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UBC Theses and Dissertations

Synthetic studies on octalones and related systems Worster, Paul Murray 1975

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SYNTHETIC AND  STUDIES RELATED  ON  OCTALONES  SYSTEMS  BY  PAUL B.Sc.  (Hons.),  MURRAY  University  WORSTER  of B r i t i s h C o l u m b i a ,  A THESIS SUBMITTED IN PARTIAL FULFILMENT OF THE REQUIREMENTS FOR THE DEGREE OF  DOCTOR  in  OF  the  PHILOSOPHY  Department of  CHEMISTRY i  We a c c e p t t h i s t h e s i s as required  conforming  to  the  standard  THE UNIVERSITY OF BRITISH COLUMBIA December,  1975  1967  In p r e s e n t i n g t h i s t h e s i s in p a r t i a l  f u l f i l m e n t o f the r e q u i r e m e n t s  an advanced degree at the U n i v e r s i t y of B r i t i s h C o l u m b i a , I agree the L i b r a r y I further  s h a l l make i t  freely  available for  agree t h a t p e r m i s s i o n f o r e x t e n s i v e  r e f e r e n c e and copying o f t h i s  of t h i s thesis f o r written  It  i s understood that c o p y i n g o r  thesis  Department of  Cfl  The U n i v e r s i t y o f B r i t i s h Columbia  2075 Wesbrook Place Vancouver, Canada V6T 1W5  or  publication  f i n a n c i a l g a i n s h a l l not be a l l o w e d w i t h o u t my  permission.  that  study.  f o r s c h o l a r l y purposes may be g r a n t e d by the Head o f my Department by h i s r e p r e s e n t a t i v e s .  for  - ii ABSTRACT This thesis  describes  i n an improved s e r i e s octalones.  a number o f i n v e s t i g a t i o n s  of p r a c t i c a l preparations for  S t a r t i n g w i t h a study of a c i d and base  of methyl v i n y l ketone  to 2 - m e t h y l c y c l o h e x a n o n e ,  that  culminated  substituted catalyzed  additions  the p r e p a r a t i o n of  4a-methyl-4,4a,5,6,7,8-hexahydro-2(3H)-naphthalenone  (234) was s i m p l i f i e d  and improved by a one pot r e a c t i o n t h a t  employed both a c i d  and b a s e .  sequentially  The advantages o f t h i s e f f i c i e n t  p r o c e d u r e were  then  demonstrated by the p r e p a r a t i o n o f  trans-4a,8-dimethy1-4,4a,5,6,7,8-  hexahydro-2(3H)-naphthalenone  from  and methyl v i n y l  (235)  2,6-dimethylcyclohexanone  ketone.  S e v e r a l approaches  to  trans-8-acetoxy-4a-methyl-4,4a,5,6,7,8-  hexahydro-2(3H)-naphthalenone  (236) were then u n d e r t a k e n .  two s t e p c o n v e r s i o n o f o c t a l o n e  234 to  by an a c i d h y d r o l y s i s which a f f o r d e d b o t h 4,4a,5,6,7,8-hexahydro-2(3H)-naphthalenone  (284) was  oxygenation  hexahydro-2(lH)-naphthalenone  followed  86,8aa-dihydroxy-4a3-methyl(292)  and the  dione 4a-me t h y 1 - 3 , 4 , 4 a , 5 , 8 , 8 a - h e x a h y d r o - 1 ( 2 H ) , 7 ( 6 H ) - n a p h The p h o t o s e n s i t i z e d  efficient  8,8a-epoxy-2,2-ethylenedioxy-  4a-methyl-4,4a,5,6,7,8-hexahydro-2(3H)-naphthalenone  (294).  An  (^C^)  of  undesireable thalenedione  4a-methyl-3,4,4a,5,6,7-  (341), p r e p a r e d i n 96% from 234,  was  a c c o m p l i s h e d w i t h Rose Bengal i n p y r i d i n e or methanol and a f f o r d e d 4a-methyl-3,4,4a,5-tetrahydro-l(2H),7(6H)-naphthalenedione r a t h e r than the expected  Y~pe acetate, r  6,7,8-hexahydro-2(3H)-naphthalenone p r o d u c t was attempted.  R e d u c t i o n of  (343),  4a-methyl-8-peracetoxy-4,4a,5,  (344), when a c e t y l a t i o n  of  the i n t e r m e d i a t e Y ~ h y c l P r o  the e r o x  icle  -  (342)  before  acetylation  iii  -  afforded  compound 236 i n low y i e l d .  work a l s o r e s u l t e d i n the i s o l a t i o n of  t r a n s - and  5,6,7,8,8a-decahydro-2(lH)-naphthalenone  cis-4a-methyl-3,4,4a,  (349 and 350),  and 4 a - m e t h y l - 4 , 4 a , 5 , 6 - t e t r a h y d r o - 2 ( 3 H ) - n a p h t h a l e n o n e The o c t a l o n e  237,  This  the dione  294,  (353).  4a,8,8-trimethyl-4,4a,5,6,7,8-hexahydro-2(3H)-  n a p h t h a l e n o n e , was s y n t h e s i z e d  i n an e f f i c i e n t  t h a t employed the n - b u t y l t h i o m e t h y l e n e was c o n v e r t e d i n two s t e p s to i t s  seven s t e p  b l o c k i n g group.  3-n-butylthiomethylene  sequence  Octalone  234  derivative  T h i s compound was d i a l k y l a t e d w i t h methyl i o d i d e to a f f o r d  (375).  3-n-butyl-  thiomethylene-1,1,4a-trimethyl-3,4,4a,5,6,7-hexahydro-2(IH)-naphthalenone (376)  and then unblocked by e x h a u s t i v e  hydrolysis  to a f f o r d  trimethyl-3,4,4a,5,6,7-hexahydro-2(lH)-naphthalenone Wolff-Kishner  reduction of  (356).  Cis-  and  naphthalenone  Successive  356 and a l l y l i c o x i d a t i o n of the p r o d u c t ,  l,l,4a-trimethyl-l,2,3,4,4a,5,6,7-hexahydronaphthalene sodium chromate a f f o r d e d  1,1,4a-  the d e s i r e d o c t a l o n e  (357), w i t h  237.  _trans-4a,5-dimethy1-4,4a,5,6,7,8-hexahydro-2(3H)(238 and 239) were b o t h p r e p a r e d as pure compounds by  employing a sequence  t h a t o r i g i n a t e d from  A l k y l a t i o n o f the n - b u t y l t h i o m e t h y l e n e 2,3-dimethylcyclohexanone chemical effect  derivative,  ( 4 0 0 ) , was s t u d i e d  of a l k y l a t i n g  stereoselectivity  2,3-dimethylcyclohexanone.  agent, solvent  6-n-butylthiomethylene-  to determine the and base.  C o n t r o l of  was demonstrated to be p r i m a r i l y dependent  choice of a l k a l i metal c a t i o n . c i s - v i c i n y l dimethyl d e r i v a t i v e ,  stereothe  on the  The most p r a c t i c a l means of p r o d u c i n g the cis-2,3-dimethy1-2(2-ethoxycarbonyl-  ethyl)-6-ii-butylthiomethylenecyclohexanone c h l o r o - or bromopropionate as a l k y l a t i n g  (415), employed  ethyl-3-  agent w i t h p o t a s s i u m j ^ - b u t o x i d e  -  i n _t-butanol whereas  iv  -  one o f the most f a v o u r a b l e means of o b t a i n i n g  t r a n s - v i c i n y l dimethyl d e r i v a t i v e ,  trans-2,3-dimethyl-2(2-ethoxycarbonyl-  ethyl)-6-n-butylthiomethylenecyclohexanone butoxide acids  in t-butanol.  cis-  (416)  H y d r o l y s i s o f 415  and 416  c i s - and  hexahydro-2(lH)-naphthalenone  (419 and 420).  t r a n s isomer r e q u i r e d s u c c e s s i v e  h y d r o l y s i s of  R e c r y s t a l l i z a t i o n of  419 i n pure form.  silica  the impure t r a n s e n o l l a c t o n e  pure t r a n s keto a c i d  cis-  (  keto 417  trans-4a,5-dimethyl-l-oxa-*3,4,4a,5,6,7-  m i x t u r e gave the c i s - d i m e t h y l e n o l l a c t o n e  lactone.  then y i e l d e d the  These compounds were r e a d i l y d e h y d r a t e d to t h e i r c o r r e s p o u n d -  ing enol lactones,  elusive  employed l i t h i u m _t-  and t r a n s - 2 , 3 - d i m e t h y 1 - 2 ( 2 - c a r b o x y e t h y l ) c y c l o h e x a n o n e  and 418).  the  (418) w i t h subsequent  The more  chromatographies,  and c r y s t a l l i z a t i o n of d e h y d r a t i o n t o the  and t r a n s - 2 , 3 - d i m e t h y 1 - 2 ( 3 - o x o b u t y l ) c y c l o h e x a n o n e base t r e a t m e n t ,  afforded  238 and 239.  yielded  (440a and 440b)  A study o f  p r o d u c t d i s t r i b u t i o n i n the m e t h y l l i t h i u m r e a c t i o n showed that isomerism played a h i t h e r t o unrecognized r o l e . r a t i o of enol lactones  the  enol  Treatment o f 419 and 420 w i t h m e t h y l l i t h i u m at - 2 5 °  which, a f t e r  this  F o r example,  the stereo-  an  419 and 420 y i e l d e d an o c t a l o n e r a t i o o f  84:16 95:5  (238:239). Authentic octalone by an e i g h t  s t e p sequence  239 was a l s o p r e p a r e d i n an unambiguous manner from o c t a l o n e 234.  Dehydrogenation o f  to 4 a - m e t h y l - 5 , 6 , 7 , 8 - t e t r a h y d r o - 2 ( 4 a H ) - n a p h t h a l e n o n e  (300) and  234 conjugate  a d d i t i o n 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 gave  trans-4,4a-dimethy1-4,4a,5,  6,7,8-hexahydro-2(3H)-naphthalenone  Deconjugation  467,  (381).  o f 381 gave  trans-4,4a-dimethyl-3,4,4a,5,6,7-hexahydro-2(lH)-naphthalenone,  h y d r i d e r e d u c t i o n o f 467 y i e l d e d 468,  trans-4,4a-dimethyl-2-hydroxy-  -  V  -  1,2,3,4,4a,5,6,7-octahydronaphthalene allylic  ., a c e t y l a t i o n  o x i d a t i o n w i t h chromic anhydride gave  of 470 produced the dienone 471,  5,6-tetrahydro-2(3H)-naphthalenone, octalone  468 and  subsequent  trans-4a,5-dimethyl-7-  acetoxy-4,4a,5,6,7,8-hexahydro-2(3H)-naphthalenone acetylation  of  (470).  Dehydro-  trans-4a,5-dimethyl-4,4a,  and s e l e c t i v e h y d r o g e n a t i o n  gave  239.  Androst-4-en-3-one  (240) was prepared as  on o x i d a t i o n and r e d u c t i o n p r o c e d u r e s . androst-5-en-17-one  (473)  the r e s u l t  In the f i r s t  was n e a r l y q u a n t i t a t i v e l y  study,  r e d u c t i o n and then o x i d i z e d under a v a r i e t y  to  240.  T h i s work l e d to new i n s i g h t s  two  of  studies  38-hydroxy-  reduced v i a  Wolff-Kishner 'octalone'  of  the  conditions  i n t o the mechanism o f  chromium t r i o x i d e o x i d a t i o n i n dimethylformamide w i t h a c i d and i n dichloromethane w i t h n i t r o g e n bases. studies  on c h o l e s t e r o l  Mechanistic explanations  o x i d a t i o n and p r a c t i c a l a p p l i c a t i o n s  systems a r e g i v e n .  In the second r o u t e to  (472)  into a series  was c o n v e r t e d  3,17-dione  (562).  trimethylenedioxy  These i n c l u d e d the methoxy  and 2 , 2 - d i m e t h y l t r i m e t h y l e n e d i o x y  mechanisms were  of C-3 d e r i v a t i v e s  (619), e t h y l e n e d i t h i o  reduction products  'octalone'  (594)  (598 ), ;  (602),  of  other  testosterone  androst-4-ene-  ethylenedioxy  trimethylenedithio  derivatives.  from these compounds were s t u d i e d  formulated.  240,  to  from  (563), (600),  The W o l f f - K i s h n e r and  plausible  24Q  - vii -  R  341  R= H  343 A-Enedione  467 R = C H  375 Y = CHSBu  376 X = 0, Y=CHSBu 356 X=0, Y=H 357 X = Y=H  n  3  n  2  2  Et0 C •  cr^o  2  419 R ^ C H g , R = H 2  4 2 0 R,= H , R = C H 2  468 X =H ,R = H  562  2  469 X = H , R = C0CH 2  470 X =0, R=C0CH  3  3  3  - viii  TABLE  OF  -  CONTENTS  Page TITLE PAGE  . .  i  .  i i  ABSTRACT TABLE OF CONTENTS  . . . .  .  LIST OF FIGURES, CHARTS, AND TABLES  . . . . . .  ACKNOWLEDGEMENTS  . , . *  INTRODUCTION I. II.  .  General  . . . . . . . . . . . . . . . . .  viii x x i i  1 1  Approaches to S t e r e o s e l e c t i v e Hydroazulene Synthesis  III.  12  Approaches t o S t e r e o s e l e c t i v e Synthesis  .  . . . . . . . .  DISCUSSION I.  . . . . . . . . . . . .  G e n e r a l Development  o f the R e a c t i o n  Sequence II.  Spirane  S y n t h e s i s o f a,B-Unsaturated Derivatives  30  49  i  . . . . . . . . . . . .  49  Hydronaphthalenone . . . . . . . . . . .  52  A. O c t a l o n e 234 (4a-Methyl-4,4a,5,6,7,8hexahydro-2(3H)-naphthalenone) . . . . . . .  56  - ix -  TABLE  OF  CONTENTS  DISCUSSION, I I Continued.  Page  B. Octalone 235 (4a,~8a-Dimethyl-4,4a,5,6,7,8hexahydro-2(3H)-naphthalenone)  62  C. Octalone 236 (8a-Acetoxy-4a-methyl-4,4a,5, 6,7,8-hexahydro-2(3H)-naphthalenone) . . .  75  D. Octalone 232 (4a,8,8-Trimethyl-4,4a,5,6,7,8hexahydro-2(3H)-naphthalenone)  99  E. Octalone 238 and 239 (4a,5-Dimethyl-4,4a,5, 6,7,8-hexahydro-2(3H)-naphthalenone) . . .  108  F. 'Octalone' 240 (Androst-4-en-3-one) Androstenone 240 from 38-Hydroxyandrost-5-en-17-one (473) . . . . . . . .  138  Androstenone 240 from Testosterone (472)  ...  EXPERIMENTAL  199  229 i  EXPERIMENTAL TABLE OF CONTENTS  302  BIBLIOGRAPHY  3 0 3  APPENDIX I  321  APPENDIX I I  354  - x -  LIST  OF  FIGURES, CHARTS,  AND  TABLES Page  CHART I  SESQUITERPENE BIOSYNTHESIS  2  CHART I I  CYCLOPROPYL KETONES FROM INTRAMOLECULAR KETOCARBENE ADDITION TO SUBSTITUTED CYCLOHEXENES  • • •  51  FIGURE I  GAS CHROMATOGRAM OF OCTALONE 234 PREPARATION • • •  58  FIGURE I I  GAS CHROMATOGRAM OF OCTALONE j!35 PREPARATION • • •  65  TABLE I  STEREOCHEMISTRY OF THE ALKYLATION PRODUCTS OF THE BLOCKED KETONE 400  TABLE I I  120  PRODUCT DISTRIBUTION OBTAINED BY METHYLLITHIUM TREATMENT OF ENOL LACTONES  TABLE I l i a  127  CHROMIUM TRIOXIDE OXIDATION OF CHOLESTEROL IN DIMETHYLFORMAMIDE  TABLE I l l b  154, 163  SNATZKE OXIDATIONS OF CHOLESTEROL OXIDATION PRODUCTS  TABLE IVa  156  CHROMIUM TRIOXIDE-PYRIDINE OXIDATION OF CHOLESTEROL IN DICHLOROMETHANE ("COLLINS") . . .  168  i  TABLE IVb  PYRIDINE DEPENDENCE OF COLLINS OXIDATION OF CHOLESTEROL  TABLE IVc  175  INFLUENCE OF AMINE BASES ON THE COLLINS OXIDATION OF CHOLESTEROL  TABLE V  180  OXIDATION WITH CHROMIUM TRIOXIDE-NITROGEN BASE REAGENTS  ,  169, 184  - xi LIST  OF  FIGURES,  CHARTS,  AND  TABLES  Page TABLE VI  CHROMIUM TRIOXIDE-DIMETHYLPYRAZOLE OXIDATION OF CHOLESTEROL IN DICHLOROMETHANE ("COREY") .  TABLE V I I  EFFECT OF p K ^  ON "COLLINS" OXIDATION  OF CHOLESTEROL . . . . TABLE V I I I  183  188  REDUCTION OF ANDROST-4-ENE-3,17-DIONE  AND  ITS C-3 DERIVATIVES BY THE BARTON MODIFICATION OF THE WOLFF-KISHNER  222  REDUCTION  i  -  xii -  ACKNOWLEDGEMENTS  I w i s h to express my s i n c e r e for  the p a t i e n c e  of my g r a d u a t e discussions of  this  shown, and the encouragement  studies.  to D r . Edward P i e r s given,  d u r i n g the p e r i o d  H i s i n v a l u a b l e a d v i c e and e n l i g h t e n i n g  throughout  thesis  thanks  the c o u r s e of t h i s r e s e a r c h and the p r e p a r a t i o n  are a pleasure  to  acknowledge.  My e x p e r i m e n t a l work has been the b e n i f i c i a r y informal discussions general interest Piers'  o f many  and p r a c t i c a l s u g g e s t i o n s r e s u l t i n g from the  shown by a l l the p r e s e n t and p a s t members of D r .  research group.  I would a l s o  of v a r i o u s members o f our c l o s e s t  l i k e to acknowledge  neighbour,  Dr. Kutney's  the h e l p group.  The work o f M i s s B e a t r i x K r i z s a n on the i l l u s t r a t i o n s and Mrs Diane Gray on the t y p i n g has added immeasureably appearance  of t h i s  thesis.  The encouragement  of my w i f e ,  to the Elizabeth,  i n the c o m p l e t i o n of t h i s work was t r u l y t e s t e d by her p r o o f of  the e n t i r e m a n u s c r i p t .  during  The c o n s i d e r a t i o n ' shown by many i n d i v i d u a l s  the c o u r s e of the p r e p a r a t i o n of t h i s  exceeded  by E l i z a b e t h ' s  reading  thesis  i s only  patience.  The f i n a n c i a l support o f the N a t i o n a l Research C o u n c i l of  Canada (1968-1971)  is gratefully  acknowledged.  - 1 -  STUDIES RELATED TO  THE  TOTAL SYNTHESIS OF SESQUITERPENES INTRODUCTION I.  General The a p p l i c a t i o n of modern a n a l y t i c a l techniques to n a t u r a l l y  occurring o i l s and p l a n t e x t r a c t s has demonstrated the widespread occurrence of the terpenoid f a m i l y of compounds i n trees and shrubs. B i o l o g i c a l l y , the d e r i v a t i o n of these terpenoids commences w i t h the common biochemical u n i t a c e t y l CoA and proceeds through mevalonic  acid  and the subsequently formed isoprene or polyisoprene pyrophosphate to mono-(C )-, s e s q u i - ( C ) - , d i - ( C ) - , s e s t e r - ( C > - , or t r i - ( C ) 10  terpenes (1).  1 5  2 Q  25  3 Q  The incomplete r e l a t i o n s h i p between h e a d - t b - t a i l linkages  of isoprene u n i t s (4) (2) and the wide s t r u c t u r a l v a r i a t i o n s  observed  i n the terpenoids i s o l a t e d gave r i s e to the Biogenetic Isoprene Rule (3) by Ruzicka, Eschenmoser, Jeger, and A r i g o n i i n 1955, p o s t u l a t i n g the p o s s i b i l i t y of rearrangement of the polyisoprene intermediates.  As  the l a r g e s t and most v a r i e d group of terpenoids, the sesquiterpenes provided the most demanding t e s t s of these concepts.  The b i o g e n e t i c  c o r r e l a t i o n of s e v e r a l sesquiterpenes was considered by Hendrickson i n 1959  (4) and l a t e r reviewed comprehensively  Ramage i n 1967  (5).  by Parker, Roberts  and  Confirmation of the general b i o s y n t h e t i c route  f o r sesquiterpene formation from a c e t y l CoA  (1_) and mevalonic acid (2)  through trans- or c i s - f a r n e s y l pyrophosphate (6,7_) has been completed,  - 2 -  CHART I  SESQUITERPENE  BIOSYNTHESIS O  Acetyl C o A  II  C H o, C — S C o A  a  OH  1  Mevalonic Acid  OPP  Isopentyl Pyrophosphate  Geranyl  Isoprene unit  Pyrophosphate  *- Monoterpenes  OPP  Farnesyl  Pyrophosphate  Sesquiterpenes  OPP  a  Acetyl C o e n z y m e A is  NH  O H CH O < N I I II f\j CH,- C- S-(CH J_ N-C- (CH_)p—N—C—C—C—CH5-(OP—), OCH H II11 II I I *~ H 11 *I, cO O OHCH3 3  2  J  <-  I .  II  I  I  I  I  O—P —O I  OH  OH  2  - 3and  t h i s s u b j e c t has  been reviewed by  i n some cases v e r i f i e d , phosphate to the  (6).  The  postulated,  d i f f e r e n t sesquiterpene  c l a s s e s completes a t h e o r e t i c a l  o r i g i n of s e s q u i t e r p e n e s  b i o l o g i c a l r o l e of s e s q u i t e r p e n e s  a l t h o u g h s e v e r a l c l a s s e s appear to be  is s t i l l  (5).  little  i n c l u d e graphinone  (8),  P l a n t growth r e g u l a t o r s  stimulant  f o r l e t t u c e seeds i n the dark a t a c o n c e n t r a t i o n  p.p.m. (7),  a b s c i s i c a c i d ( a b s c i s i n I I , dormin, 9),  dormancy i n a number of p l a n t s p e c i e s and  vernolepin  (10),  understood,  e s s e n t i a l to b o t h p l a n t s  animals.  one  and  r e l a t i o n s h i p o f t r a n s - or c i s - f a r n e s y l p y r o -  u n d e r s t a n d i n g of the b i o c h e m i c a l The  Clayton  and  and  a germination of l e s s than  an i n d u c e r  of  a promoter of l e a f a b s c i s i o n  a more r e c e n t l y d i s c o v e r e d  growth i n h i b i t o r  (8),  (9).^  The s t r u c t u r e s shown i n t h i s t h e s i s do not n e c e s s a r i l y d e p i c t the absolute c o n f i g u r a t i o n . When the a b s o l u t e c o n f i g u r a t i o n i s r e l e v a n t and known, the s i g n of the o p t i c a l r o t a t i o n of the compound i s p l a c e d b e f o r e i t s name. On t h i s b a s i s j? and 9_ c o u l d be l i s t e d as (-)-graphinone and ( + ) - a b s c i s i c a c i d , a l t h o u g h IUPAC nomenclature, such as S - ( + ) - a b s c i s i c a c i d , would be b e t t e r . The t o t a l s y n t h e s i s of s e s q u i t e r p e n e s , however, i s u s u a l l y r a c e m i c , p r o v i d i n g a 1:1 m i x t u r e of b o t h enantiomers. A b s c i s i c a c i d , 9_, c o u l d then be used to r e p r e s e n t b o t h the n a t u r a l l y o c c u r r i n g ( + ) - a b s c i s i c a c i d and a racemic s y n t h e t i c m i x t u r e , ( + ) - a b s c i s i c a c i d , where the o t h e r enantiomer i s understood to be p r e s e n t , depending on the c o n t e n t o f the d i s c u s s i o n . For the most p a r t of t h i s t h e s i s , r e l a t i v e c o n f i g u r a t i o n s , r a t h e r than a b s o l u t e , are emphasized. Sometimes a b s o l u t e c o n f i g u r a t i o n s are e s s e n t i a l , as i n the d i s c u s s 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 a l homogeneity r u l e (Appendix I ) , where the o c c u r r e n c e i n d i f f e r e n t s p e c i e s of a few (+) and (-) a n t i p o d a l s e s q u i t e r p e n e s i s an important b i o s y n t h e t i c f e a t u r e .  Sirenin  (11),  Allomyces at  attracting  sperm to the female gametes of  c o n c e n t r a t i o n s of 10  hormone to be d i s c o v e r e d . sativum)  fungus  causes  insect  and l e a f  R= -CHO) (11),  plant  1 Q  J . H . = 14)  lb  biological applications  of  spot  through  the  while helminthosporol  (+)-juvabione  (13)  (12, The  and c e c r o p i a  has been r e c o g n i z e d to have  several  —  (13)  as does the i d e n t i f i c a t i o n of  among the i n s e c t pheromones o f b u t t e r f l i e s  and bees  sex  (Helminthosporium  (-12) i s r e p o r t e d to have growth-promoting p r o p e r t i e s .  j u v e n i l e hormone ( C  (14)  was the f i r s t  The C o c h l i o b o l u s s a t i v u s  j u v e n i l e hormone a c t i v i t y  farnesanes  ® M (10),  seedling blight  t o x i n h e l m i n t h o s p o r a l (12, R= -CH^OH)  L  the water mold  (2,3-dihydro-6-trans-farnesol)  (15).  (15,  degraded R = -COOH)  - 5 -  The s t u d y  of  has been somewhat  these and o t h e r b i o l o g i c a l l y  r e s t r i c t e d by t h e i r r e s i s t a n c e  i s o l a t i o n from the v e r y complex mixtures t h a t i n minute amounts. lesser  The same d i f f i c u l t i e s  or t e t r a c y c l i c  sesquiterpene  ethers,  or e s t e r s  in essential  of i s o l a t i o n .  i n the u n p u r i f i e d e x t r a c t  appears  reaction occurring during i s o l a t i o n . terpenes, (17)  jalaric  and e p i l a k s h o l i c a c i d  while l a c c i j a l a r i c acid  a c i d B (16)  acid  is  (18),  acid,  of  o r base  (19)  corresponding alcohols  In the cedrane c l a s s  t h r e e of which  would be expected  (20) and e p i l a c c i s h e l l o l i c (not y e t  acid  (11). to  its  to be the most common s i d e of  the p r e c u r s o r o f e p i s h e l l o l i c all  i n some  sesquiterpene  the d i s p r o p o r t i o n a t i o n o f an aldehyde  c o r r e s p o n d i n g a c i d and a l c o h o l ,  alcohols,  However,  t h e i r c o r r e s p o n d i n g a c e t a l s i n the crude e x t r a c t  The C a n n i z z a r o r e a c t i o n ,  tricyclic,  neither helminthosporal  Helminthosporium s a t i v u m and o n l y appear on h e a t , of  epoxides,  o i l s of p l a n t s .  F o r example,  to a  monocyclic, b i c y c l i c ,  i s not a n a t u r a l l y o c c u r r i n g  nor h e l m i n t h o s p o r o l are p r e s e n t  treatment  chemical  c o n t a i n these compounds  hydrocarbons, ketones,  cases the compound i s o l a t e d b u t an a r t i f a c t  to  sesquiterpenes  a r e a l s o apparent  e x t e n t i n the d i s c o v e r y o f a c y c l i c ,  acids,  important  (21)  reported).  'co-ocdur'  to g i v e  sesquiacid (16),  laccishellolic  (both i s o l a t e d )  and  The v e r y r e c e n t l y  the reported  -  6 -  (May, 1972) i s o l a t i o n o f seven new cedrane d e r i v a t i v e s  (17) a l s o  a C a n n i z z a r o - d e r i v e d a l c o h o l 2_3 and a c i d 24 from 22^, w h i l e 26 c o u l d o r i g i n a t e  i n a s i m i l a r manner from the aldehyde  2 2 R=-CHO 2 3 R=-CH OH 2 4 R = -COOH  suggests the p o s s i b i l i t y suspicious  25. The  2  (27) and v a l e r e n i c  drimanes o f g e n e r a l s t r u c t u r e  the a l c o h o l  , 2 5 R=-CHO 2 6 R = -CH OH  2  isolation of valerenal  suggests  29^, JiO and  acid  (28) ( 1 8 ) , o r the  ( 1 9 ) , from the same  of a Cannizzaro r e a c t i o n .  too t h a t o n l y t h u j o p s e n o l  cl  plant  I t i s somewhat  (32) (20 ) and h i n o k i i c a c i d (33)  -  7 -  CHO  30  31  (20 ) a r e known, and t h a t o n l y cyclocopacamphenol cyclocopacamphenoic aldehydes  acid  (21 )  successful  (36),  t h e i r corresponding  steam d i s t i l l a t i o n i s e s s e n t i a l ,  but i t  is  e l i m i n a t i o n i s o c c u r r i n g (22).  e x t r a c t i o n o f Hedycarya a u g u s t i f o l i a elemol  but  (38)  their  In the case of  the i s o l a t i o n of, the germacrane h e d y c a r y o l  the elemane a r t i f a c t  ) and  a l c o h o l s and a c i d s o c c u r as e s t e r s ,  thermal o r s o l v o l y t i c is  (21  In a d d i t i o n , many o f the n a t u r a l l y  i s o l a t i o n requires disruptive techniques.  furoventalene  significant  are known, w h i l e  b  have n o t been i s o l a t e d .  occurring sesquiterpene  known i f  (35)  (34)  (37)  not Also by  l e a v e s a t room t e m p e r a t u r e ,  whereas  i s produced by steam d i s t i l l a t i o n  (23).  - 8 -  37  The c o m p l e x i t y o f  38  the i s o l a t e d m u l t i f u n c t i o n a l s e s q u i t e r p e n e  be e x e m p l i f i e d by melampodin ( 3 9 ) ,  a germacrane whose s t r u c t u r e and  c o n f i g u r a t i o n were r e p o r t e d i n 1972  by one group u s i n g  methods and an n . m . r . s h i f t  ( 2 4 ) , w h i l e a second group  reagent  confirmed these f i n d i n g s by X - r a y a n a l y s i s careful  (25) .  by the r a p i d growth i n the number o f d i f f e r e n t These d i f f e r e n t  classical  The success  i s o l a t i o n and s t r u c t u r a l e l u c i d a t i o n t e c h n i q u e s  skeletons.  can  is  demonstrated  sesquiterpene  types o f s e s q u i t e r p e n e s  of both  carbon  were reviewed  ten  -  9 -  y e a r s ago by Sorm e_t al^. (26) when t h e i r s u r v e y l i s t e d classes,  seven o f which have s u b s e q u e n t l y t>een shown to be i n c o r r e c t  or n o n - e x i s t e n t . i n 1966 while  twenty-eight  (27)  The c o l l e c t i o n o f s e s q u i t e r p e n e  gave over f o r t y  different  d a t a by O u r i s s o n ejt  sesquiterpene  the c o m p i l a t i o n completed d u r i n g the c o u r s e o f  skeletal this  al.  types,  thesis 2  provided a l i s t r a p i d aging of  o f almost n i n e t y d i f f e r e n t  is  this class  v a r i a t i o n o f the c l a s s  reviews  The  work t h a t mimics the b i o g e n e t i c  o f s t r a i n and s t e r i c  A successful  very synthetic  total  but  i n t e r a c t i o n s a r e not  i n biogenetic  schemes,  synthesis,  requirement f o r a s i m p l e s t e r e o s e l e c t i v e  s i n c e here  therefore,  generates  a  corroborates  made to the p a r t i c u l a r  sesquiterpene.  The r a p i d advances made i n s y n t h e t i c  total  of sesquiterpenes  r e q u i r e that  the  the p a r t i c u l a r  sequence which f u l l y  the s t r u c t u r a l and s t e r e o c h e m i c a l assignments  synthesis  The  concur w i t h the c o n f i r m a t i o n a l demands o f  enzyme i n v o l v e d .  provide not  r e l a t i o n s h i p s , but a l s o organic chemistry.  functional  r o u t e has w i d e s p r e a d i n t e r e s t ,  the dominant f a c t o r s  substrate w i l l  w i t h the concomitant  members t h a t makes s e s q u i t e r p e n e s  c h a l l e n g i n g problems to s y n t h e t i c  the c l a s s i c a l concepts  s h o u l d be made.  growth, however,  o n l y demanding t e s t s o f b i o g e n e t i c  necessarily  classes.  t h i s p a r t i c u l a r c o l l e c t i o n of l i t e r a t u r e i n f o r m a t i o n  s u g g e s t s t h a t more f r e q u e n t It  sesquiterpene  approaches  to  the  i n t h i s a r e a a l s o more  3  f r e q u e n t and more e x t e n s i v e l i t e r a t u r e reviews by u n d e r t a k e n . 2 The d i f f e r e n t c l a s s e s o f s e s q u i t e r p e n e s have been l i s t e d i n Appendix I to p r o v i d e an up=to-date s u r v e y o f the s t r u c t u r a l v a r i e t i e s known. Wherever p o s s i b l e , a r e c e n t l y d i s c o v e r e d member of each c l a s s i s g i v e n . Thus the e x c e l l e n t 1964 review by M e l l o r and M a n a v a l l i (28) r e q u i r e s u p d a t i n g to be r e l e v a n t to t h i s t h e s i s . A l i t e r a t u r e survey o f the g e n e r a l i z e d approaches to s e s q u i t e r p e n e s y n t h e s i s i s , t h e r e f o r e , p r e s e n t e d i n Appendix I I .  -  Synthetic an e f f i c i e n t  strategies  10  -  for sesquiterpene synthesis  often require  method o f t r a n s f o r m i n g d e c a l i n i c compounds i n t o  r e a d i l y a v a i l a b l e r i n g systems.  By n e c e s s i t y ,  this  strategy  less often  u t i l i z e s a study of n o r - s e s q u i t e r p e n e model compounds to p r o v i d e technical information required. and c y c l o d e c a d i e n e d e r i v a t i v e s  The p r e p a r a t i o n s o f  the  cyclodecadienes  are an example of t h i s a p p r o a c h .  d i s c u s s e d i n the r e v i e w o f s e s q u i t e r p e n e s y n t h e t i c thesis,  As  approaches to be  found i n Appendix I I  of t h i s  germacranes are d i f f i c u l t  obtain synthetically  and a r e r e a d i l y i s o m e r i z e d to elemanes.  to The  r e c e n t use of h e t e r o l y t i c b o r o n a t e f r a g m e n t a t i o n o f a d e c a l i n i c  mesylate  (40,A = a - H , B = &-B0 H , X = - S 0 C H  intra-  2  2  3  ( - M s ) , R = H) (29) o r the  molecular e l i m i n a t i o n of a d e c a l i n i c y - d i o l acetate H, X = - C 0 C H  3  (-Ac),  R = 1,1-(CH ) ) 3  2  (40, A = 3 - 0 H ,  B =  (30) has p r o v i d e d a method o f  OX  - . f i r *  42 R'= CH=  CH  2  o b t a i n i n g the d e s i r e d i n t e r n a l c l e a v a g e p r o d u c t (41)  r a t h e r than the  p e r i p h e r a l c l e a v a g e one ( 4 2 ) .  of further  on model systems of  However the n e c e s s i t y  studies  i s emphasized by the v e r y r e c e n t l y r e p o r t e d dependence  t h i s r e a c t i o n on the presence of a d d i t i o n a l s u b s t i t u e n t s .  While  one t r i m e t h y l d e c a l i n compound (40^, A = a - H , B = B - B O ^ , X = - M s , R = 1,1-(CH ) ) 3  41,  2  gave a s i n g l e o l e f i n i c p r o d u c t , the expected  r e s u l t i n g from i n t e r n a l f r a g m e n t a t i o n ,  cyclodecadiene  the c o r r e s p o n d i n g t r i m e t h y l -  d e c a l i n w i t h a 7 8 - h y d r o x y l a f f o r d e d o n l y the elemene d e r i v a t i v e 42_  - 11 -  (R' = CH^CHO), the p e r i p h e r a l cleavage product (31). Before c o n s i d e r i n g , s p e c i f i c a l l y , the development of methods to convert d e c a l i n i c compounds to hydroazulene  or spirane systems, the  s t e r e o r a t i o n a l approach developed by Heathcock e_t a l . f o r g u a i a z u l e n i c sesquiterpenes  (32-34) should be considered.  This group's s y n t h e t i c  strategy of (a) c o n s t r u c t i n g an a p p r o p r i a t e l y f u n c t i o n a l i z e d d e c a l i n i c intermediate, (b) e s t a b l i s h i n g the required r e l a t i v e stereochemistry of the eventual guaiazulene i n the d e c a l i n through e s t a b l i s h e d conformational p r i n c i p l e s , and (c) rearranging s o l v o l y t i c a l l y the d e c a l i n i c intermediate to the desired hydroazulene  a c t u a l l y represents  the c e n t r a l theme of the work undertaken i n t h i s t h e s i s .  While the  t h i r d part of the preceding s t r a t e g y , the r i n g transformation process, i s a s o l v o l y t i c rearrangement i n Heathcock's work and a photochemical r e a c t i o n i n the work described i n t h i s t h e s i s , the a t t r a c t i o n s y n t h e t i c a l l y i n both cases i s the s t e r e o s e l e c t i v e conversion of r e a d i l y a v a i l a b l e d e c a l i n i c compounds to more unique r i n g systems.  The completion of  Heathcock's work not only presented a comprehensively  planned  study  u t i l i z i n g model d e c a l i n i c systems, (32) but a l s o r e s u l t e d i n the t o t a l synthesis of two g u a i a z u l e n i c sesquiterpenes, a-bulnesene (44, from 43) 4 and b u l n e s o l (46 from 45) (33),  While the l a t t e r work may, at present,  be of more i n t e r e s t to some, the very r e c e n t l y published f u l l paper on the study of the s o l v o l y t i c product d i s t r i b u t i o n s from d i f f e r e n t model d e c a l i n i c t o s y l a t e s under a v a r i e t y of r e a c t i o n conditions (34) o f f e r s ^  Other s o l v o l y t i c syntheses of these compounds and the analogously prepared kessane are o u t l i n e d i n the 'eudesmane approach' i n Appendix I I .  -  12  -  an i n v a l u a b l e s o u r c e of i n f o r m a t i o n f o r b o t h f u t u r e m e c h a n i s t i c and f u t u r e  II.  synthetic  work.  Approaches t o S t e r e o s e l e c t i v e  Hydroazulene  Several preparations of hydroazulenes heptane,  cyclodecane,  Synthesis  from c y c l o p e n t a n e ,  c o n t r o l to be e x e r t e d .  sesquiterpene  to the p r e p a r a t i o n o f a z u l e n e s  synthesis.  did find,  derivatives.  M a r s h a l l and c o w o r k e r s , i n two  however,  In the f i r s t  to i t s  (36).  (35),  instance,  (36)  The c y c l o p e n t y l  hydroazulenes  and c y c l o h e p t a n e  (37)  the t r i m e t h y l h y d r i n d a n o n e 47_ was  oxime 4_8 and s o l v o l y t i c a l l y  the u n s a t u r a t e d n i t r i l e  separate  that stereoselectively-formed  fragmented  49 and 50_ i n a 60:40 r a t i o by p _ - t o l u e n e s u l f o n y l pyridine  5/7  o p p o r t u n i t y to meet the s t e r e o c h e m i c a l demands o f  c o u l d be o b t a i n e d from c y c l o p e n t a n e  converted  or  p r e c u r s o r s i n an a n n e l a t i o n method of s y n t h e s i z i n g the  little  studies,  have  stereochemical  The u t i l i z a t i o n o f preformed c y c l o p e n t a n e  fused r i n g system, w h i l e p e r t i n e n t offers  cyclo-  h y d r i n d a n e , and hydronaphthalene d e r i v a t i v e s  been r e p o r t e d , but o n l y a few o f these r o u t e s p e r m i t  cycloheptane  studies  aldehyde _51,  to the  nitriles  chloride in refluxing  o b t a i n e d by r e d u c t i o n o f  4_9_, was c y c l i z e d w i t h s t a n n i c  chloride i n  -  13  -  CN  50  49  4 1 X=0 4 8 X = NOH  OH  benzene  (or s i l i c a g e l )  (4a-OH:48-OH i s method  52  E = Electrophile  51  (37)  89:11)  to a f f o r d 5  the b i c y c i o [5. 3. 0] d e c a n o l 52_  i n nearly quantitative  used an a c i d - c a t a l y z e d  d i o n e 5_3 to produce the s u b s t i t u t e d  yield.  Marshall's  a l d o l condensation of  the  second  cycloheptyl  b i c y c i o [ 4 . 3.1]decenone e s t e r  54.  O0 Et 2  52  54  While hydronaphthalene rind hydrindqne nomenclature p r o v i d e s the b e s t d e s c r i p t i o n o f the b i c y c i o [ 4 . 4 . 0 ] d e c a n e ( i . e . d e c a l i n and o c t a l o n e ) and b i c y c i o [ 4 . 3 . l ] n o n a n e systems, the IUPAC r u l e s (39) have been f o l l o w e d f o r the o t h e r b i c y c l i c systems c o n s i d e r e d i n t h i s t h e s i s . In a l l cases where a numbered c e n t e r i s c o n s i d e r e d the a p p r o p r i a t e p o s i t i o n i s l a b e l l e d i n the c o r r e s p o n d i n g f i g u r e o f the s t r u c t u r e .  -  14  -  T h i s compound was used to p r o v i d e both of (a and b) by a r e d u c t i v e  sequence.  as t h e i r m e t h y l s u l f o n a t e s  the b r i d g e d a l c o h o l s 5_5  These compounds were  by treatment w i t h a c e t i c  to p r o v i d e t h e i r r e s p e c t i v e  hydroazulenes  (56)  solvolyzed  acid-sodium acetate  i n 80% y i e l d .  HO  a R'= H, R"= CH _b_ R'=CH , R" = H 3  55 The f i r s t synthetic further  s t u d y by M a r s h a l l ' s g r o u p , undertaken to develop  r o u t e to the v e t i v a n e after  Sfi.  3  their discovery  vetihydroazulenes  (57)  (36).  carbon s k e l e t o n , that vetivanes  stereoselective  was not p u r s u e d  were spiremes  (58) , not  The second sequence was developed i n t o a  57 total  a  52.  synthesis  of  (+)-bulnesol  acetoxymethyl-substituted  bicyclo[4.3.l]decanol  the b i c y c l o [ 5 . 3 . 0 ] d e c e n y l  derivative  by s o l v o l y z i n g mesylate  59  the  (38)  60 and then e l a b o r a t i n g the  to latter  While t h i s f i r s t method c o u l d be c o n s i d e r e d as a c o n v e r s i o n of a h y d r i n d a n e to a h y d r o a z u l e n e ( v i a a c y c l o p e n t y l d e r i v a t i v e ) M a r s h a l l l a t e r r e p o r t e d a more d i r e c t c o n v e r s i o n method t h a t w i l l be c o n s i d e r e d s u b s e q u e n t l y . However see a l s o A n d e r s o n ' s (36) r e c e n t publication.  -  to  (+)-bulnesol  (46).  15  -  However, i n g e n e r a l ,  the r e q u i s i t e  substituted  H  b i c y c l i c p r e c u r s o r s employed by these methods are d i f f i c u l t and n e i t h e r approach a l l o w s synthetically  desirable.^  the s t e r e o c h e m i c a l v a r i a t i o n s A non-stereoselective,but  p e n t y l -> h y d r o a z u l e n e s e s q u i t e r p e n e (+)-guaiol system  synthesis  (66) u s i n g a b a s e - c a t a l y z e d  (41).  cyclopentanone  to p r e p a r e ,  that  relevant  was r e c e n t l y  r i n g c l e a v a g e of a b r i d g e d  was c y c l i z e d by s e q u e n t i a l base and a c i d  to the t r i c y c l i c 1 , 5 - e n d i o n e 64.  cyclo-  reported for  The M i c h a e l a d d i t i o n p r o d u c t j53, o b t a i n e d from (61),  are  T h i s compound p r o v i d e d a 1:1  2-methyltreatments stereoisomer  The f i r s t t o t a l s y n t h e s i s o f p a t c h o u l i a l c o h o l ( i i i ) , a s e s q u i t e r p e n e b i o g e n e t i c a l l y r e l a t e d to the g u a i a n e s , used homocamphor ( i ) i n a  i  if  iii  sequence v i a i i ^ that was u n f o r t u n a t e l y s y n t h e t i c a l l y ambiguous although s t e r e o s e l e c t i v e (40). The s y n t h e s i s u t i l i z e d the r e a r r a n g e ment o f a d e r i v a t i v e of the hydroazulene i i , o b t a i n e d i n t u r n from a substituted c y c l o h e p t a n o n e ' ( i ) , to p r o v i d e i i i . 1  - 16 -  m i x t u r e of  the enone e s t e r  65_ a f t e r  F u r t h e r e l a b o r a t i o n o f the e s t e r which  (+)-guaiol  (66) was  r i n g c l e a v a g e w i t h sodium methoxide.  65_ y i e l d e d a m i x t u r e of  impetus from the b i o g e n e t i c  that  (42,43).  epoxygermacrone  by s t e r e o s e l e c t i v e  from c y c l o d e c a n e s  has  received  and c h e m i c a l d e r i v a t i o n of guaianes  The d i s c o v e r y by H i k i n o and c o l l e a g u e s (67),  from  isolated.  The p r e p a r a t i o n o f h y d r o a z u l e n e s  germacranes  isomers  from  (43 )  p r e p a r e d from the c o r r e s p o n d i n g germacrone  enzymatic e p o x i d a t i o n , was r e a d i l y c o n v e r t e d  to  the guaiane procurcumenol (68) by treatment w i t h p _ - t o l u e n e s u l f o n i c a c i d i s one o f  the more r e c e n t l y  r e p o r t e d examples  o f such a c o n v e r s i o n .  The p r e v i o u s l y known p y r o l y t i c rearrangement of 69_ to 7_0 (43 ) and the acid-catalyzed olefinic cases,  rearrangement o f 69_ to a m i x t u r e o f  a l c o h o l _72_ (43 ) are two o t h e r s .  the d i o l  7_1 and the.  In these t h r e e p u b l i s h e d  the t r a n s a n n u l a r c y c l i z a t i o n to a b i c y c l o [ 5 . 3 . 0 ] d e c a n e  system  -  is  17  -  the r e s u l t of an a n t i - M a r k o w n i k o f f opening o f the e p o x i d e ,  s i m u l t a n e o u s o r subsequent results  i m p l y t h a t epoxides  a d d i t i o n to the double bond. may be i n v o l v e d i n guaiane  the p r e v i o u s l y d i s c u s s e d d i f f i c u l t y has made s y n t h e t i c  chemical ambiguity of p r e p a r i n g hydroazulenes derivatives, approach  biosynthesis,  In s p i t e from  of  derivatives  the  stereo-  cyclodecadiene  and i n s p i t e o f M a r s h a l l ' s own e a r l i e r d i s m i s s a l o f  ( 3 8 ) , M a r s h a l l and Huffman have r e c e n t l y  preliminary findings  on a n o v e l s t e r e o s e l e c t i v e  from a c y c l o d e c a d i e n e . heterolytically provide  While these  i n p r e p a r i n g cyclodecene  work arduous i n t h i s a r e a .  with  approach to  their hydroazulenes  These workers employed t h e i r method o f  fragmenting  the c y c l o d e c a d i e n y l  d e r i v a t i v e _76_ was  disclosed  this  the b o r o n a t e of a d e c a l i n i c mesylate a l c o h o l 75_.  then s o l v o l y z e d  to  The c o r r e s p o n d i n g p_-nitrobenzoate  i n aqueous dioxane  to p r o v i d e  the  -  18  -  H  75 R = H 7 6 R = rp— N 0 C H 2  6  ZZ 4  h y d r o a z u l e n o l 7_8 i n 70% y i e l d selectivity  78  CO(44 ) .  and s t e r e o s e l e c t i v i t y  The h i g h degrees o f  observed i n the r e a c t i o n were  e x p l a i n e d i n terms of a " s i c k l e " t r a n s i t i o n s t a t e of allylic  c a t i o n 77.  regio-  the  incipient  The c r o s s e d , v e r s u s a l i g n e d , o r i e n t a t i o n o f  the  t r a n s a n n u l a r double bond systems presumably m i n i m i z e s s t e r i c  interactions,  thereby  a  f a v o u r i n g the t r a n s - f u s e d p r o d u c t .  selective  concerted  The a l t e r n a t i v e ,  stereo-  (S^2') a t t a c k by the i s o l a t e d double bond on the  a l l y l i c p _ - n i t r o b e n z o a t e , was r e c e n t l y  excluded  (44^) by the  observation  t h a t the a l l y l i c isomer of _76_ a l s o p r o v i d e d 7_8_ s t e r e o s e l e c t i v e l y  by  solvolysis. A p r e p a r a t i o n of hydroazulenes  from h y d r i n d a n e s was r e p o r t e d  i n d e p e n d e n t l y and n e a r l y s i m u l t a n e o u s l y by two groups i n 8  1971.  g  5 P r e v i o u s work on the a c e t o l y s i s o f A -19-methanesulfonoxy steroids (45) and s a t u r a t e d b i c y c l i c systems (46) p r o v i d e d l i t e r a t u r e precedence f o r t h i s work.  -  S c a n i o and H i l l hydroazulenyl  (47)  mesylate  a c e t a t e 82_.  £!3_ i n r e f l u x i n g  paper  hydroazulene  84^ to g u a i o l  (49),  derivative,  87_ a f t e r  acetic  the.  However,  ozonolysis,  r e q u i r e d compound 83.  the  prepared  acetate.  the  the  hydrindanyl  In an  then e l a b o r a t e d  the  t h i s work r e q u i r e d a  a l c o h o l j36_ p r e p a r e d i n s i x  (85),  to p r o v i d e  r e d u c t i v e workup,  then needed  (48)  by s o l v o l y z i n g  M a r s h a l l and coworkers (66).  to  c o r r e s p o n d i n g hydrindene j$0_ p r o v i d e d  acid-potassium  the p r o t e c t e d  F i v e additional s t e p s were  7_9 s o l v o l y z e d  M a r s h a l l and Greene  from 2-carbomethoxycyclohexanone aldehyde  the  a c e t a t e 84_ s t e r e o s e l e c t i v e l y  accompanying  decalinic  -  found t h a t the hydrindane  a c e t a t e £51, w h i l e  the h y d r o n a p h t h y l hydroazulenic  19  to complete  the  steps  hydrindane  and a l d o l  condensation.  the p r e p a r a t i o n of  - 20 -  a  COOCH  3  3  Steps 86  85  5  83  Steps CHO  87  The p r e p a r a t i o n s o f h y d r o a z u l e n e s  from hydronaphthalenes  have,  to d a t e , p r o v i d e d the most u s e f u l s y n t h e t i c s t r a t e g y a v a i l a b l e f o r the c o m p l e t i o n o f s e s q u i t e r p e n e s k e l e t o n s r e l a t e d are t h r e e s t e r e o s e l e c t i v e r o u t e s a v a i l a b l e , one o f the 8a-methyl-l-hydronaphthene r e c e n t work by Heathcock e_t aT. 88 and 90_ p r o v i d e d p r e d o m i n a n t l y  to g u a i a n e s .  o f which,  the  There solvolysis  d e r i v a t i v e s , i n c l u d e s the v e r y (34).  The model t r a n s - f u s e d t o s y l a t e s  (80%) the h y d r o a z u l e n e s  (89 and 91_  r e s p e c t i v e l y ) a f t e r s o l v o l y s i s , w h i l e the c o r r e s p o n d i n g c i s - f u s e d compounds 9^2 and 95^ a f f o r d e d u n r e a r r a n g e d  o c t a l o n e s i n the case of  (93:94 i s 74:13) and a m i x t u r e of octalvnifL; and hydronaphthalenes the case o f 95_ (96^97_:98. r a t i o i s 35:30:24).  The  importance  c o n f o r m a t i o n a l i n f l u e n c e s by r i n g s u b s t i t u e n t s i n these rearrangements  i s apparent  s i m i l a r compounds.  The  in  of s u b t l e  solvolytic  from the work by Y o s h i k o s h i ejt al_.  i n t r o d u c t i o n o f a 4a-methyl  92  (50)  on  i n t o 88^ l e d to an  85%  -  21  -  TsO  y i e l d of  the hydroazulenone c o r r e s p o n d i n g to 89_ as e x p e c t e d ,  4a-methy1-6-keto-cis-tosylate  total  solvolytic  stereoselective  bulnesol and  this  3  syntheses  preparative of  (103)  and  3a-methyl-5-keto-98.  t e c h n i q u e has l e d to  (+)-a-bulnesene  (46) by Heathcock and R a t c l i f f e  (+)-kessane  the  p r o v i d e d 46% of 4a-CH ~93 and 38% o f a  hydroazulenone m i x t u r e o f 3 a - m e t h y l - 5 - k e t o - 9 7 A p p l i c a t i o n of  but  (33)  (44)  and  (+)-  and ( + ) - b u l n e s o l  by Y o s h i k o s h i and coworkers  (50,51).  the  The  (46) efficiency  -  OH  22  -  MsO  104 of  this  that  aesthetically  Heathcock's  pleasing  syntheses,  approach i s  demonstrated by the  b o t h o f which r e q u i r e d seventeen  proceeded v i a compound 100,  p r o v i d e d 15-20% o v e r a l l y i e l d  sesquiterpene  a l c o h o l 9_9.  from the k e t o  o n l y known s y n t h e s i s here.  o f a pseudoguaiane,  a-santonin  in six  steps,  s h o u l d a l s o be  the d e c a l i n i c bromide 107, with s i l v e r  s t e p s and  of  An a d d i t i o n a l s y n t h e s i s ,  H e n d r i c k s o n and coworkers i n .1968 r e p o r t e d  o b t a i n e d by s o l v o l y z i n g  fact  (52  considered  ) their  derived  sulfate-sulfuric  the  results  from  a c i d at room  - 23 temperature.  The s t e r e o e l e c t r o n i c a l l y favourable trans a n t i p a r a l l e l  o r i e n t a t i o n of migrating and l e a v i n g atoms i n 107 afforded 75% y i e l d H Ref  O 106  107 Ra=  H,Re  = Br  1Q8 R a = B r , R e = H  of the unnatural pseudoguaianolide bromine was recovered unchanged.  109, while 108 w i t h i t s a x i a l Further s y n t h e t i c work has not been  reported f o r the n a t u r a l pseudoguaianes s i m i l a r to 109, probably because the n a t u r a l compounds have been discovered to r e q u i r e a t r a n s r i n g f u s i o n and a c i s - f u s e d lactone.  9  The second s t e r e o s e l e c t i v e method of preparing hydroazulenes  from  decalins i n v o l v e s the f a c i l e conversion of v i c i n y l c i s - g l y c o l monot o s y l a t e s of bicyclo[4.4.0]decanes to bicyclo[5.3.0]decanes v i a the Note added: A January 1973 p u b l i c a t i o n reports the o z o n o l y s i s of 8,y-unsaturated naphthalenona d e r i v a t i v e s (jL, R^=R2=H; or R^CH^, R2=H) provides hydroazulenedione d e r i v a t i v e s ( i i i ) - d i r e c t l y . However, the attempted conversion of i i i to a pseudoguaianolide provided only the unnatural c i s - r i n g j u n c t i o n and the preparation of R 2 = a l l y l i n i ^ f a i l e d (A^-2-one more s t a b l e ) w h i l e r e g i o s e l e c t i v e a l k y l a t i o n at C-7 of the hydroazulenedione a l s o f a i l e d ( 5 2 ) . b  -  24 -  p i n a c o l type o f rearrangement a c c o m p l i s h e d w i t h p o t a s s i u m _t-butoxide o r alumina (53) .  The o r i g i n a l work c o n v e r t e d  to o c t a l i n 110 i n t o the  p e r h y d r o a z u l e n o n e 112 and f u r t h e r s t u d i e s were then made of t h i s  111  n o  t r a n s f o r m a t i o n sequence later (118),  112  on s t e r o i d a l compounds.  adopted t h i s method f o r the t o t a l  synthesis  the enantiomer of the n a t u r a l l y - o c c u r r i n g  B u c h i and coworkers of  (-)-aromadendrene  (+)-aromadendrene,  by o b t a i n i n g the key i n t e r m e d i a t e 114 i n seven s t e p s from aldehyde  (113).  The c i s - g l y c o l m o n o t o s y l a t e  i n contact with activated  ring  (-)-perill-  116, when a l l o w e d to remain  alumina o r when t r e a t e d w i t h p o t a s s i u m  J^-butoxide i n _t-butyl a l c o h o l , r e a r r a n g e d t o a f f o r d  the p e r h y d r o a z u l e n o n e  OH  118 X = C H  2  -  117  i n 85% y i e l d .  25  A Wittig reaction with  gave the d e s i r e d s e s q u i t e r p e n e proof  118  t h a t the e a r l i e r a s s i g n e d The t h i r d ,  and o l d e s t ,  decalin derivatives conjugated  utilizes  acetylisophotosantonic  synthesis  methylenetriphenylphosphorane  a n d , as s u c h , p r o v i d e d unambiguous  1-epi  s t r u c t u r e was i n c o r r e c t .  method of p r o v i d i n g h y d r o a z u l e n e s  from  the p h o t o c h e m i c a l t r a n s f o r m a t i o n o f  cyclohexadienones.  of a - s a n t o n i n  -  cross-  The s t r u c t u r a l e l u c i d a t i o n o f "0_-  lactone",  the p h o t o c h e m i c a l rearrangement p r o d u c t  (106), o c c u r r e d over a s i x y e a r p e r i o d a f t e r  the  total  o f s a n t o n i n and proved t h a t the i s o l a t e d h y d r o a z u l e n e had  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 119  (55).  While i n v e s t i g a t i o n s  on the  106 generality  of  the r e a c t i o n (56)  and the mechanism o f the  rearrangement  were b e i n g p u r s u r e d ( 5 7 , 5 8 ) ,  the major p r o d u c t of s a n t o n i n ' s  i n a c i d i c media was used f o r  the s y n t h e s i s  sesquiterpenes.  1-Epicyclocolorenone  and d e s a c e t o x y m a t r i c a r i n while geigerin acetate artemesolactone  (122)  (125)  (61)  (120)  of s e v e r a l (59),  (124), a p h o t o p r o d u c t o b t a i n e d  the c r o s s - c o n j u g a t e d  ketone  chromophore o f  (63).  a c h i l l i n (121)  from  from  (60) 119,  8-epi-isophoto-  (56) by t r a n s f o r m i n g  (-)-artemisin  n a t u r a l l y o c c u r r i n g eudesmolide t h a t was i t s e l f 1969  guaiane  were p r e p a r e d d i r e c t l y  (62) was e l a b o r a t e d  photolysis  later  (123),  a  synthesized  in  12Q 121  O  O  122  HO  O  O O  O  123  124  These s y n t h e s e s of guaianes eudesmanes were, sequence steps.  until  recently,  from r e a d i l y a v a i l b l e more a t t r a c t i v e  u s i n g a p h o t o c h e m i c a l rearrangement  cross-conjugated  than a  as one o f  synthetic the  terminal  T h i s was p a r t l y due to the 30% y i e l d o f i s o p h o t o s a n t o n i c  obtained o r i g i n a l l y with u l t r a v i o l e t s o l u t i o n of santonin parameters  of  (56).  to date on t h i s  the  on the aqueous  W h i l e the m e c h a n i s t i c  w i l l be d i s c u s s e d  reaction,  later,  of  of  2 - f o r m y l dienone 126  base-catalyzed  deformylation of  hydroazulenone  127  and  cross-conjugated  to  acetic  reported  systematically (64)  a c i d and,  the crude p h o t o p r o d u c t ,  i n 70% o v e r a l l y i e l d .  acid  stereochemical  Caine and DeBardeleben i n aqueous  lactone  acetic  the many s t u d i e s  o n l y two have attempted  the y i e l d o f h y d r o a z u l e n e .  photolyzed  light  the p h o t o c h e m i c a l rearrangement  cyclohexadienones  maximize  125  Caine and h i s  after  obtained coworkers  the  -  subsequently substituent  27  -  r e p o r t e d t h a t the analogous (128)  photolysis  p r o v i d e d the model h y d r o a z u l e n e  stereospecifically  i n 65% y i e l d  129  131  of a - b u l n e s e n e . obtained  and 10% s p i r a n e 132  c o u l d be c o n v e r t e d  P i e r s and Cheng  from a - s a n t o n i n ,  upon p h o t o l y s i s ,  to the h y d r o a z u l e n e  conversion of 7-epi-a-cyperone  (136)  the c o r r e s p o n d i n g h y d r o a z u l e n e  (138).  functionality  directly  and  129  The work on these model systems was l a t e r  the dienone 130,  2-carboxy  (65).  128  the s y n t h e s i s  with a  i n t o 137  found to be u s e f u l (66)  afforded  found t h a t  while  79% h y d r o a z u l e n e  and w h i l e a - c y p e r o n e  135  in  (133)  i n 55% o v e r a l l y i e l d ,  p r o v i d e d o n l y a 15% y i e l d The i n t r o d u c t i o n o f a  of 2-carboxy  (R = COOH) not o n l y p e r m i t t e d the o v e r a l l  to be r a i s e d to 32%, but a l s o s i m p l i f i e d the p h o t o l y s i s  the  yield  m i x t u r e by  the  -  28 -  136  absence of  137  the s p i r a n e analogous  hydroazulenes  131,  4-epi-a-bulnesene  135 (140)  to 132.  138  F u r t h e r e l a b o r a t i o n of  and 138 p r o v i d e d 5 - e p i - a - b u l n e s e n e and ct-bulnesene  (44) ,  (139),  the  -  29  A second a p p l i c a t i o n of C a i n e ' s recently toxin-I  i n the p h o t o s y n t h e s i s (141)  (67).  of  -  synthetic  the d i t e r p e n e s k e l e t o n of  The t e t r a c y c l i c  enone 142  were c o n v e r t e d to the 2 - f o r m y l c r o s s - c o n j u g a t e d p h o t o l y z e d i n aqueous a c e t i c 12% y i e l d .  approach appeared v e r y  and i t s  epimer  (*)  dienone 144 and  a c i d to p r o v i d e a 3:1  This intramolecular photochemical ether  r e m i n i s c e n t of Y o s h i k o s h i ' s s o l v o l y t i c  C-14  grayano-  r a t i o o f 144:145 i n formation i s  p r e p a r a t i o n o f kessane  (103)  (51).  - 30 I I I . Approaches  to S t e r e o s e l e c t i v e  The s y n t h e s i s introducing  unfortunately,  of s e v e r a l monospiranes has been a c c o m p l i s h e d by  r i n g system d e r i v a t i v e s .  are completely  c o n t r o l to be e x e r t e d  at  the s i m p l e r s p i r a n e s ,  derivatives, but i t  is  Synthesis  the r e q u i r e d s p i r o c e n t e r " ^ i n t o c y c l o p e n t a n e ,  and fused b i c y c l i c  of  Spirane  While few o f  g e n e r a l , . some do p e r m i t  s e v e r a l of  and  f o r m a t i o n has become  the e a r l y work.  synthesis  thirty  y e a r o r two t h a t s t e r e o s p e c i f i c  years,  spirane  possible.  The methods r e p o r t e d by Cram and S t e i n b e r g of  The  spiro[4.5]decane  have been r e p o r t e d over a p e r i o d of n e a r l y  o n l y i n the l a s t  these methods,  stereochemical  the r i n g p o s i t i o n s .  spiro[4.4]nonane  cyclohexane,  i n 1954  The s y m m e t r i c a l s p i r o [ 4 . 5 ] d e c a n - 6 - o n e  p r e p a r e d by s u l f u r i c a c i d treatment  of cyclopentanone's  (69) (147)  are  typical  was  reductive  dimer  146  A ' s p i r o - u n i o n * i s one formed by a s i n g l e atom which i s the o n l y common atom to the two r i n g s . A monospiro compound c o n t a i n s o n l y one such u n i o n and i s named by p l a c i n g " s p i r o " b e f o r e the name of the normal a c y c l i c h y d r o c a r b o n of the same number o f carbon atoms when the s p i r a n e c o n s i s t s o f two a c y c l i c r i n g s . The number of carbon atoms l i n k e d to the s p i r o atom i n each r i n g i s i n d i c a t e d i n a s c e n d i n g o r d e r i n b r a c k e t s and the r i n g atoms are numbered c o n s e c u t i v e l y s t a r t i n g w i t h the r i n g atom next t o the s p i r o atom, f i r s t through the s m a l l e r r i n g ( i f p r e s e n t ) and then through the s p i r o atom and around the second r i n g ( 6 8 ) .  - 31 -  p r o d u c t 146,' w h i l e  the p y r o l y s i s o f  the barium s a l t  of  the d i a c i d  148,  a compound o b t a i n e d from 147 by n i t r i c a c i d o x i d a t i o n , p r o v i d e d spiro[4.4]nonanone alkylations  of  (149).  the t e t r a e s t e r  and p y r o l y s i s , a f f o r d e d overall yield.  Successive 150,  i n t r a m o l e c u l a r malonic e s t e r  f o l l o w e d by subsequent  hydrolysis  the r e l a t e d b i f u n c t i o n a l s p i r a n e 151  Catalytic  or h y d r i d e r e d u c t i o n o f 151  i n 9%  provided a product  O COEt / EtOC — ( C H ) 3 — C / ^(CH ) COEt EtOC II ^ O 2  2  3  . O  o  150 mixture of  the c i s - c i s  stereoisomers.  151 (152a), c i s - t r a n s  (152b), and t r a n s - t r a n s  (152c)  The a u t h o r s were then a b l e to r e p o r t the f i r s t known  OH  S>€3  OH  SXD  152 a  OO  152 b  HO  p r e p a r a t i o n o f i n d i v i d u a l s p i r a n e d i a s t e r e o m e r s when they  152c  successfully  a p p l i e d chromatographic and f r a c t i o n a l c r y s t a l l i z a t i o n t e c h n i q u e s the b i s - p - n i t r o b e n z o a t e s (70)  o f 152.  Subsequent work by Cram and  showed t h a t the s p i r o k e t o l p r o d u c t 154  Dieckmann c o n d e n s a t i o n of a l s o be s e p a r a t e d i n t o i t s  the s u b s t i t u t e d  to  colleagues  o b t a i n e d from the  c y c l o p e n t a n o l 153,  could  s t e r e o i s o m e r s by chromatographing the  two  - 32 -  153  154  p_-nitrobenzoate diastereomers.  The p h y s i c a l and chemical p r o p e r t i e s  of the i s o l a t e d diastereomers permitted the r e l a t i v e c o n f i g u r a t i o n s of the two p u r i f i e d l-keto-6-hydroxyspiro[4.4]nonanes  to be e l u c i d a t e d .  and three p u r i f i e d 1,6-dihydroxyThese dicyclopentane spirane  systems were u s e f u l model systems f o r asymmetric i n d u c t i o n s t u d i e s . The c a t a l y t i c reduction of the dione 151 to compound 154, f o r example, afforded a 1:2 r a t i o of c i s - k e t o l 154 to t r a n s - k e t o l 154 i n g l a c i a l a c e t i c a c i d while the reduction of 151 to 154 i n 95% ethanol gave a ^ 6:1  ratio. The s u c c e s s f u l r e s o l u t i o n i n 1968 of the trans, t r a n s - d i o l  152c,  by Gerlach (71) using (-)-camphanic a c i d (155) , provided (-)-(lR,6R.)s p i r o [4.4]nonane-l,6-diol (=152c) which was then o x i d i z e d to (-)-(5S_)spiro[4.4]nonane-l,6-dione  155  ((-)-151) by chromium t e t r o x i d e i n acetone.  (—7—151  -  33 -  The c h i r a l i t y o f the ( - ) - 1 5 1 enantiomer was determined by c h e m i c a l c o r r e l a t i o n work a n d , more r e c e n t l y , X-ray a n a l y s i s  1 1  and i n v a l e n c e - f o r c e  t h a t the c y c l o p e n t a n e the envelope  this  enantiomer was used i n an  energy  calculations  r i n g s adopt a c o n f o r m a t i o n i n t e r m e d i a t e between  and h a l f - c h a i r form (but c l o s e r  to the l a t t e r ) .  et a l . then used the p r e c e d i n g i n f o r m a t i o n to i n t e r p r e t a p p l i c a t i o n o f the Octant Rule)  the r e s u l t s  temperature c i r c u l a r d i c h r o i s m o f ( - ) - c i s [4.4]nonan-l-one  (72) to show  ( ( - ) - 1 5 7 and ( - ) - 1 5 8 )  Lightner  (through the  o b t a i n e d by v a r i a b l e and ( - ) - t r a n s - 6 - m e t h y l s p i r o -  (73) and t o c a l c u l a t e  O  O'  (-)-156  (-)-157  optical  O  (-)-l58  p r o p e r t i e s o f (+)-151 f o r comparison w i t h the e x p e r i m e n t a l l y  observed  solvent  (+)-enantiomers  of  and temperature dependent  151 and 156 ( 7 4 ) .  by the r e p o r t  c i r c u l a r d i c h r o i s m of the  T h i s v e r y r e c e n t work takes on s y n t h e t i c  (73) t h a t the s p i r e n o n e ( - ) - 1 5 6 ,  o b t a i n e d from a W i t t i g  r e a c t i o n w i t h m e t h y l e n e t r i p h e n y l p h o s p h o r a n e on the ( - ) - d i o n e was c a t a l y t i c a l l y a f f o r d a 1:2 ratio 1  1  significance  ((-)-151),  hydrogenated by a p a l l a d i u m - o n - c h a r c o a l c a t a l y s t  r a t i o of (-)-157  to ( - ) - 1 5 8 i n a c e t i c  to  a c i d and an 8:1  i n ethanol.  While the X - r a y a n a l y s i s uses the " c o r r e c t " s t e r e o c h e m i s t r y i n i t s f i g u r e s , the r e c e n t a s s e r t i o n (74) t h a t t h i s work confirms the absolute configuration i s i n c o r r e c t . The l a s t sentence on page 2045 of r e f e r e n c e 74 s h o u l d read " . . . A l t o n a e_t a l . determined the c o n f o r m a t i o n o f . . . ( 1 5 1 a ) . . . . b y X - r a y methods", not " c o n f i g u r a t i o n o f , , ,  - 34 -  Before c o n s i d e r i n g the cyclohexane  derived spiranes,  some comment  12 must be made on the remarkably s t e r e o s e l e c t i v e g-acoratriene  (161)  used a s t a n n i c a l c o h o l 160, to a f f o r d  published very  chloride catalyzed  (75).  c y c l i z a t i o n of  of  K a i s e r ejt al_. the  tertiary  i n approximately  to d i r e c t  the c y c l i z a t i o n o f  to the u n h i n d e r e d s i d e o f isomeric a-acoratriene  50% y i e l d .  the c y c l o p e n t a n e  (162)  162  the end o f  The  159,  isopropylidene  the s i d e  r i n g because none o f  c o u l d be i s o l a t e d .  (75)  allylic  d e r i v e d i n t h r e e s t e p s from racemic d e h y d r o l i n a l o o l  g-acoratriene  group appears  recently  synthesis  chain the  A s h o r t treatment  of  163  While the r e f e r e n c e c i t e d c o n s i d e r s t h i s c y c l i z a t i o n to be s t e r e o s p e c i f i c , I c o n s i d e r s t e r e o s e l e c t i v e c y c l i z a t i o n to be a more accurate d e s c r i p t i o n .  - 35 -  161 w i t h p_- toluene s u l f o n i c a c i d i n r e f l u x i n g bezene afforded the 13 cedradiene  163.  However, the a t t r a c t i o n of t h i s method f o r the  synthesis of s p i r o - c a r b o c y c l i c sesquiterpenes i s diminished by the report that the corresponding c y c l i z a t i o n of the i s o p r o p y l d e r i v a t i v e 164 provided a 2:7 r a t i o of compounds 165 and 166.  L i t t l e synthetic  work has been done on the general p r e p a r a t i o n of model from cyclopentane  spiro[4.5]decanes  d e r i v a t i v e s , but r e c e n t l y trans-6-methylspiro[4.5]-  decan-l-one (170) was obtained s t e r e o s p e c i f i c a l l y by c a t a l y t i c hydrogenation 13 This preparation of cedrane sesquiterpenes from spirane d e r i v a t i v e s mimics the proposed b i o g e n e t i c sequence and t h i s approach u s u a l l y provides a much shorter synthesis of bridged spiranes than a nonspirane approach. D e t a i l s of both spirane and nonspirane sesquiterpene synthesis are discussed i n Appendix I I i n the 'spirane approach'. The e x c e l l e n t work by Andersen and Syrdal i n June 1972 and that of Tomila and Hirose e a r l i e r i n the year showed that the chemical s t i m u l a t i o n of the biogenesis of cedrene could be accomplished i n the l a b o r a t o r y through the farnesane •+ bisabolane -* acorspirane -* cedrane sequence (76). The farnesane _i, n e r o l i d o l , was shown to be a c i d c y c l i z e d to a mixture of a- and B-bisabolene ( i i ) , then isomerized to y-bisabolene ( i i i ) to provide ions i v and v, the l a t t e r of which c y c l i z e d d i r e c t l y to a f f o r d 20% a-cedrene ( v i ) and ^15% epi-a-cedrene ( v i i ) . This d i r e c t method does not permit monospirane synthesis and i s not a s t e r e o s e l e c t i v e synthesis f o r bridged spiranes.  in  IV  v[ a - C H vii / 3 - C H  3  3  of  the D i e l s - A l d e r  (167)  adduct 169 from  and 1 , 3 - b u t a d i e n e  167  (168)  168  The s p i r o [ 4 . 5 ] d e c a n e s been s y n t h e t i c  trans-2-ethylidenecyclopentanone  (87).  169  d e r i v e d from cyclohexane  derivatives  have  t a r g e t s f o r many r e s e a r c h e r s , but o n l y v e r y l i m i t e d  s t e r e o c h e m i c a l c o n t r o l has been o b t a i n e d . of  17Q  For instance,  an e a r l y  such an a p p l i c a t i o n , the a c y l o i n c o n d e n s a t i o n of the d i e s t e r  p r o v i d e d an i n s e p a r a b l e m i x t u r e of f o u r p o s s i b l e d i a s t e r e o m e r s o f s p i r a n e 172  (77).  T h i s d i f f i c u l t y was not p r e s e n t i n the  example 171, the  completely  O  171  172  A somewhat analogous D i e l s - A l d e r r e a c t i o n was used s u c c e s s f u l l y on a s u b s t i t u t e d cyclohexene and b u t a d i e n e d e r i v a t i v e i n the s y n t h e s i s of s p i r o s e s q u i t e r p e n e , a-chamigrene (190) ( 8 5 ) . However, i n t h i s case a s y m m e t r i c a l c e n t e r s a r e p r e s e n t i n the s p i r o [ 5 . 5 ] u n d e c a n e p r e p a r e d .  - 37 -  symmetrical spirane  175  a l k y l a t i o n w i t h 1-5  a r y l n e i g h b o u r i n g group p a r t i c i p a t i o n i n the  pyrolysis  of  t h a t was o b t a i n e d by an i n t r a m o l e c u l a r  the sodium s a l t of  173  (78).  updated by two v e r y r e c e n t p u b l i c a t i o n s . displacement  of  afforded  directly  175  1959  The l a t t e r  work has  The f i r s t  reported that  the n i t r o g e n from the d i a z o methyl and i n 65% y i e l d  C-  (79)  (versus  been  c a r b o n y l of  176  40% from 173),  the second found t h a t the d i r a d i c a l a n i o n i n t e r m e d i a t e  178a,  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 177,  s p i r a n e 179  p r o v i d e d the r e l a t e d  while  from the on  OH  OH CHN  aryl  2  177  176  O  II  177  COH  ^  178 q  178b  179  -  workup i n 60% o v e r a l l y i e l d  38  (80).  The s p i r o - d i e n o n e s 181a  were a l s o p r e p a r e d i n 60% y i e l d by a 1-5  and  181b  aryl participation reaction  when the t o s y l a t e s 180a and 180b were s o l v o l y z e d w i t h p o t a s s i u m i n _t-butanol  (81).  t-butoxide  While none o f the above approaches would appear  to  R ,R T90  180a 18Qb  R= H R=CH  provide a stereoselective  181a R=H 181b R=CH^  3  r o u t e to s p i r o - c a r b o c y c l i c s e s q u i t e r p e n e s ,  two  groups o f r e s e a r c h e r s have r e p o r t e d , i n d e p e n d e n t l y and n e a r l y simultaneously, aryl of  a stereoselective  compounds.  The f i r s t  the a-bromo e s t e r  182  stereoselective^"^ a completely  f o r the s p i r a n e 184  group u t i l i z e d the b a s e - c a t a l y z e d  (82 )  184 from the 6-bromo e s t e r  synthesis  a  183  only because,  while (82^).  the second o b t a i n e d the  cyclization spirane  These l a b o r a t o r y syntheses  firstly,  s y m m e t r i c a l cyclohexane  from  are  the s p i r a n e f o r m a t i o n o c c u r s on  and, secondly,  the  cross-conjugated  OH  The r e s u l t i n g s t e r e o s e l e c t i v e s y n t h e s i s o f c e d r o l and cedrene by these two groups i s d i s c u s s e d i n Appendix I I , ' t h e s p i r a n e a p p r o a c h ' .  -  spiro-ketone  184,  substituent,  is  cyclopentyl  39  obtained after  only i s o l a t e d  as  -  base e p i m e r i z a t i o n of the t r a n s - m e t h y l ,  spirenone.  a somewhat  8-vetivone  carbomethoxy  carbomethoxy  While the p r e c e d i n g approach l e d s u c c e s s f u l l y skeleton,  the  (223),  tetrahydropyranyl to the expected  analogous  failed.  acorspirane  approach to the v e t i s p i r a n e  M u k h a r j i and Gupta  (THP) e t h e r  to the  of  (83)  sesquiterpene,  found t h a t  the bromophenol 185  the  cyclized  readily  s p i r o - d i e n o n e 186 but a l l attempts to i n t r o d u c e  the  THPO 185  186  r e q u i r e d C-10 m e t h y l i n t o 186 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 , hydrocyanation, of  were u n s u c c e s s f u l .  186 h i n d e r s the approach to C-10  dienone r e s i d u e . spiro[4.5]decane  rings prevents  i n the v e r y  r e a c t i o n sequence derivative  from e i t h e r  this  face of  affording  the  r e p o r t e d work by P i n d e r e_t a l .  187 was t r e a t e d w i t h sodium methoxide  The  (189)  was a s u c c e s s f u l  regioselective  c i s - and synthesis  also  (84) on a cyclohexenone  and underwent  i n t r a m o l e c u l a r M i c h a e l a d d i t i o n to p r o v i d e b o t h d i a s t e r e o m e r s On the o t h e r hand, the c y c l i z a t i o n o f  the  stereoselective  T h i s same problem i s  the a c o r s p i r a n e s k e l e t o n .  moiety  cyclohexa-  i n t o both of  approach from b e i n g  o f 186 are p r o d u c e d . recently  conjugate  seems t h a t the c y c l o p e n t y l  A l s o the i n t r o d u c t i o n o f asymmetry  as b o t h d i a s t e r e o m e r s apparent  It  or  an of  188.  trans-monocyclofarnesol of  (+)-a-chamigrene  - 40 -  (190) (85), a spiro[5.5]undecane  sesquiterpene, because of the absence  of asymmetric centers i n the cyclohexane p o r t i o n of 189. The f i r s t and, to t h i s date, only method f o r the d i r e c t conversion of a general b i c y c l i c [4.4.0] r i n g system to a spiro[4.5]decane i s provided by the degradation of B-rotunol (191), a sesquiterpene from Japanese nutgrass (86).  The dehydration of t h i s 5,10-cis-eudesmane  r e a d i l y afforded the cross-conjugated dienone spirane 192 when the C-5 hydroxyl and C-10 methyl were c i s , but not when they were trans  -  (ct-rotunol) . [5.4.0] one  41  -  A d i r e c t method of p r o v i d i n g s p i r a n e s from a fused  system has a l s o been d i s c o v e r e d .  (193)  Bicyclo[5.4.0]undec-l(7)-en-3-  was found to undergo a [ l , 3 ] - s i g m a t r o p i c  the s i n g l e t  state  photorearrangement  to y i e l d 6 - m e t h y l e n e s p i r o [ 4 . 5 ] d e c a n - l - o n e  O 193  r a t i o o f 193:194. substituted  to 191 first  s t a t e between 193 and 194 e s t a b l i s h e d The problems of s t e r e o s e l e c t i v e l y  difficulty  i n preparing cis-y-hydroxy  ( p l u s the l a c k o f s t e r e o s e l e c t i v e approach u n a t t r a c t i v e .  (87).  195  a 2:3  equilibrium  synthesizing  s p i r a n e by e i t h e r o f these methods would be  The s y n t h e t i c  (194)  via  O 194  A photostationary  bicyclo-  a  substantial.  octalones  r e a c t i o n s on 192)  The p h o t o c h e m i c a l s y n t h e t i c  analogous  makes entry  the to  medium r i n g s p i r o - m o l e c u l e s does not p r o v i d e a method of i n t r o d u c i n g stereochemistry  i n t o the s p i r a n e .  p r o v i d e s b o t h d i a s t e r e o m e r s of s t e r e o i s o m e r s a s e r i o u s problem  The f a c t  that hydrogenation of  194  195 makes even the i n t r o d u c t i o n o f  C-6  (87).  S p i r a n e s w i t h c o n f i g u r a t i o n a l i n t e g r i t y have been o b t a i n e d from b i c y c l i c of  u n s a t u r a t e d hydronaphthalenones  t r i c y c l i c compounds.  s e v e r a l examples aryl  1-5  and a r y l  through the  Mander e t a l . have r e c e n t l y  of i n t r a m o l e c u l a r C - a l k y l a t i o n s 1-6  of  successfully  intermediacy  reported  (79,88)  diazo-ketones  where  n e i g h b o u r i n g group p a r t i c i p a t i o n l e d to s p i r o - d i e n o n e  formation i n approximately  90% y i e l d  (196 -»• 197,  199 -> 200) .  T h i s work  -  42  -  O  198a  R =X = H  199  200  jo, R = C H , X = H 3  C R = CH , X=OH 3  was of  then extended  to ir-bond p a r t i c i p a t i o n by  the d i a z o methyl c a r b o n y l ' s  to a f f o r d h i g h o v e r a l l y i e l d s  the b e n z y l i c  n i t r o g e n from compounds of of  the b r i d g e d s p i r a n e 203.  displacement type  202  C o n t r o l of  -  the r e l a t i v e of  stereochemistry  the s t a r t i n g  permit  between the c a r b o n y l and o t h e r  readily.  synthesis  As p r e v i o u s l y  chemical c o n t r o l i n b i c y c l i c useful  for sesquiterpene  s i m p l e r monospirane systems.  ammonia/ether  p r o b l e m , would  terpenoids  i n d i c a t e d by the this  substituents  to be  l a c k of  stereo-  approach would not  be  synthesis.  dione 206 p r o v i d e s  ketone was d i s c o v e r e d  of h i g h e r  spiranes,  The two-step c o n v e r s i o n of the s p i r a n e  -  compound, a r a t h e r s t r a i g h t f o r w a r d  the s t e r e o s e l e c t i v e  accomplished  43  the W i e l a n d - M i e s c h e r ketone a unique method of o b t a i n i n g  A novel c y c l i z a t i o n  of  the  (204)  to  the  Wieland-Miescher  to o c c u r d u r i n g the r e d u c t i o n o f 204 i n a l i t h i u m /  s o l u t i o n ' a n d quenching w i t h ammonium c h l o r i d e was  found  to  O 2Q4 afford  2Q5  an 80% y i e l d of  catalyzed  the c y c l o p r o p a n o l ketone  transformation of  hetereogeneous  the sodium s a l t  benzene-methanol  s p i r o d i o n e 206 i n 75% y i e l d homogeneous  media  but  trans-indanedione,  (208),  observed  the rearrangements  205  stereospecifically  i n both  (X = H ) .  (X = Na) i n a  the use of  for  the  the  a  base-catalyzed  trans-l,6-dimethylbicyclo(90).  This  206 and 208 has not been  are believed  A base-  stereospecifically,  Surprisingly,  (benzene-dimethylformamide)  [4.3.0]nona-2,7-dione  yet,  of  205  medium p r o v i d e d ,  (89).  t r a n s f o r m a t i o n p r o v i d e d the  stereospecificity  2Q6  to be g e n e r a l l y  rationalized  applicable  for  -  44  -  the two-step c o n v e r s i o n o f a n g u l a r l y s u b s t i t u t e d 204. of  The s y n t h e t i c  advantage o f c o n f i g u r a t i o n a l r e t e n t i o n a t  the s p i r a n e i s obvious when i t  afford  is  to be removed  C-6  The h i n d e r e d environment o f  206 a l s o p e r m i t s the c y c l o h e x y l  carbonyl  regioselectively.  The o l d e s t selectively  c a r b o n y l of  to  remembered t h a t most o t h e r methods  d i a s t e r i o m e r i c C-6 m i x t u r e s .  the c y c l o p e n t y l  enediones analogous  and most p r a c t i c a l method o f o b t a i n i n g s p i r a n e s  was d i s c o v e r e d from the s t u d i e s  Along w i t h " i s o p h o t o s a n t a n o i c  lactone"  on s a n t o n i n (106)  stereo-  photolysis.  ( 2 0 9 ) , a second p h o t o p r o d u c t ,  l u r a i s a n t o n i n , was o b t a i n e d i n low y i e l d i n p r o t i c media p h o t o l y s i s and i t was a s s i g n e d  the s t r u c t u r e 210  (91).  s t u d i e d on the model hydronaphthalenone 211 the analogous initial  When t h i s (R  2  r e a c t i o n was  = H, R^ = C H ) 3  l u m i p r o d u c t 213 was o b t a i n e d i n 65% y i e l d as the  photoproduct i f  (57,92), single  the p h o t o l y s i s was conducted i n a n e u t r a l  - 45 -  a p r o t i c media such as dioxane. was  used,  the expected hydroazulenone  predominant p r o d u c t .  212  c r o s s - c o n j u g a t e d dienone  o b t a i n e d as  the  (211,  b  213  = R^  m i x t u r e o f the hydroazulenone  photoproduct,  214 was  acid  However, p h o t o l y s i s o f the c o r r e s p o n d i n g u n s u b s t i t u t e d  212 a  a 1:1  When i r r a d i a t i o n i n 45% a c e t i c  = H)  i n a c e t i c media a f f o r d e d  (214, R2 = R^  the h y d r o x y l s p i r e n o n e 215  = H) and  (R2 = R^ = H)  a  (57).  new The  s i m i l a r p h o t o r e a c t i o n w i t h the 2-methyl s u b s t i t u t e d compound 211 CH^,  R^ = H) was  found to p r o v i d e o n l y the c o r r e s p o n d i n g s p i r e n o n e  as the major p r o d u c t . and be  (R2  These s t e r e o s p e c i f i c a l l y  formed  215  hydroazulenone  s p i r e n o n e p r o d u c t s have been i n t e r p r e t e d m e c h a n i s t i c a l l y (58) to the r e s u l t of n u c l e o p h i l i c a t t a c k by water a t  o f 212a  or  212b  respectively. While  o n l y those hydroazulenones  which a r e 2 - a l k y l  can be c o n v e r t e d to s p i r e n p n e s e f f i c i e n t l y by  =  substituted  the above approach, i t  - 46 was discovered that the lumiproducts 213 can be cleaved s o l v o l y t i c a l l y to provide a mixture of spiranes (93). compound (213, R^ = CH^,  The 2 - a l k y l s u b s t i t u t e d  = H) y i e l d e d a q u a n t i t a t i v e mixture of the  three spiranes 215, 216, and 217 (88% of which was 216) i n r e f l u x i n g  45% a c e t i c a c i d , w h i l e the unsubstituted lumiproduct 213 (R^ - R^ ~ H) afforded a 10:1 r a t i o of the three spiranes to the hydroazulenone  214  and the 4 - a l k y l s u b s t i t u t e d lumiproduct (214, R^ = H, R^ = CH ) 3  provided a 1:2 r a t i o of the spirenone 216 to the r e l a t e d 214.  hydroazulenone  These s u b s t i t u e n t e f f e c t s of the a c i d - c a t a l y z e d lumiproduct  cleavages are reminiscent of those encountered above i n the photochemical conversions of the corresponding parent dienones  (211), but d i f f e r e n t  product r a t i o s and c o n f i g u r a t i o n a l l y d i f f e r e n t compounds at C-10 are i s o l a t e d from the l i g h t - and a c i d - i n i t i a t e d rearrangements.  Kropp (93)  i n t e r p r e t e d the a c i d - c a t a l y z e d spirane product formation i n terms of  -  competitive (to  216),  C-9 p r o t o n l o s s  and f r o n t s i d e  the 4,10-bond of  of  the 4,10-bond  rearrangement carbonyl  -  (to 217),  backside  a t t a c k by water  the p r o t o n a t e d  (to  a t t a c k by water  215)  d u r i n g c l e a v a g e of  c y c l o p r o p y l ketone  218.  a r e the o n l y o r b i t a l s w i t h the p r o p e r  for favourable  orbitals  geometrical the  C-3  group..  by t r a n s f o r m i n g the  known  the p h o t o c h e m i c a l - a c i d  exploited  octalone  treatment  r e l a t i o n s h i p i n the s u b s t i t u t e d  219  the above c o n v e r s i o n method i n t o the s p i r a n e 222  sequence.  The  22QA*'  through  trans-dimethyl  hydronaphthalenones  219  r e l a t i o n s h i p i n the l u m i p r o d u c t , ^ e s t a b l i s h i n g  and 220 became  the c a r b o n y l and  4  the C-6 methyl as t r a n s i n compound 221. c y c l o p r o p y l ketone  221  i n anhydrous  The rearrangement  acetic  spiro[4.5]decadienone  222.  but  stereochemical  the r e l a t i v e  C-3 c a r b o n y l i n t a c t .  of  a c i d then c l e a v e d  o v e r l a p p i n g c y c l o p r o p y l bond to p r o v i d e a h i g h y i e l d o f  left  The  o v e r l a p w i t h the p _ - o r b i t a l s of  M a r s h a l l and Johnson (94)  a cis  47  the the  the  T h i s r e a c t i o n removed the asymmetry at relationship  of  best  C-10,  the C-6 methyl and  Compound 222 was then e l a b o r a t e d  to the  sesquiterpene  A c o n s i d e r a t i o n o f the m e c h a n i s t i c p r o p o s a l s f o r the c o n f i g u r a t i o n a l changes at C-10 i s posponed u n t i l l a t e r . Formally, this reaction i s a p h o t o c h e m i c a l [o^-a + v^-a] cycloaddition reaction.  -  8-vetivone also  (223)  48 -  by s t a n d a r d c h e m i c a l r e a c t i o n s .  Compound 222 was  found by M a r s h a l l and Johnson to be c a t a l y t i c a l l y  ethanol  to y i e l d a 3:1  m i x t u r e of  the s p i r a n e s  t h a t c o u l d o n l y be s e p a r a t e d by gas  222  222  hydrogenated  in  224 and 225 > d i a s t e r e o m e r s  chromatography.  - 49 -  DISCUSSION I.  General Development of the Reaction Sequence As p r e v i o u s l y s t a t e d , our s y n t h e t i c i n t e r e s t s were oriented to  the e f f i c i e n t s t e r e o s p e c i f i c transformation of d e c a l i n i c compounds i n t o the l e s s r e a d i l y a v a i l a b l e hydroazulene and spirane systems. surveying the l i t e r a t u r e on the guaiane sesquiterpene  After  synthesis (Appendix  I I ) and the a v a i l a b l e perhydroazulene preparations, i t was f e l t that a study on maximizing the hydroazulenone (C) y i e l d from the p h o t o l y s i s of cross-conjugated  cyclohexadienone d e r i v a t i v e s (B) would be p r o f i t a b l e .  A_  B.  C_  To f u l f i l l the o b j e c t i v e s of t h i s study, octalones of type A (R^ = CH^)  would be required f o r conversion to the corresponding  system B (R^ = R^ = H, CH ; R 3  3  = H,  cross-conjugated  = H, CHO, COOH, COOR) so that p h o t o l y s i s  of B_ could be studied i n a v a r i e t y of solvents.  This approach to  hydroazulene synthesis i s fundamentally a y i e l d study on the well-known p h o t o l y s i s of cross-conjugated  ketones, with modifications o r i g i n a t i n g  -  w i t h D. C a i n e  (64,65),  In c o n t r a s t  B (^  = R  50 -  2  = H, R  3  = COOH).  to the h y d r o a z u l e n e work,  spirane synthesis  ketone be r e t a i n e d ,  b o t h on the r e d u c t i v e c l e a v a g e o f _E to F ? "  c y c l o p r o p y l ketones  analogous  Obviously,  this  diazo ketones,  the p h o t o c h e m i c a l rearrangement o f  the c r o s s - c o n j u g a t e d  (95 ) ,  cyclohexene  (R' = CH^)  question  ( w i t h subsequent dienone IL  selective  the  cyclic  hydrogenation  While the u n s a t u r a t e d  diazo  the E_ - s e r i e s  the c o r r e s p o n d i n g compounds w i t h asymmetric c e n t e r s  i n the  r i n g have been r e p o r t e d to a f f o r d m i x t u r e s c o n t a i n i n g b o t h  diastereomers.  S e v e r a l examples  o f these i n t r a m o l e c u l a r  i n s e r t i o n s are presented i n Chart II r a t i o of diastereomers o b t a i n e d .  a l o n g w i t h the  The a v a i l a b i l i t y  keto-carbene  t o t a l y i e l d and the of E from  stereo-  s e l e c t i v e p h o t o c h e m i c a l r e a c t i o n s on e i t h e r A or 13, t h e r e f o r e , led  simple  decomposition of  ketone 226 has been used to p r o v i d e the s i m p l e s t member o f (227)  of  The t h r e e g e n e r a l methods o f p r e p a r i n g t h e s e  ketone A , and the p h o t o l y s i s of D) o f  a series  necessary before  p r e r e q u i s i t e systems i n c l u d e the c o p p e r - c a t a l y z e d  '  i n v e r t e d , or  to E, but w i t h a b r i d g e h e a d a l k y l  r a t h e r than h y d r o g e n , . w e r e  c o u l d be answered.  olefinic  into  grew from the q u e s t i o n "Would the c o n f i g u r a t i o n o f  the 8 - c e n t e r of an a , 8 - c y c l o p r o p y l  substituent  the i n v e s t i g a t i o n  to the n e c e s s i t y  of p r e p a r i n g s e v e r a l o c t a l o n e s  o f type A .  naturally While  - 51 C H A R T II CYCLOPROPYL  KETONES FROM INTRAMOLECULAR  KETO-  C A R B E N E ADDITION TO S U B S T I T U T E D C Y C L O H E X E N E S .  Compound (Literature Reference) 226  (95°)  22 8  X = H (95 )  30  228  X»= (-OCH ) ( 9 5 ' )  231  R = CH(CH ) (95 )  b  2  2  b  2  Product Yield  c  2 2  d  3  2  231 ' R = C ( = C H ) C H ( 9 5 ) e  2  3  Diastereomer Ratio  %  44  229 : 230 = 1: 9  31, 4 0  2 2 9 : 2 3 0 = 1 :: 9  78  232: 233 = 3 : 5  24  232 : 233 = 1 : 1  -  52  s p i r a n e and h y d r o a z u l e n e s y n t h e s i s introduction,  are d e a l t w i t h s e p a r a t e l y  d i s c u s s i o n , and e x p e r i m e n t a l p o r t i o n s of  t h e i r common s y n t h e t i c of a s i n g l e  -  s e c t i o n on the p r e p a r a t i o n of a , 3 - u n s a t u r a t e d  Synthesis  of a,8-Unsaturated  thesis,  ketones  of cross-conjugated  dienones.  Hydronaphthalenone D e r i v a t i v e s  The approach o u t l i n e d above made the p r e p a r a t i o n o f the a,8-unsaturated objective  the  d e r i v a t i o n from A i n t h i s work l e d to the i n c l u s i o n  f o l l o w e d by a s e c t i o n on the d e r i v a t i v e s  II.  this  in  ketones  234 to 240, i n c l u s i v e ,  o f the work d e s c r i b e d i n t h i s  the f i r s t  thesis.  seven  synthetic  These compounds a r e  c o n s i d e r e d i n d i v i d u a l l y i n o r d e r o f i n c r e a s i n g c o m p l e x i t y because preparation u t i l i z e d widely d i f f e r e n t  synthetic  schemes.  the compounds 234 to 240 were l a t e r a l l dehydrogenated cross-conjugated  systems,  one s y n t h e t i c  first  (Method I) i s  derivative)  derivative  (242)  regioselective  L  ^  of  type A from  can be a c h i e v e d by one o f  ( M . V . K . E . ) " ^ to the 2-methylcyclohexanone  (or i t s  to the c o r r e s p o n d i n g  the second  (Method I I ) i s  to the c o r r e s p o n d i n g  to p r o v i d e 13 a f t e r  h y d r o g e n a t i o n o f 13.  derivative  the  two methods.  the a d d i t i o n o f one methyl v i n y l ketone  r i n g c l o s u r e to A w h i l e  since  g e n e r a l i z a t i o n s h o u l d be made.  The p r e p a r a t i o n of hydronaphthalene d e r i v a t i v e s c o r r e s p o n d i n g cyclohexanone  However,  their  The  equivalent  241 w i t h  subsequent  the a d d i t i o n of  acetone  2-formyl-2-methylcyclohexanone  r i n g c l o s u r e and then A a f t e r Because o f  the s i m i l a r i t i e s o f  these  MVKE i n c l u d e s methy]/vinyl k e t o n e , l - d i e t h y l a m i n o - 3 - b u t a n o n e m e t h i o d e , 1 , 3 - d i c h l o r o b u t - 2 - e n e , l - i o d o - 3 - b e n z y l b u t a n e w i t h subsequent o x i d a t i o n , l-bromo-butan-3-one ethylene k e t a l , 3 , 5 - d i m e t h y l - 4 - c h l o r o m e t h y l i s o x a z o l e , and e t h y l 3-bromopropionate w i t h subsequent m e t h y l l i t h i u m a d d i t i o n (96). The s y n t h e t i c approaches to the o c t a l o n e 236 p r o v i d e s e v e r a l examples o f these d i f f e r e n t r e a g e n t s .  - 53 -  24Q  - 54 -  OHC  242  B  243  two schemes and the q u a n t i t a t i v e nature of the B_ —>• A conversion, the cross-conjugated  systems prepared by the l a t t e r procedure are best  discussed under the heading of the corresponding ketone.  a,6-unsaturated  In general, Method I I i s useful- f o r the simpler  cross-conjugated  dienones that are stereochemically unambiguous w h i l e Method I , w i t h subsequent dehydrogenation, i s e s s e n t i a l f o r the preparation of h i g h l y s u b s t i t u t e d or s p e c i f i c a l l y s u b s t i t u t e d compounds.  The l i m i t a t i o n s of  Method I I are i l l u s t r a t e d by the 19% y i e l d of B_ (R = COOH) reported f o r 3  the r e a c t i o n of 242 (R^ = R  2  = H) w i t h the a c e t o a c e t i c ester 243 (R^ =  COOEt) (97) and the 1:5 r a t i o of C-6 diastereomers  of B (R = 6-C(CH )CH ; ±  a:g = 5:1) obtained from condensing the C-4 isopropenyl s u b s t i t u t e d cyclohexanone 242 w i t h acetone (243, R_ = H) (98).  2  3  - 55 -  A.  Octalone  234  (4a-Methyl-4,4a,5,6,7,8-hexahydro-2(3H)-  naphthalenone) The well-known o c t a l o n e 234  i s n o r m a l l y p r e p a r e d from  hexanone u s i n g methyl v i n y l ketone butanone m e t h i o d i d e  i n p l a c e o f the  2-methylcyclo-  l-dimethylamino-3-  o r i g i n a l l y r e q u i r e d i n the Robinson a n n e l a t i o n  method s i n c e the l a t t e r r e a c t i o n p r o v i d e s the o c t a l o n e p r o d u c t i n low y i e l d and q u e s t i o n a b l e p u r i t y Fanta  (103).  The p r o c e d u r e  (99) condenses 2-methylcyclohexanone  a t -10° afford  i n the presence  o f M a r s h a l l and  and methyl v i n y l  ketone  o f a c a t a l y t i c amount of sodium e t h o x i d e to  the c r y s t a l l i n e k e t o l 247  i n 55% y i e l d .  The  stereoselective  f o r m a t i o n of the c i s - k e t o l i s the r e s u l t o f k i n e t i c c o n t r o l i n the  OH  244  245  247  intramolecular aldol c y c l i z a t i o n . potassium hydroxide 234  then proceeds  (^ 50% o v e r a l l ) .  234  Dehydration of t h i s k e t o l with i n ^90%  yield  to the d e s i r e d o c t a l o n e  Heathcock e t a l . (100), i n December  r e p o r t e d the c o r r e s p o n d i n g a c i d - c a t a l y z e d Robinson t h i s c a s e , s u l f u r i c a c i d i s used as the c a t a l y s t d e h y d r a t i n g the k e t o l 247.  M e t h y l v i n y l ketone  1971,  annelation.  In  f o r both forming and  and  2-methylcyclohexanone  a r e r e f l u x e d f o r 16 hours i n the p r e s e n c e o f a c a t a l y t i c amount o f a c i d to a f f o r d  49-55% y i e l d  of o c t a l o n e 234  on workup.  To p r e p a r e the s u b s t a n t i a l amounts o f o c t a l o n e 234 procedure  of M a r s h a l l and Fanta was  adopted  and  r e q u i r e d , the  then m o d i f i e d  slightly  -  d u r i n g the c o u r s e o f r e p e a t i n g  56  -  the r e a c t i o n on s i x o c c a s i o n s .  The  two apparent problems were  the e x c e s s i v e p o l y m e r i z a t i o n o f methyl  ketone  dropwise a d d i t i o n to the r e a c t i o n and the  observed d u r i n g i t s  p r o h i b i t i v e l y l a r g e volumes o f d i e t h y l e t h e r - h e x a n e for  the c r y s t a l l i z a t i o n o f  the crude k e t o l  on a h i g h torque s t i r r i n g motor overcame d i r e c t dehydration of  the k e t o l  potassium hydroxide solved  247.  solution required  A Hershberg s t i r r e r rod  the f i r s t  problem and  the  i n the r e a c t i o n v e s s e l w i t h 10%  the s e c o n d .  In t h i s manner, the  aqueous  octalone  234 was p r e p a r e d i n 57% y i e l d d i r e c t l y o r 75% y i e l d on the b a s i s unrecovered  vinyl  of  2-methylcyclohexanone.  When Heathcock et a l .  published their synthetic  procedure  for 18  octalone  234,  its  e x p e r i m e n t a l s i m p l i c i t y encouraged us to a p p l y  However,  upon workup, a l l d i s t i l l a t i o n f r a c t i o n s  of  the d e s i r e d  were found to be contaminated w i t h 16% o f a second component, 2(3-oxobutyl)-cyclohexanone the b a s i s (1710  of  the s a t u r a t e d  (246).  carbonyl present  cm ^) and the d o w n f i e l d a c e t y l  protons)  A s t r u c t u r a l assignment  i n the n u c l e a r magnetic  methyl  it. octalone  2-methyl-  was made on  i n the i n f r a r e d spectrum (T  7.80,  resonance s p e c t r u m .  singlet  of  three  This impurity  was removed and o c t a l o n e  234 produced by r e f l u x i n g  the i n i t i a l l y  obtained  m a t e r i a l i n an 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 s o l u t i o n to c y c l i z e .compound  18 A p r i v a t e communication from P r o f e s s o r Heathcock i n d i c a t e d t h e i r p r o c e d u r e a c t u a l l y used 100 ml benzene i n the r e a c t i o n m i x t u r e f o r each 0.3 ml o f s u l f u r i c a c i d c a t a l y s t , a f a c t o m i t t e d from r e f e r e n c e 100. S i n c e benzene and methyl v i n y l ketone have s i m i l a r b o i l i n g p o i n t s (81° v e r s u s 7 9 - 8 0 ° ) , i t i s not s u r p r i s i n g t h a t we have found the e l i m i n a t i o n o f benzene makes v e r y l i t t l e difference to the r e a c t i o n . The d i s c u s s i o n on the p r e p a r a t i o n of o c t a l o n e 234 and 235 by a c i d - c a t a l y z e d a n n e l a t i o n was found to be u n a f f e c t e d by the presence or absence o f benzene as shown by c o n d u c t i n g the r e a c t i o n s both ways.  -  57  -  O  246  249  3  248  246 and dehydrate a side-product  the i n t e r m e d i a t e  a l d o l product  t h a t was shown to a r i s e from the  c y c l i z a t i o n was i s o l a t e d I t was i d e n t i f i e d b r i d g e d ketone  (247 ).  At t h i s  point,  acid-catalyzed  i n the d i s t i l l a t i o n f o r e r u n of o c t a l o n e  as 2 , 5 - d i m e t h y l b i c y c l o [ 3 . 3 . l ] n o n - 2 - e n - 9 - o n e ,  234.  the  248 t h a t has been o b t a i n e d by M a r s h a l l and S c h a e f f e r  i n 60% y i e l d by h y d r o l y z i n g the v i n y l c h l o r i d e 249 w i t h s u l f u r i c at  0-20° f o r 2 h .  undergoes  the  In b o t h i n s t a n c e s ,  alternative  248 i n s t e a d o f  234.  with that  shown to be u n a f f e c t e d The above  results  reported  by the base  Upon r e p e a t i n g  molar e t h a n o l i c the end of  recovered.  the a c i d - c a t a l y z e d under b a s i c  the method of Heathcock et  s o l u t i o n of sodium e t h o x i d e  procedure should  conditions al.  (100),  before a 0.5  was added b e f o r e workup s o l u t i o n was r e f l u x e d  at for  Workup then gave a 45% y i e l d o f  a 60% o v e r a l l y i e l d based on the 25%  A l i q u o t samples  is  (107), and the compound was  the r e a c t i o n p e r i o d , and the b a s i c  pure o c t a l o n e ,  afford  treatment.  suggested t h a t  an hour under a n i t r o g e n atmosphere.  acid  246  d a t a r e c o r d e d f o r compound 248  i n c o r p o r a t e a s h o r t p e r i o d of treatment workup.  dione  a l d o l c o n d e n s a t i o n and d e h y d r a t i o n to  The s p e c t r a l  i n complete agreement  the i n t e r m e d i a t e  (107)  taken b e f o r e  and a f t e r  2-methylcyclohexanone the base  treatment  -  were a n a l y z e d by gas Ignoring  59  -  chromatography  the s t a r t i n g m a t e r i a l ,  to p r o v i d e  the d a t a i n F i g u r e  2-methylcyclohexanone  r e t e n t i o n time i s ^ 2 m i n ) , the p r o d u c t r a t i o of 246  (R ):234  (R )  g  is  1 Q  7:14:75 under H e a t h c o c k ' s  F i g u r e 1)  becoming 7:0:87 a f t e r  (i.e.  i n F i g u r e 1).  (b)  compound u n a f f e c t e d i n t e r n a l standard, (a)  and the t o t a l  versus  87.  subsequent  S i n c e Rj. _ i s  octalone  procedure  sodium e t h o x i d e  and t h e r e f o r e  dione 246 p l u s o c t a l o n e  234 p r e s e n t  i n (b)  i n c r e a s i n g the amount o f a c i d c a t a l y s t d e c r e a s e d  catalyzed  but i n c r e a s e d ^ / ^ Q  work where the b r i d g e d ketone  distillation, catalyzed  M a r s h a l l and F a n t a ' s  procedure afforded  The p r e p a r a t i o n of (_B, R  1  (248:234).  = R  2  = R  3  cyclohexanone of  terms  treatment 248,  a  useful in as 89  that  to t h i s  acid-  248 had to be removed by  234 f r e e  of  in  the R^/R^Q r a t i o  careful  more arduous b a s e impurities.  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  = H ; 300) was r e p o r t e d i n the 1950 work  Woodward and Singh u s i n g two methods.  (a)  234 p r e s e n t  In c o n t r a s t  experimentally  octalone  a  (i.e.  compare f a v o u r a b l y  I t was a l s o n o t i c e d i n more q u a l i t a t i v e  (246:234),  (R^ =  compound 248 (R,. ,.):  the b r i d g e d ketone  by the base treatment the t o t a l  at R^  1.  The sodium e n o l a t e  was condensed w i t h methyl e t h i n y l ketone  cyclohexanone (104)  of  of  2-methyl-  i n an  extension  the Robinson a n n e l a t i o n to p r o v i d e compound 300 i n low y i e l d  (9%).  A 10 f o o t x 0.25 i n c h column packed w i t h 20% SE-30 on 60/80 mesh Chromosorb W was employed at 155° w i t h a f l o w - r a t e o f 97 ml/min h e l i u m c a r r i e r gas. Chromatographic samples were washed w i t h a c i d and base and then d r i e d over anhydrous magnesium s u l f a t e b e f o r e use.  - 60 The c o n d e n s a t i o n of 2-formyl-2-methylcyclohexanone with acetone,  ketone  250,  afforded  of  the t e t r a c y c l i c  compound 300  A d o p t i n g the l a t t e r  i n 62%  sequence,  o l u t i o n o f cyclohexanone  (255) on  to a f f o r d  workup  (106).  ketone  2  = H)  251  from the  tricycli  yield.  dry e t h y l  i t r o g e n to a s l u r r y o f a l c o h o l - f r e e  yclohexane  = R  adapted from the e l e g a n t method of Wilds and D j e r a s s i  f o r the s y n t h e s i s  (105)  (241,  formate was added under  sodium methoxide  i n a benzene  the d e s i r e d 2-hydroxymethyleneThe s o l u b i l i t y of the sodium s a l  -  o f a l l hydroxymethylene v i a aqueous base  (254)  i n water makes t h e i r  was m e t h y l a t e d  by C l a i s e n ' s  Because  of  method  this  (106)  A m i x t u r e o f the C - m e t h y l a t i o n were o b t a i n e d by r e f l u x i n g  i o d i d e i n an acetone  instability, immediately  compound 255  after  its  aldehyde p r o t o n o f 257 a t T 2 . 8 .  the f r e s h l y  d i s t i l l e d 255 and m e t h y l  s l u r r y of p o t a s s i u m c a r b o n a t e .  w i t h acetone  256 at x 0.48 r e l a t i v e The m e t h y l a t e d  to a f f o r d  o v e r a l l y i e l d from  A 3:1  r a t i o of  to the o l e f i n i c  p r o d u c t m i x t u r e was  the d e s i r e d c r o s s - c o n j u g a t e d  p r o d u c t was q u i t e  f o r m y l group.  sensitive  W h i l e sodium e t h o x i d e  c l e a v a g e i n the attempted piperidine with a s l i g h t 40% of compound 251  revealed  proton  condensed  and aluminum _t-butoxide  excess o f a c e t i c  a c i d gave y i e l d s  F o r the p r e p a r a t i o n of  the s t r u c t u r a l assignment  the  t h i s product f u l l y  and the d i e n o n e ' s  data i s  of  Cthe  caused  to p r o v i d e  251,  o f up to  cross-conjugated  d a t a of  The s p e c t r a l  the  to c l e a v a g e w i t h l o s s  c o n d e n s a t i o n w i t h acetone  (105).  that  a 32% y i e l d .  o v e r a l l y i e l d from  downfield  system i n 9%  r e a c t i o n was found to a f f o r d ,  synthesis  C-7  then  dienone 300, the analogous  alternate  the  cyclohexanone.  The o r i g i n a l work by W i l d s and D j e r a s s i methylated  distilla-  and O - m e t h y l a t i o n products^ 256 and  256:257 was o b t a i n e d as determined by n . m . r . i n t e g r a t i o n o f  of  isolation  s i m p l e , but a i r o x i d a t i o n and d e c o m p o s i t i o n makes  to s t o r e .  257,  -  derivatives  them d i f f i c u l t  tion.  61  i n our hands,  corroborated  d i s c u s s e d w i t h an  t h a t p r o v i d e d the pure dienone 300 i n over 30% 2-methylcyclohexanone.  -  B.  Octalone  235  62  -  (4a,8-Dimethyl-4,4a,5,6,7,8-hexahydro-2(3H)-  naphthalenone) In analogy w i t h o c t a l o n e  234,  the 8 a - m e t h y l s u b s t i t u t e d  235 has been p r e p a r e d by condensing methyl v i n y l ketone w i t h dimethylcyclohexanone.  Unfortunately,  M a r s h a l l and S c h a e f f e r  i n a s i x - s t e p sequence  (107)  (< 20%).  found A year  u t i l i z e d the W i c h t e r l e r e a c t i o n  from 2 , 6 - d i m e t h y l c y c l o h e x a n o n e  desired trans-4a,8q-dimethyl octalone The cyclohexanone  2,6-  M a r s h a l l and F a n t a (99)  t h i s method p r o v i d e d an impure p r o d u c t i n low y i e l d later,  octalone  to p r o v i d e  235 i n about 40% o v e r a l l y i e l d .  258 was a l k y l a t e d w i t h 1 , 3 - d i c h l o r o - c i s - 2 - b u t e n e  and the Y ~ c h l o r o c r o t y l c y c l o h e x a n o n e  product  dehydrobrominated to the cyclohexenone  262  259  (259)  (260) was brominated and  derivative  261.  T h i s p r o d u c t was  Cl  258  the  26Q  263  261  235  63  -  then h y d r o l y z e d to the u n s a t u r a t e d d i o n e 262 which i n t u r n was hydrogenated octalone  235.  necessary caused  to the dione 263 and c y c l i z e d w i t h base to a f f o r d The i n t r o d u c t i o n o f  because h y d r o l y s i s o f  the a l t e r n a t i v e  mediate  double bond was  the v i n y l c h l o r i n e o f 260  acid-catalyzed  aldol cyclization  immediately  of  the  inter-  dione 263 and d e h y d r a t i o n under the r e a c t i o n c o n d i t i o n s  Caine and T u l l e r (108) basic  the cyclohexene  the  subsequently  reaction conditions  Dehydrohalogenation quantitatively  r e p o r t e d a sequence  to o b t a i n o c t a l o n e  that  264.  used  235 from compound 260.  o f 260 w i t h sodium amide i n ammonia proceeded  to the k e t o a c e t y l e n e 265 and i s o m e r i z a t i o n o f  bond w i t h sodium amide i n r e f l u x i n g a c e t y l e n e 266 i n 73% y i e l d . water and m e r c u r i c s u l f a t e  t o l u e n e p r o v i d e d the  the  triple  terminal  H y d r a t i o n w i t h 2% s u l f u r i c a c i d i n methanolc a t a l y s t y i e l d e d 96% of the d i o n e 263 which  °  i 264  cyclized  to  265  i n 73% y i e l d to the o c t a l o n e  and T u l l e r ' s p r e p a r a t i o n a f f o r d e d  4  v 266  235.  The f i v e  steps of  an o v e r a l l 35% y i e l d of  235  Caine from  2,6-dimethylcyclohexanone. From the p r e c e d i n g i n f o r m a t i o n , one would not expect to f i n d Heathcock's  acid-catalyzed  Robinson a n n e l a t i o n p r o c e d u r e  (100)  that  could 19  p r o v i d e the d e s i r e d o c t a l o n e (a)  illustrates  235.  In F i g u r e 2,  the v e r y low y i e l d o f o c t a l o n e  the gas  chromatogram  235 p r e p a r e d by  refluxing  -  64  -  2,6-dimethylcyclohexanone  and methyl v i n y l ketone w i t h a  amount of s u l f u r i c a c i d .  The d e s i r e d  approximately and  octalone  (R-j^) v e r s u s  1 4 minutes  2,6-dimethylcyclohexanone  (258)  has a r e t e n t i o n time o f  the b r i d g e d ketone  at R «  However,  2  hour w i t h a r e f l u x i n g 0 . 5 molar sodium e t h o x i d e caused a d r a m a t i c s h i f t by  (b)  i n Figure 2.  to a more f a v o u r a b l e  s e p a r a t e d by d i s t i l l a t i o n .  The o c t a l o n e  was i d e n t i c a l by an a n a l y t i c a l  from t h i s o n e - p o t  reaction is  The  alternative  greater  solution  s i t u a t i o n as  illustrated  c  2,6-dimethyl-  235  ( 2 0 - 2 5 % ) were  cleanly  2 3 5 a f f o r d e d by t h i s  procedure  unambiguous  route  the y i e l d o f pure o c t a l o n e  235  than 40% based on u n r e c o v e r e d  the above p r o c e d u r e p r o v i d e s a v e r y  to the s i x -  i m p u r i t y a t R,  f o r one  i n f r a r e d comparison w i t h an a u t h e n t i c  However, s i n c e  2,6-dime'thylcyclohexanone, attractive  treatment  i n ethanol  2 3 5 p r e p a r e d by an a l t e r n a t e  described subsequently.  at  ( 4 6 - 6 4 % ) and b o t h the u n d e s i r a b l e R^  ( ^5% i n pure form) and o c t a l o n e  sample o f o c t a l o n e  (264)  Upon workup, a c o n s i d e r a b l e amount o f  cyclohexanone was r e c o v e r e d component  catalytic  ,  and f i v e - s t e p  being a v a i l a b l e  literature  sequence.  i n gram q u a n t i t i e s  on  D.J  workup, was r e a d i l y p u r i f i e d and a s s i g n e d 264.  The compound e x h i b i t e d  the s p e c t r a l d a t a p r e v i o u s l y  for  this  for  the 1 - d e s m e t h y l compound ( 2 4 8 ) .  methyl 248,  compound ( 1 0 7 )  (T 8 . 9 )  but  the b r i d g e d ketone  reported  and was v e r y s i m i l a r to t h a t observed In the n . m . r . , the C - l  C  ( C  H )-C3H  =  3  1  '  5  H Z  >  J  C  2  (C^-cV,  3 . 4 Hz were the same i n b o t h compounds. and double bond ( 1 6 7 5  cm ) L  =  2  '  2  H  z  a  n  earlier  tertiary  i n 2 6 4 r e p l a c e d the C - l one p r o t o n resonance  the J 2  structure  (T d  7.3)  in  ^ H - C ^  The i n f r a r e d c a r b o n y l ( 1 7 2 0  a b s o r p t i o n s were i d e n t i c a l and both  cm -'-) -  ultraviolet  spectrums e x h i b i t e d a weak 2 3 5 my s h o u l d e r on the s t r o n g end a b s o r p t i o n below 2 2 0 my.  =  - 66 The Rg  and R ^  components p r e s e n t i n chromatogram  F i g u r e 2 were i s o l a t e d by p r e p a r a t i v e gas chromatography to have n e a r l y superimposable a n a l y t i c a l i n f r a r e d 1710 below  (a) o f and  demonstrated  spectrum showing  cm ^ c a r b o n y l and an u l t r a v i o l e t spectrum e x h i b i t i n g end 220 my.  and 7.83  Both n.m.r. spectrums showed an a c e t y l methyl  r e s p e c t i v e l y ) , a methyl d o u b l e t w i t h J = 6.4  both s p e c t r a ) , a t e r t i a r y m e t h y l  (x 9.01  and 8.82  Hz  a  absorption (T  7.88  (x 9.01  in  respectively),  and  e l e v e n o t h e r p r o t o n s based on the i n t e g r a t i o n of the d o w n f i e l d a c e t y l methyl.  A c i d - c a t a l y z e d e p i m e r i z a t i o n o f e i t h e r pure compound w i t h  c o n c e n t r a t e d h y d r o c h l o r i c a c i d r e s u l t e d i n the growth of the o t h e r ' s t e r t i a r y m e t h y l and a c e t y l m e t h y l i n the n.m.r. spectrum u n t i l a 60:40 r a t i o was  e s t a b l i s h e d , the same r a t i o as observed i n F i g u r e 2 ( a ) .  s u b s t a n t i a l d i f f e r e n c e i n r e t e n t i o n times observed on the gas  The  chromatograph  are s u r p r i s i n g s i n c e these two compounds a r e o b v i o u s l y the two  methyl  epimers o f compound 263.  was  The s h o r t e r r e t e n t i o n time component  a s s i g n e d the c i s - 2 , 6 - d i m e t h y l d i o n e s t r u c t u r e 263a and the l o n g e r r e t a i n e d component the t r a n s - 2 , 6 - d i m e t h y l s t r u c t u r e 263b on the b a s i s that  the C - l c a r b o n y l was  t e r t i a r y methyl.  e x e r t i n g an a n i s o t r o p i c e f f e c t on the  The e q u a t o r i a l C-2 methyl o f 263a t h e r e f o r e became,  - 67 as expected, deshielded by 0.2 T i n 263b when t h i s methyl became 20 a x i a l l y oriented to the adjacent carbonyl f u n c t i o n a l i t y (109). Both isomers led co only the desired octalone 235 on sodium ethoxide treatment s i n c e , independent of the isomer that c y c l i z e s , the k e t o l 267 would be dehydrated and enolized i n base to y i e l d 268.  This intermediate  i s protonated under the r e a c t i o n conditions to a f f o r d the thermodynamically more s t a b l e 8a-methyl octalone.  The s t r u c t u r e and stereochemistry  assigned to octalone 235 was confirmed by undertaking i t s synthesis by another approach.  267  268  The cross-conjugated cyclohexanone (B,  235  = Scx-CH^, R^ = H; 301)  was prepared by a l i t e r a t u r e procedure (111) that i s completely analogous to that discussed e a r l i e r f o r 300.  Dry e t h y l formate was added under  nitrogen to a s l u r r y of a l c o h o l - f r e e sodium methoxide i n a benzene s o l u t i o n of 2-methylcyclohexanone.  The i s o l a t e d 2-hydroxymethylene-6-  methylcyclohexanone (270) from the workup was then immediately methylated with methyl i o d i d e i n r e f l u x i n g acetone s o l u t i o n containing  20  The preparation of 2,6-dimethyl-2(carbomethoxymethyl)cyclohexanone has been found to y i e l d an epimeric r a t i o that i n d i c a t e s s i m i l a r d i f f e r e n c e s i n the resonance of the t e r t i a r y methyl. A 55:45 r a t i o was assigned to the epimers analogous to 263a and 264b on the b a s i s of aromatic solvent-induced s h i f t s t u d i e s i n benzene on the mixture of isomers (110).  -  68 -  a s l u r r y of potassium c a r b o n a t e .  A 3:1 r a t i o o f 271:272 was o b t a i n e d  as determined by n . m . r . i n t e g r a t i o n o f the d o w n f i e l d aldehyde of  271 a t T 0.30 and 0.52 i n r e l a t i o n t o the o l e f i n i c  at x 2.80. isomers,  Of g r e a t e r  i s the presence  271a and 271b (271a:271b  were a s s i g n e d effect  interest  C-7 p r o t o n o f 272  o f the two aldehyde  r a t i o i s approximately  t h e i r stereochemistry  on the b a s i s  proton  2:1),  which  o f the a n i s o t r o p i c  o f the C - l c a r b o n y l on the t e r t i a r y methyl g r o u p .  The major  H  epimer 271a shows x 0.52 ( s i n g l e t , t e r t i a r y methyl) (singlet,  signals  I H , -CHO) and 8.78 ( s i n g l e t , 3H,  i n the n . m . r . w h i l e  I H , -CHO) and 8.63 ( s i n g l e t ,  The m e t h y l a t e d s o l u t i o n that  the o t h e r e x h i b i t s  3H, t e r t i a r y methyl)  p r o d u c t m i x t u r e was condensed w i t h acetone c o n t a i n e d p i p e r i d i n e and a s l i g h t  The r e a c t i o n was worked up to a f f o r d  the d e s i r e d  x 0.30  signals.  i n a refluxing  excess o f a c e t i c  acid.  cross-conjugated  system 301 i n 23% o v e r a l l y i e l d from 2 - m e t h y l c y c l o h e x a n o n e .  Analytical  -  69  -  samples were o b t a i n e d by c r y s t a l l i z a t i o n  from hexane and  p h y s i c a l and s p e c t r a l d a t a which were i n good agreement previously published  r e l a t i o n s h i p between  has been proven by Bloom (112) hydrogenation of only  to be t r a n s .  the d i s u b s t i t u t e d  c o n d i t i o n s would p r o v i d e a u t h e n t i c  benzene  the methyl groups o f Therefore,  double bond o f  octalone  the dienone 301 at  T h i s compound was i d e n t i c a l i n a l l r e s p e c t s  (235).  8a-methyl o c t a l o n e  235, but  octalones  not be c o n v e n i e n t l y  atmospheric  to t h a t  synthesis  prepared  (236 w i t h i t s  p r e p a r e d t h i s way.  the 8 - p o s i t i o n  c o n s i d e r a t i o n was g i v e n  o f the  the p r o c e d u r e l a c k e d g e n e r a l i t y 8a-acetoxy In view o f  on hand and our d e s i r e t o p r e p a r e a w i d e r v a r i e t y  unsaturated ketones.  tris(triphenyl-  Robinson a n n e l a t i o n p r o c e d u r e .  The f o r e g o i n g work p r o v i d e d a s u c c e s s f u l  at  selective  the homogeneous h y d r o g e n a t i o n c a t a l y s t  by the a c i d - c a t a l y z e d  substituted  301  301 under n e u t r a l  trans-4a,8-dimethyl  p h o s p h i n e ) c h l o r o r h o d i u m to hydrogenate  8a-substituted  that  r e d u c t i o n was a c c o m p l i s h e d i n 99% y i e l d by u s i n g a  s o l u t i o n of  pressure.  with  (111).  The s t e r e o c h e m i c a l  This selective  exhibited  (8a-acetoxy  since  f o r example)  or 8 a - a l k y l  (^CH^)), y to  phosphoryl c h l o r i d e i n  X  OAc  278a  234  hydronaphthalenones  to methods o f i n t r o d u c i n g s u b s t i t u e n t s  The V i l s m e i e r r e a g e n t ,  other  could  the o c t a l o n e of  desired  278 b  a,8-  dime thylformamide, 278b from t h e i r  70  has been used to p r e p a r e  to i t s  enol ether  r e a c t e d w i t h the V i l s m e i e r reagent hydride reduction  the s a l t  3  and w h i l e  The  steroid  conjugated  or CR^CH^) and  275 w h i c h ,  and the d e s i r e d y - m e t h y l  on  p r e c u r s o r 273  such i n t e r m e d i a t e s  another more g e n e r a l  r e a c t i o n sequence attractive.  i n 75% o v e r a l l  as 275 have been used to  ( f o r m y l , hydroxymethyl  appeared more  a,3-unsaturated  While the o c t a l o n e  (R = 5B-0Ac)  other Y ~ b s t i t u e n t s s u  the  278  278 was o b t a i n e d by a c i d h y d r o l y s i s .  chemistry  = CH  277  was prepared from i t s (50),  to y i e l d  (R'  (50,114 ) .  F u r t h e r r e d u c t i o n w i t h Raney n i c k e l gave  277 by h y d r o g e n o l y s i s  276  ketone  274  278a and the  (sodium b o r o h y d r i d e o r l i t h i u m aluminum h y d r i d e ) ,  the amine 276.  enol ether  the o c t a l o n e  c o r r e s p o n d i n g y - d e s m e t h y l compounds  enone 273 was c o n v e r t e d  afforded  -  and methylene  278a yield  obtain  (114^)),  t h a t had been u t i l i z e d i n  steroid  - 71 -  K e t a l i z a t i o n and e p o x i d a t i o n o f a , 6 - u n s a t u r a t e d r e a d i l y provide  ketones  (273)  such 8,Y-epoxy s t e r o i d a l k e t a l s as 280 i n h i g h  yield.  In 1958, Campbell e_t a l . (115) r e p o r t e d t h e p r e p a r a t i o n o f s e v e r a l 6a-methylandrostenones  (278b, X  = H, 6-OH f o r example) from  their  c o r r e s p o n d i n g androst-4-en-3-ones (273) by c l e a v i n g the epoxide  o f 280  w i t h methylmagnesium bromide, removing the k e t a l w i t h aqueous a c i d and d e h y d r a t i n g and i s o m e r i z i n g t o 278 w i t h base. have i n t r o d u c e d a p h e n y l group i n an analogous  Z d e r i c e_t a l . (116)  manner t o o b t a i n an 80%  y i e l d o f t h e 66-phenyl d e r i v a t i v e o f p r o g e s t e r o n e  (281, C-17B-C(OCH CH 0)CH ) 2  by adding phenylmagnesium bromide t o the c o r r e s p o n d i n g epoxy k e t a l  273  279  281  282  278  2  280.  3  -  When the o c t a l o n e toluene  72 -  234 was k e t a l i z e d w i t h e t h y l e n e  containing a catalytic  amount o f p - t o l u e n e s u l f o n i c  y i e l d o f doubly d i s t i l l e d d i o x o l a n e and n . m . r . a n a l y s i s observation  glycol i n  283 was o b t a i n e d .  a c i d , a 73%  Gas chromatography  i n d i c a t e d 6% o f the o c t a l o n e was s t i l l p r e s e n t , an  t h a t has been r e p o r t e d p r e v i o u s l y  methylene p r o t o n s a t x 6.03 ( s i n g l e t , s i g n a l at x 4.63 ( m u l t i p l e t ,  (117).  The d i o x o l a n e  4H,-OCI^CH^O-) and the broadened  I H , =CH-) confirmed t h a t the d e s i r e d  compound 283 had been p r e p a r e d .  E p o x i d a t i o n o f the l a t t e r w i t h m - c h l o r o -  p e r b e n z o i c a c i d i n d i c h l o r o m e t h a n e b u f f e r e d w i t h sodium b i c a r b o n a t e (118 )  then a f f o r d e d ,  a  of  after  the two epoxy k e t a l s  234  d i s t i l l a t i o n , an 87% y i e l d o f a 40:60 m i x t u r e  (284).  I n view o f the s u b s e q u e n t l y  284 a  283  differences  in reactivity  having s i g n a l s (multiplet, while  discovered  o f these two compounds,  a t x 8.92 ( s i n g l e t ,  the major  3H, t e r t i a r y methyl)  g I H , C H) i n the n . m . r . , was a s s i g n e d  the minor i s o m e r , h a v i n g s i g n a l s  284 b  isomer,  and x 7.04  the c i s - s t r u c t u r e  a t x 8.87 ( s i n g l e t ,  284b  3H, t e r t i a r y  g methyl)  and x 7.17  isomer 284a.  (multiplet,  I H , C H ) , was d e s i g n a t e d  In s u p p o r t o f these a s s i g n m e n t s ,  R = H ( 1 1 8 ) and 285, R = C H 0 H , C ( C H ) 0 H a  2  3  to y i e l d a 60:40 y i e l d o f the analogous the  2  as the t r a n s -  the d e c a l i n s 285,  ( 1 1 8 ) have been r e p o r t e d b  epoxides  286a and 286b w i t h  286, R = H compounds h a v i n g n . m . r . methyl resonances  a t x 8.88 (286a)  and T 8.94  (286b).  While these 286, R = H isomers were r e p o r t e d  to  21 be i n s e p a r a b l e by gas  chromatography,  t h e i r rigorous s t r u c t u r a l proof  have shown t h a t the t r a n s - i s o m e r 286"a predominates M a r s h a l l e_t a l .  (117)  (118  ).  However,  found the h y d r o b o r a t i o n o f the k e t a l 283  285  286q  followed  286b  by o x i d a t i o n of the r e s u l t i n g organoborane w i t h a l k a l i n e hydrogen p r o v i d e d o n l y the c i s - f u s e d  hydroxy k e t a l .  T h i s r e s u l t was  on the s t e r i c grounds t h a t the a x i a l oxygen o f b l o c k e d the a - f a c e o f the m o l e c u l e . of a : 8  e p o x i d a t i o n of  with respect  the k e t a l  T h e r e f o r e o u r observed 40:60 r a t i o  283 i s  actually  less  to the 8-isomer than might be expected  the a - e p o x i d e  unexpected  r e f l u x i n g a 60:40 m i x t u r e of  methylmagnesium under a n i t r o g e n  284a was r a p i d l y c l e a v e d ,  8-isomer was r e c o v e r e d unchanged a f t e r was not c o m p l e t e l y  stereoselective  (119).  bromide i n t e t r a h y d r o f u r a n o r hexamethylphosphoramide 35°,  expected  the k e t a l group i n 283  When the epoxide m i x t u r e 284a+b was t r e a t e d w i t h  atmosphere at  peroxide  the  p e r i o d s o f up to 60 h o u r s .  s i n c e M a r s h a l l e_t a l . 286a:286b  but  found  that  (R = H) i n anhydrous  f u r a n w i t h methylmagnesium bromide f o r 32 hours c l e a v e d  This  the  tetrahydrotrans-isomer  In c o n t r a s t , 284a and 284b were r e a d i l y s e p a r a t e d by g . l . c . u s i n g a 10 f o o t x 0.25 i n c h column packed w i t h 20% SE 30 on 60/80 mesh Chromosorb W a t 1 8 5 ° .  - 74 286a  nearly completely,  (118).  T h e i r work a l s o  be accounted  but o n l y c l e a v e d  two-thirds  of  the  showed t h a t w h i l e 85% of the t r a n s - i s o m e r c o u l d  f o r by g . l . c .  analysis  of  the p r o d u c t m i x t u r e , o n l y 63% of  the c i s - i s o m e r  c o u l d be d i s t i n g u i s h e d i n such an a n a l y s i s .  t i o n of  gem s u b s t i t u e n t s  the C-2  the a - f a c e  sufficiently  the G r i g n a r d  i n the k e t a l  sterically  The i n t r o d u c -  284a must t h e r e f o r e  h i n d e r e d to p r e v e n t  make  the a d d i t i o n of  reagent.  In e x p e c t a t i o n  t h a t a l k y l l i t h i u m s would be b e t t e r  m e t h y l l i t h i u m a d d i t i o n to the epoxides  the ct-epoxide  and a l l o f the  at 20° and 35° none of  nucleophiles  284a+b i n e t h y l  0° f o r 12 h o u r s , 20° f o r 12 hours and 35° of  cis-isomer  e t h e r was t r i e d  f o r 24 h o u r s .  m e t h y l l i t h i u m was used i n r e f l u x i n g  the 6 were r e c o v e r e d .  while  When  tetrahydrofuran for 2 hours, a l l  the  * a-epoxide,  a substantial  0-epoxide were  more r e a c t i v e and p o s s i b l y of  if  any of  the  a t i m e l y p u b l i c a t i o n appeared on the r e a c t i o n of  l i t h i u m dimethylcuprate (122).  and l i t t l e ,  opened.  By c o i n c i d e n c e ,  oxide  amount o f the k e t a l  and o t h e r organocopper r e a g e n t s on  cyclohexene  The r e p o r t i n d i c a t e d t h a t l i t h i u m d i a l k y l c u p r a t e s towards epoxides  than the c o r r e s p o n d i n g  are  alkyllithiums  are s u p e r i o r to the a l k y l l i t h i u m s w i t h r e s p e c t  the n u c l e o p h i l i c a d d i t i o n p r o d u c t .  at  At 0° o n e - t h i r d  8-epoxide were r e c o v e r e d unchanged,  the a and a l l o f  (120),  Since d i a l k y l c u p r a t e s  to  yields  a r e known  -  to be r e l a t i v e l y  75  -  i n e r t to s a t u r a t e d  carbonyls,  let  alone k e t a l s  i t was v e r y d i s a p p o i n t i n g to f i n d  that  cleaved  room temperature w i t h a  over an 18 hour p e r i o d at  even the cx-epoxide was  (123),  not  five-fold  excess o f l i t h i u m d i m e t h y l c u p r a t e .  C.  O c t a l o n e 236  (8a-Acetoxy-4a-methyl-4,4a, 5,6, 7,8-hexahydro-  2(3H)-naphthalenone) The r e s i s t a n c e  o f the a - e p o x i d e  to n u c l e o p h i l i c a t t a c k  w e l l documented by the f o r e g o i n g r e a c t i o n s  that  had been so  i t was easy to be  a p p r e h e n s i v e about opening b o t h 284a and 284b w i t h h y d r o x y l i c philes.  However,  nucleo-  the p e r c h l o r i c a c i d h y d r o l y s i s work r e p o r t e d on the  pregnenone d e r i v a t i v e s  287  (124)  was p a r t i c u l a r l y i n f o r m a t i v e  because  both the a - and B-epoxides were found to y i e l d the i d e n t i c a l d i o l  288  _  A l l the o r g a n o m e t a l l i c r e a c t i o n s were m o n i t o r e d by t a k i n g a l i q u o t samples by s y r i n g e from the above r e a c t i o n s done under a n i t r o g e n atmosphere. By these o b s e r v a t i o n s , i t was d i s c o v e r e d t h a t the B-epoxide was more s t a b l e to the d i f f e r e n t o r g a n o m e t a l l i c reagents than was the ketal. Heathcock et. al. (121) have c a l l e d a t t e n t i o n to the f a c t t h a t the d i o x o l a n e g r o u p i n g can be removed by the f o l l o w i n g f r a g m e n t a t i o n mechanism.  1  ii  While t h i s s i d e r e a c t i o n was a minor c o n s i d e r a t i o n w i t h the above G r i g n a r d r e a c t i o n s , i t was a s e r i o u s problem w i t h the o r g a n o m e t a l l i c reagents i n r e a c t i o n s done above room t e m p e r a t u r e . A p r a c t i c a l s o l u t i o n to t h i s problem i s demonstrated i n subsequent work on the p r e p a r a t i o n of the s t e r o i d 240.  - 76  under the same acetylated  conditions.  22  to the monoacetate  -  Since  this  d i o l had p r e v i o u s l y  289 and dehydrated w i t h  been  concomitant  ^CH OAc 2  ...OH  287a  OH  a-epoxide  288  287 b /3-epoxide e p i m e r i z a t i o n of  the C-6 acetoxy s u b s t i t u e n t  was some l i t e r a t u r e precedence  for treating  to a f f o r d  290 ( 1 2 5 ) ,  284a+b i n a  sequence  u t i l i z i n g aqueous p e r c h l o r i c a c i d i n a c e t o n e ,  acetic  anhydride  there  in  p y r i d i n e and anhydrous hydrogen c h l o r i d e i n c h l o r o f o r m to p r o v i d e  236.  The a d d i t i o n o f a c i d c a t a l y s t (HCIO^) a l l o w s h y d r a t i o n to be accomplished under much' m i l d e r c o n d i t i o n s and at a much f a s t e r r a t e than i n the absence of an a c i d c a t a l y s t . The expected opening o f the o x i r a n e i n a t r a n s - d i a x i a l manner i s demonstrated v e r y c l e a r l y by the r e p o r t e d c o n v e r s i o n w i t h anhydrous hydrogen c h l o r i d e o f the 8-epoxide jL ( p a r t i a l s t e r o i d a l s t r u c t u r e ) to the d i a x i a l h a l o h y d r i n 11 (A = OH, B = C l ) , whereas the a - e p o x i d e jL i s d i a x i a l l y opened to the h a l o h y d r i n i i (A = C l , B = OH) (120).  ii  B  - 77 -  284 g + b  When t h i s product of  292  sequence was a p p l i e d to the epoxy k e t a l  this  sequence  to be a m i x t u r e o f (236?).  (obtained i n  i n the aqueous reaction.  but a c o n s i d e r a b l e  layer of  While g . l . c .  p r e p a r a t i o n was not f e a s i b l e most o f first  the k e t a l  hour o f  rationalized (C-8a)  of  the  the workup o f  because  of  twenty-hour  e n o l i z a t i o n of  hydrolysis  spectra  amount o f  found  octalone  supported material  the d i o l  292  the l a b i l e n a t u r e o f  292,  to be removed a f t e r  reaction.  of d e h y d r a t i o n of  crude  the p e r c h l o r i c a c i d  monitoring of  (284) was shown by g . l . c .  to be the r e s u l t  292,  resonance  the  was  the d i o n e 294 and an a c e t o x y - s u b s t i t u t e d  the s t r u c t u r a l a s s i g n m e n t s ,  hydrolysis  284,  20% y i e l d o v e r a l l )  I n f r a r e d and n u c l e a r magnetic  was l o s t  236  the  the  The dione 294 was tertiary  293 to remove the 1 , 3 - d i a x i a l  hydroxyl interaction,  - 78 -  292  293 and e n o l i z a t i o n  294  to the dione 294 occurring much more r e a d i l y than i n  s t e r o i d a l systems.  The dione 294 was also prepared by a 20 min  steam bath treatment of the epoxy k e t a l 284 i n acetone-6 N hydrochloric acid  (126,127). However, since the isomerization of Y hydroxy-a,8-unsaturated -  ketones has been reported to occur much more slowly i n base than acid (127), some consideration was given to removing the k e t a l and opening 23 the epoxy ketone 291 with base.  The previously reported examples of  catalyzed opening of 8,Y epoxy ketones to afford Y~hydroxy-a,8unsaturated ketones were accomplished with piperidine (115), pyridine b 3. b (129 ), and methanolic potassium hydroxide (129 ' ) on 3-keto steroids -  ^ The preparation of the 8,Y epoxy ketone 291 by d i r e c t epoxidation of 341 ( i . e . deconjugated octalone 234) (155) f a i l e d since the competing Baeyer-Villiger reaction (128) led to a crude reaction product mixture that was predominantly lactones iL and i i . _  341  291  i  ii-  -  79  -  O  O 291  h a v i n g a B>Y epoxy f u n c t i o n a l i t y .  When the k e t a l o f 284a+b was  removed w i t h h y d r o c h l o r i c a c i d  N  _  (.1  2 N)  i n dioxane or  some o f the d i o n e 294 was a l s o p r o d u c e d , even a f t e r A one hour treatment  of  284 w i t h 1 ml o f 1.5  40 ml acetone was found to be b e s t , but room temperature w i t h a c e t i c  substituent  periods.  N perchloric acid i n  the subsequent  products.  treatment  Several  at yield  attempted  l e d to the same m i x t u r e of f o u r r e a c t i o n p r o d u c t s .  work on t h i s approach was t h e r e f o r e There i s  only short  a n h y d r i d e i n p y r i d i n e was found to  a mixture of a c e t a t e - c o n t a i n i n g modifications  acetone,  discontinued.  l i t e r a t u r e precedence  through sequences  that  The  f o r i n t r o d u c i n g the y - a c e t o x y employ osmium t e t r o x i d e  on the  corresponding g . y - o l e f i n  (130), p e r a c i d o x i d a t i o n o f  of  (131^), y - b r o m i n a t i o n w i t h N-bromosuccinimide  the conjugated  ketone  the e n o l  acetate  (297), or y - h y d r o x y l a t i o n w i t h s e l e n i u m d i o x i d e on a , 8 - u n s a t u r a t e d  O Br  COOH 296  297  COOH  1Q6  O  - 80 ketones (296),  or h y d r o x y l a t i o n of a,6-unsaturated ketones by  molecular oxygen (133).  This l a s t method provided the 88-hydroxy-  ketone 299 i n approximately 50% y i e l d by the a u t o x i d a t i o n of 298 i n the presence of a l k a l i hydroxide, sodium isopropoxide, or other bases. The a u t o x i d a t i o n even occurred i n aqueous p i p e r i d i n e , but a t a much slower r a t e than i t d i d i n concentrated base. 7a-substituent was demonstrated  The i n f l u e n c e of the  by the observation that the corresponding  76-compounds (307) provided only a small amount o f 309 and none o f the 25 expected 308. _ Santonin was synthesized v i a the sequence 296 -»• 297 106 (131) and A -296 ->- 106 (131). The d i f f i c u l t y of preparing the desired octalone 237 d i r e c t l y from a cyclohexanone d e r i v a t i v e was demonstrated by the d e s t r u c t i o n of the acetoxy s u b s t i t u e n t i n the r e a d i l y a v a i l a b l e compound i_ (132) when hydroxyme'thylation was attempted on t h i s ctacetoxy ketone. An approach analogous to t h i s one was considered i n one of the e a r l i e r santonin (106) syntheses (131 ). 3  a  OAc L  OAc  ii  OAc  302  The s t a b i l i t y of 299 to r e f l u x i n g aqueous a l c o h o l i c potassium hydroxide ( i . e . to i s o m e r i z a t i o n to the corresponding 2,8-dione) was r a t i o n a l i z e d to be due to the deformation of r i n g B to a boat confirmation. The i n f l u e n c e of C-7 stereochemistry was then r e l a t e d to the a c c e s s i b i l i t y of the 8a-hydrogen atom i n determining the mode of decomposition of the postulated C-8 hydroperoxide intermediate.  -  81  -  2Q9_  299 R = /3-H  298 R = /3-H 3Q7 R = a H  3Q8 R=a - H  —  While the b a s i c c o n d i t i o n s t h a t were employed i n the reaction  (to b o t h generate  the e n o l a t e  the h y d r o p e r o x i d e i n t e r m e d i a t e ) sequence  and then to reduce by h y d r o l y s i s  precluded i t s  l e a d i n g to the d e s i r e d o c t a l o n e  b e i n g used i n a  236, m o l e c u l a r oxygen  a l s o been used i n two n e u t r a l , but d i s t i n c t l y d i f f e r e n t , p r e p a r e an i s o l a t a b l e y-hydroperoxide  which, a f t e r  sodium i o d i d e o r t r i p h e n y l p h o s p h i n e , a f f o r d s unsaturated ketone.  The f i r s t o f  (triplet)  oxygen  3 ( I ) i n a free  6  the mesomeric r a d i c a l 311 excited  state  (singlet)  r a d i c a l process  *  (^Z  +  processes  to  y-hydroxy-a,8reactions  uses  ketone w i t h ground s t a t e  (133,135,142) w h i l e  oxygen  the  has  mild reduction with  these o x y g e n a t i o n  the a u t o x i d a t i o n o f a 8 , y - u n s a t u r a t e d  above  or *A ) ^  that probably  the second on a  involves  utilizes  8,Y-unsaturated  26 These two m e t a s t a b l e s i n g l e t s t a t e s d i f f e r i n the e l e c t r o n i c c o n f i g u r a t i o n of t h e i r degenerate h i g h e s t o c c u p i e d m o l e c u l a r ( a n t i bonding) o r b i t a l s . The -^Zg s t a t e (37 k c a l ) has one e l e c t r o n i n each o r b i t a l w h i l e the ^Ag s t a t e (22 k c a l ) has both e l e c t r o n s i n one o r b i t a l and the State other vacant.  Relative  Energy (Kcal)  Configuration of the highest occupied orbitals  O  f'2  37  - 82 ketone i n a concerted process that involves either a cis-"ene" (313a) or "perepoxide" (313b, peroxirane) t r a n s i t i o n state  (136,143).  These two processes are e a s i l y confused since they both are 27 commonly accomplished photochemically  and may give a product having  the same stereochemistry (312 = 314). For example, the report that a chloroform s o l u t i o n of the norandrost-5,10-en-3-one 315 (X = -C=CH), after exposure  to fluorescent l i g h t under an oxygen atmosphere, yielded  40% of the 103-hydroperoxy compound 316 (147) was l a t e r followed by a communication (136) that found the photosensitized i r r a d i a t i o n of A free r a d i c a l oxygenation process ( 02) can be accomplished with oxygen and base (133), oxygen and peroxides (146), or oxygen i n an unsensitized photolysis (135) while the excited s i n g l e t state oxygenation process ( I O 2 ) requires photo-oxygenation i n the presence of a s e n s i t i z i n g dye (139,140), p o s i t i v e halogen compounds (hypoc h l o r i t e s , etc.) with hydrogen peroxide (•'•Ag only) (137,141), or a radiofrequency (6.7 Mc) discharge i n gaseous oxygen (138). J  -  315  83 -  (X = H) i n p y r i d i n e a f f o r d e d  hydroperoxy ketone  316.  The f i r s t  45% of  the c o r r e s p o n d i n g 10B-  r e a c t i o n requires a free  radical  c h a i n p r o c e s s i n v o l v i n g the g e n e r a t i o n o f a mesomeric a l l y l i c by a b s t r a c t i o n o f  the C-4 hydrogen w h i l e the second uses 1  excited  singlet  s t a t e oxygen  c o n s i d e r e d below,  it  appears  photo-  28  ( 0^). that  the  radical  F o r reasons  t h a t w i l l be  the t r i p l e t and s i n g l e t  hydroperoxyla-  t i o n s u s u a l l y g i v e d i s t i n g u i s h a b l e p r o d u c t s i n a m o l e c u l e where diastereoisomers r a t h e r than  a r e p o s s i b l e when the oxygenated  position is  secondary  tertiary.  X  HO  HO  X  316  315  ^ The n a t u r e o f the " 02 s p e c i e s ( A g o r £g> o r both) has been d i s c u s s e d by C S . Foote and coworkers (141). T h i s group suggested the -*-Ag s t a t e might be expected to r e a c t i n t w o - e l e c t r o n , c o n c e r t e d p r o c e s s e s w h i l e the ^-Eg s t a t e s h o u l d resemble the ground s t a t e and would be expected to undergo r a d i c a l - l i k e r e a c t i o n s . A l s o the ^Ag , oxygen has a l i f e t i m e l o n g enough to be c o n s i s t e n t w i t h the l i f e t i m e o f the r e a c t i v e complex w h i l e the ^Zg s t a t e would be expected to be r a p i d l y quenched i n s o l u t i o n . However i n 1967, Kearns and coworkers (139,140) proposed t h a t both -'•Eg and -^Ag oxygen m o l e c u l e s c o u l d be i n v o l v e d as r e a c t i o n i n t e r m e d i a t e s . They observed a p r o d u c t d i s t r i b u t i o n (A -* B + C) that v a r i e d from 30:1 to 1:5 (B:C) as the t r i p l e t energy o f the d y e - s e n s i t i z e r employed was r a i s e d above 38 k c a l to 50 k c a l . A s i m i l a r v a r i a t i o n was r e p o r t e d by Nickon and Mendelson i n 1965 (148), but they proposed no m e c h a n i s t i c i m p l i c a t i o n s . T h e r e f o r e , i n the c o n t e x t o f t h i s t h e s i s the symbol ^2 i s used w i t h o u t s p e c i f y i n g -*-A o r -'-Eg s t a t e s . 8  L  e  X  X  -  In an e a r l y (146)  example o f  84  -  the a u t o x i d a t i o n p r o c e s s ,  found t h a t c h o l e s t - 5 - e n - 3 - o n e  i n a hexane  combined w i t h m o l e c u l a r oxygen i n the p r e s e n c e (a r a d i c a l i n i t i a t o r )  to g i v e  was made i n 1964 (147)  t h a t an attempted  of  the 0 , y - s t e r o i d a l  hydroperoxides  318.  of  s o l u t i o n at  chromatography  y i e l d e d a mixture of  the 6(ct p l u s  (without  A current  cholesterol  s t o r e d at  (150  from samples  (probably  i n t h i s work suggests t h a t a u t o x i d a t i o n  o n l y the 6 8 - h y d r o p e r o x i d e  from t r i p l e t  (150^) a l s o d i s c o v e r e d  can be r e a d i l y e p i m e r i z e d  oxygen.  t h a t secondary  (i.e.  ) has r e s u l t e d  70° i n a i r f o r one month.  the 6 8 - but not the 6a-isomer  6(a p l u s  a mixture  OOH  the i s o l a t i o n o f 6 8 - h y d r o p e r o x y c h o l e s t - 4 - e n - 3 - o n e  observed  and  OH  c h o l e s t e r o l a u t o x i d a t i o n by L . L . Smith e_t a l .  et a l .  8)-  (1973) r e - e x a m i n a t i o n of  317  A^-3-one)  gel  1965  a sensitizer)  OH  i s o l a t i o n of  A report  over s i l i c a  the p h o t o - p r o d u c t w i t h sodium i o d i d e a f f o r d e d  the 6(a p l u s B ) - a l c o h o l s .  crystalline  peroxide  Nickon and Mendelson then d i s c o v e r e d i n photo-oxygenation  al.  25°  of d i b e n z o y l  6(a p l u s 8 ) - h y d r o p e r o x i d e .  enone 317  that cholest-5-en-3-one reduction of  F i e s e r et  319  320).  8)-hydroperoxy mixtures  of  The  formed v i a  initially  yields  Interestingly,  allylic  in  Smith  hydroperoxides  Therefore,  the  c o u l d r e a d i l y be  earlier rationalized  - 85 -  AcO 3 2Q  319  as o c c u r r i n g from epimerization of the 68-isomer to remove the 1,3 d i a x i a l i n t e r a c t i o n with the C-10 methyl.  The report that enol  ethers ( p a r t i a l s t r u c t u r e 321) are completely o x i d i z e d i n 2 h at 30°  4 i n d i r e c t s u n l i g h t by an a u t o x i d a t i o n process to give 6-hydroxy-A 3-ketones (322) (151) supports the above argument because the r a t i o g e n e r a l l y observed between the 68- and 6a-epimers was found to be at l e a s t e i g h t - t e n to one.  322  321 R = alkyl  OH  The c h o l e s t - 5 - e n - 3 - o n e i s the only example of a photosensitized oxygenation (^C^)  studied to date where a B,Y enone y i e l d s a  secondary hydroperoxy s u b s t i t u t e d product.  -  However, oxygenations of  8,Y~enones with s i n g l e t oxygen should only be considered as an example of the extension of the conversion of a monoolefin to an a l l y l i c hydroperoxide i n the much more e x t e n s i v e l y studied general hydroperoxy<  - 86 lations  of o l e f i n s .  The f i e l d  of o x y g e n a t i o n  been r e c e n t l y  reviewed elsewhere  principles is  considered here.  of monoolefins  (142-145) and Singlet  without  the i n t e r m e d i a c y o f f r e e  products often  shows  and s t e r e o s e l e c t i v i t y the presence and  325 a l o n g  that  radicals.  a h i g h degree  i s exhibited.  of o p t i c a l l y  active  o n l y a summary o f  oxygenation  i s always accompanied by the concommitant s h i f t  of  of  the m o n o o l e f i n  of  reaction  (+)-limonene,  (+)-trans-alcohols  w i t h o t h e r compounds i n the r e a c t i o n m i x t u r e  was r e a d i l y understood i n terms o f  the  regio-selectivity  In the case o f  (-)-cis-and  the  the double bond  An a n a l y s i s  o f both  has  the c o n c e r t e d c i s - a t t a c k  324  (324-329) by ^O^  29 on the t r i s u b s t i t u t e d  326  double bond and the a l l y l i c hydrogen.  327  328  Taking  329  The m e c h a n i s t i c d i f f e r e n c e s o f a u t o x i d a t i o n ( 0 ) were i l l u s t r a t e d when the 3o o x y g e n a t i o n of 323 was found to y i e l d the racemates c o r r e s p o n d i n g to 324 and 325 and none o f the e x o c y c l i c (326, 327) products. 2  9  2  2  - 87 -  into account the conformational analysis of (+)-limonene and assuming that the t r a n s i t i o n state f o r the c y c l i c product-forming step resembles s t a r t i n g o l e f i n more than i t does the a l l y l i c hydroperoxide products, the product d i s t r i b u t i o n of 324 (5%):325 (20%):328 (34%):329  (10%):326  (10%) was r e a d i l y . r a t i o n a l i z e d .  (21%):327  Reaction on the  favoured conformation of 323 (E 330) gave ^0^ the choice of several quasi-axial (a') and quasi-equatorial ( e ) hydrogens. 1  (+)-limonene, as i s generally found, the predominant p o s i t i o n always favoured the a' hydrogen  In the case of product at each  abstraction.  331 Conformationally r i g i d s t e r o i d a l o l e f i n s provide even better examples of s t e r e o s e l e c t i v i t y since pronounced also exhibited during s i n g l e t oxygenation.  s t e r i c interactions are  In cholesterol (331, R = OH)  there are two equatorial/quasi-equatorial hydrogens, '4a-H/78-H, and two a x i a l / q u a s i - a x i a l hydrogens, 48-H/7a-H.  Since a c y c l i c step involving  the 48 a x i a l hydrogen and C-0 bond formation at C-6 ( i . e . 8-face reaction) would necessitate two 1,3-diaxial interactions with the C-10 methyl, the corresponding a-face reaction involving the 7ct-H and C-5 oxygenation i s expected to predominate.  Nickon and Bagli (149) not only found  that the 5ct-hydroperoxide 332 was the exclusive product (from 331, R = OH, OAc, or H), but also demonstrated  the s t e r e o s p e c i f i c i t y of the  -  88 -  r e a c t i o n by c o n v e r t i n g c h o l e s t e r o l - 7 8 - d  cholesterol-7ct-d_  to 332  (8.5% 7-d_) .  to 332  (95%-7-d) and  The i n e r t n e s s  of  the  allylic  e q u a t o r i a l s t e r o i d a l hydrogens was a l s o demonstrated by the f a c t coprost-6-ene  (333), c o n t a i n i n g a 5 8 - q u a s i - e q u a t o r i a l  (non-flexible)  B r i n g d i d not undergo o x y g e n a t i o n .  that  hydrogen i n  Steric  the  blocking  by the C-10 methyl o f the p s e u d o - a x i a l 88-H was a l s o apparent i n  this  work. S i n c e the p r e c e d i n g examples be s u b s t a n t i a l l y  demonstrate  that photo-oxygenation  b l o c k e d when the C - 0 bond has to be i n t r o d u c e d i n a  1 , 3 - d i a x i a l r e l a t i o n s h i p - to an a l k y l  substituent  o r when the  hydrogen i s r i g i d l y e q u a t o r i a l or q u a s i - e q u a t o r i a l that photosensitized  oxygenation  the 6 8 - h y d r o p e r o x i d e as reinvestigation  of  t h a t the expected  However,  of cholest-5-en-3-one  the major p r o d u c t  (134)  the  (334)  report yielded  was s u r p r i s i n g .  p r o d u c t o f ^0^ h y d r o p e r o x y l a t i o n , T h e i r attempted  (obtained after  i n a 27% y i e l d o f  (135),  allylic  the r e a c t i o n by Nickon and Mendelson (135)  the e x t e n t of ^35%. 5a-alcohol  can  reduction)  the dehydrated  i s o l a t i o n of  the 6 - h y d r o p e r o x y c h o l e s t - 4 - e n - 3 - o n e  concluded  335, was produced  the  to  corresponding  by column chromatography  compound  A  resulted  cholest-4,6-diene-3-one. was i s o l a t e d  i n 16%  yield  - 89 -  C H I 8 17  335  336  as the corresponding alcohol a f t e r reduction and was mixture of the 6a- and~6g-epimers.  These C-6 oxygenated  were considered to be derived from the competing 3  found to be a products  f r e e - r a d i c a l process  30  ( 0 )•  However more recently, Nakanishi et a l . (136)  2  demonstrated  (without bothering to refer to e a r l i e r work) that a concerted cycloaddition at C-6 of cholest-5-en-3-one was occurring with excited s i n g l e t state oxygen.  They employed s t e r e o s p e c i f i c a l l y deuterated  2 (90% 48- H) cholest-5-en-3-one  ( p a r t i a l structure 337) and recovered  the hydroperoxide 339 l a b e l l e d with deuterium at C-4  '  337  338  (85%).  Although  339  Nickon and coworkers had previously found examples of conventionaltype autoxidation competing with the expected photosensitized pathway, i n reactions on s t e r o i d a l o l e f i n s (152). In at least one case with -k^, a f r e e - r a d i c a l i n h i b i t o r (2 ,6-di-_t-butylphenol) has been used to suppress r a d i c a l reactions with while reactions were being studied. This technique does not appear to have been used i n any photosensitized studies.  -  this  90 -  1968 communication does not g i v e many d e t a i l s  has not y e t  appeared, a u t o x i d a t i o n would be expected  q u a s i - a x i a l 46-hydrogen almost c e r t a i n l y  ( r i n g A i n c h a i r , see  g i v e some ( a l l ? )  With some c o n s i d e r a t i o n of aspects of undertaken  and the f u l l  of  the  to a b s t r a c t  the  331 where R i s = 0) and  68-hydroperoxide.  the i n t e r e s t i n g and c o n t r o v e r s i a l  the p r e c e d i n g work, the y - a c e t y l a t i o n by a sequence  paper  of o c t a l o n e  u t i l i z i n g the p h o t o s e n s i t i z e d  234 was  y-hydroperoxyla-  31 tion  of  the c o r r e s p o n d i n g 6,y-enone  342  295  341.  T h i s unconjugated  octalone  236  ~ " While o x y g e n a t i o n o f the c o r r e s p o n d i n g e n o l e t h e r s o f conjugated ketones (151) appears to be the b e s t p r a c t i c a l p r e p a r a t i v e a u t o x i d a t i o n (-^02) method, p h o t o s e n s i t i z e d o x y g e n a t i o n appears to be the most useful 0 method. A l s o , w h i l e s y n t h e t i c a l l y , p h o t o s e n s i t i z e d oxygenat i o n has been used i n s e s q u i t e r p e n e work o n l y on o l e f i n s ( J . A . M a r s h a l l and coworkers ( 1 1 8 , 1 5 4 ) ) , the p h o t o s e n s i t i z e d y - h y d r o p e r o x y l a t i o n r e a c t i o n has been u t i l i z e d i n t r i t e r p e n e (ecdysone) s y n t h e s i s ( 1 3 6 ) . 5J  x  2  a  -  341,  91  -  p r e v i o u s l y p r e p a r e d from o c t a l o n e  234 by R i n g o l d and M a l h o t r a  through an a c i d - q u e n c h e d e n o l i z a t i o n p r o c e d u r e , was i s o l a t e d y i e l d by f o l l o w i n g octalone  t h e i r method  (155).  The e n o l a t e  a n i o n of  234 was generated w i t h potassium t^-butoxide  i n _t-butanol and  the c o r r e s p o n d i n g a n i o n 340 was t r e a t e d w i t h aqueous a c e t i c As has been p r e v i o u s l y enolate acetic  present  is  reported  (155),  w r i t t e n f o r mg q u a n t i t i e s  However, w h i l e of octalone  would r e q u i r e <200 mg o c t a l o n e )  234  C - l by the 10% aqueous  the o r i g i n a l p r o c e d u r e was (a t y p i c a l  w i t h 10 e q u i v a l e n t s  hours to o b t a i n 80% d e c o n j u g a t i o n  acid.  the v e r y h i g h c o n c e n t r a t i o n o f  i r r e v e r s i b l y p r o t o n a t e d at  a c i d to y i e l d 341.  i n high  (i.e.  example  quoted  o f base f o r  1.5  the r a t i o o f 234:341 i s  20:80),  32 a m o d i f i e d form o f 96% o f o c t a l o n e the i s o l a b l e because o f  t h e i r procedure  234 on l a r g e  was r e a d i l y i d e n t i f i e d of  scale.  y i e l d of completely  the r e l a t i v e  was found to deconjugate No attempt was made to  pure 8 , Y ~ u n s a t u r a t e d  difficulty  involved.  as 341 by i t s  spectral  ketone  absorption, a shift  a b s o r p t i o n from 1670  to 1725  data.  i n the i n f r a r e d o f  The  c e n t e r e d at  the  the 240 my carbonyl  X  X  multiplet  341  deconjugation  cm , a n d the v i r t u a l removal o f  (C H) v i n y l a b s o r p t i o n of 234 w i t h the subsequent quartet  determine  The 96% pure compound  234 to 341 was accompanied by the removal o f >90% o f  ultraviolet  up to  T 4.60 i n the n . m . r .  appearance  the T of  In a d d i t i o n ,  4.29  a the  32 Twenty grams (0.122 moles) o f o c t a l o n e was added to 14 g (0.36 moles) potassium ( i . e . 3 e q u i v a l e n t s ) t h a t had r e a c t e d w i t h 250 ml _t-butanol In 100 ml o f d i g l y m e . A f t e r s t i r r i n g under a n i t r o g e n atmosphere f o r 5-7 h , 500 ml o f 16% aqueous a c e t i c a c i d was added. T h i s homogeneous s o l u t i o n was d i l u t e d w i t h 500 ml o f 8% a c e t i c a c i d and p a r t i t i o n e d between petroleum e t h e r : w a t e r . The o r g a n i c l a y e r was washed twice w i t h water and aqueous sodium b i c a r b o n a t e , d r i e d o v e r magnesium s u l f a t e , and c o n c e n t r a t e d under reduced p r e s s u r e .  -  C°H of  341 would be expected  appear a t % 4.6 x as i t  92  -  to be c o u p l e d to the C-7 methylene and  d i d i n compound 283.  Quite  unexpectedly,  i t was found t h a t compound 341 was not i s o m e r i z e d on the chromatograph to 234 and t h e r e f o r e  the r e l a t i v e  amount of  gas deconjugation  19 c o u l d be measured v e r y a c c u r a t e l y  on a 20% SE 30 column  because 234 and 341 e x h i b i t e d d i f f e r e n t conditions.  8>Y  on s t a n d i n g a t  side  reactions. U s i n g the 8 , Y e n o n e -  (where i t  - e n o n e s  have been found  room temperature as w e l l  as the a u t o x i d a t i o n r e a c t i o n d i s c u s s e d e a r l i e r , 341 c o u l d be s t o r e d a t 0°  185°  r e t e n t i o n times under these  While even p u r i f i e d samples o f  to undergo p a r t i a l c o n j u g a t i o n  at  the deconjugated  c r y s t a l l i z e d slowly)  341 now a v a i l a b l e ,  the  without  octalone these  cholest-5-en-3-one  o x y g e n a t i o n p r o c e d u r e of i r r a d i a t i n g an oxygenated p y r i d i n e s o l u t i o n 33 s e n s i t i z e d i t h Rose Bengal w  was f o l l o w e d  (136).  To m o n i t o r  this  3~3 Rose Bengal ( i ) i s 4,5,6,7-tetrachloro-2',4',5 ,7 -tetraiiodofluoresc e i n p o t a s s i u m (or sodium) d e r i v a t i v e p o t a s s i u m (or sodium) s a l t (142). 1  1  N a k a n i s h i e_t al_. (136) used Rose Bengal i n p y r i d i n e w h i l e N i c k o n ejt a l . have used a m i x t u r e of hematoporphyrin and methylene b l u e i n a p y r i d i n e s o l u t i o n (135).  -  photolysis  of  93  -  0.2 molar o c t a l o n e  i n pyridine solution with a  watt sunlamp b u l b , a l i q u o t s were removed and worked up f o r S i n c e the o c t a l o n e expected  341 and y-hydroperoxide  to be v e r y s t a b l e ,  a n a l y z e d samples from 341,  c o n t a i n e d m a i n l y a m i x t u r e of o c t a l o n e  that  234,  to c l a r i f y  the s t e r e o c h e m i s t r y  of  342.  35  not g.l.c.  derived  and a l o n g e r r e t e n t i o n time component t h a t was i d e n t i f i e d  the enedione 343, produced by t h e r m a l d e h y d r a t i o n of attempt  analysis.  p r o d u c t 342 were  i t was not s u r p r i s i n g to f i n d  275  as  In an  the C-8 oxygenated  product  O  344  j  CH 342,  the crude p h o t o l y s i s  acetic  p r o d u c t was a c e t y l a t e d  by treatment w i t h  a n h y d r i d e i n p y r i d i n e a t room temperature or (b) a c e t y l  i n methylene  c h l o r i d e added dropwise to a p y r i d i n e b u f f e r e d  c h l o r i d e s o l u t i o n of crude p r o d u c t a t 0 ° . upon workup under n e u t r a l c o n d i t i o n s a t or h y d r o p e r o x y - s u b s t i t u t e d and g . l . c .  analysis  In b o t h c a s e s ,  room t e m p e r a t u r e ,  the enedione  (a)  chloride  methylene  however, no a c e t o x y -  compounds were found to be p r e s e n t .  confirmed t h a t  3  343 was formed.  The n . m . r . 34  34  1 The enedione was r e a d i l y i d e n t i f i e d by i t s v e r y sharp d o w n f i e l d C TA resonance i n the n . m . r . o f the crude p r o d u c t ' a c e t a t e ' . A g.l.c. i s o l a t e d sample!9 showed the expected s p e c t r o s c o p i c p r o p e r t i e s f o r 343: i n f r a r e d ( f i l m ) , 1708, 1685 ( c o n j . C=0) and 1603 ( c o n j . C=C ) cm ; n . m . r . x 3.77 ( s i n g l e t , I H , C^-H), and x 8.75 ( s i n g l e t , 3H, t e r t i a r y m e t h y l ) ; and u l t r a v i o l e t AM§OH~249 my, e= 10,000 ( C h o l e s t - 4 - e n e - 3 , 6 dione was r e p o r t e d (157) to have 251.5 my, e = 1 0 , 6 0 0 ) . When the Brackman e_t a l . method ( u s i n g a copper c a t a l y z e d a u t o x i d a t i o n of a 8 , Y u n s a t u r a t e d ketone i n a methanol s o l u t i o n of p y r i d i n e and t r i e t h y l a m i n e ) (156) was employed to o b t a i n another sample of the enedione 343 from the unconjugated enone 341, o n l y a m i x t u r e of o c t a l o n e 341 was recovered. However, as e x p e c t e d , t h i s r e a c t i o n was found to a f f o r d a good y i e l d o f c h o l e s t - 4 - e n e - 3 , 6 - d i o n e from c h o l e s t - 5 - e n - 3 - o n e . - 1  X|j|8"  -  - 94 -  probably by an unexpected quantiative loss of acetic acid in the desired y-peracetoxy-substituted octalone 344. This reaction finds precedence in the dehydration of cholesterol 24-hydroperoxide by acetic anhydride and pyridine to give 38-acetoxycholest-5-en-24-one (150 ) and the very recently reported conversion of the 3-hydroxy-7hydroperoxy steroid 345 to the corresponding 3-acetoxy-7-keto compound 346 (150^) when acetylation with acetic anhydride and pyridine was attempted.  AcO' 346 When the photosensitized oxygenation reactions i n pyridine were 35 worked up,  the crude product obtained was reduced with sodium  i n ethanol (149), r e - i s o l a t e d as the alcohol, and acetylated a c e t i c anhydride i n pyridine.  The i n i t i a l photolysis  iodide  with  reaction  was  worked up a f t e r twelve hours of i r r a d i a t i o n , carried through the above sequence and d i s t i l l e d  (95° at 0.3 mm Hg) to afford a 10% o v e r a l l y i e l d  of a 3:7 mixture of octalones 234:236.  This was encouraging enough  for such a short photolytic period that the 8,Y enone 341 was _  i35 r r a d i a t e d for 36 h, reduced and acetylated.  However, a f t e r  distilling  A petroleum ether:water p a r t i t i o n removed the water soluble Rose Bengal dye and the organic solvents were removed below 40° under reduced pressure a f t e r drying the organic layer over magnesium s u l f a t e . The g . l . c . analysis was routinely done at 185° on a 20% SE 30 column. 19  - 95 -  octalone 236 from a f r a c t i o n eluted with 60-80% benzene i n petroleum ether o f f a s i l i c a gel column, only a 15% o v e r a l l y i e l d of pure y-acetoxy enone 236 was a v a i l a b l e from octalone 234.  Also, while the  spectral properties observed f o r t h i s compound; u l t r a v i o l e t 242 my (e = 15,400), i n f r a r e d (film) 1760 carbonyl) and 1640 C ^), 1  4.60  (acetate carbonyl), 1670  (conj. o l e f i n ) cm \  ( t r i p l e t , IH, C H), x 7.89 8  and n.m.r. x 4.28  (conj.  (doublet, IH,  ( s i n g l e t , 3H, 0=C-CH ) and x 3  8.94  ( s i n g l e t , 3H, t e r t i a r y methyl), were those expected f o r 236 and were consistant with those reported f o r yacetoxy-a,8-unsaturated s t e r o i d a l ketones, the subsequent e l u t i o n of a much more polar conjugated ketone containing an acetoxy substituent made collaborative evidence f o r octalone 236 necessary.  This was done by converting the f i r s t  acetate eluted from the s i l i c a g e l column to the enedione 343.  A  sample of t h i s acetate, containing compound 248 as an i n t e r n a l standard, was reduced with excess l i t h i u m aluminum hydride i n ether f o r 1 h to y i e l d a 1:2 r a t i o of the a l l y l i c alcohols 347 and 348.  A Collins  oxidation, accomplished with a methylene chloride solution of the chromium trioxide-pyridine complex prepared i n s i t u (158), then yielded a 1:2 r a t i o of the corresponding octalone 234 and enedione 343 i n over 95% y i e l d based on the i n t e r n a l standard.  The octalone 234 probably was  produced i n this two-step sequence by hydrogenolysis of the acetate  - 96 (236) during the hydride reduction,but the i d e n t i f i c a t i o n of the major product as enedione 343 l e f t no doubt that the i n i t i a l l y eluted acetate i s indeed 8a-acetoxy-4a-methyl-4,4a,5,6,7,8-hexahydro-2(3H)-r naphthalenone (236).  I  R 234 R = H 236 R = OAc In a d d i t i o n to the u n i d e n t i f i e d very p o l a r acetate, recovered octalone  234 (^12%), small amounts of the enedione 343 and the  corresponding 2,8-diketone (294) were a l s o eluted from the s i l i c a column.  The i s o l a t i o n of an 8% y i e l d of a mixture of two saturated  ketones 349 and 350 was completely unexpected but could be r a t i o n a l i z e d  36 as the r e s u l t of photoreduction of octalone 234.  Equally s u r p r i s i n g  was the absence of s u b s t a n t i a l amounts of the dienone 353, expected to r e s u l t from the photoproduct  351.  ° Authentic samples of the trans-decalone (349), prepared by B i r c h reduction of octalone 234, and cis-decalone (350), prepared by hydrogenation of octalone 234 i n 0.3 N NaOH i n ethanol, (159), were used to demonstrate the presence of a 6:4 r a t i o of c i s : t r a n s decalones, the same r a t i o obtained when octalone 234 was hydrogenated i n e t h y l acetate under n e u t r a l c o n d i t i o n s . While the c l o s e l y r e l a t e d photoreduction of a,B-cyclopropyl ketones w i l l be discussed subsequently, the above observed reduction of octalone 234 i n oxygenated p y r i d i n e (and oxygenated methanol) s o l u t i o n s i s unusual.(However see r e f . 144).  - 97 -  349 a - H 3 5 0 /3-H  35J.R=0H 352 R = H  353  Persevering, the p h o t o s e n s i t i z e d (Rose Bengal) oxygenation of the 37 unconjugated  octalone 341 was studied i n methanol.  Results s i m i l a r  to those obtained a f t e r 50 h i r r a d i a t i o n i n p y r i d i n e were observed by running the r e a c t i o n f o r 86 h i n methanol.  However, i n c o n t r a s t  to the a l i q u o t s taken from the p y r i d i n e r e a c t i o n , the methanol 35 a l i q u o t s were found by g . l . c . a n a l y s i s a f t e r workup  to be a mixture  of the enedione 343, the octalone 341 and a s m a l l amount of octalone 234.  Washing these samples w i t h aqueous bicarbonate l e f t them  unchanged w h i l e the use of 4 N h y d r o c h l o r i c converted 341 to 234 as expected.  When e i t h e r the crude p h o t o l y s i s product obtained a f t e r  86 h or the corresponding sodium i o d i d e reduction product were o x i d i z e d w i t h chromium t r i o x i d e - p y r i d i n e complex i n methylene d i c h l o r i d e (185), the major 343 accompanied by The r product a t i o of was found d e a c t ito v a tbe i o nthe to enedione """02 consumed i n product formation i s denoted as 8 and i s a f u n c t i o n of the substrate and the solvent (142). Since the 6 values of many s t e r o i d s have been observed to be much l a r g e r i n a l c o h o l solvents than i n p y r i d i n e , most hydroperoxidations of o l e f i n s and a l l hydroperoxidations of 8,y-unsaturated ketones to date have been studied i n p y r i d i n e . However, s i n c e Nickori and Mendelson (135) have reported using methanol i n place of ethanol i n the subsequent sodium i o d i d e reduction of the crude hydroperoxide product to avoid the formation of iodoform,the use of methanol i n the photosensitized oxygenation of 341 suggested i t s e l f i n p e r m i t t i n g the immediate reduction of the crude hydroperoxide products. J /  - 98 -  o c t a l o n e 234. alcohol 352  (or h y d r o p e r o x i d e ) was  (or 351).  samples  However the i n f r a r e d  s p e c t r a demonstrated  an u n o x i d i z a b l e  p r e s e n t , s u g g e s t i n g the p r e s e n c e o f  F u r t h e r g . l . c a n a l y s i s work showed the p h o t o l y s i s  and o x i d i z e d or reduced h y d r o p e r o x i d e samples  c o n t a i n e d the  38 dienone 353 i n a < 1:10  ratio  to the enedione  343.  In c o n c l u s i o n , w h i l e the p r e p a r a t i o n o f the y-hydroxy was  o c t a l o n e 295  contaminated by o n l y s m a l l amounts of the B-hydroxy d e r i v a t i v e ,  the  p r o d u c t m i x t u r e and low y i e l d o b t a i n e d upon a c e t y l a t i o n of 295 p r e c l u d e d employing problems  this  sequence  negated  synthetically.  These unexpected  and u n s o l v e d  the o r i g i n a l work planned f o r o c t a l o n e 236 but the  s y n t h e t i c n e c e s s i t y f o r such an approach, and the n o v e l f e a t u r e s o f the 39 r e a c t i o n s employed, made the r e s u l t s o b t a i n e d worthy o f d i s c u s s i o n .  T h i s a n a l y s i s was performed w i t h a 10 f o o t x 0.25 i n c h column packed w i t h 20% FFAP on 60/80 mesh Chromosorb W a t 220° and a f l o w - r a t e o f 100 ml/min h e l i u m . Work on the d e h y d r o g e n a t i o n o f o c t a l o n e 234 had p r e v i o u s l y demonstrated t h a t o c t a l o n e 234 and 353 had the same r e t e n t i o n time on the 20% SE 30 column used f o r r o u t i n e a n a l y s i s . The f a c i l e l o s s of the 8a s u b s t i t u e n t (hydroperoxy, hydroxy, p e r a c e t o x y , o r a c e t o x y ) p r e v e n t e d the i s o l a t i o n o f these compounds. The dienone 353, i n comparison w i t h o c t a l o n e 234, e x h i b i t e d a T 4.22 a b s o r p t i o n i n the n.m.r. J  O  In a d d i t i o n , o c t a l o n e 236 was found to decompose s l o w l y i n s o l u t i o n (t-L/2 1 k ) and more s l o w l y when n e a t . While more t h a n one p r o d u c t may be produced, the - a c e t a t e was not l o s t and g . l . c . b e h a v i o u r and the v e r y sharp c^H n.m.r. resonance suggested t h a t d i m e r i z a t i o n a t C-8 may be o c c u r r i n g . 00  w e e  - 99 -  D.  O c t a l o n e 237_  (4a,8,8-Trimethyl-4,4a,5,6,7,8-hexahydro-2(3H)-  naphthalenone). A c o n s i d e r a t i o n o f the p o s s i b l e approaches to o c t a l o n e suggests e i t h e r e l a b o r a t i o n o f the gem-dimethyl s u b s t i t u t e d 354  (R = CH^ or CN)  (R = CH,,  237 cyclohexanone  to 237 o r i n t r o d u c t i o n o f gem-methyls i n t o  355  H) by m e t h y l a t i o n f o l l o w e d by c a r b o n y l t r a n s p o s i t i o n to  355  356  p r o v i d e 237.  While the former approach has been used to p r e p a r e the  o c t a l o n e 362  (160) v i a a sodium e t h o x i d e - c a t a l y z e d M i c h a e l a d d i t i o n  of methyl v i n y l ketone to the a c t i v a t e d gem-methylated cyclohexanone d e r i v a t i v e 360  (80% y i e l d ) , i t was  methyl compound not r e a c t .  ( i . e . carboethoxy s u b s t i t u e n t r e p l a c e d by methyl) d i d  Also of i n t e r e s t ,  cyclohexanone  a l s o observed t h a t the analogous  the f o u r - s t e p c o n v e r s i o n o f 2 , 2 - d i m e t h y l -  (358) to the cyanoketone 363 i n 76% o v e r a l l y i e l d  f o l l o w e d by a r e p o r t e d 88% y i e l d  o f the o c t a l o n e 364 o b t a i n e d by  condensing 363 w i t h methyl v i n y l ketone  (161).  A hydrogenation,  was  - 100 -  ketalization, hydrolysis  h y d r i d e and W o l f f - K i s h n e r r e d u c t i o n f o l l o w e d by  then a f f o r d e d  o v e r a l l y i e l d from  synthesis.  365 i n 70%  364.  The a l t e r n a t i v e into octalone  the t r i m e t h y l - t r a n s - d e c a l o n e  approach o f i n t r o d u c i n g the gem-dimethyl  355 has a l r e a d y been used on two o c c a s i o n s  Compound 356,  was then c o n v e r t e d  ketal  the i n i t i a l  to o c t a l o n e  in  substituents sesquiterpene  product p r e p a r e d by t h i s  237 by s u c c e s s i v e  Wolff-Kishner  route  - 101 reduction and chromic a c i d o x i d a t i o n r e a c t i o n s (162,163).  The subsequent  e l a b o r a t i o n of 2_37 to (±)-widdrol (366) (162) and (±)-thujopsene (367) (163) required only two and four a d d i t i o n a l steps r e s p e c t i v e l y .  In the  f i r s t s y n t h e s i s , E n z e l l (162) prepared the gem-dimethyl octalone 356 40 from the corresponding  1-methyl octalone d e r i v a t i v e 355 (R = CH^)  by  using Mukherjee and Dutta's procedure (164) of t r e a t i n g 355, R = CH^, with potassium _t-pentyloxide and methyl i o d i d e , while i n the second synthesis, Dauben and Ashcraft (163) used octalone 355, R = H (= 234) and followed the s t e r o i d r e a c t i o n method reported by Woodward et^ a l . (165) f o r obtaining gem-dimethylation of cholest-4-en-3-one. Since Dauben and Ashcraft's sequence appeared to provide the highest o v e r a l l y i e l d of octalone 237 and since the p r e r e q u i s i t e 40 This compound was derived from 2-methylcyclohexanone and 2-chloroethyl e t h y l ketone i n a manner analogous to the preparation of 355, R = H ( i . e . 234) discussed e a r l i e r . See also reference 118.  - 102  o c t a l o n e 234 was  -  a l r e a d y a t hand, t h i s l a s t s y n t h e t i c r o u t e was  A p p l y i n g the "Woodward" m e t h y l a t i o n procedure, 1:3:6:63 mole r a t i o o f ketone:potassium _t-butanol to 30 g of the o c t a l o n e 234  chosen.  a one hour r e f l u x o f a  _t-butoxide:methyl a f f o r d e d a 92% y i e l d  iodide: of a c o l o u r l e s s  41 oil.  A g . l . c . a n a l y s i s and p r e p a r a t i o n of a n a l y t i c a l samples of  product  showed t h a t t h i s o i l was  7% of the t e t r a m e t h y l o c t a l o n e  89% of the t r i m e t h y l o c t a l o n e (369)  and  (356),  3.5%  of a mixture o f the 42 s t a r t i n g (234) and monomethylated (355) compounds. The e x t e n t of ^ Woodward's r a t i o i s a c t u a l l y 1:3:6:106, the r a t i o used by Dauben and A s h c r o f t to p r o v i d e 77.4% y i e l d of 95% pure 356. 19 T h i s work r e q u i r e d e i t h e r b o t h an SE 30 column at 175° and a * __ „ t i 1 1 s i m i l a r l y constructed 20% FFAP column at 200° o r , when only small amounts  42  of 234 were present, a 10 foot x 0.25 inch column packed w i t h 20% Apiezon J on 60/80 mesh chromosorb W at 190°. When the a l k y l a t i o n was done w i t h a 1:6:13:64 mole r a t i o at room temperature overnight (Stork et a l . (166) procedure f o r the gem-dimethylation of i ) , a 94% y i e l d of OCH  3  crude product was o b t a i n e d , but i t c o n t a i n e d 30% overmethylated m a t e r i a l . From t h i s and o t h e r o v e r a l k y l a t i o n r e a c t i o n s , p r e p a r a t i v e g . l . c . work w i t h the Apiezon J column r e s u l t e d i n the i s o l a t i o n o f the p r e v i o u s l y u n r e p o r t e d compound ijL, i d e n t i f i e d from i t s s p e c t r o s c o p i c d a t a . Compound's i i i n f r a r e d and u l t r a v i o l e t behaviour was v e r y s i m i l a r to t h a t found f o r 356 and 369, but i t s n.m.r. a b s o r p t i o n s were r e a d i l y a s s i g n e d to the pentamethyl o c t a l o n e i i ; n.m.r. T 4.47. ( t r i p l e t , IH, C % , Jrj8H-c?H ^'^ =  7.96 (broadened m u l t i p l e t , 2H, C H ) , 8.27 ( s i n g l e t , 2H, C H ) and 8.73, 8.76, 8.82, 8.86 and 8.96 ( s i n g l e t s , 3H, t e r t i a r y m e t h y l s ) . Irradiation of the T 4.47 t r i p l e t s i m p l i f i e d the T 7.96 m u l t i p l e t to a t r i p l e t ( J ^ 6 Hz) w h i l e i r r a d i a t i o n a t T 7.96 c o l l a p s e d the T 4.47 t r i p l e t to a singlet. 7  4  2  2  2  -  m e t h y l a t i o n was e a s i l y cm  X  region)  103  -  d i s c o v e r e d by o b s e r v i n g  and n . m . r .  (x 8 . 7 - 9 . 2 ) s p e c t r a .  the i n f r a r e d  agreement  d a t a r e p o r t e d (162,163,167,168) f o r the compound 356.  of  between 234 and 356 were p a r t i c u l a r l y u s e f u l  singlet  the s i t e of  evidence  at x 8.78 definitely  o f u n s a t u r a t i o n w i t h the low f i e l d o l e f i n i c  observed at  (6H) and 9.01 assigned,  the x 8.78  w i t h the a x i a l methyls  __  (3H).  T 8.74  the  of  369  234 b e i n g r e p l a c e d by a t r i p l e t  The methyl s i n g l e t  with  The n . m . r .  356 shift  1460  The p h y s i c a l and c h e m i c a l  data o b t a i n e d f o r the major p r o d u c t was i n complete  differences  (1355,  ( J = 3.7  H z , AX^  system).  i n 234 was r e p l a c e d by  Although these s i g n a l s  356.  singlets  have not  a b s o r p t i o n was t e n a t i v e l y  at C - l and C-4a o f  proton  This i s  been  identified  supported by  The unconjugated monomethylated o c t a l o n e i n t e r m e d i a t e 368 i s o f m e c h a n i s t i c importance because i t i s methylated much more r e a d i l y than 355 (160,167). For the s t e r e o c h e m i s t r y of second m e t h y l a t i o n ( a : B - m e t h y l a t i o n i s 9:1) see r e f e r e n c e 168.  the  - 104 -  the recent report that the T 8.78 (6H) and 9.01 (3H) s i g n a l s observed i n chloroform are s h i f t e d to T 8.73 (6H) and 9.09 (3H) i n benzene (168). The minor (7%) product showed an a d d i t i o n a l methyl (doublet) i n the n.m.r.  absorption  When the r e a c t i o n sequence was continued on the mixture,  t h i s compound y i e l d e d 370 a f t e r carbonyl removal and 371 a f t e r a l l y l i c o x i d a t i o n as an 8% impurity i n the r e a c t i o n mixture.  The n.m.r.  spectrum of 371 was e s p e c i a l l y d e f i n i t i v e since i t was superimposable on i t s 6-desmethyl counterpart when the  T  9.08 methyl doublet  (J^6cH  =  6 Hz) was ignored.  370  371  This o v e r a l k y l a t i o n problem was found to be more serious when 100 g q u a n t i t i e s o f octalone 234 were a l k y l a t e d with a 1:3:6:60 mole r a t i o of ketone:base:methyl i o d i d e :jt-butanol.  Reactions on t h i s scale  (125 g octalone required 4 1. of dry _t-butanol) went i n 92% y i e l d , 44 but provided only 72% pure 356.  When Marshall and Hochstetler (169)  used a 1:2.2:9:19.4 mole r a t i o of ketone:base:methyl iodide :_t-butanol on octalone 234 a t 10-20° f o r 2 hours, the 94% y i e l d of c o l o u r l e s s o i l recovered by d i s t i l l a t i o n was s u c c e s s f u l l y f r a c t i o n a t e d on a spinning _ These l a r g e scale r e a c t i o n s were n e u t r a l i z e d w i t h hydrogen c h l o r i d e rather than aqueous a c i d . I t was discovered that the crude product must be washed with aqueous sodium t h i o s u l f a t e before i t i s d i s t i l l e d to avoid excessive polymerization. Henceforth the work-up of a l l a l k y l bromide or iodide a l k y l a t i o n always included treatment with t h i o s u l f a t e to remove the free halogen l i b e r a t e d by a i r o x i d a t i o n .  -  105  -  band column under reduced p r e s s u r e to g i v e a 74% y i e l d of 95% pure 356.  Earlier,  C. E n z e l l had used a s p i n n i n g band column under  reduced p r e s s u r e to p u r i f y  the o c t a l i n 357 and then he a l s o used column  chromatography o f compound 237, and p u r i f i e d the  w h i l e Dauben et^ a_l. (163)  t r i m e t h y l conjugated  octalone  column under reduced p r e s s u r e to a f f o r d group a l s o used r e c r y s t a l l i z a t i o n of  had w a i t e d  237 on a s p i n n i n g band  98% pure o c t a l o n e .  the semicarbazone  of  This 237 and  subsequent ketone r e g e n e r a t i o n w i t h p h t h a l i c a n h y d r i d e to r a i s e y i e l d o f pure  latter  the  237.  H  An attempted semicarbazone acid  (170)  p u r i f i c a t i o n of  (372)  and then r e g e n e r a t i o n o f  proved u n s u c c e s s f u l .  extraction  of 373,  the o v e r m e t h y l a t e d remove i n c o m p l e t e l y  356 v i a r e c r y s t a l l i z a t i o n of  While f o r m y l a t i o n o f  alkylated  t h i s procedure material.  separations  l e d to the development  of  base  to 356 removed  did not,  of  on the o c t a l i n m i x t u r e  the m i x t u r e c o r r e s p o n d i n g to 356 o r 237,  consumed by t h i s method a l o n g w i t h the  below.  (171)  356,  course,  The s p i n n i n g band p u r i f i c a t i o n  t e c h n i q u e was found to be more e f f e c t i v e than on  the ketone w i t h p y r u v i c  and p o t a s s i u m carbonate h y d r o l y s i s compounds,  its  tedious  but  the  (357)  time  n a t u r e o f s p i n n i n g band  the m o d i f i e d r o u t e o u t l i n e d  -  106  -  The i n t r o d u c t i o n o f a b l o c k i n g group a l l o w e d alkylation  to be o b t a i n e d w i t h o u t  the problem o f  complete overalkylation.  The r i - b u t y l t h i o m e t h y l e n e b l o c k i n g group was chosen because i t  i s known  t h a t t h i s group i s r e a d i l y i n t r o d u c e d and removed, the e n e t h i o l  ether  does not d e a c t i v a t e the ketone by a c o n j u g a t i v e  or s t e r i c e f f e c t ,  this functionality  O c t a l o n e 234 was  i s stable  to s t o r a g e  (172).  and treated  i n the u s u a l manner w i t h e t h y l formate and m e t h a n o l - f r e e sodium methoxide i n benzene to p r o v i d e the c o r r e s p o n d i n g base s o l u b l e methylene  compound 374  (64)  t h i o l and p _ - t o l u e n e s u l f o n i c butylthiomethylene  i n 90% y i e l d .  a c i d i n benzene a f f o r d e d  derivative  methyl i o d i d e i n _t-butanol  R e a c t i o n o f 374 w i t h  375 i n 91% y i e l d .  hydroxyn-butane^  the d e s i r e d 3 - n -  A l k y l a t i o n o f 375  ( 1 : 4 . 2 : 9 . 5 : 6 9 mole r a t i o of  with  ketone:base:  methyl i o d i d e : _ t - b u t a n o l ) gave a 90% y i e l d o f the gem-dimethyl b l o c k e d octalone  376.  The h y d r o l y s i s o f the r i - b u t y l t h i o m e t h y l e n e  functionality  -  of  376 was s u c c e s s f u l l y  of  356 o n l y a f t e r  refluxing  107  -  a c h i e v e d w i t h some d i f f i c u l t y ,  glycol.  356 from 234 made t h i s  However,  sequence v e r y  A d o p t i n g Dauben and A s h c r a f t ' s  the  useful.  the method developed by B a r t o n ,  o b t a i n a 92% y i e l d o f pure o c t a l i n 357.  Experimentally,  the hydrazone d e r i v a t i v e  of  glycolate solution.  356 w i t h a  The hydrazone was then decomposed to  to 2 1 0 ° .  to  170°  glycol-sodium 357 by r a i s i n g  The much l e s s d a n g e r o u s ^ method o f Nagata et  (174,175), u s i n g h y d r a z i n e d i h y d r o c h l o r i d e , 95% h y d r a z i n e , hydroxide,  Ives  t h i s work  s o l u t i o n o f anhydrous h y d r a z i n e i n a d i e t h y l e n e  the temperature  the  f o r the r e d u c t i o n of h i n d e r e d ketones was used  i n v o l v e d the f o r m a t i o n o f  in  70% o v e r a l l y i e l d o f pure  e x p e r i m e n t a l procedure f o r  p r e p a r a t i o n o f o c t a l i n 357 from 356,  refluxing  95%  a n i n e t y - h o u r treatment w i t h potassium h y d r o x i d e  diethylene  and Thomas (173)  yielding  al.  and p o t a s s i u m  was a l e s s a t t r a c t i v e method s i n c e i t p r o v i d e d y i e l d s  of  < 50% i n our hands and e x c e s s i v e foaming was observed d u r i n g the reaction. An a l l y l i c  o x i d a t i o n o f the o c t a l i n 357 w i t h anhydrous sodium  chromate i n a c e t i c a c i d - a c e t i c y i e l d of  anhydride  the d e s i r e d t r i m e t h y l o c t a l o n e  (162,163) then p r o v i d e d a 69% 237.  T h i s compound was  to samples p r e p a r e d by the d i r e c t  alkylation  but,  t h i s m a t e r i a l was not contaminated  u n l i k e the e a r l i e r p r o d u c t s ,  route  from o c t a l o n e  identical 234 with  45 The danger o f p r e p a r i n g the r e q u i r e d anhydrous h y d r a z i n e f o r the B a r t o n e_t a l . method was " o b s e r v e d " d u r i n g the d i s t i l l a t i o n o f h y d r a z i n e h y d r a t e from sodium h y d r o x i d e when a 500 ml anhydrous h y d r a z i n e g e n e r a t o r " d e t o n a t e d " i n a fume hood. The f a c t t h a t the recommended procedure of p r e p a r i n g anhydrous h y d r a z i n e i n a n i t r o g e n atmosphere was b e i n g f o l l o w e d (176) i l l u s t r a t e s the danger of h a v i n g a l e a k i n a p o s i t i v e p r e s s u r e n i t r o g e n system.  - 108 -  other octalones.  In an attempt to improve the y i e l d of the octalone  237, an a l l y l i c o x i d a t i o n with chromium t r i o x i d e - p y r i d i n e methylene c h l o r i d e (177) was employed.  complex i n  In our hands, a l e s s  than 50%  y i e l d of octalone 237 with only a 5% recovery of o l e f i n , c o u p l e d with the large volume of methylene c h l o r i d e used made the r e a c t i o n ?  i m p r a c t i c a l f o r large s c a l e work.  E.  Octalone 238 and 239 (4a,5-Dimethyl-4,4a,5,6,7,8-hexahydro2(3H)-naphthalenone).  While a mixture of the v i c i n y l dimethyl octalones 238 and 239 can be r e a d i l y prepared by sever al routes, the s t e r e o s e l e c t i v e of e i t h e r compound i s a formidable o b s t a c l e .  synthesis  The i n t r o d u c t i o n of c i s  v i c i n y l dimethyls i s of s p e c i a l importance because of the almost u n i v e r s a l occurrence of t h i s r e l a t i o n s h i p i n eremophilane sesquiterpenes. 47 As described elsewhere,  octalone 238 has been.used i n the synthesis of  members of the b i c y c l i c eremophilane (most r e c e n t l y  (+)-eremophilenolide  (377) (179 )), t r i c y c l i c a r i s t o l a n e ( ( + ) - a r i s t o l o n e (378) (179 )), and a  b  t e t r a c y c l i c ishwarane ((+)-ishwarane (379) (179 )) c l a s s e s of __ C a p s i d i o l (x), an a n t i f u n g a l compound whose s t r u c t u r e was r e c e n t l y e l u c i d a t e d by Stothers et a l . (178) i s a p o s s i b l e exception. I t was assigned a trans v i c i n y l dimethyl r e l a t i o n s h i p based on I R n . m . r . spectroscopy and 13c n . m . r . data .OH supporting r i n g B being i n a c h a i r conformation.  i  OH  See Appendix I I ,  'eremophilane approach'.  - 109 sesquiterpenes.  238/9  In the i n t e r e s t s octalones  380/1  of b r e v i t y ,  the work on the v i c i n y l methyl  can be c o n s i d e r e d i n terms of a n o n - a n n e l a t i o n p r e p a r a t i o n  or one i n v o l v i n g the Robinson a n n e l a t i o n approach to o c t a l o n e and the c l o s e l y  r e l a t e d octalone  380/1.  238/9  The n o n - a n n e l a t i o n work  is  e x e m p l i f i e d by the c y c l i z a t i o n of the t r i e n e 382 w i t h anhydrous f o r m i c a c i d to p r o v i d e o n l y the c i s v i c i n y l methyl compounds 383 and 384 i n a 2:3 r a t i o  i n 67% y i e l d  and 386 was r e c e n t l y  (180 ) while a  the D i e l s - A l d e r r e a c t i o n of  385  r e p o r t e d to y i e l d o n l y the t r a n s v i c i n y l compound  - 110 387 ( 1 8 0 ) . b  4 8  06  .-•OCHO  OCHO  383  382  3 8 4  J 387  385  To date considerable success has been achieved i n s t e r e o s e l e c t i v e l y preparing s u b s t i t u t e d octalones r e l a t e d to 380/1.  The Michael a d d i t i o n  of trans-3-penten-2-one (388) to d e r i v a t i v e s of a c t i v a t e d  cyclohexanones  (389 (181 ,183 ) 390 and 391 (181 )) was found to lead to the c i s v i c i n y l a  b  b  48 However, even more r e c e n t l y , a D i e l s - A l d e r r e a c t i o n of the diene 1 w i t h methyl a c r y l a t e ( i i ) was found to give the "masked" c i s v i c i n y l methyl compound i i i s t e r e o s e l e c t i v e l y . Elaboration of i i i to i v and the acid-catalyzed r i n g opening of the c a r b i n o l iy_'was then completed by the synthesis of (+)-nootkatone (v) (180°). OCH,  C0 CH 2  3  Y ^ O C H  R U  3  JOT"  LU R = C H  ,R'=C0 CH_, 0  iy R = - C H = C H , R = C ( C H ) O H 2  3  2  -  Ill  -  p r o d u c t 392 w h i l e 2 - m e t h y l c y c l o h e x a - l , 3 - d i o n e  (393  y i e l d e d p r e d o m i n a n t l y the t r a n s v i c i n y l d i o n e 395.  (181°)  and 394 (181  However, a  ))  much  394 more g e n e r a l r o u t e to s u b s t i t u t e d o c t a l o n e s  t h a t a r e r e l a t e d to  became a v a i l a b l e when i t was demonstrated t h a t c r o s s - c o n j u g a t e d s i m i l a r to 300 r e a c t e d 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 to a f f o r d trans product s t e r e o s e l e c t i v e l y conjugated  (182  octalones  the  ) w h i l e 4-methyl s u b s t i t u t e d  ketones c o u l d be reduced s t e r e o s e l e c t i v e l y  v i c i n y l d i m e t h y l compound such as 397  XX) — 30Q  380/1  (98, 181^,  to p r o v i d e a c i s  182^'°).  381  cross-  In a d d i t i o n ,  -  112  -  the independent d e m o n s t r a t i o n by two groups i n 1971  (183)  that  solvent  parameters c o n t r o l the s t e r e o c h e m i s t r y of the Robinson a n n e l a t i o n r e a c t i o n appears to supersede a l l o t h e r p r e v i o u s a p p r o a c h e s . 3-penten-2-one  and 2-methylcyclohexanone  d i m e t h y l o c t a l o n e 380 (> 95% c i s ) 381)  Trans-  gave almost c o m p l e t e l y the  i n d i o x a n e w h i l e the t r a n s  (> 95%  was o b t a i n e d w i t h d i m e t h y l . s u l f o x i d e . In c o n t r a s t  to the above,  2,3-dimethylcyclohexanone  the methyl v i n y l ketone a n n e l a t i o n of  has been r e p o r t e d by s e v e r a l groups to proceed  i n o n l y 15% y i e l d to a f f o r d a 3:2  cis-.trans  (238:239) r a t i o  (179  W h i l e O u r i s s o n ' s group was a b l e , by r e d u c t i o n and b r o m i n a t i o n of mixture,  to i s o l a t e  ,184). this  398 by c r y s t a l l i z a t i o n and then dehydrohalogenate  398  399  to the o c t a l o n e 399,  the a t t e n t i o n o f o t h e r s y n t h e t i c  to s t e r e o s e l e c t i v e l y  alkylating derivatives  After  cis  of  i t was d i s c o v e r e d t h a t the a l k y l a t i o n of  groups has t u r n e d  2,3-dimethylcyclohexane. 2,3-dimethy1-6-n-butyl-  -  thiomethylenecyclohexanone  113  -  (400) w i t h m e t h a l l y l c h l o r i d e produced a  4:1 m i x t u r e of the c o r r e s p o n d i n g c i s (403) and t r a n s (185  ) , the a l k y l a t i o n  afford  approximately  compounds of  (184 ) .  of 400 w i t h e t h y l  3-bromopropionate was found to  a 9:1 m i x t u r e of c i s (405) and t r a n s (406)  Subsequently,  2,3-dimethylcyclohexanone  4Q0 4Q1  (404) d e r i v a t i v e s  X= S B u X=N(CH )C H n  3  6  the N - m e t h y l a n i l i n o m e t h y l e n e  (401) was a l s o a l k y l a t e d  with  n  5  and t r a n s - 4 0 8 i n a r a t i o o f >7:1  Even when the o r d e r of i n t r o d u c i n g a s u b s t i t u e n t  blocked  the c i s v i c i n y l methyl product was found to predominate. i l l u s t r a t i o n of t h i s was the r e p o r t t h a t 402 a f f o r d e d p r o d u c t 410 when the b l o c k e d ,  observed  with methyl i o d i d e  isoxazole-substituted (185^).  (184^).  at C-2 was r e v e r s e d by  i n t r o d u c i n g a methyl group i n t o a 2 - a l k y l - 3 - m e t h y l  was a l k y l a t e d  3-bromopropionate  4 0 5 X = SBu" 4 0 6 X = SBu 4 0 7 X = N(CHjC H, 4 0 8 X = N(CH J C H,.  and found t o p r o v i d e the c i s - 4 0 7  cis  derivative  cyclohexanone,  An  o n l y the d e s i r e d cyclohexanone  The h i g h degree of  selectivity  f o r these c i s v i c i n y l methyl p r o d u c t s p e r m i t t e d 405 and 407  -  to be c o n v e r t e d ,  through 417,  114  -  to 238 w h i l e 410 gave 411  417  411  The sequence  that  elaborated  the n - b u t y l t h i o m e t h y l e n e  to o c t a l o n e  page.  experimentally  appeared to be the most e f f i c i e n t i t was hoped t h a t octalone  (239)  following  e x p l o r e d r o u t e because  method a v a i l a b l e  (186).  3  blocked  238 i s o u t l i n e d on the  it  At the  outset,  a method c o u l d be found to produce the t r a n s d i m e t h y l  efficiently  through some parameter v a r i a t i o n s i n the  alkylation  s t e p to enhance the r e l a t i v e  any e v e n t ,  i t was expected  that  a better  r e a c t i o n sequence would be o b t a i n e d .  y i e l d s of 418 and 420. u n d e r s t a n d i n g of  dimethylcyclohexanone, and keto a c i d s 417/8  through i t s  In  this  F o r the purposes of d i s c u s s i o n ,  t h i s work w i l l be c o n s i d e r e d i n t h r e e p a r t s -  p r e p a r a t i o n of  412.  238 R = H 412 R = C O C H  2,3-dimethylcyclohexanone I t was the i n i t i a l  and then  the c o n v e r s i o n of  a l k y l a t e d blocked d e r i v a t i v e  to a m i x t u r e of e n o l l a c t o n e s  419/420, the  the c o r r e s p o n d i n g i n d i v i d u a l e n o l l a c t o n e s  2,3415/6 subsequent  419 and 420,  -  and f i n a l l y ,  115  -  4J4X =CH0H  415. 3/Q-CH3  4T7 3/3-CH3  4 0 0 X = CHSBu  4J£.3a-CH  41S.3a-CH  3  the p r e p a r a t i o n of the v i c i n y l methyl o c t a l o n e s  3  238 and  239. As d i s c u s s e d e a r l i e r , the i n t r o d u c t i o n of a b l o c k i n g group on the methylene a to a c a r b o n y l p e r m i t t e d m o n o a l k y l a t i o n at p o s i t i o n when the a '  the a '  p o s i t i o n was t r i s u b s t i t u t e d and d i a l k y l a t i o n  when i t was d i s u b s t i t u t e d .  The p r e v i o u s l y demonstrated advantages  of  functionality  the i v - b u t y l t h i o m e t h y l e n e  octalone  i n the p r e p a r a t i o n of  237 l e d to the use of t h i s b l o c k i n g group f o r  cyclohexanone.  The ketone 413,  2,3-dimethyl-  o b t a i n e d by o x i d i z i n g the a l c o h o l  produced from h y d r o g e n a t i n g 2 , 3 - d i m e t h y l p h e n o l , was t r e a t e d i n the u s u a l manner w i t h e t h y l formate and sodium methoxide i n benzene to p r o v i d e the hydroxymethylene d e r i v a t i v e  414  i n 90% y i e l d .  R e a c t i o n of  414 w i t h n - b u t a n e t h i o l and p _ - t o l u e n e s u l f o n i c a c i d i n benzene  afforded  an 88% y i e l d of 2 , 3 - d i m e t h y l - 6 - n - b u t y l t h i o m e t h y l e n e c y c l o h e x a n o n e  (400).  - 116 -  Enolate formation with potassium _t-butoxide and a l k y l a t i o n with e t h y l - 3 bromopropionate i n _t-butanol (1:2.94:3.7:41 mole r a t i o of ketone: base: a l k y l a t i o n agent :t^-butanol) then gave a 94% y i e l d of a mixture of 415 and 416. The concomittant h y d r o l y s i s of the n-butylthiomethylene and e t h y l ester f u n c t i o n a l i t i e s w i t h base i n r e f l u x i n g aqueous diethylene g l y c o l proceeded i n 90% to a f f o r d a mixture of the keto acids 417 and 418. Enol lactone formation with sodium acetate i n a c e t i c anhydride  then produced a 95% y i e l d of a mixture of the correspond-  ing enol lactones 419 and 420. Under i d e a l circumstances,  the r a t i o of c i s : t r a n s v i c i n y l methyl  compounds r e s u l t i n g from the a l k y l a t i o n r e a c t i o n would be measured d i r e c t l y on the a l k y l a t i o n product mixture  (415/6), but unfortunately  the gas chromatographic and proton nuclear magnetic resonance (n.m.r.) s p e c t r a l data of t h i s mixture were found to be unsuitable f o r such an analysis.  While the i n d i v i d u a l keto acids showed small d i f f e r e n c e s i n  the n.m.r. spectra and while the corresponding methyl esters of 417 and 418 could be resolved by gas chromatography, the i n d i v i d u a l enol lactones 419 and 420 were found to e x h i b i t much more s u b s t a n t i a l a 49 d i f f e r e n c e s i n t h e i r n.m.r. (184 )  and g . l . c . behaviour.  These  d i f f e r e n c e s were then e x p l o i t e d and used to measure the a l k y l a t i o n reaction's s t e r e o s e l e c t i v i t y by c o n v e r t i n g the various a l k y l a t i o n  product  49 There was only a s l i g h t chemical s h i f t d i f f e r e n c e i n the downfield v i n y l proton of the two enol lactones. The l a r g e r s h i f t d i f f e r e n c e between the t e r t i a r y methyl of 419 and 420, along w i t h the absence of non-methyl resonances between x 8.7-9.4, permitted an accurate measurement of the c i s : t r a n s r a t i o to be made using double n.m.r. i n t e g r a l s . These i n t e g r a l s were always taken on instrument scans of 100 hertz sweep width over the x 8.7-9.4 region. The c i s enol lactone had methyl n.m.r. resonances at x 8.96 ( s i n g l e t , 3H, t e r t i a r y methyl) and 9.04 (doublet, 3H, secondary methyl, J = 6.0 Hz). The trans one (420) showed x 8.78 ( s i n g l e t , 3H, t e r t i a r y methyl) and 9.03 (doublet, 3H, secondary methyl, J = 6.4 Hz) resonances.  - 117 mixtures  (415/6) to a mixture of enol lactones.  However, the v a l i d  use of these " a l k y l a t i o n r a t i o s " required the underlying assumption that the h y d r o l y s i s and l a c t o n i z a t i o n steps d i d not d i f f e r e n t i a t e between 415 and 416 or between 417 and 418. The l a t t e r p o r t i o n of t h i s assumption was proven to be c o r r e c t when the i n d i v i d u a l c i s - and trans-keto acids were found to give s i m i l a r y i e l d s of enol lactones.  The conversion of  an enol lactone mixture to a mixture of keto acids and methyl esters and then back again to enol lactones was a l s o shown to leave the c i s : t r a n s r a t i o unchanged. The enol lactone mixture derived i n 80% o v e r a l l y i e l d from the blocked ketone 400 v i a the above potassium _t-butoxide a l k y l a t i o n was analyzed by n.m.r. and a c i s : t r a n s v i c i n y l methyl r a t i o of 82:18 was o b s e r v e d . I n considering l i t e r a t u r e precedents f o r s h i f t i n g t h i s r a t i o s u b s t a n t i a l l y , considerable recent work was found on the e f f e c t of base (188) and solvent (189) on changing the r e g i o s e l e c t i v i t y of an a l k y l a t i o n but very l i t t l e could be found on the c o n t r o l of stereochemistry. expected,  As  there were many examples of s u b s t a n t i a l s t e r i c hindrance on  one side of the molecule leading to attack on the l e s s hindered side (190 ) and one example of the a-substituent r e v e r s i n g the a l k y l a t i o n stereochemistry when a 8-keto ester was replaced by a 8-keto n i t r i l e (190^),  but f o r s u b s t i t u t e d cyclohexanones i t appeared that the nature  of the enolate s u b s t i t u e n t was of general importance.  When the enolate  Although a s i m i l a r n.m.r. a n a l y s i s (184 ) i n d i c a t e d a c i s : t r a n s r a t i o of approximately 9:1, the above would i n d i c a t e that a r a t i o of approximately 8:2 or 4:1 would be a more accurate d e s c r i p t i o n . This ^ 4:1 r a t i o was the same as that p r e v i o u s l y reported f o r the a l k y l a t i o n of 400 w i t h m e t h a l l y l c h l o r i d e (see 403/404) and confirms the observation made l a t e r that changing the halogen from C l to Br does not a f f e c t the cis:trans ratio significantly.  -  s u b s t i t u e n t was  118  -  h y d r o g e n , a p p r o x i m a t e l y e q u a l amounts o f " a x i a l "  and  " e q u a t o r i a l " p r o d u c t s were formed as, f o r example, when 421, R = H a 422a:422e r a t i o  o f 45:55 ( 1 9 1 ) . a  70-90% o f t h e " a x i a l " 423 y i e l d e d  An a l k y l  r a t i o of 83:17  (191  425 R = D  426a  427 R = Alkyl  428a  a reductive  substituent usually l e d to  p r o d u c t w i t h 421, R = CH, g i v i n g ^ 70% 422a w h i l e  a 424a:424e  the s i m p l e o c t a l o n e  ).  In an analogous  manner,  426e  425, which c o u l d be a l k y l a t e d  process,  gave  y i e l d e d a 40:60 m i x t u r e o f  regioselectively  the methyl  by  decalones  c 426a and 426e from m e t h y l a t i o n  i n tetrahydrofuran  (191  i n t r o d u c t i o n o f a C - l a l k y l group was found to permit a axial alkylation  to o c c u r and has been e x p l a i n e d  ).  The stereoselective  i n terms of  a-side 1 2  attack strain)  contracting  the C - l a l k y l  i n the a l k y l a t i o n  to C-8a methylene  transition state  the product s t e r e o c h e m i s t r y  (191  ).  d i h e d r a l angle In terms of  through the c h o i c e o f r e a c t i o n  the r e p o r t that m e t h y l a t i o n of  the  10-nor  steroid,  429,  (A '  changing  parameters,  switched  from a  - 119 -  r a t i o of 10:1 a-face a l k y l a t i o n : B - f a c e a l k y l a t i o n i n ^-butanol to a r a t i o of 3:7 i n benzene (168) suggested that the choice of solvent could be very important.  P r e l i m i n a r y studies of the a l k y l a t i o n of the blocked ketone 400 showed that changing the mole r a t i o of a given base, a l k y l a t i n g agent and solvent r e s u l t e d i n l i t t l e or no change i n the c i s : t r a n s isomer ratio.  This r a t i o was a l s o independent of the extent of the r e a c t i o n  or the y i e l d obtained.  Table I summarizes some of the r e s u l t s produced  when two gram amounts of ketone 400 were e n o l i z e d w i t h d i f f e r e n t bases i n d i f f e r e n t solvents and a l k y l a t e d w i t h e i t h e r  ethyl-3-bromopropionate  (RBr) or ethyl-3-chloropropionate (RC1) and then converted to a mixture of enol l a c t o n e s . B y i g n o r i n g the runs i n hexamethylphosphoric triamide (HMPT), the stereochemistry of the RBr a l k y l a t i o n i n r e l a t i v e percentage of c i s product can be expressed as potassium _t-butoxide (82 + 2 ) , sodium _t-butoxide ( 7 5 + 1 ) and l i t h i u m _t-butoxide (51 + 1 ) . * These runs p a r a l l e l e d each other i n the sense that the mole r a t i o of ketone:base:alkylating agent:solvent was kept at 1:3.2:3.73:72. No e f f o r t was made to maximize the y i e l d s , but i n the case of the LiOBut/ButOH/RBr r e a c t i o n , extending the r e a c t i o n time to 5 h from 1 h r a i s e d the y i e l d from 30% to 80% o v e r a l l . However, the g . l . c . a n a l y s i s s t i l l showed 50.3:49.7 c i s : t r a n s r a t i o ' i n both cases. See experimental for other d e t a i l s on Table I .  -  120 -  TABLE I. STEREOCHEMISTRY OF THE A L K Y L A T I O N PRODUCTS OF THE BLOCKED K E T O N E 4 0 0 .  Base Employed  KOBu  1  Solvent System  Alkylating Agent  BifoH  RBr  II  OH  H  H  THF  II  HMPT  II  n  NaOBu  1  LiOBu*  419  : 420  83:17 81-19 80=20 90-10  BiiOH  RBr  75=25  BuOH  RBr  50=50  M  OH  II  THF  11  Enol Lactone Ratio  H  51 =49  n  51  HMPT  =49  89-11  KOBu*  BifOH  RCl  86M4  LiOBu  Bu*OH  RCl  51 : 4 9  The  1  e x t e n s i o n of  t h i s work to o t h e r  p o t a s s i u m base l i k e  bases showed t h a t  p o t a s s i u m c a r b o n a t e i n t - b u t a n o l p r o v i d e d a 84:16  10% o v e r a l l y i e l d )  ratio  (albeit  furan  (THF) gave a 76:24 r a t i o .  i n _t-butanol and sodium methoxide  w h i l e sodium methoxide i n t e t r a h y d r Therefore, while potassium hydroxide i n _ t - b u t a n o l , m e t h a n o l , o r benzene  d i d not p r o v i d e any o f the d e s i r e d product because and w h i l e  even a weak  of s i d e  reactions,  l i t h i u m carbonate d i d n o t appear to cause any a l k y l a t i o n  - 121 -  i n _t-butanol, the stereochemistry of the a l k y l a t i o n of compound 400 appeared to be p r i m a r i l y dependent only on the a l k a l i metal c a t i o n (counterion) employed.  The i n s i g n i f i c a n c e i n the choice of a l k y l a t i n g  agent was demonstrated by the observation that r e p l a c i n g the bromo-ester (RBr) w i t h the c h l o r o - e s t e r (RC1) caused no change w i t h l i t h i u m t-butoxide i n _t-butanol and only a minor d i f f e r e n c e w i t h potassium _t-butoxide i n _t-butanol.  The importance of solvent was i l l u s t r a t e d by the large  l i t h i u m base s h i f t from ^50:50 to ^90:10 and the smaller potassium base  52 change from 82:18  to 90:10 when hexamethylphosphoric triamide  used i n place of the other s o l v e n t s .  was  The r e l a t i v e l y " f r e e " nature of  the enolate i n HMPT makes the enolate's behaviour independent of i t s counterion and leads to an i n t e r p r e t a t i o n of the a l k y l a t i o n r e s u l t s i n terms of the involvement (432).  of solvent-separated ions (431) or contact ion p a i r s  The solvent-separated p a i r would be expected to be more r e a c t i v e  and could be represented as i n v o l v i n g a mixture of the " h a l f - c h a i r "  431  432  Hexamethylphosphoric triamide (HMPT) i s a p o l a r , a p r o t i c solvent whose r e l a t i v e l y high b a s i c i t y makes i t an e x c e p t i o n a l l y good c a t i o n s o l v a t o r and an e x c e p t i o n a l l y poor anion s o l v a t o r (192) . Enolates i n p r o t i c solvents (Bu 0H) g e n e r a l l y favour C - a l k y l a t i o n but polar a p r o t i c solvents l i k e HMPT enhance O - a l k y l a t i o n w i t h the formation of enol ethers. The enol ether product of 400 would not i n t e r f e r with the c i s : t r a n s C - a l k y l a t i o n measurements but would lower the o v e r a l l y i e l d . c  -  conformations  122 -  433a and 433b i n the t r a n s i t i o n s t a t e .  to form more t i g h t l y  associated  most common p r o t i c o r a p r o t i c  ion pairs  solvents  L i t h i u m i s known  than sodium or p o t a s s i u m i n  (Bu OH or 0H) (191^), but the t  contact  i o n p a i r can be shown not to have a p r o d u c t - l i k e  state.  If a product-like  contact  ion pairs,the  t r a n s i t i o n s t a t e were  o f the more f a v o u r a b l e  dominate.  Since t h i s  appropriate of  i n v o l v e d w i t h the l i t h i u m  t r a n s v i c i n y l methyl product r e s u l t i n g  alkylation  since reactant-like  is clearly  of c o n t a c t  reactions  elsewhere  (191^), the  i o n p a i r s i s suggested.  BuSHC H 433 b  BuSHC  434a  of 434a+b  50:50 m i x t u r e of  H  433a  involvement  434a and 434b by the  H  H  generally  The involvement  i n the t r a n s i t i o n s t a t e would l e a d t o the observed  M  to  not the c a s e f o r compound 400, and •  t r a n s i t i o n s t a t e s have been found to be  for C-alkylation  from the  c o n f o r m a t i o n 435a would be expected  the r a t h e r p l a n a r t r a n s i t i o n s t a t e c o n f o r m a t i o n s  aggregation  transition  434 b  - 123 -  BuSHC  "H BuSHC 435 b  c i s : t r a n s products.  When the enolate of 400 was s h i f t e d from contact  ion p a i r s to solvent separated  ions by HMPT or by the use of a potassium  c a t i o n , the conformations 433a+b would become dominant.  The a l k y l a t i o n  of 433a gives a 1 , 3 - i n t e r a c t i o n with the C-4 hydrogen on the a-face and a 1 , 2 - e c l i p s i n g with the C-3 hydrogen on the B-face.  I f there i s  any merit i n House's recent proposal (191^) that the d i h e d r a l angle between the C - l carbon-oxygen-M and C-2 carbon-alkyl i s not +  zero  (to avoid e c l i p s i n g i n s u b s t i t u t e d e n o l a t e s ) , the r e s u l t would only lead to enhancement ( i n 433a) of trans product formation or a l t e r n a t i v e l y enhancement of the population of conformer 433b because of the increase 1 2 i n A ' s t r a i n (C-2, C-3 methyls) introduced i n t o 433a.  Conformation  433b, which could r e a d i l y reduce the C-6 b l o c k i n g group, the C - l oxygen and C-2 methyl i n t e r a c t i o n by t w i s t i n g the enolate double bond, would be subjected to predominantly B-face a l k y l a t i o n (cis-product) on the b a s i s of the s t e r i c f a c t o r introduced by the pseudoaxially oriented methyl.  In any case, while these observed changes i n stereochemistry  with c a t i o n and solvent are of s y n t h e t i c importance,the l a r g e s t energy 53 d i f f e r e n c e between t r a n s i t i o n s t a t e s i s quite s m a l l . 53  In going from l i t h i u m enolates i n ButOH ( c i s : t r a n s i s 1:1) to those i n HMPT ( c i s : t r a n s i s 9:1), the energy d i f f e r e n c e between the c i s and trans t r a n s i t i o n states changes from 0 i n ButOH to ^1 kcal/mole i n HMPT (AE «= RT l n c i s / t r a n s ) (193) .  - 124 -  In March 1973, Stork and Boeckman reported a much more dramatic dependence of n i t r i l e a l k y l a t i o n stereochemistry dn the metal c a t i o n employed (194).  The intramolecular a l k y l a t i o n of the n i t r i l e 436 w i t h  i t s a-haloketal substituent (X = Br, I) gave 95% c i s d e c a l i n 437 with potassium hexamethyldisilazane i n benzene, while the l i t h i u m base i n the same solvent provided 90% trans.  The c o n t r o l l i n g f a c t o r of the  X  anion a l k y l a t i o n was considered.to be the requirement of a more c l o s e l y held t r a n s i t i o n s t a t e f o r a l i t h i u m c a t i o n i n benzene than f o r a potassium c a t i o n i n achieving the proper alignment of the departing h a l i d e , the a l k y l a t i n g methylene, and.the t r i g o n a l n u c l e o p h i l i c centre.  This work  a l s o reported that the use of the l i t h i u m base i n tetrahydrofuran r e s u l t e d i n loosening of the i o n p a i r by c a t i o n s o l v a t i o n so that a 20:80 r a t i o of cis-437 to trans-437 r e s u l t e d .  The l a c k of a s i m i l a r  solvent e f f e c t i n Table I i s p u z z l i n g . Continuing the octalone preparation sequence, the c i s enol lactone could be r e a d i l y c r y s t a l l i z e d from a hexane s o l u t i o n of a 82:18 mixture of the c i s and trans isomers 419 and 420. A r e c r y s t a l l i z a t i o n then afforded pure enol lactone 419. The more e l u s i v e trans isomer required successive s i l i c a chromatographies of the enol lactone mixture, h y d r o l y s i s of the impure trans enol lactone product, and c r y s t a l l i z a t i o n of the pure trans keto a c i d (418) with subsequent dehydration to the enol lactone 420. Enol lactone 419 reacted with m e t h y l l i t h i u m at -25° i n  -  ethyl  ether  125  to p r o v i d e i n t e r m e d i a t e  w i t h h y d r o c h l o r i c a c i d to a f f o r d catalyzed  -  438a and the r e a c t i o n was  440a v i a 439a.  An immediate  a l d o l c o n d e n s a t i o n gave the d e s i r e d o c t a l o n e  d i r e c t y i e l d from 419  of up to 78%.  sequence was used on e n o l l a c t o n e  base-  238 i n an o v e r a l l  However, when the same  420^ o n l y  quenched  30% o c t a l o n e  experimental  239 was  238 *- or 239 419 3/3-CH org  438_X = Li  420 3a-CH orb  439 X = H  3  3  isolated.  C o n s i d e r a b l y more u n r e a c t e d  (19.4%, as the lactone for  trans keto acid)  a spontaneous  t r a n s e n o l l a c t o n e was  than had been the case of  (8-9%, as the c i s keto a c i d ) .  these r e s u l t s  440.  r i n g opening to 441 w i t h a subsequent  438 a 3/3-CH  44j_  3  438b 3 a - C H  the c i s  The most r e a s o n a b l e  suggested t h a t the l i t h i u m adduct  recovered enol  explanation  438 was  undergoing  r a p i d a d d i t i o n of  442  3  m e t h y l l i t h i u m to y i e l d  the  " d i - a d d u c t " 442.  c c t v i c i n y l m e t h y l compounds, k^ > k^ w h i l e k^ = d i s t i l l a t i o n of o c t a l o n e b o i l i n g m a t e r i a l was  239, a c o n s i d e r a b l e  isolated.  In the case of t  for  the  the t r a n s .  cis In  amount of a s l i g h t l y  the higher  The h y d r o x y l and c a r b o n y l i n f r a r e d  a b s o r p t i o n s and n . m . r . methyl resonances  are i n agreement  with  those  - 126 -  expected f o r compound  443.  54  LiO OH  444.  443  To gain a b e t t e r understanding lactones 419  of the r e a c t i o n , mixtures of enol  and 420 were used to prepare a mixture of the  corresponding  octalones. The i n i t i a l r a t e of attack of m e t h y l l i t h i u m on e i t h e r enol lactone to a f f o r d the methyl adduct 438  (k^) or the enolate 444  (k^,)  was shown to be the same f o r both the c i s and trans enol lactone since t h e i r isomer r a t i o was found to be unchanged i n the recovered material.  starting  For example, when the keto a c i d mixture recovered from a  r e a c t i o n on a 59:41  r a t i o of c i s : t r a n s enol lactones was dehydrated,  the enol lactone product analyzed f o r a 59:41 r a t i o of c i s : t r a n s enol c t t c lactone. While k^ = k^ and k^ was obviously greater than k^, the 54  The r e l a t i v e weakness of the carbonyl absorbance compared to that of the hydroxyl i n t h i s keto a l c o h o l (443, i ) suggests that the hemiketal i i predominates. G . l . c . ^ work on t h i s compound also provided a compound t e n t a t i v e l y i d e n t i f i e d as i i i . This r i n g - c h a i n tautomerism has r e c e n t l y been reported (195) f o r 5-oxo-3,5--seco-A-norcholestan-3o l , a compound analogous to i , R = H. x  i  R =  CH3  IL  R=CH3  iii R = CH  3  - 127 t observed  r a t i o s of o c t a l o n e s i s o l a t e d p e r m i t t e d an e s t i m a t e o f ^ 2 ^ 2  5 t o 10 t o be made."*"* yield  c  T a b l e I I summarizes the r e s u l t s of o p t i m i z i n g the  o f the c i s o c t a l o n e (runs 1-4) and the work comparing  reactions  =  cis/trans  (runs 5-9).  T A B L E II. PRODUCT DISTRIBUTION OBTAINED BY T R E A T M E N T OF E N O L L A C T O N E S .  METHYLLITHIUM  Experimental  Ratio of C H ^ L i  Enol Lactone  Octalone  Octalone  Recovered  Run  to Enol Lactone  419 ; 4 2 0  Yield  238:239  Keto Acid  a  l  a  1.59  100=0  61%  100--o  18.3 %  2  a  1.69  100--0  67.7  100=0  13.4%  3  1.82  100=0  78%  100=0  9 %  4  1.93  100=0  60.4%  100=0  2.7%  5  1.78  100=0  73.7%  100=0  8.2%  6  1.88  7  1.75  59=41  38.7%  92=8  12%  8  1.83  36--64  25.6%  72=28  13%  9  1.83  84=16  58%  95=5  8%  1 3 / 4 h at - 2 5 ° ,  •  otherwise 2 h  0=100  31.3%  OMOO  19.4 %  at-25°  55  t c E s t i m a t e based on a p p r o x i m a t i n g ^/k^ by the p r o d u c t t r a n s / c i s e n o l l a c t o n e r a t i o and the r e s u l t i n g c i s / t r a n s ratio.  of the observed octalone  -  To overcome  128  the low y i e l d of  -  trans v i c i n y l dimethyl  octalone  r e s u l t i n g from the a d d i t i o n of m e t h y l l i t h i u m to the e n o l l a c t o n e some c o n s i d e r a t i o n was g i v e n and Chaykovsky and l a c t o n e s  (196)  to u s i n g o t h e r p o s s i b l e methods.  had used the m e t h y l s u l f i n y l  to o b t a i n h i g h y i e l d s  d e s u l f u r i z e d w i t h aluminum amalgam ketones. lactone  Attempts  via  carbanion with  sulfoxides  the t r a n s k e t o a c i d 418  the methyl ketone  esters  which were  to use t h i s method on the c o n v e r s i o n of  on the c o n v e r s i o n of  Corey  then  to y i e l d the c o r r e s p o n d i n g methyl  420 to 440b were u n s u c c e s s f u l ,  m o d i f i c a t i o n of (197)  of B - k e t o  420,  the  but c o n s i d e r a t i o n of  enol  the  l e d to S t o r k and C l a r k e ' s work  the keto a c i d 445 to the b i c y c l i c  447 i n the s y n t h e s i s  of c e d r o l  (450).  enone 448 In  their  work, attempts to use dimethylcadmium w i t h the a c i d c h l o r i d e 446 gave  449  450  -  o n l y compound 449 by a p r o c e s s magnesium bromide. 446 y i e l d e d  yield  t h a t was b e l i e v e d  the d i a z o k e t o n e  (446, X = C H ^ ) which was c o n v e r t e d to the  (446, X = C ^ C l ) and then reduced w i t h z i n c  a c i d to the methyl ketone 447.  some a p p e a l but the r e c e n t l y  c h l o r i d e s with methyl cuprates an even more a t t r a c t i v e  o f the keto a c i d 445 gave reported r e a c t i o n of a c i d  to y i e l d methyl ketones  and i n t e r e s t i n g a l t e r n a t i v e  e i t h e r a m i x t u r e o f keto a c i d s  dust  The remarkable 79% o v e r a l l  o f 447 o b t a i n e d from the sodium s a l t  t h i s sequence  to be c a t a l y z e d by  However, excess diazomethane w i t h the a c i d c h l o r i d e  c h l o r o m e t h y l ketone in acetic  129 -  appeared t o be  (198).  Using  417+418 o r a m i x t u r e o f the sodium s a l t s  of 417+418 i n a treatment w i t h o x a l y l c h l o r i d e i n benzene a t 0° gave a r e s i d u e t h a t was i s o l a t e d under vacuum below room temperature and added to a 2 - f o l d  excess o f d i m e t h y l c u p r a t e  i n ether at - 7 8 ° .  Subsequent  treatment w i t h sodium methoxide i n methanol p r o v i d e d , i n b o t h o n l y a low y i e l d o f a m i x t u r e of the d e s i r e d o c t a l o n e s i n g methyl e s t e r s alternative  o f 417 and 418.  routes  to be e x p l o r e d ,  a c i d 418 to o c t a l o n e  and the c o r r e s p o n d -  S i n c e t h e r e were two p o s s i b l e f u r t h e r approaches  through the keto  239 were not c o n s i d e r e d .  W h i l e t h e p h y s i c a l d a t a o b t a i n e d on t h e pure k e t o a c i d s 418),  t h e i r methyl e s t e r s ,  the e n o l l a c t o n e s  (238 and 239) have n o t been d i s c u s s e d , agreed w e l l w i t h t h a t  published  observed were those e x p e c t e d . magnetic of  (417 and  (419 and 4 2 0 ) , and o c t a l o n e s  the observed s p e c t r o s c o p i c  (184) a n d , i n g e n e r a l ,  data  the a b s o r p t i o n s  The i n t e r e s t i n g e x c e p t i o n was the p r o t o n  resonance of the secondary methyl group that  these compounds.  cases,  In the case of the c i s o c t a l o n e  keto a c i d 418 (or i t s c o r r e s p o n d i n g methyl e s t e r ) ,  appears  in a l l  238 and the t r a n s  v i r t u a l coupling  - 130 (199)"^ i s observed i n both the 60 MHz and 100 MHz secondary methyl resonance, w h i l e the other compounds i n the s e r i e s show the expected methyl doublet.  For example, the keto a c i d 418 e x h i b i t e d an unresolved  m u l t i p l e t with l i n e shape 451a i n a 60 MHz spectrum and 451b i n a 100  MHz  scan, w h i l e the corresponding c i s keto acid 417 showed the normal l i n e  shape depicted i n 451c (60 MHz).  A s i m i l a r s h i f t of l i n e shape towards  the expected doublet (451c) was observed f o r the secondary methyl of octalone 238 when a 100 MHz scan  replaced the 60 MHz measurement.  In considering a general approach to octalone 238 and 239, the c l o s e r e l a t i o n s h i p of these compounds to the Wieland-Miescher ketone (204) was evident. Since a sodium borohydride reduction of the C-5 carbonyl of the l a t t e r compound occurs r e g i o s e l e c t i v e l y and stereo-  56  _/ V i r t u a l coupling r e s u l t s from the chemical s h i f t (6) of C HCH3 and C^H_2 being smaller than t h e i r coupling constant (JQ5\{-C6^) • Since the chemical s h i f t i s p r o p o r t i o n a l to the operating frequency and the coupling constant i s independent of i t , the 6/J r a t i o increases and hence the l i n e shape s i m p l i f i e s i n a higher f i e l d . V i r t u a l coupling has been reported p r e v i o u s l y f o r octalone 238 and some of i t s d e r i v a t i v e s ( 1 8 4 ) . While the trans-fused decalone and l - h y d r o x y - A ^ - o c t a l i n derived from 238 e x h i b i t v i r t u a l coupling i n t h e i r secondary methyl resonance, there was no such coupling evident i n the c i s - f u s e d decalone obtained from 238 or i n the trans-fused decalone obtained from 239. J  a  - 131 -  s e l e c t i v e l y to a f f o r d 452 (199), the question arose concerning the p o s s i b i l i t y of reducing a Wieland-Miescher ketone d e r i v a t i v e r e g i o s e l e c t i v e l y and s t e r e o s e l e c t i v e l y to octalone 238 or 239. Octalones 455 and 456 were prepared and t h e i r r e s p e c t i v e hydrogenations were studied as both of these compounds were a l s o of some i n t e r e s t i n s e v e r a l projected eremophilane syntheses.  204  The Wieland-Miescher ketone (204, 202) was  452  455 Exocyclic 456 Endocyclic  treated w i t h 2,2-dimethoxypropane and a c a t a l y t i c amount of p_-toluene^ s u l f o n i c acid to y i e l d i n 93% the enol ether 453 (200).  The presence  of one methoxyl f u n c t i o n and two v i n y l protons by n.m.r. and a saturated carbonyl by i n f r a r e d spectroscopy confirmed that a s e l e c t i v e a l k o x y l  interchange had occurred. A W i t t i g r e a c t i o n of methylenetriphenylphosphorane and compound 453 i n dimethyl s u l f o x i d e (201) then produced a 93% y i e l d of the desired enol ether o l e f i n 454, r e a d i l y i d e n t i f i e d by the replacement  204  453  454  - 132 -  0  0'  0  H  457/458  456  455  of the s a t u r a t e d c a r b o n y l i n the i n f r a r e d w i t h a two v i n y l a b s o r p t i o n a t T 5.30 i n the n.m.r. with methanolic  A s h o r t treatment  proton  o f compound 454  h y d r o c h l o r i c a c i d gave the e x o c y c l i c o l e f i n i c  455 i n 88%, w h i l e  treatment  o f 454 w i t h j D - t o l u e n e s u l f o n i c a c i d i n  r e f l u x i n g benzene o r t o l u e n e y i e l d e d the e n d o c y c l i c o l e f i n i c 456 i n 80%.  octalone  octalone  When the above r e a c t i o n s were c a r r i e d out w i t h m i n i m a l  workup o f the i n t e r m e d i a t e  s t e p s , the Wieland-Miescher ketone a f f o r d e d  h i g h e r o v e r a l l y i e l d s of 455 (95%) and 456 ( 6 4 % ) .  5 7  Both o f these  "" A p r i v a t e communication (Geraghty, 186) i n d i c a t e d t h a t an a l t e r n a t e r o u t e t o compound 456 by a d d i t i o n o f a methyl G r i g n a r d or m e t h y l l i t h i u m to t h e p r o t e c t e d W i e l a n d - M i e s c h e r ketone ( i ) and subsequent a c i d c a t a l y z e d d e h y d r a t i o n proceeded i n poor y i e l d . In a d d i t i o n t o c o n s i d e r a b l e e n o l i z a t i o n o f the c a r b o n y l r a t h e r than the d e s i r e d 1 , 2 - a d d i t i o n o f the m e t h y l n u c l e o p h i l e , the b i c y c l i c - 6 - h y d r o x y - a , 8 - e n o n e p r e c u r s o r t o 356, i i , once formed, has been shown r e c e n t l y t o undergo a rearrangement i n both a c i d s and bases to i i i (203).  0  OH  - 133 compounds had a conjugated  ketone chromophore, with compound 455  e x h i b i t i n g an e x o c y c l i c methylene i n the n.m.r., while compound 456 i n d i c a t e d the presence of a v i n y l methyl and v i n y l proton.  However, while  tris(triphenylphosphine)chlororhodium catalyzed hydrogenations are r e g i o s e l e c t i v e f o r d i s u b s t i t u t e d double bonds i n the presence of t r i s u b s t i t u t e d ones, such a hydrogenation of compound 454 y i e l d e d a 55:45 mixture of cis-238:trans-239  ( a f t e r an a c i d catalyzed removal of  the methyl e t h e r ) , while a s i m i l a r hydrogenation of compound 455 y i e l d e d a 75:25 r a t i o of 238:239 i n 98%.  An attempted r e g i o s e l e c t i v e  hydrogenation of the unconjugated t r i s u b s t i t u t e d C-5 o l e f i n i c bond of compound 456 w i t h palladium on charcoal i n a c i d i c ethanol f a i l e d to provide compounds 238-239, y i e l d i n g instead a 50:50 mixture of the keto o l e f i n s 457 and 458,while hydrogenation of 455 under s i m i l a r conditions 58 a l s o led to p r e f e r e n t i a l reduction of the conjugated  double bond.  Since the attempted approaches to an e f f i c i e n t synthesis of pure octalone 239 were not s u c c e s s f u l , the s t e r e o s e l e c t i v e l y a v a i l a b l e octalone 381 was transformed  i n t o octalone 239 by a route analogous to  The reduction of 455 or 456 under d i s s o l v i n g metal (Birch) conditions gave the desired trans decalone d e r i v a t i v e s and not the 204 -> 205 transformation i n d i c a t e d on page 43. The trans-fused d e r i v a t i v e of 455 (i_, C9H3 at x 8.79 i n the n.m.r.) was hydrogenated w i t h ((j^P^Rhd to y i e l d a 1:1 mixture of i i . to i i i . Authentic compound i i _ (C^H^ at T 9.06) was obtained by a B i r c h reduction of octalone 238 while i i i _ ( C 9 H at x 8.83) was derived by a B i r c h reduction of octalone 239. 3  H  IL  ii  - 134 the one developed by M a r s h a l l and Brady i n the s y n t h e s i s t h e i r work,  the c r o s s - c o n j u g a t e d  dienone 459  a d d i 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 ring.  The enone 460  was then deconjugated  to a f f o r d  464.  460  464  the  ' A ' •> ' B ' r i n g  U s i n g the c r o s s - c o n j u g a t e d  acetylated  dimethylcuprate  59  conjugate the  'A'  and o x i d i z e d  and s e l e c t i v e  hydrogenation  X =0  461  :  462  X = a-H,/3-0H  463  X = a-H,/3-0Ac  466  t r a n s p o s i t i o n of  dienone 300  a stereospecific  to a  In  the c a r b o n y l reduced  465  then completed  thesis,  (462)  to 461,  A dehydroacetylation  459  this  was s u b m i t t e d  to i n t r o d u c e a methyl i n t o  and the h o m o a l l y l i c a l c o h o l p r o d u c t allylically  of h i n e s o l .  the enone  functionality.  p r e p a r e d as d e s c r i b e d e a r l i e r  in  m e t h y l a t i o n was a c h i e v e d w i t h l i t h i u m  to p r o v i d e an  87% y i e l d  of  compound  381 (182a ,204).  In the absence of l a r g e s t e r i c f a c t o r s , c u p r a t e a d d i t i o n s a r e b e l i e v e d to proceed v i a a c h a i r t r a n s i t i o n s t a t e r a t h e r than a b o a t . As a a proven elsewhere (182 ,204,205 ), a c o m p l e t e l y s t e r e o s p e c i f i c axial m e t h y l a t i o n o c c u r s when compound 300 i s t r e a t e d w i t h L i C u C C H ^ ^ Compound 459, on the o t h e r hand, was found to g i v e a 1:3 r a t i o of 4a:48 m e t h y l a t i o n  (205).  -  300 of  e a r l i e r for  e q u i l i b r a t i o n - a c i d quench  a c i d ) was accomplished by the  the c o r r e s p o n d i n g 4-desmethyl  i n t h i s c a s e t h e r e was no measureable  present of  467  t h i s ketone by base  (potassium _ t - b u t o x i d e / a c e t i c  but  -  381  The d e c o n j u g a t i o n  developed  135  after  workup ( i . e .  w i t h l i t h i u m aluminum h y d r i d e . then a c e t y l a t e d  with acetic  amount of o c t a l o n e The  381  instability  The h o m o a l l y l i c a l c o h o l product was  a n h y d r i d e and sodium a c e t a t e to a f f o r d 381.  A  a  tentative  H i . A - ene  4I0_  469 R = OCCH* II  (234),  the immediate r e d u c t i o n of compound 467  76% o v e r a l l y i e l d of compound 469 from o c t a l o n e  468 R = H  compound  <1% 381 v e r s u s ^ 5% 234).  8,y-octalones necessitated  procedure  239  6  0 assignment  o f a 2:1  on the b a s i s  of  r a t i o o f the a: 8 7 - a c e t o x y s u b s t i t u e n t  the n . m . r . a b s o r p t i o n s of 469 , but these  c o m p l i c a t i o n s caused by the d i a s t e r e o m e r i c m i x t u r e s 470) were removed by the subsequent a c e t a t e 469 was o x i d i z e d a l l y l i c a l l y in acetic  (357,  spectral  (of 468, 469 and  dehydroacetylation.  The h o m o a l l y l i c  i n 80% y i e l d w i t h chromic a n h y d r i d e  a c i d by a procedure analogous  a trimethyl octalin  c o u l d be made  to  the one u t i l i z e d e a r l i e r on  the p r e c u r s o r to o c t a l o n e  237).  The  - 136 dehydroacetylation of 470 with e t h a n o l i c h y d r o c h l o r i c acid (149)  was  then accomplished c l e a n l y i n 86% y i e l d to a f f o r d the desired dienone 471. This compound showed the required spectroscopic data, unencumbered by diastereoisomerism, having a conjugated 1588 cm "S and three v i n y l protons (x 8.75)  dienone by i n f r a r e d (1660,  (x 3.85,  and a doublet methyl (x 9.09)  3.88,  1620,  4.22), a t e r t i a r y methyl  by n.m.r., but the observed  e x t i n c t i o n c o e f f i e i n t of e = 31,300 associated w i t h the X  MeOH my max  282  u l t r a v i o l e t absorption f o r 471 i n i t i a l l y appeared to be unduly high. While t h i s observation i s true i n a comparison with the and cross-conjugated the corresponding x  Et0H max  2 8 Q  ^  ketones p r e v i o u s l y encountered (e = 10,000-15,000),  5-desmethyl compound of 471 has been reported to have (206 ) and A a  ( e  =  1 9  a,3-unsaturated  4 0 0 )  278 my max  E t 0 H  (e = 26,800) ( 2 0 6 ) , while b  the analogous A^'^-3-keto s t e r o i d s have been shown to e x h i b i t X ^ ° max E T  284  (e = 28,000) (206°,135) absorptions i n the u l t r a v i o l e t , S p e c t r o s c o p i c a l l y , the chemical s h i f t changes observed f o r the downfield protons i n the n.m.r. are a u s e f u l feature of the above sequence, l e a v i n g no doubt that the enone f u n c t i o n a l i t y was t r a n s f e r r e d successfully.  Of p a r t i c u l a r s i g n i f i c a n c e i s the movement of the v i n y l  proton from a s i n g l e t at x 4.22  (381) to a m u l t i p l e t at x 4.50  468, 469) and back to a s i n g l e t at x 4.15 r e g i o s e l e c t i v e c a t a l y t i c hydrogenation  (470) and 4.22  (467,  (471).  The  of the d i s u b s t i t u t e d unsaturation  of 471 w i t h tris(triphenylphosphine)chlororhodium proved t h i s by y i e l d i n g octalone 239  (113).  However, t h i s s e l e c t i v e reduction with a  homogeneous c a t a l y s t proceeded so very slowly that a switch was made to a palladium c a t a l y s t .  By using 0.005 N potassium hydroxide i n benzene-  ethanol s o l u t i o n and pre-reducing the 5% palladium on carbon c a t a l y s t  my  - 137 (207), the dienone 471 was reduced r a p i d l y i n 93% y i e l d to octalone  239.  As expected, t h i s compound was p h y s i c a l l y and s p e c t r o s c o p i c a l l y i d e n t i c a l w i t h the one prepared  e a r l i e r from enol lactone 420 but, i n contrast to  the rhodium c a t a l y s t where c a r e f u l monitoring was not required, care was required to avoid hydrogenation mixture of  of 239 by palladium on carbon to a  decalones.  In conclusion therefore, while both c i s and trans octalones and 239 could be prepared  238  i n pure form from t h e i r r e s p e c t i v e enol lactones  (419 and 420), the novel s e l e c t i v e d e s t r u c t i o n of the trans enol lactone i n t h i s route makes the sequence u t i l i z i n g octalone 381 to prepare  239^  obviously superior i n terms of o v e r a l l e f f i c i e n c y of time and e f f o r t .  The n.m.r. spectra of octalesne 239 shows a complete absence of the T 8.88 methyl resonance from the corresponding c i s octalone 238. This i s s u r p r i s i n g since there i s one l i t e r a t u r e report- that the methyl cuprate a d d i t i o n to dieone 300 i s not as s t e r e o s p e c i f i c as i n d i c a t e d i n footnote 59. M a r s h a l l and Warne (183^) found that the conjugate a d d i t i o n of l i t h i u m dimethyl copper to dienone 300 afforded a 95:5 mixture of octalones 381:380. Since the presence of IT c i s octalone 238 could be detected i n 239, t h i s discrepancy requires an explanation.  - 138  F.  'Octalone'  240  -  (Androst-4-en-3-one)  I n c o n s i d e r i n g the p r e p a r a t i o n of androst-4-en-3-one, two inexpensive  commercially  a v a i l a b l e compounds, t e s t o s t e r o n e  equally  (472) anci  36-hydroxyandrost-5-en-17-one (473), appeared to be u s e f u l as possible precursors.  The  c o n v e r s i o n of e i t h e r of these compounds i n t o  240 would r e q u i r e the r e d u c t i v e removal of the C-17  472  240  n e c e s s i t a t i n g C-3  case of 473, isomerism  oxygen  (228).  473  c a r b o n y l p r o t e c t i o n i n the case of 472  subsequent C-3  functionality  o x i d a t i o n w i t h double bond  and,  i n the  5  4 -> A )  (A  U n f o r e s e e n d i f f i c u l t i e s w i t h the r e d u c t i v e s t e p i n  the former sequence and w i t h the o x i d a t i v e s t e p i n the l a t t e r , i n f u r t h e r experimental problems and  work b e i n g u n d e r t a k e n to e l a b o r a t e  to f o r m u l a t e  g e n e r a l methods f o r m i n i m i z i n g  resulted  these  them.  t h e r e i s a g r e a t d e a l more l i t e r a t u r e precedence f o r e l a b o r a t i n g from 473,  r a t h e r than from 472,  problems w i l l be c o n s i d e r e d  Androstenone 240  t h i s approach and  Since 240  i t s oxidation  first.  from 38-Hydroxyandrost-5-en-17-one  (473)  L i t e r a t u r e Precedence Androst-4-en-3-one has been prepared  p r e v i o u s l y , on two  occasions,  -  139  -  from compound 473 by a sequence u t i l i z i n g the Wolff-Kishner reduction and Oppenauer o x i d a t i o n r e a c t i o n s . Shoppee and Krueger (208), and then F e t i z o n and G o l f i e r (209), reduced the carbonyl of 473 by the Huang-Minion m o d i f i c a t i o n (210) of the Wolff-Kishner reduction.  Both  groups then subsequently employed the Oppenauer o x i d a t i o n (211) of androst-5-en-38-ol  (474) to a f f o r d approximately 70% androstenone 240  from 473. More r e c e n t l y , Habermehl and Haaf (212) used a f i v e step  240  sequence  to a c c o m p l i s h the same t r a n s f o r m a t i o n .  acetoxyandrost-5-en-17-one  (475)  i o d i d e p r o c e d u r e f o r ketone 476 was a c h i e v e d in  a refluxing  475.  under b a s i c  The s t e r o i d  was reduced v i a B a r t o n ' s  removal  (213).  F o r m a t i o n of  vinyl the  c o n d i t i o n s w i t h t r i e t h y l a m i n e as  e t h a n o l s o l u t i o n of h y d r a z i n e h y d r a t e and the  Oxidation with iodine i n triethylamine-tetrahydrofuran  X  475 X = 0,R = Ac  38-  hydrazone catalyst ketone solution  I  477  - 140 -  then p r o v i d e d the v i n y l i o d i d e 477 474  on Raney n i c k e l r e d u c t i o n .  reduction  (208).  w i t h the 90%  using  compound 65%  o b t a i n e d by d i r e c t  A l l t h r e e groups of w o r k e r s  c o n v e r t e d the B , y - u n s a t u r a t e d a l c o h o l 474 ketone 240  the d e s i r e d  However, the y i e l d of l e s s than  o v e r a l l does not compare f a v o u r a b l y Wolff-Kishner  which furnished  (208,209,212)  t o the a,B-unsaturated  the Oppenauer o x i d a t i o n , even though a r i v a l well-known  l i t e r a t u r e alternative did e x i s t . S t u d i e s by L.F.  F i e s e r on b o t h p a r t i a l (127)  and  exhaustive  d i c h r o m a t e o x i d a t i o n of c h o l e s t e r o l i n a c e t i c a c i d - b e n z e n e showed t h a t a complex p r o d u c t m i x t u r e was  produced.  r a t h e r t h a n the e x p e c t e d 3 , y - u n s a t u r a t e d k e t o n e 334 enedione 480,  cholest-4-ene-3,6-dione, was  (214)  solutions  In t h i s mixture, predominating,  the  found to be the major  61 product.  However, the d i c h r o m a t e o x i d a t i o n of the C-3  corresponding protected (96%)  3,y-dibromo s t e r o i d 481  y i e l d of the dibromo k e t o n e 482.  A d i e t h y l e t h e r s o l u t i o n of c h o l e s t e r o l was  (216)  the  quantitative able  to  in  81%  the f o l l o w i n g sequence,  t r e a t e d w i t h an a c e t i c  the c r y s t a l l i n e d i b r o m i d e 481  w i t h chromium t r i o x i d e i n a c e t i c a c i d to 482  was  to c h o l e s t e n o n e 478  o v e r a l l y i e l d f o r l a r g e s c a l e experiments using  a c i d s o l u t i o n of bromine and  gave a n e a r l y  Thus F i e s e r  r e p o r t the c o n v e r s i o n of c h o l e s t e r o l (331)  alcohol in  and  was  oxidized  i m m e d i a t e l y debrominated  w i t h a s l u r r y of powdered z i n c i n d i e t h y l e t h e r to a f f o r d the  3,y-  61 The s t e r e o s p e c i f i c i n t r o d u c t i o n of the t h e r m o d y n a m i c a l l y l e s s s t a b l e . 6B-oriented h y d r o x y l group i n t o compound 334 to a f f o r d 479 was not r a t i o n a l i z e d but see t h e s i s d i s c u s s i o n on pages 81-90. The i n t e r m e d i a c y of cholest-4-en-3-one (478) i n t h i s r e a c t i o n was not p o s s i b l e because the u n c o n j u g a t e d k e t o n e 334 was not i s o m e r i z e d i n a c e t i c a c i d - b e n z e n e f o r p e r i o d s up to 20 hours and the r e a c t i o n m i x t u r e was found to be f r e e of even t r a c e amounts of the c o n j u g a t e d ketone 478 (215).  - 141  482 X =  0  u n s a t u r a t e d ketone 334. en-3-one (478) was  -  I s o m e r i z a t i o n of t h i s ketone to c h o l e s t - 4 -  accomplished  e i t h e r by chromatography or by  ment w i t h m i n e r a l a c i d o r base, w i t h o x a l i c a c i d g i v i n g product.  treat-  the b e s t  - 142 -  Normally the y i e l d s reported f o r the F i e s e r or Oppenauer procedures approximate 70%.  Since both methods require s p e c i a l precautions and  workup conditions and take a day to complete, an e a s i e r a l t e r n a t i v e was  4 desirable.  Manganese dioxide oxidations of the A -3-ol a l l y l i e  alcohols to conjugated ketones have been found to be q u a n t i t a t i v e i n 15 minutes, but the corresponding A^-3-ols are o x i d i z e d by manganese  4 dioxide i n r e f l u x i n g solvents to a mixture of conjugated A -3-one and  46  A ' -dione products, w i t h the l a t t e r predominating (217). In 1961, Rao (218) reported that Attenburrow's " a c t i v e " manganese dioxide 4 afforded the conjugated A -3-one e x c l u s i v e l y because of the rapid base i s o m e r i z a t i o n of the 8,y-unsaturation to the r e l a t i v e l y s t a b l e conjugated compound. This work found such a low conversion r a t e , 6% i n eleven hours, that the method i s not of s y n t h e t i c i n t e r e s t at t h i s time. Three other p e r t i n e n t l i t e r a t u r e procedures were a v a i l a b l e f o r the conversion of s t e r o i d a l A^-3 - o l to the A^-3-one system. c o l l a b o r a t o r s , i n 1956  (219), were  D j e r a s s i and  i n t e r e s t e d i n preparing b i o l o g i c a l l y  important s t e r o i d a l A^-3-ketones by d i r e c t o x i d a t i o n of the A^-3-ol precursors.  They found the Jones procedure (220) of t i t r a t i n g the  a l c o h o l 483 (a-d.) i n an acetone s o l u t i o n w i t h aqueous c h r o m i c - s u l f u r i c acid o x i d i z i n g reagent afforded the unconjugated ketone 484 i n high y i e l d i f the r e a c t i o n was c a r r i e d out at 10° f o r two minutes (reported  89%  of  484 when  R' =  C0CH.J .  - 143 -  R' = 0 (473)  483a  484a R' = 0  b R' = 0 C 0 C H c R' = COCH d. R' = COCH OAc e-R/ = H 1 ' = C H (331) 6  b R' = 0 C 0 C H c. R' = COCH d. R' = C0CH 0Ac  5  6  3  3  2  2  e R' f R'  R  Q  O  Subsequently,  If  i n 1956, Snatzke found t h a t c h o l e s t e r o l  o x i d i z e d i n . 79% y i e l d to c h o l e s t - 5 - e n - 3 - o n e formamide s o l u t i o n of chromic a c i d i n dimethylformamide  (10 m l ) .  (311)  H C H_!H4) 8  was  (334) w i t h a d i m e t h y l -  (221,222 ) .  The s t e r o l  (0.5 mM)  (15 ml) was t r e a t e d f i r s t w i t h chromium t r i o x i d e  (2 mM) and then c o n c e n t r a t e d s u l f u r i c a c i d formamide  5  (1-3 drops)  As w i t h the Jones r e a g e n t ,  a - k e t o l s and k e t a l s were not c l e a v e d  despite  i n dimethyl-  t h i s work showed  the use of s u l f u r i c  - 144 -  acid.  A l s o , a l l y l i c o x i d a t i o n of A " ' - s t e r o l s d i d not occur."*" I n 1966, Jones and W i g f i e l d  (223) found the optimum c o n d i t i o n s  f o r the A ^ - 3 - o l -»- A^-3-one t r a n s f o r m a t i o n w h i l e e s t a b l i s h i n g the b e s t c o n d i t i o n s f o r a n d r o s t - 5 - e n e - 3 , 1 7 - d i o n e (484a) p r e p a r a t i o n .  In their  s u r v e y of a v a i l a b l e p r o c e d u r e s , the Jones o x i d a t i o n p r o d u c t was  found  to be c o n t a m i n a t e d w i t h s t a r t i n g m a t e r i a l (483a) and c o n j u g a t e d ketone w h i l e F i e s e r ' s dibromoketone i n t e r m e d i a t e underwent p h o t o l y t i c decompose i t i o n l e a d i n g t o a l o w e r e d y i e l d of pure compound 484a.  Jones and  W i g f i e l d u t i l i z e d a m o d i f i e d form of P f i t z n e r and M o f f a t ' s p r o c e d u r e (224,222^) t o dehydrogenate the h o m o a l l y l i c a l c o h o l s 483a,e,f  under  the m i l d n e u t r a l c o n d i t i o n s of N , N - d i c y c l o h e x y l c a r b o d i i m i d e (DCC) p y r i d i n i u m t r i f l u o r o a c e t a t e (PTFA).  and  By u s i n g a 1:1 b e n z e n e : d i m e t h y l  S u r p r i s i n g l y , no o x i d a t i o n of the u n u s u a l l y r e a c t i v e A" bond was r e p o r t e d i n e i t h e r c a s e , b u t D j e r a s s i and c o w o r k e r s , i n 1962, d i d f i n d the Jones o x i d a t i o n of 33-hydroxy-6,16a-dimethylpregn-5-en-r 20-one ( i ) f o r 3 minutes a t 5° produced i l , r a t h e r t h a n i i i . A l l y l i c o x i d a t i o n of i v was e x c l u d e d from the r e a c t i o n pathway when i t was found t o be s t a b l e t o the o x i d a t i o n c o n d i t i o n s . E p o x i d a t i o n of the o l e f i n i c l i n k a g e of i i i was p o s t u l a t e d , on a c i d c l e a v a g e , t o g e n e r a t e a 5 a , 6 $ - d i o l w h i c h d e h y d r a t e d to r i i n the a c i d i c medium. Other r a p i d e p o x i d a t i o n s o f t r i c y c l i c o l e f i n i c bonds w i t h the Jones r e a g e n t were demonstrated ( 1 2 9 ^ ) ,  - 145 -  s u l f o x i d e s o l u t i o n at 50°, compounds ^83a,e^,f_ y i e l d e d 60-70% of the corresponding 484 with some of the methylthiomethoxy ether (483, R = CH -S-CH -) as a byproduct. 3  2  The r e c e n t l y reported d i f f i c u l t i e s i n the preparation of 6amethylandrost-4-en-3-one (487) (225) from 38-hydroxy-6-methylandrost5-en-17-one (485) are a l s o p a r t i c u l a r l y informative. m o d i f i c a t i o n of the Wolff-Kishner  The Huang-Minion  reduction y i e l d e d 82% of the  desired 8,y-unsaturated a l c o h o l 486, but the subsequent Oppenauer  0  o x i d a t i o n afforded only 40% 6a-methylandrost-4-en-3-one  (487).  an attempt to o x i d i z e the 8,y-unsaturated a l c o h o l 486 d i r e c t l y to the corresponding ketone 488 f o r i s o m e r i z a t i o n to the desired  In  -  ketone  487,  employed.  the v e r y m i l d  146  Sarett  -  o x i d a t i o n reagent  (226 ) was  A p y r i d i n e s o l u t i o n of compound 486 was a l l o w e d to  stand  a t room temperature f o r f o r t y hours i n the p r e s e n c e of an excess of d i p y r i d i n e chromium t r i o x i d e r e a g e n t . then a f f o r d e d a 20% y i e l d of 3-one  (489) .  the  Chromatographic  63-hydroxy-6a-methylandrost-4-en-  T h i s r e s u l t was c o m p l e t e l y  bonds a r e not expected  separation  unexpected  since  double  to be i s o m e r i z e d under these c o n d i t i o n s and 63  the S a r e t t  o x i d a t i o n , as n o t e d ,  essentially donating trivalent  i n e r t towards  power of  was p r e v i o u s l y r e p o r t e d to be  them. • A p p a r e n t l y the modest  electron  these bonds u s u a l l y cannot compete w i t h  n i t r o g e n f o r the chromic t r i o x i d e  (226  the  ).  The i s o l a t i o n of p r o d u c t s from the p y r i d i n e medium o f t e n technical d i f f i c u l t i e s dimethyl s u l f o x i d e , bromide,  and Holum (226^),  i n 1961,  nitrobenzene, nitromethane,  studied  mediums to p y r i d i n e . gave g r e a t l y  Unfortunately,  reduced y i e l d s  Frank r e p o r t e d (227)  i n 1968  acetone,  ethyl acetate,  c h l o r o f o r m and carbon d i s u l f i d e as a l t e r n a t i v e  presents  ethyl  dispersing  even the b e s t s o l v e n t ,  acetone,  and i t was not u n t i l C o l l i n s , H e s s , and t h a t the anhydrous d i p y r . i d i n e - c h r o m i u m ( V I )  o x i d e complex was m o d e r a t e l y s o l u b l e i n p o l a r c h l o r o h y d r o c a r b o n s , t h a t a method f o r r a p i d a l c o h o l o x i d a t i o n s  i n a b a s i c medium became  The d i p y r i d i n e - c h r o m i u m ( V I ) o x i d e complex i n p y r i d i n e was o r i g i n a l l y r e p o r t e d ( 2 2 6 ) to be i n e r t to double bonds and t h i o l e t h e r s . K e t a l s are not c l e a v e d and i s o l a t e d double bonds a r e not i s o m e r i z e d s i n c e the medium i s b a s i c . Very p r o l o n g e d exposure does l e a d to o x i d a t i o n of a l l y l i c methylene p o s i t i o n s , sometimes w i t h concomitant m i g r a t i o n of the u n s a t u r a t i o n (177) but n o r m a l l y t h i s r e a c t i o n i s of no consequence d u r i n g a l c o h o l o x i d a t i o n s ( a l c o h o l o x i d a t i o n s > 10^ f a s t e r ) . a  -  possible. 3-one at  10  (334)  147  -  C o l l i n s ' coworkers i s o l a t e d a 64% y i e l d of after  w i t h a 6:1  cholesterol  (331)  cholest-5-en-  was o x i d i z e d f o r t h i r t y minutes  mole r a t i o of c o m p l e x - t o - a l c o h o l i n a d i c h l o r o -  methane s o l u t i o n .  No c h o l e s t - 4 - e n - 3 - o n e  (478) was d e t e c t e d  r e a c t i o n m i x t u r e but c h o l e s t - 4 - e n e - 3 , 6 - d i o n e 'cholest-4-en-3-ol-6-one'  i n the  (480 i n 10% y i e l d ) and  (490, 3 8 - h y d r o x y c h o l e s t - 4 - e n - 6 - o n e ,  i n 8%)  were r e p o r t e d to be p r e s e n t .  0 Very r e c e n t l y ,  Jones and Gordon r e - e v a l u a t e d  the  r o u t e s to v a r i o u s C - 1 7 - s u b s t i t u t e d A ^ - 3 - k e t o s t e r o i d s t h e i r hands the P f i t z n e r - M o f f a t t a l c o h o l s d i d not go to  o x i d a t i o n of  the  synthetic (229).  In  B,y-unsaturated  c o m p l e t i o n w i t h o u t s i d e r e a c t i o n s and the  d e c o m p o s i t i o n of the c o r r e s p o n d i n g a , 3 - u n s a t u r a t e d ketones gave some oxygenated compounds.  They found the use of d i p y r i d i n e chromium  t r i o x i d e i n d i c h l o r o m e t h a n e ( C o l l i n s ) p r o v i d e d the most  satisfactory  T h i s p r o b a b l y s h o u l d be 10% c h o l e s t - 4 - e n e - 3 , 6 - d i o n e and 8% 6 B - h y d r o x y - c h o l e s t - 4 - e n - 3 - o n e (479) s i n c e these a r e " t h e major p r o d u c t s o b t a i n e d on d i r e c t chromic a c i d o x i d a t i o n " (227). The d i p y r i d i n e - c h r o m i u m ( V I ) o x i d e complex i s a l s o c a l l e d t r i o x o b i s (pyridine)chromium).  - 148 4 65 route to compounds free (< 1%) of t h e i r conjugated A -3-keto isomers.  Current Synthetic Work Therefore, i n the i n t e r e s t of. obtaining high o v e r a l l y i e l d s of androstenone from the commercially a v a i l a b l e h o m o a l l y l i c a l c o h o l precursor 473, Barton's Wolff-Kishner m o d i f i c a t i o n s (173) were used i n place of those of Huang-Minion and chromium t r i o x i d e o x i d a t i o n procedures —  Jones, C o l l i n s , Snatzke —  for the Oppenauer o x i d a t i o n .  were explored as a replacement  Treatment of 38-hydroxyandrost-5-en-17-  one w i t h a 180° r e f l u x i n g diethylene g l y c o l s o l u t i o n of sodium g l y c o l a t e and anhydrous hydrazine f o r 12 h, followed by 24 h at 210°, afforded the  8,y-unsaturated a l c o h o l 474 i n 98% y i e l d a f t e r a short path 66  distillation.  Oxidation of 474 w i t h Jones (220), C o l l i n s (227), or  Snatzke (221) reagents gave a product which was analyzable by g . l . c . 67 or n.m.r.  The Jones o x i d a t i o n method was q u i c k l y discarded  68  because  65 This a n a l y s i s , while undoubtedly t r u e , i s misleading. Although there i s l i t t l e double bond i s o m e r i z a t i o n reported i n t h e i r work, t h e i r r e s u l t s are based on the approximately < 50% y i e l d of i s o l a t e d c r y s t a l l i z e d compounds and t h e i r a n a l y s i s therefore excluded the production of at l e a s t 20% i m p u r i t i e s that we have shown to be i n the r e a c t i o n mixture. 66 When t h i s was changed from 1.45 M base (60 ml) and 12 h @ 180°, 24 h @ 210° to 1.00 M (50 ml) and 6 h @ 180°, 18 h @ 210°; the y i e l d from k e t o l 473 (5.0 g) dropped to 78%. Using 2.00 M (50 ml) and 6 h @ 180°, 18 h @ 210° y i e l d e d 98% 474. 67 As proven subsequently, compounds 474, 491 + 240, and 493 + 494 were eluted separately by g . l . c . (5' x k" 20% SE 30 columnl ) with base l i n e separation and t h e i r n.m.r. v i n y l proton d i f f e r e n c e s (3.82 x for 493, 4.26 f o r 492 and 240, and 4.64 x f o r 474 and 491) could then be e x p l o i t e d to measure the product r a t i o s i n mixtures. y  T  68  The c l o s e l y r e l a t e d two phase o x i d a t i o n procedure by Brown et a_l. (230) was a l s o unsuccessful. A s t o i c h i o m e t r i c amount of sodium dichromate and s u l f u r i c acid i n water l e d to an attack on the d i e t h y l ether at room temperature while a 100% excess at 0° l e d , even a f t e r lh hours, to a mixture of s t a r t i n g m a t e r i a l and compounds 240 + 493. Employing a 200% excess of aqueous chromic a c i d with an ether s o l u t i o n of a l c o h o l 474 at 0° gave a 1:4 mixture of 240:493 a f t e r 2 hours.  - 149  -  0  of the appearance of extraneous g.l.c. peaks, but both the Collins and Snatzke reactions were found to afford only two major components in ^ 3:1 ratio. If this mixture was carefully submitted to two short path distillations, the lower boiling dominant component was obtained as a 93% pure compound while the higher boiling component was 75% pure. Alumina chromatography separated both components sharply and provided analytical samples after a recrystallization from methanol. The major compound was identified as androst-4-en-3-one (240), having the same melting point and spectral properties as those reported for this compound (208,212) and being identical to a sample of 240 that was later prepared by an unambiguous route from testosterone (472). While n.m.r. analysis showed that no 240 was present in the initial  - 150 -  C o l l i n s or Snatzke workup product, the corresponding 3,y-unsaturated ketone 491, the major r e a c t i o n product, was c l e a n l y isomerized on d i s t i l l a t i o n and alumina chromatography to 240. The more i n t e r e s t i n g minor component was shown by n.m.r. to be a 7:3 mixture of the compounds 493 and 494.  The endione 493 was  p u r i f i e d by u t i l i z i n g the base s o l u b i l i t y of i t s yellow enolate (176 ) b  and by c r y s t a l l i z i n g f i n e yellow needles of 493 from methanol s o l u t i o n s . The s t r u c t u r e of androst-4-ene-3,6-dione (493) was r e a d i l y deduced from i t s s p e c t r a l data.  The sharp C-4 v i n y l proton at x 3.82 i n the  n.m.r. had a width at h a l f peak height of 1.4 Hz, thereby demonstrating the absence of a l l y l i c coupling.  By way of comparison, androst-4-en-3-  one (240) had i t s v i n y l proton at x 4.26 w i t h a 3.4 Hz width at h a l f peak height.  Also the u l t r a v i o l e t absorption f o r 493 e x h i b i t e d X  max 251 my (e = 10,600) w i t h a s h i f t to X 372 my i n base, providing max 4  good agreement w i t h values reported f o r other s t e r o i d a l A -3,6-diones 69 (151,157,231).  The s t r u c t u r e f o r the dione 494 was then confirmed  to be androstane-3,6-dione by comparing i t w i t h the product obtained from hydrogenating the enedione 493 over palladium on carbon. I f the 240:293/4 r a t i o that was i n i t i a l l y obtained from the modified C o l l i n s procedure i s considered as a measure of the degree of mono-oxidation to overoxidation (491:492), the 72:28 r a t i o observed 69 Confirmation of the s t r u c t u r e proposed f o r the minor product was obtained by employing the procedure of Volger and Brackman (156 ) to prepare 493. Compound 240 was deconjugated to 491 with KOBut/HOAc (157) and then oxidized to 493 with a copper-catalyzed a u t o x i d a t i o n i n a methanol-pyridine-trimethylamine s o l u t i o n . See also footnote 34, page 99. a  - 151 -  above i s remarkably s i m i l a r to the mono-oxidation:overoxidation product r a t i o reported f o r c h o l e s t e r o l by C o l l i n s ejt a l . (227) — b e t t e r expressed as 78:22.  64:18,  When the androstenone experimental work  was o r i g i n a l l y undertaken, i t was thought that the desired C-3 a l c o h o l o x i d a t i o n could be done s e l e c t i v e l y .  Therefore, these r e s u l t s were  greeted w i t h some s u r p r i s e ( d i s b e l i e f ) as both the a c i d i c and b a s i c conditions y i e l d e d the same product mixture.  Since the l i t t l e explored  Snatzke method o f f e r e d s e v e r a l i n t e r e s t i n g parameter v a r i a t i o n s w h i l e the C o l l i n s o f f e r e d l e s s experimental scope f o r such work, a d d i t i o n a l Snatzke r e a c t i o n s were performed on a model B,y-unsaturated alcohol.  Snatzke Oxidations of C h o l e s t e r o l F i e s e r ' s method (216) of p u r i f y i n g commercial c h o l e s t e r o l v i a debromination of the dibromide 481 as w e l l as h i s discussed procedure f o r preparing cholest-5-en-3-one (334) and cholest-4-en-3-one (478) were used.  Authentic cholest-4-ene-3,6-dione (480) was prepared from  cholest-5-en-3-one (334) by Brackman's method (156) of using a copperVolger and Brackman found B,y-unsaturated  catalyzed a u t o x i d a t i o n .  ketones could be r e a d i l y o x i d i z e d w i t h a i r by using c u p r i c complexes i n a l k a l i n e s o l u t i o n at 0° and t h e i r f i r s t reported example i n 1965 was a 75% y i e l d of 480 from 334. The d i e n o l a t e anion (495) formation i s the rate determining step and e l e c t r o n t r a n s f e r to the cupric complex produces the dienoxy r a d i c a l (496) which i s trapped as the secondary  3 peroxy r a d i c a l 497 by  0„ and reduced to a carbonyl by cuprous i o n .  - 152 -  £8 17 H  U s u a l l y , the required 8,Tf-unsaturated ketone i s obtained by generating, with potassium _t-butoxide, the enolate of the corresponding conjugated ketone i n _t-butanol and quenching i t r a p i d l y w i t h a c e t i c a c i d (155). Without p u r i f i c a t i o n , the 8 , Y  - u n s a t  u r a t e d ketone i s then o x i d i z e d to  the enedione w i t h a i r and cupric acetate i n a methanol s o l u t i o n of p y r i d i n e - t r i e t h y l a m i n e f o r t h i r t y minutes.  I t was t h i s l a t t e r method  that was used to obtain an authentic sample of androst-4-ene-3,6-dione from androst-4-en-3-one  i n 50% y i e l d .  As noted e a r l i e r (footnote 34,  +2 page 93) the Cu  /O^ procedure sometimes f a i l s completely and Brackman  has reported the cholest-4-ene-3,6-dione product can be contaminated w i t h 6(a and/or 8)-hydroxy-A -cholestenone.  For these reasons, the  crude enedione products were p u r i f i e d v i a e x t r a c t i o n of t h e i r r e s p e c t i v e  -  potassium enolates alkali  (499,  231  153  -  ) from p e t r o l e u m e t h e r w i t h  (aqueous p o t a s s i u m h y d r o x i d e i n methanol)  recrystallized  (231  Claisen's  ) before  being  from m e t h a n o l .  R  0  42a  With the p u r i f i e d c h o l e s t e r o l and expected series  products i n hand, a  of s m a l l s c a l e m o d i f i e d Snatzke o x i d a t i o n s were a n a l y z e d and  tabulated.  T a b l e I l i a summarizes the r e s u l t s  o b t a i n e d and r e p r e s e n t s  the average r e s u l t produced from m u l t i p l e r u n s . oxidation,  cholesterol  (50 ml) was t r e a t e d chromium t r i o x i d e  In the s t a n d a r d  (1.0 mmole) i n a dimethylformamide s o l u t i o n  f o r one hour a t room temperature  ( 4 . 0 mmoles) and s u l f u r i c a c i d  I  (1.8  (23 ) i n a i r w i t h mmole).  - 154 -  Table Ilia  Chromium Trioxide Oxidation of Cholesterol in Dimethylformamide  Reaction - Changes  Yield  «  c  1 Standard Snatzke  88 %  Average Product Ratio 334 ;480 (% 331) 73 : 27 (17%)  2 Nitrogen Atmosphere  89 %  80 : 20 (17%)  0  b  3 Reaction at 0°  60 : 40 (37%)  4 f|0 (2 mmoles) Added  73 %  57 : 43  (9%)  5 F|0 (4 mmoles) Added  70 %  31 : 69  (9 % )  6 No H S 0  82 %  76 :24 (79%)  7 H S0 (Q9 mmoles)  90 %  83 ; 17 (31%)  1 H S0 (1.8 mmoles)  88 %  73 : 27 (17%)  8 H S0 (4.5 mmoles)  75 %  40 : 60  (3%)  9 H S0 (9.0 mmoles)  69 %  1 : 99  (1 %)  10 H S0 (18.0mmoles)  53 %  1 : 99  (1 %)  5  5  2  2  2  2  2  2  4  Used  4  4  4  4  4  Notes  for details see Androstenone £4Q_ experimental, section ( i ) of ( c ) . ^Quantitative measurement with internal standard. C  A measurement of cholesterol (331) recovered and the ratio of cholest5 - e n - 3 - o n e (334) to c h o l e s t - 4 - e n e - 3 , 6 - d i o n e ( 4 8 0 ) .  - 155 -  Table I l l b i l l u s t r a t e s the r e l a t i v e s t a b i l i t y of the c h o l e s t e r o l oxidation products by s u b s t i t u t i n g 1.0 mmole of c h o l e s t 5-en-3-one (344) or cholest-4-en-3-one (478) or cholest-4-ene-3,6-dione (480) f o r c h o l e s t e r o l (331) i n a Snatzke r e a c t i o n .  These experiments  are e s s e n t i a l f o r an understanding of Table I l i a because they i l l u s t r a t e , that cholest-4-en-3-one i s not found among the r e a c t i o n products' a f t e r a workup under n e u t r a l conditions.  Although the conjugated enone 478  was demonstrated to be i n e r t to a l l y l i c o x i d a t i o n and although the i n i t i a l o x i d a t i o n product of c h o l e s t e r o l , the unconjugated enone 334, was isomerized v i a i t s enol to 478 to the extent of 79% i n the absence of chromium t r i o x i d e , t h e 76% cholest-5-en-3-one isomerized i n the "standard Snatzke" went p r i m a r i l y (> 85%) t o cholest-4-ene-3,6-dione. Under a c t u a l o x i d a t i o n conditions t h i s conversion becomes e s s e n t i a l l y q u a n t i t a t i v e and cholest-4-en-3-one i s not found among the r e a c t i o n products when n e u t r a l workup conditions are employed.  Even when a  two-fold excess of a c i d to oxidant was used i n a Snatzke o x i d a t i o n of c h o l e s t e r o l , no cholest-4-en-3-one was produced. The short l i f e t i m e of the enol to a strong o x i d i z i n g agent l i k e chromic a c i d i s completely understandable when one r e a l i z e s that the enolate generated i n the Cu  2+  /O^  2+ r e a c t i o n (495) i s o x i d i z e d so q u i c k l y by Cu that the enolate  cannot protonate at C-6 even though i t i s i n methanol.  S i m i l a r reasoning  Table HI b  Snatzke Oxidations of Cholesterol Oxidation Products^  Compound Cholest-5-en-3-one (334)  'Oxidation Conditions (% Mass Recovery) Standard Snatzke Standard without C r 0  II  3  Inverse Snatzke  II  Cholest-4-ene-3,6-dione (480)  Standard(1.8 mmole H ) +  (99%)  b  (95%)  b  (91 % )  b  478: 480 (% 334)  0  14 ;: 86 (26%)  13: 87 c  0:. 100  "  (9 mmole H )  (80%) 6 6 %  c  0: 100  II  "  (18 mmole H )  (74%) 3 9 %  c  0: 100  Cholest-4-en-3-one (478)  +  Standard(1.8mmoleH ) +  (9 mmole H ) +  Notes  (83%) 8 3 % °  95: 5  (93%) 9 3 %  95:. 5  c  Non-acidic material isolated after oxalic acid isomerization except for 334 • Neutral workup employed ( NaHC0 ). 3  c  Quantitative measurement with internal standard.  ^ F o r details see Androstenone  experimental  (c)(i).  (45 %)  (82%) 7 6 %  II  +  (21 %)  100: 0  - 157 -  explains why F i e s e r ' s work on the chromic acid o x i d a t i o n of c h o l e s t e r o l i n a c e t i c a c i d medium*' l e d only to the A^-3-one and A^-3,6-dione 1  compounds.  Table I l l b also demonstrates that cholest-4-ene-3,6-dione  (480), u n l i k e cholest-4-en-3-one, i s o x i d i z e d to a considerable extent as the amount of a c i d i s increased. The o x i d a t i o n products of 480 were studied by F i e s e r and have been found to be a mixture of d i a c i d s and a c i d anhydrides (214). As an a i d i n the product a n a l y s i s f o r Table I l i a , and without introducing undue complications, the unconjugated enone product 334 was isomerized to the conjugated enone 478 w i t h d i l u t e a c i d .  The use  of a c i d i c conditions i n the o x i d a t i o n workup was also p a r t i c u l a r l y h e l p f u l i n reducing emulsions i n the aqueous:organic p a r t i t i o n .  The  r a t i o s of the nuclear magnetic resonances at x 4.21 (478), 3.82 (480) and 4.60 (331) were then taken from f i l t e r e d samples to e s t a b l i s h the product mole r a t i o s of cholest-5-en-3-one to cholest-4-ene-3,6dione and the percentage of unreacted c h o l e s t e r o l .  An i n t e r n a l standard  allowed a q u a n t i t a t i v e measurement to be made and, i n most cases, there was a discrepancy of * 10% between the weight of the i n i t i a l l y i s o l a t e d non-acidic product and the weight assigned to 334, 480 and 331.  This d i f f e r e n c e was mainly due to the n o n - i n c l u s i o n of the very  minor product 6-hydroxycholest-4-en-3-one,  which i s isomerized to  cholestane-3,6-dione, as w e l l as m a t e r i a l l o s s during sample handling. However, i n the case of an i n e r t compound l i k e cholest-4-en-3-one, the mass r e c o v e r i e s and i n t e r n a l standard a n a l y s i s gave i d e n t i c a l r e s u l t s (Table I l l b ) .  The r e p r o d u c e a b i l i t y of i n d i v i d u a l experimental runs  (Standard Snatzke was 73 - 3% of 334 f o r 6 experiments) was c e r t a i n l y  - 158 -  h e l p e d by t h e d e m o n s t r a t i o n t h a t t h e o r d e r o f a d d i t i o n , t h e use o f magnetic  s t i r r i n g , t h e e x c l u s i o n o f water and t h e use o f an a i r o r  oxygen atmosphere were o f no s i g n i f i c a n c e t o t h e p r o d u c t mole r a t i o . The o n l y t h r e e v a r i a b l e s found t o be o f any consequence were t h e amount o f a c i d used, t h e temperature employed, and t h e p r e s e n c e o r absence o f an oxygen c o n t a i n i n g atmosphere. parameter  D e c r e a s i n g t h e second  and i n c r e a s i n g t h e o t h e r two l e d t o an u n d e s i r e d i n c r e a s e  i n t h e enedione  480.  A comparison o f t h e s e r e s u l t s w i t h S n a t z k e ' s e x p e r i m e n t a l r e v e a l s a fundamental  (221)  " m i s u n d e r s t a n d i n g " i n h i s o r i g i n a l work.  The  o x i d a t i o n o f c h o l e s t e r o l o r any o t h e r a l c o h o l cannot be done w i t h a "few d r o p s " o r c a t a l y t i c amounts o f s u l f u r i c a c i d . ^ 7  The S n a t z k e  o x i d a t i o n , l i k e a l l o t h e r a c i d i c h e x a v a l e n t chromium o x i d a t i o n s ,  fits  the f o l l o w i n g s t o i c h i o m e t r i c e q u a t i o n (236 ).  2Cr0 + 3R CH0H+ 6 H 3  2  +  — ^  3R C=0 + 2  2Cr? + 6H 0 +  I n agreement w i t h t h i s , t h e a l i q u o t s t a k e n from a  2  (a)  dimethylformamide  s o l u t i o n o f anhydrous chromium t r i o x i d e and 3-hydroxyandrost-5-ene  U n f o r t u n a t e l y t h i s e r r o r has been t r a n s p o s e d i n t o E n g l i s h t h r o u g h c i t a t i o n s o f h i s work (226^) i n c l u d i n g a r e f e r e n c e i n t h e o r g a n i c a c h e m i s t ' s B i b l e , F i e s e r ' s Reagents f o r O r g a n i c S y n t h e s i s (234 ). A a second i n t e r e s t i n g e r r o r i s t h e r e p o r t i n A u g u s t i n e ' s book (222 ) t h a t c h o l e s t e r o l i s o x i d i z e d t o cholest-5-en-3-one i n 79% y i e l d w h i l e F r i e d and Edwards (235) r e p o r t t h a t 3-hydroxy-A^-system cannot be o x i d i z e d t o t h e ketone s a t i s f a c t o r i l y by S n a t z k e ' s method. The sad p a r t i s t h a t they b o t h a r e c i t i n g t h e same o r i g i n a l paper — Snatzke's.  - 159  -  (474) were found to show that l i t t l e o x i d a t i o n had occurred u n t i l q u a n t i t i e s of acid were introduced.  small  As demonstrated by g a s - l i q u i d  chromatography, the r e a c t i o n ceased as the acid was  consumed.  However the o x i d a t i o n went r a p i d l y to completion a f t e r excess a c i d had been added.  The same sequence of r e s u l t s i s reproduced i n  Table I l i a when increasing amounts of s u l f u r i c a c i d (0.9 mmole ->  1.8  mmole -> 4.5 mmole) are considered.  Important Parameters i n the Snatzke Oxidation While c h o l e s t e r o l oxidations have been studied f o r over a century, i t i s the very extensive studies of isopropanol o x i d a t i o n that has led to mechanistic i n s i g h t s on the chromic a c i d  oxidation.  The o x i d a t i o n of isopropanol by chromium(VI) i n aqueous a c e t i c a c i d has been shown to f o l l o w equation (b)  Rate of Oxidation- k [HCrO°] [(CH ) CHOH] [H°] + kjHCrQj] [(CH^CHOH] [H*] (b) 1  2  3 2  r e q u i r i n g the two competing r a t e determining steps (e)  R CH0H + HCr04 + H® « 2  R CH0 -Cr0 H + H* 3  2  [R CH0-Cr0 -H] + 2  3  2  3  lv  [R CH0-Cr0 H ]  R C=0 +  ,v  2  3  2  (c)  2  2  2  Cr  (d)  2  R C = 0 + Cr  3  H0  [R CH0-Cr0 H ]  [R CH0-Cr0 H] 2  and (f)  •  (e)  (f )  - 160  -  i n one 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 500 or 501  o.  o  0  R C= 0  (237 ) .  \Nf>°\S-  R 2  2  a  Base  ox  +  Cr  xo  l v  500 Stewart  (237  b  ) and Wiberg  c (237 ) have d i s c u s s e d  of the two mechanisms and s i n c e times k^,  has been found to be about  The Jones  o x i d a t i o n has  i t has been found to f o l l o w f i r s t  isopropanol s t a t e 501  and a c i d i t y .  to be  thirty  predominantly  a l s o been s t u d i e d  order k i n e t i c s i n  (238  chromium(VI),  The a u t h o r s f a v o u r e d the c y c l i c t r a n s i t i o n  i n t h i s case because  a less polar solvent  2  the r e l a t i v e m e r i t s  the aqueous chromic a c i d o x i d a t i o n appears  second o r d e r i n a c i d . and  X = Hor H  501  p r o t o n t r a n s f e r to an e x t e r n a l base i n  (acetone) s h o u l d r e t a r d the r e a c t i o n r a t e  and  would not e x p l a i n the observed r a t e enhancement. The  significant  r o l e o f a c i d i n chromate o x i d a t i o n s  the phosphorus p e n t o x i d e employed i n T a b l e I l i a of p h o s p h o r i c a c i d .  suggests  that  i s s e r v i n g as a s o u r c e  The a d d i t i o n of the a c i d a n h y d r i d e to a  Snatzke  r e a c t i o n ensures t h a t the water g e n e r a t e d i n the r a p i d chromate e s t e r f o r m a t i o n step w i l l p r o v i d e the a c i d i c p r o t o n s r e q u i r e d c a t a l y z e the slower r a t e d e t e r m i n i n g chromate e s t e r When a lower r e a c t i o n temperature was chromate e s t e r d e c o m p o s i t i o n was  retarded  e n o l i z a t i o n of the 8,y-unsaturated reaction  temperature  was  employed  ketone  decomposition.  (0°), the r a t e o f  relative 334.  to the r a t e of  C o n v e r s e l y , when the  r a i s e d to 37°, the enone (334)  (480) p r o d u c t r a t i o became 84:16  to  to  enedione  i n a i r (90:10 i n n i t r o g e n ) .  )  - 161 -  Unfortunately, nitrogen).  at 57°,  t h i s r a t i o had dropped to 70:30 (82:18 i n  Since two equivalents of a c i d are required to produce  one mole of the enone 334 from c h o l e s t e r o l while s i x equivalents  of  a c i d are required to produce one mole of the enedione 480 by chromate o x i d a t i o n of c h o l e s t e r o l , c o n t r o l l i n g the r e a c t i o n temperature can used to minimize the a c i d " c a t a l y s t " consumed i n the a l l y l i c  be  C-6  hydroxy o x i d a t i o n . To understand the product r a t i o change caused by going from oxidations i n a i r to those i n nitrogen requires Westheimer's  (236)  more complete a n a l y s i s of the s t o i c h i o m e t r i c equation (a) o u t l i n e d i n (g), (h) and  ( i ) below.  In an a c i d i c hexavalent chromium o x i d a t i o n , V  up to two-thirds of the a l c o h o l o x i d a t i o n i s performed by a Cr VI and one-third by a Cr species.  R CH0H + C r 0 v ,  2  H 0 + Cr0 + Cr0 2  2  3  3  2(Cr0 H + R CH0Ht3H 3  2  3R CH0H + 2Cr0 +6H 2  3  R C=0 + C r 0 + H 0  (g)  2Cr 0 H  (h)  lv  2  —>»  +  +  species  v  2  2  3  R C = 0 + Cr +- 3H 0) ,u  2  (i )  2  3R C = 0 + 2Cr + 6H 0 2  3+  (a)  2  The r e s u l t of going from an a i r to a nitrogen atmosphere i n Table I l i a suggests that oxygen traps some of the a c t i v e intermediate species.  Following t h i s hypothesis, when the Snatzke i s done under  nitrogen, the stronger oxidant Cr to perform oxidations. parent Cr  chromium  VI  IV  and i t s d e r i v a t i v e Cr  V  are l e f t  S ince these reactions are more rapid than the  d oxidations (236 ), t h i s r e s u l t s i n the s u l f u r i c a c i d being  - 162  consumed p r e f e r e n t i a l l y i n C-3  -  oxidations rather than i n oxidations  subsequent to e n o l i z a t i o n of the B,y-enone 334.  A r e l a t e d oxygen  e f f e c t has been reported by Wiberg and M i l l i n t h e i r work on o x i d a t i o n of benzaldehyde to benzoic a c i d (239). was  the  When t h i s r e a c t i o n  c a r r i e d out i n a i r , benzaldehyde disappeared as though 8% more  chromium t r i o x i d e was  present than t h e o r e t i c a l l y p o s s i b l e .  Repeating  the r e a c t i o n under nitrogen reduced the oxidant to 90% of t h e o r e t i c a l IV due  to induced o x i d a t i o n of the solvent by Unfortunately  Cr  the above i n t e r p r e t a t i o n f a i l s to e x p l a i n why  the  amount of recovered c h o l e s t e r o l at a given r e a c t i o n temperature i s independent of whether the r e a c t i o n was atmosphere.  I t does not e x p l a i n why  done i n an a i r or  nitrogen  employing excess s u l f u r i c a c i d  (4.5 mmole) gave a 40:60 r a t i o i n a i r and a 60:40 r a t i o i n nitrogen. A simpler i n t e r p r e t a t i o n i s that some autoxidation  i s occuring  and  the  oxygen uptake i s probably associated with a chromium t r i o x i d e i n t e r mediate ( C r ^ -y C r ^ ^ l ) that f a c i l i t a t e s the required one t r a n s f e r step. at C-6  Even so, the majority  (y 2/3)  electron  of the oxygen introduced  o r i g i n a t e s with the chromium t r i o x i d e and not with  the  molecular oxygen. Several a d d i t i o n a l observations were made of f a c t o r s that have mechanistic rather than synthetic overtones.  Using an extension of  Table I l i a below, the r e s u l t s are l i s t e d from the Snatzke o x i d a t i o n of c h o l e s t e r o l with 1.8 mmole of s u l f u r i c a c i d (the f i r s t two) without s u l f u r i c acid (the l a s t s i x ) .  and  The problem a r i s e s that i n the  absence of a c i d and under normal r e a c t i o n circumstances about 20% of cholesterol i s oxidized.  While hydration  the  of hydroscopic chromium  t r i o x i d e y i e l d s chromic a c i d , H„Cr0., i t has already been demonstrated  -  that  adding water  cholesterol  has no e f f e c t  163  -  on the o x i d a t i o n .  A u t o - o x i d a t i o n of  i n the workup was shown not to be o c c u r r i n g s i n c e  s i x and twelve have  the normal o x y g e n - n i t r o g e n  ratio  b l a n k run w i t h c h o l e s t e r o l was r e c o v e r e d unchanged. feature  is  that while  these r e a c t i o n s  to r e a c t w i t h 6.0 mmole of a l c o h o l ,  Table III a  changes  and a  The s u r p r i s i n g  c o n t a i n enough o x i d a n t  even l e a v i n g  entries  (4 mmoles)  reaction six  for  Chromium Trioxide Oxidation of Cholesterol in Dimethylformamide Average Product Ratio 334 :480 (%331)  Reaction - Changes 1  Standard Snatzke  73.:27  (17%)  11  Oxidant Doubled  63 :37  (6%)  6  N o H S 0 Used  76 : 24 (79%)  2  4  87 ; 13 (82 %)  12 No H S0 N Atmosphere 2  4>  2  86 ; 14  13  Volume Halved, NoH ,N  14  No H , Sodium Acetate (5.0 mmole)  15  Acetic Acid (17.5 mmole)  +  2  0 •. 0 (100%)  +  16 p-Toluenesulfonic Acid (2.0 mmole) twenty-four unchanged of  hours i n a i r w i t h o u t (76:24 (74%)  of  24 h o u r s ) .  the anhydrous chromium t r i o x i d e  produced by d o u b l i n g the o x i d a n t dimethylformamide  employed  62 :38  (75%)  43 :57  (61 %)  added s u l f u r i c a c i d l e f t  ratio after  i s also  (run 11)  (run 13).  (69%)  it  This "residual  evident  i n the  and by h a l v i n g  essentially acidity"  results the  volume  When commercial chromium  -  t r i o x i d e was r e c r y s t a l l i z e d vacuum, r e s u l t s obtained.  164  -  from d i s t i l l e d water and d r i e d under  superimposeable w i t h  That i s ,  run s i x  changed  those  found e a r l i e r  from 76:24  (79%)  w i t h commercial  chromium t r i o x i d e to 77:23 (80%) w i t h r e c r y s t a l l i z e d However,  employing sodium a c e t a t e  no o x i d a t i o n o c c u r r i n g (run 14) mmole) o r a c e t i c  acid  (17.5  a d d i t i o n of s u l f u r i c a c i d  absence  and even the a d d i t i o n o f water  a s p e c t of  20% o f  the aqueous  cholesterol.  monochromate e s t e r . bicarbonate  unchanged.  The  buffered The  employing sodium a c e t a t e was t h a t i n  reaction solution.  isolated  result  to  (55  the c h o l e s t e r o l b e i n g o x i d i z e d .  r e c o v e r e d by o r g a n i c e x t r a c t i o n of  used to a c i d i f y  this  (0.9 mmole) to the sodium a c e t a t e  o f a c i d o n l y about  aqueous  oxidant.  (5.0 mmole) as a weak base l e d  mmole) l e f t  s o l u t i o n r e s u l t e d i n ^ 40% of most i n t e r e s t i n g  were  If  the s t a r t i n g m a t e r i a l was the quenched,  either  layer,  This i s  acetic  is  and to undergo a v e r y  initially  basic  or h y d r o c h l o r i c a c i d were  the r e c o v e r y jumped to over  consistent  This ester  slightly  the  75%  w i t h the i n t e r m e d i a c y  expected  to be s o l u b l e  rapid hydrolysis  of  the  in  in dilute  acid  (242). While the e x t r a a c t i v i t y of no s y n t h e t i c be s u b t r a c t e d Acetic  acid  actually and 16)  of the chromium t r i o x i d e  i t would i n f l u e n c e  rate  from the observed o x i d a t i o n r e s u l t s  (17.5  mmole) and p - t o l u e n e s u l f o n i c  studies  to p e r m i t  acid  while  sulfuric acid  (0.9 mmole)led to 50% o f  In a d d i t i o n ,  and p _ - t o l u e n e s u l f o n i c  the p r o d u c t r a t i o s  for  is  and must comparisons,  (2.0 mmole)  caused o n l y < 5% and ^ 15% o x i d a t i o n r e s p e c t i v e l y . (runs  being o x i d i z e d . acetic  consequence  (acidity)  the  15  cholesterol  the monoprotic  a c i d s were not as' f a v o u r a b l e  as t h a t  for  - 165 -  the b i p r o t i c s u l f u r i c .  In r e t r o s p e c t , the s u l f u r i c a c i d r e s u l t s  seemed almost anomalous e s p e c i a l l y when 2.0 mmoles of n i t r i c , p e r c h l o r i c , or hydrochloric acid were found to give product r a t i o s of 43:57 (63%), 59:41 (61%) and 65:35 (74%) r e s p e c t i v e l y .  To deal with  this'wide  r e a c t i v i t y v a r i a t i o n of chromium t r i o x i d e with the a c i d employed, equations (c) to ( f ) i n the Westheimer o x i d a t i o n sequence must be replaced by ( j ) to (m).  HCr0 + HA + H 4  e  +  HCr0 A + H 0 3  R CH0H + HCr0 A 2  [R^CHO-CrC^-A] +• H 0  ( k)  R C = 0 + Cr  lv  ( I)  0 + Cr  ,v  (m)  3  [R CH0Cr0 A] 2  2  [R CH0Cr0 AH ] 2  2  +  (j)  2  2  2  R C= 2  Lee and Stewart have shown (241 ) that protonation of the a c i d cl  chromate i o n i n aqueous s o l u t i o n s i s accompanied by incorporation of the mineral a c i d anion i n t o the chromium(VI) species. suggested that the o x i d a t i o n of isopropanol  They have  i n moderately concentrated  aqueous s o l u t i o n s of the mineral a c i d (HA) then proceeds by a c y c l i c , + 71 unimolecular decomposition of the chromate e s t e r , R CH0Cr0 AH (503). ?  ?  "The t r a n s f e r of electrons toward the chromium occurs by formation of carbon-hydroxy-oxygen bonds i n the t r a n s i t i o n state as w e l l as carbon-oxygen-chromium bonds, i . e . p a r t l y occupied o r b i t a l s are used to bind the transferred hydrogen to both carbon and oxygen i n the t r a n s i t i o n s t a t e . The developing carbonyl group i n the e l e c t r o n d e f i c i e n t t r a n s i t i o n s t a t e w i l l be s t a b i l i z e d by electron-donating substituents...Protonation of the chromate p o r t i o n of the ester a l s o increases the r e a c t i o n r a t e . The conversion of ester to t r a n s i t i o n state i s thus aided by the combined p o l a r i z i n g e f f e c t s of an e l e c t r o n donating aromatic r i n g and an electron-withdrawing metal cation."(241 ).  -  S i n c e the  t r a n s i t i o n s t a t e of  electron deficient  (241^),  V  -  chromate o x i d a t i o n s  k  ••0  502  .A  base  be  (A) w i l l  R C =0  OH  2  0  HgCrOfc/S  A .  503  the o x i d a t i o n r a t e m a r k e d l y .  chromic a c i d i n a c e t o n e , withdrawing  i s known to  the i n c o r p o r a t e d conjugate  R — C-^0.  Rp-C— 0 ,0 H //\ 0 A  affect  166  ligands,  Lee e t  u s i n g dimethylformamide, a l s o be e s s e n t i a l  al_. (238 ) have shown t h a t  like nitrate,  an e l e c t r o n d o n a t i n g l i g a n d ,  I n the Jones o x i d a t i o n  enhance  retards  the i n c o r p o r a t i o n of  significance  chloride,  From our  the conjugate  f o r the o x i d a t i o n and the p a r t i c u l a r  i n c o r p o r a t e d must be o f g r e a t  electron  the r a t e w h i l e  the o x i d a t i o n .  employing  results  base must  base  i n the Snatzke  oxidation.  W h i l e Lee and Johnson i n t h e i r study on the chromic a c i d of  isopropanol i n t r i f l u o r o a c e t i c  whether (k))  the c o n j u g a t e . b a s e  or ester  acid  (238^)  group s h i f t e d  decomposition  (equation  c o u l d not  the e s t e r  (1))  the o x i d a t i o n of c h o l e s t e r o l g i v e an i n d i c a t i o n t h a t decomposition i s being a f f e c t e d . acids  It  is  as s u l f u r i c and j D - t o l u e n e s u l f o n i c  results  i n equation  considerations  (k).  It  for b i s u l f a t e  d e c o m p o s i t i o n of  502.  with p_-toluenesulfonic  difficult  and t o s y l a t e  the  would a f f e c t  on  ester  to see how such  however  T h i s i d e a was s t r e n g t h e n e d  (equation  the r e s u l t s  c o u l d g i v e such  is quite possible  distinguish  formation  reactions,  oxidation  strong  different that  electronic  the r a t e  when the  of  results  a c i d were found to be unchanged by the  addition  - 167  o of 4 A molecular sieves hydroscopic reagents  -  to the r e a c t i o n .  S i m i l a r l y , the a d d i t i o n  ( m o l e c u l a r s i e v e s , magnesium s u l f a t e , sodium  s u l f a t e , d i c y c l o h e x y l c a r b o d i i m i d e ) to the r e a c t i o n u s i n g a c i d was  shown to have no  e f f e c t on  the  results.  to c o m p l e t i o n and  s t a t e l i k e 504,  d i d suggest the  h a v i n g both the f a v o u r a b l e  R  0"  I  ,-Ht.  II  sulfuric  While the  of b i s u l f a t e s a l t s (potassium b i s u l f a t e h y d r a t e ) d i d s h i f t oxidations  of  addition these  i n t e r m e d i a c y of a t r a n s i t i o n  hydrogen bonding and  the  *0 II  R-C-0-Cr-0-S==0 I  8 +  ll  I  504 required  protonation,  mmole H^PO^  afforded  the r e l a t i v e f a i l u r e of p h o s p h o r i c a c i d 77:23 (84%)  (1.0  terminated f u r t h e r i n v e s t i g a t i o n  of a c i d c a t a l y s t s .  C o l l i n s O x i d a t i o n s of Fortunately  Cholesterol  the methods t h a t were d e v i s e d  r e a c t i o n r a p i d l y gave more g e n e r a l  and  applied  T a b l e IVa  to the  C o l l i n s oxidation.  r e s u l t produced from m u l t i p l e the  temperature, and  (50 ml)  was  (12  mmoles).  Snatzke  s i g n i f i c a n t r e s u l t s when  runs by v a r y i n g  displays  the  average  the o x i d a n t mole r a t i o ,  cholesterol  treated  (1.0  mmole) i n d i c h l o r o m e t h a n e  f o r t h i r t y minutes a t room temperature  (23 - 1°) w i t h anhydrous chromium t r i o x i d e (2,4, pyridine  the  the atmosphere employed i n a C o l l i n s r e a c t i o n .  In a s t a n d a r d o x i d a t i o n , solution  to e x p l o r e  or 6 mmoles)  and  - 168 -  Table  IVa  Chromium irioxide-Pyridine Oxidation of Cholesterol in Dichloromethane  ("Collins")  Oxidant/Alcohol Mole Ratio  Reaction-Changes  Average Product Ratio  b  334=480  (%33J)  1  Standard  2  89 :11  (51%)  2  Standard  4  85 :15  (16%)  3  Standard  6  85 :15  («S3%)  4  Nitrogen  4  91 : 9  (37%)  5  Nitrogen Atmosphere  6 -  93 : 7  (9%)  6  Reaction at 0°  4  94 : 6  (29%)  7  Reaction at 0°  6  92 : 8  (9%)  8  • mmole) 4 Standard plus H 0 (2.0  84 ;16  (79%)  9  H 0(2.0mmole) + R 0.(6.0mmole) 4  91 : 9  (41%)  Atmosphere  2  0  Notes  For details see Androstenone 2 4 0 experimental,section (ii) of (c). b  T h i s indicates the mole ratio of chromium trioxide to cholesterol.  c  A measurement of cholesterol (331.) recovered and the ratio of cholest- 5 - e n - 3 - o n e ( 3 3 4 ) to c h o ! e s t - 4 - e n e - 3 , 6 - d i o n e  Table  V  (480).  demonstrates the r e l a t i v e s t a b i l i t y of the c h o l e s t e r o l  o x i d a t i o n products by s u b s t i t u t i n g 1.0 mmole of cholest-5-en-3-one (334) or cholest-4-en-3-one (478) or cholest-4-ene-3,6-dione (480) f o r c h o l e s t e r o l (331) i n a C o l l i n s r e a c t i o n at room temperature f o r one hour with a s i x - f o l d excess of o x i d i z i n g agent.  These  experiments i l l u s t r a t e that p y r i d i n e alone does not isomerize the unconjugated double bond of compound 334, that the conjugated ketone  Table V  Oxidations with Chromium Trioxide-Nitrogen Base Reagents. Compound * 0  Chotest-5-en-3-one (234J  0  b  Collins without C r 0  II  Standard Corey Corey without C r 0  II  Cholest-4-en-3-one (478) II  Notes  (70%) (66)  Standard Collins  II  Cholest-4-ene-3,6-dione (42Q)  478:480 (% 334)  Oxidation Conditions (%Mass Recovery)  3  (99%)  b  (77 % ) 3  (94%)  c  b  2:98  (15%)  -: -  (100%)  5:95  (45%)  100:0  b  Standard Collins  (96%)(75%)  c  0 : 100  Standard Corey  (74%)(69%)  c  0:100  Standard Collins  (92%)(85%)  c  96: 4  Standard Corey  (85%)(78%)  c  93:7  .Non-acidic material isolated after oxalicacid isomerization except for 334 •  U  b  c  Neutral workup employed ( N a H C O ^ . Quantitative measurement with internal standard.  ^ For details see Androstenone experimental (c.) (ii.)..  (98%)  - 170 -  478 does not occur as a d i r e c t o x i d a t i o n product of c h o l e s t e r o l and that cholest-4-ene-3,6-dione, the o x i d a t i o n product of c h o l e s t - 5 en-3-one, i s i t s e l f o x i d i z e d f u r t h e r .  These are e s s e n t i a l l y the  same observations as those made i n the Snatzke o x i d a t i o n s (Table I l l b ) As an a i d to t a b u l a t i n g Table IVa, the r e a c t i o n mixtures were once again isomerized w i t h o x a l i c a c i d to e s t a b l i s h the product mole r a t i o s of cholest-5-en-3-one to cholest-4-ene-3,6-dione and the percentage of unreacted c h o l e s t e r o l ,  The v a r i a b l e s found to be the  most s i g n i f i c a n t were the mole r a t i o of oxidant to a l c o h o l , the temperature and atmosphere employed, and the amount of a c i d or base present. At t h i s p o i n t , i t i s worthwhile to consider part of the o r i g i n a l work by C o l l i n s , Hess, and Frank on the dipyridine-chromium(VI) oxide. They reported (227) O  " S t o i c h i o m e t r i c a n a l y s i s of the o x i d a t i o n of 2-butanol at 25 using 2:1, 4:1, and 6:1 mole r a t i o s of complex to a l c o h o l i n 6% complex s o l u t i o n s provided 56%, 79% and 98% end point conversions to 2-butanone, r e s p e c t i v e l y (vpc a n a l y s i s ) . This low o x i d a t i o n e f f i c i e n c y i s undoubtedly due to the f a c t that reduced chromium products, as w e l l as a l c o h o l , react w i t h the reagent — no a c t i v e complex remained i n s o l u t i o n f o l l o w i n g the o x i d a t i o n s even when the 6:1 r a t i o was used. Higher o x i d i z i n g e f f i c i e n c i e s were obtained at a lower temperature and by using a suspension of phosphorus pentoxide i n the reagent..." The Table IVa r e s u l t s f o r c h o l e s t e r o l are i n good agreement w i t h the l i t e r a t u r e values f o r butanol as f a r as the oxidant mole r a t i o s are concerned.  That i s , a 2:1, 4:1, and 6:1 mole r a t i o of  complex to a l c o h o l were found to provide a 49%, 84% and 97% end-point conversions of c h o l e s t e r o l .  However the molecular oxygen dependence  i l l u s t r a t e d i n Table IVa i s the f i r s t example reported that the  - 171  -  e f f i c i e n c y of the C o l l i n s r e a c t i o n i s dependent on an oxygen c o n t a i n i n g atmosphere. hygroscopic hydrated  T h i s o b s e r v a t i o n has s p e c i a l s i g n i f i c a n c e because o f n a t u r e of the d i p y r i d i n e - c h r o m i u m ( V T ) o x i d e .  complex i s c h l o r o c a r b o n - i n s o l u b l e and  as demonstrated by e n t r y e i g h t of T a b l e IVa.  The  i s quite unreactive The h y d r o p h i l i c n a t u r e  o f the o x i d a n t complex i s the main r e a s o n t h a t i t i s no l o n g e r as s u g g e s t e d i n the p r o c e d u r e of C o l l i n s e_t a l . (227).  The  isolated  current  p r o c e d u r e , s u g g e s t e d by R a t c l i f f e and R o d e h o r s t (158), u t i l i z e s i n s i t u p r e p a r a t i o n of the complex to m i n i m i z e the h a n d l i n g Two  the  the  difficulties.  molar e q u i v a l e n t s of p y r i d i n e i n d i c h l o r o m e t h a n e a r e added t o  of anhydrous chromium t r i o x i d e and  the m a g n e t i c a l l y s t i r r e d  s o l u t i o n i s ready f o r use w i t h i n t e n m i n u t e s .  one  red  S i n c e the problem  now  becomes one of h a v i n g a weighed amount of anhydrous chromium t r i o x i d e (which i s i t s e l f h y g r o s c o p i c )  s u i t a b l e f o r the r e a c t i o n , many r e a c t i o n s  a r e c o n v e n i e n t l y done by h e a t i n g the r e q u i r e d amount of c o m m e r c i a l r e a g e n t grade chromium t r i o x i d e under vacuum and n i t r o g e n atmosphere. by s y r i n g e and,  The p y r i d i n e and  then c o o l i n g i n a  d i c h l o r o m e t h a n e a r e added  a f t e r a few m i n u t e s , the a l c o h o l can be added as a 72  dichloromethane s o l u t i o n . mole r a t i o o f  8:1  E x p e r i m e n t s show t h a t f o r c h o l e s t e r o l a  of o x i d a n t t o a l c o h o l , r a t h e r than the normal  r a t i o , i s r e q u i r e d f o r the o x i d a t i o n t o go to c o m p l e t i o n  6:1  under a n i t r o g e n  atmosphere. "72 For example, R a t c l i f f e and Rodehorst (158) r e p o r t e d s t o r i n g d i c h l o r o methane s o l u t i o n s of the o x i d a n t complex f o r up to 28 days under n i t r o g e n without adverse reagent decomposition. Corey and F l e e t (232) r e p o r t d o i n g t h e i r r e l a t e d o x i d a t i o n work under an a r g o n atmosphere.  - 172  The  -  l i t e r a t u r e o b s e r v a t i o n s quoted above on the h i g h e r  e f f i c i e n c y of  the C o l l i n s o x i d a n t a t lower temperature  use of phosphorus p e n t o x i d e appear t o be m i s l e a d i n g .  oxidizing  and on  The  the  oxidizing  e f f i c i e n c y f o r a g i v e n mole r a t i o of o x i d a n t to s t e r o l o b v i o u s l y drops as the temperature 4:1  i s changed from 23  to 0 .  That i s , employing  r a t i o of complex t o a l c o h o l changes the r e a c t i o n from b e i n g  83%  6  o  complete a t 23  a  t o b e i n g 71% complete a t 0 .  On g e n e r a l p r i n c i p l e s ,  i t would be v e r y s u r p r i s i n g i f h i g h e r o x i d i z i n g e f f i c i e n c i e s were o b t a i n e d by l o w e r i n g the temperature  o f the r e a c t i o n .  Nevertheless,  s i n c e the C o l l i n s o x i d a t i o n shows an even l a r g e r dependence on m o l e c u l a r oxygen than i t does on t e m p e r a t u r e ,  the l i t e r a t u r e  might have o r i g i n a t e d w i t h oxygen d e f i c i e n t r e a c t i o n s . temperature  observations  Lowering  the  then would g i v e an oxygen d e f i c i e n t r e a c t i o n a b e t t e r chance  of c o m p l e t i o n because o f the h i g h e r s o l u b i l i t y of oxygen a t temperatures  lower  and the l o n g e r l i f e t i m e of t h e o x i d a n t complex under  these  conditions. The use by C o l l i n s e t ail. of a s u s p e n s i o n of phosphorus to g i v e h i g h e r o x i d i z i n g e f f i c i e n c i e s s u g g e s t s  the a c i d  pentoxide  anhydride  p r e v e n t s o r r e v e r s e s h y d r a t e f o r m a t i o n of the o x i d a n t complex.  From  T a b l e I V a , e n t r y n i n e , i t i s c l e a r t h a t u s i n g even a n i n e - f o l d  excess  of phosphorus p e n t o x i d e o n l y r e g e n e r a t e s  3H 0 2  +  P 0 2  5  ( d e h y d r a t e s ) about o n e - h a l f  -  2H P0 3  4  -  of  the h y d r a t e d complex.  173  -  As w i l l be demonstrated  subsequently,  most important a s p e c t of adding phosphorus p e n t o x i d e of  a good p r o t o n s o u r c e ,  as p h o s p h o r i c a c i d ,  employment of p h o s p h o r i c p e n t o x i d e  as an e f f e c t i v e  A d i s c u s s i o n of a c i d parameter e f f e c t s of b a s e s , but f i r s t  rather  w i l l follow  is  the  than  the  addition  the  dehydrating  reagent.  t h a t of  effect  the  the f a v o u r a b l e  product s h i f t  to  cholest-5-en-3-one  i n T a b l e IVa s h o u l d be c o n s i d e r e d .  The d e c r e a s e  in  cholest-4-ene-3,6-  d i o n e produced by u s i n g a n i t r o g e n atmosphere t h i s product o r i g i n a t e s Snatzke at  oxidation.  from a u t o - o x i d a t i o n ,  u n l i k e i n the S n a t z k e ,  indicates  t h a t i n the C o l l i n s  the r a t e o f e n o l i z a t i o n of  compared to the r a t e of o x i d a t i o n of  by l o w e r i n g the t e m p e r a t u r e . justification variously  C-17  substituted  formation i s  The l a t t e r  the  the r e a c t i o n to go to  Other Parameters  i s diminished  observation provides  A^-3-hydroxysteroids  at  ether  who o x i d i z e d  However t h e i r work g i v e s no i n d i c a t i o n t h a t  suppressed at  0° and they a r e unaware is  t h a t an  r e q u i r e d to p e r m i t  completion.  i n the C o l l i n s  Oxidation  was performed to e s t a b l i s h  reaction with  experimental  0° w i t h d i p y r i d i n e  The parameter work f o r T a b l e IVa was so e n c o u r a g i n g  Collins oxidation.  the  unconjugated  cholesterol  e i g h t o r ten:one mole r a t i o of o x i d a n t : s t e r o l  experiments  in  oxidation,  f o r the p r o c e d u r e of Jones and Gordon (229)  chromium t r i o x i d e complex. enedione  as was observed  half  The f a v o u r a b l e m i n i m i z a t i o n of enedione p r o d u c t i o n  i c e b a t h temperatures  ketone  suggests t h a t about  The l i t e r a t u r e  t h a t a set  the r o l e of p y r i d i n e i n  p r o c e d u r e of quenching  and then working i t  of  the  the  oxidation  up was found to g i v e  anomalous  -  results  at  174  -  low p y r i d i n e c o n c e n t r a t i o n s .  e v i d e n t when the r e s u l t s  of p e r f o r m i n g a C o l l i n s '  any p y r i d i n e were c o n s i d e r e d . chromium t r i o x i d e  The r e a s o n f o r t h i s  U s i n g a 6:1  to c h o l e s t e r o l ,  oxidation  r a t i o of  without  became without  anhydrous  p y r i d i n e , gave a A ^ - 3 - o n e :  4 A -3,6-dione  (% c h o l e s t e r o l )  m i x t u r e was added to e t h y l  analysis  of 81:19  (43%) when the  e t h e r and f i l t e r e d .  When a s i m i l a r r e a c t i o n  was added to i c e - c o l d aqueous sodium b i s u l f i t e , acid -:-  (3 N) or aqueous (100%).  ether  sodium b i c a r b o n a t e ,  Evidently,  can s e r v e  reaction  dilute hydrochloric  the product a n a l y z e d  the lone p a i r e l e c t r o n s  the same f u n c t i o n as those  of  of oxygen i n  the n i t r o g e n  as  diethyl  in 73  pyridine, a result  albeit of  this  s e v e r a l o r d e r s o f magnitude l e s s e f f e c t i v e l y . finding,  the r e a c t i o n s o l u t i o n s  quenched by f i l t r a t i o n i n t o c o l d s a t u r a t e d bicarbonate  f o l l o w e d by washing  i n T a b l e IVb were  solutions  the o r g a n i c  As  of  sodium  l a y e r w i t h water and  dilute hydrochloric acid. T a b l e IVb g i v e s a p r o g r e s s i o n of e n d - p o i n t to those observed of  complex  i n T a b l e IVa when the 2:1,  (trioxobis(pyridine)chromium)  A l s o the mass r e c o v e r i e s those  observed  results  4:1  conversions and 6:1  to s t e r o l a r e  mole  ratio  considered.  on workup f o r T a b l e IVb were even h i g h e r  f o r T a b l e I V a , p r o v i d i n g ^ 90% y i e l d s .  tabulated  similar  do not meet l i t e r a t u r e  amounts of p y r i d i n e are c o n s i d e r e d .  If  expectations  However  than  the  when d i m i n i s h i n g  the d i p y r i d i n e complex  is  73 .  The p o i n t to be s t r e s s e d i s t h a t w h i l e s l i g h t v a r i a t i o n s due to the workup procedure can be t o l e r a t e d , a n y t h i n g t h a t o b l i t e r a t e s the e f f e c t s of parameter v a r i a t i o n s , or parameter t r e n d s , i s worse than u s e l e s s . F o r t u n a t e l y , to t h i s p o i n t , the trends d i s c u s s e d are a r e independent of the method of quenching the o x i d a t i o n r e a c t i o n .  - 175 -  e s s e n t i a l f o r o x i d a t i o n , r e d u c i n g t h e p y r i d i n e below a two molar e q u i v a l e n t s h o u l d cause a d r a m a t i c f a l l i n t h e p r o d u c t y i e l d .  Table IVb  However,  Pyridine Dependence of Collins Oxidation of Cholesterol  Reaction - (Base /Oxidant Mole Ratio) 0  Oxidant/Alcohol Mole Ratio b  Average Product Ratio  0  334= 480 (%331)  1 Pyridine  (6)  6  82 .18  (6%)  2  "  (2)  6  86 :14  (2%)  3  "  (1 )  6  89 :11  (4%)  4  '*  (0.5)  6  91 : 9  (14 %)  6  — ;—  (100%)  5 No Pyridine 6 Pyridine  (3)  4  87 -.13  (15%)  7  "  (2)  4  91 : 9  (15%)  8  "  (1)  4  92 : 8  (17%)  9  "  (6)  2  80 :20  (50%)  10  "  (2)  2  84 :16  (50%)  Notes  For details see Androstenone  a  b  c  2 4 0 experimental,section (ii) of (c)  T h i s indicates the mole ratio of chromium trioxide to cholesterol. A measurement of cholesterol (331) recovered and the ratio of cholest- 5 - e n - 3 - o n e ( 3 3 4 ) t o c h o l e s t - 4 - e n e - 3 , 6 - d i o n e (480).  -  the l i s t e d r e s u l t s  show t h e r e  one or two e q u i v a l e n t s 1:1 of  176  is  -  little  of p y r i d i n e .  to  is  f i l t e r e d before  the r e s u l t s were found to be u n a f f e c t e d .  particular reaction is  consistent  the  with  responsible  7  o f a m o n o p y r i d i n e complex was a l s o  by s e v e r a l o t h e r f a c t s .  strengthened  The f i r s t of t h e s e was C o l l i n s ' own a n a l y s i s  of  the h y d r a t e d d i p y r i d i n e chromium t r i o x i d e complex to be  If  the " d i o l " water d i s p l a c e s (to form 5 0 5 ? ) ,  An a l t e r n a t i v e  C^Yl^Cr^^Oj.  a p y r i d i n e from each d i p y r i d i n e chromium(VI)  the t r a n s i t i o n s t a t e f o r  the p y r i d i n e - c h r o m i u m  t r i o x i d e system and a secondary a l c o h o l , RR'CHOH, p r o b a b l y 506a.  the  oxidation. ^  The h y p o t h e s i s  complex  addition  of T a b l e IVb a r e i n agreement  a m o n o p y r i d i n e , r a t h e r than a d i p y r i d i n e , complex b e i n g for  the  This  w i t h the i n t e r m e d i a c y of  monopyridine complex and the r e s u l t s  employing  When a r e a c t i o n c o n t a i n i n g a  r a t i o of pyridine:chromium t r i o x i d e the s t e r o l ,  or no d i f f e r e n c e  resembles  t r a n s i t i o n s t a t e 506b was l e s s a t t r a c t i v e  because  R 505 74  506a  When 3 B - h y d r o x y a n d r o s t - 5 - e n e was o x i d i z e d w i t h a 6:1 mole r a t i o o f chromium t r i o x i d e to s t e r o l and the r e a c t i o n was m o n i t o r e d by g . l . c , s i m i l a r r e s u l t s were o b s e r v e d . A f t e r t h i r t y minutes w i t h o u t p y r i d i n e , no o x i d a t i o n had o c c u r r e d . After t h i r t y minutes w i t h one h a l f e q u i v a l e n t p y r i d i n e f o r each m i l l i m o l e chromium(VI), and 88:12 (32%) a n a l y s i s of A->-3-one: A ^ - 3 , 6 - d i o n e (% S t e r o l ) was o b t a i n e d . T h i r t y minutes w i t h a 1:1 mole r a t i o of p y r i d i n e : C r O , a f f o r d e d an 89:11 (7%) a n a l y s i s .  -  177  -  0  0 H  Crv-ef  I  R'  R  508  506b  strong bases,  even those which do no c o - o r d i n a t e  a substantial  r e d u c t i o n i n the amount of o x i d a t i o n t h a t o c c u r s .  the h y d r o x y l p r o t o n was removed from 506b, should abstract I n the case o f the d e p i c t e d  a proton faster  i n the d e p i c t e d  cyclic  c o n c e r t e d p r o c e s s because o f  T a b l e IVb t h e r e  increases.  and more p y r i d i n e i s added.  T h i s amounts to the same  A more e x p l i c i t  p r o v i d e d by p e r f o r m i n g C o l l i n s o x i d a t i o n s the r e a c t i o n m i x t u r e . cholesterol  decreases  d e m o n s t r a t i o n of  for short i n t e r v a l s  Below a r e the r e s u l t s  (1.0 mmole) i n d i c h l o r o m e t h a n e  (10 ml of " c o - s o l v e n t " ) ,  sterol  to the l i s t e d o x i d a n t  at  The a n a l y s e s  0°.  requirement  for  the r a t e of o x i d a t i o n .  t h a t the r a t e of o x i d a t i o n of c h o l e s t e r o l  second s o l v e n t  discourage  In  is  the y i e l d o f enedione p r o d u c t r i s e s o r the amount  recovered c h o l e s t e r o l  dissolving  state.  i s an i n d i c a t i o n t h a t as the amount of p y r i d i n e  increased either  analyzing  If  dioxy d i a n i o n  transition  its  cause  chromium (241^).  A second p o i n t worth c o n s i d e r a t i o n i s  that i s ,  the r e s u l t a n t  t r a n s i t i o n s t a t e 506a a d i o x y d i a n i o n would  an e l e c t r o n d e f i c i e n t  of  chromium(VI),  as more this  was  and  o b t a i n e d by (5 ml) and a  c o o l i n g to 0° and adding  ( 6 . 0 mmoles)  were determined f o r  thing,  i n dichloromethane  t h r e e minute r e a c t i o n  the  (25 ml) periods  -  178  -  and g i v e the p r o d u c t r a t i o of c h o l e s t - 5 - e n - 3 - o n e 4-ene-3,6-dione (331)  (480) w i t h the p e r c e n t a g e  i n parenthesis.  acetic  of unreacted  to  cholest-  cholesterol  The f o u r t h r e a c t i o n was i n c l u d e d to show  a c i d - c h r o m i u m (VI)  chromium(VI) o x i d a t i o n s  oxidations  a r e much slower  i n the presence  "Co-solvent"  of a c e t i c  " Oxidant" Cr0 '(Pyridine)  Pyridine  Cr0 (Pyridine)  Acetic Acid  Cr0 (Pyridine)  3  3  3  Cr0  Acetic Acid  3  that  than d i p y r i d i n e -  acid. ^ 7  "Analysis"  Dichloromethane  75  (334)  2  2  2  90:10 (35%) 100: - (98%) 93 : 7 (48%) 100; - (92%)  S e v e r a l y e a r s b e f o r e C o l l i n s et a l . employed d i c h l o r o m e t h a n e , S t e n s i o and Wachmeister (243^) found t h a t a c e t i c a c i d was a useful solvent for the in s i t u g e n e r a t i o n of the complex 508. O x i d a t i o n s i n a c e t i c a c i d c o u l d be e a s i l y performed on e i t h e r a semimicro o r p r e p a r a t i v e s c a l e . An example o f the l a t t e r was T h e a n d e r ' s work i n 1964 on the o x i d a t i o n of i + (Sarett oxidation failed) (243 ). However, s i n c e the g e n e r a l y i e l d s by S t e n s i o ' s p r o c e d u r e of employing a 1:3.5 r a t i o of a l c o h o l to o x i d a n t tend to be 10-20% lower than C o l l i n s ' method w i t h i t s 1:6 mole r a t i o , a c e t i c a c i d i s r a r e l y employed as a s o l v e n t . One p o s s i b l e u s e f u l e x c e p t i o n i s t h a t S t e n s i o found c h o l e s t e r o l was o x i d i z e d to c h o l e s t - 4 - e n e - 3 , 6 - d i o n e i n 85% by h i s procedure ( 2 4 2 ) , c  a  ° s / y ° \  RA_7'X R'  0-j-  i  R  = 0  H,R' = H  iiR,R'=0  -  Obviously,  179  -  pyridine dramatically  slows the r a t e of  76 while acetic  a c i d has l i t t l e  '  effect.  C o l l i n s et  observed a s i m i l a r , but s m a l l e r r a t e d i f f e r e n c e 2-octanol pyridine  i n dichloromethane (Sarett)  e x p l a n a t i o n of  (Collins)  ai.  (227)  oxidation  The most r e a d i l y  the f a c t  have  i n the o x i d a t i o n of  compared to i t s  f o r a one hour p e r i o d .  t h i s b e h a v i o u r employs  oxidation  available  t h a t the e q u i l i b r i u m  508  507  in  ( n )  . 517  r e p r e s e n t e d by  (n)  lies  oxidized only reacts  far  to the r i g h t .  If  the a l c o h o l to be  w i t h the m o n o p y r i d i n e complex  of o x i d a t i o n c o u l d be s e v e r e l y  retarded.  can r e a c t w i t h the d i p y r i d i n e complex 508,  However, there  s t e r o l being o x i d i z e d , were o b t a i n e d . diisopropylamine  T3U  the  the unexpected  + = 11.0)  results  triethylamine  rate alcohol  oxidation.  of an amine base were i n t r o d u c e d to  As the amount of (pK  even i f  the  i s a second and much  b e t t e r r e a s o n f o r excess p y r i d i n e s l o w i n g down the When s m a l l q u a n t i t i e s  (507),  listed (pK  i n Table + = 11.0)  (233^) was i n c r e a s e d ,  the IVc or  the amount o f  Dei  cholesterol  recovered rose d r a m a t i c a l l y .  By l i t e r a t u r e  precedent,  S t r o n g e r a c i d s may p l a y a more s i g n i f i c a n t r o l e s i n c e p r o t o n s are o b v i o u s l y i m p o r t a n t to the t r a n s i t i o n s t a t e 506a. Corey and Suggs (232^) have v e r y r e c e n t l y demonstrated t h i s p o i n t w i t h p y r i d i n i u m chlorochromate. T h i s r e a g e n t , formed w i t h chromium t r i o x i d e and p y r i d i n i u m h y d r o c h l o r i d e , has been found to be f o u r times as e f f i c i e n t as the d i p y r i d i n e complex.  -  Table IVc  180  -  Influence of Amine Bases on the Collins Oxidation of Cholesterol. a  Reaction—Base (Base/Sterol Ratio)  Oxidant/Alcohol Mole Ratio  Average Product Ratio 334 -.480  (%331)  1  Triethylamine  (1)  6  90 -.10  (5 %)  2  Triethylamine  (2)  6  93 : 7  (20%)  3  Triethylamine  (3)  6  85 :15  (75%)  4  Triethylamine  (5)  6  83 :17  (91 %)  5  Diisopropylamine (2)  6  91 : 9  (7%)  6  Diisopropylamine (4)  6  75 -.25 (63%)  7  1,8-bis-(dimethyl- (0.5)  6  95 : 5  (51%)  8  amino)naphthalene (10)  6  78 -.22  (75%)  Notes  a  this  For details see Androstenone  2 4 0 experimental .section (ii) of ( c )  t r e n d i s a l l wrong s i n c e Westheimer,  i n 1951,  reported  that  i  the o x i d a t i o n o f d i i s o p r o p y l chromate to acetone was  catalyzed  i n s t a n t a n e o u s l y by the i n t r o d u c t i o n i n t o the r e a c t i o n medium o f s m a l l amounts o f p y r i d i n e or d i m e t h y l a n i l i n e The p o s s i b l e reactive  argument t h a t  complex i s u n t e n a b l e  (242  a  ).  77  the a l k y l amines a r e forming a n o n -  for several reasons.  First,  entry  To the b e s t o f our knowledge t h i s e f f e c t of bases on the C o l l i n s o x i d a t i o n has not been r e p o r t e d p r e v i o u s l y . A possible literature precedent does e x i s t however. In the f i e l d o f p a i n t and l u b r i c a n t e n g i n e e r i n g , o r g a n i c chromate e s t e r s have been s t a b i l i z e d by amines to act as a n t i o x i d a n t s . T h i s work, done p r i m a r i l y i n e a s t e r n Europe and R u s s i a , has used such bases as g u a n i d i n e , c y c l o h e x y l a m i n e , d i c y c l o h e x y l a m i n e , i s o b u t y l a m i n e and hexanediamine to reduce c o r r o s i o n (245).  -  three  for triethylamine  cholesterol,  181  -  should l e a d to no more than 50%  i n s t e a d of the 75%  observed,  if  chromium t r i o x i d e was t i e d up by the b a s e . base l , 8 - b i s ( d i m e t h y l a m i n o ) - n a p h t h a l e n e to an even more i n e x p l i c a b l e  result.  listed  E v i d e n c e was l a t e r  ( p K + = 12.3) BH  f o r m a t i o n i s almost  s i x m i l l i m o l e s of  case,  difficult  cases where  any o x i d a t i o n from o c c u r r i n g . to see how the v e r y  fast  However the p o s t u l a t e d  of b e i n g c o m p l e t e l y  equivalent right.  deprotonated  the e q u i l i b r i u m 506  As the amount o f a l k y l amine i s  increases  -> 509  is  chromate  enough  ester  by such a  506  is  or  capable  as the c o n c e n t r a t i o n of f r e e  As the amount o f p r o t o n sponge of s t e r o l ,  taking  In any  chromate  intermediate  reactions  Corey's  r e s t r i c t e d base as 1 , 8 - b i s ( d i m e t h y l a m i n o ) n a p h t h a l e n e  " p r o t o n sponge".  base r i s e s .  i n a l l the  formation i s  f o r m a t i o n s t e p c o u l d be stopped by a b a s e , e s p e c i a l l y sterically  chromium(VI)?  i n p l a c e of p y r i d i n e , t h a t  complete even i n those  to p r e v e n t  i s very  leads  o b t a i n e d from a r e l a t e d o x i d a t i o n ,  amine i s p r e s e n t it  (244)  How can one m i l l i m o l e of  t h a t chromate e s t e r  method of employing d i m e t h y l p y r a z o l e ester  amount o f  the h i n d e r e d  the c o l o u r changes t h a t were observed  i n T a b l e IVc i n d i c a t e s  place.  an e q u i v a l e n t Second,  t h i s a r y l base b l o c k the o x i d a t i o n by almost C o n s i d e r a t i o n of  recovered  to about  uncomplexed one  s h i f t e d w e l l to  i n c r e a s e d to a p p r o x i m a t e l y  the five  78 B e s i d e s h a v i n g a remarkable b a s i c i t y , bis(dimethylamino)naphthalene, o r " p r o t o n sponge", has been shown to be a v e r y poor n u c l e o p h i l e . A l d e r et a l . (244) r e c o v e r e d i t unchanged a f t e r f o u r days at r e f l u x with ethyl iodide i n a c e t o n i t r i l e . F o r the purpose of T a b l e I V c , p r o t o n sponge, u n l i k e the a l k y l a m i n e s , was demonstrated to be unable to form a complex w i t h chromium t r i o x i d e . T h e r e f o r e the above q u e s t i o n s h o u l d be r e p h r a s e d to r e a d "How does a v e r y h i n d e r e d base behave more e f f e c t i v e l y i n b l o c k i n g o x i d a t i o n than one t h a t can complex chromium(VI)?"  78  - 182 -  f  > o-c  /  / \ ,  H  R  \=/ /v  f  \=/ /V, / o  f  3NH  3  o-c  °o  ' K  /  e  / \  N  R"  R  506 equivalents, t h i s same s h i f t occurs.  R'  509 I t i s therefore not s u r p r i s i n g  that a weaker base l i k e p y r i d i n e can cause p a r t i a l deprotonation  that  leads to n o t i c e a b l e product changes when approximately t h i r t y or more excess equivalents of p y r i d i n e are employed.  The preceding  explanation  i n d i c a t e s why the Sarett o x i d a t i o n i s both catalyzed and poisoned by p y r i d i n e and why the o x i d a t i o n rates are observed to be very slow i n the Sarett r e a c t i o n . An experiment p a r t i c u l a r l y relevant to the t o p i c of base-acid e f f e c t s on the C o l l i n s o x i d a t i o n was provided by g . l . c . monitoring of the o x i d a t i o n of 33-hydroxyandrost-5-ene.  When t h i s s t e r o l (1.0  mmole) was added to dipyridine-chromium(VI) oxide (6.0 mmoles) and proton sponge (0.3 mmoles), the o x i d a t i o n gave a 1:1 mixture of s t a r t i n g m a t e r i a l to cholest-5-en-3-one w i t h i n f i f t e e n minutes.  This  r a t i o remained unchanged u n t i l a c e t i c a c i d (3.5 mmoles) was added. Within t h i r t y minutes, no s t e r o l chould be detected  and the usual  product mixture of cholestenone and cholestenedione  was obtained on  workup.  -  Corey O x i d a t i o n s o f  183  -  Cholesterol  At t h i s p o i n t , a s h o r t study of i n t r o d u c e d by Corey and F l e e t r e p o r t e d t h a t a 1:1  i n 1973  2.5:1  as a s u i t a b l e  to c a r b o n y l compounds (232 ) .  In one of  T h i s reagent was c o n s e q u e n t l y were t a b u l a t e d  i n Table V I .  after  They  3,5-dimethyl-  reagent  for  oxidizing  t h e i r examples,  mole r a t i o o f complex to 4 - _ t - b u t y l c y c l o h e x a n o l  y i e l d 98% 4 - t - b u t y l c y c l o h e x a n o n e  Table VI  s h o u l d be c o n s i d e r e d .  complex of chromium t r i o x i d e —  pyrazole i n dichloromethane serves alcohols  the g e n e r a l o x i d a t i v e method  a  was found to  t h i r t y minutes a t room temperature.  employed on c h o l e s t e r o l and the I n the s t a n d a r d o x i d a t i o n ,  results  cholesterol  Chromium Trioxide -Dimethylpyrazole Oxidation of Cholesterol in Dichloromethane ("Corey")  Reaction-Changes  Oxidant/Alcohol Mole Ratio  Average Product Ratio 334; 480 (%331)  1  Standard  3  50:50  2  Standard  2  52 :48 (35%)  3  Standard  .1  45 .55 (65%)  4  Reaction at 0°  3  60 :40 (37%)  5  Reaction under Nitrogen  3  59 :41  (26%)  6  Water(2mmole) Addition  3  50:50  (25%)  7  1,8-Bis(dimethylamino)naphthalene(05 mmole) 3  38 :62 (90%)  8  Triethylamine (1.0 mmole)  40 :60 (49%)  Notes  3  (20%)  a For details see Androstenone 240 experimental, section (ii) of (c).  -  184  -  (1.0 mmole) i n d i c h l o r o m e t h a n e s o l u t i o n (50 ml) was t r e a t e d minutes at  room temperature w i t h the i n d i c a t e d amounts of  (1.0,  or 3.0 mmoles).  2.0,  The r e s u l t s  indicate  that  for  oxidant  the Corey  p r o c e d u r e i s more comparable to the Snatzke o x i d a t i o n than to Collins.  There i s no p r e c i p i t a t i o n of  chromium s a l t s  i n the  p y r a z o l e r e a c t i o n and the a d d i t i o n of water has l i t t l e efficiency  o r outcome of  s y n o p s i s .of the r e s u l t s  Table V  effect  the dimethylon the  Also while Table V, with  its  of p e r f o r m i n g C o l l i n s and Corey r e a c t i o n s on  Oxidations with Chromium Trioxide-Nitrogen Base Reagents. Oxidation Conditions (%Mass Recovery)  Compound " 0  Cholest-5-en-3-one (334) II  b  3  (99%)  4 7 8 : 4 8 0 (% 334)  0  (70%) (66)  Standard Collins Collins without C r 0  c  b  2 : 98  (15 %)  - : -  (100%)  5:95  (45%)  100: 0  (98 %)  II  Standard Corey  (77 % )  II  Corey without CrOa  (94%)  Standard Collins  (96%)(75%)  Standard Corey  (74%) ( 6 9 % )  Standard Collins  (92%)(85%)  c  96: 4  Standard Corey  (85%)(78%)  c  93:7  Cholest-4-ene-3,6-dione 14_8_Q). II  Cholest-4-en-3-one II  Notes  the o x i d a t i o n .  thirty  (478)  b  b  0 : 100  c  c  0:100  Non-acidic materia! isolated after oxalic acid isomerization except for 334 . Neutral workup employed (NaHC0). Quantitative measurement with internal standard. ^ For details see Androstenone experimental (c) (ii).  b  3  c  -  cholest-5-en-3-one, illustrates  complex  and  cholest-4-ene-3,6-dione  causes l i t t l e  the Corey o x i d a t i v e  of b o t h c h o l e s t - 5 - e n - 3 - o n e is  -  cholest-4-en-3-one  that dimethylpyrazole  cholest-5-en-3-one,  pyrazole  185  i s o m e r i z a t i o n of  complex g i v e s e x t e n s i v e  and c h o l e s t - 4 - e n e - 3 , 6 - d i o n e .  o n l y a weak a c i d by e q u i l i b r i u m (o) below,  , f o r m u l a t e d as 512,  oxidation  Dimethylbut  the  oxidant  s h o u l d be a much b e t t e r p r o t o n s o u r c e  for  the e n o l i z a t i o n of compound 334. From the p o i n t of view of h o m o a l l y l i c a l c o h o l o x i d a t i o n ,  Corey's  79 ' p r o c e d u r e can be d i s m i s s e d ,  since,  c o l o u r e d p r o d u c t m i x t u r e tends plus substantial  as 512.  to be a 1:1  the  The o x i d a t i o n was  molecular course depicted  thought i n 513  complex c o u l d be  the o x i d a n t  in  Corey and F l e e t represented  to proceed by the c y c l i c ,  after  enedione  However the r e s u l t s  from a m e c h a n i s t i c v i e w p o i n t .  t h a t the 3 , 5 - d i m e t h y l p y r a z o l e  highly  r a t i o of enone to  amounts of r e c o v e r e d s t e r o l .  T a b l e VI a r e v e r y u s e f u l postulated  from T a b l e V I ,  intra-  complex 512  had  combined w i t h an a l c o h o l to form the chromate e s t e r complex 513 (232 ) . 79 Other r e c e n t p r o c e d u r e s can a l s o be d i s m i s s e d . Halogen a t t a c k on the double bond e l i m i n a t e s o x i d a t i o n s by bromine and s i l v e r salts (246 ), 1-chlorobenzotriazole (246^), the d i m e t h y l s u l f o x i d e c h l o r i n e complex ( 2 4 6 ) and the d i m e t h y l s u l f i d e - c h l o r i n e complex (246^). Oxidations with sulfoxonium s a l t s ( 2 4 6 ) , s u l f u r t r i o x i d e (246^) or chromic a c i d i n d i m e t h y l s u l f o x i d e at 70° (240) do not appear to compare f a v o u r a b l y w i t h the C o l l i n s or Snatzke o x i d a t i o n s . a  c  e  -  186  -  ,N—Cr—OH  513 512 This postulated i n Table VI. if  anything,  b e h a v i o u r of  R o x i d a t i v e mechanism appears u n t e n a b l e from the  The a d d i t i o n of a base such as t r i e t h y l a m i n e s h o u l d , enhance the f o r m u l a t e d o x i d a t i o n , not r e s t r i c t 1,8-bis(dimethylamino)naphthalene  on the b a s i s of 513  also  is  of  the o x i d a t i o n i s  the chromate e s t e r ,  the e l e c t r o n d e f i c i e n c y  If of  The  How can  one m i l l i m o l e of  from b e i n g o x i d i