed the wrong o r i e n t a t i o n of the isopropyl group f o r the purpose of synthesizing copacamphene 141. Consequently, t h i s keto o l e f i n 185 was f i r s t reduced with l i t h i u m i n l i q u i d ammonia to a f f o r d a 6:4 mixture of alcohols 186 and 187 r e s p e c t i v e l y . I t was f e l t that by hydrogenating 186 i n a non-polar solvent, the hydroxyl group might bond to the c a t a l y s t and thus promote hydrogenation of the o l e f i n i c double bond from the more hindered s i d e . C a t a l y t i c hydrogenation of 186 i n hexane s o l u t i o n over 10% palladium on charcoal, followed by C o l l i n s oxidation of the r e s u l t i n g product, produced a mixture of the two ketones 188 and 182. Reaction of t h i s mixture with methyllithium, followed by dehydration of the r e s u l t i n g t e r t i a r y a l c o h o l s , afforded a mixture of (+)-copacamphene 141 and (+)-sativene 8 i n a r a t i o of 85:15 r e s p e c t i v e l y . This mixture was separated by chromatography on s i l v e r nitrate-impregnated s i l i c a g e l . Copacamphene, thus obtained, exhibited s p e c t r a l properties i d e n t i c a l with those of a sample prepared from n a t u r a l l y occurring copaborneol. The f i n a l synthetic approach to copa- and ylango-type s e s q u i t e r -penoids to be considered here i s the t o t a l synthesis of helminthosporal 137 25, reported by Corey and Nozoe. The s t a r t i n g m a t e r i a l , (-)-carvo-menthone 189, (see Chart 14) was converted v i a i t s hydroxymethylene deri v a t i v e to the diketo aldehyde 190, using methyl v i n y l ketone as a l k y l a t i n g agent. Deformylation of 190 under mil d l y basic conditions - 110 -resulted In the diketone 191. The desired b i c y c l i c bridged system was constructed by subjection of t h i s diketone to c y c l i z a t i o n under a c i d i c conditions (boron t r i f l u o r i d e i n methylene c h l o r i d e ) . The r e s u l t i n g product consisted of a mixture of the desired keto o l e f i n 192 and i t s C^, epimer i n a r a t i o of 4:1 r e s p e c t i v e l y . This mixture was resolvable by preparative g . l . c . or by r e c r y s t a l l i z a t i o n of the semicarbazone d e r i v a t i v e s . Reaction of ketone 192 with methoxymethylene-triphenylphosphorane i n dimethylsulfoxide, and subjection of the r e s u l t i n g W i t t i g product 193 to a c e t a l i z a t i o n conditions, resulted i n the formation of the ethylene a c e t a l 194 (together with l e s s e r amounts of the epimer). Cleavage of the double bond i n 194 was accomplished by osmolation and oxidation of the r e s u l t i n g d i o l with lead tetraacetate, thus affordi n g the keto aldehyde 195. C y c l i z a t i o n of the l a t t e r under basic conditions produced the unsaturated aldehyde 196. Hydrolysis of 196 yielded (-)-helminthosporal 25, the properties of which were completely i d e n t i c a l with those of the n a t u r a l l y derived m a t e r i a l . - I l l -25 196 Chart 14 - 112 -PART II DISCUSSION 1. General In the construction of complex sesquiterpenoids such as ylango-camphor 7_ a v a r i e t y of synthetic approaches are p o s s i b l e . The sequence i n which the substituents or f u n c t i o n a l groups are introduced may vary considerably, but the v a r i e t y i s based mainly on the order and the manner i n which the t r i c y c l i c skeleton i t s e l f can be assembled. An analysis of the structure of ylangocamphor showed that there are a number of ways i n which the t h i r d r i n g of t h i s carbon skeleton could be formed by an intramolecular a l k y l a t i o n of a s u i t a b l y substituted b i c y c l i c precursor. For example, the t r i c y c l i c system could possibly be constructed from any one of the four d i f f e r e n t b i c y c l i c structures shown i n Chart 15. A choice of one of these intermediates, and hence, i n p r i n c i p l e , of a synthetic pathway to ylangocamphor, depended on a - 113 -number of considerations. Of importance amongst these were the synthetic a v a i l a b i l i t y of the intermediate and the p r o b a b i l i t y of the intermediate undergoing the c r u c i a l c y c l i z a t i o n . Since the factors i n f l u e n c i n g stereochemistry i n the generation of asymmetric centres i n perhydroazulene derivatives are not w e l l understood, the b i c y c l i c keto tosylate 197 was eliminated as a precursor to ylangocamphor.]_. Keto tosylate 198 was also rejected because the required c y c l i z a t i o n was considered u n l i k e l y to occur. The c y c l i z a t i o n of e i t h e r of the remaining two intermediates, 199 and 200, seemed a t t r a c t i v e , hence a choice between these two was based on other consider-a t i o n s . As was mentioned i n the i n t r o d u c t i o n , the purpose of the present synthetic study was the development of a general s t e r e o s e l e c t i v e synthetic approach to ylango-type sesquiterpenoids (see Chart 15). It was f e l t that a synthetic pathway leading to keto tosylate 199 could not be r e a d i l y adapted to the syntheses of ylango sesquiterpenoids other than ylangocamphor. In a d d i t i o n , the s t e r e o s e l e c t i v e synthesis of ylangocamphor v i a intermediate 199 required the d i f f i c u l t construction of a side-chain i n 199 containing a centre of asymmetry. By ignoring t h i s d i f f i c u l t y and synthesizing a mixture of two epimers at t h i s centre, i t should be possible to perform a c y c l i z a t i o n which leads to a mixture of ylangocamphor 7_ and copacamphor 138. This type of c y c l i z a t i o n has, i n f a c t , recently been reported1^ (see Introduction, p. 102 ) . Since the introduction of the leaving group i n the remaining keto tosylate 200 involved no stereochemical problems and since the substituted bicyclo[3.2.1]pctanone 200 could hopefully be constructed i n - 114 -X = OTs (or other l e a v i n g group) Chart 15 - 115 -a s t e r e o s e l e c t i v e fashion, t h i s approach to the synthesis of ylango-camphor was chosen. Moreover, an analysis of the other ylango-type sesquiterpenoid structures showed that the syntheses of these compounds could also be r a t i o n a l i z e d from a proposed intermediate i n t h i s ylangocamphor synthesis. These synthetic proposals w i l l now be discussed. The structures of the ylango-type sesquiterpenoids are reproduced i n Chart 16. A l l of these compounds, except a-ylangene 21, incorporate the basic s t r u c t u r a l moiety 201. In a d d i t i o n , ylangocamphor 7_, ylangoborneol 23, ylangoisoborneol 143, sativene j8, and cyclosativene 24 also have i n common a two-carbon unit attached to the one-carbon bridge as i n 202. The t h e o r e t i c a l transfer of the terminal carbon atom on th i s two-carbon side-chain to the two-carbon bridge to give structure 156, affords the basic skeleton of the helmintho sesquiterpenoids: Helminthosporal 25, prehelminthosporal 154, helminthosporol 153, and prehelminthosporol 15_5. Thus i t becomes evident that a structure such as 202, with appropriate f u n c t i o n a l groups, could act as a common intermediate i n the synthesis of a l l the sesquiterpenoids shown i n Chart 16, excepting cx-ylangene 21. (From here onwards, a-ylangene w i l l not be included i n the discussion of the synthesis of the ylango-type sesquiterpenoids.). - 116 -ylangocamphor ylangoborneol ylangoisoborneol helminthosporal prehelminthosporal helminthosporol prehelminthosporol Chart 16 - 117 -156 201 202 The i n i t i a l synthetic o b j e c t i v e , therefore, was the construction of the bicyclo[3.2.l]octane-type carbon skeleton 201, with f u n c t i o n a l i t y on the one-carbon bridge which would allow f o r the introduction of the two-carbon side-chain, and a s u i t a b l e f u n c t i o n a l group on the two-carbon bridge which would allow f or the l a t e r c y c l i z a t i o n s leading to the i n d i v i d u a l sesquiterpenoids. Keeping i n mind also the importance of synthetic a v a i l a b i l i t y , i t was f e l t that the diketone 203 best f u l f i l l e d a l l of these requirements. Even though t h i s compound contains two keto groups, i t i s possible to d i f f e r e n t i a t e between them s y n t h e t i c a l l y , since only one i s e n o l i z a b l e . By v i r t u e of t h i s d i s t i n c t i o n i t should be possible to introduce the two-carbon side-chain s e l e c t i v e l y onto the one-carbon bridge, to give the required fifteen-carbon compound with the carbon skeleton 202. 0 203 204 - 118 -The d e s i r a b i l i t y of having to synthesize j u s t one such f i f t e e n -carbon precursor to a l l of the "goal" sesquiterpenoids led to the choice of the keto o l e f i n 204 as th i s precursor. Since the synthesis of t h i s compound w i l l be discussed l a t e r (vide i n f r a ) i t seems appropriate here to show only how t h i s s i n g l e Intermediate, containing a l l f i f t e e n carbons required for sesquiterpenoid s y n t h e s i s , could be converted into each of the ylango-type sesquiterpenoids to be synthesized. Hydroboration of 204 (see Chart 17), followed by t o s y l a t i o n and c y c l i z a t i o n of the r e s u l t i n g keto tosylate 200 under basic c o n d i t i o n s , should give ylangocamphor ]_. Ylangoborneol 23_ and ylangoisoborneol 143 could then be derived from ylangocamphor by s e l e c t i v e reductions. Thermal decomposition of the tosylhydrazone d e r i v a t i v e of 204 i n the presence of methyllithium, followed by s e l e c t i v e hydroboration of the r e s u l t i n g diene 206 should give the o l e f i n i c a l c o h o l 207. A f a c i l e c y c l i z a t i o n of the t o s y l d e r i v a t i v e 208 of t h i s alcohol to give sativene J3 would be expected under s o l v o l y t i c c onditions. Oxidation of t h i s o l e f i n i c alcohol 207, and thermal decomposition of the t o s y l -hydrazone d e r i v a t i v e of the r e s u l t i n g o l e f i n i c aldehyde 209 i n the presence of methyllithium, should r e s u l t i n the formation of cyclosativene 24 d i r e c t l y , or allow f o r the subsequent formation of cyclosativene from the pyrazoline 210. Acid-catalyzed c y c l i z a t i o n of o l e f i n i c aldehyde 209 to the o l e f i n i c alcohol 211, followed by oxidation of the l a t t e r , should give the keto o l e f i n 212. Conversion of keto o l e f i n 212 into the diene 213 ( c f . 204 in t o 206), followed by s e l e c t i v e osmolation, would, r e s u l t i n the o l e f i n i c d i o l 214. Oxidative cleavage of the l a t t e r under neutral conditions would hopefully - 119 -23 143 Chart 17 - 121 -give the dialdehyde 215, which should be r e a d i l y isomerizable to helmintho sp o r a 1 2 5 under basic c o n d i t i o n s . Helminthosporal has previously 134 been converted i n t o helminthosporol 153 by reduction with sodium borohydride, followed by oxidation of the r e s u l t i n g d i o l with manganese dioxide. Treatment of helminthosporol with aqueous a c i d would a f f o r d prehelminthosporol 155. Prehelminthosporal 154 (R = H) has been i s o l a t e d only as i t s a c e t a l d e r i v a t i v e 154 (R = CH^Ct^). This der i v a t i v e could hopefully be obtained from 215 by exposure to ethanol under a c i d i c conditions. The f e a s i b i l i t y of the synthetic proposal outlined In t h i s general discussion was confirmed by the s t e r e o s e l e c t i v e t o t a l synthesis of the 9 (+)-keto o l e f i n 204, and i t s subsequent conversion i n t o the sesquiterpenoids (-)-ylangocamphor ]_, (-)-ylangoborneol 23, and (-)-ylangoisoborneol 143. This synthesis w i l l now be discussed. 2. Synthesis of (+)-Keto O l e f i n 204 The f i r s t goal i n the proposed synthetic route to the keto o l e f i n 138 204 was an unambiguous synthesis of the diketone 203. B a s i c a l l y t h i s structure i s a bridged cyclohexanone system containing two substituents, a methyl group and an isopropyl group, i n a trans r e l a t i o n s h i p to each other. Because of the s u b s t i t u t i o n p a t t e r n , one obvious approach to the synthesis of t h i s compound would be the a l k y l a t i o n of carvomenthone 189, thus leading to an intermediate such as keto ester 216. The l a t t e r could then be c y c l i z e d to the required diketone 203. - 122 -Previous work i n our laboratory had shown, however, that such an approach was not f e a s i b l e . Thus, attempts to a l k y l a t e carvomenthone d i r e c t l y with ethyl-2-bromopropionate under a v a r i e t y of re a c t i o n conditions were unsuccessful. 139 S i m i l a r l y , the use of a l l y l i c halides as 140 * a l k y l a t i n g agents did not look promising. On forming the 189 I I o 2c | 217 CO Me 216 203 I Recently, Welch and Walters have succeeded i n reacting (+)-carvomenthone 189 d i r e c t l y with 4-chloro-2-pentene.l41 The a l k y l a t e d material was obtained i n 65% y i e l d and consisted of a mixture of 218 and 219. The major product was keto o l e f i n 218. - 123 -2-n-butylthiomethylene d e r i v a t i v e of carvomenthone, however, a l k y l a t i o n with 2-iodopropionate did take place i n good y i e l d .1 (^7 The only product i s o l a t e d , however, a f t e r removal of the blocking group and r e e s t e r i f i c a t i o n of the r e s u l t i n g keto a c i d , was not the keto ester 216 required for the present synthesis, but the epimeric compound 217. In spite of these r e s u l t s , i t was s t i l l f e l t that the most d i r e c t approach to the synthesis of the desired keto ester 216 was by a l k y l a t i o n of a monoterpene such as carvomenthone. It was important however, that the stereochemical outcome of the successful a l k y l a t i o n could be e a s i l y established or be already known. For these reasons, the s t a r t i n g material chosen f o r this synthetic sequence was the known (+)-ketol 222 (see Chart 18). The structure of t h i s k e t o l had been w e l l docu-142-144 * mented, and the important trans r e l a t i o n s h i p between the C ^ Q methyl group and the isopropyl side-chain had been confirmed by other work. The absolute stereochemistry of t h i s k e t o l was known by v i r t u e * It i s now general p r a c t i c e to number eudesmane-type sesquiterpenoids according to the s t e r o i d numbering system, as indicated i n structure 222. ** 145 For example, (-)-santonin 235, of known absolute stereochemistry, has been converted!46 into (+)-a-cyperone 224, one of the dehydration products formed i n the s y n t h e s i s1 4 2*5 of (+)-ketol 222 (see Chart 18). Therefore, the other dehydration product, (-)-7-epi-a-cyperone, must possess structure 223, and t h i s compound was o b t a i n e d1 4 2" by dehydration of (+)-ketol 222. Thus, the (+)-ketol 222 has the C 1 Q stereochemistry shown. 235 - 124 -of i t s synthesis from (+)-dihydrocarvone 221, i t s e l f of known absolute stereochemistry. 14 (+)-Dihydrocarvone was obtained by a simple l i t e r a t u r e procedure, from (-)-carvone 220, a r e a d i l y a v a i l a b l e and inexpensive monoterpenoid. Thus Birch reduction of (-)-carvone, followed by oxidation of the crude product, gave a high y i e l d of (+)-dihydrocarvone (see Chart 18). The procedure used for the synthesis of (+)-ketol 222 was 142 e s s e n t i a l l y that reported by Howe and McQuillan. Thus condensation of (+)-dihydrocarvone 221 with l-diethylamino-3-pentanone methiodide JB7_ i n the presence of sodium amide, afforded as major product the (+)-ketol 222, accompanied by an epimeric mixture of (+)-a-cyperone 223 and (~)-7-epi-a-cyperone 224. The k e t o l was r e a d i l y separated from the d i s t i l l e d product mixture by r e c r y s t a l l i z a t i o n of the l a t t e r . + MeNEt-I 222 223 224 Chart 18 - 125 -In our hands, the use of a s l i g h t l y higher proportion of 142 l-diethylamino-3-pentanone methiodide § ] _ than that reported, resulted i n a reaction product which did not c r y s t a l l i z e . The product consisted mainly ° f one component which was not the desired k e t o l 222, as determined by g . l . c . Consideration of the reaction involved and of the p h y s i c a l and s p e c t r a l properties (b.p., 133-140° at 0.04 mm, i n f r a r e d spectrum, very strong carbonyl absorption at 1705 cm *") of t h i s product mixture suggested that the major component was the diketone 226. This was confirmed by the f a c i l e c y c l i z a t i o n of t h i s material to give the desired k e t o l 222. Thus, subjection of the d i s t i l l e d product mixture to c y c l i z i n g conditions (sodium methoxide i n methanol at 0 ° ) , a fforded, a f t e r workup and r e c r y s t a l l i z a t i o n of the crude product, a 68% y i e l d of the (+)-ketol 222. This represented a s u b s t a n t i a l 142 144 increase over the previously reported ' y i e l d s for the synthesis of t h i s compound. The p h y s i c a l and s p e c t r a l properties of the k e t o l were i n agreement 142 144 with structure 222, and with the data reported i n the l i t e r a t u r e ' for t h i s compound. Thus the i n f r a r e d spectrum showed hydroxyl absorptionsat 3605 and 3580-3280 cm \ and a saturated carbonyl absorption - 126 -at 1705 cm . The presence of the terminal o l e f i n i c f u n c t i o n a l i t y was evidenced i n the i n f r a r e d spectrum by bands at 1638 and 895 cm \ and i n the p.m.r. spectrum by a mu l t i p l e t at T 5.33. The quartet at T 7.13 ( J = 6.8 Hz) was assigned to the proton and consistent with t h i s the doublet at x 8.98 (J = 6.8 Hz) was assigned to the secondary methyl group. The exchangeable hydroxyl proton appeared as a s i n g l e t at x 8.14, and the v i n y l methyl group as an unresolved m u l t i p l e t at x 8.33. The sharp s i n g l e t at x 8.77 was at t r i b u t e d to the angular methyl group. Hydrogenation of the (+)-ketol 222 (one equivalent of hydrogen) over palladium on charcoal gave a quantitative y i e l d of the c r y s t a l l i n e (+)-ketol 227. The phy s i c a l and s p e c t r a l properties of t h i s compound 149 were i n accord with the published data and with structure 227. Of p a r t i c u l a r i n t e r e s t i n the i n f r a r e d spectrum was the absence of o l e f i n i c absorptions. The p.m.r. spectrum was very s i m i l a r to that of the s t a r t i n g k e t o l 222, except f or the disappearance of the sign a l s due to the o l e f i n i c protons and the v i n y l methyl group, which were replaced by two doublets (J = 6.0 Hz) at x 9.15 and 9.16, a t t r i b u t a b l e to the isopropyl methyl groups. The p o s s i b i l i t y of using (+)-carvomenthone 189 instead of (+)-dihydrocarvone 221 i n the Robinson annelation reaction was also considered. This would r e s u l t i n the d i r e c t synthesis of the saturated (+)-ketol 227,. thus eliminating the hydrogenation step. This condensation 139 reaction had already been performed i n our laboratory and the expected k e t o l 227 was formed i n reasonable y i e l d . However, t h i s k e t o l - 127 -* did not c r y s t a l l i z e from the product mixture and thus i t s i s o l a t i o n required extensive column chromatography. Consequently, t h i s approach was not attempted i n the present synthesis. 222 227 228 The (+)-ketol was dehydrated using r e f l u x i n g ethanolic potassium hydroxide to give the corresponding unsaturated ketone 228 i n 97% y i e l d . The p h y s i c a l properties of t h i s octalone were in agreement with 149 the published data and with structure 228. Thus the u l t r a v i o l e t spectrum showed the presence of the a,g-unsaturated ketone with a strong absorption at 250 mp. The i n f r a r e d spectrum supported t h i s with absorptions at 1658 and 1607 cm \ In the p..m.r. spectrum the v i n y l methyl group gave r i s e to a doublet (J = 1.1 Hz) at T 8.20, and the t e r t i a r y methyl group appeared as a s i n g l e t at T 8.96. The p a i r of doublets at x 9.04 and 9.12 (J = 6.0 Hz) were a t t r i b u t a b l e to the isopropyl methyl groups. * This reluctance of the k e t o l 227 to c r y s t a l l i z e was also noted i n the present synthesis. Hikino and co-workers, who have also performed the hydrogenation re a c t i o n described above, report t h e i r product as a c o l o r l e s s o i l . - 128 -At t h i s point i t seems appropriate to discuss the planned conversion of the octalone 228 i n t o the desired keto ester 216. In order to obtain 228 229 216 the keto ester carbon skeleton from the octalone 228, the introduction (into the l a t t e r ) of a methyl group at C^, followed by oxidative cleavage of the C^-C^ and C^-C,. bonds was required. Presumably the l a t t e r transformations would involve an intermediate such as 229, where R = H or OAc, for example. The introduction of the methyl group at could hopefully be accomplished by a s e l e c t i v e Michael-type a d d i t i o n to the dienone 230. The conversion of the octalone 228 i n t o t h i s dienone would normally be 228 230 231 c a r r i e d out by d i r e c t oxidation of the former with 2,3-dichloro-5,6-87 dicyanobenzoquinone (DDQ). However i n our laboratory the DDQ oxidation of the c l o s e l y related epi-a-cyperone 223 was found to be a - 129 -very poor y i e l d i n g r e a c t i o n . T h i s problem had been overcome by f i r s t making the hydroxymethylene d e r i v a t i v e 233 and then o x i d i z i n g t h i s compound with DDQ to give the cross-conjugated dienone aldehyde 234 i n good o v e r a l l y i e l d .1" '1 223 232 233- 234 In view of these r e s u l t s the d i r e c t DDQ oxidation of octalone 228 was not attempted. Instead, the octalone 228 was transformed f i r s t i n t o the hydroxymethylene der i v a t i v e 235 and then i n t o the dienone aldehyde 236. Presumably, the synthesis of the desired keto ester 216 from t h i s l a t t e r compound could.then be accomplished i n a manner s i m i l a r to that proposed for the conversion of the dienone 230 in t o the same keto es t e r . - 130 -Thus, treatment of the (-)-octalone 228 with e t h y l formate i n benzene, i n the presence of sodium methoxide, gave the (-)-hydroxy-methylene de r i v a t i v e 235 i n 98% y i e l d . This c r y s t a l l i n e material showed the expected s p e c t r a l p r o p e r t i e s . Of p a r t i c u l a r i n t e r e s t i n the p.m.r. spectrum was the very broad s i n g l e t at T -3.73 due to the exchangeable hydroxyl proton, and the doublet (J = 1.6 Hz) at T 2.68 due to the v i n y l proton. 228 235 236 Dehydrogenation of 235 with DDQ i n dioxan f or ten minutes afforded the c r y s t a l l i n e (+)-dienone aldehyde 236 i n 93% y i e l d . The in f r a r e d spectrum of th i s compound showed four absorptions at 1700, 1648, 1623 and 1600 cm \ due to the unsaturated bonds. Of pertinence i n the p.m.r. spectrum was the very sharp v i n y l proton s i n g l e t at T 2.51, and the s i n g l e t at x -0.31 a t t r i b u t a b l e to the aldehydic proton. The remaining assignable signals were s i m i l a r i n chemical s h i f t and m u l t i p l i c i t y to the corresponding resonances i n the octalone 228. 152 Treatment of compound 236 with excess l i t h i u m dimethylcuprate at 0 ° , followed by quenching of the r e s u l t i n g enolate with a c e t y l chloride gave the enol acetate 237, i n good y i e l d (see Chart 19). In order to prevent decomposition of the product during work-up of the reaction - 131 -mixture, the l a t t e r was poured into r a p i d l y s t i r r i n g , cold ammonium hydroxide and the product was quickly i s o l a t e d by e x t r a c t i o n of the r e s u l t i n g mixture with cold ether. Even a f t e r i s o l a t i o n , the crude product was somewhat unstable, and i t was therefore used i n the next reaction without further p u r i f i c a t i o n . However, the s p e c t r a l data obtained from the crude product supported the assigned structure 237. The i n f r a r e d spectrum showed the presence of the enol acetate f u n c t i o n a l i t y -1 with absorptions at 3110 and 1768 cm , while absorption bands at 1672 and 1612 cm indicated the presence of the a,g-unsaturated ketone f u n c t i o n a l i t y . A sharp s i n g l e t at T 1.85 i n the p.m.r. spectrum was assigned to the v i n y l proton, while a quartet (J = 7.0 Hz) at x 7.12 was at t r i b u t e d to the newly generated t e r t i a r y proton. In add i t i o n to the signals for the v i n y l methyl group (a broad s i n g l e t at x 8.13), the t e r t i a r y methyl group (a s i n g l e t at x 8.82), and the isopropyl methyl groups (poorly resolved m u l t i p l e t at x 9.06), the newly introduced a c e t y l methyl group and the secondary methyl group appeared as a s i n g l e t at x 7.76 and a doublet (J = 7.0 Hz) at x 8.96, r e s p e c t i v e l y . The crude enol acetate product consisted of only one component as shown by the p.m.r. spectrum, thus i n d i c a t i n g that the conjugate add i t i o n reaction was both r e g i o s e l e c t i v e and s t e r e o s e l e c t i v e . Although the stereochemistry of the newly introduced secondary methyl group was not rigorously e s t a b l i s h e d , i t could r e a d i l y be assigned on the basis of 153 considerable l i t e r a t u r e precedent. The l a t t e r c l e a r l y i n dicated that, i n additions of t h i s type, the expected configuration of the product i s that i n which the newly introduced group bears a trans r e l a t i o n s h i p to the angular methyl group as shown i n 237. In any case, f o r the purpose - 132 -of the present synthesis, the configuration at t h i s centre of the enol acetate 237 was not c r u c i a l , since the stereochemical i n t e g r i t y at t h i s centre would be l o s t at a l a t e r stage i n the synthetic sequence. Oxidative cleavage of compound 237 was e f f e c t e d by ozonolysis i n methylene chloride at -78° to - 2 5 ° , followed by decomposition of the r e s u l t i n g ozonide with basic hydrogen peroxide. The r e s u l t i n g crude c r y s t a l l i n e keto acid 23_ was used i n the next reaction without further p u r i f i c a t i o n . However, an a n a l y t i c a l sample of the keto a c i d was obtained by r e c r y s t a l l i z a t i o n of the crude material from hexanes-ethyl acetate, and t h i s material showed i n t e r e s t i n g s p e c t r a l p r o p e r t i e s . The i n f r a r e d spectrum of the c r y s t a l s (nujol mull) showed a strong hydroxyl absorption at 3415 cm 1 and a carbonyl absorption at 1750 cm The i n f r a r e d spectrum of a chloroform s o l u t i o n of these c r y s t a l s on the other hand, exhibited hydroxyl absorptions at 3590 and 3560-2500 cm \ and carbonyl absorptions at 1770 and 1705 cm These data indicated that the keto acid 238 c r y s t a l l i z e d i n the l a c t o l form 238b, while i n chloroform s o l u t i o n there existed an equilibrium mixture of the ring-open form 238a and the c y c l i z e d form 238b. The p.m.r. spectrum of t h i s material indicated that the r a t i o of the two forms i n deuterochloroform s o l u t i o n at 40° was approximately 1:1. Two quartets, at T 6.88 (J = 7.2 Hz) and at x 7.13 (J = 7.2 Hz), whose combined integrated area corresponded to one proton, were assigned to the protons adjacent to the carboxylic acid carbonyl (of 238a) and to the l a c t o l carbonyl (of 238b) i n the mixture. The signals due to the methyl groups were not assignable. E s t e r i f i c a t i o n of the t o t a l crude keto acid with ethereal diazomethane, followed by d i s t i l l a t i o n of the crude product, afforded the keto ester - 133 -216 i n 60% o v e r a l l y i e l d from the dienone aldehyde 236. This compound showed the expected s p e c t r a l p r o p e r t i e s . In the i n f r a r e d spectrum the presence of the two d i f f e r e n t carbonyl groups was evident from the absorptions at 1732 cm 1 and 1705 cm The p.m.r. spectrum showed a sharp s i n g l e t at T 6.30 for the methoxy methyl group and a quartet (J = 7.1 Hz) at x 6.91 which was assigned to the proton adjacent to the ester carbonyl group. Signals f or the t e r t i a r y methyl group appeared as a s i n g l e t at T 9.00, for the secondary methyl group as a doublet (J = 7.1 Hz) at T 9.03 and for the isopropyl methyl groups as doublets (J = 6.3 Hz) at T 9.07 and 9.08. Chart 19 - 134 -Having now achieved the f i r s t o bjective of t h i s synthetic sequence, namely an unambiguous and good-yielding (54% o v e r a l l y i e l d from the s t a r t i n g k e t o l 222) synthesis of the keto ester 216, the next step involved the c y c l i z a t i o n of t h i s compound to give the important bicyclo[3.2.1]octadione intermediate 203. This type of c y c l i z a t i o n had already been s u c c e s s f u l l y attempted by Roberts and 133 co-workers i n t h e i r synthesis of culmorin, and by P i e r s and co-workers i n t h e i r synthesis'*^ of (+)-copacar-iphor and relat e d compounds. Thus, 133 Roberts and co-workers discovered that treatment of the keto ester 239 with sodium hydride i n dimethoxyethane f o r 17 h at 75° gave the diketone 240 i n 67% y i e l d . It should be noted that, i n t h i s instance, the product of c y c l i z a t i o n was a bicyclo[4.2.l]nonadione system while our work required the production of a bicyclo[3.2.1]octadione system. Upon a p p l i c a t i o n of t h i s procedure to the c y c l i z a t i o n of compound 217, 139 Piers and co-workers found that the diketone 241 was formed i n only poor y i e l d . When, however, t h i s l a t t e r c y c l i z a t i o n r eaction was performed using sodium bis(trimethylsilyl)amide'*""'4 as base i n r e f l u x i n g dimethoxyethane, the diketone 241 was obtained i n 90% yield.^"^^ The intramolecular Claisen condensation of the keto ester 216 proved to be much more d i f f i c u l t and capricious than expected on the basis of the above r e s u l t s . Thus, subjection of t h i s compound to either of the condensation conditions outlined above resulted i n the formation of only poor y i e l d s of the desired diketone 203 i n each case. The crude product from both reactions contained u n i d e n t i f i e d , h i g h - b o i l i n g m a t e r i a l . At t h i s stage considerable e f f o r t was expended i n order to f i n d conditions which would increase the y i e l d of the - 135 -217 241 diketone 203. A number of d i f f e r e n t bases (sodium hydride, sodium b i s ( t r i m e t h y l s i l y l ) a m i d e , l i t h i u m b i s ( t r i m e t h y l s i l y l ) a m i d e , t r i t y l l i t h i u m , and tritylsodium) and/or d i f f e r e n t solvents (benzene, dimethyoxyethane, tetrahydrofuran) were employed under a v a r i e t y of conditions. In general, although the degree of success varied somewhat from experiment to experiment, most of the attempted reactions proved u n s a t i s f a c t o r y . Eventually i t was found that the conditions which afforded by f a r the highest y i e l d (75%), and which gave reproducible r e s u l t s , were the following. A benzene s o l u t i o n of the keto ester 216 was added over a period of 65 min to a s o l u t i o n of sodium b i s ( t r i m e t h y l s i l y l ) a m i d e - 136 -(2.6 equivalents) i n benzene kept at 79-80° ( i n t e r n a l temperature). This temperature was maintained f o r a further 75 min. The reaction mixture was then quenched by pouring i t in t o aqueous a c e t i c a c i d . I t was found that the choice of reaction temperature was c r u c i a l , because at lower temperatures some s t a r t i n g material was recovered, while at higher temperatures the crude product contained considerable amounts of hig h - b o i l i n g m a t e r i a l . S i m i l a r l y , longer reaction times also gave hig h - b o i l i n g products. The c r y s t a l l i n e material obtained from t h i s c y c l i z a t i o n reaction showed sp e c t r a l properties consistent with structure 203. The i n f r a r e d -1 155 absorptions at 1765 and 1725 cm are c h a r a c t e r i s t i c of t h i s type of 1,3-dione. In the p.m.r. spectrum, a broad s i n g l e t at T 7.07 was assigned to the bridgehead (C,.) proton, while the quartet of doublets ( J = 7.1, 1.5 Hz) at T 7.68 was at t r i b u t e d to the proton. That the l a t t e r proton was coupled ( J = 1.5 Hz) to the C,. proton was shown by a decoupling experiment i n which the C,. proton at x 7.07 was i r r a d i a t e d , thus causing the quartet of doublets at x 7.68 to. collapse to a quartet ( J = 7.1 Hz). The doublet ( J = 7.1 Hz) at x 8.80 was assigned to the secondary methyl (C^ methyl) group, the sharp s i n g l e t at x 8.88 to the bridgehead methyl group and the two doublets ( J = 6.0 Hz) - 137 -at T 8.99 and 9.12 to the isopropyl methyl groups. Although the stereochemistry at C 7 i n the diketone 203 was not rigorously e s t a b l i s h e d , the stereochemistry shown i n structure 203 was assigned on the basis of analogy with s i m i l a r compounds. For 133 example, Roberts and co-workers found that on quenching the enolate corresponding to diketone 240 with a c e t i c a c i d , the product formed was 139 240, not i t s Cg epimer. Likewise, Piers and co-workers found that the quenching, with a c e t i c a c i d , of the enolate corresponding to diketone 241, resulted i n the exclusive formation of the diketone 241, not i t s C 7 epimer. The reaction conditions employed i n the present synthesis of diketone 203 s i m i l a r l y involved the quenching, with a c e t i c a c i d , of the enolate corresponding to diketone 203, and hence the expected product was 203, not i t s C ? epimer. 139 Pier s and co-workers had also shown that the diketone 241 was thermodynamically more stable than the C 7 epimeric diketone. Likewise the diketone 203 was found to be thermodynamically more stable than i t s C? epimer. Thus, when diketone 203 (obtained by c y c l i z a t i o n of keto ester 216) was subjected to epimerizing conditions (potassium carbonate i n aqueous dioxan at room temperature), the diketone was recovered unchanged. That these conditions were s u f f i c i e n t l y strong to e f f e c t epimerization of the diketone, was shown by employing deuterium oxide, instead of water, as the cosolvent i n the above r e a c t i o n . In t h i s case, deuterium was incorporated at C 7 i n diketone 203 as shown by the p.m.r. spectrum. The p.m.r. spectrum of deuterated diketone 203a was i d e n t i c a l with that of diketone 203, except for the absence ( i n 203a) of the C7H s i g n a l , the presence ( i n 203a) of a s i n g l e t (at T 8.81) rather than a - 138 -• f t 6 240 241 203 203a doublet for the methyl group, and the sharpening ( i n 203a) of the C^H si g n a l (width at h a l f height - 3.0 Hz). F i n a l l y , the coupling constant i n diketone 241 (the stereochemistry 139 of which has been fi r m l y established ) between C^H and C^H has been 139 shown to be 1.5 Hz. A coupling constant of s i m i l a r magnitude would be expected between C^H and C^H i n diketone 203, i f the l a t t e r possessed the stereochemistry shown. T h i s , indeed, was found to be the case. Thus, i t was shown, by a proton magnetic double resonance experiment (vide supra), that J r „ r „ i n 203 was 1.5 Hz. 1 L>^ ri~*v>y H. - 139 -With the important substituted bicyclo[3.2.l]octadione 203 i n hand, the synthesis of the key intermediate, keto o l e f i n 204, now required only the introduction of a v i n y l side-chain to t h i s dione. However, i t was important to carry out t h i s transformation i n a regio-s e l e c t i v e and s t e r e o s e l e c t i v e manner. In order to s a t i s f y the 203 204 s t e r e o s e l e c t i v i t y requirement, i t was f e l t that a successive a d d i t i o n of two one-carbon u n i t s , rather than a simultaneous introduction of both of the carbon atoms, would be the more rewarding approach. The s o l u t i o n to the problem of r e g i o s e l e c t i v i t y had already been incorporated into the structure of the diketone i t s e l f , since only one of the keto groups was e n o l i z a b l e . Thus, the f i r s t carbon of the required v i n y l side-chain was introduced by an e f f i c i e n t three-step homologation sequence. The (+)-diketone 203 was reacted with excess sodium b i s ( t r i m e t h y l -s i l y l ) a m i d e i n hexamethylphosphoramide and the r e s u l t i n g enolate was trapped with isopropyl bromide to give the 0-alkylated product 242 i n 88% y i e l d . Of note i n the i n f r a r e d spectrum of t h i s material was the carbonyl absorption at 1760 cm 1 and the strong o l e f i n i c absorption at 1660 cm That 0 - a l k y l a t i o n had indeed taken place was evident from the p.m.r. spectrum of the product. A septet (J = 6.1 Hz) at T 5.95 and - 140 -doublets ( J = 6.1 Hz) at x 8.74 and 8.89 accounted f or the t e r t i a r y proton and the isopropyl methyl groups r e s p e c t i v e l y of the newly introduced isopropyl group, while the doublet ( J «= 0.9 Hz) at x 8.32 was a t t r i b u t e d to the v i n y l methyl group. The remaining assignable s i g n a l s , due to the proton, the t e r t i a r y methyl group and the isopropyl methyl groups were s i m i l a r i n chemical s h i f t and m u l t i p l i c i t y to the corresponding resonances i n the diketone 203. The a l k y l a t i o n reaction j u s t described also produced a second product, to the extent of about 10%. Consideration of the reaction involved, and of the ph y s i c a l and s p e c t r a l properties of t h i s c r y s t a l l i n e product indicated that t h i s material was the C-alkylated product 243. Thus, i n the i n f r a r e d spectrum, the carbonyl absorption region was si m i l a r to that of diketone 203 with absorptions at 1758 and 1722 cm ^ . The p.m.r. spectrum showed the C^ bridgehead proton as a broad s i n g l e t at x 7.15, and also two sharp s i n g l e t s at x 8.85 and 8.90, a t t r i b u t e d to the t e r t i a r y methyl groups. The two pair s of doublets at x 8.97 and 9.12 (J = 6.1 Hz) and at x 9.00 and 9.22 (J = 6.9 Hz), were assigned to the methyl groups of the two isopropyl moieties. While the configuration at C 7 i n t h i s product was not est a b l i s h e d , i t was evident - 141 -from a study of a molecular model of the enolate of diketone 203 that approach of the alkylating agent is much less hindered from the exo side (i.e., the side away from the three-carbon bridge), and thus the alkylation reaction should have produced a product with the stereo-chemistry shown in structure 243. The reaction conditions used in the alkylation reaction merit further comment. Hexamethylphosphoramide was selected as solvent since this medium has been found to promote O-alkylation.1"'^ The use of other solvents with similar properties 1^ was also studied in the present instance. It was found, however, that when the reaction was carried out in dimethylsulfoxide or sulfolane, the expected products 242 and 243 were indeed formed, but in each case the proportion of the desired O-alkylated material 242 was considerably less than in hexamethylphosphoramide. Treatment of the (+)-keto enol ether 242 with excess methoxymethylene-triphenylphosphorane in refluxing ether for thirty minutes afforded, in quantitative yield, a mixture of the diastereomeric diethers 244. The ratio of the two diastereomers varied considerably from experiment to experiment. No attempt was made to separate these isomers, since both gave rise to the same products in the next reaction. Of importance in the infrared spectrum of this mixture were the two olefinic absorptions at 1707 and 1664 cm 1. The presence of the two components was evident in the p.m.r. spectrum of the mixture which showed two vinyl proton singlets at T 4.43 and 4.52, two tertiary proton (adjacent to oxygen) septets (J = 6.1, 6.1 Hz) at x 5.92 and 5.97 and two methoxy methyl singlets at x 6.49 and 6.56. - 142 -Tota l hydrolysis of both of the enol ether f u n c t i o n a l i t i e s i n the mixture 244 was achieved by exposure of t h i s material to aqueous p e r c h l o r i c acid i n ether f o r 1.5 hours. The r e s u l t i n g keto aldehydes 245 and 246 were produced i n a r a t i o of approximately 1:1. On allowing the hydrolysis reaction to proceed f o r a longer time, i t was found that the r a t i o of keto aldehydes gradually changed i n favor of the desired product 245. It was f e l t , however, that an equilibrium mixture could be achieved more r a p i d l y under basic conditions. Consequently the 1:1 mixture of keto aldehydes was treated with potassium carbonate i n aqueous methanol u n t i l an equilibrium mixture of the two epimers was achieved (1.5 hours). On the basis of g a s - l i q u i d chromatographic a n a l y s i s , 0 MeO 242 244 OHC 245 246 - 143 -t h i s r a t i o was found to be approximately 82:18, with the major epimer being the desired compound 245. The o v e r a l l y i e l d f o r the hydrolysis and epimerization reactions was 80%, although the y i e l d decreased somewhat i f the crude product of hydrolysis was not d i s t i l l e d before being subjected to epimerization. Attempted separation of the two epimers (245 and 246) by column chromatography ( s i l i c a gel or a c t i v i t y I I I ne u t r a l alumina) resulted i n extensive decomposition of both compounds. Consequently, the next reaction was performed on the equilibrium mixture of the compounds. The spec t r a l data obtained from t h i s mixture supported the proposed s t r u c t u r e s , 245 and 246. Thus the i n f r a r e d spectrum exhibited absorptions at 2745, 1735, and 1715 cm \ In the p.m.r. spectrum, the presence of the two components was evident from the two doublets at T -0.10 (J = 1.0 Hz) and T -0.03 ( J = 2.0 Hz), a t t r i b u t e d to the aldehydic protons. The signals due to the methyl groups were not assignable. The f i n a l carbon required f o r the completion of the synthesis of the C^^-carbon skeleton was also added by means of a W i t t i g r e a c t i o n . The equilibrium mixture of keto aldehydes 245 and 246 was f i r s t allowed to react with methylenetriphenylphosphorane under conditions s i m i l a r to the previous high-yielding W i t t i g r e a c t i o n , but t h i s resulted i n the formation of only poor y i e l d s of the corresponding keto o l e f i n i c products 204 and 247. The use of other ether-type solvents, as we l l as experimentation with a v a r i e t y of reaction temperatures, f a i l e d to appreciably increase the y i e l d of the desired products. However, on performing the reaction i n dry dimethylsulfoxide"*""^ at room temperature, the keto o l e f i n s 204 and 247 were produced i n quantitative y i e l d , i n the expected r a t i o of approximately 82:18 r e s p e c t i v e l y . - 1 4 4 -2 4 5 2 0 4 4- > 4-2 4 6 2 4 7 The two components ( 2 0 4 and 2 4 7 ) were separable by column chromato-graphy on t . l . c . s i l i c a g e l . The p h y s i c a l and s p e c t r a l properties of each were i n agreement with the proposed s t r u c t u r e s . Thus the i n f r a r e d spectrum of the desired major epimer 2 0 4 (Figure 1 1 ) showed the presence of the terminal o l e f i n i c group with bands at 3 0 8 0 , 1 6 3 4 and 9 1 0 cm \ while the carbonyl group gave r i s e to a strong absorption at 1 7 3 0 cm \ In the p.m.r. spectrum of 2 0 4 (Figure 1 2 ) , the v i n y l group exhibited a m u l t i p l e t at T 3 . 9 9 - 4 . 3 7 for the C G proton and a m u l t i p l e t at T 4 . 8 6 - 5 . 1 0 for the C ^ Q protons. The broad s i n g l e t at T 7 . 4 1 was assigned to the bridgehead C, . proton, the doublet (J = 7 . 9 Hz) at x 7 . 7 9 to the a l l y l i c C „ proton, and the quartet (J = 7 . 2 Hz) at x 7 . 9 7 to the Figure 11. Infrared Spectrum of (+)-Keto O l e f i n 204. - 147 -C 7 proton. The secondary methyl group (C 7 methyl) appeared as a doublet ( J * 7.2 Hz) at T 9.06, while the t e r t i a r y methyl group (T 8.99) and the isopropyl methyl groups (doublets, x 8.99 and 9.20, J = 6.2 Hz) were also d i s t i n g u i s h a b l e . The s p e c t r a l data for the c r y s t a l l i n e minor keto o l e f i n i c product 247\ were s i m i l a r t o , but not i d e n t i c a l with that of i t s epimer 204. The o l e f i n i c double bond gave r i s e to absorptions at 3080, 1633 and 916 cm "*" i n the i n f r a r e d spectrum, while the carbonyl group produced a strong band at 1724 cm In the p.m.r. spectrum, the v i n y l group gave r i s e to m u l t iplets at T 3.71-4.08 and 4.68-4.92 corresponding to the Cg and C ^ Q protons r e s p e c t i v e l y . The C,. bridgehead proton appeared as a broadened doublet ( J = 5.6 Hz) at T 7.42, the Cg a l l y l i c proton as a doublet of doublets (J = 5.6, 8.3 Hz) at T 7,64 and the C 7 proton as a quartet (J = 7.0 Hz) at x 8.17. The signals for the various methyl groups were also r e a d i l y assignable. The assignment of the stereochemistry at the point of attachment of the v i n y l side-chain to the one-carbon bridge of the bicyclo[3.2.1]-octanone system merits comment. It had been assumed that i n the mixture of keto aldehydes 245 and 246, the major component at equilibrium was the desired compound 245 with the formyl group i n an equatorial o r i e n t a t i o n with respect to the six-membered r i n g . Consequently, the major product i n the corresponding mixture of keto o l e f i n s was also assumed to be 204. The f i r s t i n d i c a t i o n that t h i s assumption was indeed correct was provided by a comparison of the p.m.r. spectra of the two keto o l e f i n products. The C,. proton of the major product 204 appeared as a broad s i n g l e t (width at h a l f height = 4.5 Hz) at T 7.41 with l i t t l e or no coupling to - 148 -the Cg proton. The C,. proton of the minor product 247, on the other hand, was clearly coupled with the CQ proton with J . n . „ =• 5.6 H z . An analysis of a molecular model of keto olefin 204 showed that the dihedral angle between C^ H and CgH i s approximately 7 0°, and on the 158 basis of the Karplus equation only a very small coupling constant should exist between these two protons. This i s , in fact, the situation observed in the p.m.r. spectrum of the major keto olefinic product. On the other hand, a molecular model of the other keto olefin 247 showed that the dihedral angle between CCH and C0H in this compound i s about J o 4 5°, and for this angle the Karplus equation predicts a coupling constant (J_ „ „) of magnitude similar to that observed (5.6 Hz) in the p.m.r. J O spectrum of the minor component of the keto olefin mixture. Chemical confirmation that the major component was indeed compound 204 was provided later (vide infra) by the cyclization of a derivative of the major keto olefin to give ylangocamphor. Obviously, the analogous derivative of the keto olefin 247 could not undergo such a cyclization. The successful, stereoselective synthesis of the (+)-keto olefin 204 made available a C-15 intermediate which could hopefully be transformed into the various ylango sesquiterpenoids. The f e a s i b i l i t y of such transformations i s demonstrated by the successful synthesis of (-)-ylango-camphor _7> (-)-ylangoborneol 23, and (-)-ylangoisoborneol 143 from this (+)-ketp olef i n . - 149 -3. Synthesis of (-)-Ylangocamphor _7, (-)-Ylangoborneol 23_, and (-)-Ylangoisoborneol 143 The planned conversion of the (+)-keto o l e f i n 204 i n t o ylangocamphor required the introduction of a leaving group at the terminal p o s i t i o n of the o l e f i n i c side-chain of the former compound, so that an i n t e r n a l a l k y l a t i o n could be attempted. Hydroboration, followed by mesylation (or t o s y l a t i o n ) , seemed a promising method of accomplishing t h i s required transformation and t h i s sequence of reactions was therefore adopted. Because of the fact that ketones are susceptible to reduction by 159 diborane, and because of the proximity of the keto f u n c t i o n a l i t y to the o l e f i n i c side-chain i n compound 204, i t was f e l t that s e l e c t i v e hydroboration of the o l e f i n i c double bond i n 204 with diborane would not be f e a s i b l e . What was required was a hydroborating reagent which delivered only one hydride per molecule and which was r e l a t i v e l y unreactive towards ketone carbonyl groups. The s e l e c t i v e hydroborating 159 reagent, disiamylborane (Sia2BH), which i s e a s i l y prepared by tre a t i n g tetrahydrofuran-borine complex with two or more equivalents of 2-methyl-2-butene at 0 ° , was therefore chosen for t h i s r e a c t i o n . It should be noted that an a d d i t i o n a l advantage i n the use of d i s i a m y l -borane i s that the product of hydroboration of monosubstituted o l e f i n s (such as 204) with t h i s reagent, i s almost e x c l u s i v e l y the corresponding primary alcohol."'""'9 Subjection of the (+)-keto o l e f i n 204 to hydroboration with disiamylborane i n tetrahydrofuran at 0° for 45 minutes, followed by oxidative decomposition of the r e s u l t i n g t r i a l k y l b o r a n e with a l k a l i n e hydrogen peroxide afforded, i n 81% y i e l d , a mixture of the desired keto - 150 -alcohol 205 and the d i o l 248 In a r a t i o of approximately 85:15 r e s p e c t i v e l y . The two components were not separable by column chromatography. It was desirable at t h i s stage to separate these compounds i n order to show that the minor component was indeed the d i o l 248, and i n order to obtain an a n a l y t i c a l sample of the keto alcohol 205. However, f o r the purpose of synthesizing ylangocamphor 7_, t h i s separation was not necessary. It was f e l t that the remaining reactions (mesylation and intramolecular a l k y l a t i o n ) leading to ylangocamphor would not be disadvantageously influenced by the presence of t h i s d i o l impurity, and that ylangocamphor could r e a d i l y be separated from the f i n a l product mixture by d i s t i l l a t i o n . This proved to be the case (vide i n f r a ) . For purposes of c h a r a c t e r i z a t i o n , the keto alcohol 205 and the d i o l 248 were separated as t h e i r t r i m e t h y l s i l y l ether d e r i v a t i v e s . Thus, treatment of the hydroboration product with a mixture of trimethylchlorosilane and hexamethyldisilazane i n p y r i d i n e1^ at room temperature for f i f t e e n minutes, gave a quantitative y i e l d of the c o r r e s -ponding t r i m e t h y l s i l y l ether d e r i v a t i v e s 249 and 250 ( i n the r a t i o of approximately 85:15 r e s p e c t i v e l y ) . These d e r i v a t i v e s were r e a d i l y separated by preparative g . l . c , and both were c o l l e c t e d i n high y i e l d . The keto t r i m e t h y l s i l y l ether 249 -showed the expected carbonyl absorption 204 205 2 4 8 - 151 -at 1727 cm" and bands at 1250, 1090, 840 and 745 cm" a t t r i b u t e d to the t r i m e t h y l s i l y l ether group. Of i n t e r e s t i n the p.m.r. spectrum was the sharp s i n g l e t at x 9.88 due to the methyl groups of t r i m e t h y l s i l y l blocking group. The remainder of the p.m.r. spectrum was almost i d e n t i c a l with that of the corresponding keto alcohol 205, except f o r the absence of the hydroxyl proton. The (+)-keto alcohol 205 was e a s i l y regenerated i n pure form and i n high y i e l d from the t r i m e t h y l s i l y l ether d e r i v a t i v e 249 by hydrolysis of the l a t t e r i n r e f l u x i n g aqueous e t h a n o l .1^1 The i n f r a r e d spectrum of the product 205 exhibited a strong hydroxyl absorption at 3400 cm 1 and the usual cyclopentanone carbonyl absorption at 1724 cm \ In the p.m.r. spectrum, the complex m u l t i p l e t at x 6.34 was assigned to the pai r of protons on the oxygen-bearing carbon, and the broad s i n g l e t at x 7.46 to the C,., bridgehead proton. The angular methyl group and the secondary methyl group appeared as a s i n g l e t at x 8.96 and a doublet (J = 7.1 Hz) at x 9.03 r e s p e c t i v e l y . The two doublets (J = 6.1 Hz) at x 8.99 and 9.18 were at t r i b u t e d to the isopropyl methyl groups. The minor component c o l l e c t e d by preparative g . l . c , the b i s t r i m e t h y l s i l y l ether d e r i v a t i v e 250, showed no hydroxyl or carbonyl absorptions i n the in f r a r e d spectrum. Absorption bands due to the t r i m e t h y l s i l y l ether groups were present at 1250, 1060, 840 and 750 cm 1. Of p a r t i c u l a r i n t e r e s t i n the p.m.r. spectrum were the two s i n g l e t s at x 9.89 and 9.85 due to the methyl groups of the two t r i m e t h y l s i l y l groups. The remainder of the p.m.r. spectrum was s i m i l a r to that of d i o l 248- The l a t t e r was obtained i n high y i e l d from the b i s t r i m e t h y l s i l y l ether de r i v a t i v e 250 by the same type of mild hydrolysis as that employed - 152 -i n the ease of compound 249. The i n f r a r e d spectrum of the product 248 exhibited a strong hydroxyl absorption at 3350 cm ^ . The p.m.r. spectrum showed a doublet of doublets (J = 6.9, 10.6 Hz) at x 5.60 and a complex multiplet at x 6.41, a t t r i b u t e d to the C, proton and the protons on the + > + 248 250 248 carbon bearing the primary hydroxyl group, r e s p e c t i v e l y . The t e r t i a r y methyl group was apparent as a s i n g l e t at x 9.25, the secondary methyl group as a doublet (J =7.1 Hz) at x 9.29 and the isopropyl methyl groups as doublets (J = 6.6 Hz) at x 9.18 and 9.28, r e s p e c t i v e l y . I t seems appropriate here to comment on the stereochemistry at C, o of the d i o l 248. Molecular models indicated that the dihedral angle between the protons on C_ and C, was approximately 15-25° and i n agreement - 153 -1 5 8 with the Karplus equation the observed coupling constant, J „ „ n „ , O c n — L i , a was 6 . 9 Hz. Likewise, the dihedral angle between the C, and C_ protons o / was near to 0 ° , giving r i s e to the observed coupling constant, J o n /•• u> of 1 0 . 6 Hz, also i n good agreement with that expected on the C6H-C?H basis of the Karplus equation. If the configuration at Q,, of the d i o l o had been epimeric with that shown i n 2 4 8 , the dihedral angles between the protons on C,. and Cg would be approximately 9 0 ° , and between the protons on Cg and C 7 approximately 1 2 5 ° . On the basis of the Karplus equation, the expected coupling constants would then be approximately zero and 3 . 0 Hz r e s p e c t i v e l y . F i n a l l y , i t was evident from a consideration of a molecular model of the keto o l e f i n 2 0 4 that attack on the ketone f u n c t i o n a l i t y by the hydride complex would be more f a c i l e from the exo side of the b i c y c l o [ 3 . 2 . l ] o c t a n e system, (that i s , the side away from the three-carbon bridge) thus giving r i s e to the endo-alcohol. The pure (+)-keto alcohol 2 0 5 was treated with methanesulfonyl chloride i n pyridine for 2 . 2 5 hours at room temperature. The r e s u l t i n g crude keto mesylate 2 5 1 was subjected to c y c l i z a t i o n conditions without p u r i f i c a t i o n . This intramolecular a l k y l a t i o n proved to be very f a c i l e . Thus, exposure of 2 5 1 to sodium b i s ( t r i m e t h y l s i l y l ) a m i d e i n dimethoxy-ethane for 4 0 minutes, and d i s t i l l a t i o n of the r e s u l t i n g crude product, afforded (-)-ylangocamphor _7, i n 8 4 % o v e r a l l y i e l d from the (+)-keto alcohol 2 0 5 . This d i s t i l l e d product c r y s t a l l i z e d on c o o l i n g , and a r e c r y s t a l l i z e d sample (from hexanes) exhibited a sharp melting point of 2 6 25-25.5°, and [of]^ = -58°. The s p e c t r a l properties of t h i s compound were i n complete agreement with the assigned st r u c t u r e . Of importance i n the i n f r a r e d spectrum (Figure 1 3 ) was the carbonyl absorption at 1 7 3 3 cm \ Figure 13. Infrared Spectrum of (-)-Ylangocamphor 7_. - 156 -In the p.m.r. spectrum (Figure 14) the bridgehead proton adjacent to the carbonyl group was evident as a broad s i n g l e t (width at h a l f height • 3.0 Hz) at T 7.76, while the isopropyl methyl groups appeared as a p a i r of doublets ( J = 6.5 Hz) at T 9.02 and 9.19. The s i n g l e t s at T 9.10 and 9.11 were assigned to the two t e r t i a r y methyl groups. 205 251 I As mentioned e a r l i e r , the rather tedious though e f f i c i e n t separation of the mixture of keto alcohol 205 and d i o l 248 could be avoided by performing the mesylation and c y c l i z a t i o n reactions on the mixture, under conditions i d e n t i c a l with those used on the pure keto a l c o h o l . Thus, reaction of the mixture of 205 and 248 with methanesulfonyl chloride i n p y r i d i n e , and treatment of the r e s u l t i n g mixture of mesylate derivatives with sodium b i s ( t r i m e t h y l s i l y l ) a m i d e i n dimethoxyethane, gave a crude product which, on simple d i s t i l l a t i o n , y i e l d e d pure ylangocamphor (50% o v e r a l l y i e l d from the keto o l e f i n 204). (-)-Ylangocamphor ]_ was converted into the two corresponding a l c o h o l s , ylangoborneol 23 and ylangoisoborneol 143, by two completely stereo-s e l e c t i v e reductions. Thus treatment of ]_ with calcium i n anhydrous l i q u i d ammonia afforded (-)-ylangoborneol as the sole product, i n 95% y i e l d . This c r y s t a l l i n e compound exhibited a sharp m.p. of 60.5-61° and 25 [a] = - 2 3 ° . In the i n f r a r e d spectrum (Figure 15) the presence of the - 158 -- 159 -hydroxy group was evident from absorptions at 3610 and 3460 cm ^ . The p.m.r. spectrum ( i n CCl^, Figure 16) displayed a broad s i n g l e t (width at h a l f height = 3.2 Hz) at i 6.26 for the hydrogen on the oxygen-bearing carbon. The doublets ( J = 6.5 Hz) at T 9.06 and 9.14 and the s i n g l e t s at T 9.15 and 9.19 were assigned to the isopropyl methyl groups and the two t e r t i a r y methyl groups, r e s p e c t i v e l y . The stereochemical outcome of the r e a c t i o n , and the p a r t i c u l a r reaction conditions employed i n the reduction of (-)-ylangocamphor 1_ to (-)-ylangoborneol 23 merit further comment. The metal-ammonia reduction of keto compounds generally favors the production of the thermodynamically 162 more stable alcohol product. Consideration of molecular models of ylangoborneol 2_3 and ylangoisoborneol 143 indicates that the hydroxyl group i s i n a le s s crowded environment i n ylangoborneol, and consequently t h i s should be the thermodynamically more stable epimer. It has also been s h o w n1^ '1^ i n the reduction of camphor and related compounds that the use of calcium metal, rather than l i t h i u m , sodium or potassium, under anydrous conditions, has the combined attractiveness of favoring the formation of endo-alcohols and of producing high y i e l d s of monomeric products. While i n the reduction of ylangocamphor the use of metals other than calcium was not studied, an excellent y i e l d of monomeric product was - 160 -obtained using calcium metal under anhydrous con d i t i o n s . Furthermore, the reaction showed complete s t e r e o s e l e c t i v i t y i n favor of the endo-alcohol (endo with respect to the bicyclo[2.2.1]heptane moiety). The transformation of (-)-ylangocamphor _7 into (-)-ylangoisoborneol 143 was also accomplished i n a st e r e o s e l e c t i v e fashion. Thus subjection of ]_ to reduction with l i t h i u m aluminum hydride i n r e f l u x i n g ether for 1 hour afforded, as the sole product, (-)-ylangoisoborneol i n 91% y i e l d . This product, though pure by g a s - l i q u i d chromatographic analysis, proved d i f f i c u l t to r e c r y s t a l l i z e . However, despite i t s high s o l u b i l i t y i n the solvent, a r e c r y s t a l l i z e d sample was obtained by r e c r y s t a l l i z a t i o n from hexane at - 1 0 ° . The r e s u l t i n g c r y s t a l l i n e m a t e r i a l , which had a soft appearance at room temperature ( 2 2 ° ) , exhibited a melting point 26 range of 31-5-32.5° and [ a ] D = - 2 8 ° . The i n f r a r e d and p.m.r. spectra of t h i s material were c l e a r l y d i f f e r e n t from those of (-)-ylangoborneol 23. Of pertinence i n the i n f r a r e d spectrum (Figure 17) were the hydroxyl absorptions at 3630 and 3495 cm \ In the p.m.r. spectrum ( i n CCl^, Figure 18), the proton on the oxygen-bearing carbon gave r i s e to a doublet (J = 7.7 Hz) at x 6.27. This proton was coupled with the proton on the adjacent bridgehead carbon which appeared as a broadened doublet (J = 7.7 Hz) at x 7.91. The chemical s h i f t assigned to t h i s bridgehead hydrogen was confirmed by a decoupling experiment i n which the proton at x 6.27 was i r r a d i a t e d , thus causing the doublet at x 7.91 to collapse to a broadened s i n g l e t . The pa i r of doublets (J = 6.5 Hz) at x 9.08 and 9.20 were assigned to the isopropyl methyl groups, and the s i n g l e t s at x 9.18 and 9.20 to the two t e r t i a r y methyl groups. Figure 17. Infrared Spectrum of (-)-Ylangoisoborneol 143. - 163 -7 143 It has been pointed out above that the expected product of d i s s o l v i n g metal reduction of ylangocamphor 1_ was the alcohol 23, ylangoborneol. The expected product of hydride reduction, on the other hand, was the epimeric alcohol 1 4 3 . The l a t t e r p r e d i c t i o n arose from a study of a molecular model of ylangocamphor _7, which showed that the approach by the hydride complex to the carbonyl group i s much less hindered on the endo side (endo with respect to the bicyclo[2.2.l]heptanone moiety), and attack from t h i s side gives r i s e to the exo-alcohol 143, ylangoisoborneol. That the products of metal-ammonia reduction and hydride reduction of (-)-ylangocamphor 1_ were indeed (-)-ylangoborneol 23_ and (-)-ylango-isoborneol 143 r e s p e c t i v e l y , was confirmed by the p.m.r. spectra of the two alcohols. Thus, as shown by inspection of molecular models, the dihedral angle between the proton on the oxygen-bearing carbon and the proton on the adjacent bridgehead carbon i n ylangoborneol was about 1 1 0° . 158 Therefore i n keeping with the Karplus equation, the expected coupling constant between these two protons would be i n the order of 1.0 Hz. The observed s i g n a l f o r the proton on the oxygen-bearing carbon i n the product of metal-ammonia reduction was a broad s i n g l e t . In the p.m.r. - 164 -spectrum of the product of hydride reduction, on the other hand, t h i s proton appeared as a doublet with a coupling constant of 7.6 Hz. Again, t h i s coupling constant was i n agreement with that predicted on the basis of the Karplus equation, since an analysis of a molecular model of 143 indicated that the dihedral angle between the proton on the oxygen-bearing carbon and the proton on the adjacent bridgehead carbon was near to 0 ° . In summary, a general s t e r e o s e l e c t i v e approach to the synthesis of ylango-type sesquiterpenoids has been developed. The f e a s i b i l i t y of t h i s approach has been demonstrated by the st e r e o s e l e c t i v e t o t a l synthesis of (-)-ylangocamphor 7_> (-)-ylangoborneol 23_ and (-)-ylango-isoborneol 143, v i a the key intermediate keto o l e f i n 204. This unambiguous synthesis provides proof f or the structure and absolute stereochemistry of these three sesquiterpenoids. The synthesis of other ylango-type sesquiterpenoids from t h i s same intermediate 204 i s currently being investigated i n our laboratory. - 165 -PART II EXPERIMENTAL For general experimental information see p. 73. Preparation of (+)-Ketol 222 A s o l u t i o n of (+)-dihydrocarvone 221 (142 g, 0.93 mole) i n 1250 ml of anhydrous ether containing 40 g (1.025 moles) of sodium amide was s t i r r e d at 0° for 2 h under an atmosphere of nitrogen. To t h i s s o l u t i o n at 0° was added, over 50 min, a cold s o l u t i o n of 1-diethylamino 3-pentanone methiodide 87_ (290 g, 0.97 mole) [prepared by reaction of l-diethylamino-3-pentanone (152.5 g, 0.97 mole) with methyl iodide (142 1.0 mole)] i n 300 ml of dry p y r i d i n e . The r e s u l t i n g mixture was s t i r r e d with a mechanical s t i r r e r at 0° for 8 h and then for a further 5 h at r e f l u x . The cooled reaction mixture was poured i n t o cold water, the layers were separated and the aqueous layer extracted with ether. The ether layers were combined, the ether was removed at a s p i r a t o r pressure and most of the pyridine was taken o f f under vacuum. The r e s u l t i n g residue was dissolved i n ether and washed with a 5% s o l u t i o n of hydrochloric a c i d , with b r i n e , and then dried over anhydrous magnesium s u l f a t e . Removal of solvent afforded a yellow o i l which was d i s t i l l e d to give 60 g of the s t a r t i n g m a t e r i a l , (+)-dihydrocarvone 221 (b.p. 55-60° at 0.4 mm) and 106.8 g of a l i q u i d product with b.p. 133-140° at 0.04 mm. Analysis of t h i s material by g . l . c . (column A, - 166 -1 8 2 ° , 120) showed that only a small amount of the desired k e t o l 222 was present. (The r e l a t i v e amount of k e t o l present v a r i e d somewhat from experiment to experiment.) The p.m.r. and i n f r a r e d spectra confirmed t h i s , and the i n d i c a t i o n s were that most of the condensation product had f a i l e d to c y c l i z e under these r e a c t i o n conditions. Conse-quently t h i s material was treated with 63 ml of 0.136 M sodium methoxide so l u t i o n i n methanol at 0° for 2 h. The reaction mixture was poured into brine and the product i s o l a t e d by e x t r a c t i o n with ether. The ether s o l u t i o n was washed with brine and dried over anhydrous magnesium s u l f a t e . Removal of the solvent gave a c r y s t a l l i n e compound which was r e c r y s t a l l i z e d from hexanes to give 85.5 g of the desired (+)^ketol 222 (68% based on unrecovered (+)-dihydrocarvone). An a n a l y t i c a l sample exhibited m.p. 107 . 5 - 1 0 8°; [ a ] *8 +43.5° (c,2.5 i n CHC13) [ l i t .1 4 2 b m.p. 1 0 6° ; [ a ] D + 5 4° * (c,3.0 i n C H C l 3 ) ] ; i n f r a r e d (CHC1 3), v m a x 3605, 3580-3280, 1705, 1638, 895 cm"1; p.m.r., T 5.33 ( m u l t i p l e t , 2H, i CH3-C=CH2), 7.13 (quartet, 1H, C4H, J = 6.8 Hz), 8.14 ( s i n g l e t , 1H, exchangeable -OH), 8.33 (unresolved m u l t i p l e t , 3H, v i n y l methyl, width at h a l f height =3.0 Hz), 8.77 ( s i n g l e t , 3H, t e r t i a r y methyl), 8.98 (doublet, 3H, secondary methyl, J = 6.8 Hz). Anal. Calcd. for C^H^O,,: C, 76.23; H, 10.24. Found: C, 76.05; H, 10.03. The reason for t h i s discrepancy i s not known. The enantiomeric compound which has been synthesized by H a l s a l l and co-workers was reportedl44 to have [ct] n -48° (c,2.3 i n CHC1,). - 167 -Preparation of (+)-Ketol 227 A s o l u t i o n of the (+)-ketol 222 (114.5 g, 0.385 mole) i n 750 ml of ethanol was hydrogenated over 10.5 g of 10% palladium on charcoal at room temperature, u n t i l the uptake of hydrogen was complete (approximately 50 min). The s o l u t i o n was f i l t e r e d and the solvent was removed to give a quantitative y i e l d of the (+)-ketol 227, which c r y s t a l l i z e d on standing. An a n a l y t i c a l sample was obtained by r e c r y s t a l l i z a t i o n from 27 hexanes to give c o l o r l e s s c r y s t a l s , m.p. 6 2 . 5 - 6 3°; [ a ] D +50.1° ( c 2.5 149 * i n CHC13) [ l i t . [a] +101.5° (c,5.20 i n CHC1 3)]; i n f r a r e d (CHC1 3), v 3610, 3580-3320, 1707 cm"1; p.m.r., T 7.14 (quartet, 1H, C.H, max r ' ^ ' ' 4 J = 6.8 Hz), 8.10 ( s i n g l e t , 1H, exchangeable, -OH), 8.79 ( s i n g l e t , 3H, t e r t i a r y methyl), 8.96 (doublet, 3H, secondary methyl, J = 6.8 Hz), 9.15, 9.16 (doublets, 6H, isopropyl methyls, J = 6.0 Hz). Anal. Calcd. for C1cHo,0-: C, 75.58; H, 10.99. Found: C, 75.58; ID ZO Z H, 10.90. Preparation of (-)-ll,12-Dihydro-7-epi-a-cyperone 228 A s o l u t i o n containing 166.4 g (0.697 mole) of the (+)-ketol 227 i n 2000 ml of 10% ethanolic potassium hydroxide was refluxed gently for 10 h under an atmosphere of nitrogen. The cooled s o l u t i o n was poured into water and t h i s mixture was thoroughly extracted with petroleum ether (b.p. 3 0 - 6 0° ) . The combined extracts were washed with 2% hydrochloric * This l i t e r a t u r e r o t a t i o n was taken on a sample of n o n - c r y s t a l l i n e (+)-ketol and t h i s might account for the high reading obtained. The (-)-ketol has also been synthesized,143 and the reported data f o r t h i s compound are: m.p. 6 4 - 6 5° ; [a] -57° (c 3.8 i n CHC1 ) . - 168 -a c i d , with b r i n e , and dried over anhydrous magnesium s u l f a t e . Removal of the solvent, followed by d i s t i l l a t i o n of the residue, gave 150.5 g (97%) of the octalone 228 as a c o l o r l e s s o i l , b.p. 97° at 0.15 mm. An a n a l y t i c a l sample, obtained by preparative g . l . c . (column B , 2 2 0° , 100) exhibited n^° 1.5187; [ a ] ^6 -145° (c,0.6 i n CHC13) [ l i t .1 4 9 [ a ] D -145° (c,9.35 i n CHC1 3)]; u l t r a v i o l e t , A 250 my (E = 14,000); i n f r a r e d ( f i l m ) , v 1658, 1607 cm 1; p.m.r., x 8.20 (doublet, 3H, max v i n y l methyl, J = 1.1 Hz), 8.76 ( s i n g l e t , 3H, t e r t i a r y methyl), 9.04, 9.12 (doublets, 6H, isopropyl methyls, J = 6.0 Hz). Anal. Calcd. for C^H^O: C, 81.76; H, 10.98. Found: C, 81.62; H, 10.78. Preparation of the (-)-Hydroxymethylene Derivative 235 To a s t i r r e d suspension of powdered sodium methoxide (102.5 g, I . 9 moles) i n 1400 ml of dry benzene containing 153 ml (2.25 moles) of ethyl formate was added at 0° 140 g (0.635 mole) of the (-)-octalone 228 i n 1400 ml of dry benzene. The cooling bath was removed and the reaction mixture was s t i r r e d at room temperature i n an atmosphere of nitrogen f o r 4 days. The cooled mixture was a c i d i f i e d with 6 N hydrochloric a c i d , the layers were separated and the aqueous layer was extracted with ether. The combined organic extracts were washed twice with brine and dried over anhydrous magnesium s u l f a t e . Removal of the solvent gave 157 g (98%) of the hydroxymethylene d e r i v a t i v e 235 as yellow c r y s t a l s . An a n a l y t i c a l sample of pale yellow c r y s t a l s , obtained 27 by r e c r y s t a l l i z a t i o n from hexanes, exhibited m.p. 6 4 . 5 - 6 5°; ia]-Q - 8 . 5° (c,2.5 i n CHC1_); i n f r a r e d (CHC1.), v 1638, 1563 cm"1; p.m.r. (CC1,), j j IT13.X H* - 169 -x -3.73 (broad s i g n a l , 1H, exchangeable, =CHOH), 2.68 (doublet, 1H, =CHOH, J = 1.6 Hz), 8.17 (doublet, 3H, v i n y l methyl, J - 1.2 Hz), 8.90 ( s i n g l e t , 3H, t e r t i a r y methyl), 9.01, 9.07 (doublets, 6H, isopropyl methyls, J = 6.0 Hz). Anal. Calcd. for C,,Ho.0.: C, 77.38; H, 9.74. Found: C, 77.31; H, 9.86. Preparation of (+)-Dienone Aldehyde 236 A s o l u t i o n of 2,3-dichloro-5,6-dicyanobenzoquinone (5.0 g, 22.0 mmoles) i n 75 ml of dry dioxan was added to a s o l u t i o n of the hydroxy-methylene d e r i v a t i v e 235 (5.0 g, 20.1 mmoles) i n 75 ml of dry dioxan. The r e s u l t i n g mixture was s t i r r e d at room temperature i n an atmosphere of nitrogen for 10 min, and then 300 ml of methylene chl o r i d e was added. The p r e c i p i t a t e was removed by f i l t r a t i o n and the s o l u t i o n was passed quickly through a short column of neutral alumina ( a c t i v i t y I I I ) . The column was thoroughly eluted with methylene c h l o r i d e . Removal of the solvents gave 4.6 g (93%) of the desired dienone aldehyde 236 as pale yellow c r y s t a l s . An a n a l y t i c a l sample was obtained by r e c r y s t a l l i z a t i o n from hexanes and i t exhibited m.p. 7 8 . 5 - 7 9°; [ a ] ^7 +161° (c,2.5 i n CHCl.^); u l t r a v i o l e t , X 228 my (e = 10,200), 239 my (e = 9,800) (shoulder), max 266 my (e = 6,800) (shoulder); i n f r a r e d (CHC1 3), v 1700, 1648, 1623, 1600, 855, 824 cm"1; p.m.r., T -0.31 ( s i n g l e t , 1H, aldehydic H), 2.51 ( s i n g l e t , 1H, v i n y l H), 8.03 (doublet, 3H, v i n y l methyl, J = 1.2 Hz), 8.67 ( s i n g l e t , 3H, t e r t i a r y methyl), 9.04, 9.17 (doublets, 6H, isopropyl methyls, J = 6.0 Hz). Anal. Calcd. for C,,H-„0-: C, 78.01; H, 9.00. Found: C, 78.18; lo Li. i. H, 9.09. - 170 -Preparation of (+)-Keto Ester 216 To a s t i r r e d suspension of anhydrous cuprous iodide (15.6 g, 82.0 mmoles) i n 300 ml of anhydrous ether at -25° was added, over 5 min, 73.7 ml of 2.2 M ethereal methyllithium. The r e s u l t i n g s o l u t i o n was s t i r r e d i n an atmosphere of nitrogen for 10 min and then the temperature was raised to 0 ° . A s o l u t i o n of the (+)-dienone aldehyde 236 (11.6 g, 47.0 mmoles) i n 300 ml of anhydrous ether was added over 40 min and the r e s u l t i n g mixture was s t i r r e d at 0° for 2 h. A s o l u t i o n of a c e t y l chloride (12 ml) i n 240 ml of anhydrous ether was then added over 5 min and s t i r r i n g was continued at 0° for a further 10 min, by which time the reaction mixture was composed of a c l e a r supernatant and a s t i c k y p r e c i p i t a t e . The clear s o l u t i o n was poured i n t o a r a p i d l y s t i r r e d mixture (1200 ml) of concentrated ammonium hydroxide and crushed i c e (1:2) and the ether layer was quickly separated. The aqueous layer was r a p i d l y extracted twice with cold ether and the combined ether extracts were washed with cold brine u n t i l n e u t r a l , dried over anhydrous magnesium su l f a t e and concentrated to give 11^1 g of the enol acetate 237 as a viscous o i l . This material was somewhat unstable and was used without further p u r i f i c a t i o n i n the next re a c t i o n (ozonolysis). I t exhibited i n f r a r e d ( f i l m ) , v 3110, 1768, 1672, 1612 cm"1; p.m.r., T 1.85 max ( s i n g l e t , 1H, v i n y l H), 7.12 (quartet, 1H, Cfi^CH-, J - 7.0 Hz), 7.76 ( s i n g l e t , 3H, CH^OO-), 8.13 ( s i n g l e t , 3H, v i n y l methyl), 8.82 ( s i n g l e t , 3H, t e r t i a r y methyl), 8.96 (doublet, 3H, secondary methyl, J = 7.0 Hz), 9.06 (poorly resolved m u l t i p l e t , 6H, isopropyl methyls). The s o l i d residue remaining i n the reaction f l a s k was treated with 500 ml of concentrated ammonium hydroxide and crushed i c e (1:1) and 500 ml of ether. This mixture was s t i r r e d vigorously for 15 min, sodium - 171 -chloride was added and the layers separated. The aqueous layer was extracted twice with cold ether and the combined ether extracts were washed with cold brine u n t i l n e u t r a l . Drying over anhydrous magnesium s u l f a t e and removal of the solvent gave 3.0 g of a gum-like m a t e r i a l . Infrared and p.m.r. spectra indicated that about one-half of t h i s material was the desired enol acetate 237, so i t was combined without further p u r i f i c a t i o n with the material obtained above. The combined crude enol acetate product (14.1 g) i n 200 ml of methylene chl o r i d e was treated with ozone at -78° u n t i l the s o l u t i o n turned blue, and then for a further 30 min at - 2 5 ° . The cooling bath was removed and 300 ml of a 5% s o l u t i o n of sodium hydroxide In methanol/ water (7:1) was added, followed by the c a r e f u l a d d i t i o n of 120 ml of 30% hydrogen peroxide. This mixture was gradually heated and the methylene chloride was d i s t i l l e d o f f . The temperature was then raised to r e f l u x , and r e f l u x i n g was continued u n t i l the foaming ceased. The s o l u t i o n was cooled to 40° and 60 ml of 30% hydrogen peroxide was added, followed by r e f l u x i n g as before. This process was repeated once more with a further 60 ml of hydrogen peroxide. The methanol was removed at aspirator pressure, the residue was d i l u t e d with water and a c i d i f i e d with 6 N hydrochloric a c i d . This mixture was thoroughly extracted with ether, the ether layer was washed twice with brine and dried over anhydrous magnesium s u l f a t e . Removal of the solvent gave 10.9 g of a viscous o i l which s o l i d i f i e d overnight. A small sample of t h i s s o l i d was r e c r y s t a l l i z e d from hexanes and then from hexanes/ethyl acetate to give an a n a l y t i c a l sample of the keto acid 238 which exhibited m.p. 8 3 . 5 - 8 4°; i n f r a r e d ( i ) (CHC1 3), 3590, 3560-2500, 1770, 1702 cm"1; ( i i ) ( n u j o l ) , - 172 --1 f 3415, 1750 cm ; p.m.r., T 6.88, 7.13 (quartets, 1H, CH3CHC02H and i i CH3CHC02C(OH)- ( l a c t o l ) , J • 7.2, 7.2 Hz). Anal. Calcd. f o r C1 3H2 2 ° 3: C» 6 8« " ; H» 9.80. Found: C, 69.03; H, 9.83. The t o t a l crude keto acid 238 product was e s t e r i f i e d by treatment with excess ethereal diazomethane. The excess diazomethane was then destroyed with a c e t i c a c i d , the mixture was washed with sodium bicarbonate s o l u t i o n , with b r i n e , and dried over anhydrous magnesium s u l f a t e . Removal of the solvent and d i s t i l l a t i o n of the r e s i d u a l o i l gave 6.75 g (60% o v e r a l l from the dienone aldehyde) of the desired keto ester 216, b.p. 98-106° at 0.15 mm. An a n a l y t i c a l sample was obtained by preparative g . l . c . (column D, 2 0 5° , 180) and i t exhibited nT 1.4699; [a]tf +151° (c,2.0 i n CHC1-); i n f r a r e d ( f i l m ) , v 1732, D ' l J D 3 \ •» m a x 1705.cm"1; p.m.r., x 6.30 ( s i n g l e t , 3H, -0CH 3), 6.91 (quartet, 1H, i CH3CHC02CH3, J = 7.1 Hz), 9.00 ( s i n g l e t , 3H, t e r t i a r y methyl), 9.03 (doublet, 3H, secondary methyl, J = 7.1 Hz), 9.07, 9.08 (doublets, 6H, isopropyl methyls, J = 6.3 Hz). Anal. Calcd. for c1 ^ 2 l k ° 3: C' 6 9 , 9 65 H' 1 0-0 7- Found: C, 69.93; H, 9.93. Preparation of (+)-Diketone 203 To a s o l u t i o n of sodium b i s ( t r i m e t h y l s i l y l ) a m i d e (30 g, 164 mmoles) i n 400 ml of dry benzene, kept at 79-80° ( i n t e r n a l temperature) under an atmosphere of nitrogen, was added over 65 min a s o l u t i o n of the keto ester 216 (15.0 g, 62.5 mmoles) i n 650 ml of dry benzene. This temperature was maintained for a further 75 min, the reaction mixture was cooled and poured into 1000 ml of cold water containing 30 ml of - 173 -a c e t i c a c i d . The layers were separated and the aqueous layer was extracted once with ether. The combined organic layers were washed twice with sodium bicarbonate s o l u t i o n , with b r i n e , and d r i e d over anhydrous magnesium s u l f a t e . Removal of the solvent and d i s t i l l a t i o n of the r e s u l t i n g c r y s t a l l i n e residue gave 10.9 g of the c r y s t a l l i n e diketone 203, b.p. 90-105° at 0.2 mm. Analysis of t h i s material by g . l . c . (column A, 1 6 5° , 110) showed that i t consisted of 91% diketone and two u n i d e n t i f i e d minor components. R e c r y s t a l l i z a t i o n of t h i s material from hexane yielded 9.8 g (75%) of pure diketone. This 27 compound exhibited m.p. 7 7 . 5 - 7 8°; [ a ] D +102° (c,1.6 i n CHC13); i n f r a r e d (CHC1 ) , v 1765, 1725 cm- 1; p.m.r., T 7.07 (broad s i n g l e t , 1H, CgH, width at h a l f height =3.5 Hz), 7.68 (quartet of doublets, 1H, C?H, J = 7.1, 1.5 Hz), 8.80 (doublet, 3H, secondary methyl, J = 7.1 Hz), 8.88 ( s i n g l e t , 3H, t e r t i a r y methyl), 8.99, 9.12 (doublets, 6H, isopropyl methyls, J = 6.0 Hz). A frequency-swept decoupling experiment i n which the H at x 7.07 was i r r a d i a t e d , thus causing the quartet of doublets at x 7.68 to collapse to a quartet (J = 7.1 Hz), showed that the C^H i s coupled with the bridgehead C^H (J = 1.5 Hz). Anal. Calcd. for c 1 3H2 o 0 2 : C ' 7 4 - 9 6 ? H » 9 - 6 8 - F o u n d : c» 74.98; H, 9.80. - 174 -Attempted Epimerization of Diketone 203 To a s o l u t i o n of diketone 203 (52 mg) i n 2.5 ml of anhydrous dioxan was added a s o l u t i o n of potassium carbonate (anhydrous, 15 mg) i n 1.2 ml of d i s t i l l e d water. The r e s u l t i n g s o l u t i o n was s t i r r e d at room tempera-ture for 19 h. The dioxan was removed at aspirator pressure, the residue was d i l u t e d with water and was thoroughly extracted with ether. The combined ether extracts were washed twice with brine and dried over anhydrous magnesium s u l f a t e . Removal of the solvent afforded 51.5 mg of c r y s t a l l i n e m a t e r i a l . This material was i d e n t i c a l with the s t a r t i n g diketone 203. Deuterated Diketone 203a Diketone 203 (47.5 mg) was reacted with deuterium oxide (1.2 ml) (instead of water) under conditions i d e n t i c a l with those described above for the attempted epimerization of diketone 203. The c r y s t a l l i n e , crude product (48 mg ) thus obtained, consisted of monodeuterated diketone 203a and small amount of s t a r t i n g diketone 203 (as shown by the p.m.r. spectrum). The deuterated compound 203a exhibited p.m.r., T 7.07 ( s i n g l e t , 1H, C5H, width at h a l f height 3.0 Hz), 8.81 ( s l i g h t l y broadened s i n g l e t , 3H, C 7 methyl, width at h a l f height = 2.2 Hz), 8.88 ( s i n g l e t , 3H, t e r t i a r y methyl), 8.99, 9.12 (doublets, 6H, isopropyl methyls, J = 6.0 Hz). - 175 -Preparation of (+)-Keto Enol Ether 242 A s o l u t i o n of (+)-diketone 203 (10.4 g, 50 mmoles) i n 100 ml of dry hexamethylphosphoramide was added In one batch to a s o l u t i o n of sodium b i s ( t r i m e t h y l s i l y l ) a m i d e (25 g, 136 mmoles) i n 150 ml of dry hexamethyl-phosphoramide. This mixture was s t i r r e d at room temperature i n an atmosphere of nitrogen for 15 min, then cooled to 0° and 25 ml of 2-bromopropane was added over 3 min. The cooling bath was removed and s t i r r i n g was continued at room temperature f o r 45 min. The reaction was quenched by pouring i n t o cold brine and t h i s mixture was thoroughly extracted with ether. The ether extract was washed three times with brine and dried over anhydrous magnesium s u l f a t e . Removal of the solvent gave 12.3 g of a mobile o i l . A g . l . c . analysis of t h i s material (column C, 1 6 8° , 100) showed the presence of three components. These were shown to be s t a r t i n g material (dketone 203), the desired O-alkylated product 242, and the C-alkylated product 243 i n the r a t i o of 13:76.5:10.5 r e s p e c t i v e l y . D i s t i l l a t i o n of t h i s crude product through a 2-inch Vigreux column gave 11.0 g of material (b.p. 73-81° at 0.025 mm), which consisted of the s t a r t i n g m a t e r i a l , the desired O-alkylated product and a trace of the C-alkylated product. The keto enol ether was r e a d i l y separated from t h i s mixture by chromatography on a c t i v i t y I I I n e u t r a l alumina. E l u t i o n with 2%-15% benzene i n petroleum ether (b.p. 6 5 - 1 1 0°) separated out 9.55 g of pure keto enol ether 242 (88% based on unrecovered 20 25 s t a r t i n g m a t e r i a l ) . This material exhibited n^ 1.4747; [ a ] D +145° (c,2.0 i n CHC1 ) ; i n f r a r e d ( f i l m ) , v 1760, 1660 cm"1; p.m.r., T 5.95 J TO.3.X (septet, 1H, -OCH(CH 3) 2, J = 6.1 Hz), 6.99 (broad s i n g l e t , 1H, C^, width at half-height = 3.3 Hz), 8.32 (doublet, 3H, v i n y l methyl, J = 0.9 Hz), - 176 -8.74, 8.89 (doublets, 6H, -OCH(CH_3)2, J = 6.1 Hz), 8.98 ( s i n g l e t , 3H, t e r t i a r y methyl), 9.04, 9.13 (doublets, 6H, isopropyl methyls, J = 6.4 Hz). Anal. Calcd. for C.,Ho£0o: C, 76.75; H, 10.47. Found: C, 76.55; I D i o Z H, 10.46. Further e l u t i o n of the column with higher benzene concentrations gave 1.37 g of the c r y s t a l l i n e s t a r t i n g material (diketone 203) containing the small amount of C-alkylated m a t e r i a l . A pure sample of the l a t t e r compound was obtained as follows. Hot box d i s t i l l a t i o n of the s t i l l - p o t residue yielded 1.2 g of c r y s t a l l i n e m a t e r i a l , b.p. 115° at 0.3 mm. R e c r y s t a l l i z a t i o n of t h i s material from hexanes gave a sample with m.p. 6 0 . 5° ; i n f r a r e d (CHC1_), v 1758, 1722 cm"1; 3 max p.m.r., x 7.15 (broad s i n g l e t , 1H, C5H, width at h a l f height =4.3 Hz), 8.85, 8.90 ( s i n g l e t s , 6H, t e r t i a r y methyls), 8.97, 9.12 (doublets, 6H, isopropyl methyls, J - 6.5 Hz), 9.00, 9.22 (doublets, 6H, isopropyl methyls, J = 6.9 Hz). Anal. Calcd. for C.,H_,0_: C, 76.75; H, 10.47. Found: C, l b Zb Z 76.60; H, 10.55. Preparation of Diethers 244 A s l u r r y of methoxymethyltriphenylphosphonium ch l o r i d e (71.5 g, 208 mmoles) i n 615 ml of anhydrous ether was cooled to 0° under an atmsphere of nitrogen. To t h i s s t i r r e d mixture was added, v i a a syringe, 73.5 ml of a 2.34 M hexane s o l u t i o n of n-butyllithium over a two minute per i o d . The r e s u l t i n g phosphorane s o l u t i o n was s t i r r e d f or a further 10 min. A s o l u t i o n of the (+)-keto enol ether 242 (11.65 g, - 177 -46.5 mmoles) i n 170 ml of anhydrous ether was then added over 4 min, the cooling bath was removed and the reaction mixture was refluxed for 30 min. The cooled s o l u t i o n was poured i n t o cold water, the layers were separated and the aqueous layer was extracted once with ether. The combined ether layers were washed twice with brine and dried over anhydrous magnesium s u l f a t e . Removal of the solvent and d i s t i l l a t i o n of the resultant crude material (55.0 g) gave 14.2 g of c o l o r l e s s o i l with b.p. 94-103° at 0.2 mm. Analysis by g.I.e.(column C, 1 5 5° , 110) showed that t h i s material contained three u n i d e n t i f i e d minor components to the extent of approximately 10%, thus i n d i c a t i n g that the desired diethers 244 were formed i n qu a n t i t a t i v e y i e l d . The r a t i o of the component diastereomers 244 as determined by g . l . c . (same column and conditions) varied considerably from experiment to experiment but the average r a t i o was approximately 65:35, with the same isomer always predominating. Attempts to remove the impurities from t h i s d i s t i l l e d material by column chromatography (neutral alumina - a c t i v i t y I and I I I , and f l o r i s i l ) were unsuccessful due to poor recovery of the diethers from the columns and/or due to s i m i l a r i t y i n retention times. Consequently, t h i s mixture was used i n the next reaction without further p u r i f i c a t i o n . An a n a l y t i c a l sample of the diastereomeric diether mixture 244 was obtained, however, by preparative g . l . c . (column B, 1 8 5° , 105) and i t exhibited i n f r a r e d ( f i l m ) , v 1707, 1664 cm"1; max p.m.r., T 4.43, 4.52 ( s i n g l e t s , 1H, v i n y l hydrogens), 5.92, 5.97 (septets, 1H, J - 6.1, 6.1 Hz), 6.49, 6.56 ( s i n g l e t s , 3H, methoxy methyls). Anal. Calcd. for C 1 oH_.0„: C, 77.65; H, 10.86. Found: C, 77.52 H, 11.11. - 178 -Preparation of Keto Aldehydes 245 and 246 A s o l u t i o n of the impure diethers 244 (10.8 g) from above, i n 180 ml of ether was added to a s o l u t i o n of 70% p e r c h l o r i c a c i d (120 ml) i n 700 ml of ether. The r e s u l t i n g mixture was s t i r r e d at room temperature under a nitrogen atmosphere f o r 1.5 h. It was then washed successively with ice-water, with d i l u t e sodium bicarbonate s o l u t i o n and with b r i n e , and dried over anhydrous magnesium s u l f a t e . Removal of the solvent and d i s t i l l a t i o n of the r e s i d u a l o i l gave 7.7 g of material with b.p. 108-110° at 0.07 mm. A g . l . c . analysis (column H, 1 6 8° , 110) of t h i s material showed that the r a t i o of the keto aldehydes 24_ and 246 was approximately 1:1. This material (7.7 g) was dissolved i n 325 ml of methanol and was added to a s o l u t i o n of anhydrous potassium carbonate (9.5 g) i n 800 ml of water. The resultant mixture was s t i r r e d at room temperature under a nitrogen atmosphere f o r 1.5 h. It was then d i l u t e d with water and extracted three times with petroleum ether (b.p. 6 8° ) - e t h e r (4:1). The combined extracts were washed with water, with b r i n e , and dried over anhydrous magnesium s u l f a t e . Removal of the solvent and d i s t i l l a t i o n of the residue gave 7.05 g of a c o l o r l e s s o i l , b.p. 106-109° at 0.05 mm. A g . l . c . analysis (column H, 1 6 8° , 110) of t h i s material showed that i t was composed of the desired products (88%), keto aldehydes 245 and 246 i n a r a t i o of 82:18 r e s p e c t i v e l y , and impurities (12%) which were not i d e n t i f i e d , but were presumably r e l a t e d to those i n the s t a r t i n g m a t e r i a l . Thus the e f f e c t i v e o v e r a l l y i e l d for the hydrolysis and epimerization reactions was 80%. Because of extensive decomposition of the epimeric keto aldehydes 245 and 246 on the columns - 179 -i t was not possible to separate these epimers from each other or from the other contaminants by column chromatography ( s i l i c a g e l and a c t i v i t y I I I neutral alumina). Consequently, t h i s material was used i n the next reaction without further p u r i f i c a t i o n . The impure keto aldehyde product mixture exhibited i n f r a r e d ( f i l m ) , vm a x 2745, 1735, 1715 (shoulder) cm p.m.r., T -0.10, -0.03 (doublets, 1H, aldehydic hydrogens, J = 1.0, 2.0 Hz, r e s p e c t i v e l y ) . Preparation of Keto O l e f i n s 204 and 247 A mixture of 50% sodium hydride i n dispersion o i l (1.028 g, 22.5 mmoles) and dry dimethyl sulfoxide (52 ml) was heated to 74° i n an atmosphere of nitrogen. This temperature was maintained for 45 min, by which time the evolution of hydrogen gas had ceased. The s o l u t i o n was cooled to 2 0 ° , 9.64 g (27.0 mmoles) of methyltriphenylphosphonium bromide was added i n one batch and the r e s u l t i n g s o l u t i o n was s t i r r e d at room temperature for 10 min. To t h i s s o l u t i o n was added over a period of 3 min 1.046 g (approximately 4.15 mmoles) of the impure keto aldehyde mixture (245 and 246) from above i n 26 ml of dry DMSO. S t i r r i n g was continued f o r a further 1 h at room temperature. The s o l u t i o n was poured into ice-water and t h i s mixture was extracted three times with petroleum ether (b.p. 6 8 ° ) . The combined extracts were washed with brine and dried over anhydrous magnesium s u l f a t e . Removal of the solvent and d i s t i l l a t i o n of the residue gave 991 mg of a c o l o r l e s s o i l with b.p. (hot box) 82-95° at 0.07 mm. A g . l . c . analysis (column I, 1 7 5° , 110) showed that t h i s material was composed of a mixture of the keto o l e f i n s (92%), 204 and 247 i n a r a t i o of 82:18 - 180 -r e s p e c t i v e l y , and u n i d e n t i f i e d minor components (8%). This represents a quantitative y i e l d of keto o l e f i n s based on pure s t a r t i n g m a t e r i a l . The two epimers were only p a r t i a l l y separated by column chromatography on s i l i c a g e l . However, t o t a l separation was achieved by column chromatography using Camag K i e s e l g e l for TLC {without binder) and 98:2 petroleum ether (b.p. 6 8° ) - e t h e r as e l u t i n g solvent. A p o s i t i v e pressure (nitrogen) was required to maintain a reasonable flow r a t e . The r a t i o of compound to s i l i c a gel was 1:100. The recovery of both keto o l e f i n s from the column was q u a n t i t a t i v e . However, while the minor epimer 247, a c o l o r l e s s c r y s t a l l i n e compound, was obtained i n pure form, the major epimer 204 contained minor impurities (approximately 4% as determined by g . l . c ) . Thus an a n a l y t i c a l sample of the keto o l e f i n 204 was obtained by preparative g . l . c . (column D, 1 9 8° , 170) of the material obtained from chromatography on s i l i c a g e l . This a n a l y t i c a l 25 sample, a c o l o r l e s s o i l , exhibited [ a ] D +51.5° (c,2.0 i n CHC13); i n f r a r e d ( f i l m ) , v 3080, 1730, 1634, 910 cm-1; p.m.r., T 3.99-4.37 max ( m u l t i p l e t , IH, C gH), 4.86-5.10 ( m u l t i p l e t , 2H, C 1 0 protons), 7.41 (broad s i n g l e t , IH, C^R, width at h a l f height = 4.5 Hz), 7.79 (doublet, IH, C0H, J = 7.9 Hz), 7.97 (quartet, IH, C..H, J = 7.2 Hz), 8.99 ( s i n g l e t , 3H, t e r t i a r y methyl), 8.99, 9.20 (doublets, 6H, isopropyl methyls, J = 6.2 Hz), 9.06 (doublet, 3H, secondary methyl, J = 7.2 Hz). Anal. Calcd. for C^H^O: C, 81.76; H, 10.98. Found: C, 81.64; H, 11.07. The c r y s t a l l i n e keto o l e f i n 247 (the minor component) was r e c r y s t a l l i z e d 25 from pentane and t h i s sample exhibited m.p. 2 8 . 5 - 2 9°; [ c ] ^ +130° (c,2.5 i n CHC1J; i n f r a r e d (CHC1„), v 3080, 1724, 1633, 916 cm"1; p.m.r. 3 3 max - 181 -T 3.71-4.08 ( m u l t i p l e t , 1H, C gH), 4.68-4.92 ( m u l t i p l e t , 2H, C 1 Q protons), 7.42 (broadened doublet, 1H, C CH, J„ „ _ „ = 5.6 Hz), 7.64 (doublet of J L-H—L Qn j o doublets, 1H, CQH, J = 8.3, 5.6 Hz), 8.17 (quartet, 1H, C,H, J - 7.0 o / Hz), 9.01 (doublet, 3H, secondary methyl, J = 7.0 Hz), 9.05 ( s i n g l e t , 3H, t e r t i a r y methyl), 9.05, 9.18 (doublets, 6H, isopropyl methyls, J = 5.9 Hz). Anal. Calcd. f o r C^H^O: C, 81.76; H, 10.98. Found: C, 81.52; H, 11.10. Preparation of (+)-Keto Alcohol 205 To a s o l u t i o n of 2-methyl-2-butene (1.78 g, 25.5 mmoles) i n 7.5 ml of dry tetrahydrofuran was added 9 ml of 1.4 M borane s o l u t i o n i n tetrahydrofuran (12.6 mmoles) at 0 ° . S t i r r i n g was continued i n an atmosphere of nitrogen at 0° for 30 min. To t h i s s o l u t i o n was then added 661 mg (3 mmoles) of the (+)-keto o l e f i n 204 i n 7.5 ml of dry tetrahydrofuran and s t i r r i n g was continued at 0° fo r a further 45 min. The reaction was quenched by the c a r e f u l addition at 0° of 6 ml of 3 N aqueous sodium hydroxide followed by 6 ml of 30% hydrogen peroxide. The cooling bath was removed and s t i r r i n g was continued at room tempera-ture for 1 h. The tetrahydrofuran was removed at asp i r a t o r pressure, water was added to the residue and t h i s mixture was thoroughly extracted with ether. The organic extract was washed with brine and dried over anhydrous magnesium s u l f a t e . Removal of the solvent and d i s t i l l a t i o n of the residue gave 579 mg (81%) of a viscous o i l b.p. 135-145° (hot box) at 0.2 mm. A g.1.c.«'analysis (column G, 1 7 5° , 100) of t h i s material indicated the presence of two components i n the approximate r a t i o of - 182 -85:15 ( t h i s g . l . c . column did not t o t a l l y resolve the two components and more polar columns caused decomposition of the products. This r a t i o was confirmed l a t e r , however, by g . l . c . a nalysis of the s i l y l ether derivatives of t h i s mixture(vide i n f r a ) ) . Chromatography on s i l i c a gel or a c t i v i t y III neutral alumina afforded no u s e f u l separation of the two products. Pure samples of the desired keto a l c o h o l 205, and of the contaminating d i o l 248 were obtained for a n a l y t i c a l purposes v i a t h e i r s i l y l ether d e r i v a t i v e s . Thus 239 mg (1.0 mmole) of the product mixture i n 2 ml of dry pyridine containing 0.4 ml of hexamethyldisilazane and 0.2 ml of trimethylchlorosilane was s t i r r e d i n an atmosphere of nitrogen at room temperature for 15 min. This mixture was f i l t e r e d , the solvent was evaporated and the residue was d i s t i l l e d to give 323 mg of a mobile o i l , b.p. 125-130° (hot box) at 0.25 mm. This material showed two peaks on analysis by g . l . c . (column C, 1 9 0° , 100), i n the r a t i o of 85:15. An attempt to separate the components on a s i l i c a gel column resulted i n the p a r t i a l hydrolysis of the s i l y l ether blocking groups,but an e f f i c i e n t separation was e f f e c t e d by preparative g . l . c . (column D, 2 2 0° , 200). Thus 300 mg of the mixture y i e l d e d , a f t e r c o l l e c t i o n and d i s t i l l a t i o n , 204 mg of the pure keto t r i m e t h y l s i l y l ether 249 and 44 mg of the b i s t r i m e t h y l s i l y l d e r i v a t i v e 250. The keto t r i m e t h y l s i l y l ether exhibited i n f r a r e d ( f i l m ) , ^ m a K 1727, 1250, 1090, 840, 745 cm"1; p.m.r., T 6.39 (complex m u l t i p l e t , 2H, -CH^OTMS), 7.45 (broad s i n g l e t , IH, CgH, width at h a l f height =4.6 Hz), 8.97 ( s i n g l e t , 3H, t e r t i a r y methyl), 9.00, 9.18 (doublets, 6H, isopropyl methyls, J = 6.1 Hz), 9.04 (doublet, 3H, secondary methyl, J = 7.0 Hz), 9.88 ( s i n g l e t , 9H, - 0 S i ( C H 3 ) 3 ) . - 183 -Hydrolysis of t h i s keto t r i m e t h y l s i l y l ether 249 gave the desired keto alcohol 205. Thus a s o l u t i o n of the s i l y l ether (220 mg, 0.71 mmole) i n 3 ml of ethanol and 0.1 ml of water was refluxed i n an atmosphere of nitrogen for 4 h. The solvent was removed at as p i r a t o r pressure and the residue was d i s t i l l e d to give 150 mg (89%) of a viscous o i l b.p. 127-128° (hot box) at 0.04 mm. Analysis of t h i s material by g . l . c . (column G, 1 7 5° , 100) showed that i t was one component. It exhibited [ a ] ^5 +30.5° (c,0.7 i n CHC10); i n f r a r e d ( f i l m ) , v 3400, D ' 3 max 1724 cm"1; p.m.r., x 6.34 (complex m u l t i p l e t , 2H, -CH_20H), 7.46 (broad s i n g l e t , 1H, CgH, width at h a l f height = 4.8 Hz), 7.87 ( s i n g l e t , 1H, exchangeable, -OH), 8.96 ( s i n g l e t , 3H, t e r t i a r y methyl), 8.99, 9.18 (doublets, 6H, isopropyl methyls, J = 6.1 Hz), 9.03 (doublet, 3H, secondary methyl, J = 7.1 Hz). Anal. Calcd. for C 1 CH 0,0 0: C, 75.58; H, 10.99. Found: C, 75.32; lo Z D l H, 11.19. The minor component i n the s i l y l ether mixture was also g . l . c . c o l l e c t e d as mentioned above. It exhibited i n f r a r e d ( f i l m ) , v 1250, max 1060, 840, 750 cm"1; p.m.r., x 5.53 (doublet of doublets, 1H, -CHOTMS, J = 6.8, 10.5 Hz), 6.40 (complex m u l t i p l e t , 2H, -CHOTMS), 7.73 (broadened doublet, 1H, C5H, J = 6.8 Hz), 9.10, 9.20 (doublets, 6H, isopropyl methyls, J = 6.5 Hz), 9.15 ( s i n g l e t , 3H, t e r t i a r y methyl), 9.23 (doublet, 3H, secondary methyl, J = 7.0 Hz), 9.89, 9.95 ( s i n g l e t s , 18H, -OTMS groups). This material was hydrolyzed to the d i o l 248 i n a manner s i m i l a r to the hydrolysis of the keto s i l y l ether 249 using 0.75 ml of ethanol and 25 ml of water. From 44 mg there was obtained 25 mg of the viscous d i o l which exhibited i n f r a r e d ( f i l m ) , v 3350 cm 1; p.m.r. - 184 -i x 5.60 (doublet of doublets, IH, -CHOH, J = 6.9, 10.6 Hz), 6.41 (complex m u l t i p l e t , 2H, -CH20H), 7.83 (broadened doublet, IH, CgH, J = 6.9 Hz), 9.18, 9.28 (doublets, 6H, isopropyl methyls, J = 6.6 Hz), 9.25 ( s i n g l e t , 3H, t e r t i a r y methyl), 9.29 (doublet, 3H, secondary methyl, J - 7.1 Hz). This d i o l decomposed slowly on standing i n deuterochloroform s o l u t i o n at room temperature. (-)-Ylangocamphor 1_ (a) From pure keto alcohol 205 A s o l u t i o n of keto alcohol 205 (109 mg, 0.458 mmole) i n 3.5 ml of dry pyridine containing 229 mg (1.0 mmole) of methanesulfonyl ch l o r i d e was s t i r r e d i n an atmosphere of nitrogen at room temperature f or 2.25 h. The reaction mixture was then poured i n t o 25 ml of cold water and the water layer was extracted 3 times with ether. The combined ether extracts were washed with cold 10% hydrochloric a c i d , with water and with b r i n e , and dried over anhydrous magnesium s u l f a t e . Removal of the solvent gave 173 mg of a viscous o i l which exhibited i n f r a r e d ( f i l m ) , v max 1728 cm This crude keto mesylate i n 2 ml of dry dimethoxyethane was added to a s o l u t i o n of sodium b i s ( t r i m e t h y l s i l y l ) a m i d e (450 mg, 2.46 mmole) i n 5 ml of dry dimethoxyethane at 0 ° . The cooling bath was immediately removed, the reaction mixture was s t i r r e d at room temperature i n an atmosphere of nitrogen f or 40 min and i t was then poured into 25 ml. of cold water. The organic layer was washed with water and brine and dried over anhydrous magnesium s u l f a t e . Removal of the solvent and d i s t i l l a t i o n of the residue gave 85 mg (84% from keto alcohol) of (-)-ylangocamphor ]_ b.p. 72-74° (hot box) at 0.04 mm. This material - 185 -was pure by g a s - l i q u i d chromatographic analysis (columns: A, 1 7 0° , 115; B, 1 9 0° , 110; F, 2 0 1° , 118) and i t c r y s t a l l i z e d on r e f r i g e r a t i o n . A sample was r e c r y s t a l l i z e d from hexanes at -35° to -40° y i e l d i n g c o l o r l e s s c r y s t a l s with m.p. 2 5 - 2 5 . 5°; [a]* 6 -58° (c,1.0 i n CHC13); i n f r a r e d ( f i l m ) , v 1733 cm """; p.m.r., T 7.76 (broad s i n g l e t , 1H, bridgehead H max i adjacent to -C=0, width at h a l f height = 3.0 Hz), 9.02, 9.19 (doublets, 6H, isopropyl methyls, J = 6.5 Hz), 9.10, 9.11, ( s i n g l e t s , 6H, t e r t i a r y methyls). Anal. Calcd. for C^H^O: C, 81.76; H, 10.98. Found: C, 81.91; H, 11.18. (b) From the mixture of keto alcohol 205 and d i o l 248 The keto a l c o h o l - d i o l mixture (239 mg) obtained from hydroboration was converted into the mesylate d e r i v a t i v e mixture i n the same manner as the pure keto a l c o h o l , using 7 ml of pyridine and 229 mg (2.0 mmole) of methanesulfonyl c h l o r i d e . S i m i l a r l y , the crude keto mesylate mixture thus obtained was c y c l i z e d (without p u r i f i c a t i o n ) as above, using 915 mg (5 mmoles) of sodium b i s ( t r i m e t h y l s i l y l ) a m i d e and 14 ml of dry dimethoxyethane. Simple d i s t i l l a t i o n of t h i s product (hot box) separated out the (-)-ylangocamphor, 135 mg (50% o v e r a l l y i e l d from the keto o l e f i n 204). This material was pure by g a s - l i q u i d chromatographic a n a l y s i s . (-)-Ylangoborneol 2_3 To a reaction v e s s e l containing 12.5 ml of r e f l u x i n g anhydrous ammonia was added 50 mg (1.25 mmoles) of calcium metal followed, - 186 5 min l a t e r , by a s o l u t i o n of (-)-ylangocamphor 7 (57 mg, 0.259 mmole) i n 1.1 ml of anhydrous ether. This mixture was s t i r r e d at r e f l u x temperature f o r 30 min and 150 P i of anhydrous ethanol was then added. Care was taken at a l l times to exclude water from the system. When the blue color was discharged, ether was added and the mixture was poured into water. The water layer was thoroughly extracted with ether, and the organic layer was washed with brine u n t i l n eutral and then dried over anhydrous magnesium s u l f a t e . F i l t r a t i o n through c e l i t e and removal of the solvent gave a residue which was d i s t i l l e d to y i e l d 55 mg (96%) of c r y s t a l l i n e (-)-ylangoborneol, b.p. 108° (hot box) at 0.04 mm. This material consisted of only one component by g a s - l i q u i d chromatographic analysis (columns: B, 1 8 8° , 110; C, 1 6 8° , 100; E, 1 9 0° , 100; F, 1 9 5° , 105. Note: columns B and F resolve a mixture of ylangoborneol and ylangoisoborneol). R e c r y s t a l l i z a t i o n from hexanes gave a sample e x h i b i t i n g m.p. 6 0 . 5 - 6 1°; [ a ] ^5 -23° (c,0.4 i n CHC13); i n f r a r e d (CHCl.^), v 3610, 3460 cm"1; p.m.r., ( i ) (CDC1-), T 6.17 (broad s i n g l e t , 111, max o i -CHOH, width at h a l f height = 3.2 Hz), 8.60 ( s i n g l e t , IH, exchangeable, -OH), 9.05, 9.15 (doublets, 6H, isopropyl methyls, J = 6.4 Hz), 9.13, 9.19 ( s i n g l e t s , 6H, t e r t i a r y methyls); ( i i ) ( C C l ^ ) , 6.26 (broad s i n g l e t , i IH, -CHOH, width at h a l f height = 3.2 Hz), 8.90 ( s i n g l e t , IH, exchange-able, -OH), 9.06, 9.14 (doublets, 6H, isopropyl methyls, J = 6.5 Hz), 9.15, 9.19 ( s i n g l e t s , 6H, t e r t i a r y methyls). Anal. Calcd. f o r C^H^O: C, 81.02; H, 11.79. Found: C, 80.75; H, 11.69. - 187 -(-)-Ylangoisoborneol 143 An anhydrous ether s o l u t i o n (5 ml) of (-)-ylangocamphor 1_ (110 mg, 0.5 mmole) containing 25 mg of l i t h i u m aluminum hydride was refluxed under an atmosphere of nitrogen f o r 1 h. The reaction mixture was cooled to 0 ° , 1 ml of saturated aqueous ammonium chloride s o l u t i o n was added and s t i r r i n g was continued f o r 45 min at room temperature. This mixture was f i l t e r e d through c e l i t e and the c e l i t e was thoroughly washed with ether. The ether layer was washed with brine and dried over anhydrous magnesium s u l f a t e . Removal of the solvent followed by d i s t i l l a t i o n of the residue gave 101 mg of (-)-ylangoisoborneol 143 (91%), b.p. 100-102° (hot box) at 0.12 mm. This material consisted of only one component on analysis by g . l . c . (columns and conditions: same as ylangoborneol), and i t c r y s t a l l i z e d on r e f r i g e r a t i o n . R e c r y s t a l l i z a t i o n from hexanes at -10° gave c o l o r l e s s c r y s t a l s which were somewhat sof t at room temperature ( 2 2° ) and exhibited m.p. 3 1 . 5 - 3 2 . 5°; [a]l6 -28° (c,1.0 i n CHC1-); i n f r a r e d ( f i l m ) , v 3630, 3495 cm"1; D 3 max p.m.r. ( i ) (CDC1 3), x 6.22 (doublet, 1H, -CHOH, J = 7.6 Hz), 7.88 t (broadened doublet, 1H, bridgehead H adjacent to -CHOH, J = 7.6 Hz), 8.68 ( s i n g l e t , 1H, exchangeable, -OH), 9.04, 9.17 (doublets, 6H, isopropyl methyls, J = 6.5 Hz), 9.15, 9.21 ( s i n g l e t s , 6H, t e r t i a r y i methyls); ( i i ) (CC1 4), x 6.27 (doublet, 1H, -CHOH, J = 7.7 Hz), 7.91 t (broadened doublet, 1H, bridgehead H adjacent to -CHOH, J = 7.7 Hz), 8.87 ( s i n g l e t , 1H, exchangeable, -OH), 9.08, 9.20 (doublets, 6H, isopropyl methyls, J = 6.5 Hz), 9.18, 9.22 ( s i n g l e t s , 6H, t e r t i a r y methyls). 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