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Approaches to the synthesis of cadinene sesquiterpenes and the birch reduction of some 4-alkyl-[delta]1,9-2-octalones Phillips, Wynona M. 1971

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APPROACHES TO THE SYNTHESIS OF CADINENE SESQUITERPENES AND THE BIRCH REDUCTION OF SOME 4-ALKYL-A ' -2-OCTALONES 1  9  BY  WYNONA M. PHILLIPS B.Sc.  (Hons.)> U n i v e r s i t y of B r i t i s h  Columbia, 1966  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 required  t h e s i s as conforming t o the  standard  THE UNIVERSITY OF BRITISH COLUMBIA, August, 1971  In  presenting this  thesis  an advanced degree at the L i b r a r y s h a l l I  f u r t h e r agree  the U n i v e r s i t y of B r i t i s h  make i t  freely  that permission  available  for  the requirements  Columbia,  I agree  r e f e r e n c e and  f o r e x t e n s i v e copying o f  this  for  that  study. thesis  s c h o l a r l y purposes may be g r a n t e d by the Head of my Department o r  for  by h i s of  in p a r t i ak^fu 1 f i lment o f  this  written  representatives. thesis  for  financial  i s understood that gain s h a l l  permission.  Department  of  The U n i v e r s i t y o f B r i t i s h Vancouver 8, Canada  Date  It  *  /?  Columbia  7/  not  copying or p u b l i c a t i o n  be allowed without my  ABSTRACT  P a r t o f t h i s t h e s i s d e s c r i b e s the i n v e s t i g a t i o n of s e v e r a l s y n t h e t i c approaches first  approach  to  the cadinane group o f s e s q u i t e r p e n e s .  The  i n v e s t i g a t e d the p r e p a r a t i o n o f a p o s s i b l e key i n t e r m e d i a t e  of type 118 u s i n g the known o c t a l o n e 114 as s t a r t i n g m a t e r i a l . all  attempts  to o b t a i n o c t a l o n e 116, a n e c e s s a r y i n t e r m e d i a t e i n t h i s  sequence were u n s u c c e s s f u l . approach.  The second  conjugated dienone 1,4-conjugate  However  T h i s p r e c l u d e d f u r t h e r use o f t h i s  approach  i n v o l v e d p r e p a r a t i o n of s e v e r a l  cross-  systems (125, 133, 139 and 141) and the study o f  a d d i t i o n o f an a l k y l group by means of cuprous i o n  c a t a l y z e d G r i g n a r d reagents and l i t h i u m d i a l k y l c u p r a t e r e a g e n t s . of reagents i n which the a l k y l group was methyl o r primary the d e s i r e d 1,4-conjugate  addition.  However when  Use  effected  isopropylmagnesium  bromide o r l i t h i u m d i i s o p r o p y l c u p r a t e reagents were t r i e d no a d d i t i o n p r o d u c t s were d e t e c t e d .  Evidence i s p r e s e n t e d which i n d i c a t e s  that  e n o l i z a t i o n o f the k e t o system was the main r e a c t i o n pathway i n these cases.  The f i n a l and most s u c c e s s f u l approach  d e s c r i b e d i s the condensa-  t i o n - a n n e l a t i o n approach where condensation between a v i n y l ketone as 144 and a s u b s t i t u t e d cyclohexanone investigated.  d e r i v a t i v e of type 143 was  Octalones 162 were prepared by the enamine-annelation  r e a c t i o n employing 158.  v i n y l ketone  144 and t h e enamine o f keto  alcohol  The s t e r e o c h e m i s t r y o f o c t a l o n e s 162 was then e s t a b l i s h e d .  mixture o f e p i m e r i c o c t a l o n e s 162 was degraded 165b.  such  to decalones  The  165a and  The s t e r e o c h e m i s t r y o f these decalones was unambiguously shown  by a combination  o f c h e m i c a l and s p e c t r o s c o p i c methods.  - iii  Octalones treatment  -  (162a + 162c) were converted i n t o t h i o k e t a l 166 by  w i t h e t h a n e d i t h i o l and boron t r i f l u o r i d e e t h e r a t e .  Thioketal  166 was converted i n t o a l c o h o l 167 by d e s u l p h u r i z a t i o n employing Raney n i c k e l .  Treatment o f a l c o h o l 167 w i t h chromium t r i o x i d e i n  p y r i d i n e a f f o r d e d o c t a l o n e 168. (+)-cadinene  Octalone  d i h y d r o c h l o r i d e by treatment  f o l l o w e d by treatment  of the r e s u l t a n t  168 was c o n v e r t e d  into  o f the former w i t h m e t h y l l i t h i u m  3° a l c o h o l w i t h  anhydrous  hydrogen c h l o r i d e i n e t h e r . The B i r c h r e d u c t i o n of o c t a l o n e s of type 170 i s d e s c r i b e d . o c t a l o n e s were prepared by 1,4-conjugate a d d i t i o n of l i t h i u m cuprate reagents  t o the c r o s s - c o n j u g a t e d dienones  The  dialkyl-  of type 171.  The  p r e p a r a t i o n of the c o r r e s p o n d i n g a u t h e n t i c c i s - and t r a n s - f u s e d decalones  i s described.  The r e s u l t s o f B i r c h r e d u c t i o n o f o c t a l o n e s  188 to 192 r e v e a l e d a h i g h e r percentage  o f c i s - f u s e d decalone  1 9 than n o r m a l l y o b t a i n e d i n o t h e r s u b s t i t u t e d A ' - 2 - o c t a l o n e The r e s u l t s a l s o i n d i c a t e d  i n c r e a s e d the product decalone  systems.  t h a t as the b u l k o f the C. s u b s t i t u e n t was  4  r a t i o of c i s - f u s e d decalone  also increased.  product  The s u b s t i t u e n t a t the  e f f e c t e d the r a t i o of c i s : t r a n s decalone f o r these r e s u l t s are p r e s e n t e d .  obtained.  to t r a n s - f u s e d position  also  Possible explanations  - iv -  TABLE OF CONTENTS Page TITLE PAGE  i  ABSTRACT  i i  TABLE OF CONTENTS  iv  LIST OF FIGURES  vi  LIST OF TABLES  v i i  ACKNOWLEDGEMENTS  viii  INTRODUCTION  1  I.  General  1  II.  Sesquiterpene B i o s y n t h e s i s  4  III.  S t r u c t u r a l E l u c i d a t i o n and S t e r e o c h e m i c a l S t u d i e s  12  IV.  S y n t h e t i c Approaches t o t h e Cadinane-Type Sesquiterpenes  19  S t u d i e s o f the B i r c h Reduction o f Ketones  32  -V.  a,g-Unsaturated  DISCUSSION  39  I.  General  39  II.  Conjugate  III.  C o n d e n s a t i o n - A n n e l a t i o n Approach  59  IV.  P r o o f o f the S t e r e o c h e m i s t r y o f the Condensation Products  84  V.  Synthesis, o f Cadinene D i h y d r o c h l o r i d e  96  VI.  S t u d i e s on the B i r c h Reductions Systems  A d d i t i o n Approach  40  1 9 of A ' -2-0ctalone 1  A. '•: G e n e r a l  0  0  100  B.  S y n t h e s i s of A  C.  S y n t h e s i s of t r a n s - F u s e d Decalones  1 , 9  -2-Octalone  Systems  101 117  - v -  Page D.  Synthesis of cis-Fused Decalones  128  E.  Lithium-Ammonia Reduction Studies  135  EXPERIMENTAL  147  BIBLIOGRAPHY  206  - vi LIST OF FIGURES Figure  Page  1  N.M.R. Spectrum o f O c t a l o n e 155a  71  2  N.M.R. Spectrum of Octalone 155b  72  3  N.M.R. Spectrum o f O c t a l o n e 157a  75  4  N.M.R. Spectrum o f Octalone 157b  76  5  N.M.R. Spectrum of O c t a l o n e s  (162a + 162c)  82  6  N.M.R. Spectrum of O c t a l o n e s  (162b + 162d)  83  7  N.M.R. Spectrum o f Decalone 165a  89  8  N.M.R. Spectrum of Decalone 165b  90  9  Connected T r a n s i t i o n s f o r a Two-Spin System  92  10  .  N.M.R. Spectrum of O c t a l o n e 190  H4  11  N.M.R. Spectrum of O c t a l o n e 192  116  12  N.M.R. Spectrum o f t r a n s - F u s e d Decalone 209  124  13  N.M.R. Spectrum o f t r a n s - F u s e d Decalone 216  129  14  N.M.R. Spectrum o f c i s - F u s e d Decalone 219  132  15  N.M.R. Spectrum o f c i s - F u s e d Decalone 221  134  - vii LIST OF TABLES Table  Page  I  Chemical S h i f t s and S p l i t t i n g s f o r Decalone 165a ...  92  II  Chemical S h i f t s and S p l i t t i n g s f o r Decalone 165b ...  93  III  Results Obtained from the B i r c h Reduction of Octalones 188-192  138  - viii -  ACKNOWLEDGEMENTS I wish to express my sincere thanks to Dr. Edward P i e r s f o r h i s e x c e l l e n t guidance throughout the course of t h i s research. I t has been a very rewarding experience working under h i s d i r e c t i o n . My thanks are extended to a l l the members of Dr. P i e r s ' research group f o r t h e i r many worthwhile discussions. I wish to thank Mr. C. Grant f o r performing the INDOR experiments and f o r many h e l p f u l discussions. The able typing of t h i s thesis by Miss Diane Johnson i s greatly, appreciated. The f i n a n c i a l support from the N a t i o n a l Research Council of Canada (1966-1970) i s g r a t e f u l l y I wish to thank my fianc£  acknowledged.  f o r h i s encouragement throughout  t h i s study and f o r h i s help i n the preparation of t h i s manuscript. Also I wish to thank Mr. Paul Worster f o r proof reading the e n t i r e thesis.  - 1-  INTRODUCTION I.  General Terpenoids are a class of n a t u r a l l y occurring compounds character-  i z e d by a common b u i l d i n g block, the isoprene u n i t ( 1 ) . Terpenoids are  1  subdivided according to the number of isoprene units embodied i n their structure.  The group containing three such u n i t s , that i s  f i f t e e n carbon atoms, are c a l l e d sesquiterpenes. There i s an ever widening v a r i e t y of compounds which f a l l i n t o t h i s c l a s s - at l e a s t f o r t y d i f f e r e n t types to date (1). They may.be 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 .  Generally, each s k e l e t a l type  can possess stereochemical v a r i a t i o n s , p o s i t i o n a l isomerism, as w e l l as a range of f u n c t i o n a l groups, such as, ketones, a l c o h o l s , lactones and oxides. The common biogenesis of terpenoids was postulated by Ruzicka, Eschenmoser and Heusser, i n 1953, as the Isoprene Rule C 2 ) • The l a t t e r was restated as the Biogenetic Isoprene Rule by Ruzicka, Eschenmoser, Jeger and A r i g o n i , i n 1955, to include compounds formed  - 2 -  by the u n i o n o f i s o p r e n e u n i t s f o l l o w e d by s k e l e t a l rearrangements ( 3 ) . For example, t h i s r u l e a l l o w e d compounds such as eremophilene (2) t o be f o r m a l l y c l a s s i f i e d as  sesquiterpenes.  A l t h o u g h s e s q u i t e r p e n e s have been r e c o g n i z e d f o r over a c e n t u r y , i t has n o t been u n t i l r e c e n t y e a r s t h a t m e a n i n g f u l t i o n has been c a r r i e d out.  structural elucida-  T h i s i s m a i n l y a t t r i b u t a b l e t o the  fact  t h a t s e s q u i t e r p e n e s u s u a l l y occur i n e s s e n t i a l o i l s as v e r y complex mixtures.  I n p a s t y e a r s f r a c t i o n a l d i s t i l l a t i o n was  used f o r s e p a r a t i o n .  Hence, much work was  the o n l y means  c a r r i e d out w i t h  w h i c h were not homogeneous and o f t e n erroneous  substances  conclusions resulted.  Only i n r e c e n t y e a r s w i t h the advent of s e p a r a t i o n t e c h n i q u e s such  as  g a s - l i q u i d chromatography ( g . l . c . ) and t h i n l a y e r chromatography has s e p a r a t i o n of these complex m i x t u r e s been r e a l i z e d . One  of the l a r g e s t groups of s e s q u i t e r p e n e s i s the cadinane  class,  w h i c h c o n t a i n s the b a s i c s k e l e t o n and numbering system shown i n _3. 15  The  - 3 -  b a s i c cadinane c l a s s has been d i v i d e d i n t o f o u r subgroups, only  i n the r e l a t i v e s t e r e o c h e m i s t r y  at C. , C, and C,. 1  t i o n s are e x e m p l i f i e d  D  differing  These  classifica-  /  by the f o l l o w i n g s t r u c t u r a l formulae:  cadinane  (4) , muurolane (5_) , b u l g a r a n e (6) and amorphane (7) (4) .  t  H  6 Naturally  1_  occurring  compounds b e l o n g i n g to the cadinane c l a s s  occur as hydrocarbons, f o r example, 6-cadinene f o r example, r - c a d i n o l  (8) ( 4 , 5 , 6 ) ,  (9) ( 5 , 7 ) , i n r i n g c o n t r a c t e d  forms, f o r example, oplopanone  (10)  and  alcohols,  oxygenated  (8,9) and t r i c y c l i c s t r u c t u r a l  v a r i a n t s , f o r example, a-cubebene (11) (10).  £  H  - 4 -  10  The and  work of n a t u r a l p r o d u c t chemists  s y n t h e s i s of t e r p e n o i d s  more b i o l o g i c a l in  l l  this  i n v e s t i g a t i o n s of  the  cadinane c l a s s of  Sesquiterpene  b i o l o g i c a l C,_  m e t h y l g l u t a r y l CoA  and  synthetic  (Chart  (13).  An  of  three;  cyclization  It i s generally  C,. u n i t a r i s e s f r o m a c e t y l CoA  the p h e n o l i c  of  two  (12) b y  three  I , Route I) to a f f o r d 3-hydroxy-B-  a l t e r n a t e mode o f c o n d e n s a t i o n  groups of n a t u r a l p r o d u c t s ,  r e s i n s (Chart  of a c e t y l  intermediate  the  acetogenins  I , Route I I ) .  o f 3 - h y d r o x y - B - m e t h y l g l u t a r y l CoA  adenine d i n u c l e o t i d e phosphate This  described  t o a s t r a i g h t c h a i n d e r i v a t i v e JL4, w h i c h i s b e l i e v e d  the p r e c u r s o r  Reduction  the union  a v a r i e t y of  s k e l e t a l rearrangements.  condensations  gives r i s e  d e r i v e d by  i s o p r e n o i d u n i t s , f o l l o w e d by  (1,11) t h a t the  successive  t o be  Thus, the work  sesquiterpenes.  a r e b e l i e v e d t o be  modes, w i t h o r w i t h o u t  CoA  terpenoids.  for  Biosynthesis  Sesquiterpenes  believed  i s e s s e n t i a l for a firm foundation  t h e s i s i s , i n p a r t , concerned w i t h gaining a general  entry into  II.  in structural elucidation  (13) w i t h  nicotinamide-  (NADPH) a f f o r d s m e v a l o n i c a c i d  i s phosphorylated  w i t h adenine triphosphate  (15). (ATP)  and  - 6 -  s u b s e q u e n t l y d e c a r b o x y l a t e s to form i s o p e n t e n y l pyrophosphate (16). 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 16_ a f f o r d s  dimethylallyl  pyrophosphate  (17) , which upon c o n d e n s a t i o n w i t h 16_ a f f o r d s  pyrophosphate  ( 1 8 ) , the monoterpene p r e c u r s o r .  of  g e r a n y l pyrophosphate  f a r n e s y l pyrophosphate It either  i s believed  geranyl  Further condensation  (18) w i t h i s o p e n t e n y l pyrophosphate  yields  ( 1 9 ) , the a c t i v e p r e c u r s o r o f the s e s q u i t e r p e n e s .  (12) t h a t a l l s e s q u i t e r p e n e s can be formed  t r a n s - or c i s - f a r n e s y l pyrophosphate,  (19) and  from  (20) r e s p e c t i v e l y ,  by p r o c e s s e s i n v o l v i n g i n v i v o t r a n s f o r m a t i o n s f o r m a l l y r e s e m b l i n g c a t i o n i c a l l y induced t r a n s a n n u l a r c y c l i z a t i o n s .  I t i s understood o f ,  course, that i n t h i s d i s c u s s i o n the r e p r e s e n t a t i o n of f o r m a l charges i s o n l y a convenient symbolism,  as i n l i v i n g systems  f a r n e s y l pyro-  phosphate i s p r o b a b l y enzyme bound and the c y c l i z a t i o n s p r o b a b l y f u l l y or  p a r t i a l l y concerted. In  the r e p r e s e n t a t i o n shown i n Chart I I , the i n i t i a l  as the i o n i z a t i o n of the a l l y l i c  s t e p i s shown  pyrophosphate group from _19_ o r 20.  The c e n t r a l or t e r m i n a l double bond can p a r t i c i p a t e w i t h the r e s u l t i n g c a t i o n from c i s - f a r n e s y l pyrophosphate to  (20) to g i v e r i s e  to c a t i o n s Z l  2A_, w h i l e f o r s t e r i c reasons o n l y the t e r m i n a l double bond can  i n t e r a c t w i t h the c a t i o n from t r a n s - f a r n e s y l pyrophosphate g i v i n g to  c a t i o n s 25_ and 2^6.  These r e s u l t i n g c a t i o n s _21 to 26^ can  rise  undergo  p r o t o n l o s s , i n t e r a c t i o n w i t h n u c l e o p h i l e s or a s e r i e s of f u r t h e r rearrangements. Germacrene D (27), a n a t u r a l l y o c c u r r i n g ten-membered  carbocyclic  r i n g compound, has r e c e n t l y been i s o l a t e d by H i r o s e et a l . (13) from the  e s s e n t i a l o i l of PseudotsUga j a p o n i c a .  I t s presence has a l s o  been  - 8 -  noticed i n a v a r i e t y of other e s s e n t i a l o i l s (13).  I t has been  postulated that germacrene D (27) could be a c r u c i a l intermediate i n the biosynthesis of s e v e r a l cadinene compounds (13).  While no in vivo  experimental work has been done to v e r i f y i t s intermediacy i n b i o s y n t h e s i s , laboratory r e s u l t s strongly support t h i s hypothesis  (see  Chart I I I ) . Germacrene D (27) , was  smoothly converted  i n t o a mixture of y-  muurolene (28), a-amorphane (29), 6-cadinene (8) and y-cadinene (30), thermally, on s i l i c a g e l or by a c i d i s o m e r i z a t i o n .  From chemical  spectroscopic data, Hirose (13) proposed that the preferred  and  conformation  of germacrene D i s _3JL, where there are transannular i n t e r a c t i o n s between the endocyclic double bonds.  I t was  suggested (13) that at l e a s t the  y-isomers of the cadinane group most probably a r i s e through t h i s intermediate and the c y c l i z a t i o n was postulated as i n 32.  32  Several other postulates f o r the biosynthesis of cadinenes have been proposed and are represented  diagrammatically  i n Chart IV.  Cation  21 was postulated to deprotonate with subsequent double bond isomerizat i o n to a f f o r d t r i e n e ^33, followed by c y c l i z a t i o n to a f f o r d cation 34. This cation could then be deprotonated to y i e l d , f o r example, 5-cadinene (81.  - 9 -  Chart I I I  31  - 10 -  C h a r t IV  - 11 -  A second proposal involved c a t i o n 2_3, which could undergo a 1,3hydride s h i f t to c a t i o n _35_, followed by c y c l i z a t i o n to y i e l d c a t i o n 36. Hydration of t h i s cation from the ot-face would give r i s e to T-cadinol (9), while deprotonation from Cg or from or; 5-cadinene C8) , r e s p e c t i v e l y .  would a f f o r d a-muurolene (37)  The other members of the cadinane  family can be derived by analogous processes.  For example, i f c a t i o n  23 were to undergo two 1,2-hydride s h i f t s and then followed through the above processes, the stereochemistry of the bulgarane amorphane (_7) groups would r e s u l t .  (6) and  These t h e o r e t i c a l c y c l i z a t i o n s  have received some experimental support by Hirose and coworkers ( 4 ) , who have a r t i f i c i a l l y generated some of the above cations i n the laboratory and have indeed i s o l a t e d a mixture of cadinane-type as the rearrangement products.  7  6  sesquiterpenoids  - 12 III.  S t r u c t u r a l E l u c i d a t i o n and S t e r e o c h e m i c a l  Studies  S i n c e p a r t of t h i s t h e s i s i s concerned w i t h g a i n i n g a s y n t h e t i c e n t r y i n t o the cadinane c l a s s o f s e s q u i t e r p e n e s ,  i t i s pertinent to  d i s c u s s the s t u d i e s w h i c h l e d t o the e s t a b l i s h m e n t stereochemistry  o f the cadinene group.  of the s t r u c t u r e and  Since p u b l i c a t i o n s d e a l i n g  w i t h t h i s t o p i c a r e numerous and complex, i t i s n e c e s s a r y t o l i m i t d i s c u s s i o n to s e v e r a l examples. s t r u c t u r e and s t e r e o c h e m i s t r y  Hence, o n l y the e s t a b l i s h m e n t  this  of  o f g-cadinene, u s i n g c l a s s i c a l methods,  of a-cadinene, u s i n g modern c h e m i c a l  and s p e c t r o s c o p i c methods, and  of cadinene d i h y d r o c h l o r i d e , u s i n g a c o m b i n a t i o n of methods, w i l l be d i s c u s s e d i n any d e t a i l . Semmler and S t e n z e l ( 1 4 ) , i n 1914, and R u z i c k a and coworkers ( 1 5 ) , i n 1924, proposed s t r u c t u r e ^38 f o r cadinene.  double bonds remained u n c e r t a i n , R u z i c k a  W h i l e t h e l o c a t i o n o f the  confirmed  the b a s i c carbon  s k e l e t o n by d e h y d r o g e n a t i o n of cadinene t o c a d a l e n e ( 3 9 ) . Campbell and S o f f e r ( 1 6 ) , i n 1942, proposed s t r u c t u r e 40_ f o r cadinene r e g e n e r a t e d  40  from cadinene d i h y d r o c h l o r i d e  41  (41) .  The l a t t e r  - 13 compound was f i r s t p r e p a r e d i n 1840 by S o u b e i r a n and C a p i t a i n e from cubeba o i l ( 1 7 ) . the  From t h a t time f o r w a r d t h i s d e r i v a t i v e , a l o n g w i t h  c o r r e s p o n d i n g d i h y d r o b r o m i d e , have p l a y e d a major r o l e i n i d e n t i f i -  c a t i o n and i s o l a t i o n of cadinene compounds.  These c r y s t a l l i n e d e r i v a t i v e s  circumvented the major problem t h a t plagued workers i n t h i s  field,  t h a t i s , t h e i n s e p a r a b i l i t y o f the s t r u c t u r a l l y s i m i l a r cadinene compounds. The s t r u c t u r e and s t e r e o c h e m i s t r y of (-)-cadinene was determined by H a n i c i n 1958  (18).  dihydrobromide  He c a r r i e d out an X-ray  structural  d e t e r m i n a t i o n to c o n f i r m s t r u c t u r e 4_2 or i t s m i r r o r image f o r (-)cadinene dihydrobromide.  42  The d i p o l e moment of t h i s compound was determined and found t o be i n good a c c o r d w i t h s t r u c t u r e 42_ ( 1 9 ) . of'42 was  The a b s o l u t e c o n f i g u r a t i o n  then i n v e s t i g a t e d by Herout et a l . (19,20).  The  relative  c o n f i g u r a t i o n at p o s i t i o n s 1, 6 and 7 i s m a i n t a i n e d d u r i n g f o r m a t i o n of  the d i h y d r o h a l i d e d e r i v a t i v e s ; hence, the d e t e r m i n a t i o n of the  a b s o l u t e c o n f i g u r a t i o n of o n l y one of these c e n t e r s was n e c e s s a r y t o f i x the a b s o l u t e c o n f i g u r a t i o n of the n a t u r a l l y o c c u r r i n g compounds.  cadinene  (-)-Cadinene d i h y d r o c h l o r i d e was dehydrohalogenated w i t h  g l a c i a l a c e t i c a c i d - s o d i u m a c e t a t e to y i e l d a m i x t u r e of hydrocarbons w i t h 3-cadinene (40) p r e d o m i n a t i n g .  T h i s m i x t u r e was  then s u b j e c t e d  to o x i d a t i v e d e g r a d a t i o n to o b t a i n o n l y s l i g h t l y racemized D-(+)isopropylsuccinic  a c i d (43).  T h i s f i x e s the a b s o l u t e c o n f i g u r a t i o n a t C  - 14 -  The 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 product of a - c a d i n o l was  (o.r.d.) curve of a d e g r a d a t i o n  also investigated.  The o . r . d . curve of the  d e g r a d a t i o n p r o d u c t , decalone 44_, bore a m i r r o r image r e l a t i o n s h i p  to  the o.r.d. curve o f decalone _45, of known a b s o l u t e c o n f i g u r a t i o n . These r e s u l t s are i n agreement w i t h the a s s i g n e d a b s o l u t e c o n f i g u r a t i o n shown i n s t r u c t u r e 42 f o r (-)-cadinene  dihydrobromide.  As mentioned e a r l i e r the major product from of cadinene d i h y d r o c h l o r i d e was was  the f i r s t  cadinene  However "the v e r y pure cadinene" was Campbell with  and S o f f e r  Thus, t h i s  hydrocarbon  compound to be r e a d i l y a v a i l a b l e f o r i n v e s t i g a t i o n . g-cadinene"(21)  o b t a i n e d as  "regenerated  (16) t r e a t e d the d i e p o x i d e of r e g e n e r a t e d  cadinene  methylmagnesium i o d i d e and s u b j e c t e d the r e s u l t a n t product thus o b t a i n i n g a 3% y i e l d  (see Chart V ) .  of  (23) r e p e a t e d  this  and i s o l a t e d at l e a s t f o u r d i f f e r e n t d i e p o x i d e s .  of the d i e p o x i d e s formed was  then dehydrogenated  on  c h a r c o a l at 265° f o r 1 h t o g i v e a mixture of cadalene hydroxycadalene  to  2,7-dimethylcadalene  S u t h e r l a n d and c o l l a b o r a t o r s  e p o x i d a t i o n experiment One  (40).  shown to be a mixture w i t h at l e a s t n i n e components (22).  dehydrogenation, (46)  g-cadinene  dehydrohalogenation  (47) and  7-hydroxycadalene  (48).  palladised (39) , 2-  - 15 -  Chart V  - 16 -  Herout et a l . (22) r e i n v e s t i g a t e d t h e i r "very pure g-cadinene". an e l a b o r a t e combination of s e p a r a t i o n t e c h n i q u e s they i s o l a t e d  By  g-  cadinene which formed one c r y s t a l l i n e d i e p o x i d e , i d e n t i c a l w i t h the one which had been dehydrogenated  by S u t h e r l a n d .  Herout  then c a r r i e d out  a h y d r o b o r a t i o n - o x i d a t i o n of g-cadinene t o o b t a i n d i k e t o n e ^9_, which upon deuterium exchange i n c o r p o r a t e d s i x deuterium atoms.  Hence, a l l  these r e s u l t s s u b s t a n t i a t e s t r u c t u r e 40_ f o r g-cadinene. Naya and Kotake  (24) u s i n g modern t e c h n i q u e s e l u c i d a t e d  s t r u c t u r e of the most r e c e n t l y i s o l a t e d T h e i r work i s i n s t r i k i n g  contrast  c a d i n e n e , a-cadinene (50).  to the i n c o n s i s t e n c i e s and  c o n t r o v e r s i e s of the e a r l i e r s t r u c t u r a l e l u c i d a t i o n s . ^15^24'  w  a  S  i °l s  a t e  d>  The n u c l e a r magnetic  i-  n  1969,  from Japanese hop  resonance  structural  The s e s q u i t e r p e n e ,  (Humulus l u p u l u s L . ) .  (n.m.r.) spectrum of t h i s compound gave  evidence f o r an i s o p r o p y l group, x 9.22  and x 9.09  p r o t o n d o u b l e t s , two v i n y l methyl groups, x 8.35 s i n g l e t s , and two v i n y l hydrogens, multiplets.  the  x 4.68  as a p a i r of t h r e e -  as broad t h r e e - p r o t o n  and x 4.48  as one-proton  The mass spectrum showed a m o l e c u l a r i o n peak at m/e  a base peak at m/e  105, and an abundant  peak at m/e  161  204,  (M-43).  Upon p a r t i a l h y d r o g e n a t i o n w i t h p l a t i n u m oxide i n methanol-ether a-cadinene  (50) gave a s i n g l e p r o d u c t , which was  d i h y d r o compound prepared from y c a d i n e n e 50 w i t h dry hydrogen chloride  (41).  (31).  chloride i n ether afforded  The i n f r a r e d  from t h a t of g-cadinene.  i d e n t i c a l w i t h the Treatment  (-)-cadinene d i h y d r o -  ( i . r . ) spectrum of a-cadinene was  T h e r e f o r e , the Japanese workers  s t r u c t u r e 50 f o r a-cadinene.  of hydrocarbon  distinct  proposed  - 17 -  In 1966, Westfelt (25) i s o l a t e d y c a d i n e n e (31) from a high b o i l i n g f r a c t i o n of Swedish s u l f a t e turpentine. the c l o s e l y r e l a t e d Y 2 ~  c a  di  n e n e  Bhattacharyya i s o l a t e d  (51) from Indian v e t i v e r o i l (26).  Herout and Santany (27) proposed s t r u c t u r e j3 f o r 6-cadinene. After some controversy  (28), Hirose et a l . ( 4 ) and Dev et a l . ( 5 ) ,  i n 1968, independently confirmed s t r u c t u r e 8^ f o r 6-cadinene.  A  compound of s t r u c t u r e .52 was mistakenly c a l l e d 6-cadinene (28) but Sutherland et a l . (6) showed 5J2 to be a d i s t i n c t cadinene compound and named i t w-cadinene. Westfelt et a l . , i n 1964, (29) i s o l a t e d e-cadinene (53) which was d i f f e r e n t from the p r e v i o u s l y i s o l a t e d e-cadinene (21).  Westfelt's  d e f i n i t i v e work showed E-cadinene to have s t r u c t u r e .53 and the p r e v i o u s l y i s o l a t e d compound to be e-muurolene (54).  - 18 -  Two cadinols have been i s o l a t e d to date. They are a-cadinol (55) and T-cadinol  (9) (30,7).  There have been at l e a s t eight p u b l i c a t i o n s  dealing with the structure of 6-cadinol, with chemical and s p e c t r a l evidence being put forward to support four d i f f e r e n t s t r u c t u r e s . alcohol has been named 6-cadinol (33),  and (-)-torreyol (34).  (5,31,30), a b i c a u l o l (32), cedrelanol I t  i  s  now becoming c l e a r that t h i s alcohol does not belong to the cadinane c l a s s but rather to the muurolane c l a s s (_5). Thus, 6-cadinol i s now proposed to possess s t r u c t u r e 5_6_ (5). OH  This  - 19 -  IV«  Synthetic Approaches to the Cadinane-type  Sesquiterpenes  At the time t h i s work was undertaken there were no published syntheses of cadinene hydrocarbons.  However r e c e n t l y s e v e r a l syntheses  have been published. In 1960 Dev et al.(35,36) synthesized diketone 62^ f o r comparison w i t h the ozonolysis product from -cadinene (53). e  i s o u t l i n e d i n Chart VI.  The route involved the reduction of 4-  isopropyl-6-methoxytetralone give a l c o h o l 58.  Their approach  (57) w i t h l i t h i u m aluminum hydride to  B i r c h reduction of .58 w i t h sodium i n l i q u i d ammonia  containing ethanol as co-solvent and proton source proceeded i n 65% y i e l d to a f f o r d a l c o h o l 59.  This two-step sequence was necessary  since  B i r c h reduction of the s t a r t i n g t e t r a l o n e _57_ r e s u l t e d i n the formation  53  41  -  21  -  of a major b y - p r o d u c t , the h y d r o g e n o l y s i s  product.  t i o n o f 59_ a f f o r d e d a m i x t u r e o f o c t a l o n e  e n o l e t h e r s j>0 and 6 1 .  Octalone enol ether  6>0_ was i s o m e r i z e d  e n o l e t h e r 61_ when s u b j e c t e d  Oppenhauer  t o the f u l l y  conjugated  lithium i n liquid  f o l l o w e d by treatment o f t h e r e s u l t i n g p r o d u c t w i t h  dione ( 6 2 ) . mechanistic  and  aqueous h y d r o c h l o r i c  o f t h i s p r o d u c t was p r e d i c t e d  o f the B i r c h r e d u c t i o n .  spectrum of dione 62^ was i d e n t i c a l w i t h of e-cadinene ( 5 3 ) .  ammonia,  (±)-4-isopropyl-trans-decalin-l,6-  The s t e r e o c h e m i s t r y considerations  octalone  t o chromatography on b a s i c alumina.  O c t a l o n e e n o l e t h e r ^60 was reduced w i t h  a c i d to a f f o r d , i n 3 0 % y i e l d ,  oxida-  The i n f r a r e d  t h a t o f the o z o n o l y s i s  Dione j52 was t r e a t e d w i t h  from  excess  product  methyllithium  the r e s u l t i n g g l y c o l t r e a t e d w i t h gaseous hydrogen c h l o r i d e t o  afford, i n 20% yield,  (±)-cadinene d i h y d r o c h l o r i d e  m a t e r i a l was i d e n t i c a l an a u t h e n t i c  (41).  ( i n f r a r e d spectrum, mixed m e l t i n g  sample p r e p a r e d from  (±)-6-cadinene  The s y n t h e t i c point)  with  and anhydrous hydrogen  chloride. More r e c e n t l y , S o f f e r and Gunay ( 3 7 , 3 8 )  prepared  dihydrochloride  s t a r t i n g from the monoterpenoid  Their synthesis  i s o u t l i n e d i n Chart  VII.  (+)-cadinene  (-)-cryptone ( 6 3 ) .  The c r u c i a l step i n t h e i r  s y n t h e s i s i n v o l v e d the D i e l s - A l d e r a d d i t i o n o f the d i e n o p h i l e , 2 ethoxybutadiene-1,3  ( 6 4 ) to (-)-cryptone.  from the s i d e t r a n s to the b u l k y decalone e n o l e t h e r _6_5. decalone e n o l e t h e r  i s o p r o p y l group a f f o r d e d  syn-cis-  T h i s was f o l l o w e d by a c i d h y d r o l y s i s of the  6v5 and base-promoted e p i m e r i z a t i o n o f the c i s  r i n g j u n c t i o n t o the more s t a b l e (62).  A d d i t i o n o f the d i e n o p h i l e  (+)-4-isopropyl-trans-decalin-l,6-dione  T h i s compound was shown t o be the enantiomer o f the product o f  - 22 -  Chart V I I  - 23 -  ozonolysis of e-cadinene.  The o p t i c a l l y a c t i v e diketone 62^ was treated  with excess methyllithium and then dry hydrogen c h l o r i d e to a f f o r d (+)-cadinene d i h y d r o c h l o r i d e , m.p.  116-117°.  This product  was  i d e n t i c a l w i t h an authentic sample obtained from r e a c t i o n of (-)-y2  _  cadinene w i t h hydrogen c h l o r i d e . Within the past year several syntheses of cadinene hydrocarbons have been reported.  In each case, e i t h e r the decalone enol  ether  65 or the decalone enol ether 66_ was used as the s t a r t i n g m a t e r i a l . Soffer and Burk (39), u t i l i z e d the cis-decalone enol ether 6j5 as their starting material. enetriphenylphosphorane trans-fused product.  Treatment of the l a t t e r w i t h e i t h e r methyl-  or methyllithium afforded the  corresponding  Hence, they proposed that f i r s t a f a s t r e v e r s i b l e  e n o l i z a t i o n - e p i m e r i z a t i o n took place, followed by a n u c l e o p h i l i c attack on the carbonyl carbon.  Therefore, they converted i n one step, the  cis-decalone enol ether 65_ i n t o the trans o l e f i n i c enol ether 67 employing  methylenetriphenylphosphorane.  Hydrolysis of the enol ether  group was e f f e c t e d , i n 60% y i e l d , by treatment w i t h 0.5 N hydrogen c h l o r i d e i n 95% ethanol f o r 25 min  at room temperature.  The trans  nature of the r i n g j u n c t i o n was shown by a strong p o s i t i v e Cotton e f f e c t i n the o.r.d. curve of the r e s u l t i n g product 6>8_. ketone  The  olefinic  was converted i n 70% y i e l d i n t o (+)-e-cadinene by a second  W i t t i g r e a c t i o n using methylenetriphenylphosphorane.  The s y n t h e t i c  e-cadinene was i d e n t i c a l with the n a t u r a l l y occurring compound i n a l l respects.  The s y n t h e t i c (+)-e-cadinene was converted at low tempera-  ture i n t o (+)-cadinene dihydrochloride. This c r y s t a l l i n e d e r i v a t i v e was obtained by a second pathway (see Chart V I I I ) .  M e t h y l l i t h i u m was  - 24 -  Chart V I I I  65  -25 -  added to cis-decalone enol ether 6jj, followed by thorough e x t r a c t i o n of the ether w i t h sodium b i s u l f i t e s o l u t i o n y i e l d i n g d i r e c t l y the h y d r o l y s i s product 69_. Treatment of 69_ with m e t h y l l i t h i u m , followed by anhydrous hydrogen c h l o r i d e afforded (+)-cadinene dihydrochloride. K e l l y and Eber (40) u t i l i z e d the trans-decalone  enol ether 6j)  as s t a r t i n g m a t e r i a l f o r t h e i r synthesis of Y2~cadinene.  Their synthesis  i s o u t l i n e d i n Chart IX. Lithium aluminum hydride reduction of 66_ afforded, i n 73% y i e l d , a l c o h o l 70. Hydrolysis of the enol ether group was e f f e c t e d i n 95% y i e l d by treatment of 70. w i t h o x a l i c a c i d i n methanol.  The r e s u l t i n g keto a l c o h o l 71_ was converted i n t o the d i o l  72 by the Grignard r e a c t i o n , using  methylmagnesium i o d i d e .  Selective  dehydration of the t e r t i a r y a l c o h o l was s u c c e s s f u l l y c a r r i e d out, i n 80% y i e l d , by s t i r r i n g w i t h p_-toluenesulfonic a c i d i n benzene at 52° f o r 2 h.  Sarett o x i d a t i o n of the secondary a l c o h o l of _73 gave a 65%  y i e l d of octalone 7_4_. This compound was smoothly converted i n t o y^cadinene by r e a c t i o n w i t h methylenetriphenylphosphorane. of s y n t h e t i c y^-cadinene  Treatment  w i t h hydrogen c h l o r i d e gave a 60% y i e l d of  cadinene dihydrochloride.  The s p e c t r a l data of s y n t h e t i c Y2~ ' 'cac  :  nene  were i d e n t i c a l i n a l l respects w i t h those of the n a t u r a l l y occurring compound. Vig and coworkers (41) r e c e n t l y synthesized (+)-y-cadinene by the method o u t l i n e i n Chart X.  The key step i n t h i s synthesis involved 4 5  a D i e l s - A l d e r r e a c t i o n which f i x e d the p o s i t i o n of the A ' bond.  double  The s t a r t i n g m a t e r i a l f o r t h e i r synthesis was 2-isopropyl-4-  carbethoxybutanal  75 prepared by the a l k y l a t i o n of the p i p e r i d i n e  enamine of isovalerald.ehyde w i t h e t h y l a c r y l a t e . W i t t i g r e a c t i o n of  - 27 -  Chart X  1) MeOH-H„0-KOH  I  76  2)  Cu  80  81  -  28  -  75 w i t h m e t h a l l y l i d e n e t r i p h e n y l p h o s p h o r a n e gave, i n 65% y i e l d , e s t e r 76^  Formation  diene  of ( 3 - k e t o - s u l f o x i d e 810, f o l l o w e d by r e d u c t i o n w i t h  aluminum amalgam i n aqueous t e t r a h y d r o f u r a n c o n v e r t e d diene e s t e r 76_ i n compound 81, which was solanone 76.  (81).  i d e n t i c a l w i t h n a t u r a l l y o c c u r r i n g (+)-  T h i s c o n v e r s i o n c o n f i r m e d the s t r u c t u r e of diene  ester  The D i e l s - A l d e r a d d i t i o n of e t h y l a c r y l a t e to diene e s t e r _76  afforded mainly l-methyl-4-carbethoxy-3-(isopropyl-3-carbethoxy-n.-propyl)cyclohex-l-ene  (77).  T h i s d i e s t e r 77_ was  s u b j e c t e d t o potassium  b u t o x i d e i n t e r t - b u t a n o l to a f f o r d , i n 65% y i e l d ,  tert-  the Dieckmann  H y d r o l y s i s o f 78_ w i t h aqueous  c o n d e n s a t i o n p r o d u c t , keto e s t e r 78^.  m e t h a n o l i c potassium h y d r o x i d e , f o l l o w e d by d e c a r b o x y l a t i o n over copper powder a f f o r d e d o c t a l o n e 79.  T h i s o c t a l o n e was  W i t t i g r e a c t i o n w i t h methylenetriphenylphosphonium hydride-dimethylsulfoxide (31).  The  to y i e l d ,  subjected to  i o d i d e i n sodium  i n 75% y i e l d ,  (t)-y-cadinene  s y n t h e t i c m a t e r i a l gave an i n f r a r e d spectrum  i d e n t i c a l with  t h a t o f the n a t u r a l l y o c c u r r i n g y - c a d i n e n e . Interesting  s t r u c t u r a l v a r i a n t s o f the cadinene  e x e m p l i f i e d by a-cubebene (11) and  g-cubebene (82).  s k e l e t o n are Recently  syntheses of these compounds have appeared i n the l i t e r a t u r e  two (42,43).  Both syntheses employed as the key step 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 o l e f i n i c  diazoketone  t o generate  r e a c t i o n sequence of Y o s h i k o s h i and  the t r i c y c l i c  coworkers  skeleton.  The  (42) i s o u t l i n e d i n  Chart XI. Treatment of (-)-trans-caran-2-one  (83) w i t h  allylmagnesium  bromide, f o l l o w e d by h y d r o b o r a t i o n - o x i d a t i o n y i e l d e d 20% of d i o l 84_.  crystalline  O x i d a t i o n w i t h chromium t r i o x i d e i n p y r i d i n e a f f o r d e d the  - 29 Chart X I  90  82  11  - 30 -  spirolactone j8_5 i n q u a n t i t a t i v e y i e l d .  P y r o l y s i s of lactone 85_ i n a  sealed tube at 250° with a small amount of p y r i d i n e present a 70% y i e l d of diene a c i d 86.  afforded  The diazoketone '_87 was prepared from  the a c i d 86_ by standard procedures.  Treatment w i t h copper powder i n  r e f l u x i n g cyclohexane gave a mixture of cyclopropyl ketones 88_, 8£ and £0 i n 11, 13 and 1% y i e l d s r e s p e c t i v e l y , from s p i r o l a c t o n e 85. Hydrogenation of ketone  using 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 -  rhodium as c a t a l y s t afforded ketone 9JL which was i d e n t i c a l with the ozonolysis product of g-cubebene.  Treatment of t h i s ketone 91. with  methylenetriphenylphosphorane afforded s y n t h e t i c g-cubebene (82) which was i d e n t i c a l i n a l l respects w i t h the n a t u r a l l y occurring compound. Addition of methyllithium to ketone 9_1 r e s u l t e d i n attack of the methyl group from the side opposite to the cyclopropane r i n g to a f f o r d cubebol (92).  Dehydration of cubebol with t h i o n y l c h l o r i d e - p y r i d i n e y i e l d e d  a-cubebene (11) and g-cubebene (82) i n a 7:2 r a t i o .  The s y n t h e t i c  compounds were i d e n t i c a l i n every respect with the n a t u r a l l y occurring compounds. The synthesis of P i e r s and coworkers (43) i s o u t l i n e d i n Chart XII.  Hydroxymethylene d e r i v a t i v e S>4 was formed, i n 88% y i e l d , by  condensation of commercial (i)-menthone and  (+)-isomenthone w i t h e t h y l  formate i n the presence of sodium methoxide i n benzene.  Treatment of  94 with n-butanethiol i n the usual manner gave an 89% y i e l d of the nbutylthiomethylene  d e r i v a t i v e _95_.  sodium borohydride  afforded B-hydroxythioenol  yield.  Reduction of 95_ with b a s i c  methanolic  ether 9_6 i n q u a n t i t a t i v e  Hydrolysis of 9j5 w i t h 1% hydrochloric acid i n aqueous acetone  afforded a mixture of t h i o e n o l ether 97_ and the desired aldehyde '9_8, i n a r a t i o of 5:4, r e s p e c t i v e l y .  a,g-unsaturated  Sodium borohydride  - 32 -  r e d u c t i o n o f aldehyde £ 8 p r o v i d e d , i n 91% y i e l d , a l c o h o l 9 £ and a l c o h o l 99a, e p i m e r i c a t the carbon b e a r i n g the i s o p r o p y l group.  Preparation of  the c o r r e s p o n d i n g t r i m e t h y l s i l y l e t h e r d e r i v a t i v e s , f o l l o w e d by p r e p a r a t i v e g . l . c . i s o l a t i o n a f f o r d e d e p i m e r i c a l l y pure The  t r i m e t h y l s i l y l e t h e r 100.  s t e r e o c h e m i s t r y o f t h i s compound was demonstrated  i n s t r u c t u r e 100 by an independent  synthesis.  t o be t h a t shown  The t r i m e t h y l s i l y l e t h e r  grouping was then h y d r o l y z e d w i t h hot 2% aqueous e t h a n o l to r e g e n e r a t e , i n 98% y i e l d , a l c o h o l £ 9 .  Treatment  o f £9 w i t h phosphorus t r i b r o m i d e i n  b e n z e n e - p y r i d i n e a t 0° gave a 77% y i e l d of a l l y l i c bromide 101.  The  l a t t e r compound was then c o n v e r t e d i n t o the c o r r e s p o n d i n g W i t t i g  reagent  102 by treatment w i t h two e q u i v a l e n t s o f c a r b e t h o x y m e t h y l e n e t r i p h e n y l phosphorane i n r e f l u x i n g e t h y l a c e t a t e f o r 2.5 h. H y d r o l y s i s of phosphorane 102 was a c h i e v e d w i t h 10% potassium h y d r o x i d e i n r e f l u x i n g methanol to a f f o r d , i n 69% y i e l d ,  o l e f i n i c c a r b o x y l i c a c i d 103.  T h i s compound was  c o n v e r t e d i n the u s u a l manner to the c o r r e s p o n d i n g d i a z o k e t o n e , f o l l o w e d by c y c l i z a t i o n w i t h c u p r i c s u l f a t e i n r e f l u x i n g cyclohexane, a 5:3 r a t i o c y c l o p r o p y l ketones methylenetriphenylphosphorane  to a f f o r d i n  91a and 9_1. W i t t i g r e a c t i o n of 91. w i t h  afforded a quantitative y i e l d  of (+)-g-  cubebene, p o s s e s s i n g s p e c t r a l p r o p e r t i e s i d e n t i c a l w i t h those of n a t u r a l l y occurring V.  g-cubebene.  S t u d i e s of the B i r c h Reduction o f a,g-Unsaturated  Ketones  S i n c e p a r t of t h i s t h e s i s i s concerned w i t h the s t e r e o c h e m i s t r y o f the B i r c h r e d u c t i o n of a,g-unsaturated k e t o n e s , i t i s a p p r o p r i a t e to briefly  review the t h e o r i e s which have been proposed  In 1954, B a r t o n observed  on t h i s s u b j e c t .  t h a t i n B i r c h r e d u c t i o n s where s t e r e o -  i s o m e r i c p r o d u c t s were p o s s i b l e , the thermodynamically was almost always formed  (44). To account  more s t a b l e  product  f o r these r e s u l t s he proposed  the f o r m a t i o n o f a t e t r a h e d r a l c a r b a n i o n w h i c h was r e a d i l y c a p a b l e of inversion  ( e . g . , 104a  —>•  104b).  indicates an e l e c t r o n or e l e c t r o n pair  H  H  104a  The  104b  e l e c t r o n p a i r was  that of a C-H  and  a C-C  assumed to have s p a t i a l requirements  bond.  Hence, the c a r b a n i o n would assume i t s  more s t a b l e c o n f i g u r a t i o n , which, upon p r o t o n a t i o n would a f f o r d thermodynamically  the  more s t a b l e p r o d u c t .  S t o r k and D a r l i n g when they observed  between  (45) q u e s t i o n e d the v a l i d i t y  of Barton's  t h a t i n s e v e r a l B i r c h r e d u c t i o n s which they  performed  the p r o d u c t s o b t a i n e d were not o n l y the l e s s s t a b l e isomers but t h a t none of the more s t a b l e isomers  c o u l d be d e t e c t e d .  theory  also  For example,  1 9 i n the B i r c h r e d u c t i o n of t r a n s - 7 , 1 0 - d i m e t h y l - A  ' -2-octalone  they found e x c l u s i v e l y the t r a n s - f u s e d decalone p r o d u c t . case one energy  of the conformations  would p r e d i c t  Since i n t h i s  of the c i s e n o l a t e a n i o n 106c  than the c o r r e s p o n d i n g t r a n s - i n t e r m e d i a t e 106a;  (105),  i s of  Barton's  theory  the c i s - f u s e d decalone as p r o d u c t .  ?and/or  0  105  106a  106b  lower  106c  34 -  -  To account f o r t h i s apparent anomaly, Stork and D a r l i n g (45) modified Barton's theory to include a s t e r e o e l e c t r o n i c requirement. that only t r a n s i t i o n states which maintained  They stated  continuous overlap between  the enolate system and the forming C-H bond at the (3-carbon were allowed.  In the above example t h i s requirement means that only t r a n s i t i o n  states resembling 106a and 106b would be s t e r e o e l e c t r o n i c a l l y allowed. Hence, of the two allowed t r a n s i t i o n s t a t e s , the one resembling 106a i s of lower  energy and protonation would lead to the trans-fused  decalone. Robinson (46) continued the i n v e s t i g a t i o n w i t h a study of the sodium19 l i q u i d ammonia reductions of A ' -2-octalones and found that the observed s t e r e o s e l e c t i v i t y was f a r greater than could be accounted f o r when only thermodynamic s t a b i l i t i e s of s t e r e o e l e c t r o n i c a l l y allowed t r a n s i t i o n states were taken i n t o account. In contrast to previous workers i n t h i s area, Robinson maintained the t r a n s i t i o n state f o r protonation would resemble the h i g h l y basic, anion intermediate 107 where the (3-carbon atom remained e s s e n t i a l l y trigonal.  Robinson pointed out that i n the reduction of c y c l o a l k y l  h a l i d e s , which have t e t r a h e d r a l carbanion intermediates, the product.  107  that  - 35 -  s t a b i l i t y does c o r r e l a t e with the observed s t e r e o s e l e c t i v i t y .  Therefore,  i f the B i r c h reduction did involve a t e t r a h e d r a l carbanion as an intermediate, the same trend would be expected.  Since t h i s i s not the  case, Robinson f e l t that the t r a n s i t i o n s t a t e for protonation should be s i m i l a r to the conformation of the intermediate anion 107, i n which the g-carbon i s t r i g o n a l . possible conformations 107b and 107c.  In p a r t i c u l a r , he proposed three  f o r the t r a n s i t i o n s t a t e f o r protonation  107a,  Considering angle and t o r s i o n a l s t r a i n , Robinson  0  107a  concluded  107c  107b  that 107a would y i e l d the trans-decalone, that 107b would  y i e l d the cis-decalone, and that 107c would generally involve too high an energy (large angle s t r a i n , lack of p l a n a r i t y of the system) to be a l i k e l y t r a n s i t i o n s t a t e . and 107b  conjugated  Further examination  i n d i c a t e d , according to Robinson, that conformation  of  107a  107a  would be the only one i n which the three t r i g o n a l carbon atoms could be accommodated w i t h minimal s t r a i n .  Hence, f o r t h i s reason, Robinson  predicted a high proportion of trans-fused decalone products i n a l l 1 9 A ' -2-octalone reductions of the type studied. Johnson and coworkers (47) also Investigated the geometry of the @-carbon atom i n the protonation t r a n s i t i o n s t a t e . B i r c h reductions of compounds of type 108.  They studied (1 2) Because of A ' strain  - 36  -  R,  2  0 108  (48), R^ would be more s t a b l e i n the a x i a l o r i e n t a t i o n i n the enone r e l a t i v e to the a l t e r n a t e conformation  w i t h R^  cyclohex-  equatorial.  If  the g-carbon atom i s t r i g o n a l i n the t r a n s i t i o n s t a t e f o r p r o t o n a t i o n , Johnson p o s t u l a t e d t h a t the p r o d u c t s composition should be  should r e f l e c t  the  conformational  of the s t a r t i n g m a t e r i a l , t h a t i s to say the major  the 3 , 4 - c i s isomer.  On the other hand, i f the  s t a t e f o r p r o t o n a t i o n i s t e t r a h e d r a l , the p r o d u c t s  transition  should r e f l e c t  thermodynamic s t a b i l i t i e s of the c a r b a n i o n i n t e r m e d i a t e s 104a  104a  The  product  and  the 104b.  104b  r e s u l t s o b t a i n e d from t h e i r experiments i n d i c a t e d  t h a t the  config-  u r a t i o n of the g-carbon i n the p r o t o n a t i o n t r a n s i t i o n s t a t e v a r i e d from t e t r a h e d r a l f o r s m a l l R groups to t r i g o n a l when R^ was  phenyl  and  capable of d e l o c a l i z i n g the n e g a t i v e charge.  and  were  methyl groups the product  Thus, when R^  c o n s i s t e d of t r a n s - and c i s - 3 , 4 - d i m e t h y l c y c l o -  - 37 hexanone i n a r a t i o of 84:16 r e s p e c t i v e l y , while when R^ and  were  phenyl groups, 98% of the product was the 3,4-cis isomer. House and coworkers (49,50) i n an elegant s e r i e s of experiments further i n v e s t i g a t e d the nature of the pathway involved i n the B i r c h reduction of a,g-unsaturated ketones.  Although t h e i r experiments w i l l  not be discussed i n d e t a i l , i t i s pertinent to note the main conclusions r e s u l t i n g from t h e i r work.  Using e l e c t r o n paramagnetic resonance  (e.p.r.) studies,-House resolved several important mechanistic features of the B i r c h reduction of enones.  F i r s t l y , he demonstrated an i n i t i a l  rapid r e v e r s i b l e e l e c t r o n a d d i t i o n to unreduced enones, while c a l c u l a tions showed approximately 40-50% of the unpaired e l e c t r o n resided at the  g-carbon atom.  Furthermore, reduction of trans-enone 109a and c i s -  enone 109b indicated that the i n i t i a l l y  formed anion r a d i c a l s were  d i f f e r e n t but r a p i d l y e q u i l i b r a t e d to the more stable form.  109a  In the  109b  presence of proton donors or l i t h i u m cations the l i f e t i m e of t h i s anion r a d i c a l was s u b s t a n t i a l l y lowered.  To e x p l a i n t h i s observation House  proposed the formation of an 0-H bond i n the former case and a covalent Li-0  bond or t i g h t ion p a i r i n the l a t t e r .  Moreover, studies of polaro-  graphic reduction p o t e n t i a l s demonstrated that then and only then could a second e l e c t r o n be added to an a l i p h a t i c enone system; that i s  - 38 to say, f r e e d i a n i o n i n t e r m e d i a t e s  are g e n e r a l l y not formed.  by i s o t o p e s t u d i e s , House demonstrated t h a t d o n a t i o n a hydrogen atom, was  Lastly,  of a p r o t o n ,  the n o n - r e v e r s i b l e s t e p l e a d i n g t o the  not  final  product. As f o r the n a t u r e intermediate  of the geometry of t h e 8-carbon atom i n the  a n i o n , House f a v o r e d a p y r a m i d a l  w i t h i s o e l e c t r o n i c enamines and  anilines.  c o n f i g u r a t i o n by  analogy  - 39 -  DISCUSSION I.  General As mentioned p r e v i o u s l y , the  main purpose of the work described  i n t h i s thesis was to develop a general s y n t h e t i c entry i n t o the cadinane type of sesquiterpenes.  On i n s p e c t i o n of the general  s t r u c t u r a l formula f o r the cadinenes, i t became obvious that the most important and d i f f i c u l t part of any s y n t h e t i c approach would be the c o n t r o l of the r e l a t i v e stereochemistry at C. , C, and C .  3  The f i r s t o b j e c t i v e was,  therefore, to synthesize a compound with  f i x e d stereochemistry at these p o s i t i o n s and with f u n c t i o n a l i t i e s i n both rings A and B which would allow elaboration to the cadinene compounds.  Thus, a compound such as decalone 118 was envisaged as a  p o s s i b l e key s y n t h e t i c intermediate.  - 40 -  0  ;  H  118  II.  Conjugate A d d i t i o n Approach The s t a r t i n g m a t e r i a l w h i c h was i n i t i a l l y chosen f o r the s y n t h e s i s  o f the r e q u i r e d c r u c i a l i n t e r m e d i a t e o f type 118 was the well-known k e t a l o c t a l o n e 114.  T h i s compound was p r e p a r e d  (see Chart X I I I ) by a  114  combination (52).  of t h e p r o c e d u r e s  Thus, treatment  o f S a r e t t e t a l . (51) and I r e l a n d e t a l .  of commercial f u r y l a c r y l i c a c i d (110) w i t h  hydrogen c h l o r i d e i n m e t h a n o l , f o l l o w e d by e s t e r i f i c a t i o n o f the r e s u l t i n g p r o d u c t , u s i n g methanol i n the presence  o f a c a t a l y t i c amount  of c o n c e n t r a t e d s u l p h u r i c a c i d a f f o r d e d , i n 84% y i e l d , ketopimelate  (111).  dimethyl-a-  Treatment o f the l a t t e r under the u s u a l k e t a l i z a t i o n  conditions (p_-toluenesulfonic a c i d , ethylene g l y c o l ) r e s u l t e d i n a m i x t u r e of s t a r t i n g m a t e r i a l and d i m e t h y l - y - e t h y l e n e d i o x y p i m e l a t e I t was found t h a t 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 s c o u p l e d w i t h  (112).  repeated  - 41 -  Chart X I I I 0  '- H  121  - 42 -  k e t a l i z a t i o n reactions 112.  were n e c e s s a r y t o a f f o r d pure k e t a l  diester  By t h i s r e c y c l i z a t i o n procedure an o v e r a l l 44% y i e l d o f k e t a l  d i e s t e r 112 was r e a l i z e d . i n complete  The s p e c t r a l d a t a of compound 112 were  a c c o r d w i t h the a s s i g n e d s t r u c t u r e .  i n f r a r e d spectrum o f compound 5.78 u due t o the two e s t e r displayed  112 e x h i b i t e d  carbonyls.  In p a r t i c u l a r , the  a strong absorption at  The n.m.r. spectrum o f 112  sharp s i n g l e t s at T 6.05 and T 6.30 due to the k e t a l p r o t o n s  and methyl groups Treatment  respectively.  o f k e t a l d i e s t e r 112 w i t h sodium  hydride i n r e f l u x i n g  e t h e r f o r f i v e days a f f o r d e d , i n 80% y i e l d , the Dieckmann c o n d e n s a t i o n product 113.  The f a c t that  the d e s i r e d  t r a n s f o r m a t i o n had i n d e e d  taken p l a c e was shown by the s p e c t r a l data of the p r o d u c t 113.  The  i n f r a r e d spectrum o f 113 showed a b s o r p t i o n s a t 5.78, 5.81, 6.0 and 6.15 y w h i l e the n.m.r. spectrum e x h i b i t e d  a four-proton s i n g l e t at  T 6.01 and a t h r e e - p r o t o n s i n g l e t a t T 6.25 due to the k e t a l protons and the methyl group  respectively.  Condensation of compound methiodide  113 w i t h l - d i e t h y l a m i n o - 3 - p e n t a n o n e  i n the presence of sodium methoxide f o r t h r e e days a t room  temperature, f o l l o w e d by treatment w i t h aqueous potassium h y d r o x i d e a f f o r d e d , i n 64% y i e l d , exhibited  the d e s i r e d  o c t a l o n e 114.  the expected s p e c t r a l p r o p e r t i e s .  The l a t t e r a g a i n  Of note was the appear-  ance i n the i n f r a r e d spectrum o f a b s o r p t i o n s a t 6.0 u and 6.2 y due to the a,8-unsaturated bond r e s p e c t i v e l y . 245 my.  c a r b o n y l group  and the carbon-carbon  The u l t r a v i o l e t spectrum e x h i b i t e d  The n.m.r. spectrum o f 114 d i s p l a y e d  double  a maximum a t  s i n g l e t s at x 6.09 and  x 8.12 a t t r i b u t a b l e to the k e t a l p r o t o n s and the v i n y l methyl respectively.  group  - 43 Thus having octalone 114 r e a d i l y a v a i l a b l e , i t was next planned to introduce the trans ring f u s i o n by the well-documented l i t h i u m l i q u i d ammonia reduction (45,46,48).  Therefore, compound 114 was  subjected to B i r c h reduction conditions w i t h l i t h i u m i n l i q u i d ammonia for two hours.  The r e a c t i o n was then quenched with ammonium c h l o r i d e  and, a f t e r appropriate work-up, afforded the corresponding decalone 115, i n 97% y i e l d .  trans-fused  The f a c t that the desired reduction had  indeed taken place was c l e a r l y shown by the s p e c t r a l data of compound 115.  The i n f r a r e d spectrum of 115 e x h i b i t e d an absorption at 5.85 u  due to the saturated carbonyl.  The n.m.r. spectrum e x h i b i t e d a  doublet at T 8.96 ( J = 6 Hz) due to the secondary methyl group and a s i n g l e t at T 6.01 due to the k e t a l protons. The next steps i n the projected synthesis involved i n t r o d u c t i o n 3 4 of the A ' -double bond i n t o decalone 115, followed by cuprous i o n catalyzed 1,4-conjugate a d d i t i o n of isopropylmagnesium h a l i d e to a f f o r d , presumably, a mixture of compounds of the cadinane (118) and bulgarane 3 A (117) s k e l e t a l types. However, i n t r o d u c t i o n of the A ' -double bond  117  118  - 44 -  proved e l u s i v e .  Standard b r o m i n a t i o n - d e h y d r o h a l o g e n a t i o n  techniques,  employing  a wide v a r i e t y o f c o n d i t i o n s , r e s u l t e d i n bad m i x t u r e s o f  products.  A s p e c t r a l examination of the crude b r o m i n a t i o n product  indicated was  that under a l l o f the r e a c t i o n c o n d i t i o n s t r i e d , b r o m i n a t i o n  o c c u r r i n g not o n l y on both s i d e s of the keto group but  a d j a c e n t to the k e t a l f u n c t i o n a l i t y . e n t i r e l y unexpected,  Perhaps  also  t h i s o b s e r v a t i o n i s not  s i n c e the b r o m i n a t i o n of k e t a l s i s a w e l l -  e s t a b l i s h e d phenomenon (53,54).  Hence, t h i s method was  f o r the p r e p a r a t i o n of o c t a l o n e 116.  not  satisfactory  T h e r e f o r e , an a l t e r n a t e method  3 4 f o r i n t r o d u c t i o n of the A ' -double bond was Edwards and  coworkers  be r e a d i l y dehydrogenated  (55) had  investigated.  r e p o r t e d t h a t a - f o r m y l ketones c o u l d  by h i g h - p o t e n t i a l quinones,  dichloro-5,6-dicyanobenzoquinone  (DDQ).  been w i d e l y used i n s t e r o i d c h e m i s t r y .  such as  2,3-  Moreover, t h i s r e a c t i o n For example, a - f o r m y l  had  ketone  119 had been shown to undergo t r a n s f o r m a t i o n to compound 120 upon treatment w i t h one e q u i v a l e n t of DDQ at room temperature  119  (56).  i n dry dioxane f o r 1 to 10  minutes  - 45 -  Therefore, reactions.  i t was  decided  to make use  Treatment of decalone 115  w i t h e t h y l formate and  methoxide i n dry benzene gave r i s e to the hydroxymethylene d e r i v a t i v e 121, of 121 w i t h DDQ  initially  T h i s was  Hence, i t was  Since  required  sodium  crystalline  However, dehydrogenation  failed  to y i e l d any  p a r t i c u l a r l y surprising since  formed o x i d a t i o n p r o d u c t 122  further oxidation with  would be  not  corresponding  i n 80% y i e l d .  under the above c o n d i t i o n s  desired product.  of a s i m i l a r s e r i e s of  would a l s o be  of  the  the  susceptible  to  DDQ.  proposed that a s u b s t i t u e n t at the C^Q  other  than hydrogen  p o s i t i o n to p r o h i b i t f u r t h e r o x i d a t i o n .  the C^^ p o s i t i o n i s u n s u b s t i t u t e d  i n sesquiterpenes  e s s e n t i a l to b l o c k  the cadinane s k e l e t o n ,  i t was  a group which c o u l d be  r e a d i l y removed at a l a t e r stage i n the  The  s t a r t i n g m a t e r i a l which was  C  s u b s t i t u t e d compound was  the  possessing p o s i t i o n with  chosen f o r p r e p a r a t i o n  the well-known o c t a l o n e  synthesis.  of a s u i t a b l e  123.  This  material  - 46 -  was p r e p a r e d by c o n d e n s a t i o n o f the p r e v i o u s l y d e s c r i b e d k e t o e s t e r 113 w i t h e t h y l v i n y l ketone i n t h e presence o f a c a t a l y t i c amount o f t r i e t h y l a m i n e , t o a f f o r d dione 124, i n 84% y i e l d  123  (52).  Sodium methoxide-  124  c a t a l y z e d r i n g c l o s u r e o f d i o n e 124 a f f o r d e d , i n 97% y i e l d , o c t a l o n e 123.  The l a t t e r e x h i b i t e d the e x p e c t e d s p e c t r a l p r o p e r t i e s .  In  p a r t i c u l a r , t h e u l t r a v i o l e t spectrum e x h i b i t e d a maximum a t 245 mp. The i n f r a r e d spectrum o f 123 e x h i b i t e d a b s o r p t i o n s a t 5.8 u ( e s t e r c a r b o n y l ) , 6 . 0 u ( u n s a t u r a t e d ketone) and a t 6.2 u (carbon-carbon bond).  double  The n.m.r. spectrum o f 123 e x h i b i t e d a s s i g n a b l e s i g n a l s a t  T 8.13 ( s i n g l e t , v i n y l m e t h y l ) , T 6.30 ( s i n g l e t , m e t h y l e s t e r ) and a t x 6.08 ( s i n g l e t , k e t a l p r o t o n s ) . O c t a l o n e 123 appeared proposed r e a c t i o n sequence.  t o be p o t e n t i a l l y w e l l s u i t e d t o t h e F i r s t l y , i t had been shown t h a t o c t a l o n e s  of t h i s type d i r e c t l y underwent DDQ-promoted d e h y d r o g e n a t i o n t o a f f o r d the c o r r e s p o n d i n g c r o s s - c o n j u g a t e d dienones i n good y i e l d ( 5 7 ) .  - 47 -  Moreover, d i r e c t conjugate a l k y l a t i o n at  on the proposed dienone  1 9 125 should presumably y i e l d the corresponding 4-alkyl-A ' -2-octalone. 1 9 Retention of the A ' -double bond at t h i s stage was mandatory to permit subsequent easy removal of the C^Q carbomethoxy group by basepromoted h y d r o l y s i s and decarboxylation.  Presumably t h i s r e a c t i o n  would be accompanied by e p i m e r i z a t i o n of the C^Q proton i n the r e s u l t i n g product.  Furthermore,  i t was proposed from conformational  analysis that t h i s epimerization would f u r n i s h predominantly the compound w i t h the required stereochemistry f o r the cadinene compounds. Treatment of octalone 123 with one equivalent of DDQ (57) i n the presence of g l a c i a l a c e t i c a c i d i n r e f l u x i n g benzene f o r 36 h afforded, i n 80% y i e l d , dienone 125. The s p e c t r a l p r o p e r t i e s of C0 CH 2  C0 CH 2  3  3  123  125  compound 125 were i n complete accord w i t h the assigned s t r u c t u r e .  Thus,  the u l t r a v i o l e t spectrum showed a maximum at 243 my, w h i l e the i n f r a r e d spectrum showed absorptions at 5.82, 6.05, 6.15 and 6.25 p. The n.m.r. spectrum of 125 displayed a t y p i c a l AB p a i r of doublets at T 3.72 and T 3.28 ( J = 10 Hz) f o r the protons at In a d d i t i o n , there appeared a to the  and  respectively.  three-proton s i n g l e t at x 8.04 a t t r i b u t a b l e  v i n y l methyl, a three-proton s i n g l e t at x 6.30 due to the methyl  ester and a four-proton s i n g l e t at x 6.02 due to the k e t a l protons.  - 48 The  cuprous i o n c a t a l y z e d 1,4-conjugate a d d i t i o n o f i s o p r o p y l -  magnesium bromide to the c r o s s - c o n j u g a t e d  dienone 125 was  attempted  under a wide v a r i e t y of c o n d i t i o n s but o n l y minor amounts o f d e s i r e d product  c o u l d be d e t e c t e d .  the s t a r t i n g dienone 125 was  I n a l l c a s e s , at l e a s t 90%  r e c o v e r e d unchanged.  w i t h the o b s e r v a t i o n t h a t the r e a c t i o n m i x t u r e was i n d i c a t e d t h a t the G r i g n a r d reagent was f o r m a t i o n of the h i g h l y c o n j u g a t e d  the  This f a c t ,  of coupled  a deep r e d c o l o r  a c t i n g as a b a s e , c a u s i n g  e n o l a t e a n i o n 126.  would, of c o u r s e , be i n e r t w i t h r e s p e c t t o the d e s i r e d  This  anion  conjugate  addition reaction.  126 McMurry ( 5 8 ) , i n h i s paper on the s y n t h e s i s of s a t i v e n e , r e p o r t e d t h a t a d d i t i o n of i s o p r o p y l m a g n e s i u m bromide t o decalone  127 r e s u l t e d i n  the f o r m a t i o n of o n l y 5% o f the d e s i r e d t e r t i a r y a l c o h o l 128.  r  / \  127  o  128  0  McMurry  - 49 -  proposed t h a t e n o l a t e  formation  was r e s p o n s i b l e  However, he found t h a t t h i s u n d e s i r a b l e  f o r t h e low y i e l d .  s i d e r e a c t i o n c o u l d be s u p p r e s s e d  by c a r r y i n g out t h e r e a c t i o n a t a lower t e m p e r a t u r e .  Indeed, a t a  r e a c t i o n temperature o f -50°, i t was p o s s i b l e t o o b t a i n 50% o f t h e desired product.  However, attempted a p p l i c a t i o n o f t h i s p r i n c i p l e t o  our c o n j u g a t e a d d i t i o n r e a c t i o n proved f r u i t l e s s , s i n c e v a r y i n g t h e r e a c t i o n temperature between 33° and -78° gave no s i g n i f i c a n t  change  i n t h e amount o f p r o d u c t formed. To g a i n s u p p o r t i n g  e v i d e n c e f o r t h e proposed e n o l a t e  formation,  copper s a l t c a t a l y z e d 1,4-conjugate a d d i t i o n o f i s o p r o p y l m a g n e s i u m bromide t o dienone 129"*"was i n v e s t i g a t e d .  S i n c e b o t h o f t h e Y~P°sitions  129  (with respect  to the carbonyl  by a l k y l groups, no e n o l a t e  group) i n dienone 129 a r e f u l l y  formation  i s possible.  substituted  Indeed, t r e a t m e n t  of dienone 129 w i t h isopropylmagnesium bromide i n t h e presence o f c u p r i c acetate  r e s u l t e d i n t h e i s o l a t i o n o f two p r o d u c t s i n the r a t i o o f  3:2 r e s p e c t i v e l y .  I n contrast to s i m i l a r Grignard  additions to  dienone 125 no s t a r t i n g m a t e r i a l was r e c o v e r e d .  We thank Mr. P a u l W o r s t e r f o r a sample o f t h i s compound.  - 50 -  125 I t was shown t h a t the major p r o d u c t of t h e copper s a l t  catalyzed  1,4-conjugate a d d i t i o n of i s o p r o p y l m a g n e s i u m bromide t o dienone 129 was compound 130, t h e 1 , 4 - a d d i t i o n p r o d u c t .  The minor p r o d u c t e x h i b i t e d  s p e c t r a l d a t a i n a c c o r d w i t h e i t h e r s t r u c t u r e 131 o r 132, presumably r e s u l t i n g from a c i d - c a t a l y z e d rearrangement  ( d u r i n g work-up) of t h e  i n i t i a l l y formed 1 , 2 - a d d i t i o n p r o d u c t ( 5 9 ) . A n a l y t i c a l samples o f t h e major and minor p r o d u c t s were c o l l e c t e d  - 51  by p r e p a r a t i v e g . l . c .  -  The s p e c t r a l p r o p e r t i e s of compound 130 were i n  f u l l a c c o r d w i t h the proposed s t r u c t u r e .  Thus, the major p r o d u c t 130  gave an u l t r a v i o l e t maximum a t 240 mu and a s t r o n g a , 3 - u n s a t u r a t e d c a r b o n y l a b s o r p t i o n a t 6.0 u and carbon-carbon double bond a b s o r p t i o n at 6.25  u i n the i n f r a r e d .  The n.m.r. spectrum of compound 130  e x h i b i t e d a p a i r of t h r e e - p r o t o n  d o u b l e t s a t T 9.35  and T 9.08  (J =  7 Hz) due t o the newly i n t r o d u c e d i s o p r o p y l m e t h y l g r o u p s , t h r e e p r o t o n s i n g l e t s a t x 8.85, T 8.82, and x 8.61  due t o the t h r e e  m e t h y l groups and a o n e - p r o t o n s i n g l e t a t x 4.04 o l e f i n i c proton.  three-  tertiary  due t o the  The n.m.r. spectrum of 130 a l s o p r o v i d e s e v i d e n c e t h a t  H H  0  130  the newly i n t r o d u c e d i s o p r o p y l axial  proton e x h i b i t e d  to the A p a r t  of an ABX  r  group i s i n the  a p a i r o f d o u b l e t s at x 7.39  system, w i t h J . „ = 18 Hz AB J  the  equatorial  proton exhibited  x 7.65  due  B part  3 Hz  to the  (60).  The  p r o t o n must be introduction  s m a l l AX  and  BX This  isopropyl  angular methyl group. detail.  o f the ABX  equatorial.  of the  axial  This  and  orientation. and  x,7.21  J., = 6 Hz, AX  coupling  AD  = 18 Hz  group from the  p o i n t w i l l be  and that  J  =  the  expected  s i d e o p p o s i t e to  discussed l a t e r  and  BX  constants i n d i c a t e  i s i n agreement w i t h the  due while  R  a p a i r of d o u b l e t s at x 7.46 system, w i t h J  The  the  i n more  C  - 52 -  The minor p r o d u c t 131 o r 132 e x h i b i t e d two weak a b s o r p t i o n s , a t 6.25 and 6.4 p i n t h e i n f r a r e d , t y p i c a l o f t h e s t r e t c h i n g v i b r a t i o n s o f an a r o m a t i c n u c l e u s .  The n.m.r. spectrum o f t h e minor p r o d u c t e x h i b i t e d  a s i x - p r o t o n d o u b l e t a t T 8.80 ( J = 6.5 Hz) due t o  the i s o p r o p y l methyl  groups, a s i x - p r o t o n s i n g l e t a t T 8.75 due t o t h e gem-dimethyl  groups  a t h r e e - p r o t o n s i n g l e t a t T 7.84 due t o t h e a r o m a t i c m e t h y l group and two b r o a d one-proton s i n g l e t s a t T 3.20 and x 3.00 due t o t h e a r o m a t i c protons. S i n c e the copper s a l t c a t a l y z e d 1,4-conjugate a d d i t i o n o f i s o propylmagnesium more l i k e l y  bromide t o dienone 129 was s u c c e s s f u l , i t appeared  even  t h a t f o r m a t i o n o f e n o l a t e 126 was r e s p o n s i b l e f o r the  f a i l u r e o f the analogous a d d i t i o n s t o dienone 125. circumvent t h i s d i f f i c u l t y , aldehyde 133 were proposed. i n v o l v i n g the  I n an attempt t o  a d d i t i o n s t o t h e c o r r e s p o n d i n g dienone I t was f e l t t h a t even i f e n o l a t e f o r m a t i o n  c a r b o n y l o c c u r r e d , t h e aldehyde c a r b o n y l c o u l d  still  p r o v i d e s u f f i c i e n t a c t i v a t i o n t o make c o n j u g a t e a l k y l a t i o n a t possible.  To t h i s end, c o n d e n s a t i o n o f o c t a l o n e 123 w i t h e t h y l formate 0  C0„CH  133  i n the presence o f sodium methoxide i n benzene p r o v i d e d the 3-hydroxymethylene d e r i v a t i v e 134 i n good y i e l d .  - 53 -  C0 CH 2  C0 CH  3  2  0  3  0  HOHG 0  o-  123  /  0 II  134  H-C 0  133  Dehydrogenation of the hydroxymethylene d e r i v a t i v e 134 with DDQ (61) i n dioxane f o r 3.5 min afforded the corresponding 3-formyl cross-conjugated dienone 133 i n 43% y i e l d .  The s p e c t r a l data were  i n complete agreement w i t h the assigned s t r u c t u r e .  Of note was the  appearance i n the i n f r a r e d spectrum of absorptions at 5.75, 5.9, 6.08, 6.15 and 6.25 y due to the carbonyl groups and the carbon-carbon double bonds.  In the n.m.r. spectrum of 133 there appeared one-proton  s i n g l e t s at x -0.25 and at x 2.55 due to the aldehydic proton and the o l e f i n i c proton r e s p e c t i v e l y .  Other pertinent n.m.r. signals f o r  compound 133 appeared at x 7.97 ( s i n g l e t , v i n y l methyl), x 6.25 ( s i n g l e t , methyl ester) and x 5.98 ( s i n g l e t , k e t a l protons).  Compound  133 exhibited a maximum at 246 my i n the u l t r a v i o l e t spectrum. Unfortunately, copper s a l t catalyzed Grignard additions to 3-formyl  -  dienone 133 a g a i n  54  -  f a i l e d to give s y n t h e t i c a l l y u s e f u l y i e l d s of  a l k y l a t e d products.  A s p e c t r a l e x a m i n a t i o n o f t h e crude r e a c t i o n  m i x t u r e i n d i c a t e d t h a t some c o n d i t i o n s t r i e d gave r i s e t o bad m i x t u r e s of p r o d u c t s w h i l e o t h e r c o n d i t i o n s r e s u l t e d i n r e c o v e r y  o f unchanged  starting material. I n v i e w o f t h e f a i l u r e o f t h e copper s a l t c a t a l y z e d reagent t o i n t r o d u c e  Grignard  t h e n e c e s s a r y i s o p r o p y l group v i a 1,4-conjugate  a d d i t i o n t o t h e above enone systems, t h e p o s s i b i l i t y o f i n t r o d u c i n g t h e i s o p r o p y l group by means of l i t h i u m d i i s o p r o p y l c u p r a t e was n e x t gated.  investi-  A t t h e time t h i s work was u n d e r t a k e n , S c h u d e l e t a l . (62)  p u b l i s h e d a report concerning the s y n t h e s i s of a n a t u r a l l y o c c u r r i n g sesquiterpenoid,  nootkatone.  One o f the key s t e p s i n t h i s  i n v o l v e d the c o n j u g a t e a d d i t i o n o f a m e t h y l group t o dienone 135, u s i n g l i t h i u m  synthesis  cross-conjugated  dimethylcuprate.  3  135 A s e r i e s o f p r e l i m i n a r y r e a c t i o n s showed t h a t l i t h i u m d i m e t h y l c u p r a t e a l s o added a m e t h y l group t o t h e C^ p o s i t i o n o f dienones 125 and 133.  These r e s u l t s were p a r t i c u l a r l y e n c o u r a g i n g and i t was d e c i d e d  to study analogous r e a c t i o n s employing l i t h i u m d i i s o p r o p y l c u p r a t e . However, c u p r a t e a d d i t i o n r e a c t i o n s u s u a l l y r e q u i r e quenching w i t h acid.  I n o r d e r t o study t h e r e a c t i o n i n some d e t a i l i t was  therefore  - 55 -  133  desirable to work w i t h a more r e a d i l y a v a i l a b l e model system (lacking the k e t a l group). The sequence used f o r preparation of the model compounds i s o u t l i n e d i n Chart XIV. Meyer et a l . (63).  Octalone 138 was prepared by the procedure of  Thus, condensation of l-diethylamino-3-pentanone  methiodide w i t h 2-carbethoxycyclohexanone  (136) i n  ethanol i n the  presence of a c a t a l y t i c amount of sodium ethoxide afforded, i n 83% y i e l d , dione 137. data.  The l a t t e r compound e x h i b i t e d the expected s p e c t r a l  In p a r t i c u l a r , the i n f r a r e d spectrum e x h i b i t e d a strong  absorption at 5.8 u due to the carbonyl groups. of 137 displayed s i g n a l s at T 8.97 x 8.72  H  ( t r i p l e t , CH„CH C- , J = 7 Hz), at 0  ( t r i p l e t , CH_ CH 0- , J = 7 Hz), at x 7.59 3  The n.m.r. spectrum  2  7 Hz) and at x 5.8 (quartet, -CH--0-, J = 7 Hz).  (quartet, -CH^-C-, J =  - 56 -  C h a r t XIV I~  +  140  141  - 57 i  Sodium ethoxide-catalyzed r i n g closure of dione 137 afforded octalone 138, i n 96% y i e l d .  The f a c t that the expected r i n g closure  had taken place was shown by the s p e c t r a l data of product 138. Of note was the appearance i n the i n f r a r e d spectrum of absorptions at 5.8 u (ester carbonyl), 6.0 u (a,{^-unsaturated ketone) and at 6.2 u (carbon-carbon double bond). maximum at 247 my.  The u l t r a v i o l e t spectrum e x h i b i t e d a  In the n.m.r. spectrum of 138 were s i g n a l s due to  the e t h y l ester as a three-proton t r i p l e t at x 8.72 ( J = 7 Hz) and as a two-proton quartet at x 5.72 ( J = 7 Hz) and a s i g n a l due to the v i n y l methyl group as a three-proton s i n g l e t at x 8.12. Treatment of octalone 138 w i t h DDQ (57) i n the presence of g l a c i a l a c e t i c acid i n r e f l u x i n g benzene f o r 70 h afforded dienone 139, i n 76% y i e l d .  The fact that the expected dehydrogenation had taken place  was shown by the s p e c t r a l data of the product 139. In p a r t i c u l a r the i n f r a r e d spectrum of 139 e x h i b i t e d absorptions at 5.8, 6.05, 6.12 and 6.23 y. The n.m.r. spectrum of 139 displayed a t y p i c a l AB p a i r of doublets at x 3.77 and x 3.33 ( J = 10 Hz) f o r the C_ and C. o l e f i n i c 3  protons, r e s p e c t i v e l y .  4  Other assignable s i g n a l s i n the n.m.r. spectrum  appeared at x 8.79 ( t r i p l e t , methyl of e s t e r ) , x 5.85 (quartet, methylene of ester) and at x 8.05 ( s i n g l e t , v i n y l methyl). Condensation of octalone 138 with e t h y l formate i n the presence of sodium methoxide afforded the corresponding 3-hydroxymethylene d e r i v a t i v e 140, i n 83% y i e l d .  ,  Dehydrogenation of the hydroxymethylene  d e r i v a t i v e 140 with DDQ (61) i n dioxane f o r 3.5 min afforded the corresponding 3-formyl cross-conjugated dienone 141 i n 65% y i e l d .  The  s p e c t r a l data of dienone 141 were i n complete accord w i t h the assigned  - 58 -  0  CO„CH CH 3 0  141  structure.  Of n o t e was the appearance i n t h e n.m.r. spectrum o f 141  of two one-proton s i n g l e t s a t x -0.25 and a t x 2.55 due t o t h e a l d e h y d i c p r o t o n and t h e  o l e f i n i c proton, respectively.  s i g n a l s appeared  a t x 8.75 ( t r i p l e t , -C0 CH CH_ , J = 7 H z ) , a t x 7.97 2  2  n.m.r.  3  ( s i n g l e t , v i n y l m e t h y l ) and a t x 5.82 ( q u a r t e t , The u l t r a v i o l e t spectrum e x h i b i t e d  Other p e r t i n e n t  -C0 CH_ CH , J = 7 H z ) . 2  2  a maximum a t 247 my.  3  The i n f r a r e d  spectrum o f 141 showed a b s o r p t i o n s a t 5.8, 5.9, 6.1, and 6.2 y. W i t h t h e model compounds 139 and 141 r e a d i l y a v a i l a b l e , t h e investigation of l i t h i u m diisopropylcuprate The c o n j u g a t e a d d i t i o n conditions  reactions  additions  was c a r r i e d o u t .  were attempted under a wide v a r i e t y o f  i n c l u d i n g a wide temperature range, a v a r i e t y o f s o l v e n t s ,  a v a r i e t y o f copper s a l t s and a v a r i e t y o f a d d i t i v e s  s i m i l a r to those  used t o enhance t h e n u c l e o p h i l i c i t y of G r i g n a r d r e a g e n t s - amines, lithium halides  and hexamethylphosphoramide  a l l these c o n d i t i o n s  (64,65,66).  However, w h i l e  r e a d i l y c o n v e r t e d 2-cyclohexenone i n t o  p r o p y l c y c l o h e x a n o n e , the m a t e r i a l  3-iso-  o b t a i n e d from compounds 139 and 141  i n e x p l i c a b l y showed no s i g n s o f t h e d e s i r e d  conjugate a d d i t i o n products.  - 59 -  III.  C o n d e n s a t i o n - A n n e l a t i o n Approach In view o f the f a i l u r e o f the approach i n v o l v i n g i n t r o d u c t i o n o f  the  n e c e s s a r y i s o p r o p y l group v i a 1,4-conjugate a d d i t i o n t o an enone  system, an a l t e r n a t e method f o r t h e p r e p a r a t i o n of an i n t e r m e d i a t e of type 142 was i n v e s t i g a t e d .  The c r u c i a l proposed r e a c t i o n i n t h i s new  approach was the Robinson a n n e l a t i o n r e a c t i o n o f 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 cyclohexanone of type 143 w i t h a v i n y l ketone such as 144.  11 ll R_ = OH, OCC,H,., 0CCH ; R o  R ,R 2  Hence, the f i r s t ketone 144.  3  = -0-CH -CH -0-, H 2  2  = H  2  s y n t h e t i c o b j e c t i v e was the p r e p a r a t i o n of v i n y l  V i n y l ketone 144 was p r e p a r e d by two d i f f e r e n t  routes  which a r e o u t l i n e i n Chart XV. The g e n e r a l s y n t h e t i c procedure used i n the f i r s t  r o u t e was  analogous t o t h a t used by House and coworkers i n the p r e p a r a t i o n o f  - 60 -  C h a r t XV  Route I  CH CH CC1 3  +  2  CH N 2  CH CH CCH N  2  3  2  2  145  0  II  CH CH CCR -P(C H ) 3  2  2  147  6  5  CH CH CCH Br  3  3  Br  2  2  146  0  II  CH CH CCH=P(C H ) 3  2  6  5  3  148  144  Route I I 0  0  t  II  (CH 0) PCH COCH 3  2  2  3  + 0C1L  149 150  - 61 -  trans-3-penten-2-one (152) ( 6 7 ) . T h i s r o u t e i n v o l v e d the W i t t i g r e a c t i o n  152  between a s u b s t i t u t e d phosphorane and an a p p r o p r i a t e aldehyde o r ketone.  F o r the p r e p a r a t i o n o f 144, the two n e c e s s a r y  would be the a c y l a t e d phosphorane 148 and  reactants  isobutyraldehyde.  The s t a r t i n g m a t e r i a l used f o r the p r e p a r a t i o n o f phosphorane 148, bromomethyl e t h y l ketone (146), was p r e p a r e d  by a p r o c e d u r e  analogous t o t h a t of Catch e t a l . ( 6 8 ) . Thus, p r o p i o n y l c h l o r i d e was r e a c t e d w i t h e t h e r e a l diazomethane a t 0° f o r 30 min t o y i e l d diazomethyl  e t h y l k e t o n e (145).  immediately  converted,  The l a t t e r was n o t p u r i f i e d but was  i n 70% y i e l d  (from p r o p i o n y l c h l o r i d e ) ,  into  bromomethyl e t h y l ketone (146) by r e a c t i o n w i t h anhydrous hydrogen bromide a t 0° f o r 30 m i n u t e s . triphenylphosphine  Treatment of bromoketone 146 w i t h  i n benzene a f f o r d e d the c o r r e s p o n d i n g  bromide 147 i n 85% y i e l d .  a c y l phosphonium  The l a t t e r , compound 147, was c o n v e r t e d  into  62  -  -  phosphorane 148 i n 64% y i e l d , by treatment w i t h aqueous sodium h y d r o x i d e f o r 2 hours.  An a n a l y t i c a l sample o f 148 e x h i b i t e d s p e c t r a l d a t a i n  complete a c c o r d w i t h the a s s i g n e d s t r u c t u r e .  I n p a r t i c u l a r , i n the  n.m.r. spectrum of 148, the o l e f i n i c p r o t o n was p r o t o n s i n g l e t a t T 1.0,  T 8.85 268,  ( J = 7 Hz).  q u a r t e t a t T 7.66  w h i l e the e t h y l group  and a t h r e e - p r o t o n t r i p l e t a t  The u l t r a v i o l e t spectrum e x h i b i t e d t h r e e maxima a t  275 and 288 my.  a b s o r p t i o n s at 6.60,  one-  the p h e n y l p r o t o n s were p r e s e n t as an  u n r e s o l v e d f i f t e e n - p r o t o n m u l t i p l e t a t x 2.50, e x h i b i t e d a two-proton  e v i d e n t as a  The  i n f r a r e d spectrum of compound 148  6.98,  7.16,  and 9.07  exhibited  y.  W i t t i g r e a c t i o n of phosphorane 148 w i t h i s o b u t y r a l d e h y d e i n r e f l u x i n g methylene c h l o r i d e f o r 12 h a f f o r d e d , i n 63% y i e l d , t r a n s - 6 methyl-hept-4-en-3-one (144).  S p e c t r a l d a t a f o r t h i s compound were i n  complete a c c o r d w i t h the a s s i g n e d s t r u c t u r e .  spectrum e x h i b i t e d a b s o r p t i o n s a t 5.98 group and carbon-carbon  I n p a r t i c u l a r , the i n f r a r e d  and 6.14  y due  double bond, r e s p e c t i v e l y .  of 144 e x h i b i t e d a s i x - p r o t o n  d o u b l e t a t x 8.90  ( J = 7 Hz)  The n.m.r. spectrum  ( J = 7 Hz)  and Cg p r o t o n s , a t h r e e - p r o t o n t r i p l e t at x 8.95 at x 7.45  t o the c a r b o n y l  f o r the  and a two-proton  quartet  f o r the methyl and methylene p r o t o n s of the e t h y l  group and two one-proton  d o u b l e t o f d o u b l e t s at x 3.98  the C. and CL o l e f i n i c p r o t o n s , r e s p e c t i v e l y .  The  and x 3.20  for  coupling constants  - 63 revealed a t r a n s - o l e f i n i c coupling of 16 Hz f o r the  and C,. hydrogens,  a coupling of 6 Hz f o r the C,. and  hydrogens and a long-range  coupling of 1.5 Hz f o r the  hydrogens.  and  I t i s i n t e r e s t i n g to note that d i s t i l l a t i o n of v i n y l ketone 144 at temperatures above 75° r e s u l t e d i n a d i s t i l l a t e which showed a n.m.r. spectrum quite d i f f e r e n t from that discussed above.  This was  due to the presence, i n the d i s t i l l a t e , of s i g n i f i c a n t amounts of the corresponding 3,y-unsaturated ketone, 6-methylhept-5-en-3-one  144  (144a).  144a  Thus c a r e f u l thermal c o n t r o l had to be maintained both i n d i s t i l l a t i o n s and i n the subsequent Robinson annelation reactions employing the v i n y l ketone 144. Since the o v e r a l l y i e l d of the above sequence was not p a r t i c u l a r l y high (23%) and large scale  preparation of anhydrous diazomethane proved  very laborious, an a l t e r n a t e approach to the synthesis of 6-methylhept4-en-3-one (144) was i n v e s t i g a t e d (see Chart XV, Route I I ) .  This  route involved an i n i t i a l W i t t i g r e a c t i o n , employing sodium hydride i n DMSO, of isobutyraldehyde w i t h trimethylphosphonoacetate (149) to a f f o r d , i n 65% y i e l d , the trans o l e f i n i c ester 150 (69). This compound exhibited the expected s p e c t r a l p r o p e r t i e s .  Of pertinence were the  absorptions i n the i n f r a r e d spectrum, at 5.8 u (carbonyl group) and at  - 64 -  r^  3  2 °^OCH  :  150 6.05 u (carbon-carbon double bond).  The n.m.r. spectrum o f 150  d i s p l a y e d a s i x - p r o t o n d o u b l e t a t T 8.95 ( J = 7 Hz) f o r t h e secondary m e t h y l groups, a t h r e e - p r o t o n s i n g l e t a t T 6.30 f o r t h e m e t h y l e s t e r group and two one-proton d o u b l e t o f d o u b l e t s a t x 4.25 and T 3.05 f o r the  and  constant f o r the  protons r e s p e c t i v e l y . and  The t r a n s - o l e f i n i c c o u p l i n g  hydrogens was 16 Hz, w h i l e the c o u p l i n g  c o n s t a n t f o r t h e C„ and C. p r o t o n s was 7 Hz. 3 4 H y d r o l y s i s o f t h e o l e f i n i c e s t e r 150 w i t h p o t a s s i u m c a r b o n a t e i n aqueous methanol a f f o r d e d , i n 82% y i e l d , t h e a , g - u n s a t u r a t e d a c i d 151. T h i s compound e x h i b i t e d t h e e x p e c t e d s p e c t r a l  characteristics.  2  0  ^  OH  151  Of n o t e was the appearance, i n t h e i n f r a r e d spectrum, o f t h e c h a r a c t e r i s t i c a b s o r p t i o n bands f o r a c a r b o x y l i c a c i d , a t 3.1-4.0 u and a t 5.9 u and a carbon-carbon double bond a b s o r p t i o n a t 6.05 u.  The  n.m.r. spectrum o f 151, w h i c h e x h i b i t e d . n o s i g n a l due t o the m e t h y l e s t e r ,  - 65 -  a o n e - p r o t o n s i n g l e t a t T -2.15 f o r t h e a c i d p r o t o n ,  exhibited  a t T 2.9  proton doublet of doublets p r o t o n s r e s p e c t i v e l y (J^ and  ^  =  a n d x 4.2  15.5 H z ,  a s i x - p r o t o n d o u b l e t a t T 8.95  f o r the  ^ = 6.5 H z , £ J  two  one-  and 4  =  ( J = 6.5 H z ) f o r t h e s e c o n d a r y m e t h y l  groups. The n e x t p h a s e i n t h e p r o j e c t e d into  synthesis  was  the corresponding a c i d c h l o r i d e , followed  cadmium.  However,  resulted  to convert  acid  151  by t r e a t m e n t w i t h d i e t h y l  a l l a t t e m p t s t o p r e p a r e t h e a c i d c h l o r i d e o f 151  i n s u b s t a n t i a l i s o m e r i z a t i o n o f t h e c a r b o n - c a r b o n double bond  to the g , y - p o s i t i o n . a n o t h e r a p p r o a c h was  Due  investigated.  c a r b o x y l i c a c i d 151 w i t h followed  to this undesirable This  bond  isomerization  approach i n v o l v e d  treatment of  f r e s h l y p r e p a r e d e t h y l l i t h i u m a t -78°  by r a p i d l o w t e m p e r a t u r e q u e n c h i n g w i t h  aqueous  f o r 2 h,  hydrochloric  acid. It  should  be n o t e d t h a t  to a large extent, reactant  upon a j u d i c i o u s c h o i c e  concentration  temperatures greater resulted  On .the  solutions,  shorter  c o p i o u s amounts the  formation  tolerate  92%  yield,  temperature,  reaction  amount o f  times,  alcohol-containing  reaction conditions  (more  r e a c t i o n times) r e s u l t e d i n the recovery  of s t a r t i n g m a t e r i a l .  of a l c o h o l - c o n t a i n i n g  the recovery  recycling  of a considerable hand, m i l d e r  depended,  That i s , use o f r e a c t i o n  than -40°, b r use o f l o n g e r  other  reaction  of r e a c t i o n  and r e a c t i o n t i m e .  i n the formation  product.  the success of t h i s  However, i n o r d e r  products,  trans-6-methylhept-4-en-3-one  fairly  to eliminate  i t was n e c e s s a r y t o  o f some s t a r t i n g m a t e r i a l .  the recovered s t a r t i n g m a t e r i a l  of  dilute  I t was  found that .  s e v e r a l times a f f o r d e d , i n (144).  The l a t t e r  compound  -  66  -  e x h i b i t e d s p e c t r a l p r o p e r t i e s w h i c h were i d e n t i c a l i n every w i t h those of compound 144 p r e v i o u s l y The  above d e s c r i b e d s y n t h e s i s has  p r e v i o u s p r e p a r a t i o n of compound 144. conversion of isobutyraldehyde was  respect  prepared. s e v e r a l advantages over the The  o v e r a l l y i e l d of  i n t o 144 v i a the r o u t e j u s t  the described  50%, o b v i o u s l y a c o n s i d e r a b l e improvement over the f i r s t  C23%).  A d d i t i o n a l l y , each o f the s t e p s was  route  r e a d i l y adaptable  to  r e l a t i v e l y l a r g e s c a l e , t h e r e f o r e a l l o w i n g p r e p a r a t i o n of m o d e r a t e l y l a r g e amounts of v i n y l ketone  144.  W i t h the v i n y l k e t o n e 144 now  r e a d i l y a v a i l a b l e , i t remained  to s y n t h e s i z e the a p p r o p r i a t e cyclohexanone compounds of type  The k e t o  e s t e r 113 was  s y n t h e t i c method.  I t was  r e a d i l y a v a i l a b l e by the p r e v i o u s l y d i s c u s s e d  therefore decided  the Robinson a n n e l a t i o n r e a c t i o n .  113  143.  t o employ t h i s compound i n  - 67 -  I t i s p e r t i n e n t to note t h a t Rapson (70) had r e p o r t e d good y i e l d s of b a s e - c a t a l y z e d c o n d e n s a t i o n p r o d u c t s u s i n g the analogous ethoxycyclohexanone e t h y l i d e n e acetone  153  2-carb-  (136) and s e v e r a l v i n y l ketones f o r example, (152) and p_-methoxystyryl methyl ketone  (153).  R = p-MeOC,H -  Thus, employing keto e s t e r 113 was  the r e a c t i o n c o n d i t i o n s d e s c r i b e d by Rapson  r e a c t e d w i t h the v i n y l ketone 144 i n the presence  of potassium e t h o x i d e .  144  (70)  However, none o f the d e s i r e d o c t a l o n e c o u l d  113  d e t e c t e d a l t h o u g h a good r e c o v e r y of s t a r t i n g m a t e r i a l was Keto e s t e r 113 was  then t r e a t e d w i t h v i n y l ketone 144 employing  wide v a r i e t y of b a s e - c a t a l y z e d c o n d e n s a t i o n c o n d i t i o n s . s t a r t i n g m a t e r i a l c o u l d be i s o l a t e d I t was  felt  realized. a  Again only  from the r e a c t i o n m i x t u r e s .  t h a t the k e t a l f u n c t i o n a l i t y might be  sterically  h i n d e r i n g approach of v i n y l ketone 144 t o the c a r b a n i o n i c s i t e of  be  - 68 -  the' e n o l a t e a n i o n d e r i v e d from the k e t o e s t e r 113.  To t e s t  p o s s i b i l i t y an u n s u b s t i t u t e d cyclohexanone d e r i v a t i v e was  this  employed.  Thus, the hydroxymethylene of cyclohexanone was p r e p a r e d i n the u s u a l manner (sodium methoxide, e t h y l f o r m a t e ) ( 7 1 ) and t r e a t e d w i t h the v i n y l ketone 144 under a wide v a r i e t y of b a s e - c a t a l y z e d condensation conditions.  A g a i n no p r o d u c t c o u l d be i s o l a t e d , and i n each  case a good r e c o v e r y of s t a r t i n g m a t e r i a l was  realized.  I n view of the above f a i l u r e s of the base-promoted a n n e l a t i o n r e a c t i o n , another p o s s i b l e r o u t e was  Robinson  investigated.  Stork  e t a l . (72) had r e p o r t e d the f a c i l e c o n d e n s a t i o n o f the p y r r o l i d i n e enamine of cyclohexanone w i t h m e t h y l v i n y l k e t o n e t o a f f o r d , i n 83% y i e l d , o c t a l o n e 154.  Hence, i t was d e c i d e d t o attempt a s i m i l a r  c o n d e n s a t i o n employing the v i n y l k e t o n e 144.  H  154  Thus, the p y r r o l i d i n e enamine o f cyclohexanone and v i n y l k e t o n e 144 were s t i r r e d t o g e t h e r a t 60° f o r 40 h.  Dry d i o x a n e was  added and the s o l u t i o n r e f l u x e d f o r an a d d i t i o n a l 12 h.  then  Subsequent  h y d r o l y s i s o f the crude r e a c t i o n m i x t u r e w i t h hot aqueous a c e t i c sodium a c e t a t e s o l u t i o n a f f o r d e d , i n 83% y i e l d , o c t a l o n e 155.  acid-  - 69  -  H  +  G  0  0  N  144  155  G.l.c.  a n a l y s i s of o c t a l o n e 155  components i n the these two 155  r a t i o of 7:3,  i n d i c a t e d the  respectively,  components were e p i m e r i c at C^Q.  under b a s e - c a t a l y z e d e p i m e r i z a t i o n  methanol) r e s u l t e d i n the r a t i o of 3:1,  presence of  i t was  proposed  Treatment of  conditions  r e c o v e r y of the  same two  two that  octalone  (sodium methoxide, components, i n  the  respectively.  0  155a  155b  Upon examination of the non-bonded i n t e r a c t i o n s p r e s e n t i n and  155b,  i t i s evident  t h a t 155a  i s the more s t a b l e isomer.  155a  The  two  2 skew i n t e r a c t i o n s between the i s o p r o p y l group and centers,  p r e s e n t i n 155b,  but  for this r e l a t i v e s t a b i l i t y . was  the major component and  absent i n 155a, Hence, i t was  o c t a l o n e 155b  the  are m a i n l y  proposed that  was  and  sp  responsible octalone  the minor component.  155a  - 70 -  Y 0 0 155b  155a  These compounds were i s o l a t e d by p r e p a r a t i v e g . l . c . and showed the e x p e c t e d s p e c t r a l p r o p e r t i e s .  The major epimer e x h i b i t e d ,  i n t h e i n f r a r e d spectrum, a b s o r p t i o n s a t 6.0 u and 6.15 u due t o t h e c a r b o n y l and c a r b o n - c a r b o n double bond r e s p e c t i v e l y .  I n the n.m.r.  spectrum (see F i g u r e 1) t h e major epimer e x h i b i t e d s i g n a l s a t T 9.21 and T 9.11 as t h r e e - p r o t o n d o u b l e t s ( J = 7 Hz)due t o t h e i s o p r o p y l m e t h y l groups and a t T 8.26 as a t h r e e - p r o t o n s i n g l e t due t o t h e v i n y l m e t h y l group.  S i m i l a r l y the minor isomer e x h i b i t e d , i n t h e i n f r a r e d  spectrum, a b s o r p t i o n s a t 6.0 and 6.1 u and i n t h e n.m.r. spectrum (see F i g u r e 2 ) , s i g n a l s a t T 9.11 as a s i x - p r o t o n d o u b l e t ( J = 6 Hz) f o r the i s o p r o p y l m e t h y l groups and a t T 8.26 as a t h r e e - p r o t o n s i n g l e t f o r t h e v i n y l m e t h y l group.  Both epimers e x h i b i t e d a maximum  i n t h e u l t r a v i o l e t spectrum a t 249 mu". H a v i n g r e a l i z e d i n c o r p o r a t i o n o f an i s o p r o p y l group i n t o the p o s i t i o n o f a s i m p l e o c t a l o n e , i t was n e x t p l a n n e d t o p r e p a r e a compound w i t h f u n c t i o n a l i t y i n t h e B r i n g w h i c h would a l l o w e l a b o r a t i o n t o t h e cadinane s k e l e t o n .  Thus, h y d r o l y s i s and d e c a r b o x y l a t i o n o f k e t o e s t e r  113 employing aqueous p o t a s s i u m h y d r o x i d e , r e s u l t e d i n a 66% y i e l d of 4 - e t h y l e n e d i o x y c y c l o h e x a n o n e 156.  T h i s compound e x h i b i t e d  spectral  - 72  r  3  s  9  t  o  CM  a a__o_  - 73 -  113  156  p r o p e r t i e s i n complete a c c o r d w i t h t h e a s s i g n e d s t r u c t u r e . was t h e appearance i n t h e i n f r a r e d spectrum o f a c a r b o n y l  Of n o t e absorption  at 5.85 u and the appearance, i n the n.m.r. spectrum, o f s i g n a l s a t T 5.84 ( s i n g l e t , k e t a l p r o t o n s ) and a t x 7.17-8.00  (unresolved  multiplet, ring protons). Treatment o f t h e p y r r o l i d i n e enamine o f k e t o n e 156 w i t h v i n y l ketone 144 under the p r e v i o u s l y d e s c r i b e d c o n d i t i o n s a f f o r d e d , i n o n l y 8% y i e l d , o c t a l o n e 157.  Attempts t o improve the y i e l d o f t h i s  144  157  r e a c t i o n by v a r y i n g the r e a c t i o n c o n d i t i o n s were u n s u c c e s s f u l . 157, a f t e r e p i m e r i z a t i o n , was shown t o be a m i x t u r e 157a and 157b i n a r a t i o of 4:1 r e s p e c t i v e l y .  of o c t a l o n e s  Octalone  - 74 -  157a  157b  These compounds were i s o l a t e d by p r e p a r a t i v e g . l . c . and e x h i b i t e d t h e expected s p e c t r a l p r o p e r t i e s .  U s i n g t h e same r e a s o n i n g as above t h e  major epimer was p o s t u l a t e d t o be 157a. The, l a t t e r e x h i b i t e d a s t r o n g  157a  157b  a h s o r p t i o n a t 6.05 y i n t h e i n f r a r e d spectrum and s i g n a l s i n t h e n.m.r. spectrum (see F i g u r e 3) a t - x 9.18 and x 9.08 ( p a i r o f d o u b l e t s , i s o p r o p y l m e t h y l g r o u p s , J = 6.5 H z ) , a t x 8.23 ( s i n g l e t , v i n y l m e t h y l group) and a t x 6.06 ( s i n g l e t , k e t a l p r o t o n s ) .  S i m i l a r l y , t h e minor  epimer e x h i b i t e d a s t r o n g a b s o r p t i o n a t 6.01 y ( c a r b o n y l ) and a weak a b s o r p t i o n a t 6.15 y (carbon-carbon double bond) i n t h e i n f r a r e d . The n.m.r. spectrum o f 157b (see F i g u r e 4) e x h i b i t e d s i g n a l s a t x 9.08 and x 9.06 ( p a i r o f d o u b l e t s , i s o p r o p y l m e t h y l groups, J = 6.0 H z ) , at x 8.23 ( s i n g l e t , v i n y l m e t h y l ) and a t x 6.06 ( s i n g l e t , k e t a l p r o t o n s ) . I t was f e l t t h a t t h e k e t a l f u n c t i o n a l i t y c o u l d be s t e r i c a l l y  F i g u r e 4.  N.M.R. Spectrum of O c t a l o n e 157b.  - 77 -  h i n d e r i n g approach of the v i n y l ketone 144 enamine o f 156,  I t was  thus a c c o u n t i n g  t h e r e f o r e decided  a  t o r e p l a c e the k e t a l group by the  t o s y n t h e s i z e 4-hydroxycyclohexanone converted  the  f o r the low y i e l d of o c t a l o n e  l e s s demanding a l c o h o l f u n c t i o n a l i t y .  Q u i n t o l (159) was  to the - c a r b o n o f  To t h i s end,  i t was  157.  sterically necessary  (158).  i n t o k e t o a l c o h o l 158 by a p r o c e d u r e  s i m i l a r t o t h a t d e s c r i b e d by Jones and Sondheimer ( 7 3 ) . r e a c t i o n of one e q u i v a l e n t o f b e n z o y l  Thus,  chloride with quintol i n a  c h l o r o f o r m - p y r i d i n e s o l u t i o n a f f o r d e d , i n 62% y i e l d , q u i n t o l monobenzoate (160).  O x i d a t i o n o f 160 w i t h chromium t r i o x i d e i n g l a c i a l  a c e t i c a c i d a f f o r d e d , i n 87% y i e l d , 4-benzoyloxycyclohexanone 0 II  (161).  - 78 -  T r a n s e s t e r i f i c a t i o n o f 161 w i t h methanol i n the p r e s e n c e o f a c a t a l y t i c amount of sodium methoxide a f f o r d e d , i n 74% y i e l d  4-hydroxycyclohexanone  (158). Now w i t h 4-hydroxycyclohexanone r e a d i l y a v a i l a b l e i t remained to i n v e s t i g a t e t i o n of the  the c r u c i a l e n a m i n e - a n n e l a t i o n r e a c t i o n .  Thus, condensa-  p y r r o l i d i n e enamine o f 4-hydroxycyclohexanone w i t h  v i n y l ketone 144 was attempted under a v a r i e t y o f c o n d i t i o n s , 40% y i e l d o f o c t a l o n e 162 f i n a l l y r e a l i z e d .  with  The optimum c o n d i t i o n s  a found  162  144  were as f o l l o w s .  The enamine o f 158 was s t i r r e d w i t h t h e v i n y l k e t o n e  144 f o r 36 h a t 50°.  Aliquot  samples were t a k e n a t r e g u l a r  intervals  and more v i n y l ketone was added when the i n f r a r e d spectrum o f the material  o b t a i n e d from the a l i q u o t  showed the p r e s e n c e of enamine and  s a t u r a t e d c a r b o n y l compounds, b u t  t h e absence o f any a , 3 - u n s a t u r a t e d  c a r b o n y l - c o n t a i n i n g compounds.  The crude r e a c t i o n m i x t u r e was then  h y d r o l y z e d w i t h hot a c e t i c a c i d - s o d i u m a c e t a t e s o l u t i o n t o a f f o r d o c t a l o n e 162.  - 79 -  162  S i n c e o c t a l o n e 162 has t h r e e asymmetric c e n t e r s (C^, t h e p r o d u c t o b t a i n e d from the above c o n d e n s a t i o n or more of f o u r d i f f e r e n t d i a s t e r e o m e r s .  and  c o u l d c o n s i s t of  C^), one  These, a l o n g w i t h the c o r r e s -  ponding c o n f o r m a t i o n a l diagrams are l i s t e d below.  - 80  -  A n a l y s i s of the c o n d e n s a t i o n p r o d u c t by a c o m b i n a t i o n of g . l . c . and s p e c t r a l methods r e v e a l e d 162a,  162b,  162c  and  162d.  the presence of a l l f o u r  A g a i n i t was  e p i m e r i z a t i o n the o c t a l o n e s  possessing  would predominate o v e r the o c t a l o n e s group.  O c t a l o n e 162 was  felt  octalones  that a f t e r  base-catalyzed  an e q u a t o r i a l i s o p r o p y l group  possessing  therefore subjected  an a x i a l i s o p r o p y l  to e p i m e r i z a t i o n  conditions  (sodium methoxide, methanol) to e s t a b l i s h the f o l l o w i n g e q u i l i b r i a :  162c  162d  A f t e r t h i s base-catalyzed  e p i m e r i z a t i o n of the crude o c t a l o n e  162,  g . l . c . a n a l y s i s of the p r o d u c t e x h i b i t e d two peaks i n the r a t i o of respectively.  I t was  s u b s e q u e n t l y shown t h a t the m a t e r i a l g i v i n g  r i s e to the major peak c o n s i s t e d of a m i x t u r e of p r o d u c t s 162a while  7:3,  and  162c,  the m a t e r i a l g i v i n g r i s e t o the minor peak c o n s i s t e d of a 2  m i x t u r e of p r o d u c t s 162b  and  162d.  2 To a v o i d c o n f u s i o n i n the subsequent d i s c u s s i o n 162a p l u s 162c w i l l be t r e a t e d as one p r o d u c t and r e f e r r e d t o as the major condens a t i o n p r o d u c t , w h i l e 162b p l u s 162d w i l l be t r e a t e d as one p r o d u c t and r e f e r r e d to as the minor c o n d e n s a t i o n p r o d u c t .  - 81 T h i s was shown as d e s c r i b e d below.  The major and minor condensa-  t i o n products were i s o l a t e d by p r e p a r a t i v e g . l . c . and e x h i b i t e d s p e c t r a l p r o p e r t i e s i n complete accord w i t h the a s s i g n e d s t r u c t u r e s . condensation  product  (162a + 162c)  e x h i b i t e d a b s o r p t i o n s i n the  i n f r a r e d spectrum a t 2.75 and 2.9 u  due to the a l c o h o l f u n c t i o n a l i t y  and at 6.05 y due t o the a , ^ - u n s a t u r a t e d spectrum of the major condensation  The major  c a r b o n y l group.  product  The n.m.r.  (see F i g u r e 5) d i s p l a y e d  s i g n a l s at x 9.16 and x 9.07 as two t h r e e - p r o t o n d o u b l e t s  ( J = 6.5 Hz)  due  t o the i s o p r o p y l methyl groups, a t x 8.23 as a t h r e e - p r o t o n  due  to  singlet  the v i n y l m e t h y l group and a t x 6.15 and x 5.82 as m u l t i p l e t s  3 ( t o t a l l i n g one proton) The  f o r the protons  u l t r a v i o l e t spectrum e x h i b i t e d a maximum a t 248 my. The minor condensation  i n the i n f r a r e d ality, due  a d j a c e n t t o the a l c o h o l groups.  product  (162b plus162d) e x h i b i t e d a b s o r p t i o n s ,  spectrum, at 2.75 and 2.9 y  due to the a l c o h o l f u n c t i o n -  at 6.05 y due t o the a,B-unsaturated c a r b o n y l group and a t 6.15 y  to the carbon-carbon  material  double  bond.  The n.m.r. spectrum of t h i s  (see F i g u r e 6) d i s p l a y e d two t h r e e - p r o t o n d o u b l e t s a t x 9.07  and x 9.04 due to the i s o p r o p y l methyl groups ( J = 6.5 Hz), at x 8.26 as a t h r e e - p r o t o n s i n g l e t due to the v i n y l methyl group and a t x 6.10 and x 5.78 as u n r e s o l v e d m u l t i p l e t s ( t o t a l l i n g one proton) adjacent  to the a l c o h o l group.  4  f o r the p r o t o n  The u l t r a v i o l e t spectrum e x h i b i t e d a  maximum a t 247 my. 3  4  I n t e g r a t i o n o f the n.m.r. spectrum i n d i c a t e d that the o c t a l o n e 162c w i t h an a x i a l a l c o h o l group and the o c t a l o n e 162a w i t h an e q u a t o r i a l a l c o h o l group were p r e s e n t i n the r a t i o o f approximately 3:2, pg er c ta it vi eo ln y .o f the s i g n a l s a t x 6.10 and x 5.78 i n d i c a t e d t h a t Ir ne ts e o c t a l o n e 162b and 162d were p r e s e n t i n a r a t i o of approximately 1:1.  3  F i g u r e 6.  -  4  N.M.R. Spectrum of Octalones  5  (162b + ,162d).  6  7  8  9  10  T  •  - 84 -  A d d i t i o n a l s u p p o r t i n g e v i d e n c e f o r the n a t u r e o f the major condensat i o n p r o d u c t was o b t a i n e d as f o l l o w s :  a sample of the major  condensation  product was c o l l e c t e d by p r e p a r a t i v e g . l . c . and s u b j e c t e d t o S a r e t t oxidation  (74).  Thus, o x i d a t i o n of the major c o n d e n s a t i o n  (162a p l u s 162c) a f f o r d e d , i n 94% y i e l d , to be homogeneous by g . l . c .  162a  product  compound 163 which was shown  and s p e c t r a l a n a l y s i s .  This  162c  demonstrated  163  t h a t the two components o f the major c o n d e n s a t i o n p r o d u c t d i d i n f a c t d i f f e r o n l y i n the s t e r e o c h e m i s t r y of the C,-hydroxyl o The  s p e c t r a l p r o p e r t i e s o f dione 163 were i n complete  w i t h the a s s i g n e d s t r u c t u r e . at X 247 my. max 5.85  The u l t r a v i o l e t  The i n f r a r e d spectrum  y ( s a t u r a t e d c a r b o n y l group), a t 6.05y  group) and at 6.15 y  (carbon-carbon  spectrum  the i s o p r o p y l methyl  groups  ( J = 6.5  x 8.12 due to the v i n y l methyl  e x h i b i t e d a maximum  (a, 6 - u n s a t u r a t e d c a r b o n y l  double bond).  The n.m.r.  spectrum  and T 9.07  due to  Hz) and a t h r e e - p r o t o n s i n g l e t a t  group.  Proof o f the S t e r e o c h e m i s t r y o f the Condensation Having  accord  exhibited absorptions at  of 163 d i s p l a y e d two t h r e e - p r o t o n d o u b l e t s at T 9.20  IV.  group.  c l e a r l y shown that the proposed  Stork  Products  enamine-annelation  was a f e a s i b l e p r o c e s s , i t was n e c e s s a r y t o u n e q u i v o c a l l y determine the  - 85 r e l a t i v e stereochemistry at C, and C,„ of the major and minor condensa4 10 t i o n products. In order to accomplish t h i s o b j e c t i v e , i t was planned J  162 to convert octalones 162 i n t o the corresponding simple decalone d e r i v a t i v e s , unsubstituted at Cg.  I t was then hoped that c a r e f u l  s p e c t r a l studies would unambiguously at C^ and C^Q.  define the r e l a t i v e stereochemistry  With t h i s objective i n mind, i t was proposed that the  next two necessary steps - namely removal of the C^-hydroxyl group and s a t u r a t i o n of the conjugated carbon-carbon double bond - could be conveniently c a r r i e d out i n one main operation. I t has been w e l l documented  that a,8-unsaturated ketones undergo  s t e r e o s e l e c t i v e lithium-ammonia reduction, a f f o r d i n g the corresponding saturated ketones (45,46,48).  Furthermore, i t has been shown that  mesylate groups can be hydrogenolyzed under lithium-ammonia reduction conditions (75). Hence, i t appeared that B i r c h reduction would be the appropriate r e a c t i o n f o r degrading octalone 162. Treatment of octalone 162 w i t h methanesulfonyl c h l o r i d e i n p y r i d i n e afforded, i n 85% y i e l d , the corresponding methanesulfonate d e r i v a t i v e 164.  Evidence that t h i s transformation had indeed taken place was shown  i n the i n f r a r e d spectrum of 164. 8.55 u  I t exhibited absorptions at 7.45 and  f o r the methanesulfonate group but no absorptions f o r the hydroxyl  -  group p r e s e n t  86  -  i n the s t a r t i n g m a t e r i a l .  Treatment o f 164 w i t h l i t h i u m  i n l i q u i d ammonia, c o n t a i n i n g e t h a n o l as c o - s o l v e n t  and p r o t o n  source,  f o l l o w e d by o x i d a t i o n of the r e s u l t i n g crude a l c o h o l s w i t h Jones reagent (76) a f f o r d e d , i n 85% y i e l d , two e p i m e r i c d e c a l o n e s 165a and 165b^  i n a r a t i o o f 7:3, r e s p e c t i v e l y .  |  H  |  165a  H  165b  As p r e v i o u s l y d e s c r i b e d , b a s e - c a t a l y z e d 155  afforded octalones  155  ^  e p i m e r i z a t i o n of o c t a l o n e  155a and 155b i n t h e r a t i o o f 3:1, r e s p e c t i v e l y .  155a  155b  The f a c t t h a t 165b d i d c o n t a i n a c i s r i n g j u n c t i o n was s u b s e q u e n t l y unambiguously shown (see p. 9 5 ) .  - 87 B i r c h r e d u c t i o n of t h i s e q u i l i b r i u m m i x t u r e would be e x p e c t e d to y i e l d d e c a l o n e s 165a and 165b  i n the r a t i o of 3:1 r e s p e c t i v e l y .  As  expected  B i r c h r e d u c t i o n of a 3:1 m i x t u r e of o c t a l o n e s 155a and 155b w i t h l i t h i u m i n l i q u i d ammonia, f o l l o w e d by quenching w i t h ammonium c h l o r i d e a f f o r d e d , i n 78% y i e l d , a m i x t u r e of d e c a l o n e s 165a and 165b respectively.  i n the r a t i o of  3:1  The s p e c t r a l p r o p e r t i e s and g . l . c . r e t e n t i o n times of  the major and minor p r o d u c t s formed from B i r c h r e d u c t i o n o f o c t a l o n e 155 were i d e n t i c a l i n e v e r y r e s p e c t w i t h those of the major and minor p r o d u c t s formed from the r e d u c t i o n - o x i d a t i o n of m e s y l a t e 164 ( o b t a i n e d from o c t a l o n e 162).  The above r e s u l t s p r o v i d e d c o n f i r m a t o r y e v i d e n c e  t h a t the major c o n d e n s a t i o n p r o d u c t of o c t a l o n e 162 d i d i n d e e d c o n s i s t of o c t a l o n e s 162a and 162c w h i l e the minor c o n d e n s a t i o n p r o d u c t of o c t a l o n e 162 c o n s i s t e d of o c t a l o n e s 162b  162b  and  162d.  162d  - 88 To ensure t h a t no e p i m e r i z a t i o n was t a k i n g p l a c e p r i o r t o r e d u c t i o n i n the lithium-ammonia-ethanol c o n d i t i o n s pure o c t a l o n e 155a was i s o l a t e d by p r e p a r a t i v e g . l . c . Reduction  and s u b j e c t e d  of o c t a l o n e 155a w i t h  l i t h i u m i n l i q u i d ammonia c o n t a i n i n g  e t h a n o l as c o - s o l v e n t and p r o t o n s o u r c e , (76) o f the crude product  to these c o n d i t i o n s .  f o l l o w e d by Jones  oxidation  a f f o r d e d , i n 91% y i e l d , o n l y decalone 165a.  155a  165a  T h i s c o n t r o l experiment demonstrated t h a t the mesylate (164) o f o c t a l o n e 162 d i d not undergo e p i m e r i z a t i o n p r i o r t o r e d u c t i o n . the r a t i o s of the r e d u c t i o n p r o d u c t s , indeed  reflect  The  decalones  the o r i g i n a l composition  spectrum o f decalone c a r b o n y l group.  165a and 165b, d i d  of o c t a l o n e 162.  s p e c t r a l p r o p e r t i e s o f the decalones  complete agreement w i t h the a s s i g n e d  That i s t o say,  165a and 165b were i n  structures.  Thus, the i n f r a r e d ,  165a e x h i b i t e d an a b s o r p t i o n a t 5.85 u due t o the  I n the n.m.r. spectrum of 165a (see F i g u r e 7) s i g n a l s  were e v i d e n t  f o r the i s o p r o p y l methyl groups a t  three-proton  doublets  ( J = 7 Hz) and f o r the  x 8.99 as a t h r e e - p r o t o n  doublet  x  9.23 and  x  9.13 as two  secondary methyl a t  ( J = 6.5 H z ) .  S i m i l a r l y , decalone  165b  e x h i b i t e d i n the i n f r a r e d spectrum, an a b s o r p t i o n at 5.85 y ( c a r b o n y l group).  The n.m.r. spectrum o f 165b (see F i g u r e 8) d i s p l a y e d two t h r e e a t T 9.13 and T 9.09 a t t r i b u t a b l e to the i s o p r o p y l methyl  proton  doublets  groups  ( J = 6 Hz) and a t h r e e - p r o t o n  doublet  at T 9.02 f o r the C  - 91 -  methyl group  (J = 6.5 H z ) .  That the s t e r e o c h e m i s t r y of the two decalones 165a and 165b was as shown below was s u b s e q u e n t l y confirmed by i n t e r n u c l e a r resonance  (INDOR) s t u d i e s  (77,78).  double  S i n c e the r e s u l t s o b t a i n e d from the  165a  165b  INDOR experiments p l a y e d a c r u c i a l r o l e i n the assignment  o f the s t e r e o -  c h e m i s t r y o f the two decalones 165a and 165b, i t i s p e r t i n e n t t o b r i e f l y discuss t h i s technique.  T h i s experiment i s performed u s i n g a p e r t u r b i n g  energy beam of lower power than t h a t used i n e i t h e r s p i n - d e c o u p l i n g (79) or s p i n t i c k l i n g experiments -  (80).  The o b s e r v i n g frequency i s c e n t e r e d  e x a c t l y on a s i n g l e sharp s p e c t r a l l i n e . beam i s swept through the spectrum. enough t o s h i f t  Then the p e r t u r b i n g  energy  T h i s energy beam i s j u s t p o w e r f u l  energy l e v e l p o p u l a t i o n s .  In o r d e r to i l l u s t r a t e t h i s t e c h n i q u e , c o n s i d e r a two s p i n f o r which a diagrammatic i s g i v e n i n F i g u r e 9.  r e p r e s e n t a t i o n o f the connected  I t s h o u l d be emphasized  system  transitions  that t h i s i s not meant  to be a p r e c i s e energy l e v e l diagram but i s p u r e l y a convenient q u a l i t a t i v e r e p r e s e n t a t i o n t o a i d i n p r e d i c t i n g r e s u l t s . Now i f t r a n s i t i o n 1 i s monitored and the p e r t u r b i n g energy beam c o i n c i d e s w i t h the frequency o f t r a n s i t i o n 4, l e v e l A w i l l be depopulated and the i n t e n s i t y of the monitored s i g n a l w i l l decrease.  C o n v e r s e l y , when the p e r t u r b i n g  (+l/2,-l/2)B  CC-1/2,+1/2)  Figure 9 energy beam c o i n c i d e s w i t h the frequency o f t r a n s i t i o n 2, l e v e l B w i l l be depopulated and the i n t e n s i t y o f the monitored  signal w i l l  increase.  Hence,  t h i s technique g i v e s r i s e to a spectrum p o s s e s s i n g a f l a t b a s e l i n e except when the p e r t u r b i n g frequency c o i n c i d e s w i t h a t r a n s i t i o n connected t o the t r a n s i t i o n b e i n g monitored.  T h i s technique t h e r e f o r e p e r m i t s determin-  a t i o n of the p o s i t i o n and c o u p l i n g c o n s t a n t s of protons whose s i g n a l s might o t h e r w i s e be obscured by the methylene envelope. T h i s technique appeared p a r t i c u l a r l y  a t t r a c t i v e because o b s e r v a t i o n  of a s p e c t r a l l i n e due to one o f the p r o t o n s at  i n decalones 165a  and 165b would a l l o w d e t e r m i n a t i o n of the C^-C^ p r o t o n c o u p l i n g c o n s t a n t s and thus p r o v i d e i n f o r m a t i o n on the s t e r e o c h e m i s t r y o f the group.  isopropyl  The r e s u l t s o b t a i n e d from the INDOR spectrums of decalone 165a  and decalone 165b a r e shown i n T a b l e I and T a b l e I I r e s p e c t i v e l y . Table I.  Chemical S h i f t s and S p l i t t i n g s f o r Decalone 165a  Proton  Measured Chemical S h i f t ( i n Hz f r o m C H C 1 )  Protons  Measure  3  3e H  3a  H  4  H  l  Splittings (Hz)  495.8  H„ —H„ 3e 3 a  12.7  523.2  H_ -H. 3e 4 a  3.8  580.4  H_ —H. 3a 4 a  12.7  517.5  H -(CH ) 1  3  1  6.4  - 93 Table I I .  Proton  Chemical S h i f t s  and S p l i t t i n g s  Measured Chemical S h i f t ( i n Hz from CHC1 )  f o r Decalone 165b  Measured  Protons  3  481.7  3e H  H  463.1  l  13.0  H, -H_ 3e 3a H, -H. 3e 4a  515.7  3a  H  3.9 13.0  3a" 4a H  H -(CH ) 1  3  Splittings (Hz)  6.4  1  I t s h o u l d be n o t e d t h a t the observed s p l i t t i n g s a r e not c o r r e c t e d f o r h i g h e r o r d e r e f f e c t s but a r e almost c e r t a i n l y w i t h i n e r r o r of the t r u e c o u p l i n g c o n s t a n t s .  experimental  The o b s e r v e d s p l i t t i n g s f o r  decalone 165a a r e i n complete a c c o r d w i t h the s t e r e o c h e m i s t r y  as  d e p i c t e d i n s t r u c t u r e 165a.  165a  H  The s p l i t t i n g s observed were 12.7 Hz due t o t h e the g e m i n a l C  3  a x i a l and C  3  e q u a t o r i a l protons,  d i a x i a l c o u p l i n g between the C  3  c o u p l i n g between  12.7 Hz due t o t h e  a x i a l and C^ a x i a l p r o t o n s and 3.8 Hz  due t o the c o u p l i n g between the C  3  e q u a t o r i a l and the C^ a x i a l p r o t o n s  These s p l i t t i n g s a r e i n a c c o r d w i t h those p r e d i c t e d f o r compound 165a  - 94 from the K a r p l u s curve i s o p r o p y l group at in  (81).  Hence, these s p l i t t i n g s  confirm that  i s indeed i n the e q u a t o r i a l o r i e n t a t i o n as  the  shown  165a. The  splittings  o c t a l o n e 155  f o r the minor product of the  or mesylate 164,  major p r o d u c t , decalone 165a, contrary  Birch reduction  s u r p r i s i n g l y p a r a l l e l e d those of (discussed  above).  This  of the  indicated  that  to a l l e x p e c t a t i o n s the minor product o b t a i n e d from these  Birch reductions  was  not  the  trans-fused  decalone 165c  .  165c The INDOR spectrum of decalone 165c would be expected to reveal two small s p l i t t i n g s - one f o r the d i e q u a t o r i a l coupling between the e q u a t o r i a l and coupling between the  e q u a t o r i a l protons and one f o r the a x i a l - e q u a t o r i a l a x i a l and  e q u a t o r i a l protons. To explain  the observed s p l i t t i n g s i t was necessary to postulate that the B i r c h reduction had proceeded anomalously to produce the c i s - f u s e d decalone 165b.  165b  - 95 -  T h i s compound would be expected due  to the geminal  protons and one  due  c o u p l i n g between the to  large s p l i t t i n g s -  a x i a l and  s m a l l s p l i t t i n g due  e q u a t o r i a l and  a x i a l protons.  one  equatorial  the d i a x i a l c o u p l i n g between the  a x i a l p r o t o n s and one the  to e x h i b i t two  axial  and  t o the c o u p l i n g between  These p r e d i c t i o n s are i n  complete  accord w i t h the observed  s p l i t t i n g s o f 13.0  Hz,  13.0  3.9 Hz.  T h i s evidence combined w i t h the f o l l o w i n g c h e m i c a l  Hz  and  evidence  confirmed t h a t the minor product from the B i r c h r e d u c t i o n of e i t h e r o c t a l o n e 155 in structure In was  or mesylate  164 possessed  the s t e r e o c h e m i s t r y d e p i c t e d  165b.  o r d e r to o b t a i n f u r t h e r chemical evidence t h a t decalone  165b  the c o r r e c t s t r u c t u r e f o r the minor product o b t a i n e d from the B i r c h  r e d u c t i o n o f mesylate i n another way.  164  i t was  Examination  to synthesize t h i s  of a m o l e c u l a r model of o c t a l o n e  showed t h a t the double bond was a x i a l i s o p r o p y l group.  next planned  155b  v e r y h i n d e r e d to a t t a c k from the B-side by  Hence, h y d r o g e n a t i o n  of o c t a l o n e 155b  would be  to y i e l d o n l y the c i s - f u s e d decalone as product. Hydrogenation  0  less hindered  of octalone 155b  side  o f a c a t a l y t i c amount of p a l l a d i u m on c h a r c o a l , f o l l o w e d  by e p i m e r i z a t i o n (sodium methoxide, methanol) of the a-methyl group .in the p r o d u c t , a f f o r d e d o n l y decalone 165b. i d e n t i c a l i n a l l r e s p e c t s w i t h decalone 165b  T h i s decalone o b t a i n e d from  was the  the  expected  165b  155b  i n the presence  decalone  - 96 lithium-ammonia r e d u c t i o n o f o c t a l o n e 155b  o r m e s y l a t e 164.  c o n f i r m s t h a t the B i r c h r e d u c t i o n o f o c t a l o n e 155b  This  and m e s y l a t e  had indeed proceeded t o g i v e the c i s - f u s e d decalone  165b.  The B i r c h  r e d u c t i o n r e s u l t s w i l l be d i s c u s s e d i n d e t a i l l a t e r i n t h i s  V.  164  thesis.  S y n t h e s i s o f Cadinene D i h y d r o c h l o r i d e W i t h c o n f i r m a t i o n t h a t the r e l a t i v e s t e r e o c h e m i s t r y at C, and C, „ 4 10  of the major c o n s t i t u e n t of o c t a l o n e 162 was cadinane s k e l e t o n , i t was  next planned  t h a t r e q u i r e d f o r the  to convert t h i s  octalone  into  cadinane d e r i v a t i v e s . The major c o n s t i t u e n t s of o c t a l o n e 162, o c t a l o n e s 162a p l u s were i s o l a t e d by p r e p a r a t i v e g . l . c . and c a r r i e d through o u t l i n e d i n Chart XVI.  Thus, treatment  162c,  the sequence  of o c t a l o n e 162a p l u s  162c  w i t h e t h a n e d i t h i o l i n the p r e s e n c e of boron t r i f l u o r i d e e t h e r a t e a f f o r d e d , a f t e r r e c r y s t a l l i z a t i o n , a 66% y i e l d o f the c o r r e s p o n d i n g  thioketal  166.  occurred  was  The  f a c t t h a t the d e s i r e d t r a n s f o r m a t i o n had  shown by the s p e c t r a l d a t a of compound 166.  of compound 166 e x h i b i t e d a b s o r p t i o n s a t 3.0 f u n c t i o n a l i t y , 6.1 a b s o r p t i o n a t 6.0  u due  indeed  The  u due  i n f r a r e d spectrum  t o the a l c o h o l  t o the carbon-carbon double bond but  u (carbonyl group).  The n.m.r. spectrum of  e x h i b i t e d two t h r e e - p r o t o n d o u b l e t s a t x 9.21  and x 9.02  no 166  attributable  t o the i s o p r o p y l m e t h y l groups, a one-proton s i n g l e t a t x 8.57 the h y d r o x y l p r o t o n  (exchanged, on deuterium  p r o t o n s i n g l e t at x 8.07 at x 6.67  due  due  due  to  oxide a d d i t i o n ) , a three-  to the v i n y l m e t h y l , a f o u r - p r o t o n  singlet  to the p r o t o n s o f the t h i o k e t a l group and one m u l t i p l e t  ( l e s s than one p r o t o n ) to the h y d r o x y l group.  a t x 5.85  due  to the e q u a t o r i a l p r o t o n  adjacent  D e s u l p h u r i z a t i o n of 166 w i t h Raney n i c k e l i n  Chart XVI  - 98 r e f l u x i n g e t h a n o l a f f o r d e d , i n 77% y i e l d , o l e f i n i c a l c o h o l 167. s p e c t r a l data o f compound 167 f u l l y In p a r t i c u l a r ,  The  substantiated the assigned s t r u c t u r e .  the n.m.r. spectrum e x h i b i t e d a s s i g n a b l e s i g n a l s at  x 9.23 and T 9.09 ( p a i r o f d o u b l e t s , i s o p r o p y l methyl groups, J = 6.5 H z ) , at T 8.40 ( s i n g l e t , v i n y l methyl) a t x 8.22 ( s i n g l e t , h y d r o x y l exchanged on a d d i t i o n o f deuterium oxide)  proton,  and a t x 6.36 and x 5.85  ( m u l t i p l e t s , CHOH) but no s i g n a l f o r the k e t a l group. O x i d a t i o n o f 167 w i t h chromium t r i o x i d e i n p y r i d i n e a f f o r d e d , i n 89% y i e l d , expected  the c o r r e s p o n d i n g  ketone 168.  Confirmation  t h a t the  o x i d a t i o n had i n f a c t taken p l a c e was g i v e n by the a b s o r p t i o n  i n the i n f r a r e d  spectrum o f 168 a t 5.85 u due to a s a t u r a t e d  but no a b s o r p t i o n c h a r a c t e r i s t i c o f a h y d r o x y l group.  carbonyl  The n.m.r.  spectrum o f 168 d i s p l a y e d s i g n a l s a t x 9.21 and x 9.05 ( p a i r o f d o u b l e t s , i s o p r o p y l methyl groups, J = 6.5 H z ) , and a t x 8.36 ( s i n g l e t ,  vinyl  methyl). Treatment o f ketone 168 w i t h m e t h y l l i t h i u m r e s u l t e d i n t i o n of a l c o h o l 169 i n 91% y i e l d . was i s o l a t e d by p r e p a r a t i v e g . l . c . agreement w i t h  the a s s i g n e d  the forma-  An a n a l y t i c a l sample o f a l c o h o l 169 The s p e c t r a l data were i n complete  structure.  In p a r t i c u l a r ,  the i n f r a r e d  exhibited absorptions  a t 3.0 u ( h y d r o x y l  group) and at 6.1 u  carbon double bond).  The n.m.r. spectrum o f 169 e x h i b i t e d a s s i g n a b l e  s i g n a l s a t x 9.21 and x 9.07 ( p a i r o f d o u b l e t s ,  (carbon-  i s o p r o p y l methyl groups,  J = 6.5 Hz), a t x 8.81 ( s i n g l e t , t e r t i a r y methyl group) and a t x 8.37 ( s i n g l e t , v i n y l methyl  group).  A l c o h o l 169 was converted i n 80% y i e l d , by treatment  into  (+)-cadinene d i h y d r o c h l o r i d e (41)  w i t h anhydrous hydrogen c h l o r i d e i n anhydrous  - 99  ether  at 0°.  which was  The  -  r e c r y s t a l l i z e d m a t e r i a l e x h i b i t e d an i n f r a r e d spectrum  i d e n t i c a l w i t h t h a t of a u t h e n t i c  The m e l t i n g  p o i n t of the  s y n t h e t i c m a t e r i a l showed no  admixture w i t h the a u t h e n t i c m a t e r i a l . cadinene d i h y d r o h a l i d e  (+)-cadinene  d e r i v a t i v e had  Since  dihydrochloride.^  depression  the s t e r e o c h e m i s t r y  (18)  cadinene d i h y d r o c h l o r i d e  confirmed t h a t a l l of the p r e v i o u s l y  work was  t h i s conversion  correct.  product, a f t e r epimerization,  of a l c o h o l 169  That i s to say,  X-ray  into described  the major c o n d e n s a t i o n  of the enamine-annelation r e a c t i o n s  indeed possess the s t e r e o c h e m i s t r y cadinane  of a  been unambiguously shown by  s t r u c t u r a l determination  stereochemical  on  n e c e s s a r y f o r the s y n t h e s i s  of  did the  sesquiterpenes.  Hence, the enamine-annelation approach i s p a r t i c u l a r l y a t t r a c t i v e , s i n c e i n one features  step  required  p e r m i t s the  i t y i e l d s a compound p o s s e s s i n g  a l l the s k e l e t a l  f o r e l a b o r a t i o n to the cadinane compounds.  This  s y n t h e t i c sequence to be kept r e l a t i v e l y simple and  short.  However, t h i s sequence does p o s s e s s s e v e r a l d i s a d v a n t a g e s .  One  complication  products,  i s the p r o d u c t i o n  requiring preparative sequence.  of c l o s e l y r e l a t e d e p i m e r i c  g . l . c . p u r i f i c a t i o n at the i n i t i a l  the cadinene hydrocarbons were not i d e n t i f y to- and  of a l c o h o l 169.  that a u t h e n t i c  a v a i l a b l e hindered  6-cadinene, (52)  and  the the  double bond i n t o the B r i n g .  T h i s l a t t e r disadvantage coupled w i t h the f a c t  6  stages of  In a d d i t i o n , t h i s approach does not make allowance f o r  r e g i o s e l e c t i v e i n t r o d u c t i o n of the r e q u i r e d  and  serious  samples of  attempts to  (8) r e s p e c t i v e l y , by  obtain  dehydration  However, i f the above mentioned disadvantages c o u l d  We thank M.D. Sutherland dihydrochloride.  f o r a generous sample of  (+)-cadinene  be  - 100 -  e f f e c t i v e l y overcome, t h i s s y n t h e t i c sequence would p r o v i d e an e f f i c i e n t e n t r y i n t o t h e cadinane type o f s e s q u i t e r p e n e s .  1 9 VI.  S t u d i e s on the B i r c h R e d u c t i o n s  A.  General Although  of A ' -2-0ctalone  Systems  a number o f t h e o r i e s have been proposed t o e x p l a i n t h e 1 9  s t e r e o c h e m i s t r y o f t h e p r o d u c t s of B i r c h r e d u c t i o n of A ' - 2 - o c t a l o n e systems, r e s e a r c h t o date has f a i l e d t o a d e q u a t e l y  e x p l a i n the product  s e l e c t i v i t y observed  i n these r e d u c t i o n s ( 4 8 ) . G e n e r a l l y , l i t h i u m 1 9 ammonia r e d u c t i o n s o f A ' - 2 - o c t a l o n e s proceed t o y i e l d a h i g h p r o p o r t i o n (^98%) of the c o r r e s p o n d i n g  t r a n s - f u s e d decalone.  As p r e v i o u s l y  d i s c u s s e d , lithium-ammonia r e d u c t i o n o f o c t a l o n e 155b proceeded anomalously t o a f f o r d s t e r e o s e l e c t i v e l y , the c i s - f u s e d decalone 165b; w h i l e s i m i l a r  0  I  •= 155b  r e d u c t i o n of t h e c o r r e s p o n d i n g  H  165b C^ e q u a t o r i a l l y s u b s t i t u t e d o c t a l o n e 155a  proceeded n o r m a l l y t o a f f o r d t h e t r a n s - f u s e d decalone 165a.  z 155a  H 165a  - 101 -  S i n c e an e x p l a n a t i o n f o r the anomalous r e s u l t o b t a i n e d i n the B i r c h r e d u c t i o n o f o c t a l o n e 155b was not o b v i o u s , i t was extend the i n v e s t i g a t i o n t o i n c l u d e lithium-ammonia analogous  o c t a l o n e systems o f type 170.  I t was  decided to  r e d u c t i o n s of  thus hoped t h a t t h e s e  r e s u l t s would a s s i s t i n c l a r i f y i n g some o f the f a c t o r s g o v e r n i n g the s t e r e o c h e m i c a l outcome of B i r c h r e d u c t i o n s of t h i s type of o c t a l o n e .  19 B.  S y n t h e s i s of A ' - 2 - 0 c t a l o n e Systems The f i r s t o b j e c t i v e was,  type 170.  I t was  t h e r e f o r e , t o s y n t h e s i z e o c t a l o n e s of  d e c i d e d t h a t o f the number of p o s s i b l e r o u t e s which  might be employed i n the c o n s t r u c t i o n of these o c t a l o n e s , the scheme i n v o l v i n g 1,4-conjugate  a d d i t i o n of l i t h i u m d i a l k y l c u p r a t e s t o c r o s s -  c o n j u g a t e d dienones of type 171 was  b o t h a t t r a c t i v e and g e n e r a l .  - 102 -  I t i s obvious  t h a t i n dienones  Furthermore syntheses  o f type 171, R^ can n o t be hydrogen.  o f o c t a l o n e s o f type 170 w i t h R^ = H g e n e r a l l y  are ambiguous w i t h r e s p e c t to the r e l a t i v e s t e r e o c h e m i s t r y a t C. . lu  F o r these reasons  a methyl group was chosen as the C. 1  bridgehead  u  s u b s t i t u e n t i n c o n t r a s t t o the hydrogen s u b s t i t u e n t p r e s e n t  and  i n the  compound o r i g i n a l l y s t u d i e d , o c t a l o n e 155b. The  s t a r t i n g m a t e r i a l s which were chosen f o r the s y n t h e s i s o f  o c t a l o n e s of type 170 were the two well-known o c t a l o n e s 172 and 173 (see Chart X V I I ) . procedure  These o c t a l o n e s were prepared  of M a r s h a l l and Fanta  by the l i t e r a t u r e  ( 8 2 ) . Thus,condensation  o f 2-  methylcyclohexanone w i t h m e t h y l v i n y l ketone a t -10° i n the presence of a c a t a l y t i c amount o f sodium e t h o x i d e l a t t e r was s u b j e c t e d to potassium a f f o r d , i n 48% y i e l d , condensation  a f f o r d e d the c i s - k e t o l 174.  The  hydroxide-catalyzed dehydration to  10-methyl-A ' -2-octalone 1  9  (172).  Similarly,  o f 2-methylcyclohexanone w i t h e t h y l v i n y l ketone, f o l l o w e d  by b a s e - c a t a l y z e d d e h y d r a t i o n o f the i n t e r m e d i a t e k e t o l a f f o r d e d , i n 60% y i e l d ,  1,10-dimethyl-A ' -2-octalone 1  9  Treatment o f o c t a l o n e 172 w i t h DDQ 1  (173) ( 8 3 ) . (84) i n the presence  a c i d i n r e f l u x i n g anhydrous benzene f o r 48 h desired cross-conjugated 88:12 r e s p e c t i v e l y .  a f f o r d e d a mixture  of the  dienone 175 p l u s t r i e n o n e 176, i n a r a t i o o f  Hydrogenation  of t h i s mixture  (175 + 1 7 6 )  c a r e f u l l y c o n t r o l l e d b a s i c c o n d i t i o n s i n the presence  under  of a c a t a l y t i c  amount o f p a l l a d i u m on c h a r c o a l a f f o r d e d , i n 70% y i e l d 172),  of benzoic  (from  octalone  c r o s s - c o n j u g a t e d dienone 175 ( 8 5 ) . Dehydrogenation of o c t a l o n e 173 w i t h DDQ i n the presence  a c e t i c a c i d i n . r e f l u x i n g anhydrous benzene f o r 60 h yield,  the c o r r e s p o n d i n g  of g l a c i a l  a f f o r d e d , i n 84%  cross-conjugated, dienone 177 ( 5 7 ) . The  - 103 -  177  173  - 104 -  s p e c t r a l d a t a o f dienone 177 f u l l y c o r r o b o r a t e d t h e s t r u c t u r a l a s s i g n ment.  I n p a r t i c u l a r the i n f r a r e d spectrum e x h i b i t e d a b s o r p t i o n s a t  6.01, 6.12 and 6.21 y.  The n.m.r. spectrum o f 177 d i s p l a y e d  a typical  AB p a i r o f d o u b l e t s a t T 3.80 and T 3.31 ( J = 10 Hz) due t o the and  o l e f i n i c protons.  appeared a t T 8.78 v i n y l methyl).  Other a s s i g n a b l e s i g n a l s i n the n.m.r. spectrum  ( s i n g l e t , t e r t i a r y m e t h y l ) and a t T 8.12 ( s i n g l e t ,  The u l t r a v i o l e t spectrum e x h i b i t e d a maximum a t 240 my.  I t was next p l a n n e d t o i n v e s t i g a t e t h e 1,4-conjugate  additions  of t h e a p p r o p r i a t e l i t h i u m d i a l k y l c u p r a t e r e a g e n t s t o the now r e a d i l y a v a i l a b l e c r o s s - c o n j u g a t e d dienones 175 and 177.  Since the conjugate  a d d i t i o n o f l i t h i u m d i a l k y l c u p r a t e r e a g e n t s i s c r u c i a l t o the r e m a i n i n g synthesis,  i t would be advantageous  to digress  of the pathway of 1,4-conjugate a d d i t i o n s systems.  t o c o n s i d e r the n a t u r e  o f c u p r a t e r e a g e n t s t o enone  The proposed mechanism (65,67,86) f o r 1,4-conjugate  addition  of l i t h i u m d i a l k y l c u p r a t e r e a g e n t s i s as f o l l o w s :  While e x t r a p o l a t i o n s cuprous i o n c a t a l y z e d  of the stereochemical r e s u l t s obtained i n  1,4-conjugate a d d i t i o n o f G r i g n a r d r e a g e n t s t o  enone systems, t o the p r o d u c t s t e r e o c h e m i s t r y o f t h e analogous l i t h i u m  - 105 -  d i a l k y l c u p r a t e r e a c t i o n s must be done w i t h c a u t i o n , t h e r e are many a n a l o g i e s i n the l i t e r a t u r e where conjugate a l k y l a t i o n c a t a l y z e d G r i g n a r d reagent and the analogous  by a copper  cuprate reagent  to y i e l d p r o d u c t s w i t h the same s t e r e o c h e m i s t r y .  salt  proceed  With t h i s p r e c a u t i o n  i n mind, i t i s p e r t i n e n t t o d i s c u s s the e l e g a n t work of M a r s h a l l and Andersen (87) who s t u d i e d the cuprous of  i o n c a t a l y z e d conjugate  addition  s e v e r a l G r i g n a r d reagents to l , l - d i m e t h y l - t r a n s - 3 - o c t a l - 2 - o n e (178).  Briefly,  these workers proposed  group, by means of cuprous  t h a t the conjugate a d d i t i o n of an a l k y l  i o n c a t a l y z e d G r i g n a r d r e a g e n t s , to an  o c t a l o n e of type 178 must, f o r s t e r e o e l e c t r o n i c reasons, take p l a c e v i a the c h a i r - l i k e s t a t e 179b.  transition  s t a t e 179a and/or the b o a t - l i k e  M a r s h a l l and Andersen's experiments  179b  transition  showed t h a t , i n the  181 R = CH  5  182 R = C,H_ o 184 R = ( C H ) C H 3  2  - 106 absence of l a r g e s t e r i c f a c t o r s the former t r a n s i t i o n s t a t e 179a f a v o r e d over the l a t t e r t r a n s i t i o n s t a t e 179b.  was  Hence, the a d d i t i o n  of methylmagnesium i o d i d e to o c t a l o n e 178 produced d e c a l o n e 180 as the major c o n j u g a t e a d d i t i o n p r o d u c t , w h i l e decalone 181 was  formed i n  minor amounts.  was  increased,  However, as the b u l k o f the G r i g n a r d reagent  s t e r i c h i n d r a n c e to a x i a l a t t a c k v i a t r a n s i t i o n s t a t e  also increased.  When phenylmagnesium bromide was employed as the  G r i g n a r d reagent the o n l y p r o d u c t formed was s t a t e 179b).  179a  182 ( a t t a c k v i a t r a n s i t i o n  F i n a l l y , i n the case o f isopropylmagnesium bromide  h i n d r a n c e t o a x i a l approach i n t r i n s i c i n t r a n s i t i o n s t a t e 179a  steric was  a p p r o x i m a t e l y b a l a n c e d by the u n f a v o r a b l e n a t u r e 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 179b.  Consequently the two p r o d u c t s 183 and  184  were formed i n a p p r o x i m a t e l y e q u a l amounts. I f one now  c o n s i d e r s the c o n j u g a t e a d d i t i o n of l i t h i u m d i a l k y l -  c u p r a t e r e a g e n t s to dienones 175 and 177, by analogy w i t h the above principles  t r a n s i t i o n s t a t e s 185a and 185b  i m m e d i a t e l y o b v i o u s t h a t the states  185a  and 185b  interaction  It is  i m p o r t a n t f a c t o r s i n these t r a n s i t i o n  a r e the p r e s e n c e of the a n g u l a r m e t h y l group  at C^Q and the absence o f the C^ hydrogen R-H  can be proposed.  i n t r a n s i t i o n s t a t e 185a).  (removing one  syn-axial  - 107 -  M o l e c u l a r models i n d i c a t e t h a t 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 m a i n t a i n e d i n t r a n s i t i o n s t a t e 185b, t h e n the i n c o m i n g a l k y l must approach the m o l e c u l e i n such a way w i t h the C^Q a n g u l a r m e t h y l group.  that i t i s nearly  eclipsed  The r e s u l t i n g s t e r i c and  torsional  s t r a i n (88,89) s h o u l d be the dominant f a c t o r and s h o u l d ensure t r a n s i t i o n s t a t e 185a i s f a v o r e d over t r a n s i t i o n s t a t e 185b. i t was  group  that Hence,  f u l l y expected t h a t the i n t r o d u c t i o n of an a l k y l group i n the  l i t h i u m d i a l k y l c u p r a t e c o n j u g a t e a d d i t i o n r e a c t i o n s would be  highly  - 108 s t e r e o s e l e c t i v e and f u r t h e r m o r e i t was p r e d i c t e d t h a t t h e p r o d u c t contain the stereochemistry  depicted  i n 186 .  should  I n a l l cases s t u d i e d  R  R' 186 the l i t h i u m d i a l k y l c u p r a t e a d d i t i o n s were h i g h l y s t e r e o s e l e c t i v e as a n a l y s i s by a c o m b i n a t i o n of g . l . c . and s p e c t r a l methods o f t h e r e a c t i o n product revealed epimeric  the p r e s e n c e of o n l y one of the two p o s s i b l e  compounds.  I t s h o u l d be n o t e d t h a t i n t h e p r e v i o u s l y d i s c u s s e d  systematic  study of conjugate a d d i t i o n s of l i t h i u m d i a l k y l c u p r a t e reagents to cross-conjugated  dienone systems s e v e r a l i m p o r t a n t  r e q u i r e m e n t s were worked o u t . and  experimental  I t should be p o i n t e d out t h a t House  coworkers (65,67) had done a d e t a i l e d study o f the p r o p e r t i e s o f  l i t h i u m dimethylcuprate  but at the time t h i s work was underway no  analogous i n f o r m a t i o n was a v a i l a b l e f o r l i t h i u m d i v i n y l - o r l i t h i u m diisopropylcuprate.  I n i t i a l l y a p r o c e d u r e analogous t o t h a t used by  House e t a l . (65) f o r the p r e p a r a t i o n employed i n t h e p r e p a r a t i o n cuprate.  of the a l k y l l i t h i u m reagent were added  o f cuprous i o d i d e i n e t h e r a t 0°.  a d d i t i o n of cross-conjugated  was  o f l i t h i u m d i v i n y l - or l i t h i u m d i i s o p r o p y l -  Thus, two e q u i v a l e n t s  to one e q u i v a l e n t  of l i t h i u m dimethylcuprate  I t was found t h a t  dienones o f type 171 t o s o l u t i o n s o f  l i t h i u m d i v i n y l c u p r a t e or l i t h i u m d i i s o p r o p y l c u p r a t e , prepared i n the  - 109  -  above manner gave r i s e to o n l y poor y i e l d s o f conjugate a d d i t i o n  products  i n the former case and o n l y r e c o v e r e d s t a r t i n g m a t e r i a l or p o l y m e r i c m a t e r i a l i n the l a t t e r case. to 1,4-conjugate  In an attempt  t o enhance the  reactivity  a d d i t i o n of l i t h i u m d i i s o p r o p y l c u p r a t e s o l u t i o n s ,  r e a c t i o n s were t r i e d  i n the presence o f v a r i o u s a d d i t i v e s .  Indeed  f a i r y i e l d s of conjugate a d d i t i o n p r o d u c t s c o u l d be r e a l i z e d l i t h i u m bromide was  i f anhydrous  p r e s e n t i n the r e a c t i o n m i x t u r e .  R e p e t i t i o n of the r e a c t i o n s a t v a r i o u s temperatures  r e v e a l e d that  b e t t e r y i e l d s of conjugate a d d i t i o n p r o d u c t s were o b t a i n e d i f these r e a c t i o n s were run at -78°.  However, y i e l d s o b t a i n e d i n these r e a c t i o n s  were o n l y moderate when compared w i t h the y i e l d s o b t a i n e d i n the analogous  l i t h i u m d i m e t h y l c u p r a t e r e a c t i o n s (62).  Hence, another method o f p r e p a r i n g the cuprate reagents investigated.  In t h i s approach  the e t h e r - s o l u b l e copper  was  (I) i o d i d e -  t r i - n - b u t y l p h o s p h i n e complex prepared by the method of Kaufman et a l . (90) was  employed i n s t e a d of cuprous  iodide.  The  resulting  I s o l u t i o n s were homogeneous i n c o n t r a s t to the c o l l o i d a l of those p r e v i o u s l y p r e p a r e d . w i t h the phosphine  organocopper  appearance  L i t h i u m d i i s o p r o p y l c u p r a t e prepared  complex a g a i n r e q u i r e d the a d d i t i o n of anhydrous  l i t h i u m bromide b e f o r e 1,4-conjugate dienones would occur.  a d d i t i o n to c r o s s - c o n j u g a t e d  While use of the phosphine  complex i n p r e p a r a t i o n  of these r e a g e n t s gave r i s e to b e t t e r y i e l d s o f 1,4-conjugate p r o d u c t s i t a l s o c o m p l i c a t e d the i s o l a t i o n p r o c e d u r e s .  addition  I t was  found  that f r a c t i o n a l d i s t i l l a t i o n s of the crude r e a c t i o n m i x t u r e s , f o l l o w e d by chromatography of the low b o i l i n g i s o l a t i o n of the d e s i r e d  product.  f r a c t i o n s on s i l i c a g e l a l l o w e d T h i s p u r i f i c a t i o n procedure  was  - 110 -  used i n a l l the f o l l o w i n g r e a c t i o n s employing l i t h i u m  divinylcuprate  and l i t h i u m d i i s o p r o p y l c u p r a t e . In the  an attempt t o o p t i m i z e the y i e l d s of c o n j u g a t e a d d i t i o n p r o d u c t s ,  v a r i a b l e parameters of r e a c t i o n t i m e , t e m p e r a t u r e , c o n c e n t r a t i o n ,  and quenching p r o c e d u r e s were n e x t i n v e s t i g a t e d .  A g a i n i t was  found  t h a t use o f low temperatures (-78°) improved the y i e l d s . Y i e l d s o b t a i n e d upon v a r y i n g the r e a c t i o n time from 4 h  t o 36 h  appeared to be i n v a r i a n t a l t h o u g h use of r e a c t i o n times s h o r t e r t h a n 4 h  g e n e r a l l y r e s u l t e d i n some r e c o v e r e d s t a r t i n g m a t e r i a l .  The  r e a c t i o n s were quenched by dropwise a d d i t i o n of the r e a c t i o n m i x t u r e to a r a p i d l y s t i r r e d s o l u t i o n of aqueous a c i d .  The p r o d u c t y i e l d s  were found to be s u b s t a n t i a l l y lower i f t h i s quenching p r o c e d u r e not employed.  was  A f t e r a t t e m p t i n g the a d d i t i o n s under a v a r i e t y of con-  c e n t r a t i o n s i t was found t h a t optimum y i e l d s were o b t a i n e d when the s o l u t i o n was between 0.01  and 0.005 molar i n the organocopper I r e a g e n t .  The l i t h i u m d i a l k y l c u p r a t e c o n j u g a t e a d d i t i o n r e a c t i o n s were next attempted employing the optimum c o n d i t i o n s l i s t e d above. e t h e r e a l s o l u t i o n of dienone 175 was  added to a s o l u t i o n of l i t h i u m  d i m e t h y l c u p r a t e and s t i r r e d a t 0° f o r 2 h. the  Thus, an  A f t e r the a p p r o p r i a t e workup  crude p r o d u c t was p u r i f i e d by d i s t i l l a t i o n ,  f o l l o w e d by  chromato-  graphy of the d i s t i l l a t e on s i l i c a g e l , t o a f f o r d , i n 82% y i e l d , o c t a l o n e 188 .  That the d e s i r e d t r a n s f o r m a t i o n had taken p l a c e was shown c l e a r l y  175  188  - I l lby t h e s p e c t r a l  d a t a o f compound 188 ( 9 1 ) .  In particular  the i n f r a r e d  spectrum o f o c t a l o n e 188 showed a c a r b o n y l a b s o r p t i o n a t 6.0 y and a carbon-carbon double bond a b s o r p t i o n a t 6.15 y.  The n.m.r. spectrum  of 188 e x h i b i t e d a t h r e e - p r o t o n d o u b l e t a t T 9.02 ( J = 7 Hz) attributable  t o t h e newly i n t r o d u c e d m e t h y l group, a t h r e e - p r o t o n  singlet  a t x 8.74 due t o t h e t e r t i a r y m e t h y l group and a one-proton  singlet  a t x 4.30 due t o the  signals  due t o the  material.  and  v i n y l hydrogen.  There were no  o l e f i n i c protons present i n the s t a r t i n g  The u l t r a v i o l e t spectrum o f 188 e x h i b i t e d a maximum a t  239 my. Treatment o f dienone 175 w i t h l i t h i u m d i v i n y l c u p r a t e f o r 4 h  at  -78°, f o l l o w e d by a p p r o p r i a t e workup and p u r i f i c a t i o n , a f f o r d e d o c t a l o n e 194 i n 73% y i e l d .  That t h e v i n y l group had been i n t r o d u c e d a t t h e C.  175  position product.  194  o f dienone 175 was c l e a r l y shown by t h e s p e c t r a l The n.m.r. spectrum o f 194 d i s p l a y e d s i g n a l s  group as an u n r e s o l v e d m u l t i p l e t  data of the  due t o the v i n y l  (x 3.89-5.13) a s i g n a l due t o the  t e r t i a r y m e t h y l group as a t h r e e - p r o t o n s i n g l e t a t x 8.72 and a s i g n a l due t o the v i n y l p r o t o n a t C - l as a one-proton s i n g l e t infrared due t o  a t x 4.25.  The  spectrum o f 194 e x h i b i t e d a b s o r p t i o n s a t 6.0 y and 10.9 y the a,8-unsaturata.d  c a r b o n y l group and the v i n y l group  respectively.  O c t a l o n e 194 proved to be q u i t e u n s t a b l e and hence t h e v i n y l group was  - 112 -  immediately  transformed  t o t h e d e s i r e d e t h y l group.  feared that standard hydrogenation  procedures  r e d u c t i o n o f the e n d o c y c l i c double bond t r i s chlororhodium  S i n c e i t was  might r e s u l t i n c o n s i d e r a b l e (triphenylphosphine)  (92), a s e l e c t i v e c a t a l y s t f o r hydrogenation  double bonds, was employed.  Hydrogenation  p r e s s u r e and room temperature,  employing  o f unhindered  o f o c t a l o n e 194 a t a t m o s p h e r i c t h e above c a t a l y s t a f f o r d e d  as t h e major p r o d u c t o c t a l o n e 189, w i t h a minor amount o f t h e f u l l y s a t u r a t e d c i s - d e c a l o n e 193 a l s o b e i n g formed.  X  The minor component was  \  \  194  189  193  r e a d i l y s e p a r a t e d from t h e o c t a l o n e by chromatography on s i l i c a g e l . The  f a c t t h a t t h e s i m p l e h y d r o g e n a t i o n had i n d e e d taken p l a c e was shown  by t h e s p e c t r a l d a t a o f o c t a l o n e 189.  In p a r t i c u l a r , the i n f r a r e d  spectrum w h i l e s t i l l e x h i b i t i n g an a b s o r p t i o n a t 6.0 u f o r t h e a,3u n s a t u r a t e d c a r b o n y l , no l o n g e r e x h i b i t e d an a b s o r p t i o n a t 10.9 u for  t h e v i n y l group.  spectrum at 239 mu.  Octalone  189 e x h i b i t e d a maximum i n t h e u l t r a v i o l e t  The n.m.r. spectrum of o c t a l o n e 189 no l o n g e r  e x h i b i t e d t h e complex s i g n a l s f o r t h e p r o t o n s o f t h e v i n y l group b u t exhibited a three-proton t r i p l e t  a t x 9.07 ( J = 6.5 Hz) f o r t h e  p r i m a r y m e t h y l group, a t h r e e - p r o t o n s i n g l e t a t x 8.75 f o r the t e r t i a r y m e t h y l group and a one-proton proton.  s i n g l e t a t x 4.21 f o r the  The s p e c t r a l d a t a f o r t h e c i s - f u s e d decalone  olefinic  193 w i l l be  - 113 -  discussed  later.  Treatment of dienone 175 w i t h l i t h i u m d i i s o p r o p y l c u p r a t e f o r 5.75  h  at - 7 8 ° , f o l l o w e d by the a p p r o p r i a t e workup and p u r i f i c a t i o n  a f f o r d e d o c t a l o n e 190 i n 95% y i e l d .  The f a c t t h a t the a d d i t i o n of an  175  190  i s o p r o p y l group t o  o f dienone 175 had indeed  by the s p e c t r a l data o f o c t a l o n e 190. e x h i b i t e d a maximum a t 240 my.  taken p l a c e was shown  The u l t r a v i o l e t  spectrum  The i n f r a r e d spectrum e x h i b i t e d sharp  a b s o r p t i o n s a t 6.0 y ( c a r b o n y l ) and at 6.16 y (carbon-carbon bond). two  double  The n.m.r. spectrum of o c t a l o n e 190 (see F i g u r e 10) d i s p l a y e d  three-proton  doublets  a t x 9.20 and x 9.05 (J = 6.5 Hz), due t o  the newly i n t r o d u c e d secondary methyl groups, a t h r e e - p r o t o n  singlet  at f 8.74, due t o the t e r t i a r y methyl group and a one-proton  singlet  at T 4.22, due t o the The  hydrogen.  s y n t h e s i s of the d e s i r e d o c t a l o n e s was then c o n t i n u e d by 1,4-  conjugate  a d d i t i o n s o f organocopper (I)  dienone 177. cuprate  olefinic  Hence, treatment  for1 h  reagents  t o the d i m e t h y l  of dienone 177 w i t h l i t h i u m  dimethyl-  a t 0 ° , f o l l o w e d by quenching w i t h d i l u t e h y d r o c h l o r i c  a c i d , a f f o r d e d o c t a l o n e 191 i n 92% y i e l d . o c t a l o n e 191 e x h i b i t e d the expected i n f r a r e d spectrum o f 191 two sharp  An a n a l y t i c a l sample o f  spectral properties. absorptions  I n the  appeared a t 6.0 and .  6.2 y due to the c a r b o n y l group and the carbon-carbon double bond  - 115 -  0  0  191  177  respectively.  The n.m.r. spectrum o f 191 e x h i b i t e d s i g n a l s a t x 9.04  as a t h r e e - p r o t o n d o u b l e t ( J = 6.5 Hz) due t o t h e newly secondary m e t h y l group.  introduced  Other a s s i g n a b l e s i g n a l s i n t h e n.m.,r.  spectrum appeared a t x 8.74 and x 8.25 as two t h r e e - p r o t o n s i n g l e t s a t t r i b u t a b l e t o t h e t e r t i a r y m e t h y l group and t h e v i n y l m e t h y l group respectively. ultraviolet  O c t a l o n e 191 e x h i b i t e d a maximum a t 249 my i n t h e  spectrum.  Treatment of dienone 177 w i t h excess l i t h i u m d i i s o p r o p y l c u p r a t e at -78° a f f o r d e d , a f t e r p u r i f i c a t i o n , o c t a l o n e 192 i n 95% y i e l d .  177  192  The c o n j u g a t e a d d i t i o n p r o d u c t gave an u l t r a v i o l e t maximum a t 249 my, and a s t r o n g c a r b o n y l a b s o r p t i o n a t 6.0 y and carbon-carbon double bond a b s o r p t i o n a t 6.2 y i n t h e i n f r a r e d . (see  The n.m.r. spectrum of 192  F i g u r e 11) showed two t h r e e - p r o t o n d o u b l e t s a t x 9.23 and x 9.04  - 117  (J = .7 Hz) x 8.73  -  f o r the i s o p r o p y l methyl groups, a t h r e e - p r o t o n s i n g l e t  f o r the t e r t i a r y methyl group and  a three-proton s i n g l e t  at  at x  8.22  f o r the v i n y l methyl group.  C.  S y n t h e s i s of t r a n s - F u s e d  Decalones  Having r e a l i z e d e f f i c i e n t type 170,  i t was  i n g c i s - and  next planned  s y n t h e s i s of the d e s i r e d o c t a l o n e s of t o unambiguously s y n t h e s i z e the  t r a n s - f u s e d decalones  These decalones  to  expected  decalones  195  of type 196 were e n v i s a g e d I t was  196  as o c t a l o n e s 197  and  198  of type 196  a d d i t i o n of the a p p r o p r i a t e organocopper  (see p. 107)  of the t r a n s - f u s e d  proposed t h a t these o c t a l o n e s c o u l d be  e l a b o r a t e d to the d e s i r e d t r a n s - f u s e d decalones  a,g-unsaturated  respectively.  from the B i r c h r e d u c t i o n of  i n t e r m e d i a t e s i n the proposed syntheses  Chart X V I I I ) .  conjugate  196  192.  170  The key  and  would then s e r v e as a u t h e n t i c samples f o r d i r e c t  comparison w i t h the p r o d u c t s o c t a l o n e s 188  of type 195  correspond-  c a r b o n y l system.  (see readily  by  1,4-  (I) s p e c i e s to  the  U s i n g the same r e a s o n i n g as b e f o r e  the a l k y l group would be expected  to be i n t r o d u c e d t r a n s  to the angular methyl group to g i v e the s t e r e o c h e m i s t r y d e p i c t e d i n structure  196.  - 118 -  - 119  The  -  s t a r t i n g m a t e r i a l s chosen f o r the s y n t h e s i s of o c t a l o n e s  and 198 were the p r e v i o u s l y d i s c u s s e d o c t a l o n e s 172  and 173.  197  It is well  documented (45,46,48) t h a t lithium-ammonia r e d u c t i o n s o f s i m p l e  octalones  such as 172 and 173 s t e r e o s e l e c t i v e l y y i e l d the t r a n s - f u s e d d e c a l o n e s as p r o d u c t s , w i t h l e s s than 2% of the c o r r e s p o n d i n g detected.  c i s isomer b e i n g  Thus, lithium-ammonia r e d u c t i o n of o c t a l o n e 172 w i t h  ethanol  (93) as c o - s o l v e n t and p r o t o n s o u r c e , f o l l o w e d by Jones o x i d a t i o n of the r e s u l t i n g m i x t u r e decalone 200  (93,94).  o f a l c o h o l s 199,  (76)  gave, i n 62% y i e l d , the known  Treatment of the l a t t e r w i t h bromine i n g l a c i a l  a c e t i c a c i d a f f o r d e d , a f t e r r e c r y s t a l l i z a t i o n , a 60% y i e l d o f bromoketone 201  (93).  D e h y d r o h a l o g e n a t i o n of bromoketone 201 w i t h anhydrous  l i t h i u m bromide i n hot hexamethylphosphoramide, a f f o r d e d , i n a y i e l d , the d e s i r e d o c t a l o n e 197  76%  (95).  S i m i l a r l y lithium-ammonia r e d u c t i o n o f o c t a l o n e 173 i n the p r e s e n c e of e t h a n o l , f o l l o w e d by Jones o x i d a t i o n (76) of the r e s u l t i n g a l c o h o l s 202,  a f f o r d e d i n 70% y i e l d d e c a l o n e 203  (84).  As expected  decalone e x h i b i t e d a s t r o n g c a r b o n y l a b s o r p t i o n at 5.85 infrared.  D i r e c t bromination  this  U i n the  of decalone 203 by a p r o c e d u r e s i m i l a r  to t h a t d e s c r i b e d above a f f o r d e d an i n s e p a r a b l e m i x t u r e o f the p o s s i b l e mono-bromoketones. decalone 203 was  I n an attempt t o circumvent  this  two difficulty  t r e a t e d w i t h i s o p r o p e n y l a c e t a t e i n the presence of a  c a t a l y t i c amount of c o n c e n t r a t e d e n o l a c e t a t e s 204 and  s u l p h u r i c a c i d to a f f o r d a mixture  204a i n the r a t i o of 85:15  respectively.  of  The  crude e n o l a c e t a t e s were p u r i f i e d by chromatography on A c t i v i t y I I I n e u t r a l alumina. properties.  The p u r i f i e d m a t e r i a l e x h i b i t e d the e x p e c t e d s p e c t r a l  I n p a r t i c u l a r , the i n f r a r e d spectrum e x h i b i t e d a b s o r p t i o n s  - 120 -  at 5.7 and 5.95 y due to the a c e t a t e c a r b o n y l and the double bond r e s p e c t i v e l y . and  Treatment o f a mixture  carbon-carbon  of e n o l a c e t a t e s 204  204a w i t h a sodium a c e t a t e b u f f e r e d s o l u t i o n o f bromine i n g l a c i a l  acetic acid for 1 h  a f f o r d e d , a f t e r s e v e r a l r e c r y s t a l l i z a t i o n s , the  h i g h l y c r y s t a l l i n e bromoketone 205 i n 84% y i e l d . e x h i b i t e d the expected  s p e c t r a l data.  T h i s compound  Of note was the c a r b o n y l  a b s o r p t i o n i n the i n f r a r e d spectrum a t 5.8 y and the s i g n a l s i n t h e n.m.r. spectrum o f 205 due to the  p r o t o n a d j a c e n t t o the bromine a t  T 5.13 as the X p o r t i o n o f an ABX system w i t h the observed of 14 Hz and 6 Hz.  Other a s s i g n a b l e s i g n a l s i n the n.m.r. spectrum  appeared a t T 8.99 as a t h r e e - p r o t o n doublet secondary  ( J = 6.5 Hz) due to the  m e t h y l group and a t x 8.84 as a t h r e e - p r o t o n s i n g l e t due t o  the t e r t i a r y methyl group. treatment  splittings  with a mixture  Bromoketone 205, when dehydrobrominated by  o f anhydrous l i t h i u m bromide i n hot hexamethyl-  phosphoramide, a f f o r d e d the d e s i r e d o c t a l o n e 198 i n 76% y i e l d . latter  The  compound, which was i s o l a t e d by chromatography on s i l i c a g e l ,  e x h i b i t e d a maximum at 229 my i n the u l t r a v i o l e t  spectrum.  The o t h e r  s p e c t r a l p r o p e r t i e s a l s o c o r r o b o r a t e d the a s s i g n e d s t r u c t u r e .  Of note  was the appearance i n the i n f r a r e d spectrum o f a b s o r p t i o n s a t 6.0 y Ca,3-unsaturated c a r b o n y l ) and a t 6.15 y (carbon-carbon  double  bond).  The n.m.r. spectrum of 198 e x h i b i t e d s i g n a l s a t x 8.93 as a t h r e e - p r o t o n s i n g l e t f o r the t e r t i a r y methyl group, a t T 8.92 as a t h r e e - p r o t o n CJ = 7 Hz) f o r the secondary as two one-proton d o u b l e t s protons  doublet-  methyl group, and a t T 4.19 and x 3.35  ( J = 9 Hz) f o r the  and  olefinic  respectively.  Having a c h i e v e d  the s y n t h e s i s o f the two r e q u i r e d i n t e r m e d i a t e s 197  - 121  and 198, i t was  next planned  -  to i n v e s t i g a t e the 1,4-conjugate  r e a c t i o n s of the a p p r o p r i a t e organocopper I s p e c i e s to these mediates.  Thus, treatment  at 0° f o r 2 h (96).  I t was  of o c t a l o n e 197 w i t h l i t h i u m  dimethylcuprate 206  shown by INDOR s t u d i e s t h a t the s t e r e o c h e m i s t r y of this-  s p l i t t i n g s t h a t were observed should be noted  as d e p i c t e d by s t r u c t u r e 206.  The  f o r compound.206 a r e l i s t e d below.  It  t h a t these s p l i t t i n g s are not c o r r e c t e d f o r h i g h e r  o r d e r e f f e c t s but are almost coupling constants. Hz, J_ . 3a,(CH ) 3  c e r t a i n l y very c l o s e i n v a l u e to the t r u e  Thus J . _ = 14.5 3a,3e = 0.5 Hz and J . ,_ ^ 4  4a  s p l i t t i n g s are those expected group at  inter-  a f f o r d e d , i n 98% y i e l d , the known d i m e t h y l decalone  conjugate a d d i t i o n product was  1.4  addition  e  C  H  TT 3  )  Hz, J . , =6.2 Hz, J„ , 3a,4e 3e,4e . = 7 . 3 Hz. These observed 4a  f o r a compound p o s s e s s i n g an a x i a l  methyl  C^.  Treatment of o c t a l o n e 197 w i t h l i t h i u m d i v i n y l c u p r a t e at -78° f o r  - 122 4 h  -  f o l l o w e d by the u s u a l workup  207 i n 73% y i e l d .  Compound 207  and p u r i f i c a t i o n ,  e x h i b i t e d the expected s p e c t r a l  197  properties. at 5.85  5.2)  207  Of p e r t i n e n c e were the a b s o r p t i o n s  u ( c a r b o n y l ) and  spectrum of 207  6.15,  10.9  m u l t i p l e t and  m e t h y l group at x 8.88.  i n the i n f r a r e d spectrum  u ( v i n y l group).  e x h i b i t e d s i g n a l s due  as an u n r e s o l v e d  afforded decalone  The  n.m.r.  t o the v i n y l p r o t o n s (T  a s i g n a l due  to  the  H y d r o g e n a t i o n of d e c a l o n e 207  4.0-  tertiary  i n the p r e s e n c e  of a c a t a l y t i c amount of p a l l a d i u m on c h a r c o a l a f f o r d e d , i n 98% the c o r r e s p o n d i n g  s a t u r a t e d d e c a l o n e 208.  yield,  Absence of s i g n a l s i n the  207 i n f r a r e d and n.m.r. s p e c t r a due expected t r a n s f o r m a t i o n had Treatment of for 4 h  t o the v i n y l group confirmed  that  the  taken place.  o c t a l o n e 197 w i t h l i t h i u m d i i s o p r o p y l c u p r a t e a t  a f f o r d e d , i n 72% y i e l d , the c r y s t a l l i n e d e c a l o n e  209.  -78°  - 123 -  197  209  Decalone 209 was 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 , g . l . c . r e t e n t i o n t i m e s , m.p.) w i t h t h e compound p r e p a r e d by P i e r s e t a l . (97,98) (see F i g u r e 12 f o r t h e n.m.r. spectrum o f d e c a l o n e 2 0 9 ) . These w o r k e r s unambiguously demonstrated t h a t t h e s t e r e o c h e m i s t r y o f t h e i r compound was as shown i n s t r u c t u r e 209.  The sequence used by t h e s e w o r k e r s  to c o n f i r m t h e s t e r e o c h e m i s t r y o f d e c a l o n e 209 i s shown below.  212  211  - 125 -  212  213  214  B r i e f l y , decalone 210 (formed by cuprous i o n c a t a l y z e d 1,4c o n j u g a t e a d d i t i o n o f isopropenylmagnesium was hydrogenated  t o a f f o r d d e c a l o n e 209.  bromide t o o c t a l o n e 197) K e t a l i z a t i o n of d e c a l o n e 210,  f o l l o w e d by o z o n o l y s i s of t h e i s o p r o p e n y l double bond and chromatography (alumina) of the r e s u l t i n g p r o d u c t , a f f o r d e d a m i x t u r e o f d i o n e 211 and k e t o k e t a l 212.  The l a t t e r compound remained  subjected to epimerization conditions.  unchanged when  From e x a m i n a t i o n o f m o l e c u l a r  models o f 212 and 212a the more s t a b l e epimer and hence t h e one e x p e c t e d to predominate  a f t e r e p i m e r i z a t i o n was p r e d i c t e d t o be 212.  This  p r e d i c t i o n was based on t h e r e l i e f o f t h e 1 , 3 - d i a x i a l i n t e r a c t i o n between the a c e t y l group and t h e a x i a l oxygen o f the k e t a l group i n g o i n g compound 212a to the e q u a t o r i a l epimer 212. methylenetriphenylphosphorane,  from  R e a c t i o n o f 212 w i t h  f o l l o w e d by s u c c e s s i v e h y d r o l y s i s and  -  hydrogenation  126 -  o f the r e s u l t i n g product  213 a f f o r d e d decalone  l a t t e r compound was d i s t i n c t l y d i f f e r e n t from decalone s t e r e o c h e m i s t r y o f decalone  209.  209 was t h e r e f o r e completely  a f f o r d e d , i n 93% y i e l d decalone  215.  The  The  defined.  Treatment o f o c t a l o n e 198 w i t h l i t h i u m d i m e t h y l c u p r a t e for 2 h  214.  a t 0°  The s p e c t r a l p r o p e r t i e s  of the l a t t e r , were i n complete accord w i t h the a s s i g n e d s t r u c t u r e and stereochemistry.  Of note was the appearance i n the i n f r a r e d  198  215  of 215 o f a s t r o n g c a r b o n y l a b s o r p t i o n at 5.87 y.  The n.m.r. spectrum  of 215 e x h i b i t e d s i g n a l s a t x 9.18 and x 9.12 as two doublets  spectrum  ( J = 6.5 Hz) due t o the secondary  a t h r e e - p r o t o n s i n g l e t due t o the  methyl groups, a t x 8.89 as  t e r t i a r y methyl group, and a t x 7.97  and  x 7.21 as two one-proton doublet  and  C„ a x i a l protons  respectively  (J„  of d o u b l e t s due t o the „  =14  c o n s t a n t s c o n f i r m the a s s i g n e d s t e r e o c h e m i s t r y .  215  three-proton  Hz).  equatorial  The c o u p l i n g  The C  e q u a t o r i a l proton  - 127 coupled w i t h t h e w h i l e the  e q u a t o r i a l p r o t o n w i t h a c o u p l i n g c o n s t a n t o f 2.2 Hz,  a x i a l proton coupled w i t h the  a c o u p l i n g c o n s t a n t o f 6 Hz.  e q u a t o r i a l proton w i t h  These c o u p l i n g c o n s t a n t s t o g e t h e r w i t h  the absence o f a l a r g e d i a x i a l c o u p l i n g c o n s t a n t ( J - 14 Hz) c o n f i r m e d the a x i a l o r i e n t a t i o n o f t h e newly i n t r o d u c e d m e t h y l group a t C^. Treatment o f o c t a l o n e 198 w i t h l i t h i u m d i i s o p r o p y l c u p r a t e a t -78° for 4 h  a f f o r d e d , i n 84% y i e l d , t h e t r a n s - f u s e d decalone 216.  198  The  216  s p e c t r a l d a t a o f t h e l a t t e r compound c o n f i r m e d t h e a s s i g n e d s t r u c t u r e and s t e r e o c h e m i s t r y .  Of p a r t i c u l a r importance was the a b s o r p t i o n a t  5.85 u i n t h e i n f r a r e d spectrum s i g n a l s i n the n.m.r. spectrum  due t o t h e s a t u r a t e d c a r b o n y l and a t T 9.21, and T 9.09 as two t h r e e - p r o t o n  d o u b l e t s ( J = 6.5 Hz) due t o t h e i s o p r o p y l m e t h y l groups, a t x 9.00 as a t h r e e - p r o t o n d o u b l e t ( J = 6 Hz) due t o t h e  secondary m e t h y l  and a t x 8.87 as a t h r e e - p r o t o n s i n g l e t due t o t h e t e r t i a r y  group  methyl  group. A well-known t e c h n i q u e used i n n.m.r. s p e c t r o s c o p y t o s e p a r a t e otherwise i n d i s t i n g u i s h a b l e s i g n a l s i s solvent-induced chemical (99,100).  C o n n o l l y and M c C r i n d l e (101) have proposed  shifts  an e m p i r i c a l  r u l e t o p r e d i c t t h e e f f e c t o f s o l v e n t change on the c h e m i c a l s h i f t o f the p r o t o n s a d j a c e n t t o t h e c a r b o n y l group i n c y c l i c k e t o n e s .  This  - 128 -  r u l e s t a t e d t h a t when a p l a n e i s drawn through t h e c a r b o n y l carbon a t r i g h t a n g l e s t o t h e bonds, t h e p r o t o n s i n f r o n t o f t h e p l a n e a r e s h i f t e d d o w n f i e l d r e l a t i v e t o the p r o t o n s b e h i n d t h e p l a n e , when t h e n.m.r. s o l v e n t i s changed from d e u t e r o c h l o r o f o r m t o benzene ( s e e s t r u c t u r e 217).  Indeed, f o r compound 216, changing t h e n.m.r. s o l v e n t from  217  d e u t e r o c h l o r o f o r m t o benzene r e s u l t e d i n a s i m p l i f i c a t i o n o f t h e n.m.r. spectrum  (see F i g u r e 13) i n t h e r e g i o n T 7.40 t o x 7.90.  Application  of the above r u l e a l l o w e d assignment o f t h e d o w n f i e l d d o u b l e t o f d o u b l e t s a t x 7.56 t o t h e  e q u a t o r i a l p r o t o n and t h e d o u b l e t o f  d o u b l e t s a t x 7.74 t o t h e a x i a l C„ p r o t o n J . „ = 15.5 Hz. 3 3a,3e  The  c o u p l i n g c o n s t a n t s thus o b t a i n e d c o n f i r m e d t h e a s s i g n e d s t e r e o c h e m i s t r y of C^.  The c o u p l i n g c o n s t a n t between t h e  e q u a t o r i a l p r o t o n was 7.6 Hz w h i l e e q u a t o r i a l and  the  a x i a l p r o t o n and t h e  t h e c o u p l i n g c o n s t a n t between the  e q u a t o r i a l p r o t o n was 2.4 Hz.  Both these  v a l u e s a r e p r e d i c t e d f o r compound 216 from e x a m i n a t i o n o f t h e K a r p l u s curve ( 8 1 ) .  D.  S y n t h e s i s o f c i s - F u s e d Decalones Having r e a l i z e d t h e e f f i c i e n t s y n t h e s i s o f t h e r e q u i r e d a u t h e n t i c  t r a n s - f u s e d d e c a l o n e s , i t was n e x t planned t o unambiguously s y n t h e s i z e  i  F i g u r e 13..  N.M.R. Spectrum of t r a n s - F u s e d Decalone 216.  - 130 the corresponding c i s - f u s e d decalones.  Lowenthal (102) demonstrated  4  that the hydrogenation of A -3-keto steroids and r e l a t e d materials i n basic media produced almost e x c l u s i v e l y the c i s A/B ring-fused product. Since octalones 188 to 192 were r e a d i l y a v a i l a b l e i t was f e l t  that  hydrogenation under b a s i c conditions of these octalones should f u r n i s h the required c i s - f u s e d decalones.  Thus octalones 188 to 192 were  hydrogenated at atmospheric pressure and room temperature i n the presence of 0.3 N ethanolic potassium hydroxide to y i e l d the corresponding cis-fused decalones shown below.  218  193  220  219  221  These hydrogenations a l l proceeded i n b e t t e r than 95% y i e l d .  In  a l l cases, g . l . c . analysis of the product revealed the presence of a maximum of 6% of a minor component, which i n each case, was shown by g . l . c . r e t e n t i o n times to be the corresponding trans-fused decalone. A n a l y t i c a l samples of the major products, the c i s - f u s e d decalones 193, 218-221, were i s o l a t e d by preparative g . l . c .  The s p e c t r a l data of a l l  - 131 -  these compounds were i n complete a c c o r d w i t h t h e proposed  structures.  I n each c a s e , t h e i n f r a r e d spectrum e x h i b i t e d an a b s o r p t i o n a t 5.85 u due t o t h e s a t u r a t e d c a r b o n y l group. The n.m.r. spectrum o f d e c a l o n e 218 d i s p l a y e d a t h r e e - p r o t o n d o u b l e t a t T 9.10 ( J = 6.5 Hz) a t t r i b u t a b l e t o t h e secondary m e t h y l group and a t h r e e - p r o t o n s i n g l e t a t x 8.95 due t o t h e t e r t i a r y m e t h y l group. The o n l y a s s i g n a b l e s i g n a l i n t h e n.m.r. spectrum o f d e c a l o n e 193 appeared a t x 8.90 ( s i n g l e t , t e r t i a r y m e t h y l ) . The n.m.r. spectrum o f d e c a l o n e 219 ( s e e F i g u r e 14) d i s p l a y e d s i g n a l s a t x 9.19 and x 9.10 as two t h r e e - p r o t o n d o u b l e t s  ( J = 6.5 Hz)  due t o t h e secondary m e t h y l groups and a t x 8.88 as a t h r e e - p r o t o n s i n g l e t due t o t h e t e r t i a r y m e t h y l group. The n.m.r.  spectrum o f d e c a l o n e 220 e x h i b i t e d s i g n a l s a t x 9.08  and x 9.01 as two t h r e e - p r o t o n o v e r l a p p i n g d o u b l e t s  ( J = 6.5 Hz) due  to t h e secondary m e t h y l g r o u p s , a t x 8.92 as a t h r e e - p r o t o n s i n g l e t due t o t h e t e r t i a r y m e t h y l group, a t x 7.35 as a o n e - p r o t o n s e x t e t due t o t h e C  1  p r o t o n (J., , . la,(CH„)  * = 6 Hz, J.. U  J le 1  T  _  xa,ya  as t h e B p o r t i o n o f an ABX system due t o t h e  i-> v \ -? Q C = 13 H z ) , a t x 7.85  e q u a t o r i a l p r o t o n and  at x 7.64 as t h e A p o r t i o n o f an ABX system due t o t h e C^ a x i a l proton ( J  .  = 13 H z ) .  The c o u p l i n g c o n s t a n t s d e r i v e d from t h e  m u l t i p l e t s a t x 7.85 and x 7.64 a l l o w e d c o n f i r m a t i o n o f t h e s t e r e o c h e m i s t r y a t C^.  The c o u p l i n g c o n s t a n t f o r t h e  p r o t o n s was 14.4 Hz, w h i l e Co a x i a l p r o t o n s was 3.6 Hz.  axial-Coaxial  t h e c o u p l i n g c o n s t a n t f o r t h e C^ e q u a t o r i a l These v a l u e s c o r r o b o r a t e t h e a s s i g n e d  s t e r e o c h e m i s t r y f o r c i s - d e c a l o n e 220.  Figure  14.  N.M.R. S p e c t r u m o f c i s - F u s e d  Decalone  219.  - 133  -  The n.m.r. spectrum f o r the c i s - f u s e d decalone 15) e x h i b i t e d s i g n a l s a t T 9.19 doublets  ( J = 6.5  Hz) due  as a t h r e e - p r o t o n d o u b l e t group,  a t x 8.89  and x 9.11  as two  221  three-proton  t o the i s o p r o p y l m e t h y l groups, a t x ( J = 6 Hz)  due t o the  secondary  as a t h r e e - p r o t o n s i n g l e t due t o the  m e t h y l group, a t x 7.86  as the B p o r t i o n of an ABX  the C, e q u a t o r i a l p r o t o n ( J •j  as the A p o r t i o n o f an ABX r  14.3 Hz) and a t x 7.30  (see F i g u r e  Ja,  „  J6  = 14 Hz, J„  system due J  as a one-proton  3e,  .  4a  system due  to  = 3.6 H z ) , a t x r  by the s i g n a l s f o r the a x i a l and e q u a t o r i a l  methyl  tertiary  to the C„ a x i a l p r o t o n 3 s e x t e t due  9.01  t o the C.  7.63  (J , 3a,4a 0  proton  p r o t o n s and the s i g n a l  f o r the  p r o t o n c o n f i r m t h a t the s t e r e o c h e m i s t r y i s as d e p i c t e d i n  structure  221.  - 135 E.  Lithium-Ammonia R e d u c t i o n  -  Studies  As p r e v i o u s l y d i s c u s s e d , a s t u d y of the l i t h i u m l i q u i d ammonia -  r e a c t i o n s o f o c t a l o n e s of type 170 was  u n d e r t a k e n because of the  analogy  o f these compounds t o o c t a l o n e 155b, w h i c h under l i t h i u m - l i q u i d ammonia r e d u c t i o n c o n d i t i o n s proceeded s t e r e o s e l e c t i v e l y t o a f f o r d R„  3 the c i s - f u s e d decalone  165b.  170 I t was  hoped t h a t the a d d i t i o n a l i n f o r m a t i o n  155b  o b t a i n e d from the B i r c h r e d u c t i o n s of o c t a l o n e s o f type 170 would a i d i n c l a r i f y i n g some of the f a c t o r s a f f e c t i n g the s t e r e o c h e m i c a l outcome 1 9 of the B i r c h r e d u c t i o n of A ' - 2 - o c t a l o n e systems i n g e n e r a l . mentioned e a r l i e r o c t a l o n e s 188  t o 192.had been s y n t h e s i z e d and had been  shown t o be homogeneous by g . l . c . :  t r a n s - f u s e d decalones  As  corresponding  r e a d i l y a v a i l a b l e (by the s y n t h e s e s  I n a d d i t i o n , the a u t h e n t i c c i s - and t o the above o c t a l o n e s were  d e s c r i b e d above) f o r comparison  w i t h the p r o d u c t s o b t a i n e d from the B i r c h r e d u c t i o n s of o c t a l o n e s to 192.  now  188  I n each c a s e , g a s - l i q u i d c h r o m a t o g r a p h i c c o n d i t i o n s were found  - 136 -  191  192  i n w h i c h t h e o c t a l o n e , t h e c o r r e s p o n d i n g c i s - f u s e d d e c a l o n e and t h e c o r r e s p o n d i n g t r a n s - f u s e d decalone e x h i b i t e d d i s t i n c t r e t e n t i o n on g . l . c . c o - i n j e c t i o n .  times  Hence, i t was a n t i c i p a t e d t h a t t h e p r o d u c t  m i x t u r e s from B i r c h r e d u c t i o n o f o c t a l o n e s 188 t o 192 would be r e a d i l y a n a l y z a b l e by g . l . c . As p r e v i o u s l y noted by o t h e r workers  (49) l i t h i u m - l i q u i d ammonia  r e d u c t i o n s , i n t h e absence o f p r o t o n donors, g e n e r a l l y l e a d t o t h e r e c o v e r y o f some s t a r t i n g m a t e r i a l .  Presumably t h i s i s because some  of t h e unreduced enone a c t s as a p r o t o n s o u r c e and r e a c t s w i t h a base (e.g. amide i o n ) t o form t h e c o r r e s p o n d i n g e n o l a t e a n i o n , w h i c h i s then i n e r t t o t h e described r e d u c t i o n ( 4 9 ) .  However, i n t h e p r e s e n t  case r e c o v e r e d s t a r t i n g m a t e r i a l posed no problem the p r o d u c t m i x t u r e s .  Furthermore,  to the a n a l y s i s of  the y i e l d s of the B i r c h r e d u c t i o n  - 137 -  p r o d u c t s were h i g h e r when t h e a d d i t i o n a l o x i d a t i o n s t e p c o u l d be omitted.  Hence, t h e f o l l o w i n g c o n d i t i o n s were chosen f o r t h e B i r c h  reductions. Octalones  188 t o 192 were r e a c t e d w i t h l i t h i u m i n anhydrous  l i q u i d ammonia f o r 2 h , and the r e a c t i o n s were quenched by a d d i t i o n of ammonium c h l o r i d e as t h e p r o t o n s o u r c e .  Each r e d u c t i o n was  repeated  at l e a s t t w i c e w h i l e the m a j o r i t y o f the r e d u c t i o n s were performed f i v e times.  The r e s u l t s ( y i e l d s and p r o d u c t  composition)  f o r the  l i t h i u m - l i q u i d ammonia r e d u c t i o n s were averaged o v e r the v a r i o u s runs and a r e r e c o r d e d  i n Table  III.  7  I n each case, g . l . c . a n a l y s i s o f t h e crude r e d u c t i o n r e v e a l e d some r e c o v e r e d and c i s - f u s e d d e c a l o n e s .  product  o c t a l o n e , a l o n g w i t h the c o r r e s p o n d i n g  trans-  The t r a n s - and c i s - f u s e d d e c a l o n e s were  i s o l a t e d by p r e p a r a t i v e g . l . c . and shown t o 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 , g . l . c . r e t e n t i o n t i m e s ) w i t h t h e c o r r e s p o n d i n g t r a n s - and c i s - f u s e d d e c a l o n e s p r e v i o u s l y The p e r c e n t  composition  authentic  prepared.  o f t h e crude r e d u c t i o n p r o d u c t  was  determined by i n t e g r a t i o n ( d i s c i n t e g r a t o r ) of t h e g . l . c . t r a c e o f t h e product mixture.  I t was found t h a t t h e molar response f a c t o r was t h e  same f o r each p a i r o f c i s - and t r a n s - f u s e d d e c a l o n e s . as m o l e c u l e s o f s i m i l a r m o l e c u l a r response f a c t o r s (103).  This i s expected  c o m p l e x i t y g e n e r a l l y have i d e n t i c a l  T h i s f a c t o r was determined by w e i g h i n g samples  o f the a u t h e n t i c c i s - and t r a n s - f u s e d d e c a l o n e s and combining them so 7  The p e r c e n t c o m p o s i t i o n r e s u l t s were found t o be r e p r o d u c i b l e t o w i t h i n + 2% f o r each o f t h e c i s - and t r a n s - f u s e d d e c a l o n e s l i s t e d i n Table I I I .  - 138 -  t h a t the r a t i o r e p r e s e n t e d by t h e i r admixture would be v e r y s i m i l a r t o the observed r a t i o i n t h e B i r c h r e d u c t i o n p r o d u c t . known c o m p o s i t i o n was  then i n j e c t e d i n t o the g . l . c .  t o t r a n s - f u s e d d e c a l o n e was  The m i x t u r e of The r a t i o o f c i s -  then c a l c u l a t e d by i n t e g r a t i o n of the  g . l . c . t r a c e and found t o be w i t h i n e x p e r i m e n t a l e r r o r of the known ratio.  Table I I I .  ;  R e s u l t s Obtained from t h e B i r c h R e d u c t i o n o f O c t a l o n e s 188 to 192  Octalone  % Yield  trans:cis  ratio  % Recovered starting material  Observed stereoselectivity -RT l n c i s / t r a n s decalone Kcal/mole  2  0.91  75:25  13  0.52  98  69:31  14  0.38  191  90  82:18  8  0.72  192  . 98  65:35  7  0.29  188  93  87:13  189  94  190  B e f o r e d i s c u s s i n g the r e s u l t s o f t h e B i r c h r e d u c t i o n s of o c t a l o n e s 188 to 192 i t would be advantageous  t o d i g r e s s to c o n s i d e r the n a t u r e 1 9  of the pathway of l i t h i u m - l i q u i d ammonia r e d u c t i o n s of A ' - 2 - o c t a l o n e systems.  The mechanism r e c e n t l y proposed by House e t a l . (49) f o r  d i s s o l v i n g m e t a l r e d u c t i o n s i s summarized i n Chart XIX.  T h i s mechanism  i n v o l v e s an i n i t i a l r a p i d r e v e r s i b l e a d d i t i o n of an e l e c t r o n t o the unreduced  enone, f o l l o w e d by subsequent  f o r m a t i o n of a t i g h t i o n p a i r  - 139  Chart  -  XIX  w i t h the l i t h i u m c a t i o n (or of the c o r r e s p o n d i n g i n the presence of a p r o t o n s o u r c e ) .  The  e n o l by  second e l e c t r o n i s then added  i n a r e v e r s i b l e s t e p f o l l o w e d by a n o n - r e v e r s i b l e p r o d u c t protonation.  The  of the  determining  t r a n s i t i o n s t a t e f o r p r o t o n a t i o n can, t h e r e f o r e , be  assumed t o l i e between the i n t e r m e d i a t e 222 and product,  protonation  t h a t i s , i n the p r e s e n t  the f i n a l  c a s e , the c o r r e s p o n d i n g  protonated lithium  enolate  decalone.  As p r e v i o u s l y d i s c u s s e d the n a t u r e of the geometry of the g-carbon atom i n the t r a n s i t i o n s t a t e f o r p r o t o n a t i o n i n lithium-ammonia reductions i s uncertain.  V a r i o u s workers have proposed t h a t the  geometry of the 3 c a r b o n atom i n the t r a n s i t i o n s t a t e f o r p r o t o n a t i o n -  c o u l d be t r i g o n a l (sp  2  h y b r i d i z e d ) , pyramidal  (sp  3  h y b r i d i z e d ) or a  - 140  -  geometry somewhere between these two extremes.  I n the absence of  e x p e r i m e n t a l d a t a t o d i s t i n g u i s h between the v a r i o u s geometries  any  of  the g-carbon atom, t h i s d i s c u s s i o n w i l l c o n s i d e r s e v e r a l of the possibilities. An e x a m i n a t i o n b u l k of the decalone 192  o f the r e s u l t s i n T a b l e I I I r e v e a l e d t h a t as  the  a l k y l group i n c r e a s e d , the p e r c e n t a g e of c i s - f u s e d  p r o d u c t was  increased.  F u r t h e r m o r e , the r e s u l t s f o r o c t a l o n e  ( l i s t e d i n T a b l e I I I ) compared w i t h the r e s u l t s f o r o c t a l o n e  r e v e a l e d t h a t the  a n g u l a r m e t h y l group had a l a r g e e f f e c t on  155b the  s t e r e o c h e m i c a l outcome of the lithium-ammonia r e d u c t i o n o f o c t a l o n e  192.  As p r e v i o u s l y d i s c u s s e d i n the i n t r o d u c t i o n , many workers (44,45,50) have proposed a p y r a m i d a l c o n f i g u r a t i o n f o r the geometry of the g-carbon atom i n the t r a n s i t i o n s t a t e f o r p r o t o n a t i o n .  T h i s p r o p o s a l has been  m o d i f i e d to i n c l u d e a s t e r e o e l e c t r o n i c requirement mind t h i s s t e r e o e l e c t r o n i c r e q u i r e m e n t ,  the p r o d u c t  p r o t o n a t i o n of the i n t e r m e d i a t e c a r b a n i o n 222  could  (45).  Bearing i n  determining theoretically  proceed through one o r both o f two p o s s i b l e t r a n s i t i o n s t a t e s , one resembling  the p y r a m i d a l  r i s e to the t r a n s - f u s e d  carbanion  i n t e r m e d i a t e 223, w h i c h would g i v e  decalone p r o d u c t  and  the o t h e r r e s e m b l i n g  R. ;i  the  - 141 p y r a m i d a l c a r b a n i o n i n t e r m e d i a t e 224, w h i c h would g i v e r i s e t o a c i s f u s e d decalone p r o d u c t .  Generally a transition state for protonation  r e s e m b l i n g 223 i s f a v o r e d as i t i s o f lower energy t h a n 224,  thus  a c c o u n t i n g f o r the g e n e r a l predominance of the t r a n s - f u s e d p r o d u c t s . However, t h e lithium-ammonia  r e d u c t i o n s of o c t a l o n e s 188 t o 192  should  be e x c e p t i o n a l as the s t e r e o e l e c t r o n i c a l l y a l l o w e d t r a n s i t i o n s t a t e s l e a d i n g t o the t r a n s - and c i s - f u s e d decalones are e s s e n t i a l l y e q u i v a l e n t i n energy o r t h a t l e a d i n g to the c i s p r o d u c t i s s l i g h t l y favored.  At the p r e s e n t time e x p e r i m e n t a l c o n f o r m a t i o n a l energy  values  are not a v a i l a b l e f o r the c o n f o r m a t i o n s of A ^ - o c t a l i n d e r i v a t i v e s . o n l y r a t h e r q u a l i t a t i v e e s t i m a t e s f o r the r e l a t i v e e n e r g i e s of and 224 can be made by c o n v e n t i o n a l c o n f o r m a t i o n a l a n a l y s i s .  Hence,  223 A  q u a l i t a t i v e e x a m i n a t i o n of the non-bonded i n t e r a c t i o n s p r e s e n t i n 223 and 224 r e v e a l e d t h a t these two i n t e r m e d i a t e s s h o u l d be o f a p p r o x i m a t e l y the same energy.  That i s , the u n f a v o r a b l e n a t u r e of the  t r a n s i t i o n s t a t e p l u s the skew R-CH^  cis-like  i n t e r a c t i o n p r e s e n t i n 224  are  2 a p p r o x i m a t e l y comparable w i t h t h e skew R-sp d e v e l o p i n g syn a x i a l R-H  i n t e r a c t i o n p l u s the  i n t e r a c t i o n between the incoming p r o t o n  and  the a x i a l R group i n the t r a n s i t i o n s t a t e f o r p r o t o n a t i o n r e s e m b l i n g  223.  Thus on the b a s i s o f a p y r a m i d a l t r a n s i t i o n s t a t e f o r p r o t o n a t i o n , an a p p r o x i m a t e l y 50:50 m i x t u r e of p r o d u c t s would be  expected.  An e x a m i n a t i o n of t h e r e s u l t s i n T a b l e I I I r e v e a l e d a s t e r e o s e l e c t i v i t y h i g h e r than would be expected by t h e above q u a l i t a t i v e a p p r o x i m a t i o n s on the t r a n s i t i o n s t a t e s r e s e m b l i n g 223 and 224.  energy  However,  t h i s t r e n d seems to be i n l i n e w i t h the e m p i r i c a l t r e n d t h a t the c i s / t r a n s product r a t i o i s g e n e r a l l y l e s s than would be expected on the  - 142  -  b a s i s of the c o n f o r m a t i o n a l e n e r g i e s i n v o l v e d ( 4 6 ) . e x p l a n a t i o n s f o r the e f f e c t o f the b u l k of the  S i n c e immediate  a l k y l group and f o r  the e f f e c t of the a n g u l a r m e t h y l group on the c i s / t r a n s p r o d u c t  ratios  are not o b v i o u s , the f o l l o w i n g d i s c u s s i o n w i l l examine s e v e r a l p l a u s i b l e f a c t o r s w h i c h might be d i r e c t i n g the r e a c t i o n pathway. F i r s t l y the e f f e c t of the a n g u l a r m e t h y l group on the  stereochemical  outcome of the lithium-ammonia r e d u c t i o n s w i l l be d i s c u s s e d i n terms of a pyramidal t r a n s i t i o n state. i n product  As mentioned above, a s t r i k i n g d i f f e r e n c e  s t e r e o s e l e c t i v i t y was  e v i d e n t on comparison of the  o b t a i n e d from the B i r c h r e d u c t i o n of o c t a l o n e s 155b  155b Changing the C ^  and  products  192.  192  s u b s t i t u e n t from a hydrogen t o a m e t h y l group e f f e c t e d  a change from the s t e r e o s e l e c t i v e p r o d u c t i o n of the c i s - f u s e d decalone product  i n the case of o c t a l o n e 155b,  of c i s - f u s e d to t r a n s - f u s e d decalone  to the p r o d u c t i o n o f a 35:65 r a t i o products  i n the case of o c t a l o n e  192. Examination  of m o l e c u l a r models of the p o s s i b l e p y r a m i d a l  c a r b a n i o n i n t e r m e d i a t e s - 225, p r o t o n a t i o n trans-fused decalone,  and 226  o f w h i c h would l e a d t o the  , p r o t o n a t i o n of w h i c h would l e a d t o the  c i s - f u s e d decalone  - r e v e a l e d the i n t r o d u c t i o n of one s e r i o u s i n t e r a c t i o n  i n 226 when R was  changed from a hydrogen t o a m e t h y l group.  (That i s ,  - 143 -  H  H*  v  OLi  OLi  225  226  when R i n 226 i s a m e t h y l group, a gauche i n t e r a c t i o n between the a n g u l a r m e t h y l s u b s t i t u e n t and t h e  i s o p r o p y l group i s p r e s e n t ,  whereas when R i n 226 i s a hydrogen, t h i s gauche i n t e r a c t i o n i s a b s e n t . ) T h i s gauche i n t e r a c t i o n would, t h e r e f o r e , make t h e t r a n s i t i o n  state  r e s e m b l i n g the i n t e r m e d i a t e c a r b a n i o n 226 l e s s f a v o r a b l e when R i s a m e t h y l group than when R i s a hydrogen. p o s s i b i l i t y t h a t the  There i s a l s o t h e added  m e t h y l group i n 226 (R = CH^) m i g h t be a f f o r d i n g  a s m a l l amount o f s t e r i c h i n d r a n c e t o the i n c o m i n g p r o t o n a t i n g s p e c i e s i n t h e t r a n s i t i o n s t a t e l e a d i n g t o t h e c i s p r o d u c t w h i c h would be absent when R ( i n 226) i s a hydrogen.  I t follows that l e s s  cis-fused  decalone s h o u l d be formed on l i t h i u m - a m m o n i a r e d u c t i o n o f o c t a l o n e 192 than on r e d u c t i o n o f o c t a l o n e 155b. to be the case.  As r e p o r t e d above t h i s was found  As t h e b u l k o f the C. a l k y l s u b s t i t u e n t i n c r e a s e s t h e H  R  1  R H  "2  OLi 223  OLi  R 224  2  - 144 -  non-bonded i n t e r a c t i o n i n 223 between the center and the  a l k y l group and the  a l k y l group and the incoming protonating  sp  2  species  would be expected to i n c r e a s i n g l y make conformation 224, i n which the a l k y l group i s e q u a t o r i a l , more favorable r e l a t i v e to conformation 223.  This could p a r t i a l l y account f o r the increase i n the amount of  cis-fused product as the bulk of the  a l k y l group increases.  As discussed p r e v i o u s l y , Robinson proposed that the 3-carbon atom was t r i g o n a l , or very nearly t r i g o n a l , i n the t r a n s i t i o n s t a t e f o r protonation.  In a d d i t i o n he proposed that the reduction could proceed  v i a one or both of two p o s s i b l e t r a n s i t i o n s t a t e s , 107a which would lead predominantly to  the trans-fused decalone and 107b which would give  r i s e predominantly to the c i s - f u s e d decalone.  Other p o s s i b l e t r a n s i t i o n  states were also considered but were predicted to be of very high energy and therefore were not considered  f u r t h e r (46).  Robinson stated  0  that there would be l e s s angle and t o r s i o n a l s t r a i n involved i n a t r a n s i t i o n state resembling 107a than there would be i n one resembling 107b. we consider octalones 155b  and 188 to 192, i t i s p o s s i b l e that the  s t a b i l i t y gained by changing the i n 227  (analogous to 107a)  If  a l k y l group from an a x i a l o r i e n t a t i o n  to a n " e q u a t o r i a l - l i k e " o r i e n t a t i o n i n 228  - 145  -  ( a n a l o g o u s t o 107b) w o u l d a t l e a s t p a r t i a l l y  offset  t h e a n g l e and R. R  Ri  R, 2  227  228  R, 2  torsional strain intrinsic  i n c o n f o r m a t i o n 228.  a lowering of the energy of the t r a n s i t i o n r e l a t i v e t o t h a t r e s e m b l i n g 227.  1  This would r e s u l t i n  s t a t e r e s e m b l i n g 228  Robinson's theory would  thus  predict  a h i g h e r p r o p o r t i o n o f c i s - f u s e d d e c a l o n e i n t h e p r e s e n t examples relative 155b,  to that normally found.  o c t a l o n e s 188  from changing t h e a l k y l group from the a x i a l  o f f s e t by t h e i n c r e a s i n g  t h e amount o f c i s - f u s e d  r e d u c t i o n w o u l d be p r e d i c t e d  the  ( i n 228).  stabiliza-  orientation  (227 ->• 228) w o u l d t h u s b e  skew i n t e r a c t i o n b e t w e e n t h e  a l k y l g r o u p and t h e C ^ Q m e t h y l g r o u p t o 192  interaction  I n t h e c a s e o f o c t a l o n e s 188 t o 192  to the " e q u a t o r i a l - l i k e " o r i e n t a t i o n  188  to octalone  t o 192 p o s s e s s an a d d e d d e s t a b i l i z i n g  i n c o n f o r m a t i o n 228. tion arising  However, i n c o n t r a s t  partially  equatorial  Hence, i n t h e s e o c t a l o n e s  d e c a l o n e formed on l i t h i u m - a m m o n i a  t o be l e s s t h a n i n t h e c a s e o f  octalone  155b w h e r e t h e r e i s no d e v e l o p i n g i n t e r a c t i o n b e t w e e n t h e C ^ Q h y d r o g e n and  alkyl  group.  As t h e b u l k o f t h e stabilization arising  a l k y l group i n c r e a s e s i t i s p r o b a b l e t h a t  from changing the a l k y l group from the  o r i e n t a t i o n t o the " e q u a t o r i a l - l i k e " o r i e n t a t i o n would a l s o This increased  s t a b i l i z a t i o n w o u l d make t h e t r a n s i t i o n  the  axial increase.  state resembling  - 146  -  228 i n c r e a s i n g l y more f a v o r e d , and c o u l d thus account f o r the observed f a c t t h a t as the  a l k y l group i n c r e a s e s i n s i z e , the amount of c i s -  d e c a l o n e o b t a i n e d i n the r e d u c t i o n a l s o i n c r e a s e s . I t i s a l s o p o s s i b l e t h a t i n the t r a n s i t i o n s t a t e l e a d i n g t o the t r a n s - f u s e d d e c a l o n e t h e r e i s an i n c r e a s i n g degree of s t e r i c to p r o t o n a t i o n as the b u l k of the  substituent increases.  make p r o t o n a t i o n of 228 more l i k e l y as the b u l k of the increases.  The e f f e c t of the  hindrance T h i s would  substituent  a l k y l s u b s t i t u e n t on the s t e r e o -  c h e m i s t r y of lithium-ammonia r e d u c t i o n s has b o t h p r a c t i c a l and i n t e r e s t . The  theoretical  B i r c h r e d u c t i o n of o c t a l o n e s 188 t o 192 r e v e a l e d a h i g h e r  centage of c i s - f u s e d decalone product  than n o r m a l l y o b t a i n i n o t h e r  per-  substitutEd  1.9 A ' - 2 - o c t a l o n e systems. A l t h o u g h use of a t r a n s i t i o n s t a t e model ing  a pyramidal  3-carbon atom a l o n g w i t h crude e s t i m a t e s of  conformational  e n e r g i e s would p r e d i c t a h i g h e r p e r c e n t a g e of c i s - f u s e d decalone observed,  possess-  than  use of a t r a n s i t i o n s t a t e model p o s s e s s i n g a t r i g o n a l 3-carbon  atom would g i v e r i s e to q u a l i t a t i v e p r e d i c t i o n s i n a c c o r d w i t h the observed r e s u l t s .  The magnitude of the e f f e c t of changing the  s u b s t i t u e n t from a hydrogen to a m e t h y l group was  not expected  However, i n r e t r o s p e c t the r e s u l t s can at l e a s t q u a l i t a t i v e l y  a priori. be  accounted f o r (see above). F i n a l l y the f a c t t h a t the r e d u c t i o n of o c t a l o n e 155b s e l e c t i v e l y t o a c i s - f u s e d d e c a l o n e has obvious  led stereo-  synthetic applications.  For example, use of t h i s o b s e r v a t i o n c o u l d p r o v i d e a s y n t h e t i c e n t r y i n t o the amorphane c l a s s of  sesquiterpenes.  - 147 -  EXPERIMENTAL General M e l t i n g p o i n t s , which were determined  on a F i s h e r - J o h n s m e l t i n g  p o i n t a p p a r a t u s , and b o i l i n g p o i n t s a r e u n c o r r e c t e d .  Routine  infrared  s p e c t r a were r e c o r d e d on a P e r k i n - E l m e r I n f r a c o r d model 137 o r a P e r k i n - E l m e r I n f r a r e d Spectrophotometer  model 710, w h i l e  s p e c t r a were r e c o r d e d on P e r k i n - E l m e r s p e c t r o p h o t o m e t e r s 457.  comparison model 421 o r model  U l t r a v i o l e t s p e c t r a were, u n l e s s o t h e r w i s e n o t e d , measured i n  methanol s o l u t i o n on a Unicam, SP. 800, s p e c t r o p h o t o m e t e r .  N.m.r.  s p e c t r a were, u n l e s s o t h e r w i s e n o t e d , r e c o r d e d i n d e u t e r o c h l o r o f o r m s o l u t i o n on V a r i a n A s s o c i a t e s s p e c t r o m e t e r s , models A-60, T-60 and/or HA-100, XL-100.  L i n e p o s i t i o n s a r e g i v e n i n the T i e r s x 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 i n t e r n a l s t a n d a r d ; 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 p r o t o n assignments  are i n d i c a t e d i n parentheses.  l i q u i d chromatography ( g . l . c . ) was c a r r i e d o u t on e i t h e r an Autoprep, model 700 o r a V a r i a n Aerograph, model 90-P. columns (10 f t x 1/4 i n  Gas-  Aerograph  The f o l l o w i n g  u n l e s s o t h e r w i s e noted) were employed, w i t h  the i n e r t s u p p o r t i n g m a t e r i a l b e i n g 60/80 mesh Chromosorb W ( u n l e s s otherwise noted):  column A,3% SE-30; column B, 15% QF-1; column C  }  (10 f t x 3/8 i n ) 20% SE-30; column D, 20% FFAP; column E, 8% FFAP (60/80 mesh Chromosorb G); column F, 20% Carbowax 20 M; column G (10 f t x 3/8 i n . ) 30% Carbowax 20 M; column H, 20% SE-30.  The  - 148 -  s p e c i f i c column used, a l o n g w i t h the column temperature and gas  carrier  (helium) f l o w - r a t e ( i n ml/min) a r e i n d i c a t e d i n p a r e n t h e s e s .  High r e s o l u t i o n mass s p e c t r a were r e c o r d e d on an A E I , type mass s p e c t r o m e t e r .  MS-9,  M i c r o a n a l y s e s were performed by Mr. P.  Borda,  M i c r o a n a l y t i c a l L a b o r a t o r y , U n i v e r s i t y of B r i t i s h Columbia, Vancouver.  P r e p a r a t i o n of D i m e t h y l a - k e t o p i m e l a t e The procedure used was  (111)  t h a t of Lukes, Poos and S a r e t t ( 5 1 ) .  Through a s o l u t i o n o f 100 g (0.725 mole) of commercial  furylacrylic  a c i d (110) i n 400 ml o f methanol was  passed hydrogen c h l o r i d e u n t i l the  s o l u t i o n reached the b o i l i n g p o i n t .  The gas f l o w was  s o l u t i o n was m a i n t a i n e d at t h e b o i l i n g p o i n t f o r 4 h.  reduced and  the  Then the s o l u t i o n  was  c o n c e n t r a t e d on the r o t a r y e v a p o r a t o r to o n e - f o u r t h the volume. >  One  l i t r e of benzene was  added t o the r e s i d u e and d i s t i l l a t i o n c o n t i n u e d  a t a t m o s p h e r i c p r e s s u r e u n t i l the vapour temperature reached 80°. the r e m a i n i n g benzene was r e s i d u e was  removed under reduced p r e s s u r e .  To  Then  the  added 350 ml of methanol and o n e - t h i r d ml of 95% s u l p h u r i c  a c i d and the m i x t u r e r e f l u x e d o v e r n i g h t .  The methanol was  then removed  under reduced p r e s s u r e and the r e s i d u e d i s s o l v e d i n 650 ml of benzene. The benzene s o l u t i o n was washed s u c c e s s i v e l y w i t h w a t e r , 1 N sodium carbonate s o l u t i o n ( u n t i l b a s i c ) , water and b r i n e and d r i e d over anhydrous magnesium s u l f a t e . i n vacuo, b.p.  The  c o n c e n t r a t e d benzene e x t r a c t was  110-115° a t 0.65  mm;  lit.  (51) b.p.  distilled  90-93° a t 0.1  to a f f o r d 122 g (84%) o f d i m e t h y l a - k e t o p i m e l a t e ( 1 1 1 ) , m.p. lit. T 7.29  (51) m.p.  mm,  49-50°;  49-50°.  Infrared ( C H C l J , X 5.8, 6.97, 8.5 u; n.m.r., 3 max ( m u l t i p l e t , 8 H, - C H ^ C H ^ ) , 6.33 ( s i n g l e t , 6 H, C 0 C H ) . 2  3  - 149 -  P r e p a r a t i o n o f D i m e t h y l - Y - e t h y l e n e d i o x y p i m e l a t e (112) The  procedure used was analogous t o t h a t o f L u k e s , Poos and S a r e t t  (51). I n a 1.0 1 f l a s k , equipped w i t h a Dean-Stark water s e p a r a t o r , was p l a c e d 120 g (0.59 mole) o f k e t o d i e s t e r 111, 41.5 g (0.64 mole) o f ethylene benzene.  g l y c o l and 220 mg o f p _ - t o l u e n e s u l f o n i c a c i d i n 600 m l o f d r y The m i x t u r e was r e f l u x e d u n t i l t h e c a l c u l a t e d amount o f  water had been c o l l e c t e d .  The c o o l e d s o l u t i o n was washed s u c c e s s i v e l y  w i t h s a t u r a t e d sodium b i c a r b o n a t e over anhydrous magnesium s u l f a t e . distilled  s o l u t i o n , w a t e r and b r i n e , and d r i e d The c o n c e n t r a t e d  r e s i d u e was  through a V i g r e u x column s e v e r a l times t o a f f o r d 34 g (23%) o f  dimethyl-y-ethylenedioxypimelate  (112) , w h i c h was g r e a t e r than 97% pure  by g . l . c . (column A, 220°, 8 5 ) , b.p. 115-120° a t 0.6 mm; l i t . (51) b.p. 96-98° a t 0.08mm, n X  D  1.4504; l i t . (51) n ^  1.4501.  Infrared  5.77, 7.0 ; n.m.r., x 6.30 ( s i n g l e t , 6 H, C0 CH.), 6.04 u  o  TD3X  (singlet,  Z. j  4 H, k e t a l p r o t o n s ) .  I t s h o u l d be n o t e d t h a t a f t e r d i s t i l l a t i o n  s u b s t a n t i a l amount of h i g h b o i l i n g m a t e r i a l was r e c o v e r e d . m a t e r i a l was s u b j e c t e d  to methanol-sulfuric  r e g e n e r a t e d k e t o d i e s t e r 111. had  (film),  a  This  a c i d treatment w h i c h  I t was t h e r e f o r e f e l t t h a t t h i s m a t e r i a l  t r a n s e s t e r i f i e d under t h e k e t a l i z a t i o n c o n d i t i o n s .  Recyclization  of r e c o v e r e d k e t o d i e s t e r 111 s e v e r a l times r a i s e d the o v e r a l l y i e l d o f t h i s r e a c t i o n t o 44%.  P r e p a r a t i o n o f Keto E s t e r 113 The  p r o c e d u r e employed was t h a t o f Lukes, Poos and S a r e t t ( 5 1 ) .  - 150 -  A s o l u t i o n o f 58 g (0.24 mole) o f k e t a l d i e s t e r 112 and 5.7 g (0.24 mole) o f sodium h y d r i d e i n 350 ml d r y e t h e r was r e f l u x e d w i t h e f f i c i e n t s t i r r i n g f o r 5 days under a n i t r o g e n atmosphere.  A t the end  of t h i s time 20 m l o f g l a c i a l a c e t i c a c i d and 20 ml o f w a t e r were added s u c c e s s i v e l y .  The e t h e r l a y e r was washed w i t h 1 N sodium c a r b o n a t e  s o l u t i o n , w a t e r and b r i n e and d r i e d over anhydrous magnesium s u l f a t e . The e t h e r l a y e r was c o n c e n t r a t e d and t h e r e s i d u e d i s t i l l e d t o a f f o r d a c o l o r l e s s o i l w h i c h c r y s t a l l i z e d on s t a n d i n g , b.p. 124° a t 0.35  mm.  R e c r y s t a l l i z a t i o n from methanol a f f o r d e d 40.5 g (80%) o f k e t o e s t e r 113, m.p.  60-61°; l i t .  (51) m.p.  6.03, 6.20 y; n.m.r., x 6.23  60-61°.  I n f r a r e d (CHCl.), X 5.75, 3 max  ( s i n g l e t , 3H, C0 CH_ ) , 5.97 2  3  5.85,  (singlet,  4H,  k e t a l protons).  P r e p a r a t i o n o f O c t a l o n e 114 The p r o c e d u r e used was s i m i l a r t o t h a t o f I r e l a n d e t a l . ( 5 2 ) . A s o l u t i o n of 14.6 g (68 mmoles) o f k e t o e s t e r 113 and 4.0 g (73 mmoles) o f sodium methoxide i n 120 ml of anhydrous methanol was s t i r r e d at room temperature under a n i t r o g e n atmosphere.  To t h i s  s o l u t i o n was added 30.8 g (102 mmoles) of l - d i e t h y l a m i n o - 3 - p e n t a n o n e m e t h i o d i d e i n 80 ml of anhydrous methanol and t h e r e a c t i o n a l l o w e d t o s t i r f o r 3 days.  At t h e end o f t h i s p e r i o d , the methanol was removed  i n vacuo and 1 g o f p o t a s s i u m h y d r o x i d e i n 200 ml o f w a t e r was  added.  An a d d i t i o n a l 9 g of p o t a s s i u m h y d r o x i d e i n 150 ml of w a t e r was added dropwise o v e r 3 h and the s o l u t i o n r e f l u x e d f o r an a d d i t i o n a l 5 h.  The  c o o l e d r e a c t i o n m i x t u r e was t h o r o u g h l y e x t r a c t e d w i t h e t h e r and the combined e t h e r e x t r a c t s were washed w i t h w a t e r and b r i n e and d r i e d o v e r  - 151  anhydrous sodium s u l f a t e . d i s t i l l e d , b.p.  (30-60°) a f f o r d e d 9.5 (52) m.p.  (nujol), X  The e t h e r e x t r a c t was  117-120° a t 0.1 mm,  c r y s t a l l i z e d on s t a n d i n g .  lit.  -  concentrated  and  to a f f o r d a c o l o r l e s s o i l which  R e c r y s t a l l i z a t i o n from p e t r o l e u m  ether  g (64%) of t h e d e s i r e d o c t a l o n e 114, m.p.  61-62°;  61-63°. 6.03,  Ultraviolet, X 245 mu (e = 14,400); i n f r a r e d max ^ ' 6.24 u; n.m.r., T 8.13 ( s i n g l e t , 3H, v i n y l m e t h y l ) ,  H13.X  6.08  ( s i n g l e t , 4H, k e t a l p r o t o n s ) .  R e d u c t i o n of O c t a l o n e  114  To 150 ml of l i q u i d ammonia ( f r e s h l y d i s t i l l e d was  added 108 mg  d i s s o l v e d 500 mg d r y e t h e r was  o f f i n e l y cut l i t h i u m w i r e .  from sodium m e t a l )  A f t e r a l l the l i t h i u m  had  (2.24 mmoles) of o c t a l o n e 114 d i s s o l v e d i n 25 ml of  added dropwise o v e r 0.5  h.  The s o l u t i o n was  a l l o w e d to  s t i r f o r an a d d i t i o n a l 2 h and then the b l u e c o l o r was  d i s c h a r g e d by  a d d i t i o n of ammonium c h l o r i d e .  allowed to  evaporate  The  l i q u i d ammonia was  and the r e s i d u e d i l u t e d w i t h w a t e r .  thoroughly extracted w i t h ether.  The aqueous s o l u t i o n  was  The combined e t h e r e x t r a c t s were  washed w i t h w a t e r and b r i n e and d r i e d over anhydrous sodium s u l f a t e . The at  e t h e r e x t r a c t was 2 mm)  c o n c e n t r a t e d and the r e s i d u e d i s t i l l e d  t o a f f o r d 491 mg  of the r e a c t i o n p r o d u c t  (97%) of the d e s i r e d decalone  (column B, 195°,  (column C, 200°, 110)  120°  G.l.c. analysis  85) r e v e a l e d a p p r o x i m a t e l y  of r e c o v e r e d s t a r t i n g m a t e r i a l p l u s the d e s i r e d decalone a n a l y t i c a l sample of the l a t t e r was  115.  (b.p.  115.  10%  An  c o l l e c t e d by p r e p a r a t i v e g . l . c .  and e x h i b i t e d the f o l l o w i n g s p e c t r a l d a t a :  25 n^  1.4954; i n f r a r e d ( f i l m ) , X 5.85 u ; n.m.r., x 8.96 ( d o u b l e t , 3H, ' max secondary m e t h y l group, J = 6 H z ) , 6.01 ( s i n g l e t , 4H, k e t a l p r o t o n s ) .  - 152  Mol. Wt.  Calcd.  for 23 20°3 C  spectrometry):  Preparation  H  :  -  224.141. Found ( h i g h r e s o l u t i o n mass  224.138.  of Hydroxymethylene D e r i v a t i v e  121  To an i c e - c o l d s o l u t i o n of 4 g (18 mmoles) of d e c a l o n e 115, of sodium methoxide i n 20 ml of dry benzene was formate.  The  r e a c t i o n m i x t u r e was  under n i t r o g e n and  f o r 14 h.  The  t o s t i r a t room temperature  aqueous l a y e r was  (80%) X  max  The  e t h e r e x t r a c t was  6.4  ti.  Due  The  with  combined  d r i e d o v e r anhydrous  c o n c e n t r a t e d to a f f o r d 3.7  of the d e s i r e d hydroxymethylene d e r i v a t i v e 121. 6.1,  added  acidified  thoroughly extracted with ether.  e t h e r e x t r a c t s were washed w i t h w a t e r and b r i n e and sodium s u l f a t e .  g  added 3 ml of e t h y l  At the end of t h i s time i c e w a t e r was  the benzene l a y e r s e p a r a t e d .  g l a c i a l a c e t i c a c i d and  allowed  1.95  Infrared  g (film),  to the i n s t a b i l i t y of t h i s compound i t was . J  v  o x i d i z e d immediately without f u r t h e r c h a r a c t e r i z a t i o n .  Preparation  of Dione  124  T h i s compound was  p r e p a r e d by the p r o c e d u r e of I r e l a n d et a l . ( 5 2 ) .  A s o l u t i o n c o n t a i n i n g 25 g (0.127 mole) of k e t o e s t e r 113, (0.2 mole) of e t h y l v i n y l k e t o n e , 5 ml of t r i e t h y l a m i n e methanol was  allowed  The methanol was  c r y s t a l l i z e d on s t a n d i n g .  afforded  29.1  g (84%)  max  of  of dione 124,  then removed i n vacuo.  The  R e c r y s t a l l i z a t i o n from methanol m.p.  83-85°; l i t .  Dione 124 X  g  t o s t a n d f o r 48 h at room temperature under an  atmosphere of n i t r o g e n . residue  i n 250 ml  16.8  (52) m.p.  83-85°.  e x h i b i t e d the f o l l o w i n g s p e c t r a l p r o p e r t i e s . Infrared (nujol), 0 5. 85p; n.m.r., T 8.97 ( t r i p l e t , 3H, CH CH_C-, J = 7 H z ) , 6.30 (singlet, . > *> » _3 2 0  - 153  -  3H, m e t h y l e s t e r ) , 6.08  ( s i n g l e t , AH, k e t a l p r o t o n s ) .  P r e p a r a t i o n of Octalone  123  The procedure  used to p r e p a r e t h i s compound was  t h a t of I r e l a n d  et a l . (52). A s u s p e n s i o n o f 10 g (0.034 mole) o f dione 124 i n 75 ml of a b s o l u t e methanol c o n t a i n i n g 1 g of sodium m e t a l was warmed i n a n i t r o g e n atmosphere a t 40°  f o r 1 h.  T h i s s o l u t i o n was  then r e f l u x e d f o r 2 h.  At the end o f t h i s time 3.1 g (0.05 mole) o f g l a c i a l a c e t i c a c i d was s l o w l y at 15°. was  The  r e a c t i o n m i x t u r e was  c o n c e n t r a t e d under reduced p r e s s u r e .  w i t h benzene.  The benzene e x t r a c t was  then f i l t e r e d .  The  The r e s i d u e was  filtrate  extracted  then washed w i t h w a t e r ,  sodium  b i c a r b o n a t e s o l u t i o n ( u n t i l n e u t r a l ) , w a t e r and b r i n e and d r i e d  over  anhydrous sodium s u l f a t e .  and  The benzene e x t r a c t was  the r e s i d u e c r y s t a l l i z e d on s t a n d i n g .  o c t a l o n e 123 from methanol-water a f f o r d e d 9.02 (52) m.p.  n.m.r., x 8.13 e s t e r ) , 6.08  101.5-103°.  concentrated  These c r y s t a l s were combined  w i t h those o b t a i n e d from the f i r s t f i l t r a t i o n .  lit.  added  R e c r y s t a l l i z a t i o n of g ( 9 7 % ) , m.p.  I n f r a r e d (CHC1-), A 5.8, 3 max  ( s i n g l e t , 3H, v i n y l m e t h y l ) , 6.30  6.0,  102-103°; 6.2  ( s i n g l e t , 3H,  ( s i n g l e t , 4H, k e t a l p r o t o n s ) ; u l t r a v i o l e t , ^  m a x  u; methyl  247  my  (e = 13,000).  P r e p a r a t i o n o f Dienone  125  A s o l u t i o n o f 5 g (18 mmoles) of o c t a l o n e 114, 4.4 DDQ,  g (19 mmoles) of  6.2 ml of g l a c i a l a c e t i c a c i d i n 100 ml of anhydrous benzene was  r e f l u x e d f o r 36 h under n i t r o g e n .  At the end of t h i s t i m e , the c o o l e d  - 154 r e a c t i o n m i x t u r e was f i l t e r e d and c o n c e n t r a t e d i n vacuo.  The r e s i d u e was  t a k e n up i n e t h e r and washed w i t h w a t e r , s a t u r a t e d sodium b i c a r b o n a t e s o l u t i o n , water and b r i n e and d r i e d over anhydrous magnesium s u l f a t e . The  d r i e d e x t r a c t was c o n c e n t r a t e d t o a f f o r d 4 g (80%) o f a w h i t e  crystalline solid.  An a n a l y t i c a l sample was p r e p a r e d by r e c r y s t a l l i z a t i o n  from e t h y l a c e t a t e - p e t r o l e u m e t h e r (30-60°) t o a f f o r d w h i t e m.p. 143-144°.  T h i s sample e x h i b i t e d u l t r a v i o l e t , A  m a x  needles,  243 my (e = 10,300);  infrared (nujol), X 5.82, 6.05, 6.15, 6.25 y; n.m.r., T 8.04 ( s i n g l e t , m 3.x 3H, v i n y l m e t h y l ) , 6.30 ( s i n g l e t , 3H, C 0 C H ) , 6.02 ( s i n g l e t , 4H, k e t a l 2  p r o t o n s ) , 3.72, 3.28 ( p a i r o f d o u b l e t s , 2H,  3  and  protons  r e s p e c t i v e l y , J = 10 H z ) . Anal. Calcd. f o r C-Jff- 0 : o  IJ  l o  c  C, 64.74; H, 6.52.  Found:  C, 64.84;  _>  H, 6.49.  Isopropylmagnesium Bromide A d d i t i o n t o Dienone 129 To an i c e - c o l d s u s p e n s i o n o f 326 mg o f magnesium f i l i n g s i n 12 ml anhydrous t e t r a h y d r o f u r a n (THF) was added 1.55 ml o f i s o p r o p y l bromide. A f t e r a l l the magnesium had r e a c t e d 12 mg o f cuprous c h l o r i d e was added and t h e s o l u t i o n p l a c e d i n an e x t e r n a l i c e b a t h .  To t h i s  190 mg o f dienone 129 i n 4 m l o f anhydrous e t h e r was added  solution  dropwise  over 15 min and t h e s o l u t i o n a l l o w e d t o s t i r f o r an a d d i t i o n a l 2 h. The  r e a c t i o n m i x t u r e was poured i n t o a r a p i d l y s t i r r e d 1 N h y d r o c h l o r i c  acid solution.  The e t h e r l a y e r was s e p a r a t e d and washed w i t h w a t e r  and b r i n e and d r i e d o v e r anhydrous magnesium s u l f a t e .  The e t h e r  e x t r a c t was c o n c e n t r a t e d i n vacuo t o a f f o r d 207 mg o f a y e l l o w o i l . A n a l y s i s o f t h e p r o d u c t by g . l . c . r e v e a l e d two major p r o d u c t s i n t h e  - 155 -  r a t i o o f 2:3 r e s p e c t i v e l y , (column B, (131 o r 132) e x h i b i t e d i n f r a r e d  180°, 85).  (film), X  The minor  3.45, 6.25  product  (w), 6.4  (w) y;  D13X  n.m.r., T 8.80  ( d o u b l e t , 3H, secondary m e t h y l s , J = 6.5 H z ) ,  ( s i n g l e t , 6H, t e r t i a r y m e t h y l s ) ,  7.84  3.00  protons).  (broad s i n g l e t s , 2H, phenyl Anal. Calcd. f o r C ^ H ^ :  H,  8.75  ( s i n g l e t , 3H, v i n y l m e t h y l ) ,  C, 88.82; H, 11.18.  Found:  C, 88.70;  11.07. The major product  exhibited infrared  (film), X  6.0,  6.25  u;  max ultraviolet,  X  ( =13,000); n.m.r., T 9.35,  240 my  gem-dimethyl g r o u p s ) , 7.21  7.65  3 H z ) , 4.04  ( p a i r of d o u b l e t s , ( s i n g l e t , IH, C  Anal. Calcd. f o r  C  H 1  6  (singlets,  proton, J ,  ,  =18  Hz, J  proton, J  =18  81.99; H, 11.18.  Found:  IH, C  .  6H,  7.39, = 6 Hz),  Hz, J  ,  =  proton). 0  2  8.82  ( p a i r of  ( s i n g l e t , 3H, C^Q t e r t i a r y m e t h y l ) ,  8.61  ( p a i r of d o u b l e t s , IH, C„  7.46,  K  9.08  e  d o u b l e t s , 6H, secondary m e t h y l s , J = 7 H z ) , 8.85,  H,  3.20,  :  6  c  »  C,  81.89;  11.09.  P r e p a r a t i o n o f Hydroxymethylene D e r i v a t i v e 134 To an i c e - c o l d s o l u t i o n o f 1.75  g (6.25 mmoles) o f o c t a l o n e  0.756 g of sodium methoxide i n 17.5 ml of dry benzene was of e t h y l formate.  The r e a c t i o n mixture was  temperature under n i t r o g e n f o r 14 h. was  allowed  123,  added 463 mg  t o s t i r a t room  At the end of t h i s time i c e water  added and the benzene l a y e r s e p a r a t e d .  The aqueous l a y e r was  a c i d i f i e d w i t h g l a c i a l a c e t i c a c i d and t h o r o u g h l y  extracted with  ether.  The combined e t h e r e x t r a c t s were washed w i t h water and b r i n e and d r i e d over anhydrous sodium s u l f a t e .  The e t h e r e x t r a c t was  concentrated  to  - 156 a f f o r d 1.34 Infrared  g (70%)  (film), X  compound i t was  -  of the d e s i r e d hydroxymethylene d e r i v a t i v e 5.8,  max  6.1,6.4 u.  Due  to the i n s t a b i l i t y of t h i s  o x i d i z e d immediately without f u r t h e r  Dehydrogenation o f Hydroxymethylene D e r i v a t i v e To  700 mg  (2.26  of anhydrous d i o x a n e . min.  characterization.  134  mmoles) of hydroxymethylene d e r i v a t i v e 134  i n 10 ml of anhydrous d i o x a n e was  3.5  134.  At the end  The  added 570 mg  r e a c t i o n was  (2.5 mmoles) of DDQ  The  s o l u t i o n was  f i l t e r e d and  added t o  the f i l t r a t e washed  w i t h w a t e r , 2% sodium h y d r o x i d e s o l u t i o n ( u n t i l b a s i c ) , water neutral)  and b r i n e and  o r g a n i c e x t r a c t was standing.  d r i e d over anhydrous sodium s u l f a t e .  then c o n c e n t r a t e d and  the r e s i d u e  c r y s t a l s , m.p.  5.9,  6.08,  6.15,  6.25  6.25  ( s i n g l e t , 3H,  ( s i n g l e t , IH,  142-144°.  y; n.m.r., x 7.97  C0 CH_ ) , 5.98 2  3  v i n y l proton),  ultraviolet, X  246 my  Infrared  The  292 mg  (nujol), ^  on (43%)  5.75,  m a x  ( s i n g l e t , 3H, v i n y l m e t h y l ) ,  ( s i n g l e t , 4H, -0.25  (until  crystallized  R e c r y s t a l l i z a t i o n from n-hexane-ether a f f o r d e d  of p a l e y e l l o w  i n 10  allowed to s t i r r a p i d l y f o r  of t h i s t i m e , methylene c h l o r i d e was  quench the r e a c t i o n .  dissolved  k e t a l protons),  ( s i n g l e t , IH, a l d e h y d i c  2.55 H);  (e=14,700).  max Anal. H,  Calcd.  for  C  H 1  6  1  8  °  : 6  C, 62.74; H,  5.92.  Found:  C,  62.81;  5.97.  Preparation  of Dione  137  To a s o l u t i o n of 60 g of l-N,N-diethylamino-3-pentanone i n 250 of dry benzene a t 0° was methyl iodide.  The  ml  added over 2 h 60 g of freshly d i s t i l l e d  r e s u l t i n g s o l u t i o n was  a l l o w e d t o s t i r at 0° f o r  an  ml  - 157 -  a d d i t i o n a l 15 h.  A t t h e end o f t h i s time t h e benzene and excess  m e t h y l i o d i d e were removed i n vacuo and 200 m l o f anhydrous e t h a n o l were added.  A s o l u t i o n o f 60 g o f 2-carbethoxycyclohexanone  and 20 g  of sodium e t h o x i d e i n 900 ml o f anhydrous e t h a n o l was c o o l e d t o 0°. To t h i s s o l u t i o n was added dropwise 3-pentanone m e t h i o d i d e  solution.  over 2 h t h e above  1-diethylamino-  The r e a c t i o n m i x t u r e was a l l o w e d t o  s t i r f o r an a d d i t i o n a l 4 h a t 0° and r e f l u x e d f o r 0.5 h.  A t t h e end o f  t h i s p e r i o d , most o f t h e e t h a n o l was removed on t h e r o t a r y e v a p o r a t o r and t h e r e s i d u e d i l u t e d w i t h w a t e r . extracted with ether.  The aqueous l a y e r was t h o r o u g h l y  The combined e t h e r e x t r a c t s were washed w i t h  w a t e r , d i l u t e h y d r o c h l o r i c a c i d , water and b r i n e and d r i e d anhydrous sodium s u l f a t e . residue d i s t i l l e d  The e t h e r e x t r a c t was c o n c e n t r a t e d and t h e  t o a f f o r d 64.8 g (83%) o f a p a l e y e l l o w o i l , b.p.  130-135° a t 0.9 mm. peak o n l y .  over  G . l . c . a n a l y s i s (column D, 200°, 75) e x h i b i t e d one  Infrared (film), X  m  5.8 u; n.m.r., x 8.97 ( t r i p l e t ,  3H,  CH CH J ! , J = 7 H z ) , 8.72 ( t r i p l e t , 3H, CH CH - 0 , J = 7 H z ) , 7.59 ( q u a r t e t , 0 : 2H, CH C, J = 7 H z ) , 5.8 ( q u a r t e t , 2H, -CH -0-, J = 7 H z ) . 2  2  P r e p a r a t i o n o f Octalone  138  To a s o l u t i o n o f 530 mg o f sodium d i s s o l v e d i n 35 m l o f d r y e t h a n o l was added 5 g o f dione 137. for  T h i s s o l u t i o n was a l l o w e d t o s t i r a t 40°  2 h, under a n i t r o g e n atmosphere.  A t the end o f t h i s p e r i o d , t h e  e t h a n o l was removed i n vacuo and t h e r e s i d u e d i l u t e d w i t h w a t e r . aqueous s o l u t i o n was t h o r o u g h l y e x t r a c t e d w i t h e t h e r .  The  The e t h e r l a y e r  was washed w i t h w a t e r and b r i n e and d r i e d over anhydrous magnesium sulfate.  The e t h e r e x t r a c t was c o n c e n t r a t e d and the r e s i d u e  distilled  to a f f o r d 4.2 g (96%) o f t h e d e s i r e d o c t a l o n e 138, b.p. 135° a t 0.2 mm;  - 158 -  lit.  (105) b.p. 135-136° a t 0.2 mm. r  infrared (film), X  Ultraviolet,  X max  247 my (e 13,000);  5.8, 6.0, 6.2 y; n.m.r., T 8.72 ( t r i p l e t , 3H,  IU3.X  CH_ CH -0, J = 7 Hz) , 8.12 ( s i n g l e t , 3H, v i n y l m e t h y l ) , 5.72 ( q u a r t e t , 3  2  2H, CH -CH -0-, J = 7 H z ) . 3  2  Dehydrogenation o f O c t a l o n e 138 A s o l u t i o n o f 3.2 g (13.6 mmoles) o f o c t a l o n e 138, 4.8 g (21 mmoles) of DDQ, 6.4 m l o f g l a c i a l a c e t i c a c i d i n 128 m l o f anhydrous benzene was r e f l u x e d under n i t r o g e n f o r 70 h. A t t h e end o f t h i s time t h e c o o l e d r e a c t i o n m i x t u r e was f i l t e r e d , and c o n c e n t r a t e d i n vacuo.  The  r e s i d u e was taken up i n e t h e r and washed t h r i c e w i t h w a t e r , w i t h s a t u r a t e d sodium b i c a r b o n a t e s o l u t i o n , w i t h w a t e r and w i t h b r i n e and d r i e d o v e r anhydrous magnesium s u l f a t e .  The c o n c e n t r a t e d e x t r a c t was  d i s t i l l e d , b.p. 120° a t 0.2 mm, t o a f f o r d 2.4 g (76%) o f dienone 139, w h i c h c r y s t a l l i z e d on s t a n d i n g , m.p. 55-57°. (e = 9,680), sh 265 my (e = 6,700);  Ultraviolet, ^  i n f r a r e d (CHC1 ), X 3  m a x  m a x  245 my  5.8, 6.05,  6.12, 6.23 y; n.m.r., T 8.79 ( t r i p l e t , 3H, C 0 C H C H , J = 7 H z ) , 8.05 2  2  3  ( s i n g l e t , 3H, v i n y l m e t h y l ) , 5.85 ( q u a r t e t , 2H, -CH -0, J = 7 H z ) , 3.77, 2  3.33  ( p a i r o f d o u b l e t s , 2H, C  3  Anal. Calcd. f o r C ^ H ^ O ^  and  p r o t o n s r e s p e c t i v e l y , J = 10 H z ) .  C, 71.77; H, 7.74. Found:  C, 71.61;  H, 7.91.  P r e p a r a t i o n o f Hydroxymethylene D e r i v a t i v e 140 To a s o l u t i o n o f 4 g (17.1 mmoles) o f o c t a l o n e 138 and 1.84 g (34.1 mmoles) o f sodium methoxide d i s s o l v e d i n 20 m l o f d r y benzene,  - 159 -  a t 0°, was added 3.15 ml (39 mmoles) o f e t h y l formate.  The r e a c t i o n  v e s s e l was then p u t under a n i t r o g e n atmosphere and s t i r r i n g at room temperature  f o r 24 h.  continued  A t t h e end o f t h i s t i m e , i c e w a t e r was  added and t h e benzene l a y e r s e p a r a t e d .  The aqueous l a y e r was n e u t r a l i z e d  w i t h d i l u t e h y d r o c h l o r i c a c i d and t h e s o l u t i o n t h o r o u g h l y e x t r a c t e d with ether.  The combined e t h e r e x t r a c t s were washed w i t h w a t e r and  b r i n e and d r i e d o v e r anhydrous sodium s u l f a t e .  The e t h e r l a y e r was  c o n c e n t r a t e d i n vacuo t o a f f o r d 3.7 g (83%) o f an orange c o l o r e d o i l . Infrared (film), \  5.8, 6.1, 6.4 u; n.m.r., T 8.82 ( t r i p l e t , 3H,  TIlcLX  C H C H 0 C , J = 7 H z ) , 8.09 ( s i n g l e t , 3H, v i n y l m e t h y l ) , 5.89 ( q u a r t e t , 3  2  2  2H, CH -0, J = 7 H z ) , 2.65 ( s i n g l e t , I H , =CH0H). 2  P r e p a r a t i o n o f 3-Formyl Dienone 141 To a s o l u t i o n o f 2.6 g (0.01 mole) o f hydroxymethylene d e r i v a t i v e 140 i n 20 ml o f d r y dioxane was added 2.3 g (0.01 mole) o f DDQ i n 20 ml o f d r y dioxane.  The s o l u t i o n was a l l o w e d t o s t i r w i t h a r a p i d f l o w  of n i t r o g e n p a s s i n g through t h e s o l u t i o n f o r 3.5 min.  The r e a c t i o n  m i x t u r e was then d i l u t e d w i t h methylene c h l o r i d e and f i l t e r e d a column o f n e u t r a l a l u m i n a .  through  The f i l t r a t e was c o n c e n t r a t e d and  d i s t i l l e d , b.p. 200° a t 0.1 mm, t o a f f o r d 1.68 g (65%) o f a l i q u i d which c r y s t a l l i z e d on s t a n d i n g .  R e c r y s t a l l i z a t i o n from n-hexane-ether  a f f o r d e d an a n a l y t i c a l sample, m.p. 46-48°, w h i c h gave t h e f o l l o w i n g s p e c t r a l data: (nujol), x  ultraviolet, x 247 m,, ( max  P  = 8,270):  infrared  5.8, 5.9, 6.1, 6.2 y; n.m.r., x 8.75 ( t r i p l e t , 3H,  TUclX  C 0 C H C H , J = 7 H z ) , 7.97 ( s i n g l e t , 3H, v i n y l m e t h y l ) , 5.82 ( q u a r t e t , 2  2  3  2H, -CH -0, J = 7 H z ) , 2.55 ( s i n g l e t , I H , 2  ( s i n g l e t , IH, a l d e h y d i c H).  v i n y l hydrogen), -0.25  - 160 -  A n a l . C a l c d . f o r C._H_ 0.: • 15 18 4 o  H,  C, 68.69; H, 6.92.  Found:  C, 68.52;  7.09.  P r e p a r a t i o n of Bromomethyl e t h y l Ketone (146) A p r o c e d u r e s i m i l a r t o t h a t o f C a t c h e t a l . was used ( 6 8 ) . To an i c e - c o l d e t h e r e a l s o l u t i o n o f 12 g (0.3 mole) o f anhydrous diazomethane was added 14 g (0.15 mole) o f f r e s h l y d i s t i l l e d chloride.  T h i s s o l u t i o n was a l l o w e d t o s t i r f o r 30 min  propionyl  a t 0°.  Then  anhydrous hydrogen bromide was b u b b l e d t h r o u g h the s o l u t i o n and t h e s o l u t i o n m a i n t a i n e d a t 0° f o r an a d d i t i o n a l 30 min.  The e t h e r e a l  s o l u t i o n was then washed w i t h w a t e r , 5% sodium b i c a r b o n a t e s o l u t i o n and b r i n e and d r i e d o v e r anhydrous magnesium s u l f a t e .  Removal o f t h e  s o l v e n t and d i s t i l l a t i o n o f t h e o i l y r e s i d u e under reduced p r e s s u r e a f f o r d e d 15.8 g (70%) o f bromomethyl e t h y l k e t o n e ( 1 4 6 ) , b.p. 48° a t ? n  10 mm;  l i t . (68) b.p. 154-155°; n~ D  5.85 u; n.m.r., x 8.88  Infrared (film), X max  ( t r i p l e t , 3H, CH -, J = 6.5 H z ) , 7.27 3  2H, CH -CH -, J = 6.5 H z ) , 6.06 3  1.4673.  2  (quartet,  ( s i n g l e t , 2H, -CH - B r ) .  P r e p a r a t i o n of A c y l Phosphonium S a l t  147  To a s o l u t i o n of 20 g of t r i p h e n y l p h o s p h i n e i n 20 ml anhydrous benzene was added 15 g of bromomethyl e t h y l k e t o n e .  The r e a c t i o n  m i x t u r e was a l l o w e d t o s t a n d o v e r n i g h t a t room temperature. p r e c i p i t a t e d phosphonium s a l t filtration.  (147) was t h e n c o l l e c t e d by s u c t i o n  R e c r y s t a l l i z a t i o n from methanol gave 33.6 g (82%) o f  w h i t e n e e d l e s , m.p. X  The  253-255°.  An a n a l y t i c a l sample gave i n f r a r e d  5.85, 6.90, 7.00, 9.05 y; n.m.r., x 9.08  (triplet,  (nujol),  3H, CH -, J =  - 161 -  6.5 H z ) , 6.97 ( q u a r t e t , 2H, -CH ~c\ J = 6.5 H z ) , 4.03 ( d o u b l e t , 2H, -CH 2  2  J = 11 H z ) , 2.30 ( u n r e s o l v e d m u l t i p l e t , 15H, ( C g H ^ ) . Anal. Calcd. f o r C^H^OPBr: Found:  C, 63.93; H, 5.37; B r , 19.33.  C, 63.65; H, 5.61; B r , 19.21.  P r e p a r a t i o n o f A c y l Phosphorane 148 To a s o l u t i o n o f 34 g o f sodium h y d r o x i d e i n 330 m l o f w a t e r was added 33.5 g o f t h e a c y l phosphonium s a l t 2 h.  147  and a l l o w e d t o s t i r f o r  The p r o d u c t was c o l l e c t e d by s u c t i o n f i l t r a t i o n ,  r e c r y s t a l l i z e d from e t h y l a c e t a t e - p e t r o l e u m  ether  a i r - d r i e d and  (30-60°) t o a f f o r d  17.3 g (64%) o f t h e a c y l phosphorane 148, m.p. 224-226°. (CHC1J, X  6.60, 6.98, 7.16, 9.07 y; n.m.r.,  CH„, J = 7 H z ) , 7.66 ( q u a r t e t , 2H, -CH -C, 3=1  T  Infrared  8.85 ( t r i p l e t , H z ) , 2.50  3H,  (unresolved  Pi m u l t i p l e t , 15 H, p h e n y l p r o t o n s ) , 1.0 ( s i n g l e t , I H , =CHC-); u l t r a v i o l e t , X  268 my (e = 6,600), 275 my (e = 6,200), 288 my (e = 5,500).  IU9.X  Anal. Calcd. f o r C^H^PO:  C, 79.49; H, 6.37.  Found:  C, 79.22;  H, 6.38. P r e p a r a t i o n o f trans-6-methylhept-4-en-3-one (144) To a s o l u t i o n c o n s i s t i n g o f 11.3 g (0.034 mole) o f a c y l phosphorane 148 i n 50 ml o f methylene c h l o r i d e was added 7 ml (0.085 mole) o f isobutyraldehyde  and t h e s o l u t i o n r e f l u x e d o v e r n i g h t .  was removed by c a r e f u l d i s t i l l a t i o n  through a V i g r e u x column and t h e  r e s i d u e d i l u t e d w i t h 40 ml o f n-pentane. to c o l l e c t t h e t r i p h e n y l p h o s p h i n e as above.  The c o n c e n t r a t e d  The s o l v e n t  The s o l u t i o n was f i l t e r e d  o x i d e and t h e f i l t r a t e  concentrated  f i l t r a t e was then f r a c t i o n a l l y d i s t i l l e d  - 162 -  to a f f o r d 4.28 g (63%) o f a c o l o r l e s s o i l , b.p. 54° a t 10 mm; l i t . b.p. was  55-58° a t 10 mm.  An a n a l y t i c a l sample o f t h e u n s a t u r a t e d k e t o n e  c o l l e c t e d by p r e p a r a t i v e g . l . c .  (film), X  (column D, 200°, 100).  Infrared  5.98, 6.14 y; n.m.r., x 8.90 ( d o u b l e t , 6H, C-CH , J = 7 H z ) ,  nicix  8.95  (104)  si  ( t r i p l e t , 3H, CH^-CH^, J = 7 Hz) , 7.45 ( q u a r t e t , 2H, -CH_ -C, J = 2  7 H z ) , 3.98 ( d o u b l e t o f d o u b l e t s , I H , C. p r o t o n , J . = 16 Hz, J . , = 4 4,5 4,6 1.5 H z ) , 3.20 ( d o u b l e t o f d o u b l e t s , I H , C p r o t o n , = 16 Hz, ^ = c  5  6 Hz); u l t r a v i o l e t ,  X  5  5 6  221 my ( s i n c e i t was n o t p o s s i b l e t o o b t a i n  max  r  v i n y l ketone 144 w i t h o u t i t s (3,Y isomer a q u a n t i t a t i v e u l t r a v i o l e t -  25 spectrum was n o t r u n ) , n ^  1.4425.  A n a l . C a l c d . f o r CgH^O:  C, 76.19; H, 11.11.  Found:  C, 76.10;  H, 11.12. P r e p a r a t i o n o f O l e f i n i c E s t e r 150 A s t i r r e d s u s p e n s i o n o f 4.3 g o f a 56% sodium h y d r i d e d i s p e r s i o n i n m i n e r a l o i l i n 50 m l o f d i m e t h y l s u l p h o x i d e (DMSO) was s l o w l y heated under a n i t r o g e n atmosphere t o 75° and m a i n t a i n e d u n t i l a l l f r o t h i n g had ceased room temperature  (y 45 m i n ) .  temperature  The s o l u t i o n was c o o l e d t o  and a s o l u t i o n o f 18.2 g o f t r i m e t h y l p h o s p h o n o a c e t a t e  (149) i n 30 m l o f DMSO was added. for  at that  10 m i n and then dropwise  i n 30 m l o f DMSO was begun.  The s o l u t i o n was a l l o w e d t o s t i r  a d d i t i o n o f 5.76 g o f i s o b u t y r a l d e h y d e The r e a c t i o n was v e r y e x o t h e r m i c .  After  the a d d i t i o n was complete t h e r e a c t i o n m i x t u r e was a l l o w e d t o s t i r f o r an a d d i t i o n a l hour.  Water was added t o t h e c o o l e d r e a c t i o n m i x t u r e  and i t was t h o r o u g h l y e x t r a c t e d w i t h p e t r o l e u m e t h e r (30-60°). The  - 163 -  combined p e t r o l e u m e t h e r e x t r a c t s were washed t h r i c e w i t h w a t e r , b r i n e and d r i e d o v e r anhydrous magnesium s u l f a t e .  The s o l v e n t was  removed a t a t m o s p h e r i c p r e s s u r e and t h e r e s i d u a l o i l d i s t i l l e d a t a s p i r a t o r pressure  (10 mm) t o a f f o r d 6.5 g (65%) o f a c l e a r c o l o r l e s s  o i l , b.p. 65° a t 10 mm; l i t . ( 1 0 6 ) b.p. 145-148° a t 640 mm; n ^ lit.  25 (106) n^ 1.4302. D  This product r  exhibited infrared  5  1.4309;  (film), \ max  5.8,  6.05 u; n.m.r., T 8.95 ( d o u b l e t , 6H, gem-dimethyl g r o u p s , J = 7 H z ) , CH3 C H 7.50 ( m u l t i p l e t , I H , \ / ) , 6.30 ( s i n g l e t , 3H, m e t h y l e s t e r ) , 3  —L>—ri  4.25 ( d o u b l e t o f d o u b l e t s , I H ,  proton, J  3.05 ( d o u b l e t o f d o u b l e t s , I H ,  proton,  23  = 16 Hz,  ^ = 1Hz),  3  = 16 Hz,  ^ = 7 Hz);  ultraviolet, \ 227 mu (e = 5,600). max ' ' P r e p a r a t i o n o f O l e f i n i c A c i d 151 To a s t i r r e d s o l u t i o n o f 34 g o f p o t a s s i u m c a r b o n a t e d i s s o l v e d i n 200 ml of methanol-water was added 23 g o f u n s a t u r a t e d r e a c t i o n m i x t u r e was s t i r r e d a t r e f l u x f o r 3 h.  e s t e r 150. The  Most o f the methanol  was then removed under reduced p r e s s u r e and water added t o the r e s i d u e . T h i s aqueous s o l u t i o n was t h o r o u g h l y  extracted with ether.  The  e t h e r e a l l a y e r was washed w i t h water and w i t h b r i n e and d r i e d over anhydrous magnesium s u l f a t e . of s t a r t i n g e s t e r 150.  The c o n c e n t r a t e d  extract afforded 2 g  The aqueous l a y e r was a c i d i f i e d w i t h d i l u t e  h y d r o c h l o r i c a c i d and t h o r o u g h l y  extracted w i t h ether.  The e t h e r  e x t r a c t was washed w i t h w a t e r and b r i n e and d r i e d over anhydrous magnesium s u l f a t e .  Removal o f t h e s o l v e n t and vacuum d i s t i l l a t i o n  afforded  15 g (82%) o f a c o l o r l e s s o i l , b.p. 75° a t 0.6 mm; l i t . (106) b.p. 99-110°  - 164  at 10 mm; (film), X  1.4454. in 3.x  T h i s u n s a t u r a t e d a c i d 151 e x h i b i t e d  3.1-4.0, 5.9,  d i m e t h y l groups, J = 6.5  6.1  proton, J  2  ( d o u b l e t of d o u b l e t s , I H , C  -2.15  u; n.m.r., x 8.95  3  =  proton, J  3  1 5 , 5  2  3  ( s i n g l e t , I H , C0„H); u l t r a v i o l e t , X Z  =  H z  '  J  1 5 , 5  2  217 my  proton), 4  H z  '  gem-  =  J  1 , 5  3  4  H z  =  4.2  ^ '  6 , 5  H z  ^»  (e =3634).  ITlcLX  A n a l . C a l c d . f o r C,H .0 : 6 10 2 8.76. 1r  H,  2  infrared  ( d o u b l e t , 6H,  H z ) , 7.25-7.8 ( m u l t i p l e t , IH,  ( d o u b l e t of d o u b l e t s , IH, C 2.9  -  o  C, 63.14; H, 8.83.  Found:  C, 62.85;  P r e p a r a t i o n of E t h y l l i t h i u m To 600 ml of anhydrous e t h e r under n i t r o g e n was f i n e l y cut l i t h i u m w i r e .  To the s t i r r e d m i x t u r e was  added 25.8  g of  added dropwise  a  s o l u t i o n of 120 ml of e t h y l bromide ( d i s t i l l e d from c a l c i u m h y d r i d e ) i n 300 ml of anhydrous e t h e r . was  kept a t -10°  the a d d i t i o n was f i l t e r e d and used  D u r i n g the a d d i t i o n the r e a c t i o n  by an e x t e r n a l d r y i c e - a c e t o n e c o o l i n g b a t h .  mixture After  complete the s o l u t i o n was warmed t o 0° f o r 1 h, immediately.  P r e p a r a t i o n of trans-6-methylhept-4-ene-3-one  (144)  A s o l u t i o n o f 32 g of u n s a t u r a t e d a c i d 151 i n 540 ml o f anhydrous e t h e r was' c o o l e d t o -78°  by an e x t e r n a l  s o l u t i o n 600 ml of the p r e v i o u s l y added dropwise. s l u r r y was b a t h was  dry i c e - a c e t o n e b a t h .  To  prepared e t h y l l i t h i u m s o l u t i o n  A f t e r the a d d i t i o n was  complete,  a l l o w e d t o s t i r f o r an a d d i t i o n a l hour.  this was  the r e s u l t i n g w h i t e Then the  cooling  removed and the s t i r r i n g c o n t i n u e d u n t i l a c l e a r s o l u t i o n  resulted.  - 165 -  I t was then poured i n t o a s t i r r e d and c o o l e d 1 N h y d r o c h l o r i c a c i d solution.  The r e s u l t i n g s o l u t i o n was t h o r o u g h l y e x t r a c t e d w i t h e t h e r .  The e t h e r l a y e r was washed w i t h d i l u t e ammonium h y d r o x i d e , w a t e r and b r i n e and dried over anhydrous magnesium s u l f a t e . then c a r e f u l l y removed by d i s t i l l a t i o n atmospheric  pressure.  The s o l v e n t was  t h r o u g h a V i g r e u x column a t  The r e s i d u e was f r a c t i o n a l l y d i s t i l l e d  to give  17 g (92%, based on r e c o v e r e d s t a r t i n g m a t e r i a l ) o f u n s a t u r a t e d ketone b.p.  54° a t 10 mm.  T h i s p r o d u c t gave i n f r a r e d , n.m.r. and u l t r a v i o l e t  s p e c t r a w h i c h were superimposable  w i t h those o b t a i n e d f o r t r a n s - 6 - m e t h y l -  hept-4-ene-3-one (144) by t h e p r e v i o u s p r e p a r a t i o n .  P r e p a r a t i o n o f O c t a l o n e 155 The et  al.  enamine o f cyclohexanone was p r e p a r e d by t h e method o f S t o r k (66).  A s o l u t i o n o f 6 g o f f r e s h l y d i s t i l l e d cyclohexanone and 9 g o f p y r r o l i d i n e i n 20 ml o f benzene were r e f l u x e d under a Dean-Stark w a t e r s e p a r a t o r u n t i l no f u r t h e r s e p a r a t i o n o f w a t e r o c c u r r e d 3 h).  The excess  (approximately  p y r r o l i d i n e and benzene were removed on a r o t a r y  e v a p o r a t o r and t h e r e s i d u e d i s t i l l e d under vacuum t o a f f o r d 6 g (79%) of t h e lit.  p y r r o l i d i n e enamine o f cyclohexanone,  (66) b.p./105-107° a t 13 mm.  b.p. 60-70° a t 0.6 mm;  Infrared (film), X 6.1 y. max  A s o l u t i o n o f 6 g (0.02 mole) o f t h e p y r r o l i d i n e enamine o f cyclohexanone and 2.6 g (0.02 mole) o f trans-6-methylhept-4-en-3-one (144) were s t i r r e d t o g e t h e r under n i t r o g e n a t 60° f o r 40 h.  Then  12 ml o f anhydrous dioxane was added and t h e r e a c t i o n m i x t u r e r e f l u x e d  - 166 -  overnight.  To  the r e a c t i o n m i x t u r e was  added 1 ml  glacial acetic  a c i d , 2 ml water and  0.5  g anhydrous sodium a c e t a t e  m a i n t a i n e d f o r 4 h.  The  c o o l e d r e a c t i o n m i x t u r e was  water and The  the r e s u l t i n g s o l u t i o n thoroughly  combined e t h e r  b r i n e before being  The  removed and  a f f o r d 3.5 was 155b,  g (83%)  reflux  d i l u t e d with  extracted with  ether.  e x t r a c t s were washed w i t h water, d i l u t e h y d r o c h l o r i c  a c i d , water and s o l v e n t was  and  d r i e d over anhydrous magnesium s u l f a t e .  the r e s i d u e d i s t i l l e d under vacuum to  of a p a l e y e l l o w  oil,  b.p.  100°  at 0.2  mm.  shown by g . l . c . to c o n t a i n a 70:30 m i x t u r e of o c t a l o n e respectively.  A n a l y t i c a l samples of these two  This  155a  and  components were  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 E, 200°, 86)  and  exhibited  the f o l l o w i n g s p e c t r a l p r o p e r t i e s : Major epimer: 9.11  Infrared  ( p a i r of d o u b l e t s ,  ( s i n g l e t , 3H, Mol.  Wt.  (doublet,  6H,  v i n y l methyl); Mol.  Wt.  Calcd. f o r  C 1A  6.0,  m a x  6.15  y; n.m.r., T  9.21,  i s o p r o p y l methyl groups, J = 7 Hz), ultraviolet, A  ^ 2°''  2 0 6  2  •  1 6 7  •  ( E = 13,600).  249 my Found  8.26  (high r e s o l u t i o n  206.166.  Infrared  (film),  A  max  6.0,  6.1  y; n.m.r., x '  i s o p r o p y l methyl groups, J = 6 Hz), ultraviolet Calcd. f o r  mass s p e c t r o m e t r y ) :  Preparation  6H,  v i n y l methyl);  mass s p e c t r o m e t r y ) : Minor epimer:  (film), ^  C 1  ^ ^  249  m a K  H 2  2  0 :  my  8.26  9.11  (singlet,  3H,  (e = 13,400).  206.167.  Found  (high r e s o l u t i o n  206.166.  of 4-ethylenedioxycyclohexanone  (156)  A s o l u t i o n of 3 g (14 mmoles) of k e t o e s t e r 113, potassium h y d r o x i d e and  30 ml  of 1:1  1.5  methanol-water was  g of  refluxed for  - 167  4 h.  -  At the end o f t h i s time the methanol was  aqueous l a y e r was  removed i n vacuo.  a c i d i f i e d w i t h g l a c i a l a c e t i c a c i d and  extracted with ether.  The  s o l u t i o n , w a t e r and b r i n e  d r i e d over anhydrous magnesium s u l f a t e .  The  and the r e s i d u e c r y s t a l l i z e d on s t a n d i n g .  e t h e r l a y e r was  g (66%) o f w h i t e p l a t e s , m.p.  (nujol), X  5.85 ,:y;  69-70°.  concentrated  Infrared  n.m.r., T 7.17-8.00 ( u n r e s o l v e d m u l t i p l e t ,  8H, r i n g p r o t o n s ) , 5.84  ( s i n g l e t , 4H, k e t a l p r o t o n s ) .  Preparation of Octalone  157  The  and  R e c r y s t a l l i z a t i o n from n-  hexane a f f o r d e d 1.5 3.45,  thoroughly  combined e t h e r e x t r a c t s were washed w i t h  w a t e r , s a t u r a t e d sodium b i c a r b o n a t e  m a x  The  enamine of k e t o k e t a l 156 was  prepared  by the method o f  Stork  et a l . (66). A s o l u t i o n o f 1 g of k e t o k e t a l 156 and 0.5  g of f r e s h l y  distilled  p y r r o l i d i n e i n 10 ml of anhydrous benzene were r e f l u x e d under a DeanS t a r k water s e p a r a t o r u n t i l no f u r t h e r s e p a r a t i o n o f w a t e r  occurred.  The  excess p y r r o l i d i n e and benzene were removed on the r o t a r y  and  the r e s i d u e d i s t i l l e d under vacuum t o y i e l d 1 g (86%) o f a c o l o r l e s s  o i l , b.p. Infrared  128-138° at 0.3 (film), X  6.1  mm;  l i t . (66) b.p.  evaporator  110-120° a t 0.1-0.15  mm.  u.  max A s o l u t i o n of 1 g o f the p r e v i o u s l y prepared of 156,  500 mg  of v i n y l k e t o n e 144 i n 4 ml o f dry d i o x a n e were  r e f l u x e d t o g e t h e r f o r 48 h. was  added:  Then 1.1 ml o f the f o l l o w i n g s o l u t i o n  1 ml a c e t i c a c i d , 2 ml w a t e r and  These r e a g e n t s were r e f l u x e d t o g e t h e r f o r 1.5 m i x t u r e was  p y r r o l i d i n e enamine  0.5  g sodium a c e t a t e .  h.  then d i l u t e d w i t h w a t e r and t h o r o u g h l y  The  cooled r e a c t i o n  extracted with ether.  - 168 The  combined e t h e r e x t r a c t s were washed w i t h w a t e r , sodium carbonate  solu-  t i o n , w a t e r and b r i n e and d r i e d over anhydrous magnesium s u l f a t e . The  c o n c e n t r a t e d e t h e r e x t r a c t was d i s t i l l e d t o a f f o r d 121 mg (8%)  b.p. 180°,  150° a t 0.1 mm, o f a v i s c o u s o i l .  G . l . c . a n a l y s i s (column E,  85) r e v e a l e d two components i n t h e r a t i o 1:4 r e s p e c t i v e l y .  A n a l y t i c a l samples were c o l l e c t e d by p r e p a r a t i v e g . l . c . u s i n g t h e above c o n d i t i o n s .  The minor i s o m e r , o c t a l o n e 157a, e x h i b i t e d t h e  following spectra: (film), A max  ultraviolet, X 243 mu (e =13,000): i n f r a r e d max 6.05 u; ri.m.r., x 9.18, 9.08 ( p a i r o f d o u b l e t s , 6H, r  i s o p r o p y l m e t h y l groups, J = 6.5 H z ) , 8.23 ( s i n g l e t - , 3H, v i n y l  methyl),  6.06 ( s i n g l e t , 4H, k e t a l p r o t o n s ) . M o l . Wt. C a l c d . f o r mass s p e c t r o m e t r y ) :  c  H l 6  2  4°3  :  264.172.  Found ( h i g h r e s o l u t i o n  264.172.  The major i s o m e r , o c t a l o n e 157b, e x h i b i t e d t h e f o l l o w i n g s p e c t r a : ultraviolet, A 243 mp (e = 18,900); i n f r a r e d max  (film), A  6.01, 6.15 u; max  n.m.r., x 9.08, 9.06 ( p a i r o f d o u b l e t s , 6H, i s o p r o p y l m e t h y l groups, J = 6.0 H z ) , 8.23 ( s i n g l e t , 3H, v i n y l m e t h y l ) , 6.06 ( s i n g l e t , 4H, ketal protons). M o l . Wt.  C a l c d . f o r C,,H..0_: 16 24 3 mass s p e c t r o m e t r y ) : 264.172.  264.172.  Found ( h i g h r e s o l u t i o n  P r e p a r a t i o n o f Q u i n t o l Monobenzoate (160) T h i s compound was p r e p a r e d  u s i n g t h e p r o c e d u r e o f Jones and  Sondheimer ( 7 3 ) . To a s o l u t i o n o f 125 g (1.0 mole) o f q u i n t o l (159) d i s s o l v e d i n a m i x t u r e o f 355 m l o f anhydrous c h l o r o f o r m and 292 m l o f anhydrous  - 169 -  p y r i d i n e , was added dropwise o v e r 5 h 148 g (1.04 mole) o f b e n z o y l c h l o r i d e i n 307 ml o f anhydrous c h l o r o f o r m . The temperature was kept at 0° d u r i n g t h e a d d i t i o n by an e x t e r n a l i c e b a t h .  A f t e r standing  at room temperature f o r 2 d a y s , t h e c h l o r o f o r m s o l u t i o n was t h o r o u g h l y washed w i t h w a t e r , d i l u t e s u l p h u r i c a c i d , w a t e r and b r i n e and d r i e d over anhydrous magnesium s u l f a t e .  A f t e r removal o f t h e s o l v e n t t h e  o i l y r e s i d u e was f r a c t i o n a l l y d i s t i l l e d t o a f f o r d 140 g (62%) o f q u i n t o l monobenzoate 160, b.p. 160-165° a t 0.3 mm; l i t . 178° a t 0.2 mm.  (73) b.p. 175-  The p r o d u c t e x h i b i t e d i n f r a r e d ( f i l m ) , A 2.93, 5.85, max  6.3, 6.35 u; n.m.r.,x 1.95-2.55  ( u n r e s o l v e d m u l t i p l e t , 5H, p h e n y l  p r o t o n s ) , 4.95 (broad s i n g l e t , I H , -CH-Oc'cglL.) , 6.25 (broad s i n g l e t , IH, -CH-OH), 6.64 ( s i n g l e t , I H , exchangeable, OH), 8.20 ( m u l t i p l e t , 8H, r e m a i n i n g r i n g p r o t o n s ) .  P r e p a r a t i o n o f 4-Benzoyloxycyclohexanone (161) To a c o o l e d and s t i r r e d s o l u t i o n o f 50 g o f q u i n t o l monobenzoate (160) i n 85 ml o f g l a c i a l a c e t i c a c i d was added 22 g o f chromium t r i o x i d e i n 12.5 ml o f w a t e r and 50 m l o f g l a c i a l a c e t i c a c i d .  The  temperature was m a i n t a i n e d below 35° d u r i n g t h e a d d i t i o n and then a t room temperature f o r an a d d i t i o n a l 12 h.  A f t e r t h i s period ether  was added and t h e s o l u t i o n t h o r o u g h l y washed w i t h w a t e r , d i l u t e h y d r o x i d e s o l u t i o n , w a t e r and b r i n e and d r i e d over anhydrous  sodium  magnesium  sulfate.  Removal o f t h e s o l v e n t a f f o r d e d 48 g o f a w h i t e c r y s t a l l i n e  product.  R e c r y s t a l l i z a t i o n from e t h e r - p e t r o l e u m e t h e r (30-60°) gave  42 g (87%) o f t h e keto e s t e r 161 m.p. 59-61°; l i t . keto e s t e r 161 e x h i b i t e d i n f r a r e d  (nujol), X  (73) m.p., 62°.  5.85, 6.25, 6.3 u;  The  - 170 n.m.r., T 1.95-2.55 ( u n r e s o l v e d m u l t i p l e t , 5H, p h e n y l p r o t o n s ) , (broad s i n g l e t , I H ,  4.55  CH-oiicgH ) , 7.50 ( u n r e s o l v e d m u l t i p l e t , 8H,  remaining r i n g protons).  P r e p a r a t i o n o f 4-Hydroxycyclohexanone  (158)  T h i s compound was p r e p a r e d by a p r o c e d u r e analogous t o Jones and Sondheimer ( 7 3 ) . A s o l u t i o n of 80 g of 4 - b e n z o y l o x y c y c l o h e x a n o n e (161) i n 320 ml of dry m e t h a n o l , c o n t a i n i n g 18 h.  0.8 g o f sodium m e t a l , was r e f l u x e d f o r  To the c o o l e d r e a c t i o n m i x t u r e w a t e r and d r y i c e were added.  A f t e r the s o l u t i o n became homogeneous, the methanol was removed on the rotary evaporator.  To t h i s v i s c o u s s o l u t i o n , w a t e r and e t h e r were added.  The s o l u t i o n was t h o r o u g h l y e x t r a c t e d benzoate.  w i t h e t h e r t o remove the m e t h y l  The aqueous l a y e r was t h e n c a r e f u l l y d i s t i l l e d t o g i v e  30.6 g (74%) of a c l e a r c o l o r l e s s o i l , b.p. 92° a t 1.1 mm; b.p. 83-85 a t 0.6 mm. g.l.c. analysis (film), X max  lit.  (73),  The p r o d u c t was shown t o be homogeneous by  (column F, 180°, 8 5 ) .  The a l c o h o l e x h i b i t e d  2.95, 5.85 y; n.m.r., x 5.85  ( s i n g l e t , I H , exchangeable on D^O  ( m u l t i p l e t , IH, C  addition,  infrared OH ) , 6.25  OH).  P r e p a r a t i o n o f O c t a l o n e 162 A s o l u t i o n of 18 g (0.16 mole) of 4-hydroxycyclohexanone  (158)  and 20.7 ml of p y r r o l i d i n e i n 234 ml of benzene were r e f l u x e d  under  a Dean-Stark w a t e r s e p a r a t o r u n t i l no f u r t h e r s e p a r a t i o n of w a t e r occurred (approximately 3 h ) . removed under vacuum (0.1 mm)  The benzene and e x c e s s p y r r o l i d i n e were t o y i e l d a w h i t e c r y s t a l l i n e enamine.  - 171 -  Infrared  (nujol), A 3.0, 6.1 u. • max ^  To t h e above enamine under  n i t r o g e n was added 13.5 g (0.1 mole) o f trans-6-methylhept-4-en-3-one (144).  These r e a g e n t s were s t i r r e d t o g e t h e r a t 50° f o r 17 h.  At  t h i s time t h e i n f r a r e d spectrum o f t h e enamine m i x t u r e e x h i b i t e d a b s o r p t i o n s f o r t h e s t a r t i n g enamine, t h e enamine o f t h e o c t a l o n e 162 but no v i n y l ketone.  Hence, an a d d i t i o n a l 5 g o f v i n y l k e t o n e 144  was added and s t i r r i n g c o n t i n u e d f o r an a d d i t i o n a l 19 h.  Dry  d i o x a n e was then added and t h e s o l u t i o n r e f l u x e d f o r 16 h.  To t h i s  r e a c t i o n m i x t u r e was added t h e h y d r o l y s i s s o l u t i o n , c o n s i s t i n g o f 5 g anhydrous sodium a c e t a t e , 10 m l g l a c i a l a c e t i c a c i d and 20 m l o f w a t e r and t h e s o l u t i o n r e f l u x e d f o r 4 h.  The c o o l e d r e a c t i o n m i x t u r e  was then d i l u t e d w i t h water and t h o r o u g h l y e x t r a c t e d w i t h e t h e r .  The  combined e t h e r e x t r a c t s were washed s u c c e s s i v e l y w i t h w a t e r , d i l u t e h y d r o c h l o r i c a c i d , w a t e r and b r i n e and d r i e d over anhydrous magnesium sulfate.  The e t h e r was removed under reduced p r e s s u r e and t h e o i l y  r e s i d u e d i s t i l l e d t o a f f o r d 14 g (40%) o f t h e d e s i r e d o c t a l o n e 162, b.p.  200° a t 0.1 mm.  T h i s was shown by g . l . c . a n a l y s i s (column G, 215°,  170)  t o be a 3:2 m i x t u r e o f o c t a l o n e  (162a p l u s 162c) and o c t a l o n e  (162b p l u s 162d), r e s p e c t i v e l y . These two components were i s o l a t e d by g . l . c . and then d i s t i l l e d t o g i v e t h e f o l l o w i n g s p e c t r a l d a t a : Infrared (CHCl ), A 2.75, 2.9, 3 max 6.05 u; n.m.r., x 9.16, 9.07 ( p a i r o f d o u b l e t s , 6H, i s o p r o p y l m e t h y l  Major epimer o c t a l o n e s 162a + 162c: J  n  r  groups, J = 6.5 H z ) , 8.23 ( s i n g l e t , 3H, v i n y l m e t h y l ) , 6.15, 5.82 OH (unresolved m u l t i p l e t s , IH, C ); u l t r a v i o l e t , A 248 mu (e = \ -rj m 3.x n 10,900). Mol-  Wt. C a l c d . f o r 4 C  1  H 2  2°2  :  2 2 2  •  1 6 2  •  Found ( h i g h r e s o l u t i o n  - 172  mass s p e c t r o m e t r y ) :  -  222.162.  Minor epimer o c t a l o n e s 162b + 162d: 6.05,  6.15  y; n.m.r., T 9.07,  9.04  I n f r a r e d (CHC1J , A 2.75, 2.9, 3 max ( p a i r of d o u b l e t s , 6H, i s o p r o p y l  m e t h y l g r o u p s , J = 6 H z ) , 8.26  ( s i n g l e t , 3H, v i n y l m e t h y l g r o u p ) , OH 5.78 ( u n r e s o l v e d m u l t i p l e t , IH, C ); u l t r a v i o l e t , A 247 my n 9,272). M o l . Wt.  Calcd. f o r  mass s p e c t r o m e t r y ) :  C  4 22 2 H  X  methanol was  •  1 6 2  •  Found ( h i g h r e s o l u t i o n  o f sodium m e t a l d i s s o l v e d i n 20 ml of  added 2 g of the 3:2  s o l u t i o n was  2 2 2  162  To a s o l u t i o n of 100 mg  The  :  (E =  222.162.  E p i m e r i z a t i o n of Octalone  methanol was  0  6.10,  e p i m e r i c m i x t u r e of o c t a l o n e s  r e f l u x e d under n i t r o g e n f o r 12 h.  Then most of  removed a t a s p i r a t o r p r e s s u r e and w a t e r added.  r e s u l t i n g s o l u t i o n was  162.  thoroughly e x t r a c t e d w i t h ether.  The  the  The combined  e t h e r e x t r a c t s were washed w i t h w a t e r , d i l u t e h y d r o c h l o r i c a c i d , water and b r i n e and d r i e d over anhydrous magnesium s u l f a t e . e t h e r e a l e x t r a c t was a f f o r d 1.8  c o n c e n t r a t e d and d i s t i l l e d under vacuum t o  g (90%) of a p a l e y e l l o w o i l , b.p.  a n a l y s i s (column G, 215°, r a t i o of 7:3.  The d r i e d  170)  200° a t 0.1 mm.  showed the epimers t o now  be i n the  These two components were i s o l a t e d by g . l . c .  e x h i b i t e d g . l . c . r e t e n t i o n t i m e s , i n f r a r e d , n.m.r. and s p e c t r a i d e n t i c a l w i t h the two s t a r t i n g  epimers.  G.l.c.  and  ultraviolet  - 173  P r e p a r a t i o n of Dione  -  163  A s o l u t i o n of 60 mg  of chromium t r i o x i d e i n 1.5 ml o f methylene  c h l o r i d e c o n t a i n i n g 0.09  ml p y r i d i n e was  temperature  f o r 15 min.  To t h i s s o l u t i o n was  162a + 162c  i n 0.5  to  stir  allowed to s t i r  at room  added 30 mg  of o c t a l o n e s  ml methylene c h l o r i d e and the s o l u t i o n  f o r 25 min  r e a c t i o n mixture was  at room temperature.  allowed  At the end of t h i s time  d i l u t e d w i t h 8 ml of e t h e r .  The  the  ether l a y e r  was  washed twice w i t h water and b r i n e and d r i e d over anhydrous magnesium sulfate.  The  c o n c e n t r a t e d r e s i d u e a f f o r d e d 28 mg  (94%) of dione  163,  o  m.p.  108-110.  (column  T h i s compound e x h i b i t e d one peak on g . l . c .  E, 180°, 86); i n f r a r e d  n.m.r., x 9.20, J = 6.5  9.07  (CHC1„), X  5.85,  ( p a i r of d o u b l e t s , 6H,  6.05,  analysis 6.15  i s o p r o p y l methyl  Hz), 8 . 1 2 ( s i n g l e t , 3H, v i n y l m e t h y l ) ; u l t r a v i o l e t ,  u; groups,  X max  247  mp  (e = 13,000). Anal. Calcd. for C ^ H ^ O ^ H,  To a s o l u t i o n of 200 mg 0 ° , was  mixture was was  76.33; H,  9.15.  Found:  C,  76.28;  9.18.  P r e p a r a t i o n of Methanesulfonate  at  C,  Derivative  o f o c t a l o n e 162  added 0.1 ml of m e t h a n e s u l f o n y l then a l l o w e d t o s t i r  added and  i n 5 ml of dry p y r i d i n e ,  chloride.  at room temperature  the s o l u t i o n a l l o w e d t o s t i r  The s o l u t i o n was  164  The  reaction  f o r 3.5  h.  Ice  f o r an a d d i t i o n a l 10  min.  then t h o r o u g h l y e x t r a c t e d w i t h e t h e r .  The  ether e x t r a c t s were washed w i t h water, d i l u t e s u l f u r i c a c i d  combined (until  a c i d i c ) , aqueous sodium b i c a r b o n a t e ( u n t i l n e u t r a l ) , and b r i n e and d r i e d over anhydrous magnesium s u l f a t e .  Removal o f the s o l v e n t i n vacuo  - 174  afforded  250 mg  (85%)  Infrared  (film), X  -  of an o i l y m e t h a n e s u l f o n a t e d e r i v a t i v e 6.0,  7.45,  8.55  164.  y.  max  R e d u c t i o n of O c t a l o n e To  150 ml of l i q u i d ammonia ( d i s t i l l e d from sodium m e t a l )  added 200 450 mg  155  mg  of f i n e l y cut l i t h i u m w i r e .  of o c t a l o n e 155 h.  an a d d i t i o n a l 1.5  h, and  and  A f t e r the l i t h i u m had  dissolved  d i s s o l v e d i n 25 ml of anhydrous e t h e r was  dropwise over 0.5  blue color.  was  The  r e a c t i o n m i x t u r e was  allowed to s t i r  added for  then ammonium c h l o r i d e added t o d i s c h a r g e  A f t e r a l l the ammonia had  e v a p o r a t e d w a t e r was  the  added  t h i s aqueous s o l u t i o n t h o r o u g h l y e x t r a c t e d w i t h e t h e r .  The  combined  e t h e r e x t r a c t s were washed s u c c e s s i v e l y w i t h w a t e r , d i l u t e h y d r o c h l o r i c a c i d , water The  and  e t h e r was  b r i n e and  removed i n vacuo and  t o a f f o r d 350 mg e x h i b i t e d two 215°,  110).  d r i e d o v e r anhydrous magnesium s u l f a t e .  (78%)  of a p a l e y e l l o w o i l , b.p.  components i n a 3:1  n.m.r., T 9.23,  Anal. H,  at 0.6  mm.  This  (column  F,  components were c o l l e c t e d  e x h i b i t e d the f o l l o w i n g s p e c t r a l p r o p e r t i e s :  M a j o r component (decalone 165a):  8.99  125°  r a t i o on g . l . c . a n a l y s i s  A n a l y t i c a l samples of t h e s e two  by g . l . c . and  7 Hz),  the o i l y r e s i d u e vacuum d i s t i l l e d  9.13  (doublet, Calcd.  Infrared  ( p a i r of d o u b l e t s , 3H,  (film), ^  6H,  C,  3.42,  3.51,  5.85  i s o p r o p y l methyl groups, J =  secondary m e t h y l , J = 6.5  for C^H^O:  m a x  80.71; H,  11.61.  Hz). Found:  C,  80.48;  11.31.  M i n o r component (decalone 165b): n.m.r., T 9.13,  9.09  J = 6 Hz),  (doublet,  9.02  Infrared  ( p a i r of d o u b l e t s , 3H,  6H,  (film), ^  m a x  3.45,  5.85  y;  i s o p r o p y l methyl groupsj  secondary m e t h y l , J = 6.5  Hz).  - 175  Mol. Wt.  C a l c d . f o r C^H^O: 208.183-  mass s p e c t r o m e t r y ) :  Reduction  -  Found ( h i g h r e s o l u t i o n  208.182.  of M e t h a n e s u l f o n a t e  D e r i v a t i v e 164  A s o l u t i o n of 280 mg of the m e t h a n e s u l f o n a t e d e r i v a t i v e 164 i n 1.8 ml of a b s o l u t e e t h a n o l was  added dropwise t o a s o l u t i o n of 1.35  of l i t h i u m d i s s o l v e d i n 50 ml of l i q u i d m e t a l ) a t -7 8°. 1.5 h at -33°. ethanol. added.  The  The m i x t u r e was The  r e a c t i o n was  liquid  ammonia was  T h i s aqueous s o l u t i o n was  g  ammonia ( d i s t i l l e d from sodium  stirred  a t -78°  f o r 1 h then f o r  quenched by c a r e f u l a d d i t i o n of then a l l o w e d t o evaporate thoroughly  and w a t e r  extracted w i t h ether.  The combined e t h e r e x t r a c t s were washed w i t h w a t e r and b r i n e and d r i e d over anhydrous magnesium s u l f a t e . and the r e s i d u e vacuum d i s t i l l e d  The s o l v e n t was to a f f o r d 160 mg  of a l c o h o l - c o n t a i n i n g p r o d u c t s , b.p. X max  3.0  u. e  T h i s product was r  ( d i s t i l l e d from p o t a s s i u m  120°  immediately  a t 0.25 J  (98%) of a m i x t u r e mm.  Infrared  added dropwise u n t i l  The orange c o l o r was  standard  the orange c o l o r  then d i s c h a r g e d by a d d i t i o n of i s o p r o p a n o l  and most of the acetone removed on the r o t a r y e v a p o r a t o r . was  (film),  d i s s o l v e d i n 12 ml of acetone  permanganate) and 0.8 ml of a  chromic a c i d s o l u t i o n (76) was persisted.  removed i n vacuo  The  residue  then d i l u t e d w i t h w a t e r and the s o l u t i o n t h o r o u g l y e x t r a c t e d w i t h  ether.  The  combined e t h e r e x t r a c t s were washed w i t h w a t e r and b r i n e and  d r i e d over anhydrous magnesium s u l f a t e .  The  s o l v e n t was  removed i n ,  vacuo and vacuum d i s t i l l a t i o n of the r e s i d u e a f f o r d e d 136 mg the decalones  165a  and 165b,  b.p.  125°  (85%)  at 0.6mm. Decalones 165a  were shown by g . l . c . a n a l y s i s (column F, 215°,  110)  and  t o be i n the  of 165b  ratio  - 176 -  of  70:30. A n a l y t i c a l samples of these two p r o d u c t s were c o l l e c t e d  and shown t o have i d e n t i c a l g . l . c . r e t e n t i o n t i m e s , i n f r a r e d and n.m.r. s p e c t r a w i t h the two p r o d u c t s from t h e B i r c h r e d u c t i o n o f o c t a l o n e s 155a and  155b.  B i r c h R e d u c t i o n o f O c t a l o n e 155a To a s o l u t i o n of 35 mg of l i t h i u m m e t a l i n 100 ml o f l i q u i d ammonia ( f r e s h l y d i s t i l l e d 103 mg  from sodium m e t a l ) was  added o v e r 15 min  (0.5 mmole) of o c t a l o n e 155a i n 5 ml of anhydrous  0.094 ml of anhydrous s t i r f o r 2 h.  ethanol.  The r e a c t i o n was  ether containing  The r e a c t i o n m i x t u r e was a l l o w e d to then quenched by c a r e f u l a d d i t i o n of  excess e t h a n o l , and the ammonia a l l o w e d t o e v a p o r a t e .  The  residual  m a t e r i a l was  diluted with saturated  b r i n e and e x t r a c t e d t h r e e times  with ether.  The e t h e r was removed a t a s p i r a t o r p r e s s u r e and the crude  m a t e r i a l o x i d i z e d by Jones reagent as d e s c r i b e d above. a f f o r d e d 94.6 mg g.l.c.  (91%) of d e c a l o n e 165a.  (column F, 215°,  component.  T h i s procedure  A n a l y s i s of the p r o d u c t by  110) r e v e a l e d the p r e s e n c e o f o n l y one  The s p e c t r a l d a t a of t h i s p r o d u c t (n.m.r., i . r . , 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 o f d e c a l o n e 165a  previously  prepared.  H y d r o g e n a t i o n of O c t a l o n e  155b  A s o l u t i o n of 100 mg of o c t a l o n e 155b g.l.c.  (column F, 180°,  [ i s o l a t e d by p r e p a r a t i v e  110)] d i s s o l v e d i n 10 ml of f r e s h l y  distilled  e t h y l a c e t a t e was hydrogenated a t a t m o s p h e r i c p r e s s u r e and room temperature over 10 mg of 10% p a l l a d i u m on c h a r c o a l .  After  filtration  - 177 ~  and removal o f t h e s o l v e n t t h e r e s i d u e was vacuum d i s t i l l e d t o a f f o r d 96 mg (92%) o f a c o l o r l e s s  o i l , b.p. 125° a t 0.6mm. T h i s m a t e r i a l  was s u b j e c t e d t o t h e p r e v i o u s l y d e s c r i b e d sodium methoxide e p i m e r i z a t i o n c o n d i t i o n s t o e p i m e r i z e t h e a-methyl group.  The r e s u l t i n g p r o d u c t was  shown t o c o n t a i n 98% o f one component by g . l . c . a n a l y s i s (column F, 180°, 100).  An a n a l y t i c a l sample gave i n f r a r e d and n.m.r. s p e c t r a t h a t were  superimposable  w i t h those o f t h e minor isomer o f the B i r c h r e d u c t i o n  of o c t a l o n e 155 o r m e s y l a t e 164.  P r e p a r a t i o n o f T h i o k e t a l 166 The major epimer o f o c t a l o n e 162 was 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, 230°, 110). To a 3.6 g sample o f o c t a l o n e s 162a and  162c was added 3.0 ml o f e t h a n e d i t h i o l . T h i s s o l u t i o n was c o o l e d t o 0° and 1.4 m l o f boron t r i f l u o r i d e e t h e r a t e was added.  The s o l u t i o n was  a l l o w e d t o warm t o room temperature and a l l o w e d t o s t i r f o r 1 h.  The  s o l u t i o n was then d i l u t e d w i t h water and t h o r o u g h l y e x t r a c t e d w i t h chloroform.  The c h l o r o f o r m e x t r a c t s were combined and washed w i t h  water and b r i n e and d r i e d over anhydrous magnesium s u l f a t e . c o n c e n t r a t e d e x t r a c t gave 5.2 g o f crude t h i o k e t a l .  The  T h i s m a t e r i a l was  then f i l t e r e d through a 20 g bed o f Woelm a c t i v i t y I n e u t r a l alumina. The  concentrated  f i l t r a t e c r y s t a l l i z e d on s t a n d i n g .  I t was r e c r y s t a l l i z e d  from e t h e r t o a f f o r d 3.2 g (66%) o f w h i t e r e c t a n g u l a r c r y s t a l s , m.p. 109-110°. properties:  An a n a l y t i c a l sample e x h i b i t e d t h e f o l l o w i n g s p e c t r a l infrared  (nujol), ^  m a x  3.0, 6.1 u; n.m.r., x 9.21, 9.02  ( p a i r o f d o u b l e t s , 6H, i s o p r o p y l m e t h y l g r o u p s , 3 = 1 H z ) , 8.57 IH, exchanges on D„0 a d d i t i o n , C-OH), 8.07 ( s i n g l e t , 3H, v i n y l  (singlet, methyl),  - 178 -  6.67  ( s i n g l e t , 4H, t h i o k e t a l p r o t o n s ) ,  5.86 ( u n r e s o l v e d m u l t i p l e t , I H ,  CHOH ( e q u a t o r i a l ) ) . Mol.  Wt. C a l c d . f o r C ^ H ^ O S ^  mass s p e c t r o m e t r y ) :  Preparation  298.142.  Found ( h i g h  resolution  298.144.  o f A l c o h o l 167  To a s o l u t i o n o f 700 mg (1.44 mmoles) o f t h i o k e t a l 166 i n 100 m l of a b s o l u t e e t h a n o l was added 10 g of commercial Raney n i c k e l . s o l u t i o n was r e f l u x e d  f o r 5 h.  The  The s o l u t i o n was then c o o l e d and t h e  Raney n i c k e l removed by s u c t i o n f i l t r a t i o n t h r o u g h a bed o f C e l i t e . The f i l t r a t e was c o n c e n t r a t e d and t h e r e s i d u a l o i l vacuum d i s t i l l e d to a f f o r d 350 mg (77%) o f a v i s c o u s c o l o r l e s s a l c o h o l 167, b.p. 120° at 0.25 mm.  On g . l . c . a n a l y s i s  (column F, 215°, 110) t h i s p r o d u c t  e x h i b i t e d one major peak a l o n g w i t h t r a c e amounts o f u n i d e n t i f i e d components.  An a n a l y t i c a l sample o f t h e major component was c o l l e c t e d  by p r e p a r a t i v e (film), X  g.l.c.  (column G, 215°, 110) and e x h i b i t e d  infrared  3.0, 6.0 u; n.m.r., x 9.23, 9.09 ( p a i r o f d o u b l e t s , 6H,  IT13.X  i s o p r o p y l m e t h y l groups, J = 6.5 H z ) , 8.40 ( s i n g l e t , 3H, v i n y l m e t h y l ) , 7.52  ( s i n g l e t , I H , exchanges on D 0 a d d i t i o n , h y d r o x y l p r o t o n ) , 6.36,  5.85  ( u n r e s o l v e d m u l t i p l e t s , t o t a l l i n g I H , CHOH).  2  Mol.  Wt. C a l c d . f o r C ^ H ^ O :  mass s p e c t r o m e t r y ) :  Preparation  208.183.  Found ( h i g h  resolution  208.183.  o f O c t a l o n e 168  To an i c e - c o l d s o l u t i o n o f 720 mg o f chromium t r i o x i d e d i s s o l v e d i n 18 ml o f anhydrous p y r i d i n e was added 350 mg o f a l c o h o l 167 i n 9 ml  - 179 -  of anhydrous p y r i d i n e . t u r e f o r 40 h.  The s o l u t i o n was a l l o w e d t o s t i r a t room tempera-  The r e a c t i o n m i x t u r e was then poured i n t o  anhydrous e t h e r .  C e l i t e was then added and t h e m i x t u r e  stirred  filtered.  The  f i l t r a t e was t h o r o u g h l y washed w i t h w a t e r and b r i n e and d r i e d o v e r anhydrous magnesium s u l f a t e .  A f t e r removal o f t h e s o l v e n t t h e o i l y  r e s i d u e was d i s t i l l e d under vacuum t o y i e l d 307 mg (89%) o f a c o l o r l e s s o i l , b.p. 130° a t 0.35 mm.  T h i s product was shown to be homogeneous  by g . l . c . (column F, 180°, 8 5 ) . An a n a l y t i c a l sample e x h i b i t e d i n f r a r e d (film), \ 5.85 u; n.m.r., T 9.21, 9.05 ( p a i r of d o u b l e t s , 6H, max r  i s o p r o p y l m e t h y l groups, J = 6.5 H z ) , 8.36 ( s i n g l e t , 3H, v i n y l Mol. Wt. C a l c d . f o r C ^ H ^ O : mass s p e c t r o m e t r y ) :  206.167.  methyl).  Found ( h i g h r e s o l u t i o n  206.168.  P r e p a r a t i o n o f A l c o h o l 169 A s o l u t i o n o f 230 mg (1.06 mmoles) o f o c t a l o n e 168 d i s s o l v e d i n 30 ml o f anhydrous e t h e r was c o o l e d t o 0°.  To t h i s s o l u t i o n was added,  d r o p w i s e , 2 ml o f 2.16 M m e t h y l l i t h i u m (4.32 mmoles).  A f t e r the  a d d i t i o n was complete t h e s o l u t i o n was a l l o w e d t o s t i r f o r 2 h a t room t e m p e r a t u r e .  I t was then poured onto a m i x t u r e  The e t h e r l a y e r was s e p a r a t e d  and washed w i t h w a t e r and b r i n e and  d r i e d o v e r anhydrous magnesium s u l f a t e . a s p i r a t o r pressure  of i c e and w a t e r .  The s o l v e n t was removed a t  and t h e o i l y r e s i d u e vacuum d i s t i l l e d t o a f f o r d  224 mg (91%) o f a v i s c o u s o i l , b.p. 130° a t 0.25 mm.  T h i s o i l was  shown t o c o n t a i n one major component a l o n g w i t h t r a c e amounts o f u n i d e n t i f i e d m a t e r i a l on g . l . c . a n a l y s i s (column G, 200°, 110). major component was g . l . c . i s o l a t e d and shown t o be a w h i t e  The  crystalline  - 180 -  s u b s t a n c e , m.p.  79-80°.  Infrared (nuiol), A 3.0, 6.1 y; n.m.r., x ' max ' ' J  9.21, 9.07 ( p a i r of d o u b l e t s , 6H, i s o p r o p y l m e t h y l g r o u p s , J = 6.5 H z ) , 8.81 ( s i n g l e t , 3H, t e r t i a r y m e t h y l g r o u p ) , 8.37 ( s i n g l e t , 3H, v i n y l methyl). Mol. Wt. C a l c d . f o r C mass s p e c t r o m e t r y ) :  H^O:  222.198.  Found ( h i g h r e s o l u t i o n  222.198.  P r e p a r a t i o n o f Cadinene D i h y d r o c h l o r i d e 4J_ A s o l u t i o n o f 100 mg o f c r y s t a l l i n e g . l . c . i s o l a t e d a l c o h o l 169 i n 10 ml of anhydrous e t h e r was c o o l e d t o 0° and d r y hydrogen c h l o r i d e gas passed i n . At t h e end o f 15 m i n , t h e gas f l o w vas stopped and t h e s o l u t i o n s t i r r e d f o r an a d d i t i o n a l hour.  The e t h e r was t h e n removed  under vacuum and t h e r e s i d u e c r y s t a l l i z e d t o a f f o r d 100 mg (80%) o f compound 41.  An a n a l y t i c a l sample was r e c r y s t a l l i z e d from n-hexane-  methanol t o a f f o r d w h i t e c r y s t a l s , m.p.  104.5-106°.  This  sample  showed no d e p r e s s i o n of m e l t i n g p o i n t on a d m i x t u r e w i t h an a u t h e n t i c sample of cadinene d i h y d r o c h l o r i d e and i t s i n f r a r e d spectrum was s u p e r i m p o s a b l e w i t h t h a t o f t h e a u t h e n t i c sample.  Infrared (nujol),  X 3.45, 6.95, 8.75, 11.75 y. max Anal. Calcd. f o r C  1 5  H  2 6  C1 : 2  C, 65.01; H, 9.39.  Found:  C, 64.75;  H, 9.52.  P r e p a r a t i o n o f O c t a l o n e 172 T h i s compound was p r e p a r e d by t h e p r o c e d u r e o f M a r s h a l l and F a n t a (82).  - 181 -  A s o l u t i o n of 56 g (0.5 mole) of 2-methylcyclohexanone of  and 3 ml  3 N e t h a n o l i c sodium e t h o x i d e were p l a c e d under n i t r o g e n i n a  f l a m e - d r i e d f l a s k equipped w i t h a dropping f u n n e l and mechanical stirrer.  The r e a c t i o n v e s s e l and c o n t e n t s were then c o o l e d to -10°  by a t h e r m o s t a t i c a l l y c o n t r o l l e d c o n s t a n t temperature  bath.  r e a c t i o n mixture was added 35 g (0.5 mole) o f methyl v i n y l  To the ketone  over a 6 h p e r i o d .  The r e a c t i o n m i x t u r e was then allowed t o s t i r f o r  an a d d i t i o n a l 6 h.  The i n t e r m e d i a t e k e t o l 174 was then dehydrated by  the a d d i t i o n o f 400 ml of 15% potassium h y d r o x i d e and the r e s u l t i n g o c t a l o n e 172 removed from the r e a c t i o n mixture by continuous distillation.  The steam d i s t i l l a t e was s a t u r a t e d w i t h sodium  and e x t r a c t e d w i t h e t h e r .  The e t h e r e x t r a c t s were d r i e d  anhydrous magnesium s u l f a t e and then c o n c e n t r a t e d . distilled b.p.  steam chloride  over  The r e s i d u e was  under reduced p r e s s u r e t o a f f o r d 39.3 g (48%) o f o c t a l o n e 172,  73° a t 0.4 mm;  l i t . (82) b.p. 82-83° a t 0.7 mm.  An a n a l y t i c a l 20  sample c o l l e c t e d by g . l . c . lit.  (82) n  (film), X  25 D n  1.5230.  (column H, 200°, 8 5 ) , e x h i b i t e d n  Ultraviolet, X  max 5.96, 6.17 u; n.m.r., x 8.74  239 mu  Q  1.5249;  (e = 14,400); i n f r a r e d  ( s i n g l e t , 3H, t e r t i a r y  methyl),  TT13.X  4.29  ( s i n g l e t , IH, v i n y l p r o t o n ) .  P r e p a r a t i o n of Dienone 175  To a s o l u t i o n of 20.4 g (90 mmoles) o f 2 , 3 - d i c h l o r o - 5 , 6 - d i c y a n o benzoquinone and 1 g of b e n z o i c a c i d i n 150 ml dry benzene was added 10 g (61 mmoles) of o c t a l o n e 172.  T h i s s o l u t i o n was r e f l u x e d under  - 182 -  n i t r o g e n f o r a 48 h p e r i o d .  To t h e c o o l e d r e a c t i o n m i x t u r e was added  w i t h s t i r r i n g 150 ml o f methylene  c h l o r i d e and C e l i t e .  After  filtra-  t i o n , t h e s o l u t i o n was passed t h r o u g h a 100 g bed o f Woelm a c t i v i t y I I I n e u t r a l alumina.  An a d d i t i o n a l 400 m l o f methylene  c h l o r i d e was  passed through t h e a l u m i n a and t h e combined e l u t a n t s f l a s k e v a p o r a t e d and vacuum d i s t i l l e d t o y i e l d 7.1 g (72%) o f a y e l l o w o i l , b.p. 110115° a t 0.5 mm; l i t .  (84) b.p. 129° a t 4 mm.  The d i s t i l l e d p r o d u c t was  s u b j e c t e d t o g . l . c . a n a l y s i s (column H, 200°, 85) and showed 88% dienone and 12% t r i e n o n e .  An a n a l y t i c a l sample o f dienone was  c o l l e c t e d by p r e p a r a t i v e g . l . c . 21 n„ 1.5470; i n f r a r e d D  (column C, 200°, 110) w h i c h e x h i b i t e d  (film), X 6.0, 6.15, 6.2 u; n.m.r., T 8.74 ' max ' ' ' '  ( s i n g l e t , 3H, t e r t i a r y m e t h y l ) , 3.94 ( s i n g l e t , I H , 3.84 ( p a i r o f d o u b l e t s , 2H,  and  1  p r o t o n ) , 3.31,  protons r e s p e c t i v e l y , J = 9 H z ) ;  ultraviolet, X 240 my (e = 10,500). max  H y d r o g e n a t i o n o f Dienones 175 + 176 A s u s p e n s i o n o f 300 mg o f 5% p a l l a d i u m on c h a r c o a l i n 200 ml o f 0.005 N e t h a n o l i c p o t a s s i u m h y d r o x i d e was p l a c e d i n an a t m o s p h e r i c p r e s s u r e h y d r o g e n a t i o n apparatus a t room temperature and a l l o w e d t o e q u i l i b r a t e f o r 1.5 h.  A s o l u t i o n o f dienones 175 + 176 was then  i n t r o d u c e d by s y r i n g e .  A f t e r 45 m i n t h e r e q u i r e d amount o f hydrogen  had been absorbed.  The r e a c t i o n m i x t u r e was f i l t e r e d t h r o u g h a bed o f  C e l i t e and t h e f i l t r a t e c o n c e n t r a t e d  i n vacuo.  The r e s i d u e was  chromatogrammed on 1 k g o f Woelm a c t i v i t y I I I n e u t r a l a l u m i n a . fractions  e l u t e d w i t h 90%  benzene-petroleum  14.3 g (70%) o f t h e d e s i r e d dienone 175.  The  e t h e r (30-60°) a f f o r d e d  G . l . c . a n a l y s i s (column C,  - 183 -  200°, 110) r e v e a l e d t h e p r e s e n c e o f up t o 3% i m p u r i t i e s .  P r e p a r a t i o n o f O c t a l o n e 173 T h i s compound was prepared  by t h e p r o c e d u r e o f M a r s h a l l and F a n t a  (82). To a f l a m e - d r i e d f l a s k under n i t r o g e n was added 56 g o f 2-methylcyclohexanone and 3 ml o f 3 N e t h a n o l i c sodium e t h o x i d e . y e l l o w s o l u t i o n was c o o l e d t o -10°. e t h y l v i n y l ketone was added.  The r e s u l t i n g  Over a p e r i o d o f 6 h , 42 g o f  The v i s c o u s r e a c t i o n m i x t u r e was a l l o w e d  to s t i r f o r an a d d i t i o n a l 6 h.  A t t h e end o f t h i s p e r i o d , 400 ml o f  15% p o t a s s i u m h y d r o x i d e was added and t h e s o l u t i o n s u b j e c t e d t o cont i n u o u s steam d i s t i l l a t i o n . were t h o r o u g h l y  The 4 1. o f steam d i s t i l l a t e  extracted with ether.  collected,  The combined e t h e r e a l e x t r a c t s  were washed w i t h b r i n e and d r i e d o v e r anhydrous magnesium s u l f a t e . The  e t h e r was removed a t a s p i r a t o r p r e s s u r e and t h e r e s i d u e  under vacuum t o a f f o r d two d i s t i n c t f r a c t i o n s .  The f i r s t  c o n t a i n e d 11 g o f s t a r t i n g m a t e r i a l , 2 - m e t h y l c y c l o h e x a n o n e ,  distilled  fraction b.p. 36-42°  at 2.5 mm, w h i l e t h e second f r a c t i o n c o n t a i n e d 53 g (60%) o f t h e d e s i r e d o c t a l o n e 173, b.p. 96-100° a t 0.6 mm; l i t . (57) b.p. 74-78° a t 0.4 mm.  An a n a l y t i c a l sample was 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 H, 200°, 85) and e x h i b i t e d n  22 1.5439, i n f r a r e d D  (film), X  6.0, 6.2 y; n.m.r., x 8.77 ( s i n g l e t , 3H, t e r t i a r y m e t h y l ) , ( s i n g l e t , 3H, v i n y l m e t h y l ) ; u l t r a v i o l e t , X  max  8.22  246 my (e = 15,500).  P r e p a r a t i o n of Dienone 177 T h i s compound was p r e p a r e d Kropp ( 5 7 ) .  by a p r o c e d u r e s i m i l a r t o t h a t used by  - 184 -  To a s o l u t i o n of 7.7 benzoquinone and was  g  (33 mmoles) of  2,3-dichloro-5,6-dicyano-  25 ml g l a c i a l a c e t i c a c i d i n 250 ml anhydrous benzene  added 4 g (22 mmoles) of o c t a l o n e 173.  to r e f l u x f o r 60 h under n i t r o g e n .  T h i s s o l u t i o n was  Then the r e a c t i o n mixture  c o o l e d , f i l t e r e d , c o n c e n t r a t e d and e t h e r added. was  washed s u c c e s s i v e l y w i t h water, 10%  water and The  s a t u r a t e d b r i n e and  c o n c e n t r a t e d e x t r a c t was  allowed  The  was  ethereal layer  sodium b i c a r b o n a t e  solution,  d r i e d over anhydrous magnesium s u l f a t e . distilled  at 154°  a t 0.2  mm  to a f f o r d  25 6.5  g (84%)  of a p a l e y e l l o w o i l ;  n^  1.5234.  The  product was  than 95% pure by g . l . c . a n a l y s i s (column B,180°, 80). exhibited ultraviolet, A ' max 6.0,  6.15,  6.2  240 mu  (e = 10,500); i n f r a r e d  u; n.m.r., x 8.78  (singlet,  3.80,  protons  Hz).  r e s p e c t i v e l y , J = 10  3.31  P r e p a r a t i o n of T r i - n - b u t y l p h o s p h i n e procedure  A suspension 10.15  of 13.15  3H,  t e r t i a r y methyl),  (AB q u a r t e t , 2H,  C  3  and  8.12 C^  Copper I I o d i d e  g of cuprous i o d i d e , 130 g of potassium  t o g e t h e r u n t i l the i n i t i a l l y  and  100 ml of water were shaken  formed greasy p r e c i p i t a t e became  p r e c i p i t a t e was  filtered  i s o p r o p a n o l - e t h a n o l to a f f o r d 17.6 complex, m.p.  (film), A  employed i s t h a t of Kaufman et a l . (90).  g of t r i - n - b u t y l p h o s p h i n e  c r y s t a l l i n e . The  dienone  max  ( s i n g l e t , 3H, v i n y l m e t h y l ) ,  The  The  greater  74.5-75.5°; l i t .  g  and  (89%)  (90) m.p.  recrystallized  of white  75°.  from  crystalline  iodide,  - 185 -  P r e p a r a t i o n o f O c t a l o n e 188 To an i c e - c o l d s l u r r y o f 6.84 g o f cuprous i o d i d e i n 150 ml of anhydrous e t h e r was added 34.3 ml o f 2.1 M m e t h y l l i t h i u m i n e t h e r solution.  To the r e s u l t i n g c l e a r s o l u t i o n was added, dropwise over 1 h ,  1 g (6.2 mmoles) o f dienone 175. was immediately solution.  The r e s u l t i n g  thick yellow  solution  quenched by a d d i t i o n t o a s a t u r a t e d ammonium c h l o r i d e  The ammonium c h l o r i d e s o l u t i o n was t h o r o u g h l y e x t r a c t e d  with ether.  The e t h e r e x t r a c t was washed w i t h water, d i l u t e ammonium  h y d r o x i d e , water and b r i n e and d r i e d over anhydrous magnesium s u l f a t e . The  e t h e r e x t r a c t was c o n c e n t r a t e d and d i s t i l l e d  The  d i s t i l l a t e was chromatogrammed on 40 g o f MN s i l i c a g e l and the  f r a c t i o n s e l u t e d w i t h 15% e t h e r - p e t r o l e u m 900 mg (82%) o f a c l e a r c o l o r l e s s o i l . on a n a l y s i s by g . l . c . infrared secondary 4.30  ether  (b.p.  124° a t 0.3 mm).  (30-60°) a f f o r d e d  T h i s o i l showed a s i n g l e peak  (column E, 190°, 8 6 ) . The product e x h i b i t e d  (film), A 6.0, 6.15 u; n.m.r., x 9.02 ( d o u b l e t , 3H, max methyl,  J = 7 Hz), 8.74 ( s i n g l e t , 3H, t e r t i a r y  ( s i n g l e t , IH, v i n y l H); u l t r a v i o l e t ,  A 239 my max  methyl),  (e = 14,000).  P r e p a r a t i o n o f Octalone 191 The  c r o s s - c o n j u g a t e a d d i t i o n t o dienone 177 by l i t h i u m  dimethyl-  c u p r a t e was c a r r i e d out by a procedure  i d e n t i c a l t o the above.  1 g of dienone 177 a f t e r d i s t i l l a t i o n ,  b.p. 125° a t 0.3 mm, was  o b t a i n e d l;.g (92%) o f o c t a l o n e 191. homogeneous by g . l . c .  From  T h i s product was shown t o be  (column E, 200°, 8 6 ) . I n f r a r e d (film),'-A TTlciX  6.0,  6.2 u; n.m.r., x 9.04 ( d o u b l e t , 3H, secondary  methyl,  J = 6.5 H z ) ,  - 186  8.74  -  ( s i n g l e t , 3H, t e r t i a r y m e t h y l ) , 8.25  J = 1 Hz); u l t r a v i o l e t , X max T h i s compound was  249 my  ( d o u b l e t , 3H, v i n y l  (e = 13,800).  f u r t h e r c h a r a c t e r i z e d as a r e d 2 , 4 - d i n i t r o p h e n y l -  hydrazone, r e c r y s t a l l i z e d from e t h a n o l , m.p. Anal. Calcd. f o r C ^ H ^ N ^ : C, 60.98; H, 6.42;  N,  methyl,  174-175°.  C, 61.28; H, 6.50;  N, 15.04.  Found:  15.11.  P r e p a r a t i o n of O c t a l o n e  194  A s o l u t i o n of 15 g of t r i - n - b u t y l p h o s p h i n e copper (I) i o d i d e i n ' 150 ml of anhydrous e t h e r was acetone bath. of 3.2  by an e x t e r n a l dry i c e -  To t h i s c o l o r l e s s s o l u t i o n was  M v i n y l l i t h i u m i n tetrahydrofuran.  green s o l u t i o n was  added by s y r i n g e 22.8  a l l o w e d to s t i r  r e a c t i o n m i x t u r e was  The  175  resulting thick yellow solution  f o r an a d d i t i o n a l 4 h.  At the end of t h i s time the  a l l o w e d t o warm t o room temperature and  quenched by p o u r i n g onto 250 ml of 10% h y d r o c h l o r i c a c i d . s o l u t i o n was  thoroughly extracted w i t h ether.  The  The  was aqueous  combined e t h e r  e x t r a c t s were washed w i t h w a t e r , d i l u t e ammonium h y d r o x i d e , water b r i n e and d r i e d o v e r anhydrous magnesium s u l f a t e . s o l v e n t , the p r o d u c t was  roughly  ml  To the r e s u l t i n g p a l e  added o v e r 1 h, 1 g (6.1 mmoles) of dienone  i n 50 ml of anhydrous e t h e r . was  c o o l e d t o -78°  separated  and  A f t e r removal o f  the  from the h i g h b o i l i n g  m a t e r i a l by c o l l e c t i n g a l l m a t e r i a l w i t h a b o i l i n g p o i n t l e s s than 130°  a t 0.2  s i l i c a gel.  mm. The  The  distillate  was  t h e n chromatogrammed on 100 g of  f r a c t i o n s e l u t e d w i t h 10% e t h e r - p e t r o l e u m  (30-60°) a f f o r d e d 870 mg  (73%) of o c t a l o n e 194.  MN  ether  On a n a l y s i s by g . l . c .  t h i s m a t e r i a l e x h i b i t e d o n l y one peak (column E, 195°,  100).  All  - 187  -  t r a c e s of s o l v e n t were removed on the vacuum pump a f f o r d an a n a l y t i c a l sample.  0.1 mm)  Infrared (film), X  6.0,  to  6.2,  10.9  u;  max n.m.r., T 8.72  ( s i n g l e t , 3H, t e r t i a r y m e t h y l ) , 3.89-5.13 ( u n r e s o l v e d  m u l t i p l e t , 3H, v i n y l p r o t o n s ) , 4.25  ( s i n g l e t , IH, v i n y l p r o t o n ) .  t o i t s i n s t a b i l i t y t h i s compound was immediately  Due  not c h a r a c t e r i z e d f u r t h e r but  hydrogenated.  Hydrogenation of Octalone The h y d r o g e n a t i o n  194  of o c t a l o n e 194 was  c a r r i e d out i n benzene  (50 ml) a t room temperature and atmospheric phenylphosphine)chlororhodium  (120 mg)  pressure using  as c a t a l y s t .  tris(tri-  At the end  of  the hydrogen uptake the r e a c t i o n m i x t u r e was  f i l t e r e d through  column o f Woelm a c t i v i t y I I I n e u t r a l a l u m i n a  (20 g) and e l u t e d w i t h  an a d d i t i o n a l 100 ml of benzene. o c t a l o n e 194 was less o i l .  From 708 mg  by g . l . c .  showed t h a t i t c o n s i s t e d of 10% decalone The m i x t u r e was fractions 57 mg  189.  color-  (column E, 180°,  193 and 90% o c t a l o n e  e l u t e d w i t h 8% e t h e r - p e t r o l e u m The  100) 189. The  e t h e r (30-60°) c o n t a i n e d  f r a c t i o n s e l u t e d w i t h 15%  e t h e r (30-60°) c o n t a i n e d 413 mg  ether-  (58%) of the d e s i r e d o c t a l o n e  An a n a l y t i c a l sample o f o c t a l o n e 189 e x h i b i t e d the f o l l o w i n g  spectral properties:  infrared  (film), ^  ( t r i p l e t , 3H, CH CH_ , J = 4 H z ) , 8.73 2  4.21  of a c l e a r  chromatogrammed on a 50 g MN s i l i c a g e l column.  of c l s - d e c a l o n e 193.  petroleum  (3.73 mmoles) of  o b t a i n e d a f t e r d i s t i l l a t i o n 650 mg  A n a l y s i s of t h i s p r o d u c t  a  3  m a x  6.0,  6.2  u; n.m.r., x  ( s i n g l e t , 3H, t e r t i a r y  (broad s i n g l e t , IH, v i n y l H ) ; u l t r a v i o l e t ,  X  239 mu  9.07  methyl), (e = 11,000).  TT13.X  This compound was f u r t h e r characterized as a red 2,4-dinitrophenyl-  - 188  -  hydrazone d e r i v a t i v e , r e c r y s t a l l i z e d from e t h a n o l , m.p. Anal. Calcd. f o r C ^ H ^ N ^ : C, 61.07; H, 6.42;  N,  C, 61.28; H, 6.50;  118-120°. N, 15.04.  Found:  15.05.  P r e p a r a t i o n of Octalone  190  A s o l u t i o n of 15 g (38 mmoles) of t r i - n - b u t y l p h o s p h i n e copper ( I ) i o d i d e , 0.5 was  g anhydrous l i t h i u m bromide i n 150 ml of anhydrous e t h e r  c o o l e d to -78°  w i t h an e x t e r n a l dry i c e - a c e t o n e b a t h .  (73 mmoles) of 1.86  M i s o p r o p y l l i t h i u m i n n-pentane was  f i r s t a dark r e d and then a p a l e aqua s o l u t i o n . added 1 g (6.1 mmoles) of dienone 175 over a 0.75  h period.  The  s l o w l y warm t o room temperature.  The  r e a c t i o n was  allowed  to  then allowed  T h i s r e s u l t e d i n the f o r m a t i o n The  to of  reaction  f u n n e l and  slowly  added to a r a p i d l y s t i r r e d s o l u t i o n of 10% h y d r o c h l o r i c a c i d . separated  was  i n 50 ml of anhydrous e t h e r  t r a n s f e r r e d under n i t r o g e n t o a dropping  aqueous l a y e r was  ml  forming  To t h i s complex  a copper m i r r o r on the w a l l s of the r e a c t i o n v e s s e l . m i x t u r e was  added,  dark r e d r e a c t i o n m i x t u r e was  s t i r f o r an a d d i t i o n a l 5 h p e r i o d .  Then 39  and t w i c e e x t r a c t e d w i t h e t h e r .  The The  combined e t h e r e a l e x t r a c t s were washed s u c c e s s i v e l y w i t h w a t e r , d i l u t e ammonium h y d r o x i d e , water and s a t u r a t e d b r i n e and d r i e d over anhydrous magnesium s u l f a t e . distilled The  A f t e r removal of the s o l v e n t , the r e s i d u e  and the d i s t i l l a t e  chromatogrammed on 25 g o f MN  f r a c t i o n s e l u t e d w i t h 20% e t h e r - p e t r o l e u m  395 mg  (95%) of o c t a l o n e 190.  by g . l . c . (column E, 180°,  86).  n.m.r., T 9.2,  9.05  Infrared (film), A  ( p a i r o f d o u b l e t s , 6H,  s i l i c a gel.  e t h e r (30-60°) a f f o r d e d  T h i s sample e x h i b i t e d one  J  was  component  6.0,  6.15  y;  max i s o p r o p y l methyl groups,  - 189  J = 6.5  H z ) , 8.74  -  ( s i n g l e t , 3H, t e r t i a r y m e t h y l ) , 4.22  IH, v i n y l H ) ; u l t r a v i o l e t , X  240 my  c h a r a c t e r i z e d as i t s  d e r i v a t i v e , r e c r y s t a l l i z e d from e t h a n o l , m.p. Anal. Calcd. f o r C, 62.01; H, 6.80;  c  o 26 4°4 H  2  :  C  '  6 2  '  1 6  ' » H  2,4-dinitrophenylhydrazone 153-155°. 6 l 7 8 ;  N  >  -  1 4  5 0  -  Found:  N, 14.40.  P r e p a r a t i o n of O c t a l o n e The  N  singlet,  (e = 9,370). '  max T h i s compound was  (broad  192  cross-conjugate  d i i s o p r o p y l c u p r a t e was  a d d i t i o n to dienone 177 by  lithium  c a r r i e d out by a p r o c e d u r e i d e n t i c a l to t h a t  d e s c r i b e d above. From 2 g of dienone 177,  a f t e r chromatography on 140 g of  s i l i c a g e l , the f r a c t i o n s e l u t e d w i t h 15% e t h e r - p e t r o l e u m (30-60°) a f f o r d e d 2.38  g (95%) of o c t a l o n e 192.  were removed on the vacuum pump (0.1 mm)  (column E, 190°,  ether  A l l t r a c e s of s o l v e n t  t o a f f o r d an a n a l y t i c a l sample  w h i c h e x h i b i t e d the f o l l o w i n g s p e c t r a l p r o p e r t i e s : g.l.c.  MN  86); i n f r a r e d ( f i l m ) , X  one 6.0,  component on 6.2  y; n.m.r.,  THcSX  x 9.23, 8.73  9.04  ( p a i r of d o u b l e t s , 6H, i s o p r o p y l m e t h y l groups, J = 7 H z ) ,  ( s i n g l e t , 3H, t e r t i a r y m e t h y l ) , 8.22  ultraviolet X  249 my  methyl);  (G = 14,000). '  max T h i s compound was  ( s i n g l e t , 3H, v i n y l  f u r t h e r c h a r a c t e r i z e d as a r e d  hydrazone d e r i v a t i v e , r e c r y s t a l l i z e d from e t h a n o l , m.p. A n a l . C a l c d . f o r C H. N.0.: 21 28 4' 4 C, 63.13; H, 6.90; N, 13.76. ol  o  C, 62.98; H, 7.05;  2,4-dinitrophenyl134-135°. N, 13.99.  Found:  - 190  P r e p a r a t i o n of Decalone  -  200  To 800 ml o f l i q u i d ammonia, w h i c h had been d i s t i l l e d sodium m e t a l , was  added 4 g of l i t h i u m .  from  A f t e r t h e l i t h i u m had d i s s o l v e d  10 g (61 mmoles) of o c t a l o n e 172 i n 80 ml of anhydrous e t h e r added dropwise.  A f t e r 1 h, 11 ml o f anhydrous e t h a n o l was  the r e a c t i o n m i x t u r e was  was  added and  a l l o w e d t o s t i r f o r an a d d i t i o n a l 1.5  h.  The  r e a c t i o n was  quenched w i t h excess e t h a n o l and the l i q u i d ammonia  was  a l l o w e d to e v a p o r a t e .  was  added and the r e s u l t i n g s o l u t i o n t h o r o u g h l y e x t r a c t e d w i t h e t h e r .  The  combined e t h e r e x t r a c t s were washed w i t h w a t e r and b r i n e and  A f t e r removal o f most of the e t h a n o l , b r i n e  d r i e d over anhydrous magnesium s u l f a t e .  The  e t h e r was  removed a t  a s p i r a t o r p r e s s u r e and the r e s u l t i n g m a t e r i a l c r y s t a l l i z e d t o a f f o r d 7.7  g of d e c a l o l .  d e s i r e d decalone  The  crude d e c a l o l was  added dropwise  g (46 mmoles) o f d e c a l o l i n 177 ml acetone a s t a n d a r d s o l u t i o n o f chromic  the orange c o l o r p e r s i s t e d .  I s o p r o p a n o l was  excess o x i d i z i n g agent and the s o l v e n t was pressure.  Water was  w i t h ether.  The  o x i d i z e d t o the  200.  To a s o l u t i o n of 7.7 a t 0° was  immediately  t h e n added  removed under  added to t h e r e s i d u e and i t was  acid  (76)  until  t o d e s t r o y the reduced  thoroughly e x t r a c t e d  combined e t h e r e x t r a c t s were washed w i t h water  and  b r i n e and d r i e d over anhydrous magnesium s u l f a t e and c o n c e n t r a t e d i n vacuo.  Vacuum d i s t i l l a t i o n o f the o i l y r e s i d u e a f f o r d e d 6.5  of the d e s i r e d decalone  200, b.p.  80-82° a t 0.8 mm;  lit.  g  (88%)  (93) b.p.  20 a t 0.1 mm; X  max  5.85  n  D  1.4943.  The  u; n.m.r., T 8.95  decalone  200 e x h i b i t e d i n f r a r e d  ( s i n g l e t , 3H, t e r t i a r y m e t h y l ) ,  (film),  69°  - 191  Bromination  of Decalone  -  200  To a s o l u t i o n of 8.7  g (0.052 mole) of t r a n s - f u s e d d e c a l o n e  d i s s o l v e d i n 100 ml of g l a c i a l a c e t i c a c i d was 1 h, 8.4  added, d r o p w i s e over  g (0.052 mole) of bromine i n 100 ml g l a c i a l a c e t i c a c i d .  A f t e r the a d d i t i o n was an a d d i t i o n a l 15 min  complete, the r e a c t i o n was  and  then i c e was  water and g l a c i a l a c e t i c a c i d was The  200  r e s i d u e was  added.  The major p a r t of  the  t h e n removed a t a s p i r a t o r p r e s s u r e .  d i s s o l v e d i n e t h e r and washed t w i c e w i t h w a t e r , t w i c e  w i t h 5% sodium b i c a r b o n a t e  s o l u t i o n , once w i t h w a t e r and b r i n e  d r i e d o v e r anhydrous magnesium s u l f a t e . a f f o r d 13.1  allowed to s t i r f o r  The  s o l v e n t was  g of a c r y s t a l l i n e bromoketone 201.  r e c r y s t a l l i z e d from p e t r o l e u m e t h e r  removed to  T h i s m a t e r i a l was  (65-110°) t o a f f o r d 7.7  of a w h i t e c r y s t a l l i n e bromoketone, m.p.  and  g  100-102°; l i t . (93)  (60%) m.p.,  101-102°. The bromoketone 201 e x h i b i t e d i n f r a r e d x 8.86 IH,  ( s i n g l e t , 3H,  -HcHBr, J . —  v  =  12  t e r t i a r y CH ), 3  Hz,  =  AX  6  5.32  (KBr), X  max  5.78  (X p o r t i o n of an ABX  A s o l u t i o n of 7.7  Hz).  201  g of bromoketone 201 and  3 g o f anhydrous  l i t h i u m bromide d i s s o l v e d i n 75 ml of hexamethylphosphoramide  was  system,  BX  D e h y d r o h a l o g e n a t i o n of Bromoketone  heated at 120°  u; n.m.r.,  f o r 3 h under n i t r o g e n .  d i l u t e d w i t h w a t e r and  thoroughly  The  was  cooled r e a c t i o n mixture  extracted with ether.  The  combined e t h e r e a l e x t r a c t s were washed t h r i c e w i t h w a t e r , once w i t h b r i n e and d r i e d over anhydrous magnesium s u l f a t e . e t h e r the r e s i d u e was  A f t e r removal o f  chromatogrammed on 100 g of MN  s i l i c a gel.  the  The  - 192  -  f r a c t i o n s e l u t e d w i t h 10%  ether-benzene a f f o r d e d  197  (76%)  one  The  compound was  which e x h i b i t e d  t r a c e s of s o l v e n t the  following  placed  3.9  peak o n l y on g . l . c .  octalone  (column E,  on the vacuum pump (a, 0.1  mm)  to a f f o r d an a n a l y t i c a l sample.  s p e c t r a l data:  g of  to remove  This  infrared (film), X  180°,  86).  any  sample gave  5.95,  6.15  u: n.m.r.,  max T 8.96  ( s i n g l e t , 3H,  ft ft CCH=CH and —  t e r t i a r y m e t h y l ) , 4.24,  CCH=CH r e s p e c t i v e l y , J = 9.8  3.33  Hz);  ( p a i r of d o u b l e t s ,  ultraviolet, X  20  (e = 9,200); n^  173  To a s o l u t i o n of 4 g of l i t h i u m m e t a l d i s s o l v e d l i q u i d ammonia ( d i s t i l l e d from sodium m e t a l ) was h, 10 g  (0.056 mole) of o c t a l o n e 173  anhydrous e t h e r . a d d i t i o n was stirring  The  r e a c t i o n was  complete.  allowed  a c i d and  The  The  r e s i d u a l m a t e r i a l was  extracted  brine  i n 80 ml  and  for 1 h after  the  ammonia  combined  sodium b i c a r b o n a t e  decalol.  Without f u r t h e r p u r i f i c a t i o n the  a s o l u t i o n of 8.9  g  g of  10% ether  solution  d r i e d over anhydrous magnesium s u l f a t e .  w i t h a s t a n d a r d chromic a c i d s o l u t i o n  and  then  liquid  The  removed at a s p i r a t o r p r e s s u r e to a f f o r d 8.9  at 0° was  added  neutralized with  e t h e r was  To  of  r e a c t i o n was  t h r i c e with ether.  e x t r a c t s were then washed w i t h water, 5% saturated  litre  Then 11 ml of anhydrous e t h a n o l was  allowed to evaporate.  and  to s t i r  c a r e f u l a d d i t i o n o f excess e t h a n o l and  hydrochloric  in 1  added, dropwise over  dissolved  c o n t i n u e d f o r an a d d i t i o n a l hour.  quenched by  mu  1.5088.  B i r c h R e d u c t i o n of O c t a l o n e  0.75  229  max  2H,  The  crude  crude d e c a l o l was  oxidized  (76).  (56 mmoles) of d e c a l o l i n 150  ml  acetone  added dropwise a s t a n d a r d s o l u t i o n o f chromic a c i d u n t i l  the  - 193 orange c o l o r p e r s i s t e d .  I s o p r o p a n o l was  excess o x i d i z i n g agent and Water was ether.  t h e n added t o d e s t r o y  the s o l v e n t was  added to the r e s i d u e and i t was  The  the  removed under reduced p r e s s u r e . thoroughly e x t r a c t e d w i t h  combined e t h e r e x t r a c t s were washed w i t h w a t e r and b r i n e  d r i e d over anhydrous magnesium s u l f a t e and c o n c e n t r a t e d Vacuum d i s t i l l a t i o n of the 89°  o i l y r e s i d u e a f f o r d e d 7.1  decalone  203, b.p.  at 1.5 mm;  decalone  exhibited infrared (film), X  To a s o l u t i o n of 7.9  g (81%)  a t 3 mm.  g (44 mmoles) o f d e c a l o n e  203 d i s s o l v e d i n acid.  h under a n i t r o g e n atmosphere.  the end of t h i s time most o f the i s o p r o p e n y l a c e t a t e was The  The  added 0.1 ml o f 98% s u l f u r i c  r e f l u x e d f o r 2.5  r o t a r y evaporator.  of  204  50 ml of i s o p r o p e n y l a c e t a t e was T h i s m i x t u r e was  (84) 99°  i n vacuo.  5.85 u; n.m.r., T 8.98 ( d o u b l e t , max H z ) , 8.84 ( s i n g l e t , 3H, t e r t i a r y m e t h y l ) .  3H, secondary m e t h y l , J = 6.5  P r e p a r a t i o n of E n o l A c e t a t e  lit.  and  r e s i d u e was  At  removed on  the  d i s s o l v e d i n e t h e r and washed  s u c c e s s i v e l y w i t h w a t e r , 5% sodium b i c a r b o n a t e s o l u t i o n , w a t e r and s a t u r a t e d b r i n e and d r i e d over anhydrous magnesium s u l f a t e . removal o f the e t h e r the product was a c t i v i t y I I I n e u t r a l alumina. 9.5  g of an 85:15  predominating.  The  After  chromatogrammed on 150 g of .Woelm  f r a c t i o n s e l u t e d w i t h benzene gave  m i x t u r e of e n o l a c e t a t e s , w i t h e n o l a c e t a t e  The m i x t u r e e x h i b i t e d i n f r a r e d ( f i l m ) , ^  P r e p a r a t i o n o f Bromoketone To a s o l u t i o n of 9.5  m a %  204  5.7,  5.95  u.  205 g o f e n o l a c e t a t e s 204 and  204a and 10 g o f  anhydrous sodium a c e t a t e d i s s o l v e d i n 100 ml o f g l a c i a l a c e t i c a c i d  was  - 194 -  added d u r i n g 1 h, 7.2 g of bromine i n 50 ml o f g l a c i a l a c e t i c a c i d . A f t e r the a d d i t i o n was c o m p l e t e , t h e " r e a c t i o n was a l l o w e d t o s t i r f o r an a d d i t i o n a l 15 min.  The g l a c i a l a c e t i c a c i d was then removed i n  vacuo and t h e r e s i d u e d i s s o l v e d i n w a t e r and t h o r o u g h l y ether.  extracted with  The combined e t h e r e a l e x t r a c t s were washed s u c c e s s i v e l y w i t h  w a t e r , t h r i c e w i t h 5% sodium b i c a r b o n a t e s o l u t i o n , w a t e r and b r i n e and d r i e d over anhydrous magnesium s u l f a t e .  A f t e r removal o f the  s o l v e n t the r e s i d u e c r y s t a l l i z e d and was r e c r y s t a l l i z e d from p e t r o l e u m e t h e r (30-60°) t o a f f o r d 4.7 g o f a w h i t e c r y s t a l l i n e bromoketone 205, m.p.  67-69°.  C o n c e n t r a t i o n of the mother l i q u o r s gave  an a d d i t i o n a l 4.5 g (84%) c r y s t a l l i n e bromoketone, m.p. The c r y s t a l l i n e bromoketone 205 e x h i b i t e d i n f r a r e d . J  5.8 u; n.m.r., T 8.99 8.84 IH,  69-70°. (CHC1„), X 3 max  ( d o u b l e t , 3H, secondary m e t h y l , J = 6.5 H z ) ,  ( s i n g l e t , 3H, t e r t i a r y m e t h y l ) , 5.13 (X p o r t i o n o f ABX system,  EcH B r , —  J.  V  = 14 Hz,  AA  J„  V  = 6 Hz).  £>A  Anal. Calcd. f o r C H 0 B r : 1 2  i g  C, 55.60; H, 7.34; B r , 30.89.  Found:  C, 55.59; H, 7.26; B r , 30.86. P r e p a r a t i o n of O c t a l o n e 198 A s o l u t i o n o f 4 g (15 mmoles) o f c r y s t a l l i n e bromoketone 205 and 1.5 g o f anhydrous l i t h i u m bromide d i s s o l v e d i n 35 ml of h e x a m e t h y l phosphoramide was heated t o 120° f o r 3 h under n i t r o g e n . of t h i s time the s o l u t i o n was d i l u t e d w i t h w a t e r and extracted with ether.  A t the end  thoroughly  The combined e t h e r e x t r a c t s were washed  thrice  w i t h w a t e r and once w i t h s a t u r a t e d b r i n e and d r i e d over anhydrous magnesium  sulfate.  The s o l v e n t was removed a t a s p i r a t o r p r e s s u r e t o  - 195  y i e l d the crude o c t a l o n e 198.  -  The  l a t t e r was  chromatogrammed on 100  of s i l i c a g e l t o a f f o r d , w i t h benzene as e l u t a n t , 2.1 198  (76%).  T h i s was  shown t o be a m i x t u r e  o c t a l o n e 173 by g . l . c . (column E, 185°, (4 g) was  separated  on 150 g of MN  w i t h 3% e t h e r - b e n z e n e gave 3.8 e l u t e d w i t h &%  exhibited:  of o c t a l o n e 198  86).  The m i x t u r e  s i l i c a gel.  ether-benzene gave 100 mg  86) and  octalone  The  and of  octalones  fractions eluted  g of o c t a l o n e 198 w h i l e the f r a c t i o n s  sample of the major p r o d u c t was E, 185°,  g of  g  o f o c t a l o n e 173.  An  analytical  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  infrared (film), X  6.0,  6.15  u: n.m.r.,  max x 8.93  ( s i n g l e t , 3H,  t e r t i a r y methyl),  m e t h y l , J = 7 Hz) , 4.19,  3.35  8.92  ( d o u b l e t , 3H,  secondary  ( p a i r of d o u b l e t s , 2H, CCH=CH and (lcH=CH  r e s p e c t i v e l y , J = 9 Hz); u l t r a v i o l e t , X  229 mu  (e = 9,200).  max T h i s compound was  f u r t h e r c h a r a c t e r i z e d as a r e d 2 , 4 - d i n i t r o -  p h e n y l h y d r a z o n e d e r i v a t i v e , r e c r y s t a l l i z e d from e t h a n o l , m.p. Anal. Calcd. f o r C, 60.51; H,  6.11;  N,  C  H 1 8  2 4°4 N  2  C,-60.32; H,  :  N, 15.63.  206  To an i c e - c o l d s l u r r y of 2.3 e t h e r under n i t r o g e n , was  g cuprous i o d i d e i n 67 ml  added 11.4  To the r e s u l t i n g c l e a r s o l u t i o n was (2 mmoles) of o c t a l o n e 197  anhydrous  ml of 2.1 N m e t h y l l i t h i u m s o l u t i o n . added, dropwise o v e r 0.5  i n 40 ml of anhydrous e t h e r .  a l l o w e d t o s t i r f o r an a d d i t i o n a l 1.5  h.  Then i t was  The  h, 328  The  and  mg  reaction  poured  s l o w l y i n t o a s t i r r e d 10% aqueous h y d r o c h l o r i c a c i d s o l u t i o n . l a y e r s were s e p a r a t e d  Found:  15.73.  P r e p a r a t i o n of Decalone  was  6.19;  198-199°.  the aqueous l a y e r e x t r a c t e d t w i c e w i t h  combined e t h e r e a l e x t r a c t s were washed w i t h w a t e r and b r i n e  The ether. and  - 196 d r i e d o v e r anhydrous magnesium s u l f a t e .  The c o n c e n t r a t e d  e x t r a c t was d i s t i l l e d b.p. 110° a t 0.2 mm; l i t . 9 mm.to a f f o r d 345 mg (98%) o f a c l e a r o i l .  ethereal  (96) b.p. 133-137° a t  T h i s o i l e x h i b i t e d , one  peak on g . l . c . (column E, 190°, 1 0 0 ) ; i n f r a r e d ( f i l m ) , A 3.45, max 5.85 u; n.m.r., T 9.08 ( d o u b l e t , 3H, secondary m e t h y l , J = 6 . 5 H z ) , 8.87 ( s i n g l e t , 3H, t e r t i a r y  methyl).  P r e p a r a t i o n o f Decalone 207 A s o l u t i o n o f t r i - n - b u t y l p h o s p h i n e copper ( I ) i o d i d e (4 g) i n anhydrous e t h e r (50 ml) was c o o l e d t o -78° by an e x t e r n a l d r y i c e acetone c o o l i n g b a t h .  A s o l u t i o n o f 3.1 M v i n y l l i t h i u m  i n tetrahydro  f u r a n (6.4 ml) was added dropwise u n t i l t h e i n i t i a l l y formed r e d s o l u t i o n became c o l o r l e s s .  To t h i s s o l u t i o n was added, dropwise o v e r  0.5 h, 328 mg (2 mmoles) o f o c t a l o n e 197 i n 50 ml anhydrous e t h e r . The  r e s u l t i n g brown s o l u t i o n was a l l o w e d t o s t i r f o r an a d d i t i o n a l  5 h a t -78° and then a l l o w e d t o warm s l o w l y t o room temperature. r e a c t i o n m i x t u r e was then 10% h y d r o c h l o r i c a c i d .  The  added dropwise w i t h s t i r r i n g t o 100 ml o f  The l a y e r s were s e p a r a t e d  layer extracted twice with ether.  and t h e aqueous  The combined e t h e r e a l e x t r a c t s were  washed w i t h d i l u t e ammonium h y d r o x i d e , w a t e r and b r i n e and d r i e d over anhydrous magnesium s u l f a t e .  The e t h e r was removed a t a s p i r a t o r  p r e s s u r e t o a f f o r d 4.6 g o f a v i s c o u s y e l l o w o i l .  T h i s m a t e r i a l was  s u b j e c t e d t o column chromatography on 50 g o f MN s i l i c a g e l . f r a c t i o n s e l u t e d w i t h 15% e t h e r - p e t r o l e u m (73%) o f the d e s i r e d d e c a l o n e 207.  The  e t h e r (30-60°) c o n t a i n e d 280  T h i s m a t e r i a l was d i s t i l l e d , b.p.  - 197 -  130° a t 0.15 mm, t o a f f o r d an o i l w h i c h e x h i b i t e d one peak o n l y on g.l.c. analysis  (column E, 190°, 100).  An a n a l y t i c a l sample o f t h i s  material exhibited the following spectral properties: A  infrared  (film),  5.85, 6.1, 10.9 u; n.m.r., T 8.88 ( s i n g l e t , 3H, t e r t i a r y m e t h y l ) ,  IT13.X  4.0-5.2 ( u n r e s o l v e d m u l t i p l e t , 3H, v i n y l g r o u p ) . further characterized  as a dark r e d 2 , 4 - d i n i t r o p h e n y l h y d r a z o n e d e r i v a -  t i v e , m.p. 186°, r e c r y s t a l l i z e d from Anal. Calcd.  T h i s compound was  for C  H N.0.: 19 24 4 4 C, 60.98; H, 6.41; N, 14.94. 1ft  o/  ethanol.  C, 61.28: H, 6.50; N, 15.04.  Found:  H y d r o g e n a t i o n o f Decalone 207 The h y d r o g e n a t i o n o f t h e v i n y l s u b s t i t u t e d d e c a l o n e 207 was done at a t m o s p h e r i c p r e s s u r e and room temperature u s i n g 10% p a l l a d i u m charcoal  as c a t a l y s t and a b s o l u t e e t h a n o l as s o l v e n t .  on  From 675 mg  (3.5 mmoles) o f decalone 207 was o b t a i n e d 670 mg (98%) o f e t h y l s u b s t i t u t e d d e c a l o n e 208. The p r o d u c t e x h i b i t e d one component by g . l . c . (column E, 180°, 8 6 ) .  Infrared  (film), A 5.85 u; n.m.r., x 8.88 max ( s i n g l e t , 3H, t e r t i a r y m e t h y l ) . T h i s compound was f u r t h e r c h a r a c t e r i z e d as a p a l e orange 2 , 4 - d i n i t r o p h e n y l h y d r a z o n e d e r i v a t i v e , r e c r y s t a l l i z e d from e t h a n o l , m.p. 192-193°. Anal.  f o r C. H~-N.0.: 19 26 4 4 C, 60.74; H, 6.89; N, 14.92.  Preparation  Calcd.  ft  C, 60.95; H, 7.00; N, 14.96. Found:  of Decalone 209  To a s o l u t i o n o f 4 g o f t r i - n - b u t y l p h o s p h i n e  copper ( I ) i o d i d e i n  - 198  60 ml of anhydrous e t h e r a t -78° l i t h i u m i n n-pentane. w i s e over 0.5  m i x t u r e was dropwise  was  added 11 ml of 1.86  M isopropyl-  To the r e s u l t i n g aqua s o l u t i o n was  h, 328 mg  anhydrous e t h e r .  -  added, drop-  (2 mmoles) of o c t a l o n e 197 i n 10 ml o f  A f t e r the a d d i t i o n was  complete the dark r e d r e a c t i o n  a l l o w e d t o s t i r f o r an a d d i t i o n a l 3 h and then quenched by  a d d i t i o n to 50 ml of 10% h y d r o c h l o r i c a c i d s o l u t i o n .  r e s u l t i n g s o l u t i o n was  thoroughly extracted w i t h ether.  The  The combined  e t h e r e x t r a c t s were washed w i t h w a t e r , d i l u t e ammonium h y d r o x i d e , water and b r i n e and d r i e d over anhydrous magnesium s u l f a t e .  The  c o n c e n t r a t e d e t h e r e x t r a c t was  mm)  d i s t i l l e d under vacuum  and a l l m a t e r i a l b o i l i n g a t l e s s than 150° d i s t i l l a t e was  was  0.1  collected.  chromatogrammed on 35 g of MN s i l i c a g e l .  The The  fractions  e l u t e d w i t h 20% e t h e r - p e t r o l e u m e t h e r (30-60°) a f f o r d e d 297 mg t r a n s - d e c a l o n e 209  (72%).  A n a l y s i s o f the  product by g . l . c .  of o n l y one component.  on s t a n d i n g .  R e c r y s t a l l i z a t i o n from ri-hexane gave an a n a l y t i c a l sample,  49-50°; l i t . (97,98) m.p.  spectral properties: 9.17  49-50°.  crystallized  T h i s compound gave the f o l l o w i n g  i n f r a r e d (CHC1„) , A 5.87 3 max  ( p a i r o f d o u b l e t s , 6H, secondary  209  demonstrated  the presence  m.p.  The d e c a l o n e  of  u: n.m.r., x  m e t h y l s , J = 6.8  9.08,  H z ) , 8.89  (singlet,  3H, t e r t i a r y m e t h y l ) . P r e p a r a t i o n of Decalone  215  To an i c e - c o l d s l u r r y o f 1.36 15 ml anhydrous e t h e r was s o l u t i o n i n ether. 200 mg  added 6.8  g (7.3 mmoles) of cuprous i o d i d e i n ml  (14 mmoles) o f 2.1 M m e t h y l l i t h i u m  To t h i s c l e a r s o l u t i o n was  added, dropwise  over 1 h,  (1.2 mmoles) of o c t a l o n e 198 i n 10 ml of anhydrous e t h e r .  After  - 199  the a d d i t i o n was  -  complete, the y e l l o w r e a c t i o n m i x t u r e was  s t i r f o r an a d d i t i o n a l 1.5  h and  t h e n quenched  of 5% h y d r o c h l o r i c a c i d s o l u t i o n . thoroughly  The  extracted with ether.  The  was  trans-decalone  215.  ether  The  ml  combined e t h e r e x t r a c t s were and w a t e r and d r i e d over  s i l i c a gel.  The  residue  fractions eluted  (30-60°) a f f o r d e d 189 mg  product  to  then  A f t e r removal o f the e t h e r , the  chromatogrammed on 20 g of MN  w i t h 5% e t h e r - p e t r o l e u m  by a d d i t i o n t o 30  r e s u l t i n g m i x t u r e was  washed w i t h w a t e r , d i l u t e ammonium h y d r o x i d e anhydrous magnesium s u l f a t e .  allowed  (93%)  of  e x h i b i t e d on g . l . c . (column E, 220°,  8 6 ) , one major p r o d u c t w i t h ^ 3 % of a s h o r t e r r e t e n t i o n time i m p u r i t y . 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 E, 86) e x h i b i t e d :  infrared  190°,  5.85 u; n.m.r., x 9.1, 9.02 max ( p a i r of d o u b l e t s , 6H, secondary m e t h y l s , 3 = 7 H z ) , 8.77 ( s i n g l e t ,  t e r t i a r y methyl), J  7.97  „ = 14 H z ) , 7.21 3a,3e  0  J„ . = 6 Hz). 3a,4e  (film), X  ( d o u b l e t of d o u b l e t s , IH, H ^ ,  e  ^  - 2.2  ( d o u b l e t of d o u b l e t s , IH, H„ , J„ . = 14 3a 3a,3e  T h i s compound was r  2,4-dinitrophenylhydrazone m.p.  J^  3H, Hz,  Hz,  f u r t h e r c h a r a c t e r i z e d as an orange °  d e r i v a t i v e , r e c r y s t a l l i z e d from e t h a n o l ,  167-168°. Anal. Calcd. f o r C  C, 60.66; H, 6.87;  N,  H^N^:  C, 60.95; H,  7.00;  N, 14.96.  Found:  15.06.  P r e p a r a t i o n o f Decalone  216  To a s t i r r e d s o l u t i o n of 4 g (10.1 mmoles) of t r i - n - b u t y l p h o s p h i n e copper ( I ) i o d i d e i n 50 ml anhydrous e t h e r at -78° 1.86  was  M (20.2 mmoles) of i s o p r o p y l l i t h i u m i n ri-pentane.  added 11 ml To the  of  resulting  - 200 -  b l u e s o l u t i o n was  added, dropwise o v e r 0.5 h, 356 mg  o c t a l o n e 198 i n 20 ml anhydrous e t h e r .  (2.1 mmoles) of  The s o l u t i o n was  allowed to  s t i r f o r an a d d i t i o n a l 3 h and then quenched by d r o p w i s e a d d i t i o n t o 100 ml of 10% 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 s o l u t i o n was  then  thoroughly extracted w i t h ether.  The combined e t h e r e x t r a c t s were  washed w i t h w a t e r , d i l u t e ammonium h y d r o x i d e , water and b r i n e and d r i e d o v e r anhydrous magnesium s u l f a t e . was hot-box d i s t i l l e d  (b.p. 120°  The r e s i d u e a f t e r c o n c e n t r a t i o n  a t 0.3 mm)  chromatogrammed on 20 g of MN s i l i c a g e l . e l u t e d w i t h benzene a f f o r d e d 262 mg  The t h i r d and f o u r t h f r a c t i o n s  (column E, 198°,  u; n.m.r., x 9.21,  d o u b l e t s , 6H, i s o p r o p y l m e t h y l s , J = 6.5 H z ) , 9.00 secondary m e t h y l , J = 6 H z ) , 8.87 n.m.r., (benzene), 15.5 Hz, J  Ja,4-e  7.74  86).  9.09  The  product  ( p a i r of r  ( d o u b l e t , 3H,  ( s i n g l e t , 3H, t e r t i a r y m e t h y l ) ;  Hz).  , J = Ja ja,je (doublet of d o u b l e t s , IH, H , J~ Je  The p r o d u c t was  ,  J a , Je  =  f u r t h e r c h a r a c t e r i z e d as a  yellow 2,4-dinitrophenylhydrazone d e r i v a t i v e , r e c r y s t a l l i z e d e t h a n o l , m.p.  This  (doublet of d o u b l e t s , IH, H  = 7.6 H z ) , 7.56  15.5 Hz, J„ . = 2.4 3e,4e  distillate  (84%) of t r a n s - d e c a l o n e 216.  p r o d u c t e x h i b i t e d one peak by g . l . c . gave i n f r a r e d ( f i l m ) , X 5.85 & ' max  and the  from  145-146°.  Anal. Calcd. f o r C ^ H ^ N ^ :  C, 62.67; H, 7.51; N, 13.92.  Found:  C, 62.55; H, 7.50; N, 13.73.  H y d r o g e n a t i o n of O c t a l o n e  188  A s u s p e n s i o n of 20 mg of 10% p a l l a d i u m on c h a r c o a l i n 15 ml o f 0.3 N e t h a n o l i c sodium h y d r o x i d e s o l u t i o n was  equilibrated for 1 h i n  an a t m o s p h e r i c p r e s s u r e h y d r o g e n a t i o n apparatus at room temperature.  - 201 -  A f t e r t h i s p e r i o d 122 mg (0.68 mmole) o f o c t a l o n e 188 i n 10 m l e t h a n o l was  added by s y r i n g e .  A f t e r t h e c a l c u l a t e d amount o f hydrogen had  been absorbed, t h e m i x t u r e was f i l t e r e d and t h e f i l t r a t e The  r e s i d u e was d i l u t e d w i t h w a t e r and then t h o r o u g h l y  ether.  concentrated.  extracted with  The combined e t h e r e x t r a c t s were washed s u c c e s s i v e l y w i t h 5%  h y d r o c h l o r i c a c i d , 5% sodium b i c a r b o n a t e  s o l u t i o n , w a t e r and b r i n e  and d r i e d over anhydrous magnesium s u l f a t e .  The r e s i d u e , a f t e r  removal o f t h e s o l v e n t , was d i s t i l l e d , b.p. 110° a t 0.2 mm, t o a f f o r d 119 mg (97%) o f c i s - f u s e d d e c a l o n e 218. T h i s sample was shown t o be homogeneous by g . l . c . (column E, 190°, 86).  Decalone 218 e x h i b i t e d  infrared (film), X 5.85 u; n.m.r., x 9.10 ( d o u b l e t , 3H, secondary max m e t h y l , J = 7 H z ) , 8.95 ( s i n g l e t , 3H, t e r t i a r y m e t h y l ) . was  f u r t h e r c h a r a c t e r i z e d as a y e l l o w  T h i s compound  2,4-dinitrophenylhydrazone  d e r i v a t i v e , r e c r y s t a l l i z e d from e t h a n o l , m.p. 161-162°. A n a l . C a l c d . f o r C, H N.0.: 18 24 4 4 C, 59.99; H, 6.80; N, 15.46. o  o/  C, 59.99; H, 6.71; N, 15.55.  Found:  H y d r o g e n a t i o n o f O c t a l o n e 189 The  hydrogenation  was c a r r i e d o u t as above.  From 100 mg o f  o c t a l o n e 189 was o b t a i n e d 96 mg o f c i s - d e c a l o n e 193. The product e x h i b i t e d one major peak by g . l . c . w i t h a p p r o x i m a t e l y r e t e n t i o n time i m p u r i t y (column E, 180°, 86). was  3% o f a s h o r t e r  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 . aid e x h i b i t e d :  infrared  X 5.85 u; n.m.r., x 8.90 ( s i n g l e t , I H , t e r t i a r y m e t h y l ) . max compound was f u r t h e r c h a r a c t e r i z e d as a y e l l o w  (film), This  2,4-dinitrophenylhydrazone  d e r i v a t i v e , r e c r y s t a l l i z e d from e t h a n o l , m.p. 174°.  - 202  A n a l . C a l c d . f o r C, „H„.N.0.: 19 26 4 4 C, 60.81; H, 6.85; N, 14.88.  C, 60.95; H, 7.00;  N, 14.96.  Found:  H y d r o g e n a t i o n o f O c t a l o n e 190 The  o c t a l o n e 190 was hydrogenated as above.  From 100 mg o f  o c t a l o n e 190 was o b t a i n e d 96 mg o f c i s - d e c a l o n e 219 ( 9 6 % ) . The decalone  e x h i b i t e d one major peak on g . l . c .  (column E , 190°,  86) w i t h  a 5% i m p u r i t y o f i d e n t i c a l r e t e n t i o n time t o the t r a n s - d e c a l o n e 209. An a n a l y t i c a l sample o f c i s - d e c a l o n e 219 was c o l l e c t e d by p r e p a r a t i v e g.l.c. T 9.19, 8.88  (column E , 190°,  86).  Infrared (film), X max  5.85 u ; n.m.r.,  9.10 ( p a i r o f d o u b l e t s , 6H, i s o p r o p y l m e t h y l s , J = 6.5 H z ) ,  ( s i n g l e t , 3H, t e r t i a r y m e t h y l ) .  T h i s compound was f u r t h e r  c h a r a c t e r i z e d as an orange 2 , 4 - d i n i t r o p h e n y l h y d r a z o n e  derivative,  r e c r y s t a l l i z e d from e t h a n o l , m.p. 180-181°. Anal. Calcd. f o r C, 61.86; H, 7.35;  C  0 28 4°4 H  2  N  :  C  '  6 1  *  8 4  > > - '•> > 14.42. H  1  21  Found:  N  N, 14.30.  H y d r o g e n a t i o n o f Octalone 191 The m a t e r i a l was hydrogenated by a p r o c e d u r e i d e n t i c a l t o t h a t d e s c r i b e d above.  From 130 mg o f o c t a l o n e 191 was o b t a i n e d 125 mg  o f a c o l o r l e s s o i l , b.p. peak by g . l . c . n.m.r., x 9.08, 8.92 Jo  (column E , 180°,  86).  This product  e x h i b i t e d one  Infrared (film), X  5.85 u ;  max  9.01 ( p a i r o f d o u b l e t s , 6H, secondary m e t h y l s , J = 6.5 H z ) ,  ( s i n g l e t , 3H, t e r t i a r y m e t h y l ) , 7.85 ( d o u b l e t o f d o u b l e t s , IH, H  ,  o = 13 Hz, J . = 3.6 H z ) , 7.64 ( d o u b l e t o f d o u b l e t s , I H , H., , >3a 3e,4a ' 3a  J eD  J„  115° a t 0.2 mm.  (95%)  0  „  3a,3e  = 13 Hz, J .  .  3a,4a  =14.4 Hz),  7.35 ( s e x t e t , I H , H, , J .  l a  .  la,9a  = 13 Hz,  -  /™T  J\J H  la'  its  ( C  \  =  Vle  6 Hz).  The decalone 2 2 0 was f u r t h e r c h a r a c t e r i z e d as  2,4-dinitrophenylhydrazone  m.p.,  60.85;  H,  C  7 . 0 8 ; N,  H 1  Octalone  6 4°4 N  9  2  :  C  >  6 n  -  9 5  5  »  H  7  -  From 100 mg  N  14.96.  Found:  192  (0.45 mmoles) o f o c t a l o n e T h i s product  (column E, 1 8 0 ° , 86).  (pair of doublets,  192 was o b t a i n e d  Infrared (film), A max  ( m u l t i p l e t , IH, H  , J, J  5.85 y; n.m.r., T 9.19,  '  J  =14  = 14 Hz, J , = 13 Hz, J  la  188-189° from  ( s i n g l e t , 3H, Hz, J  .  tertiary  = 3.6 H z ) ,  = 14.3 H z ) , 8.30  (CH ) = 6 Hz). 3 le  c i s - d e c a l o n e was c h a r a c t e r i z e d f u r t h e r as i t s d e r i v a t i v e , m.p.  (95%)  6H, i s o p r o p y l m e t h y l s , J = 6.5 H z ) , 9.01  ( m u l t i p l e t , IH, H  (multiplet,IH, H  96 mg  e x h i b i t e d one component on g . l . c .  ( d o u b l e t , 3H, secondary m e t h y l , J = 6 H z ) , 8.89 7.86  ; >  188.  of c i s - d e c a l o n e 221.  methyl),  0 0  192 was hydrogenated by a procedure i d e n t i c a l t o t h a t  used f o r o c t a l o n e  7.63  from e t h a n o l ,  14.93.  H y d r o g e n a t i o n of Octalone  9.11  derivative, recrystallized  213-214°.  Anal. Calcd. f o r C,  203 -  This  2,4-dinitrophenylhydrazone  ethanol.  A n a l . C a l c d . f o r C-H-.N.O. : 21 30 4 4 C, 62.46; H, 7.28; N, 14.01.  C, 62.67; H, 7.51; N, 13.92.  Found:  B i r c h Reductions General: Each B i r c h r e d u c t i o n was r e p e a t e d  at l e a s t  of the r e d u c t i o n s were performed f i v e times.  twice w h i l e  The r e s u l t s  the m a j o r i t y  ( y i e l d s and  - 204 -  p r o d u c t c o m p o s i t i o n ) a r e l i s t e d i n T a b l e I I I . These r e s u l t s a r e the average of t h e v a r i o u s r u n s .  I n each c a s e , g a s - l i q u i d  chromatographic  T a b l e I I I . R e s u l t s Obtained from the B i r c h R e d u c t i o n o f O c t a l o n e s 188 t o 192.  Octalone  % Yield  trans:cis Ratio  % Recovered starting material  188  93  87:13  2  189  94  75:25  13  190  98  69:31  14  191  90  82:18  8  192  98  65:35  7  c o n d i t i o n s were found i n w h i c h the o c t a l o n e , the c o r r e s p o n d i n g c i s f u s e d decalone and the c o r r e s p o n d i n g t r a n s - f u s e d d e c a l o n e distinct retention 86).  times on g . l . c . c o - i n j e c t i o n ,  I n each c a s e , the c i s - f u s e d  exhibited  (column E, 160-190°,  and t r a n s - f u s e d d e c a l o n e s were  c o l l e c t e d by p r e p a r a t i v e g . l . c . and t h e i n f r a r e d and n.m.r. s p e c t r a were i d e n t i c a l w i t h those of the a u t h e n t i c c i s - f u s e d  and  trans-fused  decalones p r e v i o u s l y p r e p a r e d . Sample P r o c e d u r e :  Reduction of Octalone  188  To 60 ml of l i q u i d ammonia ( f r e s h l y d i s t i l l e d from sodium m e t a l ) was  added 55 mg of f i n e l y cut l i t h i u m w i r e .  dissolved,  A f t e r a l l the l i t h i u m had  100 mg o f o c t a l o n e 188 i n 10 ml of anhydrous e t h e r was  added  - 205  dropwise over 0.5 was  -  h to the b l u e ammonia s o l u t i o n .  c o m p l e t e , the r e a c t i o n m i x t u r e was  2 h.  The  b l u e c o l o r was  ammonium c h l o r i d e .  a l l o w e d t o s t i r f o r an  A f t e r the l i q u i d ammonia had  a c i d was  s o l u t i o n was  d i l u t e d w i t h w a t e r and  thoroughly extracted  vacuum d i s t i l l e d , b.p.  of c i s - and  trans-fused  p r o d u c t p r o v e d to bean 87:13 analysis  (column E, 180°,  product.  decalone 206  with  brine  110°  at 0.2  mm,  The  ether,  starting material.  p e r c e n t c o m p o s i t i o n was  Samples of c i s - f u s e d d e c a l o n e 218  and  The g.l.c.  crude trans-fused  combined to a f f o r d an  authentic  m i x t u r e of known c o m p o s i t i o n a p p r o x i m a t i n g t h a t observed i n the reduction the g . l . c .  of o c t a l o n e 188. (column E, 180°,  t r a c e c o n f i r m e d t h a t no  I n j e c t i o n of t h i s a u t h e n t i c 86)  followed  compensation was  response f a c t o r s of d e c a l o n e s 218  and  206  Birch  mixture i n t o  by i n t e g r a t i o n of the required  mg  determined  of the g . l . c . t r a c e of the  were then weighed out and  ether.  to a f f o r d 94  m i x t u r e of t r a n s : c i s d e c a l o n e by  86).  This  and  A f t e r removal of the  d e c a l o n e s and  by i n t e g r a t i o n ( d i s c i n t e g r a t o r ) reduction  of  added u n t i l the s o l u t i o n became n e u t r a l .  d r i e d over anhydrous magnesium s u l f a t e .  (93%)  additional  evaporated d i l u t e  combined e t h e r e x t r a c t s were washed w i t h w a t e r and  the r e s i d u e was  addition  t h e n d i s c h a r g e d by c a r e f u l a d d i t i o n  hydrochloric  The  A f t e r the  g.l.c.  ( i . e . the m o l a r  were i d e n t i c a l ) .  - 206 -  BIBLIOGRAPHY  1.  G. O u r i s s o n , S. M u n a r a l l i , and C. E h r e t . " I n t e r n a t i o n a l T a b l e s of S e l e c t e d C o n s t a n t s , V o l . 15, Data R e l a t i v e t o S e s q u i t e r p e n o i d s " , Pergamon P r e s s , New Y o r k , 1966.  2.  L. R u z i c k a , A. Eschenmoser, and H. Heusser. E x p e r i e n t i a , 9_, 357 (1953),  3.  L. R u z i c k a , A. Eschenmoser, 0. J e g e r , and A. A r i g o n i . A c t a . , 38, 1890 (1955).  4.  Y. Ohta, K. Ohara, and Y. H i r o s e .  5.  B.A. Nagasampagi, L. Yankov, and Sukh Dev. i b i d . , 1913 (1968).  6.  D.W. C o n n e l l , R.P. H i l d e b r a n d , and M.D. S u t h e r l a n d , i b i d . , 519 (1968).  7.  Y.S. Cheng, Y . J . Kuo, Y.T. L i n .  8.  K. Takeda, H. M i n a t o , and M. I s h i k a w a .  9.  K. Takeda, H. M i n a t o , and M. I s h i k a w a . 219 (1966).  H e l v . Chim.  T e t r a h e d r o n L e t t e r s , 4181 (1968).  Chem. Comm., 565 (1967). i b i d . , 79 (1965). T e t r a h e d r o n , S u p p l . No. 7,  10.  Y. Ohta, T. S a k a i , and Y. H i r o s e .  T e t r a h e d r o n L e t t e r s , 6365 (1965).  11.  J.B. H e n d r i c k s o n .  12.  W. P a r k e r , J . S . R o b e r t s , and R. Ramage.  13.  K. Y o s h i h a r a , Y. Ohta, T. S a k a i and Y. H i r o s e . 2263 (1969).  14.  F.W. Semmler and H. S t e n z e l .  15.  L. R u z i c k a and M. S t o l l .  16.  W.P. Campbell and M.D. S o f f e r .  17.  E. S o u b e i r a n and H. C a p i t a i n e .  18.  F. H a n i c .  19.  V. Herout and V. Sykora.  T e t r a h e d r o n , 4_, 246 (1958).  20.  V. Herout and V. Sykora.  Chem. and I n d . , 130 (1958).  21.  V. Herout and V. Sykora.  C o l l . Czech. Chem. Comm., 23, 2181 (1958).  22.  V. H e r o u t , A. Banassek, and M. Romanuk.  T e t r a h e d r o n , ]_, 82 (1959). Quart. Rev., 2 1 , 331 (1967). Tetrahedron  Letters,  B e r . , 4 7 , 2555 (1914).  H e l v . Chim. A c t a , ]_, 84 (1924). J . Am. Chem. S o c . , 6 4 , 417 (1942). L e i b i g s A n n . , 3 4 , 323 (1840).  Chem. L i s t y , 52^, 165 (1958).  i b i d . , 31, 3012 (1966).  - 207 -  23.  M.J. G a l l a g h e r , R.P. H i l d e b r a n d , and M.D. S u t h e r l a n d . L e t t e r s , 3715 (1964).  24.  Y. Naya and M. Kotake.  25.  L. W e s t f e l t .  26.  C C . K a r t h a , P.S. K a l s i , A.M. S h a l i g r a m , K.K. C h a a k r a v a r t i , and S.C. B h a t t a c h a r y y a . T e t r a h e d r o n , 19, 241 (1963).  27.  V. Herout and F. Santany.  28.  R. V l a h o v , M. Holub, and V. Herout.  29.  L. W e s t f e l t .  30.  0. M o t l , V. S y k o r a , V. H e r o u t , and F. Sorm. C o l l . Czech. Chem. Comm., 23, 1297 (1958).  31.  R.R. Smolders.  32.  W.G. Dauben, B. W e i n s t e i n , P. L i m , and A. Anderson. 15, 217; (1961).  33.  R.R. Smolders.  34.  L. W e s t f e l t .  35.  M.V.R. Rao, G.S.K. Rao, and S. Dev. T e t r a h e d r o n L e t t e r s , ( 2 7 ) , 27 (1960).  36.  M.V.R.K. Rao, G.S.K. Rao, and S. Dev. T e t r a h e d r o n , 22., 1977 (1966).  37.  M.D. S o f f e r , G.E. Gunay, 0. Korman, and M. Adams. L e t t e r s , 389 (1963).  38.  M.D. S o f f e r and G.E. Gunay.  39.  M.D. S o f f e r and L.A. Burk.  40.  R.B. K e l l y and J . Eber.  41.  O.P. V i g , O.P. Chugh, and K.L. M a t t a .  I n d i a n J . Chem., 8, 29 (1970).  42.  A. Tanaka, H. Uda, and A. Y o s h i k o s h i .  Chem. Comm., 308 (1969).  43.  E. P i e r s , R.W. B r i t t o n , and W. de Waal.  44.  D.H.R. B a r t o n and C H . Robinson.  45.  G. S t o r k and S.D. D a r l i n g .  B u l l . Chem. Soc.  Tetrahedron  ( J a p a n ) , 4^2, 1468 (1969).  A c t a Chem. Scand., 20, 2841 (1966).  C o l l . Czech. Chem. Comm., 19, 118 (1954). i b i d . , 32, 822 (1967).  A c t a Chem. Scand., 18, 572 (1964).  Can. J . Chem.,45, 889 (1967). Tetrahedron,  Can. J . Chem., 42, 2836 (1964). A c t a . Chem. Scand. , 20, 2893 (1966).  Tetrahedron  i b i d . , 1355 (1965). i b i d . , 211 (1970).  Can. J . Chem., 48, 2246 (1970).  Can. J . Chem. 49, 12 (1971).  J . Chem. S o c , 3045 (1954).  J . Am. Chem. Soc., 86, 1761 (1964).  - 208 46.  M.J.T. Robinson.  T e t r a h e d r o n , 21, 2475 (1965).  47.  S.K. M a l h o t r a , D.F. Moakley and F. Johnson. 1089 (1967).  48.  F. Johnson.  49.  K.W. Bowers, R.W. G i e s e , J . Grimshaw, H.O. House, N.H. Kolodny, K. K r o n b e r g e r , and D.K. Roe. J . Am. Chem. S o c . , 9 2 , 2783 (1970).  50.  H.O. House, R.W. G i e s e , K. Konberger, J . Am. Chem. Soc., 92, 2800 (1970).  51.  R.M. Lukes, G.I. Poos, and L.H. S a r e t t . 1401 (1952).  52.  R.F. Church, R.E. I r e l a n d , and D.R. S h r i d h a r . 707 (1962).  53.  A.A. Amos and P. Z i e g l e r .  54.  A. Marquet, M. D v o l a i t z k y , H.B. Kagan, L. Mamlok, C. Ouannes, and J . Jacques. B u l l . Soc. Chim. F r a n c e , 1822 (1961).  55.  J.A. Edwards, M.C. C a l z a d a , L.C. I b a n e z , M.E. Cabezas R i v e r a , R. U r q u i z a , L. Cardona, J.C. O r r , and A. Bowers. J . Org. Chem., 29_, 3481 (1964). ~~  56.  D. Walker and J.D. H i e b e r t .  57.  P.J. Kropp.  58.  J.E. McMurry.  59.  L . J . Chinn.  60.  E.D. Becker. "High R e s o l u t i o n N.M.R.", Academic P r e s s , I n c . , New York and London (1969), p. 149-163.  61.  D. Caine and J.F. DeBardeleben,  62.  M. P e s a r o , G. B o z z a t o , and P. S c h u d e l .  63.  W.L. Meyer and A.S. L e v i n s o n .  64.  G. F r a e n k e l , S.H. E l l i s , and D.T. D i x . (1965).  65.  H.O. House and W.F. F i s c h e r , J r .  66.  G. S t o r k , M. Gregson, (1969).  Tetrahedron  Letters,  Chem. Rev., 68, 375 (1968).  J . P . K a p l a n , and J.F. Simeone.  J . Am. Chem. S o c , 74,  J . Org. Chem., 27,  Can. J . Chem., 37, 345 (1959).  Chem. Rev., 67, 153 (1967).  J . Org. Chem., 29, 3110 (1964). J . Am. Chem. S o c , 90, 6821 (1968). J . Org. Chem., 27, 2703 (1962).  Jr.  T e t r a h e d r o n L e t t e r s , 4583 (1965) Chem. Comm., 1152 (1968).  J . Org. Chem., 28, 2184 (1963). J . Am. Chem. S o c . , 8 7 , 1406  J..Org.  and P.A. G r i e c o .  Chem., 33, 949 (1968).  T e t r a h e d r o n L e t t e r s , 1391  - 209 -  67.  H.O. House, W.L. Respess, and G.M. W h i t e s i d e s . 31, 3128 (1966).  J . Org. Chem.,  68.  J.R. C a t c h , D.F. E l l i o t t , D.H. Hey, and E.R.H. Jones. Soc., 278 (1947).  69.  W.S. Wadsworth and W.D. Emmons.  70.  W.S. Rapson.  71.  W.S. Johnson and H. P o s v i c .  72.  G. S t o r k , A. B r i z z o l a r a , H. Landesman, J . S z m u s z k o v i c z , and R. T e r r e l l . i b i d . , 8 5 , 207 (1963).  73.  E.R. Jones and F. Sondheimer.  74.  G . l . Poos, G.E. A r t h , R.E. B e y l e r , and L.H. S a r e t t . Soc., 75, 422 (1953).  75.  J.A. M a r s h a l l and H. Roebke.  76.  K. Bowden, I.M. H e i l b r o n , E.R.H. J o n e s , and B.C.L. Weedon. J . Chem. Soc., 39 (1946).  77.  E.B. Baker.  J . Chem. P h y s . , 3 7 , 911 (1962).  78.  E.B. Baker,  i b i d . , 4 5 , 609 (1966).  79.  J.D. B a l d e s c h w i e l e r and E.W. R a n d a l l .  80.  R. Freeman and W.A. Anderson.  81.  N.S. Bhacca and D.H. W i l l i a m s . " A p p l i c a t i o n s o f N u c l e a r M a g n e t i c Resonance S p e c t r o s c o p y i n O r g a n i c C h e m i s t r y " , Holden-Day, I n c . , San F r a n c i s c o (1964), p. 50.  82.  J.A. M a r s h a l l and W.I. F a n t a .  83.  F.D. Gunstone and R.M. Heggie. J . Chem. S o c , 1437 (1952).  84.  M. Y a n a g i t a and R. F u t a k i .  85.  P.M. Worster and E. P i e r s , u n p u b l i s h e d work.  86.  H.O. House, R.A. Latham, and C D . S l a t e r . (1966).  87.  J.A. M a r s h a l l and N.H. Andersen,  88.  M. C h e r e s t , H. F e l k i n , and N. P r u d e n t . (1968).  J . Chem.  J . Am. Chem. S o c . , 83, 1733 (1961).  J . Chem. S o c . , 1626 (1936). J . Am. Chem. Soc. , 69, 1361 (1947).  J . Chem. Soc. 43, 615 (1949). J . Am. Chem.  J . Org. Chem., 34, 4190 (1969).  Chem. R e v . , 6 3 , 81 (1963).  J . Chem. P h y s . , 3 7 , 2053 (1962).  J . Org. Chem., 29, 2501 (1964).  J . Org. Chem.,21, 949 (1956).  J . Org. Chem. , 31, 2667  i b i d . , 31, 667 (1966). T e t r a h e d r o n L e t t e r s , 2199  - 210 -  89.  M. Cherest and H. F e l k i n .  i b i d . , 2205 (1968).  90.  G.B. Kaufman and L.A. T e t e r .  91.  T.M. Warne, J r . , Ph.D. T h e s i s , N o r t h w e s t e r n U n i v e r s i t y , June 1970, p. 40.  92.  J.A. Osborn, E.F. J a r d i n e , J . F . Young and G. W i l k i n s o n . J . Chem. Soc. [ A ] , 1711 (1966).  93.  J.A. M a r s h a l l , N. Cohen, and K.R. Arenson. 762 (1965).  94.  R.B. Woodward, F. Sondheimer, 0. Taub, K. H e u s l e r , and W.M. McLamore. J . Am. Chem. Soc. , 74, 4223 (1952).  95.  E . J . Corey and A.G. Hartmann.  96.  R.M. Coates and J.E. Shaw.  97.  E. P i e r s , W. de Waal and R.W. B r i t t o n .  Chem. Comm., 188 (1968).  98.  E. P i e r s , W. de Waal and R.W. B r i t t o n . (1969).  Can. J . Chem., 47, 4299  99.  A.A. Bothner-By  I n o r g . Syn. , ]_, 9 (1963).  J . Org. Chem., 30,  i b i d . , 87, 5736 (1956).  i b i d . , 92, 5657 (1970).  and R.E. G l i c k .  J . Chem. P h y s . , 2 6 , 1651 (1957).  100.  L.W. Reeves and W.G. S c h n e i d e r .  Can. J . Chem., 35 ( 1 ) , 1651 (1957).  101.  J.D. C o n n o l l y and R. M c C r i n d l e .  Chem. and I n d . , 379 (1965).  102.  H.J.E. L o w e n t h a l .  103.  G.G.S. D u t t o n , K.B. Gibney, G.D. J e n s e n , and P.E. R e i d . J . Chromatog., 36, 152 (1968).  104.  O.P. V i g , S.D. Sharma, S. Chander, and I . R a j . 4_, 275 (1966).  105.  F . J . M c Q u i l l i n and R. Robinson.  106.  J.B.. Rogan.  T e t r a h e d r o n , 6_, 269 (1959).  I n d i a n J . Chem.,  J . Chem. Soc., 586 (1941).  J . Org. Chem. , 27, 3910 (1962).  

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