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Total syntheses of sesquiterpenoids (±)-aristolone, (±)-[alpha]-cubebene, (±)-[beta]-Cubebene Britton, Ronald William 1970

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TOTAL SYNTHESES OF SESQUITERPENOIDS (JO-ARISTOLONE, (+)-oc-CUBEBENE, (±)-g-CUBEBENE BY RONALD W. BRITTON B.Sc. Un i v e r s i t y of V i c t o r i a , 1965 M.A. Dartmouth College, 1967 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 February, 1970 In p r e s e n t i n g t h i s t h e s i s in p a r t i a l f u l f i l m e n t o f the r e q u i r e m e n t s f o r an advanced degree at the U n i v e r s i t y o f B r i t i s h C o l u m b i a , I a g r e e 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 tha p e r m i s s i o n f o r e x t e n s i v e c o p y i n g o f t h i s t h e s i s f o r s c h o l a r l y p u r p o s e s may be g r a n t e d by the Head o f my Department o r by h i s r e p r e s e n t a t i v e s . It i s u n d e r s t o o d t h a t c o p y i n g o r p u b l i c a t i o n o f t h i s t h e s i s f o r f i n a n c i a l g a i n s h a l l not be a l l o w e d w i t h o u t my w r i t t e n p e r m i s s i o n . Department o f The U n i v e r s i t y o f B r i t i s h C o l u m b i a V a n c o u v e r 8, Canada Date YUuJL ^ . 1 ^ 1 0 ABSTRACT An e f f i c i e n t , 10-step synthesis of ( i ) - a r i s t o l o n e (7) from 2,3-dimethylcyclohexanone (86) i s described. A l k y l a t i o n with m e t h a l l y l c h l o r i d e of 86, v i a the corresponding n-butylthiomethylene d e r i v a t i v e 119, followed by removal of the n-butylthiomethylene b l o c k i n g group, gave the two ketones 121 and 122. A c i d c a t a l y z e d isemerizatibn of 121 gave the ketone 136 which, upon treatment with d i e t h y l cyanomethylphosphorane, followed by base h y d r o l y s i s of the r e s u l t i n g n i t r i l e s 139 and 140, gave c a r b o x y l i c a c i d 141. The l a t t e r was converted i n t o the corresponding diazoketone 144 which, upon heating w i t h c u p r i c s u l f a t e i n cyclohexane, afforded (±)-aristolone (7_) and (±)-6,7-epi-aristolone (145) i n good y i e l d . The stereochemistry of the ketone 121 was proven unambiguously by converting i t i n t o the alkane 133. Authentic 133 was prepared by an a l t e r n a t e route. Thus, o z o n o l y s i s of the known o c t a l i n 125, followed by chromic a c i d o x i d a t i o n and e s t e r i f i c a t i o n w i t h diazomethane gave the keto e s t e r 126. B a e y e r - V i l l i g e r o x i d a t i o n of 126 gave the d i e s t e r 127, which was t r e a t e d w i t h m e t h y l l i t h i u m to a f f o r d the d i o l 128. Dehydration of 128 followed by hydrogenation of the r e s u l t i n g hydroxy alkenes 130 gave the a l c o h o l 131, which was converted to the t o s y l a t e 132. Reduction of 152 with l i t h i u m aluminum hydride afforded authentic 133. The stereochemistry o f a r i s t o l o n e (7) was proven by an unambiguous synthesis of the B i r c h r e d u c t i o n product of d i h y d r o a r i s t o l o n e (53). Thus, treatment of the known octalone 92 with isopropenylmagnesium bromide i n the presence of cuprous c h l o r i d e afforded the decalone 159 which upon - i i i -hydrogenation gave 160 i d e n t i c a l with the product of the lithium-ammonia r e d u c t i o n of d i h y d r o a r i s t o l o n e (53). An e f f i c i e n t , 12-step synthesis of (± ) -g-cubebene (14) from d , l -menthone (171) i s described. Thus, 171 was converted i n t o the aldehyde 175, v i a the corresponding n-butylthiomethylene d e r i v a t i v e 173. Thus, sodium borohydride r e d u c t i o n of the l a t t e r and a c i d c a t a l y z e d h y d r o l y s i s of the r e s u l t i n g g-hydroxy-thioenol ether 174, produced aldehyde 175. Reduction of 175 w i t h sodium borohydride gave the epimeric a l c o h o l s 177a,b which were separated v i a 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 . Pure 177a was converted to the bromide 181 w i t h phosphorous t r i b r o m i d e . Treatment of 181 w i t h carbethoxymethyltriphenylphosphorane, followed by base h y d r o l y s i s , gave the a c i d 186. A c i d 186 was converted i n t o the diazoketone 170 which, upon heating w i t h c u p r i c s u l f a t e i n cyclohexane, gave (± ) -g-cubebene norketone (104) and the epimeric ketone 189. Treatment of 104 w i t h methylenetriphenylphosphorane gave (± ) -g-cubebene (14) i n q u a n t i t a t i v e y i e l d . The stereochemistry of the intermediate a l c o h o l 177a was proven by converting 177a i n t o the bromide 181, followed by l i t h i u m aluminum hydride r e d u c t i o n of the l a t t e r to the alkene 190. Authentic 190 was prepared i n the f o l l o w i n g manner. Treatment of (-)-trans-caran-2-one (108) w i t h m e t h y l l i t h i u m followed by p y r o l y s i s of the r e s u l t i n g a l c o h o l 195 gave the diene 196. R e g i o s e l e c t i v e hydrogenation of the d i s u b s t i t u t e d double bond of 196 w i t h the homogeneous c a t a l y s t t r i s ( t r i p h e n y l p h o s p h i n e ) -chlororhodium gave auth e n t i c alkene 190. The e f f i c i e n c y o f the i n t r a m o l e c u l a r c y c l i z a t i o n of the two o l e f i n i c diazoketones 144 and 170 i l l u s t r a t e s the u t i l i t y of t h i s s y n t h e t i c method i n the synthesis of n a t u r a l products. - i v -TABLE OF CONTENTS Page TITLE PAGE 1 ABSTRACT 1 1 TABLE OF CONTENTS i v LIST OF FIGURES , v i ACKNOWLEDGEMENTS v i i DEDICATION ; v i i i INTRODUCTION 1 1. General 1 2. Sesquiterpene Biosynthesis 6 3. Structure and Stereochemistry of Aristolone 14 4. Other Syntheses of Aristolane Type Sesquiterpenes... 26 5. Structure and Stereochemistry of a-and g-Cubebene.. 30 6. Other Syntheses of Cubebenes 38 DISCUSSION PART I 41 1. The Total Syntheses of (+)-Aristolone and (±)-6,7-Ep i - a r i s t o l o n e 41 i' 2. Stereochemical Proof of (±)-Aristolone 60 EXPERIMENTAL I 76 DISCUSSION PART II 104 1. The Total Synthesis of g-Cubebene 104 2. Stereochemical Proof of Alcohol 177a 118 - V -Page EXPERIMENTAL II . . .. 128 BIBLIOGRAPHY 143 - v i -LIST OF FIGURES Figure Page 1 N.M.R. Spectrum of (±)-Aristolone (7) 57 2 N.M.R. Spectrum of (±)-6,7-Epi-aristolone (145) 59 3 N.M.R. Spectrum of (±)-Compound 160 70 4 N.M.R. Spectrum of (-)-Compound 160 75 5 N.M.R. Spectrum of (±)-g-Cubebene (14) 117 6 N.M.R. Spectrum of (±)-trans-2-Methyl-p-mentha-2-ene (190) 121 7 N.M.R. Spectrum of (+)-trans-2-Methyl-p-mentha-2-ene (190) 126 - v i i -ACKNOWLEDGEMENTS I t i s my s i n c e r e pleasure to thank Dr. Edward P i e r s . His guidance, both as a teacher and a s c i e n t i s t throughout the course of t h i s research have made t h i s t h e s i s p o s s i b l e . I would a l s o l i k e to thank Mr. W i l l i a m de Waal f o r h i s c o l l a b o r a -t i o n w i t h me i n t h i s r esearch, and a l s o the other members of the group -past and present - f o r h e l p f u l d i s c u s s i o n s and suggestions. S p e c i a l thanks are due t o Mr. Dean S m i l l i e f o r proof reading the e n t i r e t h e s i s and to Miss Diane Johnson f o r her very capable t y p i n g . Receipt of a f i n a n c i a l award from the B r i t i s h Columbia Sugar R e f i n i n g Company and an H.R. MacMillan Family Fellowship are g r a t e f u l l y acknowledged. - v i i i -DEDICATION To ray wife INTRODUCTION I. General With the i n t r o d u c t i o n of the Isoprene Rule i n 1953 by the Swiss group of Ruzicka, Eschenmoser and Heusser ( 1 ) , and i t s subsequent r e f o r m u l a t i o n to the Biogenetic Isoprene Rule by Ruzicka, Eschenmoser, Jeger and A r i g o n i i n 1955 (2) to account f o r the wide range of a c y c l i c , monocyclic and fused r i n g s t r u c t u r e s c o l l e c t i v e l y c a l l e d the terpenoids, much work has been expended i n the i s o l a t i o n , s t r u c t u r a l e l u c i d a t i o n and synthesis of t h i s l a rge f a m i l y of n a t u r a l l y o c c u r r i n g compounds. One group w i t h i n t h i s l a rge f a m i l y i s the sesquiterpenes. Normally c o n t a i n i n g f i f t e e n carbon atoms, they are b i o g e n e t i c a l l y r e l a t e d and are considered to be synthesized i n nature by the union of three isoprene u n i t s (1) with or without carbon s k e l e t a l rearrangement during the course of t h e i r b i o s y n t h e s i s (1,2). 1 - 2 -Although sesquiterpenes have been known as c o n s t i t u e n t s of the e s s e n t i a l o i l s , and have formed the b a s i s f o r a wide range of e x o t i c scents and perfumes f o r more than a century, t h e i r chemistry had remained untouched u n t i l comparatively recent times. One of the reasons f o r t h i s was that i n the e s s e n t i a l o i l s sesquiterpenes o f t e n occur as very complex mixtures which could not be r e s o l v e d by the c l a s s i c a l methods a v a i l a b l e . As a consequence of t h i s , much of the e a r l y work i n the sesquiterpene f i e l d was c a r r i e d out on inseparable mixtures which at the time appeared homogeneous. This often l e d to inaccurate r e s u l t s and c o n c l u s i o n s . With the advent of modern se p a r a t i o n techniques such as t h i n l a y e r chromatography and g a s - l i q u i d chromatography, and modern sp e c t r o s c o p i c methods such as nuclear magnetic resonance and o p t i c a l r o t a t o r y d i s p e r s i o n , the s t r u c t u r e and stereochemistry of a large number of sesquiterpenes have been e s t a b l i s h e d . As a r e s u l t of these i n v e s t i g a t i o n s i t has been found that over f o r t y d i f f e r e n t sesquiterpene s k e l e t a l types e x i s t i n nature (3). Sesquiterpenes 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 s t r u c t u r e s as widely d i f f e r i n g as l o n g i c y c l e n e (jp(4,5) a n ^ t e l e k i n (3) (6). - 3 -One large c l a s s of sesquiterpenes i s the eremophilane c l a s s which possess the b a s i c carbon s k e l e t o n 4_ as e x e m p l i f i e d by eremophilenolide 5_. 4 The numbering system of t h i s c l a s s of sesquiterpenes i s as shown i n 4_. An i n t e r e s t i n g v a r i a n t of t h i s general s k e l e t o n i s the a r i s t o l a n e s k e l e t o n 6 of which a r i s t o l o n e (7) i s an example. 6 7 Another l a r g e group of sesquiterpenes i s the cadinane c l a s s which 15 - 4 -possesses the b a s i c s k e l e t o n and numbering system shown i n 8_, ^  With the i s o l a t i o n and s t r u c t u r a l e l u c i d a t i o n o f compounds which d i f f e r e d only i n stereochemistry at C - l , C-6, and C-7, i t has become necessary to f u r t h e r subdivide t h i s c l a s s of sesquiterpenes i n t o the cadinane ( 9 ) , muurolane (10), amorphane (11) and bulgarane (12) types (7). An i n t e r e s t i n g v a r i a n t of the muurolane (10) c l a s s o f sesquiterpenes 9 10 11 12 are the cubebenes, a-(13) and g-cubebene (14). One obvious s t r u c t u r a l s i m i l a r i t y between the s t r u c t u r e s of a r i s t o l o n e The numbering system of t h i s s k e l e t o n i s based on the p r i n c i p l e formulated by Barton and h i s c o l l a b o r a t o r s , and i t r e l a t e s the cadin-ane carbon atoms with those of other sesquiterpenes such as the eudesmanes and the guaianes. See r e f . (12) c i t e d i n V. Herout and V.Sykdra, Tetrahedron, 4_, 246 (1958). - 5 -(7) and the cubebenes (13 and 14) i s the i n c o r p o r a t i o n of a c y c l o -propane r i n g . In t h i s regard i t should be mentioned that s e v e r a l of the more r e c e n t l y i s o l a t e d sesquiterpenes such as l o n g i c y c l e n e (2) (4,5) and c y c l o s a t i v e n e (15) (5) a l s o incorporate c y c l o p r o p y l groups i n 15 t h e i r s t r u c t u r e s and i t became of i n t e r e s t f o r s e v e r a l groups (8,9) to develop s y n t h e t i c pathways to these types of compounds. In our own l a b o r a t o r y (10,11) the s u c c e s s f u l c y c l i z a t i o n of diazoketone 16^  to a f f o r d a mixture c o n t a i n i n g 4-demethylaristolone (17) had already shown the u t i l i t y of t h i s method and i t was decided t o extend t h i s work. Thus, the work described i n t h i s t h e s i s was concerned with the s u c c e s s f u l attempt to synthesize racemic a r i s t o l o n e (7_) , a-cubebene (15) and g-cubebene (14). - 6 -2. Sesquiterpene B i o s y n t h e s i s As was p r e v i o u s l y s t a t e d , the b i o s y n t h e s i s of sesquiterpenes i s b e l i e v e d to a r i s e from the combination of three isoprene u n i t s followed by subsequent c y c l i z a t i o n of the r e s u l t i n g f i f t e e n carbon u n i t i n any of a wide v a r i e t y of modes. The s p e c i f i c f i f t e e n carbon u n i t i n v o l v e d i n these transformations i s g e n e r a l l y considered to be f a r n e s y l pyrophosphate (18), and a recent review (7) summarises w e l l the current s t a t e of t h i s hypothesis. The b i o s y n t h e s i s of 18_ from a c e t y l CoA (19), v i a the intermediacy of mevalonic a c i d (20) (12) has been experimentally v e r i f i e d (12,13,14) and i s b r i e f l y o u t l i n e d i n Chart I. The successive condensation of three molecules of 19 can occur i n e i t h e r of two ways. The f i r s t of these (Path A ) , a l i n e a r condensation, leads to a s t r a i g h t chain product, 21, g e n e r a l l y considered to be the precursor of other groups of n a t u r a l products such as the p h e n o l i c r e s i n s and the aceto-genins. The second mode of condensation (Path B) leads to the branched 3-hydroxy-g-methyl g l u t a r y l CoA (22) . Reduction of 22_ w i t h nicotinamide-adenine d i n u c l e o t i d e phosphate (NADPH) a f f o r d s mevalonic a c i d (20) which upon phosphorylation with adenine triphosphate (ATP) 3 and subsequent dec a r b o x y l a t i o n gives A -isopentenylpyrophosphate (23). I s o m e r i z a t i o n of the t e r m i n a l double bond of 23 r e s u l t s i n the formation of dimethyallylpyrophosphate (24) which upon condensation with 23 a f f o r d s geranyl pyrophosphate (25) . Subsequent condensation of 25_ with 23 a f f o r d s f a r n e s y l pyrophosphate (18). From t h i s hypothesis i t i s evident that the simplest sesquiterpene i s f a r n e s o l (26) and i t i s g e n e r a l l y b e l i e v e d , (1,16) that the carbon SCoA 0 o o : _ ^ S G o A / A ^ ^ S C o A 19 Path B ^ A s C o A Path A ¥ ^ OH H0 2C ^ H 0 2 C 0'^ SCoA 22 0 0 0 o CoA 4± SCoA etc . p h e n o l i c r e s i n s and acetogenins 20 | ATI -CO, H0 2C 0PP OPP 23 24 0PP 1 ^ 0PP OPP OPP 25 18 R = OPP 26 R = OH •OPP 27 Chart I - 9 -skeletons of v i r t u a l l y a l l of the sesquiterpenes can be obtained by a s u i t a b l e c y c l i z a t i o n of e i t h e r c i s - ( 2 7 ) or t r a n s - f a r n e s y l pyrophosphate (18) as i n d i c a t e d i n Chart I I (7,16). The i n i t i a l step i n these c y c l i z a t i o n s can be considered as i o n i z a t i o n of the a l l y l i c pyro-phosphate, accompanied by p a r t i c i p a t i o n of e i t h e r the c e n t r a l or the t e r m i n a l double bond leading to representations such as c a t i o n s 28 to 33. I t i s understood, of course, that the r e p r e s e n t a t i o n of a formal c a t i o n i n t h i s and subsequent d i s c u s s i o n s i s only a convenient symbolism, sin c e the b i o s y n t h e t i c c y c l i z a t i o n s are undoubtedly enz y m a t i c a l l y c o n t r o l l e d and probably occur v i a p a r t i a l l y or f u l l y concerted processes. Ourisson and coworkers (17) have suggested t h a t 1,3-deprotonation of a c a t i o n such as 32 or 33 could lead to an intermediate such as 34. - 10 -A c o n s i d e r a t i o n of the various conformers of 34_ can lead t o a r a t i o n a l i z a t i o n of the main stereochemical features of both the maaliane (35) and a r i s t o l a n e (6) f a m i l i e s of sesquiterpenes. Thus, c y c l i z a t i o n of 34, co n f o r m a t i o n a l l y drawn as 36_, i n a Markownikoff manner would lead d i r e c t l y to m a a l i o l (37) . Backbone rearrangement of 35 36 37 c a t i o n 38, e a s i l y derived from m a a l i o l (37), would a f f o r d d i r e c t l y 1 ( 1 0 ) - a r i s t o l e n e (39) or 9 - a r i s t o l e n e (40). Subsequent a l l y l i c o x i d a t i o n of the l a t t e r would give a r i s t o l o n e (7). I t i s of i n t e r e s t 38 39 40 7 to note that r e c e n t l y (18) a sesquiterpene enantiomeric with 40_ has been i s o l a t e d which has been given the name a-ferulene (41). 41 The b i o s y n t h e s i s of the cadinane (8) type sesquiterpenes can be thought to a r i s e by one of at l e a s t two d i s t i n c t l y d i f f e r e n t pathways. In the f i r s t of these, as shown i n Chart I I I , c a t i o n 28_ can be seen to undergo successive deprotonation, r e p r o t o n a t i o n , and f i n a l l y deprotona-2 t i o n to a f f o r d t r i e n e 4_2_. Subsequent c y c l i z a t i o n of 42_ would then a f f o r d c a t i o n 43_. In the second pathway, c a t i o n 30_ can be seen to undergo a 1,3-hydride s h i f t to c a t i o n 44 followed by a Markownikoff c y c l i z a t i o n and subsequent 1,2-hydride s h i f t to form the same c a t i o n 43. Cation 43, which can be w r i t t e n i n i t s corresponding n o n - c l a s s i c a l form 45, i s probably the precursor of the cubebenes (13 and 14), cubebol (48) and the two epimeric cubenols (46a and 46b). I t can be seen that simple h y d r a t i o n of c a t i o n 45 from the B-face a f f o r d s cubenol 2 This same process can be looked upon also as a 1,2-hydride s h i f t f o l l o wed by deprotonation. I t should again be emphasized that i n t h i s and subsequent treatments the formalism of these mechanisms must be t r e a t e d with c a u t i o n as i n a l l cases the t o t a l process probably takes place on an enzyme surface and i s probably concerted. Chart III - 13 -(46a) while h y d r a t i o n from the a-face gives epi-cubenol (46b). On the other hand c o l l a p s e of c a t i o n 45_ to c a t i o n 47 followed by subsequent proton loss or h y d r a t i o n leads r e s p e c t i v e l y to a-cubebene (13) and g-cubebene (14), or to cubebol (48). Therefore, i t i s probably not j u s t coincidence that these f i v e sesquiterpenes co-occur i n cubeb o i l (Piper cubeba L.) (19,20,21). I f one were to consider the case where c a t i o n _30 undergoes two 1,2-hydride s h i f t s then the r e s u l t i n g c a t i o n (49) when c a r r i e d through the above arguments would end up with the stereochemistry of the amorphane (11) and bulgarane (12) c l a s s e s of sesquiterpenes. That the transformations described f o r c a t i o n 4_5_ are p o s s i b l e i f not probable has been e l e g a n t l y shown by the Japanese group of Hirose (22) who found t h a t simple a c i d treatment of a-cubebene (13) r e s u l t s i n complete transformation t o a mixture of the three hydrocarbons, - 14 -cadina-4,6(1)-diene (50), g-cadinene (51) and cadina-1,4-diene (52) and the two a l c o h o l s cubenol (46a) and epi-cubenol (46b) . 50 51 52 3. S t r u c t u r e and Stereochemistry of A r i s t o l o n e The f i r s t h a l f of t h i s t h e s i s w i l l be concerned with the t o t a l s y nthesis of a r i s t o l o n e ( 7 ) , and t h e r e f o r e , i t i s p e r t i n e n t to discuss the work which l e d to the establishment of the s t r u c t u r e and stereochemistry of t h i s novel sesquiterpene. A r i s t o l o n e (7) ( C ^ I ^ O ) w a S £ ^ r s T : i s o l a t e d by Kariyone and Naito (23) i n 1955 and l a t e r reexamined by Furukawa and Soma (24) i n 1961, as a component of the e s s e n t i a l o i l obtained from the roots of A r i s t o l o c h i a d e b i l i s Sieb. et Zucc. I t has a l s o been i s o l a t e d as a minor component of the mixture obtained by steam d i s t i l l a t i o n of the I pentane e x t r a c t of the rhizomes of Asarum canadense (Canada snakeroot, w i l d ginger) (25) . - 15 -The gross s t r u c t u r e of a r i s t o l o n e (7_), e l u c i d a t e d by Furukawa et a l (24,26,27), followed from i t s s p e c t r a l p r o p e r t i e s , chemical degradation and a n a l y s i s of the degradation products. The stereochemistry of 7_, determined by Buchi et_ al_ (28) was i n f e r r e d by c o r r e l a t i o n w i t h l ( 1 0 ) - a r i s t o l e n e (39). A strong absorption at 6.03 y i n the i n f r a r e d spectrum of 1_, and the u l t r a v i o l e t maxima at 235 my (e 12,900) and 310 my (e 117) were c o n s i s t e n t w i t h the presence of an a,g-unsaturated ketone chromophor. In a d d i t i o n , hydrogenation of 1_ over platinum oxide (see Chart IV) (27) r e s u l t e d i n the uptake of only one mole of hydrogen. The dihydro-a r i s t o l o n e (53) thus formed showed an i n f r a r e d a bsorption at 5.92 y and u l t r a v i o l e t maxima at 213 my (e 4,900) and 278 my (e 46) which i n d i c a t e d that the carbonyl group was probably conjugated with a c y c l o p r o p y l group. The double bond and the carbonyl accounted f o r two degrees of u n s a t u r a t i o n and so these authors concluded that a r i s t o l o n e (7) was t r i c y c l i c . Selenium dehydrogenation of 1_ gave 5-methyl-g-naphthol (54) , c h a r a c t e r i z e d as i t s p i c r a t e , w h i l e l i t h i u m aluminum hydride r e d u c t i o n of 7_ afforded a r i s t o l o l (55) :, which upon selenium dehydrogenation aff o r d e d 1-methylnaphthalene (56) . This same product could be obtained by Wolff-Kishner r e d u c t i o n of 7_ to deoxyaristolone ( 9 - a r i s t o l e n e ) (40) followed by selenium dehydrogenation. Thus p a r t i a l s t r u c t u r e s 57a or 57b could be assigned t o 7_. Support f o r these p a r t i a l s t r u c t u r e s was found i n the f a c i l e a c i d c a t a l y z e d rearrangement of 7 to a p h e n o l i c product presumed to be 58. 61 Chart IV - 17 -Oxidation o f e i t h e r 1_ or 40_ with potassium permanganate allowed the i s o l a t i o n of a C^,_ d i a c i d , a r i s t o i c a c i d (59). A c i d 59, when heated with mineral a c i d , smoothly underwent rearrangement to a f f o r d what was presumed, from i t s s p e c t r a l p r o p e r t i e s and c l a s s i c a l C-methyl determina-t i o n , to be a meta-hydroxy benzoic a c i d d e r i v a t i v e possessing a methyl and an i s o p r o p y l group. Based on t h i s assumption authentic 3-isopropyl-5-hydroxy-2-toluic a c i d (60) was synthesized and proved to be i d e n t i c a l i n a l l respects with the degradation product. With the i s o l a t i o n of a benzoic a c i d d e r i v a t i v e the remaining fragment from the rearrangement of 59_ was presumed to be a monocarboxylic a c i d . This presumption was born out with the i s o l a t i o n from the r e a c t i o n mixture of c r o t o n i c a c i d (61). On t h i s chemical evidence Furukawa (27) suggested that a r i s t o l o n e indeed had s t r u c t u r e 7_. In 1962 Buchi (28) i s o l a t e d a sesquiterpene hydrocarbon from Chinese Spikenard O i l (Nardostachys j atamans i (Roxb.) DC, Valerinacea) which, by i t s i n f r a r e d spectrum, was i d e n t i c a l w i t h calarene i s o l a t e d by Sorm (29) i n 1953 from Sweet Flag (Acorus calamus L . ) . In a d d i t i o n , Sorm (30) had stu d i e d the s t r u c t u r e of a hydrocarbon c a l l e d g-gurjunene i s o l a t e d from gurjunbalsam (Dipterocarpus sp.). Calarene and g-guijunene had s i m i l a r but not i d e n t i c a l p h y s i c a l and s p e c t r a l p r o p e r t i e s and upon hydrogenation afforded calarane (62). A l s o , both calarene and g-gurjunene were d i f f e r e n t from 9 - a r i s t o l e n e (40) prepared by Wolff-Kishner r e d u c t i o n of a r i s t o l o n e (7). Since 40_ a l s o a f f o r d e d calarane (62) upon hydrogenation,it was apparent that calarene and g-gurjunene d i f f e r e d from 40_ only i n the p o s i t i o n of the double bond. Further i n v e s t i g a t i o n (30) of the m a t e r i a l c a l l e d calarene revealed - 18 -that i t was a c t u a l l y a mixture of 3-gurjunene and 9 - a r i s t o l e n e (40), i n a r a t i o of approximately 4:1, thus accounting f o r the minor d i f f e r e n c e s i n t h e i r p h y s i c a l p r o p e r t i e s . Ourisson (17) had independently a r r i v e d at t h i s same c o n c l u s i o n and i t was decided that both calarene and 3-gurjunene (which were i d e n t i c a l ) would be b e t t e r described as 1(10)-a r i s t o l e n e (39) and the saturated hydrocarbon calarane as a r i s t o l a n e (62). The hydrogenation of 40_ to a f f o r d 62_ al s o served to confirm the gross s k e l e t o n of a r i s t o l o n e as shown by Furukawa (24,26,27). The absolute stereochemistry of 1 ( 1 0 ) - a r i s t o l e n e (39) was e s t a b l i s h e d by Buchi (28) by an i n d i r e c t c o r r e l a t i o n w i t h m a a l i o l (37), of known absolute c o n f i g u r a t i o n . Treatment of 39_ with formic a c i d at 100° f o r 5 h r e s u l t e d i n the formation of diene 63, which was a l s o - 19 -a v a i l a b l e by formic a c i d c a t a l y z e d dehydration of maaliol (37). This r e s u l t confirmed that the angular methyl group at i n 1 ( 1 0 ) - a r i s t o l e n e (39) had an a - o r i e n t a t i o n . Buchi next turned h i s a t t e n t i o n to the stereochemistry of the c y c l o p r o p y l r i n g . Treatment of 3_9_ (see Chart V) with N-bromoacetamide afforded the bromohydrin 64, which upon Raney-n i c k e l r e d u c t i o n afforded the t e r t i a r y a l c o h o l 65. Dehydration of t h i s a l c o h o l w i t h t h i o n y l c h l o r i d e i n p y r i d i n e a f f o r d e d diene 66. Treatment of epi-maaliol (67) with t h i o n y l c h l o r i d e i n p y r i d i n e followed by treatment with hot c o l l i d i n e afforded hydrocarbons 66, 68, and 63; i n the r a t i o 52:25:23. This r e s u l t can be r a t i o n a l i z e d i f dehydration of both 65 and 67_ proceed through the same c y c l o p r o p y l - c a r b i n y l c a t i o n 69, formed from 65 and 67 by methyl and hydride s h i f t s , r e s p e c t i v e l y . In any event, s i n c e i n the formation of diene 66_ the stereochemistry at remained unchanged...the ^ - o r i e n t a t i o n of the c y c l o p r o p y l group of 39 was confirmed. This l e f t only one assymetric center undefined, the secondary methyl group at . Having shown th a t the angular methyl group at had the ct-o r i e n t a t i o n and that the gem-dimethyl c y c l o p r o p y l moiety had the 3-o r i e n t a t i o n , Buchi reasoned that a d d i t i o n to the double bond of _39_ should proceed from the a-face of the molecule i r r e s p e c t i v e of the c o n f i g u r a t i o n of the secondary methyl group at C^. Reaction at the double bond from the 3-face of 3_9_ would be subject to considerable s t e r i c hindrance by one of the geminal methyl groups at C^. Thus, hyd r o b o r a t i o n - o x i d a t i o n (see Chart VI) of 39_ was presumed to form the a x i a l a l c o h o l 70. O x i d a t i o n of a l c o h o l 70 wit h chromic a c i d a f f o r d e d the c i s ketone 71, which showed a strong p o s i t i v e Cotton e f f e c t i n i t s - 20 -Chart V - 21 -o p t i c a l rotatory dispersion (ORD) curve. This was i n agreement with the octant r u l e , since the methylene at Cg i s i n a p o s i t i v e quadrant., Treatment of ketone 71 with base res u l t e d i n almost quantitative Octant Diagram of 71_ Octant Diagram of 72 conversion to the more stable trans-ketone 72, now showing only a weakly negative Cotton e f f e c t i n i t s ORD curve. Both 7l_ and 72_ on exposure to t r i f l u o r o a c e t i c acid afforded the same unsaturated ketone 73, and i t became important to asce r t a i n the stereochemistry of the r i n g junction i n t h i s compound. C a t a l y t i c hydrogenation of ketone 73_ afforded ketone 74, which was converted to the t h i o k e t a l 75_. Desulfuriza-t i o n of 75 with Raney-nickel gave the saturated hydrocarbon 76. Al t e r n a t e l y , Wolff-Kishner reduction of ketone 72, with known r i n g junction stereochemistry, followed by isomerization with anhydrous hydrogen chloride afforded the unsaturated hydrocarbon 77_. C a t a l y t i c hydrogenation of 77_ afforded 76_ i d e n t i c a l i n a l l respects with 7_6_ obtained from compound 73_ by the former sequence. This r e s u l t confirmed that ketones 73_ and - 23 -74 had trans r i n g junctions. Therefore, ketone 73_ with an a x i a l i s o -propenyl substituent i s favored at equilibrium over the unknown c i s isomer 78. This r e s u l t could only be r a t i o n a l i z e d i f the secondary methyl group at had the a-configuration. Since the stereochemistry at C ^ Q , C,., and of ketone 73 had been established, and since ketone 73 i s the only product i s o l a t e d at equilibrium, i t would have to be one of either 73a or 73b. Inspection of the molecular models (see Chart VII) 73a 73b of the corresponding c i s isomers 78a (78a') and 78b (78b') reveals that i n equilibrium A, conformation 78a i s c l e a r l y favoured over conformation 78a' whereas i n equilibrium B, conformations 78b and 78b' are a c t u a l l y 3 comparable i n conformational free energy. Since the conformational free energy i s large i n equilibrium A, only 78a and 73a need to be considered i n equilibrium C (see Chart V I I I ) . However, i n equilibrium B the conformational free energy i s small, and therefore, either conformer 78b or 78b' may be considered with 73b i n equilibrium D. Analysis of the 3 Because the conformational free energies for many of the i n t e r a c t i o n s involved have not been accurately measured i t i s impossible to assign numerical values to the energy differences between the respective p a i r s . However, i t i s safe to assume that the arguments are s t i l l v a l i d . - 24 -78a 78a 1 Interactions 1 syn-axial CH^-H 3 " 11 CH.-H I 1 1,3-diaxial CH^-isopropenyl 1 3-methyl ketone 1 skew methyl-methyl 1 " " isopropenyl 1 1,3-diaxial isopropenyl-sp C 1 " " CH 2 4 syn-axial CH3-H 1 3-alkyl ketone 1 skew methyl-methyl 1 syn-axial isopropenyl-H 78b1 Interactions 2 1,3-diaxial CH 3-CH 2 2 syn-axial CH^-H isopropenyl-H CH2-H 1 skew CH^-isopropenyl 1 3-methyl ketone 1 1,3-diaxial isopropenyl-CH^ 1 " " -sp 2 1 syn-axial " -H 1! It CH3-H 1. 3-alkyl ketone 1 skew CH 3-CH 3 Chart VII - 25 -73a Interactions 4 syn-axial CH^-H 3 " " isopropenyl-H 1 3-methyl ketone 1 skew methyl 1 syn-axial CH^-H 3 " " CH2-H 1 1,3-diaxial CH^-isopropenyl 1 3-methyl ketone 1 skew methyl-methyl 1 skew methyl-isopropenyl 73b Interactions 5 syn-axial CH^-H 2 " " isopropenyl-H 1 1,3-diaxial isopropanyl-CH, 1 3-methyl-ketone 2 1,3-diaxial CH 3~CH 2 2 syn-axial CH3-H 1 " " isopropenyl-H 1 " " CH2-H 1 skew CH 3~isopropenyl 1 3-methyl ketone Chart VIII - 26 -energy difference i n equilibriums C and D (see Chart VIII) reveals that i n the former case 73a should be c l e a r l y favoured over 78a. However, the energy differences i n equilibrium D are minimal. Therefore, since only one ketone was i s o l a t e d at equilibrium Buchi argued that the stereochemistry of t h i s compound must be that depicted by 73a. Now, since 9-aristolene (40) and therefore a r i s t o l o n e (7) had been correlated with 1(10)-aristolene (39), the above r e s u l t s established the absolute stereochemistry of a r i s t o l o n e to be as shown below. 4. Other Syntheses of Aristolane Type Sesquiterpenes Early i n 1968, Coates and Shaw (8) reported the t o t a l synthesis of (+)-1(10)-aristolene (39) (calarene, g-gurjunene) by a sequence 2 which employed as i t s most important step the decomposition of the A -pyrazoline 79_ i n the presence of powdered potassium hydroxide at 240-255° to afford a 44% y i e l d of 39_. The sequence employed i n t h i s synthesis i s outlined i n Chart IX. The mixture of diketones 80_ afforded, upon Raney n i c k e l reduction of the corresponding mono-th i o k e t a l s , the mixture of octalones 81_ and 8_2 which were separated by means of f r a c t i o n a l d i s t i l l a t i o n through a spinning band column. Treat-ment of octalone 82_ with sodium hydride and diethylcarbonate i n dimethoxy-ethane afforded the g-keto ester 8_3. Upon treatment with methyllithium - 27 -Chart IX - 28 -i n ether, keto e s t e r 83_ afforded the k e t o l 84, which was dehydrated with h y d r o c h l o r i c a c i d i n methanol to give the i s o p r o p y l i d e n e d e r i v a t i v e 85. Reaction of 8_5_ w i t h one equivalent of hydrazine i n absolute ethanol 2 gave r i s e to the unstable A - p y r a z o l i n e 79_. Decomposition of the l a t t e r over powdered potassium hydroxide a f f o r d e d a homogeneous l i q u i d , which a f t e r p r e p a r a t i v e g.I.e.afforded (±)-1(10)-aristolene (59) . The l a t t e r e x h i b i t e d s p e c t r a i d e n t i c a l with those obtained from the n a t u r a l m a t e r i a l . In May of 1968, Ourisson and coworkers (9) reported the t o t a l s ynthesis of racemic a r i s t o l o n e (7). As i n the synthesis of Coates and Shaw (8), Ourisson's synthesis i n v o l v e d the decomposition of a p y r a z o l i n e . The r e a c t i o n scheme employed by t h i s group i s shown i n Chart X. Robinson a n n e l a t i o n of 2,3-dimethylcyclohexanone (86) with methyl v i n y l ketone (87) afforded a 3:2 mixture of octalones 88. Reduction of t h i s mixture w i t h l i t h i u m i n l i q u i d ammonia gave a mixture of decalones 89_. Treatment of t h i s mixture with bromine i n a c e t i c a c i d afforded the bromo ketones 90_ and 91_ which were separated by f r a c t i o n a l c r y s t a l l i z a t i o n . That the bromo ketone 91_ e v e n t u a l l y afforded a r i s t o l o n e was considered proof of the r e l a t i v e stereochemistry of the v i c i n a l methyl groups of 91_. Bromo ketone 91, upon heating i n hexamethylphosphoramide, f u r n i s h e d octalone 9_2_. A 1,3-dipolar a d d i t i o n of 2-diazopropane to octalone 92 a f f o r d e d the A^-pyrazoline 93, which upon i r r a d i a t i o n (pyrex f i l t e r , benzene s o l u t i o n , HPK 125 P h i l i p s lamp) affor d e d d i h y d r o a r i s t o l o n e jv3_. Reaction of 53_ w i t h one equivalent of phenyltrimethylammonium bromide perbromide i n t e t r a h y d r o f u r a n gave the e q u a t o r i a l bromo ketone 94, which upon heating w i t h l i t h i u m bromide i n - 30 -hexamethylphosphoramide afforded ( t ) - a r i s t o l o n e (7). The l a t t e r e x h i b i t e d sp e c t r a i d e n t i c a l w i t h those of the n a t u r a l m a t e r i a l . 5. S t r u c t u r e and Stereochemistry of c t - and g-Cubebene Since the second h a l f of t h i s t h e s i s w i l l be concerned with the t o t a l s ynthesis of (±)-a-cubebene (13) and (± ) -g-cubebene (14), i t i s appropriate to describe the work which l e d to the establishment of the s t r u c t u r e s and stereochemistry of these two r e l a t e d sesquiterpenes. In 1966 Hirose (20) reported the s t r u c t u r a l e l u c i d a t i o n of the two hydrocarbons a-cubebene (13) and g-cubebene (14) i s o l a t e d from commercial o i l of cubeb (Piper cubeba L.) . In each case the s t r u c t u r a l assignment was based upon s p e c t r a l properties,, chemical degradation, and c o r r e l a t i o n w i t h known cadinane d e r i v a t i v e s . Recently, i s o l a t i o n of the cubebenes from c i t r u s o i l s has been reported by Veldhuis and Hunter (31). Sorm (32) had reported i n 1960 the i s o l a t i o n of a compound from f a l s e cubeb o i l to which he assigned s t r u c t u r e 95 and erroneously named copaene. However, r e c e n t l y , the s t r u c t u r e of copaene, i s o l a t e d from Cedrela toona Roxb.,was e l u c i d a t e d by de Mayo (33) and Sukh Dev(34) who p o s t u l a t e d - 31 -s t r u c t u r e 96_ f o r t h i s compound. The "copaene" reported by Sorm showed an i n f r a r e d spectrum d i f f e r e n t from that of the one i s o l a t e d from Cedrela toona, but i d e n t i c a l to that of a-cubebene (13) reported by Hirose. a-Cubebene (13), C^^H^^, showed, i n the nuclear magnetic resonance (n.m.r.) spectrum, s i g n a l s due to two cyclopropane protons at T 8.90 and T 9.79. Based on the u l t r a v i o l e t spectrum, ^ m a x 208 my (e, 4,260) the c y c l o p r o p y l group was assumed to be conjugated with one double bond. Upon c a t a l y t i c hydrogenation, compound 1_3_ took up one mole of hydrogen to a f f o r d compound 97 (see Chart XI) and, t h e r e f o r e , L3 was assumed to be t r i c y c l i c . Upon treatment with gaseous hydrogen c h l o r i d e i n dry ether, . 13 was converted i n t o (-)-cadinene d i h y d r o c h l o r i d e (98) . Hydroboration-o x i d a t i o n o f 1_3 followed by chromic a c i d o x i d a t i o n a f f o r d e d ketone 99, which upon treatment with methylmagnesium i o d i d e gave the corresponding t e r t i a r y a l c o h o l . Dehydrogenation of the l a t t e r with selenium affo r d e d 7-methyl cadalene (100) i d e n t i f i e d as i t s p i c r a t e . This sequence showed that the double bond of 13_ was i n the C -C. p o s i t i o n . Chart XI - 33 -The p o s i t i o n of the c y c l o p r o p y l group i n 13 was proven by the f o l l o w i n g method. Ozonolysis of 13, followed by treatment of the r e s u l t i n g product w i t h diazomethane a f f o r d e d a keto e s t e r (101). This s t r u c t u r e was assigned on the b a s i s of s p e c t r a l evidence. Thus, the i n f r a r e d spectrum showed two carbonyl absorptions at 1690 and 1740 cm * c h a r a c t e r i s t i c of the keto ester, while the n.m.r. spectrum revealed the presence of two 3-proton s i n g l e t s at T 7.80 and x 6.37, due to an a c e t y l methyl and a methoxy methyl, r e s p e c t i v e l y , and a two proton s i n g l e t at x 7.59 c h a r a c t e r i s t i c of a methylene adjacent to a carbonyl R group and a f u l l y s u b s t i t u t e d center [-C-C1L-C-]. In the mass spectrum of 101, the remarkably strong l i n e s at m/e M-73 and m/e M-43 (M = molecular ion) s t r o n g l y suggested the presence of a carbomethoxy methylene group (M = 73) and an a c e t y l group (M = 43). Upon treatment w i t h concentrated h y d r o c h l o r i c a c i d keto.ester 101 afforded aketo lactone 102, r e s u l t i n g from cleavage of the cyclopropane r i n g . The s t r u c t u r e of compound 102 was again assigned on the b a s i s of s p e c t r a l data. Thus,the i n f r a r e d spectrum showed absorptions at 1770 and 1720 cm * c h a r a c t e r i s t i c of a Y _ l a c t o n e ar>d an a l i p h a t i c ketone r e s p e c t i v e l y , whereas the mass spectrum now showed a parent peak at m/e 252 (C^H^O^) , a base peak at m/e 43 (CH^CO) as w e l l as a peak at m/e 194, which i s c h a r a c t e r i s t i c of e l i m i n a t i o n of one molecule of acetone. From the r e s u l t s described above, two s t r u c t u r e s were p o s s i b l e f o r a-cubebene, namely L3 and 13a. Of these two p o s s i b i l i t i e s Hirose and coworkers (20) chose s t r u c t u r e 13 on b i o g e n e t i c grounds. - 34 -The stereochemistry of 13 was e s t a b l i s h e d by comparing i t s a c i d c a t a l y z e d rearrangement products with the authentic o l e f i n s obtained from cubenol (46a) and epi-cubenol (46b) by dehydration (see Chart XII) . Thus, treatment of a-cubebene (13) with d i l u t e h y d r o c h l o r i c a c i d i n aqueous dioxane afforded cadina-4,6(1)-diene (50), 6-cadinene (51), and cadina-1,4-diene (52). Cadina-1,4-diene (52) had the absolute s t e r e o -chemistry shown at C^, Cj, and C^^ si n c e hydrogenation afforded amongst other products (-)-cadinane (105) of known absolute stereo-chemistry. Therefore, since i t was thought to be h i g h l y u n l i k e l y that the conversion o f a-cubebene i n t o (-)-cadinane (103), v i a the diene 52, was accompanied by any stereochemical change at C^, C^, or C^Q, the absolute stereochemistry of a-cubebene was proposed as shown i n s t r u c t u r e 13, (22). Chart XII - 36 -B-Cubebene (14), C^^H^^, was considered to be a double bond isomer of a-cubebene (13) f o r the f o l l o w i n g reasons: 1) upon treatment w i t h gaseous hydrogen c h l o r i d e (see Chart X I I I ) i n dry ether 14_ a l s o afforded cadinene d i h y d r o c h l o r i d e (98); 2) when passed through a h a l f -exhausted c a p i l l a r y column coated with polypropylene g l y c o l at 150°, 14_ was p a r t i a l l y isomerized to a-cubebene (13); and 3) upon hydrogenation with platinum oxide i n ethanol 1_4_ afforded two dihydro d e r i v a t i v e s , one of which was i d e n t i c a l w i t h dihydro-a-cubebene (97) . The i n f r a r e d spectrum of 14_ revealed the presence of a t e r m i n a l methylene group (3080, 1650, and 860 cm ^ ) , and the u l t r a v i o l e t spectrum revealed a te r m i n a l methylene conjugated to a c y c l o p r o p y l r i n g (A 210 my ( E , ITlclX 4,340)). The n.m.r. spectrum showed the presence of three secondary methyl groups and the two terminal methylene protons. Upon ozo n o l y s i s (see Chart X I I I ) , B-cubebene (14) afforded a ketone (104), which showed a molecular i o n at m/e 206 (C^H^'^O) i n i t s mass spectrum. The u l t r a v i o l e t spectrum of ketone 104 showed A 209 my ^ F max (e, 2,210), c h a r a c t e r i s t i c of a ketone conjugated with a c y c l o p r o p y l r i n g . An i n f r a r e d absorption at 1715 cm ^ was i n accord with a ketone i n a f i v e membered r i n g conjugated with a c y c l o p r o p y l r i n g . On the b a s i s of t h i s i n f o r m a t i o n s t r u c t u r e 14 or 14a could be a t t r i b u t e d to Chart XIII - 38 -B-cubebene. Of these two p o s s i b i l i t i e s s t r u c t u r e 1_4_ was chosen f o r B-cubebene si n c e 14_was isomerized to a-cubebene (13) on a g a s - l i q u i d chromatography column, an impossible transformation f o r 14a. 6. Other Syntheses of Cubebenes S h o r t l y a f t e r the work described i n t h i s t h e s i s was p u b l i s h e d , a communication appeared from the Japanese group of Yoshikoshi (35) concerning the t o t a l synthesis of a-cubebene (13), B-cubebene (14), and cubebol (48). The c r u c i a l step i n t h i s s y n t h e s i s , as i n our own, concerned the c y c l i z a t i o n of a diazoketone (105) to a mixture of t r i -c y c l i c ketones (106), having the r e q u i r e d f u n c t i o n a l i t y f o r f u r t h e r 105 106 transformations to the cubebenes and cubebol. The s p e c i f i c diazoketone employed by Yoshikoshi and coworkers i s represented by 107 (see Chart XIV) . Treatment of (-)-trans-caran-2-one (108) w i t h allylmagnesium bromide followed by h y d r o b o r a t i o n - o x i d a t i o n of the crude product afforded a mixture, from which the c r y s t a l l i n e d i o l 109 was i s o l a t e d i n approximately 20% y i e l d . Oxidation of d i o l 109 w i t h chromium t r i o x i d e - 39 -i n p y r i d i n e r e s u l t e d i n almost q u a n t i t a t i v e conversion i n t o the s p i r o -lactone 110. P y r o l y s i s of 110 i n the presence of a small amount of p y r i d i n e at 250° i n a sealed tube afforded the unsaturated a c i d 111 i n approximately 70% y i e l d . The crude a c i d 111 was converted by normal procedures to the diazoketone 107, which without p u r i f i c a t i o n was heated with copper powder i n cyclohexane to give a mixture of c y c l o p r o p y l ketones 112, 113 and 114 i n 13, 11 and 1% y i e l d s r e s p e c t i v e l y from the s p i r o l a c t o n e 110. Hydrogenation of 113 with t r i s ( t r i p h e n y l -phosphine)rhodium c h l o r i d e a f f o r d e d ketone 104, i d e n t i c a l i n a l l respects w i t h that d e r i v e d by oz o n o l y s i s of g-cubebene (see Chart X I I I ) . Treatment of ketone 104 with methylenetriphenylphosphorane i n dimethyl s u l f o x i d e a f f o r d e d g-cubebene (14) , i d e n t i c a l i n a l l respects with a sample of the n a t u r a l m a t e r i a l . Reaction of ketone 104 with methyl-l i t h i u m or methylmagnesium i o d i d e gave, as the major product, the c r y s t a l l i n e a l c o h o l , cubebol (48), i d e n t i c a l i n a l l respects with the n a t u r a l m a t e r i a l . The stereochemistry assigned to C^ of 48_ i s based on the p r e f e r e n t i a l attack of a l k y l m e t a l reagents on the s i d e opposite to the c y c l o p r o p y l r i n g i n compounds of t h i s type (36) . Dehydration of 48 with t h i o n y l c h l o r i d e i n p y r i d i n e gave a mixture of a-cubebene (13) and g-cubebene (14), (7:2 i n r e l a t i v e r a t i o ) and other hydrocarbons. Successive treatment of 48_ with d i m e t h y l s u l f i n y l carbanion, carbon d i s u l f i d e and methyl i o d i d e gave r i s e to the methyl xanthate 115, which upon heating decomposed to give a mixture of 1_3_ and 14, (1:2 i n r e l a t i v e r a t i o ) and other products . The cubebenes were i s o l a t e d by p r e p a r a t i v e g a s - l i q u i d chromatography and the s y n t h e t i c a-cubebene was i d e n t i c a l i n a l l respects with a sample of the n a t u r a l m a t e r i a l . DISCUSSION PART I 1. The T o t a l Synthesis of (±)-Aristolone and (±)-6,7-Epi-aristolone On i n s p e c t i o n of the s t r u c t u r a l formula presented by Furukawa and coworkers (27) f o r a r i s t o l o n e (7_), i t became obvious t h a t the most d i f f i c u l t and complex pa r t of any s y n t h e t i c approach to t h i s i n t e r e s t i n g sesquiterpene would i n v o l v e the c o n s t r u c t i o n of r i n g B, co n t a i n i n g the o l e f i n i c double bond and the gem-dimethyl c y c l o p r o p y l moiety conjugated to the carbonyl group. I t was decided that of the number of p o s s i b l e routes which might be employed i n the c o n s t r u c t i o n of these f u n c t i o n a l -i t i e s , the scheme which can be i l l u s t r a t e d by the h y p o t h e t i c a l c y c l i z a -t i o n of diazoketone 116 to ketone 53_ was both a t t r a c t i v e and p o t e n t i a l l y e f f i c i e n t . The use of o l e f i n i c diazoketones in i n t r a m o l e c u l a r c y c l i z a t i o n s was already w e l l documented (37) , and success of the above proposed 116 53 conversion (116 i n t o 53) appeared to be q u i t e l i k e l y . The s t a r t i n g m a t e r i a l which was chosen f o r the synthesis of the r e q u i r e d c r u c i a l intermediate of type 116 was the r e a d i l y a v a i l a b l e 2,3-dimethylcyclohexanone (86) (38) (see Chart XV). Treatment of 86 w i t h e t h y l formate and sodium methoxide i n benzene gave r i s e to the corresponding hydroxymethylene compound 118 i n 90% y i e l d . Reaction of 118 with n - b u t y l t h i o l and p_-toluenesulfonic a c i d i n the usual manner (39) gave the 6-n-butylthiomethylene d e r i v a t i v e 119 i n 87% y i e l d . A l k y l a t i o n of 119 with m e t h a l l y l c h l o r i d e i n t - b u t y l a l c o h o l i n the presence of potassium t_-butoxide (39) gave, i n 87% y i e l d , a mixture of the corresponding a l k y l a t e d products 120 . The n-butylthiomethylene b l o c k i n g group was removed from 120 by treatment with potassium hydroxide i n r e f l u x i n g aqueous di e t h y l e n e g l y c o l (39) to a f f o r d a mixture of cis-(121) and trans-2,3-dimethy1-2-metha1ly1eye1ohexanone (122) i n 90% y i e l d - A n a l y s i s of t h i s mixture by g . l . c . i n d i c a t e d that these two compounds were present i n the r a t i o of approximately 4:1> r e s p e c t i v e l y . An a n a l y t i c a l sample of each epimer was obtained by p r e p a r a t i v e - 44 -g . l . c . and each e x h i b i t e d s p e c t r a l data i n complete accord with the assigned s t r u c t u r e . Thus, i n the n.m.r. spectrum of the ci s - i s o m e r , 121, two unresolved m u l t i p l e t s at T 5.17 and T 5.27 could be a t t r i b u t e d to the t e r m i n a l methylene protons at Cg. A broadened AB-type p a i r of doublets ( J = 14 Hz) at T 7.33 and T 7.84 could be assigned to the v i n y l methylene protons at C_,; whereas, a broad s i n g l e t at T 8.38, and a sharp s i n g l e t at x 9.13 were assigned to the v i n y l methyl at C c, and o the t e r t i a r y methyl at r e s p e c t i v e l y . Furthermore, a doublet ( J = 6.5 Hz) due to the secondary methyl at was apparent at x 9.28. S i m i l a r l y , the n.m.r. spectrum of the trans-isomer, 122, d i s p l a y e d two unresolved m u l t i p l e t s at x 5.22 and x 5.32 which could be assigned to the ter m i n a l methylene protons at Cg. A broadened AB-type p a i r of doublets ( J = 14 Hz) at x 7.62 and x 8.04 were a t t r i b u t e d to the v i n y l methylene protons at C^, and s i n g l e t s at x 8.42 and x 8.84 were due to the methyl groups at C D and C„ r e s p e c t i v e l y . F i n a l l y , a doublet ( J = 6.5 Hz) at x 9.27 was assigned to the secondary methyl group at C^. Since the f a c t o r s which a f f e c t the stereochemical outcome of the a l k y l a t i o n of cyclohexanone d e r i v a t i v e s are not w e l l understood i n d e t a i l and were, i n f a c t , the subject of very recent d i s c u s s i o n (40), i t 121 122 - 45 -was r a t h e r d i f f i c u l t to p r e d i c t w i t h c e r t a i n t y the stereochemistry of the a l k y l a t i o n products 121 and 122. Therefore i t became necessary to obt a i n unambiguous proof concerning t h i s p o i n t and i t was shown that the major a l k y l a t i o n product was, i n f a c t , the d e s i r e d c i s compound 121. The proof of stereochemistry was c a r r i e d out i n the f o l l o w i n g manner (see Chart XVI). Reaction of the w e l l known and r e a d i l y a v a i l a b l e (41) trans-10-methyl-2-decalone (125) with excess m e t h y l l i t h i u m i n r e f l u x i n g ether provided a high y i e l d of a s e m i c r y s t a l l i n e m a t e r i a l , c o n s i s t i n g of a mixture of the epimeric t e r t i a r y a l c o h o l s 124. Dehydration of t h i s m a t e r i a l with a c a t a l y t i c amount of p_-toluenesulfonic a c i d i n r e f l u x i n g benzene produced 2,10-dimethyl-trans-2-octalin (125) (see r e f . 42). The l a t t e r was obtained as a c l e a r , c o l o r l e s s o i l and was shown by g . l . c . a n a l y s i s to be greater than 95% pure. Furthermore, the n.m.r. spectrum e x h i b i t e d only one o l e f i n i c proton s i g n a l , an unresolved m u l t i p l e t at x 4.72 with a h a l f - h e i g h t width of 8 Hz. This was c l e a r l y i n accord with the o c t a l i n s t r u c t u r e having the o l e f i n i c double bond at the 2 - p o s i t i o n . The o c t a l i n 125 was subjected to a modified o z o n o l y s i s r e a c t i o n (43) and the r e s u l t i n g crude keto aldehyde was immediately o x i d i z e d with Jones reagent (44). The keto a c i d thus obtained was e s t e r i f i e d with e t h e r e a l diazomethane, a f f o r d i n g an o v e r a l l 68% y i e l d (from the o c t a l i n 125) of the keto e s t e r 126. The keto e s t e r 126 was shown to be homogeneous by g . l . c . a n a l y s i s and a n.m.r. spectrum of the g . l . c . pure m a t e r i a l was i n complete accord wit h the assigned s t r u c t u r e . Thus, a s i n g l e t at x 6.34 could be - 46 -assigned to the methoxy group, whereas a s i n g l e t at x 7.73 was a t t r i b u t e d to the i s o l a t e d methylene a to the e s t e r . In a d d i t i o n two s i n g l e t s at x 7.85 and x 9.07 could be assigned to the a c e t y l methyl group and the t e r t i a r y methyl group, r e s p e c t i v e l y . In order to o b t a i n , from the keto e s t e r 126, a compound s u i t a b l e f o r appropriate comparison with the a l k y l a t i o n products(121 and/or 122) i t can r e a d i l y be seen that the a c e t i c e s t e r s i d e chain of 126 r e q u i r e d conversion to an i s o b u t y l - t y p e group, w h i l e the keto c o n t a i n i n g s i d e chain r e q u i r e d degradation to a methyl group. This was accomplished as f o l l o w s . B a e y e r - V i l l i g e r o x i d a t i o n of the keto e s t e r 126 with t r i f l u o r o -p e r a c e t i c a c i d i n dichloromethane i n the presence of disodium hydrogen phosphate (see r e f . 45) gave, i n 83% y i e l d , the d i e s t e r 127• I n t e r e s t i n g l y , the n.m.r. spectrum of t h i s compound e x h i b i t e d , i n a d d i t i o n to the expected s i g n a l s , a p a i r of quartets (AB of ABX system) between x 5.65 and x 6.32, r e a d i l y a t t r i b u t a b l e to the methylene protons on the carbon bearing the acetate group. However, the magnetic nonequivalence of methylene protons found i n an asymmetric environment i s a w e l l - e s t a b l i s h e d phenomenon (46), and t h i s t h e r e f o r e deserves no f u r t h e r comment. Reaction of the d i e s t e r 127 with excess r e f l u x i n g e t h e r e a l m e t h y l l i t h i u m afforded the d i o l 128 i n 97% y i e l d . Treatment of the l a t t e r w i t h a c a t a l y t i c amount of p_-toluenesulfonic a c i d i n r e f l u x i n g benzene, followed by c a r e f u l d i s t i l l a t i o n of the crude product afforded two major f r a c t i o n s . The lower b o i l i n g f r a c t i o n (44%, b.p. 64-66° at 0.1 mm) c o n s i s t e d of the c y c l i c ether 129. The sp e c t r a of a g . l . c . - 47 -129 133 Chart XVI - 48 -i s o l a t e d sample of t h i s material were i n complete accord with the assigned structure. Thus, the i n f r a r e d ( i . r . ) spectrum showed strong absorptions at 6.97, 7.30, 9.40, and 9.57_u; while i n the n.m.r. spectrum a broad peak at x 6.25-6.80 could be a t t r i b u t e d to the methylene protons a to the ether oxygen, and three three-proton s i n g l e t s at x 8.71, 8.81, and 4 8.97 were assigned to the three t e r t i a r y methyl groups. The higher b o i l i n g f r a c t i o n (46%, b.p. 104-108° at 0.1 mm) consisted of a mixture of the two o l e f i n i c alcohols 130. Hydrogenation of the l a t t e r over Adam's ca t a l y s t i n ethanol at room temperature and atmospheric pressure afforded the primary alcohol 131. The spectral properties of a g . l . c . i s o l a t e d sample of 131 were i n complete accord with the assigned struc-ture. Thus, the i . r . spectrum showed strong absorptions at 3.04, 6.90, and 9.83 y, while the n.m.r. spectrum displayed at x 6.12-6.88, a p a i r of overlapped quartets (AB of ABX system) due to the protons of the carbinol carbon. At x 9.07, a s i x proton doublet (J = 6.2 Hz) was assigned to the secondary methyls of the side chain, and a s i n g l e t appearing at x 9.22 was a t t r i b u t e d to the t e r t i a r y methyl group. This material was converted, by treatment with p_-toluenesulfonyl chloride i n pyridine at 0°, into the corresponding tosylate (152) and the crude material thus obtained was subjected to l i t h i u m aluminum hydride reduction i n r e f l u x i n g tetrahydrofuran. The product, cis-1,2-4 Although the formation of the c y c l i c ether 129 was not desired, i t s presence did not a f f e c t the outcome of the stereochemical proof. However, i t s formation could have been avoided by f i r s t forming the acetate of the primary alcohol of 128, followed by dehydration of the t e r t i a r y alcohol and removal of the acetate by treatment with base. Such a sequence would be the best a l t e r n a t i v e i f alcohols 130 were desired for synthetic purposes. - 49 -dimethyl-1-isobutylcyclohexane (153) was obtained i n 66% o v e r a l l y i e l d from the a l c o h o l 131, and e x h i b i t e d s p e c t r a l data i n complete accord w i t h the assigned s t r u c t u r e . When the major a l k y l a t i o n product 121 was subjected to successive c a t a l y t i c hydrogenation (ethanol, Adam's c a t a l y s t ) and Huang-Minion r e d u c t i o n (47) the corresponding hydrocarbon was obtained i n high y i e l d . The l a t t e r was shown to be i d e n t i c a l ( r e f r a c t i v e index, i n f r a r e d and n.m.r. s p e c t r a , g . l . c . r e t e n t i o n time) with c i s - l , 2 - d i m e t h y l - l - i s o -butylcyclohexane (133) obtained from a l c o h o l 131 as described above. This comparison unambiguously proved that the major a l k y l a t i o n product was, i n f a c t , the des i r e d cis-2,3-dimethyl-2-metha1ly1eyelohexanone (121). Having obtained a s u i t a b l e s y n t h e t i c intermediate with appropriate stereochemistry, i t became necessary at t h i s p o i n t , bearing i n mind the i n i t i a l l y proposed s y n t h e t i c approach, to convert the m e t h a l l y l group of 121 i n t o the methylpropenyl moiety. In t h i s connection i t had been found i n a model study (10,11) that 2-methyl-2-methallylcyclo-hexanone (134) was smoothly converted, by treatment w i t h p_-toluene-s u l f o n i c a c i d i n r e f l u x i n g benzene, i n t o a mixture c o n s i s t i n g mainly of the s t a r t i n g m a t e r i a l and 2-methyl-2-methylpropenylcyclohexanone (155) i n a r a t i o of approximately 1:3, r e s p e c t i v e l y . This procedure was there f o r e adopted i n the present work. - 50 -A s o l u t i o n of compound 121 i n benzene c o n t a i n i n g p - t o l u e n e s u l f o n i c a c i d was r e f l u x e d f o r three days and the r e a c t i o n mixture was then subjected to aqueous work-up. G.l.c. a n a l y s i s of the crude product showed t h a t i t c o n s i s t e d of a mixture, c o n t a i n i n g the s t a r t i n g m a t e r i a l 121 (approximately 12%), the d e s i r e d cyclohexanone d e r i v a t i v e 156 (46%), the c y c l i c hemiketal 137 (57%) and an u n i d e n t i f i e d compound ( 5 % ) . D i s t i l l a t i o n of t h i s m a t e r i a l (b.p. 66-68° at 2.8 mm) allowed the i s o l a t i o n (see Experimental) of a small amount of the c r y s t a l l i n e hemi-k e t a l 157, m.p. 74-74.5°. The i . r . spectrum of t h i s m a t e r i a l c l e a r l y showed the presence of a hydroxyl at 2.92 u, while i n the n.m.r. spectrum, one exchangeable proton at x 7.69, two protons as a s i n g l e t i i at x 8.14 (-C-CH -C- ), three three-proton s i n g l e t s at x 8.58, 8.65 and 9.06, and a three proton doublet at x 9.15 were i n f u l l accord with the assigned s t r u c t u r e . I t should be noted that the hemiketal 157, OH 138 when heated at temperatures greater than 120° r e a d i l y dehydrated to a f f o r d the corresponding c y c l i c enol ether 138 (see below) . When the bulk of the m a t e r i a l obtained from the above d i s t i l l a t i o n - 51 -was r e d i s t i l l e d , at 53 mm pressure, through a spinning band column, the i n i t i a l f r a c t i o n s c o n s i s t e d of a mixture of water and the enol ether 138 (the dehydration product of hemiketal 137) . The s t r u c t u r e assigned to compound 138, b.p. 128° at 53 mm, was f u l l y s u b s t a n t i a t e d by s p e c t r a l data. I t should be noted that t h i s compound was extremely s e n s i t i v e to moisture and, even upon exposure to the atmosphere, r e a d i l y hydrated to re-form the c r y s t a l l i n e hemiketal 157. A l a t e r f r a c t i o n from the above spinning-band d i s t i l l a t i o n con-s i s t e d of n e a r l y pure d e s i r e d cis-2,5-dimethyl-2-methylpropenylcyclo-hexanone 136, b.p. 143-144° at 53 mm. The i s o l a t e d y i e l d of t h i s compound was approximately 22% and thus, i n contrast to the equivalent r e a c t i o n i n the model study (10,11) the d i r e c t a c i d - c a t a l y z e d conversion of compound 121 i n t o compound 136 was not p a r t i c u l a r l y e f f i c i e n t . ^ The n.m.r. spectrum of compound 136, p a r t i c u l a r l y when compared with that of the s t a r t i n g m a t e r i a l 121, c l e a r l y showed that the carbon-carbon double bond had undergone the d e s i r e d m i g r a t i o n . Thus, while 121 e x h i b i t e d s i g n a l s f o r two o l e f i n i c protons ( T 5.17 and x 5.27) and one v i n y l methyl group (x 8.38), the isomerized m a t e r i a l 136 showed s i g n a l s f o r only one o l e f i n i c proton (x 4.59) and two v i n y l methyl groups (x 8.27 and x 8.57). I t was subsequently shown i n our l a b o r a t o r y (48) that the conversion of 121 i n t o 136 could be c a r r i e d out more e f f i c i e n t l y by use of a modified sequence i n which the keto group of 121 was f i r s t p r otected by formation of the corresponding ethylene k e t a l . Subsequent a c i d -c a t a l y z e d i s o m e r i z a t i o n of the carbon-carbon double bond, followed by removal of the k e t a l p r o t e c t i n g group (p_-toluenesulfonic a c i d i n r e f l u x i n g dry acetone) and separation of isomers allowed the i s o l a t i o n of cyclohexanone 136 i n 50% o v e r a l l y i e l d (from 121). Having obtained i n s u f f i c i e n t q u a n t i t y a cyclohexanone d e r i v a t i v e with the d e s i r e d f u n c t i o n a l i t y and stereochemistry, the keto group of 136 was used as a "handle" f o r the i n t r o d u c t i o n of the r e q u i r e d d i a z o -ketone-containing s i d e c hain. I n i t i a l l y considered f o r t h i s purpose was the r e a c t i o n of 136 w i t h the modified W i t t i g reagent, t r i e t h y l phosphonoacetate (49). However, t h i s r e a c t i o n proved very s l u g g i s h and even when c a r r i e d out at elevated temperatures, produced no u s e f u l r e s u l t . Since i t was f e l t t hat the f a i l u r e of t h i s r e a c t i o n was due, at l e a s t i n p a r t , to the s t e r i c a l l y hindered nature of the carbonyl group i n 136, i t was decided to attempt the use of a reagent which was s t e r i c a l l y l e s s demanding, namely, d i e t h y l cyanomethylphosphonate (49). This approach proved s u c c e s s f u l . Thus, r e a c t i o n of cyclohexanone 136 w i t h d i e t h y l cyanomethylphosphonate i n the presence of methyl-s u l f i n y l carbanion i n dimethyl s u l f o x i d e (50) at 100° f o r one hour, produced, In 87% y i e l d , a mixture of the a,p-unsaturated n i t r i l e 139 and the g,y-unsaturated n i t r i l e 140, i n a r a t i o of approximately 2:1, r e s p e c t i v e l y . ^ The f a c t that these compounds were isomeric was c l e a r l y 136 139 140 The r e l a t i v e amounts of these two isomers i n the product depended somewhat on the r e a c t i o n c o n d i t i o n s and r e a c t i o n time. - 53 -shown by the s p e c t r a l data. The a,g-unsaturated isomer 139 e x h i b i t e d a strong u l t r a v i o l e t absorption at 220 my (e = 12,300) and, i n the n.m.r. spectrum, showed a one-proton s i n g l e t at x 4.75 (=CHCN). The g,y-unsaturated isomer 140, on the other hand, gave no strong u l t r a v i o l e t a b s o r p t i o n and, i n the n.m.r. spectrum, e x h i b i t e d a broad one-proton s i g n a l at x 4.07 ( y - v i n y l H) and a two-proton m u l t i p l e t at x 7.01 (-CH^CN). Hy d r o l y s i s o f the mixture of n i t r i l e s (139 and 140) w i t h potassium hydroxide i n r e f l u x i n g aqueous ethanol a f f o r d e d , i n 82% y i e l d , the 0,y-unsaturated c a r b o x y l i c a c i d 141. That the double bond had now completely isomerized i n t o the B > Y _ P o s i ' t i o n w a s again c l e a r l y shown by the lack of an appropriate absorption i n the u l t r a v i o l e t and by the n.m.r. spectrum which showed, i n a d d i t i o n to a two-proton m u l t i p l e t at x 7.07 (-CH_C00H), the Y - v : L n y l proton as a po o r l y res o l v e d t r i p l e t 139 140 141 at x 4.35. Although the base-promoted e q u i l i b r a t i o n of ct,g- and g,y-unsaturated c a r b o x y l i c acids i s a well-known process (51), i t i s i n t e r e s t i n g that i n the present case the e q u i l i b r i u m l i e s completely on the side of the g,Y-unsaturated isomer. One of the major f a c t o r s (1 3) c o n t r i b u t i n g to t h i s phenomenon may w e l l be the A s t r a i n (52) which would be a s s o c i a t e d with the e x o c y c l i c double bond i n the,a,g-- 54 -unsaturated isomer 142, as shown i n conformations 142a and 142b. 141a 141b (I 2") Presumably t h i s i s more severe than the A ' s t r a i n (52) which i s i n h e r e n t l y present i n the (5,y-unsaturated isomer 141, as shown i n conformations 141a and 141b. The c a r b o x y l i c a c i d 141 was converted i n t o i t s sodium s a l t and the l a t t e r was reacted w i t h o x a l y l c h l o r i d e i n benzene at 0°. The crude a c i d c h l o r i d e 143 (X 5.62 u) thus obtained was, due to i t s A max y i n s t a b i l i t y , immediately converted, by r e a c t i o n w i t h dry e t h e r e a l - 55 -diazomethane, i n t o the corresponding diazoketone 144 (A "• 4.79, 6.15 y) . ' r . b A M A X The n.m.r. spectrum of the crude diazoketone i n d i c a t e d that during the sequence 141 -*• 145 -*• 144, the o l e f i n i c double bond had remained i n the 3,y- p o s i t i o n w i t h respect to the carbonyl group. This was of some importance s i n c e any m i g r a t i o n of the double bond i n t o conjugation with the carbonyl would undoubtedly have r e s u l t e d i n a la r g e predominance of the geometric isomer having the diazoketone moiety trans to the r i n g carbon bearing the methylpropenyl s u b s t i t u e n t , thus making the subsequent i n t r a m o l e c u l a r c y c l i z a t i o n (see below) of the diazoketone impossible. 141 145 144 When the crude diazoketone 144 was r e f l u x e d i n cyclohexane i n the presence of c u p r i c s u l f a t e (57) and the crude product d i s t i l l e d under - 56 -reduced pressure, a c l e a r o i l (70%, based on the c a r b o x y l i c a c i d 141) was obtained. This m a t e r i a l was shown by g . l . c . a n a l y s i s to c o n s i s t of approximately 42% ( + ) - a r i s t o l o n e ( 7 ) , 20% ( i ) - 6 , 7 - e p i - a r i s t o l o n e (145) and a number of minor u n i d e n t i f i e d components. P u r i f i c a t i o n of t h i s mixture by a combination of p r e p a r a t i v e t h i n l a y e r chromatography and p r e p a r a t i v e g . l . c . allowed the i s o l a t i o n of both of the major products. Thus, (±)-aristolone (7) was obtained as a c r y s t a l l i n e s o l i d which, upon r e c r y s t a l l i z a t i o n from petroleum ether, e x h i b i t e d m.p. 62-63°. This m a t e r i a l was shown to be i d e n t i c a l (m.p., mixed m.p., 7 i n f r a r e d and n.m.r. spectra) w i t h a r e c r y s t a l l i z e d ( petroleum ether) g 1:1 mixture of ( - ) - a r i s t o l o n e and a-ferulone [ ( + ) - a r i s t o l o n e ] (18). Thus, the n.m.r. spectrum of s y n t h e t i c a r i s t o l o n e (7_) (see f i g u r e 1) c l e a r l y showed the presence of an o l e f i n i c proton at x 4.28 as an unresolved m u l t i p l e t . Furthermore, at x 8.28, a p a i r of doublets (J = 8 and 1.2 Hz) could be a t t r i b u t e d to the c y c l o p r o p y l hydrogen at C and a f u r t h e r doublet at x 8.61 (J = 8 Hz) was assigned t o the c y c l o -p r o p y l proton at C^. The three t e r t i a r y methyl groups were c l e a r l y evident at x 8.74, x 8.80, and x 8.81, while the secondary methyl group appeared at x 8.93 (J = 6.5 Hz). (+)-6,7-Epi-aristolone (145) was obtained as an o i l . I t was shown to be isomeric with ( i ) - a r i s t o l o n e (7) by high r e s o l u t i o n mass spectrometry 7 For an a n a l y s i s of the n.m.r. spectrum of ( - ) - a r i s t o l o n e , see r e f . 53. 8 Generous samples of ( - ) - a r i s t o l o n e and a-ferulone were k i n d l y s u p p l i e d by P r o f e s s o r A. M a r s i l i , and a generous sample of (-)-a r i s t o l o n e was s u p p l i e d by Professor F. Sorm. - 58 -and gave s p e c t r a l data i n complete accord with the assigned s t r u c t u r e . Although c l e a r l y d i f f e r e n t from the n.m.r. spectrum of (+ ) - a r i s t o l o n e (7) > the n.m.r. spectrum of 145 (see f i g u r e 2) d i s p l a y e d s i m i l a r f e a t u r e s . Thus, the o l e f i n i c proton was c l e a r l y d i s c e r n a b l e as an unresolved m u l t i p l e t at T 4.24. At x 8.38 a p a i r of doublets (J = 8 and 1.1 Hz) could be a t t r i b u t e d to the c y c l o p r o p y l hydrogen, and a doublet at x 8.45 (J = 8 Hz) was assigned to the c y c l o p r o p y l hydrogen. The three t e r t i a r y methyl groups appeared as sharp s i n g l e t s at x 8.80, x 8.81, and x 8.84; while the secondary methyl group appeared as a doublet (J = 6.0 Hz) at x 9.02. - 60 -2. Stereochemical Proof of (t)-Aristolone The r e l a t i v e and absolute stereochemistry of a r i s t o l o n e (23,24,26,27) had been proposed (28) as shown i n formula 7_. However, even though two independent and e n t i r e l y d i f f e r e n t t o t a l syntheses of the racemic form of t h i s i n t e r e s t i n g n a t u r a l product had r e c e n t l y been reported (9, 54), the stereochemical proposal (28) had not as yet r e c e i v e d s y n t h e t i c v e r i f i c a t i o n , s i n c e both of the syntheses were ste r e o c h e m i c a l l y ambiguous. For example, i n the synthesis c a r r i e d out as described above (54), the key step i n v o l v e d the c u p r i c s u l f a t e c a t a l y z e d i n t r a -molecular c y c l i z a t i o n of the o l e f i n i c diazoketone 144. This r e a c t i o n was not completely s t e r e o s e l e c t i v e , s i n c e i t produced not only (±)-a r i s t o l o n e ( 7 ) , but a l s o the isomeric ( i ) - 6 , 7 - e p i - a r i s t o l o n e (145) . Therefore, although the stereochemistry of the c r u c i a l s y n t h e t i c i n t e r -mediate 144 was c l e a r l y and unambiguously determined (54), the above synthesis d i d not u n e q u i v o c a l l y e s t a b l i s h the t o t a l r e l a t i v e stereo-chemistry of a r i s t o l o n e (7). I t was t h e r e f o r e decided to o b t a i n d i r e c t - 61 -independent s y n t h e t i c evidence which would f u l l y corroborate the stereo-chemical assignment (28) of a r i s t o l o n e (7). P r e v i o u s l y , i n a model study (10,11) i t had been shown that (±)-4-demethylaristolone (17) (see Chart XVII) gave upon r e d u c t i o n w i t h l i t h i u m i n ammonia, a n e a r l y q u a n t i t a t i v e y i e l d of (i)-9,10-dihydro-4-demethyl-a r i s t o l o n e (146). The l a t t e r , when again subjected to lithium-ammonia r e d u c t i o n , afforded the s u b s t i t u t e d decalone 147. Furthermore i t had a l s o been shown (10,11) that the cuprous c h l o r i d e c a t a l y z e d conjugate a d d i t i o n of isopropenylmagnesium bromide to the octalone 148 gave, completely s t e r e o s e l e c t i v e l y , the decalone 149 which, upon hydrogenation, produced compound 147 i d e n t i c a l with that obtained from the l i t h i u m -ammonia re d u c t i o n o f 146. From the fore g o i n g , i t was c l e a r l y apparent that a s i m i l a r s e r i e s o f r e a c t i o n s i n v o l v i n g a r i s t o l o n e (7) and the octalone 92_ would provide unambiguous s y n t h e t i c proof f o r the r e l a t i v e stereochemistry of the n a t u r a l product. I t appeared h i g h l y u n l i k e l y that the presence of an ex t r a ( e q u a t o r i a l ) methyl group (7_ and 92_ as compared with 17_ and 148, r e s p e c t i v e l y ) would a l t e r the stereochemical outcome of e i t h e r the lithium-ammonia r e d u c t i o n (of 7) or the conjugate a d d i t i o n of i s o p r o p e n y l -magnesium bromide (to 92). The f i r s t s y n t h e t i c o b j e c t i v e , then, was the octalone 150 which 150 - 6 2 -Chart XVII - 63 -presumably could be r e a d i l y converted by standard r e a c t i o n s i n t o the r e q u i r e d isomeric compound 9_2. One obvious way to prepare 150 would be to c a r r y out the Robinson a n n e l a t i o n (55) of 2,3-dimethylcyclohexanone with methyl v i n y l ketone or i t s e q u i v a l e n t . In f a c t , Ourisson and co-workers (9) had already reported t h i s r e a c t i o n , although no y i e l d was given by these workers. When the Robinson a n n e l a t i o n of 2,3-dimethyl-cyclohexanone (86) with e i t h e r methyl v i n y l ketone or 4-diethylamino-2-butanone methiodide was attempted under a v a r i e t y of experimental c o n d i t i o n s the annelated m a t e r i a l was never obtained i n y i e l d s exceeding approximately 15%. Furthermore, the octalone which was obtained c o n s i s t e d , i n each case, of a mixture of two epimers i n a r a t i o of approximately 3:2, making i t extremely d i f f i c u l t to o b t a i n a reasonable q u a n t i t y of the d e s i r e d octalone 150 i n a pure s t a t e . Therefore, s i n c e the Robinson a n n e l a t i o n d i d not appear to be a p a r t i c u l a r l y e f f i c i e n t method f o r the p r e p a r a t i o n of 150 a l t e r n a t i v e routes t o t h i s compound were considered. During work on the t o t a l s ynthesis of ( i ) - a r i s t o l o n e (54), i t had been shown that the a l k y l a t i o n of 2,3-dimethyl-6-n-butylthiomethylene-cyclohexanone (119) w i t h m e t h a l l y l c h l o r i d e produced i n high y i e l d , a mixture of c i s - (151) and t r a n s - 2 , 3 - d i m e t h y l - 2 - m e t h a l l y l - 6 - n - b u t y l t h i o -methylenecyclohexanone (152), i n a r a t i o of approximately 4:1, r e s p e c t i v e l y . - 64 -The f a i r l y high s t e r e o s e l e c t i v i t y of t h i s process i n s p i r e d the con-s i d e r a t i o n of an a l t e r n a t e p r e p a r a t i o n of 150 which was based upon a l k y l a t i o n of 119. This approach proved to be very s a t i s f a c t o r y . A l k y l a t i o n of compound 119 (see Chart XVIII) with e t h y l 3-bromo-propionate i n the presence of potassium t_-butoxide i n t - b u t y l a l c o h o l (39) proved to be a very f a c i l e r e a c t i o n and produced, i n 85% y i e l d , a mixture of the keto e s t e r s 153. Removal of the n-butylthiomethylene b l o c k i n g group from the l a t t e r was accomplished i n the normal way (39) (potassium hydroxide i n hot aqueous di e t h y l e n e g l y c o l ) and was accompanied by h y d r o l y s i s of the ester group. The product, a mixture of keto acids 154, was obtained i n 90% y i e l d . When the mixture of keto acids 154 was r e f l u x e d i n a c e t i c anhydride c o n t a i n i n g sodium acetate (see r e f . 56), there was produced, i n 85% y i e l d , a c r y s t a l l i n e m a t e r i a l which c o n s i s t e d of a mixture of the two epimeric enol lactones 155 and 156. The r a t i o of the two epimers, as judged by the n.m.r. spectrum of the mixture, was approximately 9:1, r e s p e c t i v e l y . The major, d e s i r e d epimer 155 could r e a d i l y be obtained i n 80% y i e l d from the mixture 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. An a n a l y t i c a l sample of t h i s m a t e r i a l e x h i b i t e d s p e c t r a l data i n complete accord w i t h the assigned s t r u c t u r e . In p a r t i c u l a r , i n the n.m.r. spectrum of 155, the o l e f i n i c proton was c l e a r l y evident as a t r i p l e t ( J = 3.5 Hz) at x 4.72. The t e r t i a r y methyl group was apparent at T 8.97 while a doublet ( J = 6.0 Hz) at x 9.04 could be assigned to the secondary methyl group. An a n a l y t i c a l sample of the trans isomer 156 was obtained from the - 65 -154 155 156 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 by means of p r e p a r a t i v e g . l . c . and remained as an o i l . The n.m.r. spectrum of pure 156 showed the presence o f an o l e f i n i c proton at x 4.68 as a t r i p l e t (J = 4.0 Hz), while a s i n g l e t at x 8.79 and a doublet (J = 6.5 Hz) at x 9.04 could be assigned to the t e r t i a r y and secondary methyl groups r e s p e c t i v e l y . Although, i n order to convert the enol lactone 155 i n t o the r e q u i r e d octalone 150, the use of a number of d i f f e r e n t reagents was i n v e s t i g a t e d , ^ i t was e v e n t u a l l y found that m e t h y l l i t h i u m was the most convenient and gave the most c o n s i s t e n t r e s u l t s . Thus, r e a c t i o n of 155 with m e t h y l l i t h i u m i n dry ether at -25° f o r 1.75 h, followed by successive a c i d i c h y d r o l y s i s and base-catalyzed a l d o l c y c l i z a t i o n a f f o r d e d , i n a d d i t i o n to a small amount (10%) of s t a r t i n g m a t e r i a l ( i n the form of the keto a c i d 154, c i s epimer) a 70% y i e l d of the d e s i r e d octalone. A pure sample of t h i s m a t e r i a l 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 was the u l t r a v i o l e t spectrum, which e x h i b i t e d a maximum at 9 For previous examples of ann e l a t i o n v i a enol l a c t o n e s , see r e f s . 57-61 i n c l u s i v e . Chart XVIII - 67 -240 my, and the n.m.r. spectrum which showed the o l e f i n i c proton as a broad s i n g l e t at x 4.33. In a d d i t i o n a sharp s i n g l e t at x 8.90 and an unresolved m u l t i p l e t ^ at x 9.09vcould be assigned to the t e r t i a r y and secondary methyl groups, r e s p e c t i v e l y . The o v e r a l l y i e l d o f pure octalone 150, based on 2,3-dimethylcyclohexanone, was, t h e r e f o r e , approximately 30%, o b v i o u s l y a considerable improvement over the Robinson a n n e l a t i o n method. I t should be noted that the success of the r e a c t i o n of the enol lactone 155 with m e t h y l l i t h i u m depended, to a l a r g e extent, upon a j u d i c i o u s choice of the r e a c t i o n temperature and r e a c t i o n time. That i s , use of r e a c t i o n temperatures greater than -25°, or use of longer r e a c t i o n times, r e s u l t e d i n the formation of a considerable amount of a l c o h o l - c o n t a i n i n g product, presumably due to " d i - a d d i t i o n " of methyl-l i t h i u m to the enol lactone. On the other hand, m i l d e r r e a c t i o n condi-t i o n s (lower temperatures, shorter r e a c t i o n times) r e s u l t e d i n the recovery of f a i r l y copious amounts of s t a r t i n g m a t e r i a l , i n the form of the corresponding keto a c i d (154, c i s epimer). Reduction of the octalone 150 with l i t h i u m i n ammonia i n the presence of ethanol (see r e f . 41) gave, i n 75% y i e l d , the d e c a l o l 157 which, upon o x i d a t i o n w i t h Jones reagent (44) gave the decalone 158. The l a t t e r e x h i b i t e d i n f r a r e d spectrum and g a s - l i q u i d chromatographic r e t e n t i o n times i d e n t i c a l w i t h those of the (+)-antipode of 158, which In the n.m.r. spectrum of each of the compounds 91, 92, 150, 157 and 158, 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 . Presumably, t h i s was due to v i r t u a l coupling (see r e f . 62). - 68 -had p r e v i o u s l y been prepared, v i a a lengthy s y n t h e t i c sequence, by D j e r a s s i arid co-workers ( 6 3 ) . ^ This comparison c o n c l u s i v e l y showed that the i n i t i a l a l k y l a t i o n of compound 119 with g-bromopropionate had been s t e r e o s e l e c t i v e i n the d e s i r e d sense and t h a t , t h e r e f o r e , the s y n t h e t i c intermediates indeed possessed a c i s stereochemistry with respect to the two methyl groups. Bromination of the decalone 158 with bromine i n a c e t i c a c i d (64) affor d e d the known (9) bromo ketone 91_. Dehydrobromination of the l a t t e r with a mixture of l i t h i u m bromide and l i t h i u m carbonate i n hot dimethyl-formamide (65) gave, i n 86% y i e l d , a mixture of compounds which contained, i n a d d i t i o n to a number of minor components, the d e s i r e d octalone 92_ as the major (80%) c o n s t i t u e n t . This m a t e r i a l was i s o l a t e d from the mixture by means of p r e p a r a t i v e g . l . c , and 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 pertinence was the u l t r a v i o l e t spectrum, which e x h i b i t e d a maximum at 230 my, and the n.m.r. spectrum, which showed the v i n y l protons as an AB p a i r of doublets (J = 10 Hz) at x 2.88 and x 4.11. When the octalone 92 was reacted with isopropenylmagnesium bromide i n the presence of cuprous c h l o r i d e i n t e t r a h y d r o f u r a n (11) , the decalone 159 was produced as the only conjugate a d d i t i o n product. Hydrogenation of 159 over Adam's c a t a l y s t a f f o r d e d the racemic decalone 160, which was subsequently shown to be i d e n t i c a l ( i n f r a r e d and n.m.r. s p e c t r a , and g . l . c . r e t e n t i o n times) with the l e v o r o t a t o r y decalone 160 obtained from ^ A small sample of t h i s compound was k i n d l y provided by Professor C. Dj e r a s s i . - 69 -the lithium-ammonia r e d u c t i o n of (+)-9,10-dihydroaristolone (53). The n.m.r. spectrum (see f i g u r e 3) of racemic decalone 160 was i n complete accord w i t h the assigned s t r u c t u r e . Thus, the t e r t i a r y methyl appeared as a sharp s i n g l e t at x 9.02, while the three secondary methyl groups gave r i s e to two doublets at x 9.06 and x 9.07 (J = 6.8 Hz) which i n t e g r a t e d f o r three protons and s i x protons r e s p e c t i v e l y . The stereochemical outcome of the above conjugate a d d i t i o n r e a c t i o n r e q u i r e s comment. In t h i s connection, i t i s important to take note of the elegant work of M a r s h a l l and Andersen (66) who s t u d i e d the c u p r i c acetate c a t a l y z e d conjugate a d d i t i o n of various Grignard reagents to 1,1-dimethy1-trans-3-octal-2-one (161). B r i e f l y , these workers proposed that the conjugate i n t r o d u c t i o n of a Grignard reagent to octalones of the type 161 (or 92) must, f o r s t e r e o e l e c t r o n i c reasons, take place v i a one (or both) of the two t r a n s i t i o n s t a t e s A or B_. In p a r t i c u l a r , they found t h a t , i n the absence of any large s t e r i c f a c t o r s , the c h a i r -l i k e t r a n s i t i o n s t a t e A was favored over" the b o a t - l i k e t r a n s i t i o n s t a t e B_. Thus the c u p r i c acetate c a t a l y z e d a d d i t i o n of methylmagnesium i o d i d e to 161 produced compound 162 as the major conjugate a d d i t i o n product, with 163 being formed i n minor amounts. However, as the s t e r i c bulk of the Grignard reagent was i n c r e a s e d , s t e r i c hindrance to a x i a l attack ( t r a n s i t i o n s t a t e A) a l s o increased and, w i t h phenylmagnesium bromide, the only product formed ( v i a t r a n s i t i o n s t a t e B) was 164. F i n a l l y , i n the case of isopropylmagnesium bromide, s t e r i c hindrance to a x i a l approach was approximately balanced by the unfavorable nature of the b o a t - l i k e t r a n s i t i o n s t a t e B_, and the two products 165 and 166 were formed i n n e a r l y equal amounts. Figure 3. N.M.R. Spectrum of (±).-Compound 160. - 71 -163 R=CH3, R1=H, R 2 = C H 3 164 R=C 6H 5, R1=H, R 2=CH 3 166 R=CH(CH 3) 2, R1=H, R 2=CH 3 I f one now considers the conjugate a d d i t i o n of isopropenylmagnesium bromide to the octalone 92_, i t i s immediately obvious that the important f a c t o r i n t h i s case i s the presence of the angular methyl group. Molecular models show that i f s t e r e o e l e c t r o n i c c o n t r o l i s to be maintained i n the b o a t - l i k e t r a n s i t i o n s t a t e j}, then the incoming Grignard reagent must - 72 -approach the molecule i n such a way that i t i s n e a r l y e c l i p s e d with the angular methyl group. The r e s u l t i n g s t e r i c s t r a i n and t o r s i o n a l s t r a i n (67,68) should o v e r r i d e the s t e r i c hindrance present i n t r a n s i t i o n s t a t e A and should ensure that the l a t t e r i s favored over t r a n s i t i o n s t a t e B_. Therefore, even though M a r s h a l l and Andersen (66) found that the conjugate a d d i t i o n of isopropylmagnesium bromide to octalone 161 gave approximately equal amounts of the two epimers 165 and 166, i t was f u l l y expected that the cuprous c h l o r i d e c a t a l y z e d 1,4-addition of isopropenylmagnesium bromide to octalone 9_2_ would be h i g h l y stereo-s e l e c t i v e and, that the product should possess the stereochemistry depicted i n 159. In t h i s connection, i t had been shown (10,11) that t h i s p r e d i c t i o n was c o r r e c t i n the case of the cuprous c h l o r i d e c a t a l y z e d a d d i t i o n of isopropenylmagnesium bromide to octalone 148, which produced decalone 149 as the only 1,4-addition product. H H Lithium-ammonia r e d u c t i o n of ( - ) - a r i s t o l o n e (7) gave, i n high y i e l d , (+)-9,10-dihydroaristolone (53) . The l a t t e r gave an u l t r a v i o l e t a bsorption maximum at 213 my (see r e f . 69) and, i n the n.m.r. spectrum, showed no s i g n a l due to a v i n y l proton, thus c l e a r l y demonstrating that only the double bond had been reduced. - 7 3 -7 53 I t had been shown by Dauben and co-workers (70) that i n the l i t h i u m -ammonia r e d u c t i o n of c y c l o p r o p y l conjugated ketones, the c y c l o p r o p y l bond which i s cleaved i s g e n e r a l l y that which possesses the maximum over-lap with the T T - o r b i t a l system of the carbonyl group. Thus these workers found t h a t i n the lithium-ammonia r e d u c t i o n of (+)-carone (167), the product mixture c o n s i s t e d e n t i r e l y of (-)-carvomenthone (168) and (-)-isocarvomenthone (169) . Owing to the geometry of the r i n g system of 167, 168 169 the i n t e r n a l C^-C^ bond does not overlap to any great extent with the -rr-system of the carbonyl group, whereas the e x t e r n a l C^-C^ bond i s so placed to permit e x c e l l e n t overlap. Therefore, even though the formation - 74 -of a secondary carbanion (C^-C^ cleavage) should be favored thermodynamically, the t e r t i a r y carbanion (C^-C^ cleavage) i s the s o l e route to products. Consequently, i n the present case i t seemed reasonable to p r e d i c t that cleavage of the C_,-C^ bond of (+) - d i h y d r o a r i s t o l o n e (53) should be the predominant i f not only pathway to product formation. When compound 5_3 was reduced w i t h l i t h i u m i n ammonia, the expected l e v o r o t a t o r y decalone 160 was obtained i n v i r t u a l l y q u a n t i t a t i v e y i e l d . This compound gave spec t r a [ i n f r a r e d , n.m.r. (see f i g u r e 4)] and g a s - l i q u i d chromatographic r e t e n t i o n times i d e n t i c a l w i t h those of the racemic decalone 160 obtained as o u t l i n e d above (see f i g u r e 3 f o r the n.m.r. spectrum of racemic 160). Since by analogy with previous work (11) , the stereochemistry of racemic 160 was completely d e f i n e d , t h i s comparison provided unambi-quous s y n t h e t i c evidence f o r the stereochemistry of a r i s t o l o n e (7). 10T Figure 4. N.M.R. Spectrum of (-)-Compound 160• EXPERIMENTAL I M e l t i n g p o i n t s , which were determined on a K o f l e r b l o c k , and b o i l i n g p o i n t s are uncorrected. U l t r a v i o l e t spectra were, unless otherwise noted, measured i n methanol s o l u t i o n on e i t h e r a Cary, model 14, or a Unicam, model SP. 800, spectrophotometer. Routine i n f r a r e d s p e c t r a were recorded on a Perkin-Elmer I n f r a c o r d model 137 spectrophotometer, while a l l comparison spectra were recorded on a Perkin-Elmer model 421 spectrophotometer. N.m.r. spec t r a were taken i n deuterochloroform s o l u t i o n on V a r i a n Associates spectrometers, models T-60, A-60 and/or model HA-100. Line p o s i t i o n s are given i n the T i e r s T s c a l e , w i t h t e t r a m e t h y l s i l a n e as an i n t e r n a l standard; the m u l t i p l i -c i t y , i n t e g r a t e d peak areas, and proton assignments are i n d i c a t e d i n parentheses. G a s - l i q u i d chromatography ( g . l . c . ) was c a r r i e d out on an Aerograph Autoprep, model 700. The f o l l o w i n g columns (10 f t x 1/4 i n , unless otherwise noted) were employed, with the i n e r t , supporting m a t e r i a l being 60/80 mesh Chromosorb W i n each case: column A, 20% FFAP; column B (10 f t x 3/8 i n ) , 30% FFAP; column C, 15% QF-1; column D, 3% SE-30; column E, 20% SE-30; column F (10 f t x 3/8 i n ) , 30% Apiezon J; column G, 10% Apiezon J; column H, 10% FFAP; column I (20 f t x 3/8 i n ) , 30% SE-30; column J (10 f t x 3/8 i n ) , 30% Carbowax 20 M; column K (30 f t x 3/8 i n ) , 30% Zonyl E-7; column L, 20% Carbowax 20 M. The s p e c i f i c - 77 -column used, along with column temperature and carrier gas (helium) flow-r a t e ( i n ml/min), are i n d i c a t e d i n parentheses. Microanalyses were performed by Mr. P. Borda, M i c r o a n a l y t i c a l Laboratory, U n i v e r s i t y of B r i t i s h Columbia, Vancouver. 6-Hydroxymethylene-2,3-dimethylcyclohexanone (118) To an i c e - c o o l e d , s t i r r e d suspension of powdered sodium methoxide 78 g, 1.44 moles) i n 800 ml of dry benzene, kept under an atmosphere of dry n i t r o g e n , was added 71 g (0.564 mole) of 2,3-dimethylcyclohexanone (86). The r e s u l t i n g mixture was s t i r r e d f o r 10 min, and then 70 g (0.945 mole) of e t h y l formate (117) was added. The mixture was warmed to room temperature and allowed to stand overnight. Water was added, the mixture was thoroughly shaken, and the l a y e r s separated. The organic l a y e r was e x t r a c t e d w i t h two p o r t i o n s of 10% aqueous sodium hydroxide. The combined aqueous l a y e r and a l k a l i n e e x t r a c t s were cooled, a c i d i f i e d w i t h 6 N h y d r o c h l o r i c a c i d and thoroughly e x t r a c t e d with ether. The combined e x t r a c t s were washed with water and d r i e d over anhydrous magnesium s u l f a t e . Removal of the s o l v e n t , 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 under reduced pressure, gave 77.5 g (90%) of the hydroxymethylene d e r i v a t i v e 118 as a pale yellow o i l , b.p. 60-63° at 20 2 mm, n n 1.5135. U l t r a v i o l e t ; X 281 my, A (NaOH added) 316 my; ' D max max ^ J i n f r a r e d ( f i l m ) , ^ m a x 6.05, 6.25 y. The i n s t a b i l i t y of t h i s compound precluded the a c q u i s i t i o n of s a t i s f a c t o r y a n a l y t i c a l data. - 78 -6-n-Butylthiomethylene-2,3-dimethylcyclohexanone (119) A s o l u t i o n of the hydroxymethylene d e r i v a t i v e (118) (77.5 g, 0.504 mole), n-butyl mercaptan (55.5 g, 0.615 mole), and p_-toluenesulfonic a c i d (50 mg) i n 500 ml of dry benzene was r e f l u x e d i n a n i t r o g e n atmosphere under a Dean-Stark water separator f o r 6 h, at which time 6 ml of water had been c o l l e c t e d . The cooled s o l u t i o n was washed w i t h saturated aqueous sodium bicarbonate, then with water and f i n a l l y d r i e d 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 99.4 g (87%) of the 20 n-butylthiomethylene d e r i v a t i v e (119), b.p. 116-118° at 0.3 mm, n Q 1.5368. U l t r a v i o l e t , X 309 my (e = 15,400); i n f r a r e d ( f i l m ) , X 6.01, 6.48 u. ITlclX IflcLX Anal. Calcd. f o r C^H^OS: C, 68.97; H, 9.79. Found: C, 68.59; H, 9.71. 2,3-Dimethyl-2-methallyl-6-n-butylthiomethylenecyclohexanone (120) The n-butylthiomethylene d e r i v a t i v e (119) (99.4 g, 0.440 mole) was added t o 1800 ml of dry t_-butanol c o n t a i n i n g 144 g (1.40 moles) potassium t^butoxide 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 f o r 10 min and then cooled to 0°. Fr e s h l y d i s t i l l e d m e t h a l l y l c h l o r i d e (255 g, 2.82 moles) was added slowly and the r e a c t i o n mixture was r e f l u x e d under an atmosphere of dry n i t r o g e n f o r 2 h. Most of the solvent was removed under reduced pressure and the residue was d i l u t e d w i t h water. The r e s u l t i n g mixture was ext r a c t e d t h r i c e w i t h ether. The combined ether e x t r a c t s were washed with water and d r i e d over anhydrous magnesium s u l f a t e . Removal of the solvent gave an o i l , which, - 79 -upon d i s t i l l a t i o n under reduced pressure, a f f o r d e d 107 g (87%) of 2,3-dimethyl-2-methallyl-6-n-butylthiomethylenecyclohexanone (120) 20 (mixture of epimers), b.p. 106-109° at 0.25 mm, n Q 1.5043. U l t r a -v i o l e t , x 281 my ( e = 14,700); i n f r a r e d ( f i l m ) , \ 6.00, 6.32, n i c t x n i c i x 11.10 y. Anal. Calcd. f o r C^H o o0S: C, 72.80; H, 10.06. Found: C, 73.09; 1 / lo H, 10.11. c i s - and trans-2,3-Dimethyl-2-methallylcyclohexanone (121 and 122) To a s o l u t i o n of the above a l k y l a t e d m a t e r i a l (120) (107 g) i n 700 ml of d i e t h y l e n e g l y c o l was added 650 ml of 25% aqueous potassium hydroxide and the r e s u l t i n g s o l u t i o n was r e f l u x e d under n i t r o g e n f o r 18 h. The r e a c t i o n mixture was steam d i s t i l l e d u n t i l the d i s t i l l a t e was c l e a r . The d i s t i l l a t e was saturated with s a l t and extracted t h r i c e w i t h ether. The combined ether e x t r a c t s were washed with water, d r i e d (anhydrous magnesium s u l f a t e ) , and evaporated. The r e s i d u a l o i l , upon d i s t i l l a t i o n under reduced pressure, gave 66 g (96%) of a mixture of c i s - and trans-2,3-dimethyl-2-methallylcyclohexanone (121 and 122), b.p. 76-80° at 3.6 mm. A n a l y s i s of t h i s mixture by g . l . c . (column A, 140°, 85) i n d i c a t e d that the r a t i o of the c i s compound (121) to the trans compound (122) was approximately 4:1. An a n a l y t i c a l sample of each epimer was obtained by p r e p a r a t i v e g . l . c . (column B, 250°, 120). 20 The d e s i r e d c i s epimer (121) e x h i b i t e d n D 1.4809. I n f r a r e d ( f i l m ) , \ 5.89, 6.13, 11.25 u ; n.m.r., x 5.17, 5.27 (unresolved m u l t i p l e t s , max 2H, =CH 2), 7.33, 7.84 (broadened AB-type p a i r of doublets, 2H, v i n y l -CH„, J = 14 Hz), 8.38 (broad s i n g l e t , 3H, v i n y l methyl), 9.13 ( s i n g l e t , - 80 -3H, t e r t i a r y methyl), 9.28 (doublet, 3H, secondary methyl, J = 6.5 Hz). Anal. Calcd. f o r Culi200: C, 80.01; H, 11.11. Found: C, 79.78; H, 11.31. 20 The trans epimer (122) e x h i b i t e d n„ 1.4812. I n f r a r e d ( f i l m ) , A r v 1 D J max 5.88, 6.11, 11.28 IJ; n.m.r., T 5.22, 5.32 (unresolved m u l t i p l e t s , 2H, =CH 2), 7.62, 8.04 (broadened AB-type p a i r of doublets, 2H, v i n y l . - C H 2 , J = 14 Hz), 8.42 (broad s i n g l e t , 3H, v i n y l methyl), 8.84 ( s i n g l e t , 3H, t e r t i a r y methyl), 9.27 (doublet, 3H, secondary methyl, J =6.5 Hz). Anal. Calcd. f o r C 1 2H 0: C, 80.01; H, 11.11. Found: C, 79.78; H, 11.27. 2,10-Dimethyl-trans-2-octalin (125) To-a s o l u t i o n of trans-10-methyl-2-decalone (41) (123, 44.5 g, 0.236 mole) i n 1 1 of dry ether was added 9 g (0.41 mole) of methyl-l i t h i u m i n 200 ml of ether. The s o l u t i o n was r e f l u x e d f o r 8 h, cooled, and the excess m e t h y l l i t h i u m was destroyed by c a r e f u l a d d i t i o n of d i l u t e h y d r o c h l o r i c a c i d . The ether l a y e r was washed with water, d r i e d (anhydrous magnesium s u l f a t e ) , and evaporated. D i s t i l l a t i o n of the r e s i d u a l m a t e r i a l under reduced pressure gave 42.7 g (88%) of a mixture of epimeric a l c o h o l s (124) as a s e m i - c r y s t a l l i n e mass, b.p. 62-67° at 0.2 mm. This m a t e r i a l was not f u r t h e r p u r i f i e d , but was used d i r e c t l y f o r the,next step. A s o l u t i o n of the above mixture of a l c o h o l s (124) (2.0 g) and p_-toluene-s u l f o n i c a c i d (25 mg) i n 25 ml of dry benzene was r e f l u x e d under a Dean-Stark water separator u n t i l the required amount of water had been c o l l e c t e d . The s o l u t i o n was cooled, washed with d i l u t e aqueous sodium hydroxide and evaporated. 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 1.15 g (70%) of 2,10-dimethyl-trans-2-octalin (125) as a c l e a r c o l o r l e s s o i l , b.p. 91-93° at 11 mm. G.l.c. a n a l y s i s (column C, 170°, 85) i n d i c a t e d that t h i s m a t e r i a l was greater than 95% pure. An a n a l y t i c a l sample, 20 c o l l e c t e d by p r e p a r a t i v e g . l . c . (column C, 150°, 85) e x h i b i t e d n^ 1.4873. i n f r a r e d ( f i l m ) , X 6.94, 7.33, 12.73 y; n.m.r. T 4.72 ^ • max ' ^ (unresolved m u l t i p l e t , 1 H, o l e f i n i c proton, width at h a l f - h e i g h t = 8 Hz), 8.37 (broad s i n g l e t , 3H, v i n y l methyl), 9.23 ( s i n g l e t , 3H, t e r t i a r y methyl). Anal. Calcd. f o r C 1 2 H 2 : C, 87.73; H, 12.27. Found: C, 87.58; H, 12.40. Preparation of Keto Est e r 126 A s o l u t i o n of the o c t a l i n 125 (19.6 g, 0.12 mole) i n 1 1 of dry methanol was cooled by means of a dry ice-acetone bath. Ozone was bubbled through the s o l u t i o n u n t i l a permanent blue c o l o r p e r s i s t e d , and then continued f o r an a d d i t i o n a l 15 min. Dimethyl s u l f i d e (11.9 ml, 0.162 mole) was added and the s o l u t i o n was allowed to warm to room temperature. The methanol and excess dimethyl s u l f i d e were removed under reduced pressure and the residue was taken up i n ether. The ether s o l u t i o n was washed with water, d r i e d (anhydrous magnesium s u l f a t e ) and evaporated. The r e s i d u a l crude keto aldehyde was immediately o x i d i z e d with Jones reagent (44) (30 ml) and, a f t e r the normal work-up, afforded 22.7 g of the corresponding keto a c i d . Treatment of the l a t t e r crude m a t e r i a l - 82 -w i t h excess e t h e r e a l diazomethane, followed by removal of the ether and d i s t i l l a t i o n of the r e s i d u a l o i l , gave 18.2 g (68%) of the d e s i r e d keto e s t e r (126), b.p. 85-85.5° at 0.1 mm. An a n a l y t i c a l sample 20 i s o l a t e d by p r e p a r a t i v e g . l . c . (column D, 160°, 80) showed n^ 1.4712. I n f r a r e d ( f i l m ) , X 5.83, 6.97, 9.83 u; n.m.r., T 6.34 ( s i n g l e t , 3H, TTlcLX -C00CH 3J, 7.73 ( s i n g l e t , 2H, -CH2COOCH3), 7.85 ( s i n g l e t , 3H, -C0CH 3), 9.07 ( s i n g l e t , 3H, t e r t i a r y methyl). Anal. Calcd. f o r C 1 3 H 2 2 0 3 : C, 68.99; H, 9.79. Found: C, 69.30; H, 10.01. The 2,4-dinitrophenylhydrazone d e r i v a t i v e of the e s t e r 126 e x h i b i t e d m.p. 111-112°. Anal. Calcd. f o r C i nH_N.O,: C, 56.15; H, 6.44; N, 13.78. Found: i y ZD 4 O C, 55.85; H, 6.65; N, 13.61. Prep a r a t i o n of D i e s t e r 127 To a s o l u t i o n of the keto e s t e r 126 (18.2 g, 85 mmoles) i n 1.7 1 of dichloromethane was added 220 g of anhydrous disodium hydrogen phosphate. The r e s u l t i n g mixture was s t i r r e d v i g o r o u s l y and a s o l u t i o n of t r i f l u o r o p e r a c e t i c a c i d (prepared by adding 13.5 ml of 90% hydrogen peroxide to 86.5 ml of t r i f l u o r o a c e t i c anhydride i n 42 ml of d i c h l o r o -methane) was added. The mixture was s t i r r e d at room temperature f o r I. 5 h and then at r e f l u x f o r 3.5 h. E t h y l acetate (500 ml) was added and the mixture was washed with saturated aqueous sodium bicarbonate, water, saturated b r i n e , and then d r i e d over anhydrous magnesium s u l f a t e . Removal of the s o l v e n t s , f ollowed 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 - 83 -afforded 16.2 g (83%) of the d i e s t e r 127, b.p. 96-102° at 0.1 mm. An a n a l y t i c a l sample, c o l l e c t e d by p r e p a r a t i v e g . l . c . (column D, 190°, 90), 20 e x h i b i t e d nfr 1.4658. I n f r a r e d ( f i l m ) , X 5.77, 6.97, 9.71 y ; n.m.r., D max K x 5.65-6.32 ( p a i r of q u a r t e t s , 2H, -CH_2-0Ac, AB of ABX system), 6.35 ( s i n g l e t , 3H, -C00CH 3), 7.64 ( s i n g l e t , 2H, CH 2C00CH 3), 7.96 ( s i n g l e t , 3H, -0C0CH 3), 9.03 ( s i n g l e t , 3H, t e r t i a r y methyl). Anal. Calcd. for 'C13H 0 : C, 64.43; H, 9.14. Found: C, 64.28; H, 9.23. P r e p a r a t i o n of D i o l 128 To a s o l u t i o n of the d i e s t e r 127 (15.8 g, 65.5 mmoles) i n 250 ml of dry ether was added 300 ml of 1.7 M m e t h y l l i t h i u m i n ether. The s o l u t i o n was r e f l u x e d overnight, cooled and quenched by c a r e f u l a d d i t i o n of water. The ether s o l u t i o n was d r i e d over anhydrous magnesium s u l f a t e . Removal of the ether and d i s t i l l a t i o n of the r e s i d u a l o i l provided 12.6 g (97%) of the d i o l 128, b.p. 109-110° at 0.15 mm. I n f r a r e d ( f i l m ) , 3.08, 6.89, 9.80 u; n.m.r., x 6.17-6.83 ( p a i r of q u a r t e t s , 2H, -CH_20H, AB of ABX system), 6.65 ( s i n g l e t , 2H, 2-0-H), 8.15, 8.54 (doublets, 2H, OH OH -CH 2-C(CH 3) 2, AB system, J = 15 Hz), 8.64, 8.76 ( s i n g l e t s , 6H, -C(CH_ 3) 2), 9.12 ( s i n g l e t , 3H, t e r t i a r y methyl). Due to the ease with which t h i s compound dehydrated, i t was v i r t u a l l y impossible to o b t a i n pure d i o l which was not contaminated w i t h small amounts of i t s dehydration products. S a t i s f a c t o r y a n a l y t i c a l data were t h e r e f o r e not obtained. - 84 -Dehydration of D i o l 128 A s o l u t i o n of the d i o l 128 (5.0 g) i n 250 ml of dry benzene con-ta i n i n g 50 mg of p_-toluene s u l f o n i c acid was refluxed under a Dean-Stark water separator f o r 4 h, at which time the required amount of water had been c o l l e c t e d . The s o l u t i o n was cooled, washed with d i l u t e aqueous sodium bicarbonate, and dried over anhydrous magnesium s u l f a t e . Removal of the benzene gave an o i l , which, upon d i s t i l l a t i o n gave two d i s t i n c t f r a c t i o n s . The f i r s t f r a c t i o n (2.0 g, 44%, b.p. 64-66° at 0.1 mm) was shown by g . l . c . analysis (column E, 135°, 100) to consist of nearly pure c y c l i c ether 129. An a n a l y t i c a l sample was c o l l e c t e d by 20 preparative g . l . c . (column F, 230°, 150), and exhibited n Q 1.4747. Infrared ( f i l m ) , X 6.97, 7.30, 9.40, 9.57 y; n.m.r., T 6.25-6.80 lTlcLX ( d i f f u s e , 2H, -CH -0-, overlapped AB of ABX system), 8.71, 8.81, 8.97 ( s i n g l e t s , 9H, t e r t i a r y methyls). Anal. Calcd. f o r C 1 2H 2 20: C, 79.07; H, 12.15. Found: C, 79.19; H, 12.17. The second f r a c t i o n (2.1 g, 46%) was a mixture of the two o l e f i n i c alcohols 130, b.p. 104-108° at 0.1 mm, n^ 1.4919. Infrared ( f i l m ) , X 3.05, 6.12, 6.98, 9.80, 10.19, 11.28 y. max ' ^ Anal. Calcd. f o r C H^O: C, 79.07; H, 12.15. Found: C, 79.17; H, 12;35. Preparation of Alcohol 131 The hydrogenation of the mixture of the o l e f i n i c alcohols 130 was c a r r i e d out i n ethanol at room temperature and atmospheric pressure - 85 -using platinum as the c a t a l y s t . From 1.85 g of 150 there was obtained 1.23 g (71%) of pure saturated a l c o h o l 151, b.p. 110-115° (bath 20 temperature) at 0.15 mm, n Q 1.4749. I n f r a r e d ( f i l m ) , A m a x 5.04, 6.90, 9.83 u ; n.m.r., x 6.12-6.88 ( p a i r of q u a r t e t s , 2H, -CH_20H, AB of ABX system), 9.07 (doublet, 6H, -CH(CH_ 3) 2, J = 6.2 Hz), 9.22 ( s i n g l e t , 3H, t e r t i a r y methyl). Anal. Calcd. f o r C-^H^O: C, 78.19; H, 13.12. Found: C, 78.33; H, 13.20. ci s - 1 , 2 - D i m e t h y l - l - i s o b u t y l c y c l o h e x a n e (133) (a) From A l c o h o l 131 A s o l u t i o n of a l c o h o l 131 (1 g, 5.4 mmoles) i n 5 ml of dry p y r i d i n e was cooled t o 0° and 1.09 g (5.75 mmoles) of p - t o l u e n e s u l f o n y l c h l o r i d e was added. The s o l u t i o n was s t i r r e d at 0° f o r 1.5 hand then d i l u t e d w i t h i c e - c o l d water. The mixture was ex t r a c t e d with ether and the ether s o l u t i o n was washed with saturated aqueous sodium bicarbonate, water, satura t e d b r i n e , and then d r i e d over anhydrous magnesium s u l f a t e . Removal of the ether gave 1.77 g of the crude t o s y l a t e 132 as a pale yellow o i l . The l a t t e r was d i s s o l v e d i n 32 ml of dry te t r a h y d r o f u r a n and 380 mg (10 mmoles) of l i t h i u m aluminum hydride was added. The mixture was r e f l u x e d , with s t i r r i n g , f o r 22 h, cooled, and the excess hydride was destroyed by c a r e f u l a d d i t i o n of i c e - c o l d water. Ether was added and the organic l a y e r was separated and d r i e d over anhydrous magnesium s u l f a t e . Removal of the s o l v e n t s , 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 , a f f o r d e d 500 mg (66%) of c i s - 1 , 2 - d i m e t h y l - l - i s o b u t y l -cyclohexane (153), b.p. 110° at 10 mm. An a n a l y t i c a l sample was c o l l e c t e d - 86 -20 by p r e p a r a t i v e g . l . c . (column G, 165°, 85) and e x h i b i t e d n Q 1.4544. The n.m.r. spectrum of t h i s compound showed s i g n a l s only i n the expected r e g i o n , between T 8.0 and T 9.3. Anal. Calcd. f o r C ^ H ^ : C, 85.65; H, 14.37. Found: C, 85.73; H, 14.41. (b) From cis-2,3-Dimethyl-2-methallylcyclohexanone (121) Hydrogenation of 202 mg of cis-2,3-dimethyl-2-methallylcyclohexanone (121) i n ethanol at room temperature and atmospheric pressure, u s i n g platinum as the c a t a l y s t , gave 195 mg of u n d i s t i l l e d cis-2,3-dimethyl-2-isobutylcyclohexanone, which e x h i b i t e d one component by g . l . c . (column G, 200°, 80). The l a t t e r was not f u r t h e r p u r i f i e d , but was d i r e c t l y subjected to Huang-Minion r e d u c t i o n (47). Thus, a s o l u t i o n of the cyclohexanone (190 mg) i n di e t h y l e n e g l y c o l (1.5 ml) co n t a i n i n g 0.5 g of potassium hydroxide and 0.2 ml of hydrazine hydrate was r e f l u x e d f o r 2 h. The r e f l u x condensor was removed and replaced by a d i s t i l l a t i o n head, and the temperature o f the r e a c t i o n mixture was slo w l y r a i s e d to 195° and kept at t h i s temperature f o r 1 h. The d i s t i l l a t e and the cooled r e a c t i o n mixture were combined, d i l u t e d w i t h water, and thoroughly e x t r a c t e d with ether. The combined ether e x t r a c t s were washed with ' d i l u t e h y d r o c h l o r i c - a c i d , water, saturated b r i n e , and d r i e d over anhydrous magnesium s u l f a t e . C a r e f u l removal of the ether afforded 176 mg (94%) of a pale yellow o i l which e x h i b i t e d one component by g . l . c . (column G, 155°, 80). An a n a l y t i c a l sample, c o l l e c t e d by p r e p a r a t i v e g . l . c . (column G, 155°, 80), e x h i b i t e d r e f r a c t i v e index, i n f r a r e d and n.m.r. s p e c t r a , and g . l . c . r e t e n t i o n time i d e n t i c a l w i t h those of c i s -I , 2-dimethyl-l-isobutylcyclohexanone (133) obtained from the a l c o h o l 131, as described above. - 87 -A c i d - c a t a l y z e d Isomerization of cis-2,3-dimethyl-2-methallylcyclohexanone (121) A s o l u t i o n of compound 121 (62 g, c o n t a i n i n g approximately 5% of i t s epimer 122) i n 1 1 of dry benzene c o n t a i n i n g 1 g of p - t o l u e n e s u l f o n i c a c i d was r e f l u x e d under an atmosphere of n i t r o g e n f o r 3 days. The cooled s o l u t i o n was e x t r a c t e d twice w i t h saturated aqueous sodium bicarbonate, then w i t h water and f i n a l l y with saturated b r i n e . A f t e r d r y i n g (anhydrous magnesium s u l f a t e ) the benzene was removed, y i e l d i n g a yellow o i l , which was shown by g . l . c . a n a l y s i s (column H, 140°, 85) to c o n s i s t of approximately 46% of the d e s i r e d cyclohexanone 136, 12% of 12 the s t a r t i n g m a t e r i a l , 37% of the c y c l i c hemiketal 137, and 5% of an u n i d e n t i f i e d compound. D i s t i l l a t i o n of the o i l under reduced pressure (2.8 mm) gave the f o l l o w i n g f r a c t i o n s : f r a c t i o n 1, b.p. 66-66.5°, 7 g; f r a c t i o n 2, b.p. 66.5°, 7 g; f r a c t i o n 3, b.p. 66.5-67.5°, 37.5 g; f r a c t i o n 4, b.p. 67.5-68°, 3.5 g. F r a c t i o n 3 contained a small amount of c r y s t a l l i n e m a t e r i a l , while f r a c t i o n 4 was n e a r l y e n t i r e l y c r y s t a l l i n e . I s o l a t i o n of t h i s m a t e r i a l , followed by r e c r y s t a l l i z a t i o n from petroleum ether (b.p. 60-80°) gave pure hemiketal 137 (3.2 g ) , m.p. 74-74.5°. I n f r a r e d ( n u j o l ) , A 2.92, 6.92, 7.28, 9.16, 9.85, 10.08 y; n.m.r.; fllclX 7.69 (broad s i n g l e t , IH, -0-H, D 20 exchange), 8.14 ( s i n g l e t , 2H, i i -C-CFL-C-), 8.58, 8.65, 9.06 ( s i n g l e t s , 9H, 3 t e r t i a r y methyls), 9.13 i —z t  12 I t should be noted that the hemiketal 137 was not s t a b l e to the high temperatures used i n the g . l . c . a n a l y s i s , but, i n f a c t , dehydrated to the enol ether 138• Thus, both a u t h e n t i c hemiketal and enol ether e x h i b i t e d i d e n t i c a l g . l . c . r e t e n t i o n times. However, d i s t i l l a t i o n of the crude r e a c t i o n product under reduced pressure at a r e l a t i v e l y low temperature c l e a r l y showed that none of the r e l a t i v e l y low b o i l i n g enol ether was present i n the i n i t i a l l y obtained mixture. - 88 -(doublet, 3H, secondary methyl, J = 6.2 Hz). / Anal. Calcd. f o r C 1 2 H 2 2 ° 2 : C ' 7 2 - 6 8 ' H> 1 1 - 1 8 - Found: C, 73.00; H, 11.00. F r a c t i o n 2 and the o i l of f r a c t i o n 3 from the above d i s t i l l a t i o n were combined and subjected to c a r e f u l f r a c t i o n a l d i s t i l l a t i o n through a spinning-band column ( s t a i n l e s s s t e e l , 8mm x 24 i n ) . The d i s t i l l a t i o n was c a r r i e d out at a pressure of 53 mm, and the various f r a c t i o n s were subjected to g . l . c . a n a l y s i s (column H, 140°, 85). The i n i t i a l three f r a c t i o n s (5.5 g) co n s i s t e d mainly of a mixture of the c y c l i c enol ether 138 and water (due to dehydration of the hemiketal 137) . F r a c t i o n 4 (11.1 g, b.p. 128°) was nearly pure enol ether 138, f r a c t i o n 7 (13.7 g, b.p. 143-144°) was shown to be greater than 90% pure ketone 136, whi l e f r a c t i o n s 5 and 6 (6.4 g, b.p. 128-143°) c o n s i s t e d of a mixture of compounds 136 and 138. F r a c t i o n s 8 and 9 (5 g, b.p. 144-147°) contained ketone 156 and s t a r t i n g m a t e r i a l 121 i n a r a t i o of approximately 5:2, r e s p e c t i v e l y . An a n a l y t i c a l sample of the c y c l i c enol ether 138 was obtained from f r a c t i o n 4 by p r e p a r a t i v e g . l . c . (column B, 200°, 110). This compound was extremely s e n s i t i v e to moisture and, even upon exposure to the atmosphere, r e a d i l y hydrated to a f f o r d the c r y s t a l l i n e hemiketal 137. 20 The pure enol ether e x h i b i t e d n p 1.4760. U l t r a v i o l e t (cyclohexane) X 200 my (e = 8,760); i n f r a r e d ( f i l m ) , X 5.92 y; n.m.r., x 5.36 fflcLX fflclX ( t r i p l e t , IH, o l e f i n i c H, J = 3.5 Hz), 8.57, 8.74, 8.90 ( s i n g l e t s , 9H, t e r t i a r y methyls), 9.10 (doublet, 3H, secondary methyl, J = 6 Hz). Anal. Calcd. f o r C^H 0: C, 80.01; H, 11.11. Found: C, 80.19; H, 11.10. - 89 -An a n a l y t i c a l sample of cis-2,3-dimethyl-2-methylpropenylcyclo-hexanone (136) was obtained from f r a c t i o n 7 by p r e p a r a t i v e g . l . c . 20 (column B, 200°, 110) and e x h i b i t e d nl~ 1.4822. I n f r a r e d ( f i l m ) , X K ' ' J D >• j ' m a x 5.85 p; n.m.r., T 4.59 ( m u l t i p l e t , IH, v i n y l H), 8.27, 8.57 (doublets, 6H, v i n y l methyls, J = 1.5, 1.3 Hz, r e s p e c t i v e l y ) , 8.91 ( s i n g l e t , 3H, t e r t i a r y methyl), 9.17 (doublets 3H, secondary methyl, J = 7 Hz). Anal. Calcd. f o r C12H2o°: C, 80.01; H, 11.11. Found: C, 80.08; H, 11.02. Reaction of Ketone 136 w i t h D i e t h y l Cyanomethylphosphonate A s t i r r e d suspension of sodium hydride (9.3 g, 0.387 mole) i n dry dimethyl s u l f o x i d e (200 ml) was slowly heated under an atmosphere of n i t r o g e n , to 75° and kept at t h i s temperature u n t i l f r o t h i n g had ceased (approximately 45 min). The s o l u t i o n was cooled to room temper-ature and a s o l u t i o n o f d i e t h y l cyanomethylphosphonate (72.6 g, 0.387 mole) i n 125 ml of dimethyl s u l f o x i d e was added. The s o l u t i o n was s t i r r e d f o r 10 min and then a s o l u t i o n o f compound 136 (13 g, 64.2 mmoles) i n 125 ml of dimethyl^sulfoxide was added. The r e a c t i o n mixture was heated at 100° f o r 1 h, cooled, d i l u t e d w i t h water and then thoroughly e x t r a c t e d w i t h petroleum ether (b.p. 30-60°). The combined e x t r a c t s were washed twice with water, once with s a t u r a t e d b r i n e and then d r i e d over anhydrous magnesium s u l f a t e . Removal of the s o l v e n t , 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 under reduced pressure y i e l d e d 12.7 g (89%) of a pale yellow o i l , b.p. 89-91° at 0.25 mm. This m a t e r i a l was shown, by g . l . c . a n a l y s i s (column C, 190°, 100), to c o n s i s t of a - 90 -mixture of the a , g-unsaturated n i t r i l e 139 and the g ,y-unsaturated n i t r i l e 140, i n a r a t i o of approximately 2:1, r e s p e c t i v e l y . An a n a l y t i c sample o f each of these compounds was i s o l a t e d by p r e p a r a t i v e g . l . c . 20 (column F, 230°, 120). The a , g-unsaturated n i t r i l e 139 e x h i b i t e d n Q 1.5109. U l t r a v i o l e t , \ 220.5 my ( e = 12,300); i n f r a r e d ( f i l m ) , X ITlcLX TflclX 4.53, 6.20 y; n.m.r., T 4.75 ( s i n g l e t , IH, =CHCN), 4.82 (unresolved m u l t i p l e t , IH, v i n y l H), 8.25, 8.44 (doublets, 6H, v i n y l methyls, J = 1.4, 1.6 Hz, r e s p e c t i v e l y ) , 8.84 ( s i n g l e t , 3H, t e r t i a r y methyl), 9.13 (doublet, 3H, secondary methyl, J = 6.5 Hz). Anal. Calcd. f o r C 1 4H 2 1N: C, 82.70; H, 10.41. Found: C, 82.85; H, 10.25. 20 The g ,y-unsaturated n i t r i l e 140 e x h i b i t e d n^ 1.4981. I n f r a r e d ( f i l m ) , X 4.48, 6.06.y; n.m.r., T 4.07 (unresolved m u l t i p l e t , IH, I f l c l X y - v i n y l H), 4.94 (unresolved m u l t i p l e t , IH, v i n y l H), 7.01 (unresolved m u l t i p l e t , 2H, -CH 2CN), 8.31, 8.40 (doublets, 6H, V i n y l methyls, J = 1.5, 1.7 Hz r e s p e c t i v e l y ) , 9.00 ( s i n g l e t , 3H, t e r t i a r y methyl), 9.11 (doublet, 3H, secondary methyl). A n a l . Calcd. f o r C 1 4H 2 ]N: C, 82.70; H, 10.41. Found: C, 82.71; H, 10.45. Pr e p a r a t i o n of C a r b o x y l i c A c i d 141 Potassium hydroxide (77 g) was d i s s o l v e d i n a mixture of ethanol (380 ml) and water (20 ml), and a mixture of the two n i t r i l e s ( 1 3 9 and 140) (13.2 g) was added. The s o l u t i o n was r e f l u x e d under an atmosphere of n i t r o g e n f o r 3 days and then most of the?solvent was removed under - 91 -reduced pressure. The r e s i d u a l m a t e r i a l was d i l u t e d with water and the r e s u l t i n g s o l u t i o n was washed w i t h ether. The aqueous l a y e r was a c i d i f i e d with 6 N h y d r o c h l o r i c a c i d and e x t r a c t e d thoroughly with ether. The combined e x t r a c t s were washed with water, saturated b r i n e , and then d r i e d over anhydrous sodium s u l f a t e . Removal of the solvent gave a viscous yellow o i l which, upon d i s t i l l a t i o n under reduced pressure, y i e l d e d 12 g (82%) of the 3,y-unsaturated c a r b o x y l i c a c i d 141 as a 20 c l e a r viscous o i l , b.p. 130-134° at 0.25 mm, n Q 1.5040. I n f r a r e d (CHC1 3), X 2.9-4.2 (broad), 5.88 p ; n.m.r., x 4.35 (poorly r e s o l v e d t r i p l e t , nic ix IH, y - v i n y l H), 4.93 (unresolved m u l t i p l e t , IH, v i n y l H), 7.07 (unresolved m u l t i p l e t , 2H, -CH^COOH), 8.32, 8.38 (doublets, 6H, v i n y l methyls, J = 1.5, 1.3 Hz, r e s p e c t i v e l y ) , 8.99 ( s i n g l e t , 3H, t e r t i a r y methyl), 9.11 (doublet, 3H, secondary methyl, J = 6.5 Hz). Anal. Calcd. f o r C 1 4 H 2 2 0 2 : C, 75.63; H, 9.97. Found: C, 75.61; H, 10.00. ( i ) - A r i s t o l o n e (7) and (+)-6,7-Epi-aristolone (145) The B,y-unsaturated c a r b o x y l i c a c i d 141 (5.0 g, 22.4 mmoles) was d i s s o l v e d i n aqueous sodium hydroxide (25.0 mmoles), the water was evaporated under reduced pressure, and the residue was d r i e d i n a vacuum oven at 70°. A s t i r r e d suspension of the r e s u l t i n g dry sodium s a l t i n 140 ml of dry benzene c o n t a i n i n g 0.5 ml of p y r i d i n e was cooled to 0° and 56 g (0.44 mole) of o x a l y l c h l o r i d e was added. The r e a c t i o n mixture was s t i r r e d at 0° f o r 15 min, f i l t e r e d , and evaporated under reduced pressure (vacuumn pump). The s o l u t i o n was kept at 0° during - 92 -t h i s process. The crude a c i d c h l o r i d e 143 [ i n f r a r e d ( f i l m ) , X — — max 5.62 y; n.m.r., very s i m i l a r to that of the c a r b o x y l i c acid] thus obtained was taken up i n 250 ml of dry ether and the r e s u l t i n g s o l u t i o n was added to excess a l c o h o l f r e e e t h e r e a l diazomethane which had been d r i e d over potassium hydroxide. The s o l u t i o n was s t i r r e d f o r 15 min and evaporated under reduced pressure a f f o r d i n g the crude diazoketone 144. I n f r a r e d ( f i l m ) , X 4.79, 6.15 u. The crude diazoketone 144 was • max ' p  d i s s o l v e d i n 600 ml of cyclohexane and c u p r i c s u l f a t e (15 g) was added. The r e s u l t i n g suspension was r e f l u x e d , w i t h s t i r r i n g , u n t i l the i n f r a r e d absorption at 4.79 y had disappeared (approximately 4 h ) . The cooled mixture was f i l t e r e d and the f i l t r a t e was washed with saturated aqueous sodium bicarbonate, water, saturated b r i n e and then d r i e d over anhydrous sodium s u l f a t e . Removal of the s o l v e n t , followed by d i s t i l l a t i o n of the r e s i d u a l m a t e r i a l under reduced pressure, y i e l d e d 3.5 g (approximately 70%, based on the a c i d 141) of a c l e a r o i l , b.p. 100-110° (bath temperature) at 0.1 mm. This m a t e r i a l was shown by g . l . c . a n a l y s i s (column G, 220°, 110) to c o n s i s t of approximately 42% of (±)-aristolone (7), 20% of (±)-6,7-epi-aristolone (145) and a number of minor u n i d e n t i f i e d components. This mixture was p a r t i a l l y p u r i f i e d by p r e p a r a t i v e t h i n l a y e r chromatography. Neutral alumina p l a t e s (20 x 60 cm, 0.5 mm t h i c k ) were used, with 3:2 n-hexane-ether being employed as developing solvent. Approximately 150 mg of the d i s t i l l e d m a t e r i a l was a p p l i e d per p l a t e and the appropriate band of each p l a t e , c o n t a i n i n g ( + ) - a r i s t o l o n e (7) and i t s isomer 145, was el u t e d w i t h ether. From 5.5 g of d i s t i l l e d m a t e r i a l there was thus obtained 2.1 g of a c l e a r o i l which c o n s i s t e d mainly of - 93 -(±)-aristolone (7) and i t s isomer 145, i n a r a t i o of approximately 2.4:1, r e s p e c t i v e l y . F i n a l p u r i f i c a t i o n was e f f e c t e d by p r e p a r a t i v e g . l . c . (column I , 240°, 110). C r y s t a l l i n e ( - ) - a r i s t o l o n e ( 7 ) , thus obtained was r e c r y s t a l l i z e d from petroleum ether (b.p. 60-80°), and e x h i b i t e d m.p. 62-63°. U l t r a v i o l e t , A 236 my (e = 10,300); i n f r a r e d (CHC1_), ^ 6.09 u; n.m.r., T 4.28 (unresolved m u l t i p l e t , IH, -C nH, width max ' y at h a l f - h e i g h t = 3.5 Hz), 8.28 ( p a i r of doublets, IH, -C yH, J = 8 and 1.2 Hz), 8.61 (doublet, IH, -C 6H, J = 8 Hz), 8.74, 8.80, 8.81 ( s i n g l e t s , 9H, t e r t i a r y methyls), 8.93 (doublet, 3H, secondary methyl, J = 6.5 Hz). This m a t e r i a l was found to be i d e n t i c a l (m.p., mixed m.p., i n f r a r e d , n.m.r., g . l . c . r e t e n t i o n time) with a u t h e n t i c ( + ) - a r i s t o l o n e , prepared by r e c r y s t a l l i z i n g , from petroleum ether (b.p. 60-80°), a 1:1 mixture of ( - ) - a r i s t o l o n e and a-ferulone [ ( + ) - a r i s t o l o n e ] (18). M.W. Calcd. f o r C 1 5 H 2 2 ° : 218.167. Found (high r e s o l u t i o n mass spectrometry): 218.166. Pure (±)-6,7-epi-aristolone (145) was obtained as a c o l o r l e s s o i l . U l t r a v i o l e t , A 233 (e = 10,000); i n f r a r e d (CHC1_), A 6.08 u ; max o max n.m.r.,T 4.24 (unresolved m u l t i p l e t , IH, -C^H, width at h a l f - h e i g h t = 2.5 Hz), 8.38 ( p a i r of doublets, IH, -C yH, J = 8 and 1.1 Hz), 8.45 (doublet, IH, -C^ 'H, J = 8 Hz), 8.80, 8.81, 8.84 ( s i n g l e t s , 9H, t e r t i a r y methyls), 9.02 (doublet, 3H, secondary methyl, J = 6.0 Hz). M.W. Calcd. f o r C^H^O: 218.167. Found (high r e s o l u t i o n mass spectrometry): 218.167. - 94 -A l k y l a t i o n of 2,3-Dimethyl-6-n_-butylthiomethylenecyclohexanone (119) with E t h y l 3-Bromopropionate The n-butylthiomethylene d e r i v a t i v e 119 (100 g, 0.44 mole) was added to 1800 ml of dry t - b u t y l a l c o h o l c o n t a i n i n g 144 g (1.4 moles) of potassium t-butoxide 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 f o r 10 min. E t h y l 3-bromopropionate (250 g, 1.38 mole) was added slowly from a dropping f u n n e l . The a l k y l a t i o n was exothermic and, a f t e r the a d d i t i o n was complete, the r e a c t i o n mixture was s t i r r e d f o r an a d d i t i o n a l 15 min. Most of the solvent was removed under reduced pressure and the residue was d i l u t e d w i t h water. The r e s u l t i n g mixture was ex t r a c t e d t h r i c e with ether. The combined ether e x t r a c t s were washed w i t h water and d r i e d over 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 124 g (86%) of the keto e s t e r 153 (mixture of epimers), b.p. 70 190-195° at 0.2 mm, n^ 1.5261. U l t r a v i o l e t , A 311 my (e = 14,900); ' D max ^ i n f r a r e d ( f i l m ) , A 5.79, 6.03, 6.52 u. v • max h Anal. Calcd. f o r C 1 oH„_0,S: C, 66.22, H, 9.26. Found: C, 66.14; H, 9.33. Pre p a r a t i o n of Keto A c i d 154 To a s o l u t i o n o f the above a l k y l a t e d m a t e r i a l (153) (124 g, 0.38 mole) i n 600 ml of die t h y l e n e g l y c o l was added 600 ml of 25% aqueous potassium hydroxide, and the r e s u l t i n g s o l u t i o n was r e f l u x e d , under an atmosphere o f n i t r o g e n , f o r 18 hr. The s o l u t i o n was cooled, d i l u t e d with water, and ext r a c t e d twice with ether. The ether e x t r a c t s were discarded. The aqueous l a y e r was a c i d i f i e d with 6 N h y d r o c h l o r i c a c i d , - 95 -and then e x t r a c t e d with ether. The combined ether l a y e r s were washed with water and saturate d b r i n e , then d r i e d over 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 a fforded 67.5 g (90%) of the keto a c i d 154 (mixture of epimers) as a c l e a r 20 viscous o i l , b.p. 142-147° at 0.15 mm, n Q 1.4868. I n f r a r e d ( f i l m ) , Xmax 2 - 7 - 4 - 2 ( v e r Y broad), 5.78, 5.85 u . Anal. Calcd. f o r C,M,o0„: C, 66.64; H, 9.15. Found: C, 66.83; H, 9.07. Prepa r a t i o n of Enol Lactones 155 and 156 A s o l u t i o n of the mixture of keto acids 154 (64 g, 0.32 mole) i n 140 ml of a c e t i c anhydride c o n t a i n i n g 14 g of anhydrous sodium acetate was r e f l u x e d under an atmosphere of n i t r o g e n f o r 2 h. The a c e t i c anhydride was removed under reduced pressure, and the r e s i d u a l m a t e r i a l was d i l u t e d with water. The aqueous l a y e r was ext r a c t e d with ether, and the ether l a y e r d r i e d over 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 crude product gave 49 g (85%) of c r y s t a l l i n e m a t e r i a l , b.p. 90-94° at 0.15 mm. This m a t e r i a l , as judged by i t s n.m.r. spectrum, c o n s i s t e d of a mixture of the enol lactones 155 and 156, i n a r a t i o of approximately 9:1, 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 t h i s mixture from n-hexane produced pure 155 (40 g). An a n a l y t i c a l sample of 155 was obtained by vacuum sub l i m a t i o n and e x h i b i t e d m.p. 51-51.5°. I n f r a r e d (CS ) , A 5.72, 5.98 y; n.m.r., z nicLx T 4.72 ( t r i p l e t , IH, v i n y l H, J = 3.5 Hz), 8.97 ( s i n g l e t , 3H, t e r t i a r y methyl), 9.04 (doublet, 3H, secondary methyl, J = 6.0 Hz). - 96 -Anal. Calcd. f o r C..H..O.: C, 73.30; H, 8.95. Found: C, 73.60; 11 16 z H, 8.93. An a n a l y t i c a l sample of the minor epimer 156, an o i l , was obtained from the mother l i q u o r s of the above r e c r y s t a l l i z a t i o n by means of 20 p r e p a r a t i v e g . l . c . (column B, 225°, 200) and e x h i b i t e d n D 1.4910. I n f r a r e d (film),X 5.71, 5.98 p; n.m.r., x 4.68 ( t r i p l e t , IH, v i n y l H, TRcLX J = 4.0 Hz), 8.79 ( s i n g l e t , 3H, t e r t i a r y methyl), 9.04 (doublet, 3H, secondary methyl, J = 6.5 Hz). Mol. Wt. Calcd. f o r C 1 1 H 1 6 ° 2 : 180.115. Found (high r e s o l u t i o n mass spectrometry): 180.113. Prep a r a t i o n of Octalone 150 A s o l u t i o n of the c r y s t a l l i n e enol lactone 155 (19.6 g, 0.11 mole) i n 200 ml of dry ether was cooled to -25° by means of an e x t e r n a l carbon t e t r a c h l o r i d e - d r y i c e s l u s h bath. An e t h e r e a l s o l u t i o n of methyl-l i t h i u m (75 ml, 2.35 M) was added over a p e r i o d of 3 min, and the r e s u l t i n g s o l u t i o n was<stirred at -25°, under an atmosphere of dry n i t r o g e n , f o r 1.75 h. The r e a c t i o n mixture was poured i n t o d i l u t e h y d r o c h l o r i c a c i d and the product was extracted three times with ether. The combined ether l a y e r s were washed with water and d r i e d over magnesium s u l f a t e . The ether was removed at a s p i r a t o r pressure and a s o l u t i o n of potassium hydroxide (16 g) i n 120 ml of water and 1000 !ml of methanol was added to the crude o i l y product. The r e s u l t i n g s o l u t i o n was r e f l u x e d under an atmosphere of n i t r o g e n f o r 2 h. The methanol was removed under reduced pressure and the r e s i d u a l o i l was d i l u t e d with water. The b a s i c aqueous l a y e r was e x t r a c t e d three times with ether. The combined - 97 -ether extracts were dried over magnesium s u l f a t e and the solvent was removed at aspirator pressure. D i s t i l l a t i o n of the crude yellow o i l thus obtained gave 13.5 g (70%) of the octalone 150, b.p. 96-99° at 20 0.2 mm, n^ 1.5155. U l t r a v i o l e t , A 240 my (e = 12,100); i n f r a r e d ' D max ( f i l m ) , A 5.98, 6.19 y; n.m.r., T 4.33 (broad s i n g l e t , IH, v i n y l H), iricLX 8.90 ( s i n g l e t , 3H, t e r t i a r y methyl), 9.09 (unresolved m u l t i p l e t , 3H, secondary methyl). Anal. Calcd. f o r C 1 O H 1 o 0 : C, 80.85; H, 10.18. Found: C, 80.96; 1Z l o H, 10.29. The basic aqueous layer from the above extraction was a c i d i f i e d with concentrated hydrochloric acid and the a c i d i c product was i s o l a t e d by extraction with ether. D i s t i l l a t i o n of the crude product provided 2.1 g (10%) of a carboxylic acid (154, c i s epimer) which, upon treatment with sodium acetate i n r e f l u x i n g a c e t i c anhydride, as described above, gave the enol lactone 155. Preparation of Decalol 157 To a s o l u t i o n of 6 g of lithium metal i n 1500 ml of l i q u i d ammonia was slowly added, from a dropping funnel, a s o l u t i o n of the octalone 150 (15 g, 0.084 mole) i n 100 ml of anhydrous ether. A f t e r 1 h, 16 ml of anhydrous ethanol was added and the r e a c t i o n mixture was allowed to s t i r f o r an a d d i t i o n a l 1.5 h. The reaction was then quenched by c a r e f u l addition of excess ethanol, and the ammonia was allowed to evaporate. The r e s i d u a l material was d i l u t e d with saturated brine and then extracted three times with ether. The ether layer was dried over - 98 -magnesium s u l f a t e , the ether was removed at a s p i r a t o r pressure and the crude product was d i s t i l l e d under reduced pressure to a f f o r d 11.5 g (75%) of the d e c a l o l 157, b.p. 86-90° at 0.2 mm, as a c l e a r , vicous o i l which r e s i s t e d c r y s t a l l i z a t i o n . An a n a l y t i c a l sample, c o l l e c t e d 20 by p r e p a r a t i v e g . l . c . (column J , 250°, 200), e x h i b i t e d n^ 1.4944. In f r a r e d ( f i l m ) , X 3.01, 9.54 y ; n.m.r., T 6.40 (broad s i g n a l , IH, n i c i x -CHOH), 9.24 (unresolved m u l t i p l e t , 3H, secondary methyl), 9.29 ( s i n g l e t , 3H, t e r t i a r y methyl). Anal. Calcd. f o r C^H^O: C, 79.06; H, 12.16. Found: C, 79.03; H, 11.97. Prep a r a t i o n of Decalone 158 Standard chromic a c i d s o l u t i o n (44) was added to a s o l u t i o n o f the d e c a l o l 157 (8.7 g, 0.048 mole) i n acetone (200 ml) at 0° u n t i l the orange c o l o r p e r s i s t e d . Isopropyl a l c o h o l was added to destroy the excess o x i d i z i n g reagent, and the s o l u t i o n was evaporated under reduced pressure. The r e s i d u a l m a t e r i a l was d i l u t e d with water and the product was ex t r a c t e d t h r i c e with ether. The combined ether l a y e r s were d r i e d over magnesium s u l f a t e and the ether was removed at a s p i r a t o r pressure. D i s t i l l a t i o n of the r e s u l t i n g crude o i l gave 7 g (81%) of the decalone 158, b.p. 83-86° at 1.0 mm, nt~ 1.4943. I n f r a r e d ( f i l m ) , X 5.84 y ; n.m.r., T 9.08 ( s i n g l e t , 3H, t e r t i a r y methyl), 9.13 (unresolved m u l t i p l e t , 3H, secondary methyl). Anal. Calcd. f o r C^H^O: C, 79.94; H, 11.18. Found: C, 80.21; H, 11.24. This compound e x h i b i t e d i n f r a r e d spectrum and g a s - l i q u i d chromato-- 99 -graphic r e t e n t i o n time (column I , 245°, 190) i d e n t i c a l w i t h those of the (+)-antipode of 158, which had been p r e v i o u s l y prepared by D j e r a s s i and co-workers (63). P r e p a r a t i o n of the Bromo Ketone 91_ A s o l u t i o n of bromine (4.7 g, 29.5 mmoles) i n g l a c i a l a c e t i c a c i d (40 ml) was added s l o w l y , at room temperature, to a s t i r r e d g l a c i a l a c e t i c a c i d (40 ml s o l u t i o n of the decalone 158 (5.3 g, 29.5 mmoles). A f t e r the addition-was complete, the s o l u t i o n was s t i r r e d f o r an a d d i t i o n a l 30 min and then poured i n t o i c e - c o l d water. The r e s u l t a n t mixture was e x t r a c t e d with ether. The combined ether e x t r a c t s were washed twice w i t h water, then with saturated aqueous sodium bicarbonate u n t i l f r e e of a c i d , and f i n a l l y w i t h saturated b r i n e . The ether l a y e r was d r i e d over-magnesium s u l f a t e and the ether removed at a s p i r a t o r pressure to a f f o r d crude c r y s t a l s of 91_. R e c r y s t a l l i z a t i o n of the crude product from ether afforded 5.6 g (72%) of the bromo ketone 91. An a n a l y t i c a l sample was obtained by vacuum sublimation and e x h i b i t e d m.p. 132-133° [ l i t . m.p. 132-133° (9) ]. I n f r a r e d (CHC1J, X 5.80;y; j n ic ix n.m.r., x 5.22 ( p a i r of doublets, IH, -CHBr, J = 6.5 Hz and 13.5 Hz), 8.98 ( 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. f o r C-^H^OBr: C, 55.61; H, 7.37; Br, 30.83. Found: C, 55.68; H, 7.48; Br, 31.02. - 100 -P r e p a r a t i o n of Octalone 9_2 A s t i r r e d suspension of l i t h i u m bromide (0.3 g) and l i t h i u m carbonate (0.4 g) i n 6 ml of dry dimethylformamide was heated to 120°, under an atmosphere of n i t r o g e n . The bromo ketone 91_ (0.57 g, 2.2 mmoles) was added and the r e a c t i o n mixture was s t i r r e d at 120° f o r 75 min. The suspension was cooled and f i l t e r e d . The f i l t r a t e was d i l u t e d with water and e x t r a c t e d w i t h n-heptane. The n-heptane l a y e r was d r i e d over magnesium s u l f a t e . The n-heptane was removed at a s p i r a t o r pressure and the product d i s t i l l e d under reduced pressure to give 0.34 g (86%) of a c l e a r , c o l o r l e s s o i l , b.p. 100° (bath temperature) at 0.4 mm. A n a l y s i s of t h i s m a t e r i a l by g . l . c . (column J , 250°, 240) showed that i t was a mixture c o n s i s t i n g of approximately 80% of the d e s i r e d octalone 92, 5% of the isomeric octalone 150 (on the b a s i s of g . l . c . r e t e n t i o n time o n l y ) , and some minor u n i d e n t i f i e d components. The d e s i r e d compound 92_was i s o l a t e d by p r e p a r a t i v e g . l . c . (column J , 250°, 2f) 240) and e x h i b i t e d ntr 1.5122. U l t r a v i o l e t , X 230 mu ( £ = 9,400): D max ^ J i n f r a r e d ( f i l m ) , X 5.97, 6.15 p; n.m.r., T 2.88 (doublet, IH, in 3.x 3 - v i n y l H, J = 10 Hz), 4.11 (doublet, IH, a - v i n y l H, J = 10 Hz), 9.03 (unresolved m u l t i p l e t , 3H, secondary methyl), 9.07 ( s i n g l e t , 3H, t e r t i a r y methyl). Anal. Calcd. f o r C 1 2H 0: C, 80.85; H, 10.18. Found: C, 80.83; H, 10.16. Pr e p a r a t i o n of Decalone 159 To a s t i r r e d s o l u t i o n of isopropenylmagnesium bromide (0.29 g, 2 mmoles) i n 2 ml of dry t e t r a h y d r o f u r a n was added approximately 6 mg of anhydrous cuprous c h l o r i d e and the r e s u l t i n g mixture was cooled t o - 101 -0°. A s o l u t i o n of the octalone 92_ (0.1 g, 0.56 mmoles) i n tetrahydro-furan (4 ml) was added by means of a s y r i n g e , and the r e a c t i o n mixture was s t i r r e d , under an atmosphere of n i t r o g e n , at 0° f o r 15 min and then r e f l u x e d f o r 1 h. The cooled r e a c t i o n mixture was poured slowly i n t o r a p i d l y s t i r r e d , i c e - c o l d d i l u t e h y d r o c h l o r i c a c i d , and the aqueous l a y e r was ex t r a c t e d three times with ether. The ether l a y e r was d r i e d over magnesium s u l f a t e and the ether removed at a s p i r a t o r pressure. D i s t i l l a t i o n of the crude product gave 110 mg (89%) of a c l e a r o i l , b.p. 100° (bath temperature) at 0.4 mm. G a s - l i q u i d chromatographic a n a l y s i s (column I , 245°, 190) of t h i s m a t e r i a l showed t h a t i t contained, i n a d d i t i o n to a number of minor components, approximately 80-85% of the d e s i r e d decalone 159. The l a t t e r was i s o l a t e d by p r e p a r a t i v e g . l . c . ?o (column I , 245°, 190) and showed n„ 1.5147. I n f r a r e d ( f i l m ) , \ v ' ' •> D *•-'». m a x 5.87, 6.15, 11.22 u; n.m.r., x 5.10, 5.36 (unresolved m u l t i p l e t s , 2H, = C H 2 J width at h a l f - h e i g h t 4.5 and 3.5 Hz, r e s p e c t i v e l y ) , 8.24 (unresolved m u l t i p l e t , 3H, v i n y l methyl, width at h a l f - h e i g h t - 3 Hz), 9.00 ( s i n g l e t , 3H, t e r t i a r y methyl), 9.12 (poorly r e s o l v e d doublet, 3H, secondary methyl). Anal. Calcd. f o r C ^ H ^ O : C, 81.76; H, 10.98. Found: C, 81.99; H, 11.08. Prep a r a t i o n of Racemic Decalone 160 Hydrogenation of the decalone 159 was c a r r i e d out i n ethanol, at atmospheric pressure and room temperature, over Adam's c a t a l y s t . From 50 mg of 159 there was obtained a q u a n t i t a t i v e y i e l d of racemic decalone 160 as a c r y s t a l l i n e s o l i d . R e c r y s t a l l i z a t i o n from n-hexane affo r d e d - 102 -an a n a l y t i c a l sample, m.p. 49-51°. I n f r a r e d ( C S 0 ) , A 5.87 p; n.m.r., x 9.02 ( s i n g l e t , 3H, t e r t i a r y methyl), 9.06, 9.17 (doublets, 3H and 6H, r e s p e c t i v e l y , secondary methyls, J = 6.8 Hz). Mol. Wt. Calcd. f o r C^H^O: 222.198. Found (high r e s o l u t i o n mass spectrometry): 222.198. (+)-9,10-Dihydroaristolone (53) Small pieces of f r e s h l y cut l i t h i u m metal (210 mg) were added to 150 ml of l i q u i d ammonia which had been d i s t i l l e d from sodium metal. The r e s u l t i n g s o i u t i o n was s t i r r e d f o r 30 min. A s o l u t i o n of (-)-a r i s t o l o n e (7) (300 mg) i n 25 ml of dry ether was added and the r e a c t i o n mixture was s t i r r e d f o r 45 min. A f t e r the r e a c t i o n had been quenched by c a r e f u l a d d i t i o n of excess dry ammonium c h l o r i d e , the ammonia was allowed to evaporate under a stream of n i t r o g e n . The r e s i d u a l m a t e r i a l was d i l u t e d w i t h saturated b r i n e and the product was i s o l a t e d by e x t r a c t i o n w i t h ether. The ether l a y e r was d r i e d over magnesium s u l f a t e and the ether was removed at a s p i r a t o r pressure to a f f o r d a pale yellow o i l . D i s t i l l a t i o n o f the crude product gave 275 mg (92%) of (+)-9,10-dihydroaristolone (53) as a c l e a r c o l o r l e s s o i l , b.p. 100° 24 (bath temperature) at 0.1 mm, +7° (c, 0.76 i n methanol). U l t r a v i o l e t , A 213 mp (e = 4,300); i n f r a r e d ( f i l m ) , A 5.98 p; nicLx nicLX 7 f\ n.m.r., x 8.36 (doublet, IH, -C H, J = 8 Hz), 8.70 (doublet, IH, -C H, J = 8 Hz), 8.59, 8.83, 9.08 ( s i n g l e t , 9H, t e r t i a r y methyls), 8.99 (doublet, 3H, secondary methyl, J = 6 Hz). Mol.. Wt. Calcd. f o r C^H^O: 220.183. Found (high r e s o l u t i o n mass spectrometry): 220.182. - 103 -Pr e p a r a t i o n of (-)-Decalone 160 The lithium-ammonia r e d u c t i o n of (+)-9,10-dihydroaristolone (53) was c a r r i e d out by a procedure i d e n t i c a l with that described above f o r the r e d u c t i o n of ( - ) - a r i s t o l o n e . From 120 mg of 53, there was obtained 110 mg (91%) of the c r y s t a l l i n e (-)-decalone 160. R e c r y s t a l l i z a -t i o n from n-hexane provided an a n a l y t i c a l sample, m.p. 80-82°, -30° (c, 0.59 i n methanol). This m a t e r i a l gave spe c t r a ( i n f r a r e d , n.m.r.) and g a s - l i q u i d chromatographic r e t e n t i o n times (column E, 210°, 90; column I, 260°, 200) i d e n t i c a l with those of the racemic decalone 160, prepared as described p r e v i o u s l y . Mol. Wt. Calcd. f o r C ti 0: 222.198. Found (high r e s o l u t i o n mass spectrometry): 222.197. DISCUSSION PART I I 1. The T o t a l Synthesis of ct-Cubebene and g-Cubebene In order to corroborate the s t r u c t u r a l proposal presented by Hirose and co-workers (20) f o r the sesquiterpenes a-cubebene (13) and g-cubebene (14) i t was decided to attempt the t o t a l syntheses of these compounds. In the pr o j e c t e d s y n t h e s i s , the key step was envisaged to be the i n t r a m o l e c u l a r c y c l i z a t i o n of an a p p r o p r i a t e l y s u b s t i t u t e d o l e f i n i c diazoketone, a r e a c t i o n which had already been s u c c e s s f u l l y employed i n the t o t a l synthesis of (±)-aristolone (7). In the l a t t e r s y n t h e s i s , the c y c l i z a t i o n of diazoketone 144 had l e d d i r e c t l y to a mixture of ( i ) - a r i s t o l o n e (7) and ( 1 ) - 6 , 7 - e p i - a r i s t o l o n e (145). 144 7 145 I t was f e l t that a s i m i l a r c y c l i z a t i o n of a diazoketone such as 105 would lead to a s y n t h e t i c intermediate (106) with f u n c t i o n a l i t y appropriate f o r f u r t h e r e l a b o r a t i o n to a-(13) and g-cubebene (14). - 105 -The f i r s t problem, t h e r e f o r e , i n v o l v e d the unambiguous synthesis of a diazoketone such as 105, and, more p a r t i c u l a r l y , the unambiguous synthesis of diazoketone 170 (71). 170 The s y n t h e s i s of t h i s c r u c i a l intermediate i s described below. Condensation (see Chart XIX) of the commercially a v a i l a b l e mixture of 13 (+)-menthone and (±)-isomenthone (171) with e t h y l formate i n the presence of sodium methoxide i n benzene gave, i n 88% y i e l d , the hydroxy-methylene d e r i v a t i v e s 172. Treatment of 172 under the usual c o n d i t i o n s 13 Compounds 171, 172, 173, and 175 represent racemic diastereomeric p a i r s . A n a l y t i c a l and s p e c t r a l data of these mixtures were i n each case, i n f u l l accord with the assigned s t r u c t u r e s . - 106 -(39) w i t h n-butanethiol afforded i n 98% y i e l d the corresponding n - b u t y l -thiomethylene d e r i v a t i v e s 173. Reduction of 173 w i t h a b a s i c s o l u t i o n of methanolic sodium borohydride provided a q u a n t i t a t i v e y i e l d of the crude 3-hydroxythioenol ether 174, which was not p u r i f i e d but was immediately hydrolyzed w i t h 1% h y d r o c h l o r i c a c i d i n aqueous acetone to a f f o r d a mixture of products. D i s t i l l a t i o n of t h i s m a t e r i a l under reduced pressure afforded two major f r a c t i o n s . The f i r s t f r a c t i o n (40% b.p. 66-68° at 0.35 mm) c o n s i s t e d of the d e s i r e d a ,3-unsaturated aldehydes 175, while the second f r a c t i o n (50%, b.p. 120-126° at 0.35 mm) 14 c o n s i s t e d e n t i r e l y of the t h i o e n o l ether 176. I t i s g e n e r a l l y b e l i e v e d (73,74) that the h y d r o l y s i s of 3-hydroxy-enol ethers (or 3-hydroxy-thioenol ethers) proceeds by a l l y l i c rearrangement of the a l c o h o l to form the hemi-acetal (hemi-thioacetal) which then undergoes h y d r o l y s i s to give the corresponding a ,3-unsaturated aldehyde. However, i n the present case a considerable amount of d i r e c t dehydration must be o c c u r r i n g p r i o r to a l l y l i c rearrangement (see Chart XIX). Various attempts were made to hydrolyze the t h i o e n o l ether 176, i n order t o improve the y i e l d of the aldehydes 175. Under m i l d c o n d i t i o n s ( d i l u t e aqueous a c i d , room temperature) only s t a r t i n g m a t e r i a l was recovered, and when more d r a s t i c c o n d i t i o n s were used (stronger aqueous a c i d , r e f l u x temperatures, a d d i t i o n of heavy metal s a l t s , etc.) the s t a r t i n g m a t e r i a l was destroyed a f f o r d i n g only b r i g h t l y coloured t a r s and o i l s . 14 Normally, the h y d r o l y s i s of 3-hydroxy-thioenol ethers s i m i l a r to 174 a f f o r d s , i n good y i e l d , the corresponding a ,3-unsaturated aldehyde (see r e f . 72 and 73). However, i n the present case, although a v a r i e t y of c o n d i t i o n s were used the i s o l a t e d y i e l d of the aldehydes 175 never exceeded 40%. - 107 -As the above sequence produced enough of the aldehydes 175 to continue the s y n t h e s i s , no a l t e r n a t i v e methods f o r the p r e p a r a t i o n of 175 were attempted. However, the above sequence might have been improved by making use of enol ethers i n s t e a d of e n o l - t h i o e t h e r s , even though, i n g e n e r a l , enol ethers, such as I , are not as s a t i s f a c t o r y as the corresponding s u l f u r d e r i v a t i v e s , such as I I . This i s due i n part to the i n s t a b i l i t y of enol ethers to moisture, but more i m p o r t a n t l y , due to t h e i r tendency, on sodium borohydride r e d u c t i o n , to undergo 1,4-reduction as w e l l as the d e s i r e d 1,2-reduction (72). - 108 -- 109 -The s p e c t r a l p r o p e r t i e s of the aldehydes 175 and the t h i o e n o l ether 176 were i n complete accord w i t h the assigned s t r u c t u r e . In p a r t i c u l a r , the u l t r a v i o l e t spectrum of the aldehydes 175 showed a maximum at 233.5 my, while the i n f r a r e d spectrum c l e a r l y showed absorptions at 3.75 y (aldehydic C-H s t r e t c h ) and 5.95 y. In a d d i t i o n , the n.m.r. spectrum of 175 c l e a r l y showed the presence of an aldehydic proton as a s i n g l e t at x 0.6 and the o l e f i n i c proton as a m u l t i p l e t centered at x 3.35. The t h i o e n o l ether 176 d i s p l a y e d , i n i t s u l t r a -v i o l e t spectrum, a very strong absorption maximum at 278 my with a shoulder at 286 my, while the i n f r a r e d spectrum showed no carbonyl absorptions, but contained a r a t h e r strong absorption at 6.4 y. The two o l e f i n i c protons were evident i n the n.m.r. spectrum of 176 as broadened s i n g l e t s at x 4.08 and x 4.37. The aldehydes 175 upon r e d u c t i o n w i t h sodium borohydride afforded i n 91% y i e l d the corresponding mixture of a l c o h o l s 177. To t h i s stage i n the synthesis no attempt had been made to separate the isomers, s i n c e a l l o f the intermediates which would be amenable to sep a r a t i o n contained an epimerizable i s o p r o p y l group. However, once the aldehyde 175 had been reduced with sodium borohydride there was no f u r t h e r chance of e p i m e r i z a t i o n and t h e r e f o r e , attempts were made to separate the mixture of alc o h o l s 177. G a s - l i q u i d chromatographic a n a l y s i s o f t h i s mixture on many d i f f e r e n t columns at v a r y i n g flow rates and column temperatures f a i l e d to r e v e a l any appreciable separation of the two isomers (177a and 177b) . Therefore, a search was made f o r a s u i t a b l e d e r i v a t i v e which might prove to be separable by p r e p a r a t i v e g . l . c . The acetate d e r i v a t i v e s 178 of a l c o h o l s 177 were found to be - 110 -u n s u i t a b l e s i n c e they again proved to be completely inseparable. However, the corresponding 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 , 179 and 180, which were e a s i l y formed i n v i r t u a l l y q u a n t i t a t i v e y i e l d from the al c o h o l s 177 (75), were found to separate reasonably w e l l on a p r e p a r a t i v e column*'' [3/8" x 30', 30% Zonyl E-7, on 60-80 Chromosorb-W (a c i d washed)]. In t h i s manner, a s u f f i c i e n t q u a n t i t y of the t r i m e t h y l -s i l y l ethers 179 and 180 were obtained. I t was subsequently shown that 180 179 177a,b 178 the isomer 179 had the d e s i r e d t r a n s - c o n f i g u r a t i o n (vide i n f r a ) . The s p e c t r a l data f o r compounds 179 and 180 were i n complete accord with the assigned s t r u c t u r e s . Thus, i n the i n f r a r e d spectrum of ether 179, strong absorptions at 8.00, 9.4, 11.4 and 11.9 u i n d i c a t e d the presence of the t r i m e t h y l s i l y l ether. In the n.m.r. spectrum of 179, the o l e f i n i c proton was c l e a r l y evident as a broad s i n g l e t at x 4.43. In a d d i t i o n , a n unresolved m u l t i p l e t at x 5.92 could be assigned to the methylene protons alpha to the ether oxygen. Three overlapping doublets ^ We are g r a t e f u l to Mr. J . Booker, Varian Aerograph, C a l i f o r n i a , f o r h i s h e l p f u l advice i n the s e l e c t i o n of a column f o r t h i s s e p a r a t i o n . - I l l -at x 8.99, T 9.09 and x 9.13 (J = 7 Hz) could be assigned to the three secondary methyl groups, and a nine proton s i n g l e t at x 9.87 was assigned to the t r i m e t h y l s i l y l group. S i m i l a r l y , i n the i n f r a r e d spectrum of the cis-isomer 180, strong absorptions at 8.03, 9.45, 11.4, and 11.9 y were assigned to the t r i m e t h y l s i l y l ether group. The n.m.r. spectrum of 180 showed a broad s i n g l e t at x 4.43 due to the o l e f i n i c proton and an unresolved m u l t i p l e t at x 5.92 was a t t r i b u t e d to the methylene protons alpha to the ether oxygen. Furthermore, three ovelapping doublets at x 8.98, x 9.08, and x 9.13 (J = 7 Hz) were assigned to the three secondary methyl groups and a nine proton s i n g l e t at x 9.87 was once again due to the t r i m e t h y l s i l y l group. The trans-isomer, 179 was r e f l u x e d i n 2% aqueous ethanol (75) f o r two hours to give the pure t r a n s - a l c o h o l 177a i n 98% y i e l d . The s p e c t r a l data f o r t h i s compound was i n complete accord with the assigned 179 177a s t r u c t u r e . Thus the i n f r a r e d spectrum now showed a strong hydroxyl a b s o r p t i o n at 3.0 y, and the t r i m e t h y l s i l y l ether absorptions at 8.00, 9.4, 11.4 and 11.9 y had been completely removed. The n.m.r. spectrum of 177a was very s i m i l a r to that of 179 with the a d d i t i o n of one exchangeable - 112 -proton at t 8.22 and the absence of the nine proton s i n g l e t at T 9.87. Reaction of the a l c o h o l 177a with phosphorous tr i b r o m i d e i n benzene c o n t a i n i n g a small amount of p y r i d i n e at 0° (77) r e s u l t e d i n the formation of the corresponding a l l y l i c bromide 181 i n 77% y i e l d . That the secondary a l l y l i c bromide 182 had not formed during t h i s 182 177a 181 t r a n s f o r m a t i o n , v i a an a l l y l i c rearrangement, was c l e a r l y shown by the n.m.r. spectrum of the product 181. Thus, the o l e f i n i c proton appeared as a broad s i n g l e t at x 4.30 and the bromo-methyl protons were evident as an AB p a i r of doublets centered at x 6.03 (J = 10 Hz). In a d d i t i o n , t h e three secondary methyl groups appeared as doublets (J = 7 Hz) at x 8.95,x9.09, and x 9.12. Treatment of the bromide 181 (see Chart XX) w i t h two equivalents of carbethoxymethylenetriphenylphosphorane (185)(78) i n r e f l u x i n g e t h y l acetate f o r 2.5 hours (79) gave, i n a d d i t i o n to the c r y s t a l l i n e carbethoxy-methyltriphenylphosphonium bromide (184), a v i r t u a l l y q u a n t i t a t i v e y i e l d of the corresponding a l k y l a t e d phosphorane (185) as a yellow o i l . H y d r o l y s i s of the crude 185 w i t h 10% potassium hydroxide i n r e f l u x i n g aqueous methanol f o r one hour aff o r d e d a 69% y i e l d of the corresponding - 113 -c a r b o x y l i c a c i d 186. The s p e c t r a l p r o p e r t i e s of 186 were i n complete accord w i t h the assigned s t r u c t u r e . For example, i n the i n f r a r e d specfrum of 186 absorptions at 3.1-3.9 and 5.85 y were c h a r a c t e r i s t i c o f a c a r b o x y l i c a c i d . In the n.m.r. spectrum of 186 the v i n y l proton was present as a broadened s i n g l e t at T 4.69, while the four methylene protons of the c a r b o x y l i c a c i d s i d e chain were evident . as a r e l a t i v e l y sharp s i n g l e t at T 7.40. Three doublets at x 9.00, x 9.13 and x 9.17 (J = 7 Hz) were assigned t o the three secondary methyl groups. With the c a r b o x y l i c a c i d 186 now i n hand the stage was set f o r the sequence of r e a c t i o n s which would lead to the formation of the c r u c i a l diazoketone 170. To t h i s end, 186 was t r e a t e d w i t h 0.1 N aqueous sodium hydroxide to form the sodium s a l t 187, (54) which was d r i e d i n a vacuum oven overnight at 60-70°. The sodium s a l t was then t r e a t e d w i t h o x a l y l c h l o r i d e i n benzene at 0° to a f f o r d the crude a c i d c h l o r i d e 188. The s p e c t r a l p r o p e r t i e s of the crude a c i d c h l o r i d e were i n complete accord with the assigned s t r u c t u r e . Thus, the i n f r a r e d spectrum now d i s p l a y e d a carbonyl absorption at 5.58 y. The n.m.r. spectrum was very s i m i l a r to that of 186 except that the four methylene protons of the si d e chain now appeared as a very complex m u l t i p l e t centered at x 7.00. When the a c i d c h l o r i d e 188 was t r e a t e d with dry ethe r e a l diazomethane the corresponding diazoketone 170 was formed almost immediately. The i n f r a r e d spectrum of 170 di s p l a y e d strong peaks at 3.27, 4.78, and 6.10 y c h a r a c t e r i s t i c of the diazoketone moiety. I n t e r e s t i n g l y , i n the n.m.r. spectrum of 170 the o l e f i n i c proton and the diazomethyl proton overlapped as a broad s i n g l e t at x 4.75, and the four methylene protons of the side chain had again c o l l a p s e d to form a - 114 -Chart XX - 115 -broad s i n g l e t at x 7.64. When the diazoketone 170 was r e f l u x e d i n cyclohexane i n the presence of c u p r i c s u l f a t e (37) f o r 1.5 hours, a remarkably clean and h i g h - y i e l d i n g i n t r a m o l e c u l a r c y c l i z a t i o n occurred, producing the two isomeric ketones (104 and 189) i n a r a t i o ( g . l . c . a n a l y s i s ) of approximately 3:5 r e s p e c t i v e l y . The two isomers were separated by pr e p a r a t i v e g . l . c , and i n each case the spectral', p r o p e r t i e s were i n complete accord with the assigned s t r u c t u r e . Thus, (±)-g-cubebene norketone (104) d i s p l a y e d a maximum i n the u l t r a v i o l e t spectrum at 206 mp (69), and a carbonyl absorption i n the i n f r a r e d spectrum at 5.85 p. In the n.m.r. spectrum of 104 three doublets at x 9.00, x 9.05, and x 9.07 (J = 6.5 Hz) were a t t r i b u t e d to the three secondary methyl groups. S i m i l a r l y , (±)-1,6-epi-g-cubebene norketone (189) d i s p l a y e d a maximum i n i t s u l t r a v i o l e t spectrum at 205 mp (69), and a carbonyl absorption i n the i n f r a r e d spectrum at 5.82 p. In the n.m.r. spectrum of ketone 189, a doublet at x 8.91 (J = 7 Hz) was assigned to the methyl group. The i s o p r o p y l methyl groups appeared as a r a t h e r p o o r l y r e s o l v e d m u l t i p l e t at T 8.98.^ Upon treatment with methylenetriphenylphosphorane i n dimethyl s u l f o x i d e (50), (-)-g-cubebene norketone (104) gave a q u a n t i t a t i v e y i e l d of (t)-g-cubebene (14) as a c l e a r c o l o u r l e s s o i l . The s p e c t r a l p r o p e r t i e s ( i n f r a r e d , n.m.r., mass spectrum and u l t r a v i o l e t absorption maximum) as w e l l as the g . l . c . r e t e n t i o n time were i d e n t i c a l w i t h those This was presumably due to v i r t u a l c o u p l i n g , see reference 62. - 116 -17 of the n a t u r a l m a t e r i a l . Of p a r t i c u l a r i n t e r e s t was the n.m.r. spectrum of racemic 14_ [see Figure 5) which c l e a r l y showed the two o l e f i n i c protons as a p a i r of unresolved m u l t i p l e t s at x 5.28 and x 5.47.. In a d d i t i o n , the three secondary methyl groups appeared as doublets at x 9.04, x 9.06, and x 9.10 (J = 6.0, 6.5 and 6.5 Hz) r e s p e c t i v e l y . Since n a t u r a l g-cubebene (14) had already been converted to ct-cubebene (13) (20) v i a p a r t i a l i s o m e r i z a t i o n of the former on a h a l f -exhausted polypropylene c a p i l l a r y column at 150°, the above synthesis of racemic B-cubebene (14) a l s o represented a t o t a l synthesis of a-cubebene (13). Natu r a l B-cubebene (14) has a l s o been correlated' (20) with a-cubebene (13) by comparison of t h e i r respective.dihydro^ d e r i v a t i v e s . This comparison was a l s o c a r r i e d out i n the present case us i n g racemic 17 Na t u r a l B-cubebene was i s o l a t e d from O i l of Cubeb, E x t r a , k i n d l y s u p p l i e d by F r i t z s c h e Brothers, Inc., New York. The sp e c t r a ( i n f r a r e d and n.m.r.) of n a t u r a l B-cubebene (14) , i s o l a t e d by pr e p a r a t i v e g . l . c , were i d e n t i c a l w i t h those k i n d l y s u p p l i e d by Pro f e s s o r Y. Hirose. In a d d i t i o n , upon o z o n o l y s i s , the B-cubebene which was i s o l a t e d from O i l of Cubeb, E x t r a gave the known B-cubebene norketone (104) which e x h i b i t e d m.p. 60-60.5° [ l i t . m.p. 58.5-59.5° (20)]. - 118 -3-cubebene. Thus, c a t a l y t i c hydrogenation (Adam's c a t a l y s t , room temperature, atmospheric pressure) of racemic 3-cubebene (14) gave a mixture of two dihydro d e r i v a t i v e s i n a r a t i o ( g . l . c . a n a l y s i s ) of 45:55. These epimers were separated by p r e p a r a t i v e g . l . c . and the minor product was shown to be i d e n t i c a l ( i n f r a r e d spectrum, g . l . c . r e t e n t i o n time on three d i f f e r e n t columns) with dihydro-a-cubebene (97) (20) obtained by c a t a l y t i c hydrogenation of an a u t h e n t i c sample of 18 a-cubebene (13). 2. Stereochemical Proof of the A l c o h o l 1 7 7 a Since one of the o b j e c t i v e s of the synthesis of a n a t u r a l product i s g e n e r a l l y to provide unambiguous evidence f o r a s t r u c t u r a l p r o p o s a l , i t was important to prove u n e q u i v i c a l l y the r e l a t i v e stereochemistry of the diazoketone intermediate 170. I t can be seen that i n the sequence 177a ->• 181 186 188 •> 170 no change i n the r e l a t i v e stereochemistry 18 A sample of a-cubebene was k i n d l y s u p p l i e d by Professor Y. Hir o s e . - 119 -170 takes p l a c e . Therefore, a s y n t h e t i c proof of the stereochemistry of any of the above intermediates would c o n s t i t u t e a stereochemical proof of a l l of the others. 188 - 120 -The s e p a r a t i o n of the a l c o h o l s 177a,b ( v i a the corresponding t r i m e t h y l s i l y l ethers 179 and 180) as described above provided a convenient s t a r t i n g p o i n t f o r the stereochemical proof o u t l i n e d below (see Chart XXI). Treatment of the a l c o h o l 177a w i t h phosphorous t r i b r o m i d e as p r e v i o u s l y described afforded the a l l y l i c bromide 181. Lithium aluminum hydride r e d u c t i o n of 181 gave a v i r t u a l l y q u a n t i t a t i v e y i e l d of racemic trans-2-methyl-p-mentha-2-ene (190). The s p e c t r a l p r o p e r t i e s of t h i s compound were i n complete accord with the assigned s t r u c t u r e . In the n.m.r. spectrum (see Figure 6) of racemic 190, the o l e f i n i c proton was c l e a r l y evident as a broad s i n g l e t at x 4.87, while the v i n y l methyl group appeared as a s i n g l e t at x 8.37. Three doublets at x 9.05, x 9.15, and x 9.18 (J = 6.6 Hz) were assigned t o the three secondary methyl groups. An unambiguous synthesis of (+)-trans-2-methyl-p-mentha-2-ene (190) was c a r r i e d out as described below. (-)-trans-Caran-2-one (108) was prepared by the l i t e r a t u r e procedure (80,81) from (-)-carvone (191) . Thus, l i t h i u m i n l i q u i d ammonia r e d u c t i o n of (-)-carvone followed by chromic a c i d o x i d a t i o n (81) a f f o r d e d a 70% y i e l d of (+)-cis (192a) and (+)-trans-dihydrocaryone (192b) i n a r a t i o ( g . l . c . a n a l y s i s ) of 14:86 r e s p e c t i v e l y . Treatment of 192a,b with 10% hydrogen bromide i n g l a c i a l a c e t i c a c i d followed by r e a c t i o n of the crude hydrobromide (193) so formed with potassium hydroxide i n ethanol r e s u l t e d i n the formation of (-)-trans-caran-2-one (108) i n 80% y i e l d . Ketone 108 could be con-v e n i e n t l y p u r i f i e d by r e c r y s t a l l i z a t i o n from hexane at -78°, and a Figure 6. N.M.R. Spectrum of (±) - trans - 2 -Methy 1 -p_-mentha- 2 - ene (190). sample of 108 p u r i f i e d i n t h i s manner had [ a ] Q = -181° (c 1.2, MeOH) [ L i t . [a]p° -162.9° (81), -153° (82)]. The n.m.r. spectrum of 108 19 showed no absorptions due to o l e f i n i c protons, but the two t e r t i a r y methyl groups were c l e a r l y evident as sharp s i n g l e t s at x 8.81 and x 8.86. In addition>the secondary methyl group was apparent as a doublet at x 8.98 (J = 6.3 Hz). Reaction of bicyclo[3.1.0]hexan-2-one (194) systems with a l k y l m e t a l reagents i s known to occur p r e f e r e n t i a l l y from the s i d e opposite the cyclopropane r i n g (36). Presumably, t h i s i s due to the f a c t that a t t a c k at the carbonyl carbon from the other side i s s t e r i c a l l y hindered R R by the c y c l o p r o p y l moiety. In the case of the r e a c t i o n of ketone 108 with m e t h y l l i t h i u m , i t was expected that the a d d i t i o n a l s t e r i c hindrance of the gem-dimethyl groups on the cyclopropane r i n g should ensure v i r t u a l l y complete s t e r e o s e l e c t i v i t y to t h i s r e a c t i o n , and t h i s Samples of 108 which had not been r e c r y s t a l l i z e d c l e a r l y showed the presence of small amounts of dihydrocarvone (192a,b) and i n a d d i t i o n d i s t i l l a t i o n at temperatures above 100° or g . l . c . p u r i f i c a -t i o n of 108 was attended by rearrangement to 192. - 123 -Chart XXI - 124 -was observed. Thus*the a d d i t i o n of e t h e r e a l m e t h y l l i t h i u m to ketone 108 gave only one product, which was presumed t o possess the s t r u c t u r e and stereochemistry depicted by 195. The n.m.r. spectrum of a l c o h o l 195 c l e a r l y showed the presence of the three t e r t i a r y methyl groups as s i n g l e t s at T 8.74, x 8.75 and x 8.95 while the secondary methyl group appeared as a doublet at x 9.09 (J = 6.5 Hz). P y r o l y s i s o f a l c o h o l 195 i n the presence of a small amount of p y r i d i n e i n a sealed tube at 190-200° f o r 2 hours (81,35) gave 20 approximately 70% of (+)-trans-2-methyl-p-mentha-2,8-diene (196), 20 [ct]p +139.3°, which was p u r i f i e d by p r e p a r a t i v e g . l . c . The i n f r a r e d spectrum of 196 c l e a r l y showed the presence of the isopropenyl group with absorptions at 3.25, 6.08, and 11.28 u. In the n.m.r. spectrum of 196, the o l e f i n i c proton was evident as a broad s i n g l e t at x 4.72 while the o l e f i n i c methylene protons at Cg produced a f a i r l y sharp s i n g l e t at x 5.27. The two v i n y l methyl groups gave r i s e to a broad s i n g l e t at x 8.27, while the secondary methyl group c o n t r i b u t e d a doublet at x 8.99 (J = 6.4 Hz). 20 This m a t e r i a l had to be analyzed immediately as i t tended to a u t o x i d i z e on standing f o r even short periods of time. This type of behaviour has been p r e v i o u s l y noted by Cocker, Hanna, and Shannon (see r e f . 81), i n the analogous (+)-trans-p-mentha-2,8-diene (197). 6 197 - 125 -The p y r o l y s i s o f a l c o h o l s such as 195, has been s t u d i e d by Cocker, Hanna, and Shannon (81) who suggested that at elevated temperatures the e l i m i n a t i o n o f a molecule of water occurs i n a concerted manner. Therefore, s i n c e the stereochemistry at C 1 and C . remains unchanged 7 195 196 throughout the r e a c t i o n , the stereochemistry of the diene produced must be as shown i n 196. Hydrogenation of diene 196 i n the presence of the homogeneous c a t a l y s t t r i s ( t r i p h e n y l p h o s p h i n e ) c h l o r o r h o d i u m (83) stopped a f t e r the uptake of one equivalent of hydrogen. I s o l a t i o n of the product a f f o r d e d 20 (+)-trans-2-methy1-p-mentha-2-ene (190), [ a ] ^ +25.4°, which e x h i b i t e d i n f r a r e d and n.m.r. (see f i g u r e 7) s p e c t r a and g . l . c . r e t e n t i o n times i d e n t i c a l w i t h the racemic 190, prepared as described above. The above proof of the stereochemistry of the a l c o h o l 177a thus, unambiguously f i x e d the stereochemistry of the diazoketone 170 and thus, provided unambiguous evidence f o r the stereochemistry at and C - ^ Q of g-cubebene norketone (104) and, t h e r e f o r e , of g-cubebene (14) i t s e l f . On the other hand, t h i s stereochemical proof does not provide any i n f o r m a t i o n about the stereochemistry at C , of g-cubebene. However, Figure 7. N.M.R. Spectrum of (+)-trans-2-Methyl-p_-mentha-2-ene (190). - 127 -177a 170 the studies (22) described i n the i n t r o d u c t i o n of t h i s t h e s i s (see page 35 ) concerning the a c i d c a t a l y z e d rearrangement of a-cubebene (13) c l e a r l y i n d i c a t e that the stereochemistry at i s as shown i n formulae 13 and 14. EXPERIMENTAL I I For the general experimental i n f o r m a t i o n see page 76. Prep a r a t i o n o f Hydroxymethylene D e r i v a t i v e s (172) of d,l-Menthone and d,1-Isomenthone (171) To an i c e - c o o l e d , s t i r r e d suspension of powdered sodium methoxide (135 g, 2.46 moles) i n 1500 ml of dry benzene, kept under an atmosphere of dry n i t r o g e n , was added 154 g (1 mole) of a mixture of d,l-menthone and d,1-isomenthone (171) . The r e s u l t i n g mixture was s t i r r e d f o r 10 min, and then 125 g (1.7 moles) of e t h y l formate was added. The mixture was warmed to room temperature and allowed to stand overnight. Water was added, and the l a y e r s separated. The organic l a y e r was ex t r a c t e d w i t h two p o r t i o n s of 10% aqueous sodium hydroxide. The combined aqueous l a y e r and a l k a l i n e e x t r a c t s were cooled, a c i d i f i e d w i t h 6 N h y d r o c h l o r i c a c i d , and thoroughly e x t r a c t e d with ether. The combined e x t r a c t s were washed with water and d r i e d over anhydrous magnesium s u l f a t e . Removal of the s o l v e n t , 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 under reduced pressure, gave 171 g (94%) of the hydroxymethylene d e r i v a t i v e s 172 as a pale yellow o i l , b.p. 71-73° at 0.2 20 M i , n n 1.4983. U l t r a v i o l e t s 294 my (e = 7,950), X (NaOH added) D max ^ ' max ^ J - 129 -319 my ( e = 17,500); i n f r a r e d ( f i l m ) , X 6.15, 6.35 y. fflclX Anal. Calcd. f o r C.-H^CL: C, 72.49; H, 9.95. Found: C, 72.49; 11 1 o Z H, 10.06. Prep a r a t i o n of n-Butylthiomethylene D e r i v a t i v e s 173 A s o l u t i o n of the hydroxymethylene d e r i v a t i v e s 172 (137.5 g, 0.755 mole), n-butanethiol (75 g, 0.825 mole), and p_-toluenesulfonic a c i d (50 mg) i n 500 ml of dry benzene was r e f l u x e d i n a n i t r o g e n atmosphere under a Dean-Stark water separator f o r 12 h at which time 13 ml of water had been c o l l e c t e d . The cooled s o l u t i o n was washed with saturated aqueous sodium bicarbonate, then wit h water and f i n a l l y d r i e d 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 170 g (89%) of the ii-butylthiomethylene d e r i v a t i v e s 173, b.p. 130-136° at 0.35 mm, 20 n n 1.5292; u l t r a v i o l e t , X 311 my: (e= 13,600); i n f r a r e d ( f i l m ) , X D max ^ v • max 6.02, 6.50 y. Anal. Calcd. f o r C l rH o^0S: C, 70.83; H, 10.30; S, 12.61. Found: 1 b ZD C, 71.09; H, 10.45; S, 12.30. Prep a r a t i o n of Aldehydes 175 To a s o l u t i o n of the n-butylthiomethylene d e r i v a t i v e s 173 (140.7 g, 0.555 mole) i n 1.8 1 of methanol was added 21.25 g (0.555 mole) of sodium borohydride d i s s o l v e d i n 55.5 ml of 0.1 N sodium hydroxide. The mixture was s t i r r e d at room temperature f o r 2 h then a f u r t h e r 21.25 g (0.555 mole) of sodium borohydride d i s s o l v e d i n 55.5 ml of 0.1 N sodium - 130 -hydroxide was added. A f t e r a f u r t h e r 2 h, the methanol was removed at a s p i r a t o r pressure and the remaining aqueous l a y e r was e x t r a c t e d three times w i t h ether. The ether l a y e r s were washed"with water then d r i e d ' over anhydrous magnesium s u l f a t e . Removal of the solvent gave 142 g (100%) of 174 as a pale yellow o i l ; i n f r a r e d ( f i l m ) , X 3.00, 6.23 y. in 3.x This m a t e r i a l was used without f u r t h e r p u r i f i c a t i o n i n the h y d r o l y s i s step as described below. To a s o l u t i o n of the crude a l c o h o l 174 (25.6 g, 0.1 mole) i n 500 ml of acetone was added 100 ml of 1% aqueous h y d r o c h l o r i c a c i d . The r e s u l t i n g mixture was heated on a steam bath f o r 20 min, then the acetone was removed at water a s p i r a t o r pressure. The remaining aqueous l a y e r was s a t u r a t e d w i t h sodium c h l o r i d e and e x t r a c t e d three times w i t h ether. The combined ether l a y e r s were washed with water and d r i e d over anhydrous magnesium s u l f a t e , then the ether was removed at water a s p i r a t o r pressure. D i s t i l l a t i o n of the r e s u l t i n g o i l under reduced pressure (0.35 mm) gave two f r a c t i o n s : f r a c t i o n 1, b.p. 66-68°, 6.65 g (40%), c o n s i s t e d of the d e s i r e d a,g-unsaturated aldehydes 175, 20 as a c l e a r c o l o u r l e s s o i l , n^ 1.4878. U l t r a v i o l e t , X 233.5 my ' D '• max K (e = 18,750); i n f r a r e d ( f i l m ) , X 3.75, 5.95, 6.15 y; n.m.r., x 0.6 fflciX ( s i n g l e t , IH, CHO), 3.35 ( m u l t i p l e t , IH, g - v i n y l H), 8.82-9.16 ( m u l t i p l e t , 9H, secondary methyls). Anal. Calcd. f o r C.,H 1 o0: C, 79.46; H, 10.91. Found: C, 79.64; 11 l o H, 10.85. F r a c t i o n 2, b.p.. 120-126°, 11.9 g (50%), c o n s i s t e d of the pure 20 t h i o e n o l ether 176, as a p a l e yellow o i l ; n Q 1.5363. U l t r a v i o l e t , X 278 my (e = 22,600), X , 286 my (e = 21,100); i n f r a r e d ( f i l m ) , - 131 -X 6.4, 11.4 y; n.m.r. x 4.08 ( m u l t i p l e t , IH, v i n y l H) , 4.37 . ( s i n g l e t , nicix IH, v i n y l H), 8.85-9.15 ( m u l t i p l e t , 12H, three secondary methyls and one primary methyl). Anal. Calcd. f o r C F L ^ S : C, 75.56; H, 10.99. Found: C, 75.71; l b ZD H, 11.10. Prep a r a t i o n of A l c o h o l s 177a,b To a s o l u t i o n of sodium borohydride (4.5 g, 0.12 mole) i n 500 ml of methanol, cooled to 0° i n an i c e bath, was added the aldehyde 175 (20 g, 0.12 mole) d i s s o l v e d i n 100 ml of methanol. The r e a c t i o n mixture was s t i r r e d under an atmosphere of n i t r o g e n f o r 30 min then the methanol was removed at water a s p i r a t o r pressure. Cold water (200 ml) was added and the aqueous l a y e r was e x t r a c t e d three times w i t h ether. The combined ether l a y e r s were d r i e d over anhydrous magnesium s u l f a t e and the ether was removed at water a s p i r a t o r pressure. D i s t i l l a t i o n of the r e s u l t i n g o i l under reduced pressure a f f o r d e d 18.4 g (91%) of the a l c o h o l s 177a,b, b.p. 77-78° at 0.25 mm. P r e p a r a t i o n of T r i m e t h y l s i l y l Ethers 179 and 180 To a s o l u t i o n of the a l c o h o l s 177a,b (9 g, 0.053 mole) i n 150 ml of dry p y r i d i n e was added 30 ml of hexamethyldisilazane and 15 ml of t r i m e t h y l s i l y l c h l o r i d e . The mixture was s t i r r e d under an atmosphere of n i t r o g e n f o r 10 min, then the mixture was f i l t e r e d and the excess reagents and p y r i d i n e were removed at water a s p i r a t o r pressure. The crude product was d i s t i l l e d under reduced pressure to give 12.2 g (95%) - 132 -of the mixture o f 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 179 and 180, b.p. 62-63° at 0.35 mm. A n a l y s i s of t h i s mixture by g . l . c . (column K, 150°, 200) revealed that the two isomers were present i n a r a t i o of approximately 1:1. P u r i f i c a t i o n of the two isomers was achieved by pr e p a r a t i v e g . l . c . (column K, 140°, 240). The pure trans-isomer 179, thus obtained was a 20 c l e a r c o l o u r l e s s o i l and e x h i b i t e d n_ 1.4544; i n f r a r e d ( f i l m ) , A 8.00, D v J max 9.4, 11.4, 11.9 y. N.m.r., x 4.43 (broad s i n g l e t , IH, v i n y l H, width at h a l f - h e i g h t = 4 Hz), 5.92 (unresolved m u l t i p l e t , 2H, -CH_2-0TMS) , 8.99, 9.09, 9.13 (doublets, 9H, secondary methyls, J = 7 Hz), 9.87 ( s i n g l e t , 9H, S i ( C H 3 ) 3 ) . Mol. Wt. Calcd. f o r C ^ H ^ O S i : 240.191. Found (high r e s o l u t i o n mass spectrometry): 240.190. 20 The pure cis-isomer 180 was c l e a r c o l o u r l e s s o i l and e x h i b i t e d n Q 1.4540; i n f r a r e d ( f i l m ) , A 8.03, 9.45, 11.4, 11.9 y. N.m.r., x 4.43 ^ J max (broad s i n g l e t , IH, v i n y l H, width at h a l f - h e i g h t = 4 Hz), 5.92 (unresolved m u l t i p l e t , 2H, -CH_2-0TMS), 8.98, 9.08, 9.13 (doublets, 9H, secondary methyls, J = 7 Hz), 9.87 ( s i n g l e t , 9H, Si ( C H _ 3 ) 3 ) . Mol. Wt. Calcd. f o r C,.H„o0Si: 240.191. Found (high r e s o l u t i o n mass spectrometry): 240.191. Prep a r a t i o n of A l c o h o l 17?a The pure t r a n s - t r i m e t h y l s i l y l ether 179 (600 mg, 2.5 mmoles) was r e f l u x e d i n 6 ml of ethanol c o n t a i n i n g 0.2 ml of water f o r 2 hours. The solvents were removed at water a s p i r a t o r pressure and the r e s u l t i n g o i l was d i s t i l l e d at reduced pressure to a f f o r d 413 mg (98%) of the - 133 -a l c o h o l 177a as a c l e a r c o l o u r l e s s o i l , b.p. 80° (hot-box) at 0.15 mm; 20 n„ 1.4825. I n f r a r e d ( f i l m ) , A , 3.0, 6.02, 9.9 u; n.m.r., T 4.39 D m a x (broad s i n g l e t , IH, v i n y l H, width at h a l f - h e i g h t = 5 Hz), 5.92 (unres-olved m u l t i p l e t , IH, CH_2-0H), 8.22 ( s i n g l e t , IH, exchangeable, CH20H) , 8.98, 9.10, 9.14 (doublets, 9H, secondary methyls, J = 6.8, 6.4, and 6.4 Hz r e s p e c t i v e l y ) . Anal. Calcd. f o r C n H 2 0: C, 78.51; H, 11.98. Found: C, 78.76; H, 12.03. Pre p a r a t i o n of Bromide 181 A s o l u t i o n of the a l c o h o l 177a (400 mg, 2.38 mmoles) i n 10 ml of benzene c o n t a i n i n g 0.08 ml of dry p y r i d i n e was cooled to 0° i n an i c e - b a t h . To t h i s c o l d s t i r r e d s o l u t i o n was added, from a dropping f u n n e l , 312 mg (1.15 mmoles) of phosphorous tr i b r o m i d e i n 1.1 ml of dry benzene. The r e a c t i o n mixture was s t i r r e d f o r 30 min and then d i l u t e d w i t h 5 ml of c o l d d i l u t e aqueous sodium bicarbonate s o l u t i o n . The mixture was ext r a c t e d with ether and the combined organic l a y e r s were d r i e d over anhydrous magnesium s u l f a t e . The solvents were removed at a s p i r a t o r pressure and the r e s u l t i n g crude product was d i s t i l l e d under reduced pressure to a f f o r d 425 mg (77%) of the bromide 181, b.p. 75° 20 at 0.2 mm; n " 1.5027. I n f r a r e d ( f i l m ) , A 6.08, 8.30 y; n.m.r.. D J max ' x 4.30 (broad s i n g l e t , IH, v i n y l H, width at h a l f - h e i g h t = 5 Hz), 6.03 (quartet, 2H, -CF^Br, J A B = 10 Hz), 8.95, 9.09, 9.12 (doublets, 9H, secondary methyls, J = 7 Hz). Anal. Calcd. f o r C n H 1 9 B r : C, 57.15; H, 8.28. Found: C, 57.25; H, 8.27. - 134 -Carbethoxymethylenetriphenylphosphorane (183) A s o l u t i o n of carbethoxymethyltriphenylphosphonium bromide (184) (8.6 g, 0.2 mole) i n 250 ml of water was t i t r a t e d (84) w i t h 1% aqueous sodium hydroxide u n t i l the s o l u t i o n was j u s t b a s i c to phenolphthalein. The crude phosphorane 183 which p r e c i p i t a t e d from the mixture was f i l t e r e d and r e c r y s t a l l i z e d twice from e t h y l acetate to a f f o r d 6.5 g (93%) of pure white c r y s t a l l i n e 183, m.p. 122-123°, [ l i t . m.p. 116-117° (78), 121-122° (85)]. P r e p a r a t i o n of C a r b o x y l i c A c i d (186) To a hot s o l u t i o n o f 183 (1.28 g, 3.7 mmoles) d i s s o l v e d i n 10 ml of e t h y l acetate was added 425 mg of the bromide 181 (1.84 mmoles). The r e s u l t i n g mixture was r e f l u x e d f o r 5 h, then cooled and the p r e c i p i t a t e d carbethoxymethyltriphenylphosphonium bromide (184) (575 mg, 73%) was f i l t e r e d o f f . The solvent was removed at a s p i r a t o r pressure, and the r e s u l t i n g crude product (185) was d i s s o l v e d i n 12 ml of 10% potassium hydroxide i n 1:1 methanol:water, and r e f l u x e d f o r 1 h. The r e a c t i o n mixture was cooled and the methanol removed at water a s p i r a t o r pressure. The b a s i c aqueous l a y e r was e x t r a c t e d w i t h ether and then n e u t r a l i z e d w i t h 6 N h y d r o c h l o r i c a c i d . The aqueous l a y e r was e x t r a c t e d with ether and the ether l a y e r was d r i e d 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 o i l y r e s i d u e under reduced pressure afforded 270 mg (69%) of the c a r b o x y l i c a c i d 186, b.p. 120° (hot-box) at 0.15 mm, n^ 1.4818. I n f r a r e d ( f i l m ) , X 3.1-3.9, 5.85 u; n.m.r., x 4.69 (broad s i n g l e t , IH, v i n y l H, width - 135 -at h a l f - h e i g h t = 4 Hz), 7.40 ( s i n g l e t , 4H, CF^CH^CO^) , 9.00, 9.13, 9.17 (doublets, 9H, secondary methyls). Anal. Calcd. f o r C ^ H ^ O ^ C, 74.24; H, 10.54. Found: C, 74.22; H, 10.53. (±) - |3-Cubebene Norketone (104) and (!)-1,6-Epi-g-cubebene Norketone (189) The c a r b o x y l i c a c i d 186 (242 mg, 1.15 mmoles) was d i s s o l v e d i n aqueous sodium hydroxide (1.32 mmoles), the water was evaporated under reduced pressure, and the residue was d r i e d i n a vacuum oven at 70°. A s t i r r e d suspension of the r e s u l t i n g dry sodium s a l t (187) i n 20 ml of dry benzene co n t a i n i n g 0.02 ml of p y r i d i n e was cooled to 0° and 1.5 g (12 mmoles) of o x a l y l c h l o r i d e was added. The r e a c t i o n mixture was s t i r r e d at 0° f o r 15 min, f i l t e r e d , and evaporated under reduced pressure (vacuum pump). The s o l u t i o n was kept at 0° during t h i s process. The crude a c i d c h l o r i d e 188 [ i n f r a r e d ( f i l m ) , X^^ 5.58 y; n.m.r. very s i m i l a r to that of the c a r b o x y l i c a c i d 186 except at x 7.00 (complex m u l t i p l e t , 4H, CF^CH^COCl) ] thus obtained was taken up i n 15 ml of dry ether and the r e s u l t i n g s o l u t i o n was added to excess a l c o h o l f r e e e t h e r e a l d i a z o -methane which had been d r i e d over potassium hydroxide. The s o l u t i o n was s t i r r e d f o r 15 min and evaporated under reduced pressure a f f o r d i n g the crude diazoketone 170. I n f r a r e d ( f i l m ) , X 3 .27, 4 .78, 6.10 u; ' max n.m.r., x 4.75 (broad s i n g l e t , 2H, v i n y l H and COCHN , width at h a l f -height = 4 Hz), 7.64 ( s i n g l e t , 4H, CF^CH^COCFB^) . The crude diazo-ketone 170 was d i s s o l v e d i n 30 ml of cyclohexane and c u p r i c s u l f a t e (750 mg) was added. The r e s u l t i n g suspension was r e f l u x e d with, s t i r r i n g f o r 1.5 h a f t e r which time the i n f r a r e d absorption at 4.78 y - 136 -had disappeared. The cooled mixture was f i l t e r e d and the cyclohexane was removed at a s p i r a t o r pressure. D i s t i l l a t i o n o f the o i l y r esidue under reduced pressure gave 185 mg (78%) of a pale yellow o i l , b.p. 100-103° (hot-box) at 0.2 mm. This m a t e r i a l was shown by g . l . c . analys (column G, 190°, 90) to c o n s i s t of approximately 36% of (i)-g-cubebene norketone (104) and 64% (J:)-epi-1,6-g-cubebene norketone (189) . Prep a r a t i v e g . l . c . (column F, 235°, 135) provided pure samples of 104 and 189. Pure (i)-g-cubebene norketone (104) thus obtained e x h i b i t e d 20 n D 1.4940. U l t r a v i o l e t , > m a x 206 my (e = 6,150); i n f r a r e d ( f i l m ) , A 5.85 y; n.m.r., T 9.00, 9.05, 9.07 (doublets, 9H, secondary methyl J = 6.5 Hz). Anal. Calcd. f o r C^H^O: C, 81.49; H, 10.74. Found: C, 81.79; H, 10.59. Pure (+)-l,6-epi-g-cubebene norketone (189) obtained i n the same 20 manner e x h i b i t e d 1.4984; u l t r a v i o l e t , X 205 my (E = 6,280); D max H v ' J ' i n f r a r e d ( f i l m ) , A 5.82 y; n.m.r., x 7.95 (broadened s i n g l e t , 4H, width at h a l f - h e i g h t = 2 Hz), 8.91 (doublet, 3H, C-10 CH_3, J = 7 Hz), 8.98 (poorly r e s o l v e d m u l t i p l e t , 6H, CH(CH_ 3) 2). Mol. Wt. Calcd. f o r C^H 0: 206.166. Found (high r e s o l u t i o n mass spectrometry): 206.167. (+)-g-Cubebene (14) A s t i r r e d suspension o f sodium hydride (300 mg, 12.5 mmoles), i n dry dimethyl s u l f o x i d e (14 ml) was slo w l y heated under an atmosphere of n i t r o g e n , to 75° and kept at t h i s temperature u n t i l f r o t h i n g had - 137 -ceased (approximately 30 min). The s o l u t i o n was cooled to room temperature and a s o l u t i o n of methyltriphenylphosphonium bromide (5.32 g, 14.8 mmoles) i n 8 ml of dimethyl s u l f o x i d e was added. The s o l u t i o n was s t i r r e d f o r 10 min and then a s o l u t i o n of (±)-g-cubebene norketone (104) (515 mg, 2.5 mmoles) i n 15 ml of dimethyl s u l f o x i d e was added. The r e a c t i o n mixture was heated to 50° f o r 6 h, cooled, d i l u t e d with water, and then thoroughly e x t r a c t e d with hexane. The combined e x t r a c t s were washed w i t h water and b r i n e , then d r i e d over anhydrous magnesium s u l f a t e . Removal of the s o l v e n t , 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 under reduced pressure a f f o r d e d 506 mg (99%) of 14_ as a c l e a r c o l o u r l e s s o i l , b.p. 80-82° (hot-box) at 0.2 mm. A n a l y s i s of t h i s m a t e r i a l by g . l . c . (column L, 170°, 90) revealed that i t was only one 20 component and i t e x h i b i t e d n^ 1.4975. U l t r a v i o l e t , X 208 mp (e = r D max H 9,850); i n f r a r e d ( f i l m ) , X 3.26, 6.10, 11.72 p; n.m.r., x 5.28, max x 5.47 (unresolved m u l t i p l e t s , 2H, ^C=CH_2), 9.04, 9.06, 9.10 (doublets 9H, secondary methyl groups, J = 6.0, 6.5, 6.5 Hz r e s p e c t i v e l y ) . This m a t e r i a l was found to be i d e n t i c a l ( i n f r a r e d , n.m.r., u l t r a v i o l e t , g . l . c . r e t e n t i o n time) with authentic g-cubebene, i s o l a t e d from O i l of Cubeb E x t r a (see footnote 17, page 116 ). Mol. Wt. Calcd. f o r C ^ H ^ : 204.187. Found (high r e s o l u t i o n mass spectrometry): 204.186. (+)-trans-2-Methyl-p-mentha-2-ene (190) To a s o l u t i o n of l i t h i u m aluminum hydride (50 mg, 1.3 mmoles) i n 6 ml of dry tetrahydrofuran was added 300 mg (1.3 mmoles) of the a l l y l i c - 138 -bromide 181. The mixture was r e f l u x e d under an atmosphere of n i t r o g e n f o r 1,5 h, then cooled to 0°. Water (1 ml) was c a u t i o u s l y added, and the r e s u l t i n g mixture was ex t r a c t e d with ether. The combined ether l a y e r s were d r i e d over anhydrous magnesium s u l f a t e and the solvent was removed at water a s p i r a t o r pressure. D i s t i l l a t i o n of the r e s u l t i n g o i l under reduced pressure gave 188 mg (95%) of (i)-2-methyl-p_-mentha-2-ene (190) as a c l e a r c o l o u r l e s s o i l , b.p. 80° (hot-box) at 10 mm; n 2, 0 1.4602. I n f r a r e d ( f i l m ) , X 6.93, 7.23, 7.32, 11.5, 11.9 y; D v max K n.m.r., x 4.87 (broad s i n g l e t , IH, v i n y l H, width at h a l f - h e i g h t = 5 Hz), 8.37 ( s i n g l e t , 3H, v i n y l Cti^), 9.05, 9.15, 9.18 (doublets, 9H, secondary methyls, J = 6.6 Hz). This m a t e r i a l was found to be i d e n t i c a l ( i n f r a r e d , n.m.r., g . l . c . r e t e n t i o n time) with an authentic sample of (+)-trans-2-methyl-p-mentha-2-ene (190), the synt h e s i s of which i s described below. Mol. Wt. Calcd. f o r C-^H^: 152.156. Found (high r e s o l u t i o n mass spectrometry): 152.156. (-)-trans-Caran-2-one (108) To a s o l u t i o n of (-)-carvone (191) (60 g, 0.4 mole) i n 200 ml of dry ether and 1 1 of dry l i q u i d ammonia at -33° was added 14 g (2.0 moles) of l i t h i u m i n small p i e c e s . A f t e r a l l the l i t h i u m was added the r e a c t i o n was s t i r r e d f o r 2 h, then 80 ml of dry ethanol was added during 1 h. To the r e s u l t i n g s o l u t i o n was added 400 ml of ether and 200 ml of water. The ammonia was allowed to evaporate and the remaining mixture was e x t r a c t e d three times with ether. The combined ether l a y e r s were d r i e d over anhydrous magnesium s u l f a t e and concentrated on the r o t a r y evaporator - 139 -to approximately 300 ml. A s o l u t i o n of sodium dichromate (50 g) and concentrated s u l f u r i c a c i d (27 ml) i n 250 ml of water was then added over 1 h at 0° and the mixture was warmed to room temperature and s t i r r e d overnight. The ether l a y e r was removed and the aqueous l a y e r was ex t r a c t e d w i t h two po r t i o n s of ether. The combined ether lay e r s were d r i e d over anhydrous magnesium s u l f a t e and the ether was removed at water a s p i r a t o r pressure. D i s t i l l a t i o n of the r e s u l t i n g o i l under reduced pressure gave 42 g (70%) of a mixture of (+)-cis-(192a) and (+)-trans-dihydrocarvone (192b), b.p. 90-92° at 10 mm [ l i t . 60° at 1 mm (81)] , i n a r a t i o ( g . l . c . a n a l y s i s , column J . , 140°, 200) of 14:86 r e s p e c t i v e l y . A s o l u t i o n of dihydrocarvone (192a,b) (15.2 g, 0.1 mole) i n 130 g of 9.4% hydrogen bromide i n g l a c i a l a c e t i c a c i d was s t i r r e d at room temperature f o r 15 min, then poured onto 500 g of crushed i c e . The r e s u l t i n g mixture was extr a c t e d three times with ether and the combined ether l a y e r s were ext r a c t e d w i t h d i l u t e aqueous sodium bicarbonate and water u n t i l a l l of the a c e t i c a c i d had been removed. The ether l a y e r was d r i e d over anhydrous magnesium s u l f a t e and the ether was removed at water a s p i r a t o r pressure to a f f o r d 23.3 g (100%) of the crude hydrobromide 193. To a s o l u t i o n of potassium hydroxide (5.9 g, 0.105 mole) i n 250 ml of ethanol at 0° was added the crude hydrobromide 193 (23.3 g, 0.1 mole), and the r e s u l t i n g mixture was s t i r r e d f o r 2 h at 0°. The p r e c i p i t a t e d potassium bromide was f i l t e r e d o f f and the ethanol was removed from the f i l t r a t e at water a s p i r a t o r pressure. D i s t i l l a t i o n of the r e s u l t i n g o i l under reduced pressure gave 12.18 g (80%) of (-)-trans-caran-2-one (108), b.p. 38-40° at 0.15 mm [ l i t . b.p. 60° at 1 mm (81)]. This - 140 -m a t e r i a l was c r y s t a l l i z e d by d i s s o l v i n g i t i n hexane and c o o l i n g the r e s u l t i n g s o l u t i o n t o -78° (acetone-dry i c e ) . The mother l i q u o r s were removed with a p i p e t and the c r y s t a l s were warmed to room tempera-ture to give a c l e a r c o l o u r l e s s o i l " . The r e s u l t i n g m a t e r i a l was r e c r y s t a l l i z e d under the same con d i t i o n s and any excess hexane was removed under reduced pressure (vacuum pump, 0.1 mm). A sample of 20 22 m a t e r i a l p u r i f i e d i n t h i s way e x h i b i t e d n^ 1.4773; [ a ] ^ -181° (c, 1Q 1.2 i n methanol) [ l i t . [a]J -162.9° (81), -153° (c, 5.0) (82)]. I n f r a r e d ( f i l m ) , X 5.96 y; n.m.r., T 8.81, 8.96 ( s i n g l e t s , 6H, max „ \ x C H 3 t e r t i a r y methyls, ), 8.98 (doublet, 3H, secondary methyl, CH 3 J = 6.3 Hz). Prepa r a t i o n of A l c o h o l 195 To a s o l u t i o n of (-)-trans-caran-2-one (108) (1.52 g, 0.01 mole) i n 50 ml of dry ether was added 15 ml of 2.13 M et h e r e a l m e t h y l l i t h i u m (0.032 mole), and the r e s u l t i n g mixture was s t i r r e d f o r 3 days. The excess methyl l i t h i u m was destroyed by the cautious a d d i t i o n of 2 ml of water, and the ether l a y e r was d r i e d over anhydrous magnesium s u l f a t e . Removal of the ether at water a s p i r a t o r pressure gave 2.1 g of a pale yellow o i l . This m a t e r i a l was p u r i f i e d by column chromatography on 60 g of f l o r i s i l . The f r a c t i o n s e l u t e d w i t h 1:9 ether:hexane and 1:4 ether:hexane were combined to give 1.65 g (98%) of the a l c o h o l 195, 2fl 21 n n 1.4800; [ a ] n -9.36° (c, 1.0 i n methanol). I n f r a r e d ( f i l m ) , X D D ^ J max 2.95, 9.15, 10.95 y; n.m.r., x 8.3 ( s i n g l e t , IH, exchangeable, 0-H), 8.74, 8.75, 8.95 ( s i n g l e t s , 9H, t e r t i a r y methyls), 9.09 (doublet, 3H, - 141 -secondary methyl, J = 6.5 Hz). Anal. Calcd. f o r CnH2Q0: C, 78.51; H, 11.98. Found: C, 78.63; H, 11.80. (+)-trans-2-Methy1-p-mentha-2,8-diene (196) A mixture o f the a l c o h o l 195 (836 mg, 5 mmoles) and 0.17 ml of p y r i d i n e was placed i n a p y r o l y s i s tube and sealed under an atmosphere of n i t r o g e n . The tube was heated i n an o i l bath at 190° f o r 2 h (35) a f t e r which time i t was cooled and c a r e f u l l y opened. The mixture was d i l u t e d w i t h ether and d r i e d over anhydrous magnesium s u l f a t e . Removal of the solvents at water a s p i r a t o r pressure afforded 730 mg of c o l o u r l e s s o i l . A n a l y s i s of t h i s mixture by g . l . c . (column I , 155°, 200) revealed that i t c o n s i s t e d of a mixture of 70% (+)-trans-2-methyl-p-mentha-2,8-diene (196) and s e v e r a l other u n i d e n t i f i e d components. A sample of 196 p u r i f i e d by p r e p a r a t i v e g . l . c . (column I , 155°, 200) 20 20 e x h i b i t e d n^ 1.4736; +139.3° (c, 3.7 i n methanol). I n f r a r e d ( f i l m ) , X 3.25, 6.08, 11.28 y; n.m.r., T 4.72 (broad s i n g l e t , IH, C 3 v i n y l H, width at h a l f - h e i g h t = 5 Hz), 5.27 (broad s i n g l e t , 2H, i CH3-C=CH_2, width at h a l f - h e i g h t = 3 Hz), 8.27 ( s i n g l e t , 6H, v i n y l methyls), 8.99 (doublet, 3H, secondary methyl, J = 6.4 Hz). Anal. Calcd. f o r C ^ H ^ : C, 87.93; H, 12.07. Found: C, 88.20; H, 11.85. (+)-trans-2-Methyl-p-mentha-2-ene (190) The hydrogenation of the o l e f i n 196 was c a r r i e d out i n benzene at room temperature and atmospheric pressure using t r i s ( t r i p h e n y l p h o s p h i n e ) -- 142 -chlororhodium (83) as the c a t a l y s t . The r e a c t i o n s o l u t i o n was f i l t e r e d through a small column of a c t i v i t y I I alumina. From 240 mg of 196 there was obtained 225 mg of a c l e a r c o l o u r l e s s o i l . A n a l y s i s of t h i s m a t e r i a l by g . l . c . (column E, 110°, 100) showed that i t c o n s i s t e d of 78% (+)-trans-2-methyl-p-mentha-2-ene (190) and s e v e r a l other minor, u n i d e n t i f i e d components. A sample o f d e x t r a r o t a t o r y 190 p u r i f i e d by 20 22 pr e p a r a t i v e g . l . c . (column F, 145°, 200) e x h i b i t e d n^ 1.4602; [ a ] ^ +25.4° (c, 0.6 i n methanol). 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