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UBC Theses and Dissertations

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

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SYNTHETIC STUDIES ON OCTALONES AND RELATED SYSTEMS BY PAUL MURRAY WORSTER B . S c . ( H o n s . ) , U n i v e r s i t y of B r i t i s h Columbia, 1967 A THESIS SUBMITTED IN PARTIAL FULFILMENT OF THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY i n the Department of CHEMISTRY i We accept t h i s t h e s i s as conforming to the r e q u i r e d standard THE UNIVERSITY OF BRITISH COLUMBIA December, 1975 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 requirements f o r an advanced degree at the U n i v e r s i t y of B r i t i s h Columbia, I agree that the L i b r a r y s h a l l make i t f r e e l y a v a i l a b l e f o r re ference and study. I f u r t h e r agree t h a t permiss ion for e x t e n s i v e copying o f t h i s t h e s i s f o r s c h o l a r l y purposes may be granted by the Head o f my Department or by h i s r e p r e s e n t a t i v e s . I t i s understood that copying or p u b l i c a t i o n o f t h i s t h e s i s f o r f i n a n c i a l ga in s h a l l not be a l lowed without my w r i t t e n p e r m i s s i o n . Department of Cfl The U n i v e r s i t y of B r i t i s h Columbia 2075 Wesbrook Place Vancouver, Canada V6T 1W5 - i i -ABSTRACT T h i s t h e s i s d e s c r i b e s a number of i n v e s t i g a t i o n s that culminated i n an improved s e r i e s of p r a c t i c a l p r e p a r a t i o n s f o r s u b s t i t u t e d o c t a l o n e s . S t a r t i n g w i t h a study of a c i d and base c a t a l y z e d a d d i t i o n s of methyl v i n y l ketone to 2-methylcyclohexanone, the p r e p a r a t i o n of 4 a - m e t h y l - 4 , 4 a , 5 , 6 , 7 , 8 - h e x a h y d r o - 2 ( 3 H ) - n a p h t h a l e n o n e (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 that s e q u e n t i a l l y employed both a c i d and base. The advantages of t h i s e f f i c i e n t procedure were then demonstrated by the p r e p a r a t i o n of t r a n s - 4 a , 8 - d i m e t h y 1 - 4 , 4 a , 5 , 6 , 7 , 8 -hexahydro-2(3H)-naphthalenone (235) from 2,6-dimethylcyclohexanone and methyl v i n y l ketone. S e v e r a l approaches to t r a n s - 8 - a c e t o x y - 4 a - m e t h y l - 4 , 4 a , 5 , 6 , 7 , 8 -hexahydro-2(3H)-naphthalenone (236) were then undertaken. An e f f i c i e n t two step c o n v e r s i o n of octalone 234 to 8 , 8 a - e p o x y - 2 , 2 - e t h y l e n e d i o x y -4 a - m e t h y l - 4 , 4 a , 5 , 6 , 7 , 8 - h e x a h y d r o - 2 ( 3 H ) - n a p h t h a l e n o n e (284) was fol lowed by an a c i d h y d r o l y s i s which afforded both 8 6 , 8 a a - d i h y d r o x y - 4 a 3 - m e t h y l -4 , 4 a , 5 , 6 , 7 , 8 - h e x a h y d r o - 2 ( 3 H ) - n a p h t h a l e n o n e (292) and the u n d e s i r e a b l e 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 thalenedione (294). The p h o t o s e n s i t i z e d oxygenation (^C^) of 4 a - m e t h y l - 3 , 4 , 4 a , 5 , 6 , 7 -hexahydro-2(lH)-naphthalenone (341), prepared i n 96% from 234, was accomplished w i t h Rose Bengal i n p y r i d i n e or methanol and afforded 4 a - m e t h y l - 3 , 4 , 4 a , 5 - t e t r a h y d r o - l ( 2 H ) , 7 ( 6 H ) - n a p h t h a l e n e d i o n e (343), r a t h e r than the expected Y ~ p e r a c e t a t e , 4 a - m e t h y l - 8 - p e r a c e t o x y - 4 , 4 a , 5 , 6,7,8-hexahydro-2(3H)-naphthalenone (344), when a c e t y l a t i o n of the product was attempted. Reduction of the i n t e r m e d i a t e Y ~ h y c l r o P e r o x i c l e - i i i -(342) before a c e t y l a t i o n afforded compound 236 i n low y i e l d . T h i s 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 c i s - 4 a - m e t h y l - 3 , 4 , 4 a , 5 , 6 , 7 , 8 , 8 a - d e c a h y d r o - 2 ( l H ) - n a p h t h a l e n o n e (349 and 350), the dione 294, 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 (353). The octalone 237, 4 a , 8 , 8 - t r i m e t h y l - 4 , 4 a , 5 , 6 , 7 , 8 - h e x a h y d r o - 2 ( 3 H ) -naphthalenone, was s y n t h e s i z e d i n an e f f i c i e n t seven step sequence that employed the n - 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. Octalone 234 was converted i n two steps to i t s 3 - n - b u t y l t h i o m e t h y l e n e d e r i v a t i v e (375). 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 3 - n - b u t y l -t h i o m e t h y l e n e - 1 , 1 , 4 a - t r i m e t h y l - 3 , 4 , 4 a , 5 , 6 , 7 - h e x a h y d r o - 2 ( I H ) - n a p h t h a l e n o n e (376) and then unblocked by exhaustive h y d r o l y s i s to a f f o r d 1 ,1 ,4a-t r i m e t h y l - 3 , 4 , 4 a , 5 , 6 , 7 - h e x a h y d r o - 2 ( l H ) - n a p h t h a l e n o n e (356). Successive W o l f f - K i s h n e r r e d u c t i o n of 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 , 4 a - t r i m e t h y l - l , 2 , 3 , 4 , 4 a , 5 , 6 , 7 - h e x a h y d r o n a p h t h a l e n e (357), w i t h sodium chromate af forded the d e s i r e d o c t a l o n e 237. C i s - and _ t r a n s - 4 a , 5 - d i m e t h y 1 - 4 , 4 a , 5 , 6 , 7 , 8 - h e x a h y d r o - 2 ( 3 H ) -naphthalenone (238 and 239) were both prepared as pure compounds by employing a sequence that o r i g i n a t e d from 2,3-dimethylcyclohexanone. A l k y l a t i o n of the n - b u t y l t h i o m e t h y l e n e d e r i v a t i v e , 6 - n - b u t y l t h i o m e t h y l e n e -2,3-dimethylcyclohexanone (400), was s t u d i e d to determine the s t e r e o -chemical e f f e c t of a l k y l a t i n g agent, s o l v e n t and base. C o n t r o l of the s t e r e o s e l e c t i v i t y was demonstrated to be p r i m a r i l y dependent on the choice of a l k a l i metal c a t i o n . The most p r a c t i c a l means of producing the c i s - v i c i n y l d i m e t h y l d e r i v a t i v e , c i s - 2 , 3 - d i m e t h y 1 - 2 ( 2 - e t h o x y c a r b o n y l -e t h y l ) - 6 - i i - 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 (415), employed e t h y l - 3 -c h l o r o - or bromopropionate as a l k y l a t i n g agent w i t h potassium j^-butoxide - i v -i n _t-butanol whereas one of the most favourable means of o b t a i n i n g the t r a n s - v i c i n y l d i m e t h y l d e r i v a t i v e , t r a n s - 2 , 3 - d i m e t h y l - 2 ( 2 - e t h o x y c a r b o n y l -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 (416) employed l i t h i u m _t-butoxide i n t - b u t a n o l . H y d r o l y s i s of 415 and 416 then y i e l d e d the keto a c i d s c i s - 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 ( 417 and 418). These compounds were r e a d i l y dehydrated to t h e i r correspound-i n g e n o l l a c t o n e s , c i s - and t r a n s - 4 a , 5 - d i m e t h y l - l - o x a-*3 , 4 , 4 a , 5 , 6 , 7 -hexahydro-2(lH)-naphthalenone (419 and 420). R e c r y s t a l l i z a t i o n of t h i s mixture gave the c i s - d i m e t h y l e n o l l a c t o n e 419 i n pure form. The more e l u s i v e trans isomer r e q u i r e d s u c c e s s i v e s i l i c a chromatographies, h y d r o l y s i s of the impure trans e n o l l a c t o n e and c r y s t a l l i z a t i o n of the pure t r a n s keto a c i d (418) w i t h subsequent d e h y d r a t i o n to the e n o l l a c t o n e . Treatment of 419 and 420 w i t h m e t h y l l i t h i u m at -25° y i e l d e d c i s - 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 (440a and 440b) which, a f t e r base treatment, a f f o r d e d 238 and 239. A study o f the product 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 s t e r e o -isomerism played a h i t h e r t o unrecognized r o l e . For example, an 84:16 r a t i o o f e n o l l a c t o n e s 419 and 420 y i e l d e d an o c t a l o n e r a t i o of 95:5 (238:239). A u t h e n t i c octalone 239 was a l s o prepared i n an unambiguous manner by an e i g h t step sequence from o c t a l o n e 234. Dehydrogenation of 234 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 conjugate a d d i t i o n w i t h l i t h i u m dimethylcuprate gave t r a n s - 4 , 4 a - d i m e t h y 1 - 4 , 4 a , 5 , 6,7,8-hexahydro-2(3H)-naphthalenone (381). Deconjugation of 381 gave 467, t r a n s - 4 , 4 a - d i m e t h y l - 3 , 4 , 4 a , 5 , 6 , 7 - h e x a h y d r o - 2 ( l H ) - n a p h t h a l e n o n e , h y d r i d e r e d u c t i o n of 467 y i e l d e d 468, t r a n s - 4 , 4 a - d i m e t h y l - 2 - h y d r o x y -- V -1,2,3,4,4a,5,6,7-octahydronaphthalene ., a c e t y l a t i o n of 468 and subsequent a l l y l i c o x i d a t i o n w i t h chromic anhydride gave t r a n s - 4 a , 5 - d i m e t h y l - 7 -a c e t o x y - 4 , 4 a , 5 , 6 , 7 , 8 - h e x a h y d r o - 2 ( 3 H ) - n a p h t h a l e n o n e (470). Dehydro-a c e t y l a t i o n of 470 produced the dienone 471, t r a n s - 4 a , 5 - d i 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 , and s e l e c t i v e hydrogenation gave octalone 239. A n d r o s t - 4 - e n - 3 - o n e (240) was prepared as the r e s u l t of two s t u d i e s on o x i d a t i o n and r e d u c t i o n procedures. In the f i r s t s t u d y , 38-hydroxy-androst-5-en-17-one (473) was n e a r l y q u a n t i t a t i v e l y reduced v i a the W o l f f - K i s h n e r 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 of c o n d i t i o n s to ' o c t a l o n e ' 240. T h i s work l e d to new i n s i g h t s i n t o the mechanism of 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. M e c h a n i s t i c e x p l a n a t i o n s from s t u d i e s on c h o l e s t e r o l 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 to other systems a r e g i v e n . In the second route to ' o c t a l o n e ' 240, t e s t o s t e r o n e (472) was converted i n t o a s e r i e s of C-3 d e r i v a t i v e s of a n d r o s t - 4 - e n e -3,17-dione (562). These i n c l u d e d the methoxy (602), ethylenedioxy (563), t r i m e t h y l e n e d i o x y (619), e t h y l e n e d i t h i o (598 ;), t r i m e t h y l e n e d i t h i o (600), 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 (594) d e r i v a t i v e s . The W o l f f - K i s h n e r r e d u c t i o n products from these compounds were s t u d i e d and p l a u s i b l e mechanisms were formulated. 24Q - v i i -343 A-Enedione R 341 R = H 467 R = C H 3 375 Y = CHSBun 376 X = 0, Y=CHSBun 356 X=0, Y=H2 357 X = Y=H2 Et02C • c r ^ o 419 R ^ C H g , R 2 = H 4 2 0 R,= H , R 2 = C H 3 4 6 8 X = H 2 , R = H 469 X = H 2 , R = C0CH3 470 X =0, R=C0CH3 562 - v i i i -TABLE OF CONTENTS Page TITLE PAGE . . i ABSTRACT . i i TABLE OF CONTENTS . . . . . v i i i LIST OF FIGURES, CHARTS, AND TABLES . . . . . . x ACKNOWLEDGEMENTS . , . * x i i INTRODUCTION . . . . . . 1 I. General . . . . . . . . . . . . 1 II . Approaches to Ster e o s e l e c t i v e Hydroazulene Synthesis 12 II I . Approaches to Ste r e o s e l e c t i v e Spirane Synthesis . . . . . . . . . 30 DISCUSSION . . . . . . . . . . . . 49 I. General Development of the Reaction i Sequence . . . . . . . . . . . . 49 II. Synthesis of a,B-Unsaturated Hydronaphthalenone Derivatives . . . . . . . . . . . 52 A. Octalone 234 (4a-Methyl-4,4a,5,6,7,8-hexahydro-2(3H)-naphthalenone) . . . . . . . 56 - ix -TABLE OF CONTENTS DISCUSSION, I I Continued. Page B. Octalone 235 (4a,~8a-Dimethyl-4,4a,5,6,7,8-hexahydro-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,5,6,7,8-hexahydro-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-Hydroxy-androst-5-en-17-one (473) . . . . . . . . 138 Androstenone 240 from Testosterone (472) . . . 199 EXPERIMENTAL 229 i EXPERIMENTAL TABLE OF CONTENTS 302 BIBLIOGRAPHY 3 0 3 APPENDIX I 321 APPENDIX II 354 - x -LIST OF FIGURES, CHARTS, AND TABLES Page CHART I SESQUITERPENE BIOSYNTHESIS 2 CHART I I CYCLOPROPYL KETONES FROM INTRAMOLECULAR KETO-CARBENE 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 400 120 TABLE I I PRODUCT DISTRIBUTION OBTAINED BY METHYLLITHIUM TREATMENT OF ENOL LACTONES 127 TABLE I l i a CHROMIUM TRIOXIDE OXIDATION OF CHOLESTEROL IN DIMETHYLFORMAMIDE 154, 163 TABLE I l l b SNATZKE OXIDATIONS OF CHOLESTEROL OXIDATION PRODUCTS 156 TABLE IVa CHROMIUM TRIOXIDE-PYRIDINE OXIDATION OF CHOLESTEROL IN DICHLOROMETHANE ("COLLINS") . . . 168 i TABLE IVb PYRIDINE DEPENDENCE OF COLLINS OXIDATION OF CHOLESTEROL 175 TABLE IVc INFLUENCE OF AMINE BASES ON THE COLLINS OXIDATION OF CHOLESTEROL 180 TABLE V OXIDATION WITH CHROMIUM TRIOXIDE-NITROGEN BASE REAGENTS , 169, 184 - xi -LIST OF FIGURES, CHARTS, AND TABLES TABLE VI CHROMIUM TRIOXIDE-DIMETHYLPYRAZOLE OXIDATION OF CHOLESTEROL IN DICHLOROMETHANE ("COREY") . TABLE VII EFFECT OF p K ^ ON "COLLINS" OXIDATION OF CHOLESTEROL . . . . TABLE VIII REDUCTION OF ANDROST-4-ENE-3,17-DIONE AND ITS C-3 DERIVATIVES BY THE BARTON MODIFICATION OF THE WOLFF-KISHNER REDUCTION Page 183 188 222 i - x i i -ACKNOWLEDGEMENTS I wish to express my s i n c e r e thanks to D r . Edward P i e r s for the p a t i e n c e shown, and the encouragement g i v e n , d u r i n g the p e r i o d of my graduate s t u d i e s . H i s i n v a l u a b l e advice and e n l i g h t e n i n g d i s c u s s i o n s throughout the course 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 of t h i s t h e s i s a r e a p l e a s u r e to acknowledge. My experimental work has been the b e n i f i c i a r y of many i n f o r m a l d i s c u s s i o n s and p r a c t i c a l suggestions r e s u l t i n g from the g e n e r a l i n t e r e s t shown by a l l the present and past members of D r . P i e r s ' r e s e a r c h group. I would a l s o l i k e to acknowledge the help of v a r i o u s members of our c l o s e s t neighbour, Dr. Kutney's group. The work of Miss 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 typing has added immeasureably to the appearance of t h i s t h e s i s . The encouragement of my w i f e , E l i z a b e t h , i n the completion of t h i s work was t r u l y tested by her proof reading of the e n t i r e ma nu script . 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 d u r i n g the course of the p r e p a r a t i o n of t h i s t h e s i s i s only exceeded by E l i z a b e t h ' s p a t i e n c e . The f i n a n c i a l support of the N a t i o n a l Research C o u n c i l of Canada (1968-1971) i s g r a t e f u l l y acknowledged. - 1 -STUDIES RELATED TO THE TOTAL SYNTHESIS OF SESQUITERPENES INTRODUCTION I. General The application of modern a n a l y t i c a l techniques to naturally occurring o i l s and plant extracts has demonstrated the widespread occurrence of the terpenoid family of compounds i n trees and shrubs. B i o l o g i c a l l y , the derivation of these terpenoids commences with the common biochemical unit acetyl CoA and proceeds through mevalonic acid and the subsequently formed isoprene or polyisoprene pyrophosphate to mono-(C 1 0)-, s e s q u i - ( C 1 5 ) - , d i - ( C 2 Q ) - , sester-(C 2 5>-, or t r i - ( C 3 Q ) -terpenes (1). The incomplete relationship between head-tb-tail linkages of isoprene units (4) (2) and the wide s t r u c t u r a l variations observed i n the terpenoids isol a t e d gave r i s e to the Biogenetic Isoprene Rule (3) by Ruzicka, Eschenmoser, Jeger, and Arigoni i n 1955, postulating the p o s s i b i l i t y of rearrangement of the polyisoprene intermediates. As the largest and most varied group of terpenoids, the sesquiterpenes provided the most demanding tests of these concepts. The biogenetic correl a t i o n of several sesquiterpenes was considered by Hendrickson i n 1959 (4) and l a t e r reviewed comprehensively by Parker, Roberts and Ramage i n 1967 (5). Confirmation of the general biosynthetic route for sesquiterpene formation from acetyl 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 S E S Q U I T E R P E N E BIOSYNTHESIS Acetyl C o A a O II C H , C — S C o A o OH 1 Mevalonic Acid OPP Isopentyl Pyrophosphate Isoprene unit Geranyl Pyrophosphate *- Monoterpenes OPP Farnesyl Pyrophosphate Sesquiterpenes OPP a Acetyl Coenzyme A is NH2 < O H CH 3 O N I I II f\j CH,- C- S-(CH J_ N-C- (CH_)p—N—C—C—C—CH5-(OP—), OCH2 J < - I . 11 *~ 11 II I I *- I c- I H IIO H   IO OHCH3 , O—P —O OH I OH - 3 -and t h i s subject has been reviewed by Clayton ( 6 ) . The postulated, and i n some cases v e r i f i e d , r e l a t i o n s h i p of trans- or c i s - f a r n e s y l pyro-phosphate to the d i f f e r e n t sesquiterpene classes completes a t h e o r e t i c a l understanding of the biochemical o r i g i n of sesquiterpenes ( 5 ) . The b i o l o g i c a l r o l e of sesquiterpenes i s s t i l l l i t t l e understood, although several classes appear to be e s s e n t i a l to both plants and animals. Plant growth regulators include graphinone ( 8 ) , a germination stimulant for l e t t u c e seeds i n the dark at a concentration of l e s s than one 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), an inducer of dormancy i n a number of plant species and a promoter of l e a f a b s c i s i o n ( 8 ) , and vernolepin (10), a more recently discovered growth i n h i b i t o r (9).^ The structures shown i n t h i s thesis do not n e c e s s a r i l y depict the absolute c o n f i g u r a t i o n . When the absolute configuration i s relevant 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 placed before i t s name. On t h i s basis j? and 9_ could be l i s t e d as (-)-graphinone and (+)-abscisic a c i d , although IUPAC nomenclature, such as S-(+)-abscisic acid, would be b e t t e r . The t o t a l synthesis of sesquiterpenes, however, i s u s u a l l y racemic, providing a 1:1 mixture of both enantiomers. A b s c i s i c a c i d , 9_, could then be used to represent both the n a t u r a l l y occurring (+)-abscisic a c i d and a racemic synthetic mixture, (+)-abscisic a c i d , where the other enantiomer i s understood to be present, depending on the content of the discussion. For the most part of t h i s t h e s i s , r e l a t i v e configurations, rather than absolute, are emphasized. Sometimes absolute configurations are e s s e n t i a l , as i n the discussion of the absolute c o n f i g u r a t i o n a l homogeneity r u l e (Appendix I ) , where the occurrence i n d i f f e r e n t species of a few (+) and (-) antipodal sesquiterpenes i s an important b i o s y n t h e t i c feature. S i r e n i n (11), a t t r a c t i n g sperm to the female gametes of the water mold Allomyces at c o n c e n t r a t i o n s of 10 L® M (10), was the f i r s t p l a n t sex hormone to be d i s c o v e r e d . The C o c h l i o b o l u s s a t i v u s (Helminthosporium sativum) fungus causes s e e d l i n g b l i g h t and l e a f spot through the t o x i n h e l m i n t h o s p o r a l (12, R= -CHO) (11), w h i l e h e l m i n t h o s p o r o l (12, R= -CH^OH) (-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 . The i n s e c t j u v e n i l e hormone a c t i v i t y of (+)-juvabione (13) and c e c r o p i a j u v e n i l e hormone ( C 1 Q J . H . = 14) has been recognized to have s e v e r a l l b — b i o l o g i c a l a p p l i c a t i o n s (13) as does the i d e n t i f i c a t i o n of degraded farnesanes among the i n s e c t pheromones of b u t t e r f l i e s (15, R = -COOH) (14) and bees (2 , 3 - d i h y d r o - 6 - t r a n s - f a r n e s o l ) (15). - 5 -The study of these and other b i o l o g i c a l l y important sesquiterpenes has been somewhat 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 to chemical i s o l a t i o n from the very complex mixtures that c o n t a i n these compounds i n minute amounts. The same d i f f i c u l t i e s are a l s o apparent to a l e s s e r extent i n the d i s c o v e r y of a c y c l i c , m o n o c y c l i c , b i c y c l i c , t r i c y c l i c , or t e t r a c y c l i c sesquiterpene hydrocarbons, ketones, epoxides, a l c o h o l s , e t h e r s , a c i d s , or e s t e r s i n e s s e n t i a l o i l s of p l a n t s . However, i n some cases the compound i s o l a t e d i s not a n a t u r a l l y o c c u r r i n g sesquiterpene but an a r t i f a c t of i s o l a t i o n . For example, n e i t h e r h e l m i n t h o s p o r a l nor h e l m i n t h o s p o r o l are present i n the u n p u r i f i e d e x t r a c t of Helminthosporium sativum and only appear on h e a t , a c i d , or base treatment of t h e i r corresponding a c e t a l s i n the crude e x t r a c t (11). The Cannizzaro r e a c t i o n , the d i s p r o p o r t i o n a t i o n of an aldehyde to i t s corresponding a c i d and a l c o h o l , appears to be the most common s i d e r e a c t i o n o c c u r r i n g d u r i n g i s o l a t i o n . In the cedrane c l a s s of s e s q u i -t e r p e n e s , j a l a r i c a c i d B (16) i s the p r e c u r s o r of e p i s h e l l o l i c a c i d (17) and e p i l a k s h o l i c a c i d (18), a l l three of which ' c o - o c d u r ' (16), w h i l e l a c c i j a l a r i c a c i d (19) would be expected to g i v e l a c c i s h e l l o l i c a c i d (20) and e p i l a c c i s h e l l o l i c a c i d (21) (both i s o l a t e d ) and the corresponding a l c o h o l s (not yet r e p o r t e d ) . The very r e c e n t l y r e p o r t e d - 6 -(May, 1972) i s o l a t i o n of seven new cedrane d e r i v a t i v e s (17) a l s o suggests 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^, while the a l c o h o l 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 25. The 2 2 R=-CHO , 2 5 R=-CHO 2 3 R=-CH2OH 2 6 R = -CH2OH 2 4 R = -COOH i s o l a t i o n o f v a l e r e n a l (27) and v a l e r e n i c a c i d (28) (18), or the drimanes of g e n e r a l s t r u c t u r e 29^ , JiO and (19), from the same p l a n t suggests the p o s s i b i l i t y of a Cannizzaro r e a c t i o n . I t i s somewhat cl s u s p i c i o u s too that only thujopsenol (32) (20 ) and h i n o k i i c a c i d (33) - 7 -CHO 3 0 31 (20 ) are known, and that only cyclocopacamphenol (34) (21 ) and cyclocopacamphenoic a c i d (35) (21 b ) are known, w h i l e t h e i r corresponding aldehydes have not been i s o l a t e d . In a d d i t i o n , many of the n a t u r a l l y o c c u r r i n g sesquiterpene a l c o h o l s and a c i d s occur as e s t e r s , but t h e i r s u c c e s s f u l i s o l a t i o n r e q u i r e s d i s r u p t i v e t e c h n i q u e s . In the case of furoventalene (36), 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 i s not known i f thermal or s o l v o l y t i c e l i m i n a t i o n i s o c c u r r i n g (22). A l s o s i g n i f i c a n t i s the i s o l a t i o n of, the germacrane h e d y c a r y o l (37) by e x t r a c t i o n of Hedycarya a u g u s t i f o l i a leaves at room temperature, whereas the elemane a r t i f a c t elemol (38) i s produced by steam d i s t i l l a t i o n (23). - 8 -37 3 8 The complexity of the i s o l a t e d m u l t i f u n c t i o n a l sesquiterpene can be e x e m p l i f i e d by melampodin (39), 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 c l a s s i c a l methods and an n . m . r . s h i f t reagent (24), w h i l e a second group confirmed these f i n d i n g s by X - r a y a n a l y s i s (25) . The success of both c a r e f u l 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 techniques i s demonstrated by the r a p i d growth i n the number of d i f f e r e n t sesquiterpene carbon s k e l e t o n s . These d i f f e r e n t types of sesquiterpenes were reviewed ten - 9 -years ago by Sorm e_t al^. (26) when t h e i r survey l i s t e d twenty-eight c l a s s e s , seven of which have subsequently 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 . The c o l l e c t i o n of sesquiterpene data by O u r i s s o n ejt a l . i n 1966 (27) gave over f o r t y d i f f e r e n t sesquiterpene s k e l e t a l types, while the c o m p i l a t i o n completed d u r i n g the course of t h i s t h e s i s 2 p r o v i d e d a l i s t of almost n i n e t y d i f f e r e n t s e s q u i t e r p e n e c l a s s e s . The r a p i d aging of 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 suggests that more frequent reviews should be made. I t i s t h i s c l a s s growth, however, with the concomitant f u n c t i o n a l v a r i a t i o n of the c l a s s members that makes sesquiterpenes p r o v i d e not o n l y demanding t e s t s of b i o g e n e t i c r e l a t i o n s h i p s , but a l s o v e r y c h a l l e n g i n g problems to s y n t h e t i c o r g a n i c c h e m i s t r y . The s y n t h e t i c work that mimics the b i o g e n e t i c route has widespread i n t e r e s t , but the c l a s s i c a l concepts of s t r a i n and s t e r i c i n t e r a c t i o n s are not n e c e s s a r i l y the dominant f a c t o r s i n b i o g e n e t i c schemes, s i n c e here the s u b s t r a t e w i l l concur w i t h the c o n f i r m a t i o n a l demands of the p a r t i c u l a r enzyme i n v o l v e d . A s u c c e s s f u l t o t a l s y n t h e s i s , t h e r e f o r e , generates a requirement f o r a s imple s t e r e o s e l e c t i v e sequence which f u l l y c o r r o b o r a t e s 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 made to the p a r t i c u l a r s e s q u i t e r p e n e . The r a p i d advances made i n s y n t h e t i c approaches to the t o t a l s y n t h e s i s of sesquiterpenes r e q u i r e that i n t h i s area a l s o more 3 frequent and more e x t e n s i v e l i t e r a t u r e reviews by undertaken. 2 The d i f f e r e n t c l a s s e s of sesquiterpenes have been l i s t e d i n Appendix I to p r o v i d e an up=to-date survey of 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 iven. 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 updating 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 of the g e n e r a l i z e d approaches to sesquiterpene s y n t h e s i s i s , t h e r e f o r e , presented i n Appendix I I . - 10 -S y n t h e t i c s t r a t e g i e s f o r s e s q u i t e r p e n e s y n t h e s i s o f t e n r e q u i r e an e f f i c i e n t method of transforming d e c a l i n i c compounds i n t o l e s s 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 , t h i s s t r a t e g y o f t e n 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 the t e c h n i c a l i n f o r m a t i o n r e q u i r e d . The p r e p a r a t i o n s of cyclodecadienes and cyclodecadiene d e r i v a t i v e s are an example of t h i s approach. As d i s c u s s e d i n the review of s e s q u i t e r p e n e s y n t h e t i c approaches to be found i n Appendix II of t h i s t h e s i s , germacranes are d i f f i c u l t to o b t a i n s y n t h e t i c a l l y and are r e a d i l y i s o m e r i z e d to elemanes. The r e c e n t use of h e t e r o l y t i c boronate fragmentation of a d e c a l i n i c mesylate (40,A = a - H , B = &-B0 H 2 , X = - S 0 2 C H 3 ( - Ms), R = H) (29) or the i n t r a -m o l e c u l a r e l i m i n a t i o n o f a d e c a l i n i c y - d i o l a c e t a t e (40, A = 3 - 0 H , B = H, X = - C 0 C H 3 ( - A c ) , R = 1 , 1 - ( C H 3 ) 2 ) (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 cleavage product (41) r a t h e r than the p e r i p h e r a l cleavage one (42). However the n e c e s s i t y o f f u r t h e r s t u d i e s on model systems i s emphasized by the very r e c e n t l y r e p o r t e d dependence of 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 - ( C H 3 ) 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 cyclodecadiene 41, 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 , 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 78-hydroxyl afforded only the elemene d e r i v a t i v e 42_ - 11 -(R' = CH^CHO), the peripheral cleavage product (31). Before considering, s p e c i f i c a l l y , the development of methods to convert decalinic compounds to hydroazulene or spirane systems, the stereorational approach developed by Heathcock e_t a l . for guaiazulenic sesquiterpenes (32-34) should be considered. This group's synthetic strategy of (a) constructing an appropriately functionalized d e c a l i n i c intermediate, (b) establishing the required r e l a t i v e stereochemistry of the eventual guaiazulene i n the decalin through established 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 decalinic intermediate to the desired hydroazulene actually represents the central theme of the work undertaken i n t h i s thesis. While the t h i r d part of the preceding strategy, the ring transformation process, i s a s o l v o l y t i c rearrangement i n Heathcock's work and a photochemical reaction i n the work described i n this thesis, 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 stereoselective conversion of readily available decalinic compounds to more unique ring systems. The completion of Heathcock's work not only presented a comprehensively planned study u t i l i z i n g model decalinic systems, (32) but also resulted i n the t o t a l synthesis of two guaiazulenic sesquiterpenes, a-bulnesene (44, from 43) 4 and bulnesol (46 from 45) (33), While the l a t t e r work may, at present, be of more interest to some, the very recently 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 decalinic tosylates under a variety of reaction conditions (34) offers ^ Other s o l v o l y t i c syntheses of these compounds and the analogously prepared kessane are outlined i n the 'eudesmane approach' i n Appendix I I . - 12 -an i n v a l u a b l e source of i n f o r m a t i o n f o r both future m e c h a n i s t i c s t u d i e s and future s y n t h e t i c work. I I . Approaches to S t e r e o s e l e c t i v e Hydroazulene Synthesis S e v e r a l p r e p a r a t i o n s o f hydroazulenes from c y c l o p e n t a n e , c y c l o -heptane, cyclodecane, hydrindane, and hydronaphthalene d e r i v a t i v e s have been r e p o r t e d , but only a few of these routes permit s t e r e o c h e m i c a l c o n t r o l to be e x e r t e d . The u t i l i z a t i o n of preformed cyclopentane or cycloheptane 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 5/7 fused r i n g system, w h i l e p e r t i n e n t to the p r e p a r a t i o n of azulenes (35), o f f e r s l i t t l e 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 of sesquiterpene s y n t h e s i s . M a r s h a l l and coworkers, i n two separate s t u d i e s , d i d f i n d , however, that s t e r e o s e l e c t i v e l y - f o r m e d hydroazulenes c o u l d be obtained from cyclopentane (36) and cycloheptane (37) d e r i v a t i v e s . In the f i r s t i n s t a n c e , the trimethylhydrindanone 47_ was converted to i t s oxime 4_8 and s o l v o l y t i c a l l y fragmented to the n i t r i l e s 49 and 50_ i n a 60:40 r a t i o by p_-toluenesulfonyl c h l o r i d e i n r e f l u x i n g p y r i d i n e (36). The c y c l o p e n t y l aldehyde _51, obtained by r e d u c t i o n of the unsaturated n i t r i l e 4_9_, was c y c l i z e d with s t a n n i c c h l o r i d e i n - 13 -CN 4 1 X=0 4 8 X = NOH 49 5 0 OH 51 E = Electrophile 5 2 benzene (or s i l i c a g e l ) to a f f o r d the b i c y c i o [5. 3. 0] decanol 52_ (4a-OH:48-OH i s 8 9 : 1 1 ) 5 i n n e a r l y q u a n t i t a t i v e y i e l d . M a r s h a l l ' s second method (37) used an a c i d - c a t a l y z e d a l d o l condensation of the c y c l o h e p t y l dione 5_3 to produce the s u b s t i t u t e d b i c y c i o [ 4 . 3.1]decenone e s t e r 54. While hydronaphthalene rind hydrindqne nomenclature provides the best d e s c r i p t i o n of 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 fol lowed for the other b i c y c l i c systems considered i n t h i s t h e s i s . In a l l cases where a numbered center i s considered 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 corresponding f i g u r e of the s t r u c t u r e . O0 2 Et 5 2 5 4 - 14 -T h i s compound was used to p r o v i d e both of the bridged a l c o h o l s 5_5 (a and b) by a r e d u c t i v e sequence. These compounds were s o l v o l y z e d as t h e i r methylsulfonates by treatment w i t h a c e t i c a c i d - s o d i u m a c e t a t e 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) i n 80% y i e l d . HO a R'= H, R"= CH 3  5 5 _b_ R'=CH3, R" = H Sfi. The f i r s t study by M a r s h a l l ' s group, undertaken to develop a s y n t h e t i c route to the v e t i v a n e carbon s k e l e t o n , was not pursued f u r t h e r a f t e r t h e i r d i s c o v e r y that v e t i v a n e s were spiremes (58) , not v e t i h y d r o a z u l e n e s (57) (36). The second sequence was developed i n t o a 57 5 2 . t o t a l s t e r e o s e l e c t i v e s y n t h e s i s of ( + ) - b u l n e s o l by s o l v o l y z i n g the a c e t o x y m e t h y l - s u b s t i t u t e d b i c y c l o [ 4 . 3 . l ] d e c a n o l mesylate 59 (38) to the b i c y c l o [ 5 . 3 . 0 ] d e c e n y l d e r i v a t i v e 60 and then e l a b o r a t i n g the l a t t e r 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 hydrindane to a hydroazulene ( 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 that w i l l be c o n s i d e r e d subsequently. However see a l s o Anderson's (36) recent p u b l i c a t i o n . - 15 -to ( + ) - b u l n e s o l (46). However, i n g e n e r a l , the r e q u i s i t e s u b s t i t u t e d 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 to p r e p a r e , and n e i t h e r approach allows 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 that are s y n t h e t i c a l l y d e s i r a b l e . ^ A n o n - s t e r e o s e l e c t i v e , b u t r e l e v a n t c y c l o -p e n t y l -> hydroazulene sesquiterpene s y n t h e s i s was r e c e n t l y r e p o r t e d f o r ( + ) - g u a i o l (66) u s i n g a b a s e - c a t a l y z e d r i n g cleavage of a b r i d g e d system (41). The M i c h a e l a d d i t i o n product j53, obtained from 2-methyl-cyclopentanone (61), 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 treatments to the t r i c y c l i c 1,5-endione 64. T h i s compound p r o v i d e d a 1:1 stereoisomer The f i r s t t o t a l s y n t h e s i s of p a t c h o u l i a l c o h o l ( i i i ) , a sesquiterpene b i o g e n e t i c a l l y r e l a t e d to the guaianes, 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 of a d e r i v a t i v e of the hydroazulene i i , obtained i n t u r n from a s u b s t i t u t e d 1 cycloheptanone' ( i ) , to p r o v i d e i i i . - 16 -mixture of the enone e s t e r 65_ a f t e r r i n g cleavage w i t h sodium methoxide. F u r t h e r e l a b o r a t i o n of the e s t e r 65_ y i e l d e d a mixture of isomers from which ( + ) - g u a i o l (66) was i s o l a t e d . The p r e p a r a t i o n of hydroazulenes from cyclodecanes has r e c e i v e d impetus from the b i o g e n e t i c and chemical d e r i v a t i o n of guaianes from germacranes (42,43). 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 (43 ) that epoxygermacrone (67), prepared from the corresponding germacrone by s t e r e o s e l e c t i v e enzymatic e p o x i d a t i o n , was r e a d i l y converted to the guaiane procurcumenol (68) by treatment with p_-toluenesulfonic a c i d i s one of the more r e c e n t l y r e p o r t e d examples of 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 a c i d - c a t a l y z e d rearrangement of 69_ to a mixture of the d i o l 7_1 and the. o l e f i n i c a l c o h o l _72_ (43 ) are two o t h e r s . In these three p u b l i s h e d cases, 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 - 17 -i s the r e s u l t of an anti -Markownikoff opening of the epoxide, w i t h simultaneous or subsequent a d d i t i o n to the double bond. While these r e s u l t s imply that epoxides may be i n v o l v e d i n guaiane b i o s y n t h e s i s , 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 i n p r e p a r i n g cyclodecene d e r i v a t i v e s has made s y n t h e t i c work arduous i n t h i s a r e a . In s p i t e of the s t e r e o -chemical ambiguity of p r e p a r i n g hydroazulenes from cyclodecadiene d e r i v a t i v e s , 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 t h i s approach (38), M a r s h a l l and Huffman have r e c e n t l y d i s c l o s e d t h e i r p r e l i m i n a r y f i n d i n g s on a n o v e l s t e r e o s e l e c t i v e approach to hydroazulenes from a c y c l o d e c a d i e n e . These workers employed t h e i r method of h e t e r o l y t i c a l l y fragmenting the boronate of a d e c a l i n i c mesylate to p r o v i d e the c y c l o d e c a d i e n y l a l c o h o l 75_. The corresponding p_-nitrobenzoate d e r i v a t i v e _76_ was then s o l v o l y z e d i n aqueous dioxane to p r o v i d e the - 18 -H 7 5 R = H ZZ 78 76 R = rp— N 0 2 C 6 H 4 C O -h y d r o a z u l e n o l 7_8 i n 70% y i e l d (44 ) . The h i g h degrees of r e g i o -s e l e c t i v i t y and s t e r e o s e l e c t i v i t y 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 the i n c i p i e n t a l l y l i c c a t i o n 77. The c r o s s e d , versus a l i g n e d , o r i e n t a t i o n of the t r a n s a n n u l a r double bond systems presumably minimizes s t e r i c i n t e r a c t i o n s , thereby 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 . The a l t e r n a t i v e , a s t e r e o -s e l e c t i v e concerted (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_-nitrobenzoate, was r e c e n t l y excluded (44^) by the o b s e r v a t i o n that 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 s o l v o l y s i s . A p r e p a r a t i o n of hydroazulenes from hydrindanes was r e p o r t e d g independently 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 1971. 8 5 Previous work on the a c e t o l y s i s of A -19-methanesulfonoxy s t e r o i d s (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. - 19 -Scanio and H i l l (47) found that the hydrindane 7_9 s o l v o l y z e d to the h y d r o a z u l e n y l acetate £51, w h i l e the corresponding hydrindene j$0_ p r o v i d e d the hydronaphthyl acetate 82_. M a r s h a l l and Greene (48) prepared the h y d r o a z u l e n i c acetate 84_ s t e r e o s e l e c t i v e l y by s o l v o l y z i n g the h y d r i n d a n y l mesylate £!3_ i n r e f l u x i n g a c e t i c a c i d - p o t a s s i u m a c e t a t e . In an accompanying paper (49), M a r s h a l l and coworkers then e l a b o r a t e d the hydroazulene 84^  to g u a i o l (66). However, t h i s work r e q u i r e d a d e c a l i n i c d e r i v a t i v e , the p r o t e c t e d a l c o h o l j36_ prepared i n s i x steps from 2-carbomethoxycyclohexanone (85), to p r o v i d e the hydrindane aldehyde 87_ a f t e r o z o n o l y s i s , r e d u c t i v e workup, and a l d o l condensation. F i v e additional steps were then needed to complete the p r e p a r a t i o n of the. r e q u i r e d compound 83. - 20 -a C O O C H 3 Steps 3 8 5 8 6 Steps 5 8 3 C H O 87 The preparations of hydroazulenes from hydronaphthalenes have, to date, provided the most us e f u l synthetic strategy a v a i l a b l e f o r the completion of sesquiterpene skeletons r e l a t e d to guaianes. There are three s t e r e o s e l e c t i v e routes a v a i l a b l e , one of which, the s o l v o l y s i s of the 8a-methyl-l-hydronaphthene d e r i v a t i v e s , includes the very recent work by Heathcock e_t aT. (34). The model trans-fused tosylates 88 and 90_ provided predominantly (80%) the hydroazulenes (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 , while the corresponding c i s - f u s e d compounds 9^2 and 95^ afforded unrearranged octalones i n the case of 92 (93:94 i s 74:13) and a mixture of octalvnifL ; and hydronaphthalenes i n the case of 95_ (96^97_:98. r a t i o i s 35:30:24). The importance of subtle conformational influences by r i n g substituents i n these s o l v o l y t i c rearrangements i s apparent from the work by Yoshikoshi ejt al_. (50) on s i m i l a r compounds. The i n t r o d u c t i o n of a 4a-methyl into 88^  led to an 85% - 21 -TsO y i e l d of the hydroazulenone corresponding to 89_ as expected, but the 4 a - m e t h y 1 - 6 - k e t o - c i s - t o s y l a t e p r o v i d e d 46% of 4a-CH 3 ~93 and 38% of a hydroazulenone mixture of 3a-methyl-5-keto-97 and 3 a - m e t h y l - 5 - k e t o - 9 8 . A p p l i c a t i o n of t h i s s o l v o l y t i c p r e p a r a t i v e technique has l e d to the t o t a l s t e r e o s e l e c t i v e syntheses of (+)-a-bulnesene (44) and (+)-b u l n e s o l (46) by Heathcock and R a t c l i f f e (33) and ( + ) - b u l n e s o l (46) and (+)-kessane (103) by Y o s h i k o s h i and coworkers (50,51). The e f f i c i e n c y - 22 -OH MsO 104 of t h i s a e s t h e t i c a l l y p l e a s i n g approach i s demonstrated by the f a c t that Heathcock's syntheses, both of which r e q u i r e d seventeen steps and 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 of sesquiterpene from the keto a l c o h o l 9_9. An a d d i t i o n a l s y n t h e s i s , the only known s y n t h e s i s of a pseudoguaiane, should a l s o be considered here. Hendrickson and coworkers i n .1968 r e p o r t e d (52 ) t h e i r r e s u l t s obtained by s o l v o l y z i n g the d e c a l i n i c bromide 107, d e r i v e d from a - s a n t o n i n i n s i x s t e p s , w i t h s i l v e r s u l f a t e - s u l f u r i c a c i d at room - 23 -temperature. The stereoelectronically favourable trans a n t i p a r a l l e l orientation of migrating and leaving atoms i n 107 afforded 75% y i e l d H R e f 1 0 6 O 107 Ra= H , R e = B r 1Q8 R a = B r , R e = H of the unnatural pseudoguaianolide 109, while 108 with i t s a x i a l bromine was recovered unchanged. Further synthetic work has not been reported for the natural pseudoguaianes s i m i l a r to 109, probably because the natural compounds have been discovered to require a trans-9 r i n g fusion and a cis-fused lactone. The second stereoselective method of preparing hydroazulenes from decalins involves 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 mono-tosylates of bicyclo[4.4.0]decanes to bicyclo[5.3.0]decanes v i a the Note added: A January 1973 publication reports the ozonolysis of 8,y-unsaturated naphthalenona derivatives (jL, R^=R2=H; or R^CH^, R2=H) provides hydroazulenedione derivatives ( 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 junction and the preparation of R2=allyl i n i ^ f a i l e d (A^-2-one more stable) while regioselective a l k y l a t i o n at C-7 of the hydroazulenedione also f a i l e d (52 b). - 24 -p i n a c o l type of rearrangement accomplished w i t h potassium _t-butoxide or alumina (53) . The o r i g i n a l work converted to o c t a l i n 110 i n t o the perhydroazulenone 112 and f u r t h e r s t u d i e s were then made of t h i s r i n g n o 111 112 t r a n s f o r m a t i o n sequence on s t e r o i d a l compounds. Buchi and coworkers l a t e r adopted t h i s method f o r the t o t a l s y n t h e s i s of (-)-aromadendrene (118), the enantiomer of the n a t u r a l l y - o c c u r r i n g (+)-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 steps from ( - ) - p e r i l l -aldehyde (113). The c i s - g l y c o l monotosylate 116, when allowed to remain i n contact w i t h a c t i v a t e d alumina or when t r e a t e d w i t h potassium J^-butoxide i n _t-butyl a l c o h o l , rearranged to a f f o r d the perhydroazulenone OH 118 X= C H 2 - 25 -117 i n 85% y i e l d . A W i t t i g r e a c t i o n w i t h methylenetriphenylphosphorane gave the d e s i r e d sesquiterpene 118 and, as such, p r o v i d e d unambiguous proof that the e a r l i e r assigned 1-epi s t r u c t u r e was i n c o r r e c t . The t h i r d , and o l d e s t , method of p r o v i d i n g hydroazulenes from d e c a l i n d e r i v a t i v e s u t i l i z e s the photochemical t r a n s f o r m a t i o n of c r o s s -conjugated cyclohexadienones. The s t r u c t u r a l e l u c i d a t i o n of "0_-a c e t y l i s o p h o t o s a n t o n i c l a c t o n e " , the photochemical rearrangement product of a - s a n t o n i n (106), o c c u r r e d over a s i x year p e r i o d a f t e r the t o t a l s y n t h e s i s of s a n t o n i n and proved that the i s o l a t e d hydroazulene 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 g e n e r a l i t y of the r e a c t i o n (56) and the mechanism of the rearrangement were being pursured (57,58), the major product of s a n t o n i n ' s p h o t o l y s i 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 of s e v e r a l guaiane s e s q u i t e r p e n e s . 1 - E p i c y c l o c o l o r e n o n e (120) (59), a c h i l l i n (121) (60) and d e s a c e t o x y m a t r i c a r i n (122) (61) were prepared d i r e c t l y from 119, w h i l e g e i g e r i n a c e t a t e (125) (62) was e l a b o r a t e d from 8 - e p i - i s o p h o t o -artemesolactone (124), a photoproduct obtained (56) by transforming the c r o s s - c o n j u g a t e d ketone chromophore of ( - ) - a r t e m i s i n (123), a n a t u r a l l y o c c u r r i n g eudesmolide that was i t s e l f l a t e r s y n t h e s i z e d i n 1969 (63). 12Q O O 121 1 2 2 HO O O O O 123 1 2 4 125 These syntheses of guaianes from r e a d i l y a v a i l b l e c r o s s - c o n j u g a t e d eudesmanes were, u n t i l r e c e n t l y , more a t t r a c t i v e than a s y n t h e t i c sequence u s i n g a photochemical rearrangement as one of the t e r m i n a l s t e p s . T h i s was p a r t l y due to the 30% y i e l d of i s o p h o t o s a n t o n i c l a c t o n e obtained o r i g i n a l l y with u l t r a v i o l e t l i g h t on the aqueous a c e t i c a c i d s o l u t i o n of s a n t o n i n (56). While the m e c h a n i s t i c and s t e r e o c h e m i c a l parameters of the photochemical rearrangement of c r o s s - c o n j u g a t e d cyclohexadienones w i l l be d i s c u s s e d l a t e r , of the many s t u d i e s r e p o r t e d to date on t h i s r e a c t i o n , only two have attempted to s y s t e m a t i c a l l y maximize the y i e l d of hydroazulene. Caine and DeBardeleben (64) photolyzed the 2-formyl dienone 126 i n aqueous a c e t i c a c i d and, a f t e r b a s e - c a t a l y z e d d e f o r m y l a t i o n of the crude photoproduct, obtained the hydroazulenone 127 i n 70% o v e r a l l y i e l d . Caine and h i s coworkers - 27 -subsequently r e p o r t e d that the analogous p h o t o l y s i s w i t h a 2-carboxy s u b s t i t u e n t (128) p r o v i d e d the model hydroazulene 129 d i r e c t l y and s t e r e o s p e c i f i c a l l y i n 65% y i e l d (65). 128 129 The work on these model systems was l a t e r found to be u s e f u l i n the s y n t h e s i s of a - b u l n e s e n e . P i e r s and Cheng (66) found that w h i l e the dienone 130, obtained from a - s a n t o n i n , af forded 79% hydroazulene 131 and 10% s p i r a n e 132 upon p h o t o l y s i s , and w h i l e a-cyperone (133) c o u l d be converted to the hydroazulene 135 i n 55% o v e r a l l y i e l d , the c o n v e r s i o n of 7 - e p i - a - c y p e r o n e (136) p r o v i d e d only a 15% y i e l d of the c o r r e s p o n d i n g hydroazulene (138). The i n t r o d u c t i o n of a 2-carboxy f u n c t i o n a l i t y i n t o 137 (R = COOH) not only p e r m i t t e d the o v e r a l l y i e l d 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 mixture by the - 28 -1 3 6 1 3 7 1 3 8 absence of the s p i r a n e analogous to 132. F u r t h e r e l a b o r a t i o n of the hydroazulenes 131, 135 and 138 p r o v i d e d 5 - e p i - a - b u l n e s e n e (139), 4 - e p i - a - b u l n e s e n e (140) and ct-bulnesene (44) , - 29 -A second a p p l i c a t i o n of C a i n e ' s s y n t h e t i c approach appeared very r e c e n t l y i n the p h o t o s y n t h e s i s of the d i t e r p e n e s k e l e t o n of grayano-t o x i n - I (141) (67). The t e t r a c y c l i c enone 142 and i t s C-14 epimer (*) were converted to the 2-formyl c r o s s - c o n j u g a t e d dienone 144 and photolyzed i n aqueous a c e t i c a c i d to p r o v i d e a 3:1 r a t i o of 144:145 i n 12% y i e l d . T h i s i n t r a m o l e c u l a r photochemical ether formation i s 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 p r e p a r a t i o n of kessane (103) (51). - 30 -I I I . Approaches to S t e r e o s e l e c t i v e Spirane Synthesis The s y n t h e s i s of s e v e r a l monospiranes has been accomplished by i n t r o d u c i n g the r e q u i r e d s p i r o center"^ i n t o cyclopentane, cyclohexane, and fused b i c y c l i c r i n g system d e r i v a t i v e s . While few of these methods, u n f o r t u n a t e l y , are completely g e n e r a l , . some do permit s t e r e o c h e m i c a l c o n t r o l to be exerted at s e v e r a l of the r i n g p o s i t i o n s . The s y n t h e s i s of the s i m p l e r s p i r a n e s , s p i r o [ 4 . 4 ] n o n a n e and s p i r o [ 4 . 5 ] d e c a n e d e r i v a t i v e s , 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 t h i r t y y e a r s , but i t i s only i n the l a s t year or two that s t e r e o s p e c i f i c s p i r a n e formation has become p o s s i b l e . The methods r e p o r t e d by Cram and S t e i n b e r g i n 1954 (69) are t y p i c a l of the e a r l y work. The symmetrical spiro[4.5]decan-6-one (147) was prepared by s u l f u r i c a c i d treatment of cyclopentanone's r e d u c t i v e 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 only one such union and i s named by p l a c i n g " s p i r o " before the name of the normal a c y c l i c hydrocarbon of the same number of carbon atoms when the s p i r a n e c o n s i s t s of 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 ascending order i n brackets 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 to 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 present) and then through the s p i r o atom and around the second r i n g (68). - 31 -product 146,' w h i l e the p y r o l y s i s of the barium s a l t of the d i a c i d 148, a compound obtained 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 (149). Successive i n t r a m o l e c u l a r malonic e s t e r a l k y l a t i o n s o f the t e t r a e s t e r 150, fol lowed by subsequent h y d r o l y s i s and p y r o l y s i s , a f f o r d e d 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 i n 9% o v e r a l l y i e l d . C a t a l y t i c or h y d r i d e r e d u c t i o n of 151 p r o v i d e d a product EtOC — ( C H 2 ) 3 — C COEt / O / ^ ( C H 2 ) 3 C O E t EtOC II . ^ O O o 150 151 mixture of the c i s - c i s (152a), c i s - t r a n s (152b), and t r a n s - t r a n s (152c) s t e r e o i s o m e r s . The authors were then a b l e to r e p o r t the f i r s t known OH OH S>€3 SXD OO 152 a 152 b HO 152c p r e p a r a t i o n of i n d i v i d u a l s p i r a n e diastereomers when they s u c c e s s f u l l y 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 techniques to the b i s - p - n i t r o b e n z o a t e s o f 152. Subsequent work by Cram and c o l l e a g u e s (70) showed that the s p i r o k e t o l product 154 obtained from the Dieckmann condensation of the s u b s t i t u t e d c y c l o p e n t a n o l 153, c o u l d a l s o be separated i n t o i t s stereoisomers by chromatographing the two - 32 -153 154 p_-nitrobenzoate diastereomers. The physical and chemical properties of the isol a t e d diastereomers permitted the r e l a t i v e configurations of the two p u r i f i e d l-keto-6-hydroxy- and three p u r i f i e d 1,6-dihydroxy-spiro[4.4]nonanes to be elucidated. These dicyclopentane spirane systems were useful model systems for asymmetric induction studies. The c a t a l y t i c reduction of the dione 151 to compound 154, for example, afforded a 1:2 r a t i o of c i s - k e t o l 154 to trans-ketol 154 i n g l a c i a l acetic acid while the reduction of 151 to 154 i n 95% ethanol gave a ^ 6:1 r a t i o . The successful resolution i n 1968 of the trans, t r a n s - d i o l 152c, by Gerlach (71) using (-)-camphanic acid (155) , provided (-)-(lR,6R.)-spiro [4.4]nonane-l,6-diol (=152c) which was then oxidized to (-)-(5S_)-spiro[4.4]nonane-l,6-dione ((-)-151) by chromium tetroxide i n acetone. 155 (—7—151 - 33 -The c h i r a l i t y of the (-)-151 enantiomer was determined by chemical c o r r e l a t i o n work and, more r e c e n t l y , t h i s enantiomer was used i n an X - r a y 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 energy c a l c u l a t i o n s (72) to show that the cyclopentane r i n g s adopt a conformation i n t e r m e d i a t e between the envelope 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 ) . L i g h t n 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 (through the a p p l i c a t i o n of the Octant Rule) the r e s u l t s obtained by v a r i a b l e temperature c i r c u l a r d i c h r o i s m of ( - ) - c i s - and ( - ) - t r a n s - 6 - m e t h y l s p i r o -[ 4 . 4 ] n o n a n - l - o n e ( ( - ) - 1 5 7 and (-)-158) (73) and to c a l c u l a t e o p t i c a l O O ' O (-)-156 (-)-157 (-)-l58 p r o p e r t i e s of (+)-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 s o l v e n t and temperature dependent c i r c u l a r d i c h r o i s m of the (+)-enantiomers of 151 and 156 (74). T h i s very recent work takes on s y n t h e t i c s i g n i f i c a n c e by the r e p o r t (73) that the spirenone ( -) -156, obtained from a W i t t i g r e a c t i o n with methylenetriphenylphosphorane on the ( - ) - d i o n e ( ( - ) - 1 5 1 ) , was c a t a l y t i c a l l y 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 to a f f o r d a 1:2 r a t i o of (-)-157 to (-)-158 i n a c e t i c a c i d and an 8:1 r a t i o i n e t h a n o l . 1 1 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 recent a s s e r t i o n (74) that t h i s work confirms the absolute c o n f i g u r a t i o n i s i n c o r r e c t . The l a s t sentence on page 2045 of reference 74 should read " . . . A l t o n a e_t a l . determined the conformation 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 d e r i v e d s p i r a n e s , some comment 12 must be made on the remarkably s t e r e o s e l e c t i v e s y n t h e s i s of g - a c o r a t r i e n e (161) p u b l i s h e d very r e c e n t l y (75). K a i s e r ejt al_. (75) used a s t a n n i c c h l o r i d e c a t a l y z e d c y c l i z a t i o n of the t e r t i a r y a l l y l i c a l c o h o l 160, d e r i v e d i n three steps from racemic d e h y d r o l i n a l o o l 159, to a f f o r d g - a c o r a t r i e n e i n approximately 50% y i e l d . The i s o p r o p y l i d e n e group appears to d i r e c t the c y c l i z a t i o n of the end of the s i d e c h a i n to the unhindered s i d e of the cyclopentane r i n g because none of the i s o m e r i c a - a c o r a t r i e n e (162) could be i s o l a t e d . A s h o r t treatment of 162 163 While the reference 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 with p_- toluene sulfonic acid i n refluxing bezene afforded the 13 cedradiene 163. However, the a t t r a c t i o n of this method for the synthesis of spiro-carbocyclic sesquiterpenes i s diminished by the report that the corresponding c y c l i z a t i o n of the isopropyl derivative 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 preparation of model spiro[4.5]decanes from cyclopentane derivatives, but recently 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 derivatives mimics the proposed biogenetic sequence and this approach usually provides a much shorter synthesis of bridged spiranes than a non-spirane approach. Details of both spirane and nonspirane sesquiterpene synthesis are discussed i n Appendix I I i n the 'spirane approach'. The excellent 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 stimulation of the biogenesis of cedrene could be accomplished i n the laboratory through the farnesane •+ bisabolane -* acorspirane -* cedrane sequence (76). The farnesane _i, n e r o l i d o l , was shown to be acid cycli 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 cyclized d i r e c t l y to afford 20% a-cedrene (vi) and ^15% epi-a-cedrene ( v i i ) . This direct method does not permit monospirane synthesis and i s not a stereoselective synthesis for bridged spiranes. in IV v[ a - C H 3 vii /3 - C H 3 of the D i e l s - A l d e r adduct 169 from t r a n s - 2 - e t h y l i d e n e c y c l o p e n t a n o n e (167) and 1 ,3-butadiene (168) (87). 167 168 169 17Q The s p i r o [ 4 . 5 ] d e c a n e s d e r i v e d from cyclohexane d e r i v a t i v e s have been s y n t h e t i c t a r g e t s f o r many r e s e a r c h e r s , but only very 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 . For i n s t a n c e , an e a r l y example of such an a p p l i c a t i o n , the a c y l o i n condensation of the d i e s t e r 171, p r o v i d e d an i n s e p a r a b l e mixture of f o u r p o s s i b l e diastereomers of the spirane 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 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 butadiene 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) (85). However, i n t h i s case asymmetrical centers are present i n the spiro[5.5]undecane p r e p a r e d . - 37 -symmetrical s p i r a n e 175 that was obtained by an 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 w i t h 1-5 a r y l neighbouring group p a r t i c i p a t i o n i n the 1959 p y r o l y s i s of the sodium s a l t of 173 (78). The l a t t e r work has been 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 . The f i r s t r e p o r t e d that a r y l displacement of the n i t r o g e n from the diazo methyl c a r b o n y l of 176 afforded 175 d i r e c t l y and i n 65% y i e l d (79) (versus 40% from 173), while the second found that the d i r a d i c a l anion i n t e r m e d i a t e 178a, from the lithium-ammonia r e d u c t i o n of 177, p r o v i d e d the r e l a t e d s p i r a n e 179 on C H N 2 1 7 6 O H O H 177 177 ^ 178 q 178b O II C O H 179 - 38 workup i n 60% o v e r a l l y i e l d (80). The s p i r o - d i e n o n e s 181a and 181b were a l s o prepared i n 60% y i e l d by a 1-5 a r y l p a r t i c i p a t i o n r e a c t i o n 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 potassium t - b u t o x i d e i n _t-butanol (81). While none of the above approaches would appear to R ,R T 9 0 180a R = H 181a R=H 18Qb R=CH 3 181b R=CH^ p r o v i d e a s t e r e o s e l e c t i v e route 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 of r e s e a r c h e r s have r e p o r t e d , independently and n e a r l y s i m u l t a n e o u s l y , a s t e r e o s e l e c t i v e s y n t h e s i s f o r the s p i r a n e 184 from a r y l compounds. The f i r s t group u t i l i z e d the b a s e - c a t a l y z e d c y c l i z a t i o n of the a-bromo e s t e r 182 ( 8 2 a ) w h i l e the second obtained the s p i r a n e 184 from the 6-bromo e s t e r 183 (82^). These l a b o r a t o r y syntheses are stereoselective^"^ only because, f i r s t l y , the s p i r a n e formation occurs on a completely symmetrical cyclohexane and, s e c o n d l y , the c r o s s - c o n j u g a t e d 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 of 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 , ' the s p i r a n e a p p r o a c h ' . - 39 -s p i r o - k e t o n e 184, obtained a f t e r base e p i m e r i z a t i o n of the carbomethoxy s u b s t i t u e n t , i s only i s o l a t e d as the t r a n s - m e t h y l , carbomethoxy c y c l o p e n t y l s p i r e n o n e . 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 to the a c o r s p i r a n e s k e l e t o n , a somewhat analogous approach to the v e t i s p i r a n e s e s q u i t e r p e n e , 8-vetivone (223), f a i l e d . Mukharji and Gupta (83) found that the t e t r a h y d r o p y r a n y l (THP) ether of the bromophenol 185 c y c l i z e d r e a d i l y to the expected 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 methyl 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 , or conjugate h y d r o c y a n a t i o n , were u n s u c c e s s f u l . I t seems that the c y c l o p e n t y l moiety of 186 h i n d e r s the approach to C-10 from e i t h e r face of the c y c l o h e x a -dienone r e s i d u e . A l s o the i n t r o d u c t i o n of asymmetry i n t o both of the s p i r o [ 4 . 5 ] d e c a n e r i n g s prevents t h i s approach from being s t e r e o s e l e c t i v e as both diastereomers of 186 are produced. T h i s same problem i s a l s o apparent i n the very r e c e n t l y r e p o r t e d work by Pinder e_t a l . (84) on a r e a c t i o n sequence a f f o r d i n g the a c o r s p i r a n e s k e l e t o n . The cyclohexenone d e r i v a t i v e 187 was t r e a t e d w i t h sodium methoxide and underwent an 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 both diastereomers o f 188. On the other hand, the c y c l i z a t i o n of c i s - and t r a n s - m o n o c y c l o f a r n e s o l (189) was a s u c c e s s f u l r e g i o s e l e c t i v e s y n t h e s i s of (+)-a-chamigrene - 40 -(190) (85), a spiro[5.5]undecane sesquiterpene, because of the absence of asymmetric centers i n the cyclohexane portion of 189. The f i r s t and, to th i s date, only method for the direct conversion of a general b i c y c l i c [4.4.0] ring 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 this 5,10-cis-eudesmane readily 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 - 41 -(ct-rotunol) . 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 b i c y c l o -[5.4.0] system has a l s o been d i s c o v e r e d . B i c y c l o [ 5 . 4 . 0 ] u n d e c - l ( 7 ) - e n - 3 -one (193) was found to undergo a [ l , 3 ] - s i g m a t r o p i c photorearrangement v i a the s i n g l e t s t a t e 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 (194) (87). O O 193 194 195 A p h o t o s t a t i o n a r y s t a t e between 193 and 194 e s t a b l i s h e d a 2:3 e q u i l i b r i u m r a t i o of 193:194. The problems of s t e r e o s e l e c t i v e l y s y n t h e s i z i n g a s u b s t i t u t e d s p i r a n e by e i t h e r of these methods would be s u b s t a n t i a l . The s y n t h e t i c d i f f i c u l t y i n p r e p a r i n g c i s - y - h y d r o x y o c t a l o n e s analogous to 191 (plus the l a c k of s t e r e o s e l e c t i v e r e a c t i o n s on 192) makes the f i r s t approach u n a t t r a c t i v e . The photochemical s y n t h e t i c e n t r y 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 s t e r e o c h e m i s t r y i n t o the s p i r a n e . The f a c t that hydrogenation of 194 p r o v i d e s both diastereomers of 195 makes even the i n t r o d u c t i o n of C-6 stereoisomers a s e r i o u s problem (87). Spiranes 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 obtained s u c c e s s f u l l y from b i c y c l i c unsaturated hydronaphthalenones through the i n t e r m e d i a c y of t r i c y c l i c compounds. Mander et a l . have r e c e n t l y r e p o r t e d (79,88) s e v e r a l examples 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 of diazo-ketones where a r y l 1-5 and a r y l 1-6 neighbouring 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 1 9 8 a R = X = H 199 2 0 0 jo, R = CH 3, X = H C R = CH 3, X=OH was then extended to i r-bond p a r t i c i p a t i o n by the b e n z y l i c displacement of the diazo methyl c a r b o n y l ' s n i t r o g e n from compounds of type 202 to a f f o r d h i g h o v e r a l l y i e l d s of the b r i d g e d s p i r a n e 203. C o n t r o l of - 43 -the r e l a t i v e s t e r e o c h e m i s t r y between the c a r b o n y l and other s u b s t i t u e n t s of the s t a r t i n g compound, a r a t h e r s t r a i g h t f o r w a r d problem, would permit the s t e r e o s e l e c t i v e s y n t h e s i s of h i g h e r terpenoids to be accomplished r e a d i l y . As p r e v i o u s l y i n d i c a t e d by the l a c k of s t e r e o -chemical c o n t r o l i n b i c y c l i c s p i r a n e s , t h i s approach would not be u s e f u l f o r sesquiterpene s y n t h e s i s . The two-step c o n v e r s i o n of the Wieland-Miescher ketone (204) to the s p i r a n e dione 206 p r o v i d e s a unique method of o b t a i n i n g the s i m p l e r monospirane systems. A n o v e l c y c l i z a t i o n of the Wieland-Miescher ketone was d i s c o v e r e d to occur d u r i n g the r e d u c t i o n of 204 i n a l i t h i u m / ammonia/ether 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 2 Q 4 2Q5 2Q6 a f f o r d an 80% y i e l d of the c y c l o p r o p a n o l ketone 205 (X = H ) . A b a s e -c a t a l y z e d t r a n s f o r m a t i o n of the sodium s a l t of 205 (X = Na) i n a hetereogeneous benzene-methanol medium p r o v i d e d , s t e r e o s p e c i f i c a l l y , the s p i r o d i o n e 206 i n 75% y i e l d (89). S u r p r i s i n g l y , the use of a homogeneous media (benzene-dimethylformamide) f o r the b a s e - c a t a l y z e d t r a n s f o r m a t i o n p r o v i d e d the t r a n s - i n d a n e d i o n e , t r a n s - l , 6 - d i m e t h y l b i c y c l o -[ 4 . 3 . 0 ] n o n a - 2 , 7 - d i o n e (208), s t e r e o s p e c i f i c a l l y (90). T h i s s t e r e o s p e c i f i c i t y observed i n both 206 and 208 has not been r a t i o n a l i z e d y e t , but the rearrangements are b e l i e v e d to be g e n e r a l l y a p p l i c a b l e f o r - 44 -the two-step c o n v e r s i o n of a n g u l a r l y s u b s t i t u t e d enediones analogous to 204. The s y n t h e t i c advantage of c o n f i g u r a t i o n a l r e t e n t i o n at C-6 of the s p i r a n e i s obvious when i t i s remembered that most other methods a f f o r d 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 hindered environment of the c y c l o p e n t y l c a r b o n y l of 206 a l s o permits the c y c l o h e x y l c a r b o n y l to be removed r e g i o s e l e c t i v e l y . The o l d e s t and most p r a c t i c a l method of o b t a i n i n g s p i r a n e s s t e r e o -s e l e c t i v e l y was d i s c o v e r e d from the s t u d i e s on s a n t o n i n (106) p h o t o l y s i s . Along w i t h " i s o p h o t o s a n t a n o i c l a c t o n e " (209), a second photoproduct, l u r a i s a n t o n i n , was obtained 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 assigned the s t r u c t u r e 210 (91). When t h i s r e a c t i o n was s t u d i e d on the model hydronaphthalenone 211 (R 2 = H, R^ = CH 3 ) (57,92), the analogous lumiproduct 213 was obtained i n 65% y i e l d as the s i n g l e i n i t i a l photoproduct i f the p h o t o l y s i s was conducted i n a n e u t r a l - 45 -ap r o t i c media such as dioxane. When i r r a d i a t i o n i n 45% a c e t i c acid was used, the expected hydroazulenone 214 was obtained as the predominant product. However, photolysis of the corresponding unsubstituted 2 1 2 a 2 1 2 b 213 cross-conjugated dienone (211, = R^ = H) i n a c e t i c media afforded a 1:1 mixture of the hydroazulenone (214, R2 = R^ = H) and a new photoproduct, the hydroxyl spirenone 215 (R2 = R^ = H) (57). The s i m i l a r photoreaction with the 2-methyl substituted compound 211 (R2 = CH^, R^ = H) was found to provide only the corresponding spirenone 215 as the major product. These s t e r e o s p e c i f i c a l l y formed hydroazulenone and spirenone products have been inte r p r e t e d mechanistically (58) to be the r e s u l t of n u c l e o p h i l i c attack by water at of 212a or 212b r e s p e c t i v e l y . While only those hydroazulenones which are 2-alkyl substituted can be converted to spirenpnes e f f i c i e n t l y by 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). The 2-alkyl substituted compound (213, R^ = CH^, = H) yielded a quantitative mixture of the three spiranes 215, 216, and 217 (88% of which was 216) i n refluxing 45% acetic acid, while 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-alkyl substituted lumiproduct (214, R^  = H, R^ = CH3) provided a 1:2 r a t i o of the spirenone 216 to the related hydroazulenone 214. These substituent effects of the acid-catalyzed lumiproduct cleavages are reminiscent of those encountered above i n the photochemical conversions of the corresponding parent dienones (211), but di f f e r e n t product r a t i o s and configurationally d i f f e r e n t compounds at C-10 are isolated from the l i g h t - and a c i d - i n i t i a t e d rearrangements. Kropp (93) interpreted the acid-catalyzed spirane product formation i n terms of - 47 -c o m p e t i t i v e C-9 p r o t o n l o s s (to 217), backside a t t a c k by water (to 216), and f r o n t s i d e a t t a c k by water (to 215) during cleavage of the 4,10-bond of the protonated c y c l o p r o p y l ketone 218. The o r b i t a l s of the 4,10-bond are the only o r b i t a l s w i t h the proper g e o m e t r i c a l rearrangement f o r favourable overlap w i t h the p_-orbitals of the C-3 c a r b o n y l g r o u p . . M a r s h a l l and Johnson (94) e x p l o i t e d the above c o n v e r s i o n method by transforming the known o c t a l o n e 219 i n t o the s p i r a n e 222 through the p h o t o c h e m i c a l - a c i d treatment sequence. The t r a n s - d i m e t h y l 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 hydronaphthalenones 219 and 220 became a c i s 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 the c a r b o n y l and 2 2 Q A * ' 4 the C-6 methyl as trans i n compound 221. The rearrangement of the c y c l o p r o p y l ketone 221 i n anhydrous a c e t i c a c i d then cleaved the best 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 of the s p i r o [ 4 . 5 ] d e c a d i e n o n e 222. T h i s r e a c t i o n removed the asymmetry at C-10, but l e f t the r e l a t i v e s t e r e o c h e m i c a l r e l a t i o n s h i p of the C-6 methyl and C-3 c a r b o n y l i n t a c t . 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 of 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 . F o r m a l l y , t h i s r e a c t i o n i s a photochemical [o^-a + v^-a] c y c l o a d d i t i o n r e a c t i o n . - 48 -8-vetivone (223) by standard chemical r e a c t i o n s . Compound 222 was a l s o 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 hydrogenated i n e t h a n o l to y i e l d a 3:1 mixture of the s p i r a n e s 224 and 225 > diastereomers that c o u l d only be separated by gas chromatography. 222 222 - 49 -DISCUSSION I. General Development of the Reaction Sequence As previously stated, our synthetic interests were oriented to the e f f i c i e n t stereospecific transformation of decalinic compounds into the less readily available hydroazulene and spirane systems. After surveying the l i t e r a t u r e on the guaiane sesquiterpene synthesis (Appendix II) and the available perhydroazulene preparations, i t was f e l t that a study on maximizing the hydroazulenone (C) y i e l d from the photolysis of cross-conjugated cyclohexadienone derivatives (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 objectives of this study, octalones of type A (R^ = = H, CH^) would be required for conversion to the corresponding cross-conjugated system B (R^ = R^  = H, CH3; R 3 = H, CHO, COOH, COOR) so that photolysis of B_ could be studied i n a variety of solvents. This approach to hydroazulene synthesis i s fundamentally a y i e l d study on the well-known photolysis of cross-conjugated ketones, with modifications o r i g i n a t i n g - 50 -w i t h D. Caine (64,65) , B ( ^ = R 2 = H , R 3 = COOH). In c o n t r a s t to the hydroazulene work, the i n v e s t i g a t i o n i n t o s p i r a n e s y n t h e s i s 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 of the 8 -center of an a,8 - c y c l o p r o p y l ketone be r e t a i n e d , i n v e r t e d , or both on the r e d u c t i v e cleavage of _E to F ? " O b v i o u s l y , a s e r i e s of simple c y c l o p r o p y l ketones analogous to E, but w i t h a bridgehead a l k y l (R' = CH^) s u b s t i t u e n t r a t h e r than hydrogen,.were necessary before t h i s q u e s t i o n c o u l d be answered. The three g e n e r a l methods o f p r e p a r i n g these 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 decomposition of o l e f i n i c diazo ketones, the photochemical rearrangement of the c y c l i c ketone A , and the p h o t o l y s i s (with subsequent s e l e c t i v e hydrogenation ' of D) of the c r o s s - c o n j u g a t e d dienone IL While the unsaturated d i a z o 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 the E_ -series (227) (95 ) , the corresponding compounds w i t h asymmetric c e n t e r s i n the cyclohexene r i n g have been r e p o r t e d to a f f o r d mixtures c o n t a i n i n g both d i a s t e r e o m e r s . S e v e r a l examples of these i n t r a m o l e c u l a r keto-carbene i n s e r t i o n s are presented i n Chart II along w i t h the t o t a l y i e l d and the r a t i o of diastereomers o b t a i n e d . The a v a i l a b i l i t y of E from s t e r e o -s e l e c t i v e photochemical 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 , n a t u r a l l y l e d 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 of type A . While - 51 -CHART II C Y C L O P R O P Y L K E T O N E S F R O M I N T R A M O L E C U L A R K E T O -C A R B E N E ADDITION TO SUBSTITUTED C Y C L O H E X E N E S . Product Compound (Literature Reference) Yield Diastereomer Ratio 2 2 6 (95°) 3 0 % 22 8 X 2= H 2 ( 9 5 b ) 4 4 2 2 8 X»= (-OCH ) ( 9 5 b ' c ) 31, 4 0 2 2 2 231 R = C H ( C H 3 ) 2 ( 9 5 d ) 7 8 231 ' R = C ( = C H 2 ) C H 3 ( 9 5 e ) 2 4 2 2 9 : 2 3 0 = 1 : 9 2 2 9 : 2 3 0 = 1 : : 9 2 3 2 : 2 3 3 = 3 : 5 2 3 2 : 2 3 3 = 1 : 1 - 52 -s p i r a n e and hydroazulene s y n t h e s i s are d e a l t w i t h s e p a r a t e l y i n the i n t r o d u c t i o n , d i s c u s s i o n , and experimental p o r t i o n s of t h i s t h e s i s , t h e i r common s y n t h e t i c 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 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 ketones fol lowed by a s e c t i o n on the d e r i v a t i v e s of c r o s s - c o n j u g a t e d dienones. I I . Synthesis o f a,8 -Unsaturated 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 seven a,8 -unsaturated ketones 234 to 240, i n c l u s i v e , the f i r s t s y n t h e t i c o b j e c t i v e of the work d e s c r i b e d i n t h i s t h e s i s . These compounds are c o n s i d e r e d i n d i v i d u a l l y i n order o f i n c r e a s i n g complexity because t h e i r p r e p a r a t i o n u t i l i z e d widely d i f f e r e n t s y n t h e t i c schemes. However, s i n c e the compounds 234 to 240 were l a t e r a l l dehydrogenated to the corresponding c r o s s - c o n j u g a t e d systems, one s y n t h e t i c g e n e r a l i z a t i o n should 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 of type A from the corresponding cyclohexanone can be achieved by one of two methods. The f i r s t (Method I) i s the a d d i t i o n of one methyl v i n y l ketone e q u i v a l e n t ( M . V . K . E . ) " ^ to the 2-methylcyclohexanone d e r i v a t i v e 241 w i t h subsequent r i n g c l o s u r e to A w h i l e the second (Method II) i s the a d d i t i o n of acetone (or i t s d e r i v a t i v e ) to the corresponding 2-formyl-2-methylcyclohexanone d e r i v a t i v e (242) to p r o v i d e 13 a f t e r r i n g c l o s u r e and then A a f t e r r e g i o s e l e c t i v e hydrogenation of 13. Because of the s i m i l a r i t i e s of these L ^ MVKE i n c l u d e s methy]/vinyl ketone, l - d i e t h y l a m i n o - 3 - b u t a n o n e methiode, 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 with 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 with 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 octalone 236 p r o v i d e s e v e r a l examples of these d i f f e r e n t reagents. - 53 -24Q - 54 -O H C 242 2 4 3 B two schemes and the quantitative 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 a,6-unsaturated ketone. In general, Method I I i s useful- for the simpler cross-conjugated dienones that are stereochemically unambiguous while Method I, with subsequent dehydrogenation, i s es s e n t i a l for the preparation of highly substituted or s p e c i f i c a l l y substituted 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 3 = COOH) reported for the reaction of 242 (R^ = R 2 = H) with the acetoacetic ester 243 (R^ = COOEt) (97) and the 1:5 r a t i o of C-6 diastereomers of B (R± = 6-C(CH2)CH3; a:g = 5:1) obtained from condensing the C-4 isopropenyl substituted cyclohexanone 242 with acetone (243, R_ = H) (98). - 55 -A. Octalone 234 (4a-Methyl-4,4a,5,6,7,8-hexahydro-2(3H)-naphthalenone) The well-known octalone 234 i s normally prepared from 2-methylcyclo-hexanone using methyl v i n y l ketone i n place of the l-dimethylamino-3-butanone methiodide o r i g i n a l l y required i n the Robinson annelation method since the l a t t e r r e a c t i o n provides the octalone product i n low y i e l d and questionable p u r i t y (103). The procedure of Marshall and Fanta (99) condenses 2-methylcyclohexanone and methyl v i n y l ketone at -10° i n the presence of a c a t a l y t i c amount of sodium ethoxide to a f f o r d 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 s t e r e o s e l e c t i v e formation of the c i s - k e t o l i s the r e s u l t of k i n e t i c c o n t r o l i n the O H 2 4 4 245 2 4 7 2 3 4 intramolecular a l d o l c y c l i z a t i o n . Dehydration of t h i s k e t o l with potassium hydroxide then proceeds i n ^90% y i e l d to the desired octalone 234 (^  50% o v e r a l l ) . Heathcock et a l . (100), i n December 1971, reported the corresponding acid-catalyzed Robinson annelation. In t h i s case, 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 for both forming and dehydrating the k e t o l 247. Methyl v i n y l ketone and 2-methylcyclohexanone are refluxed f o r 16 hours i n the presence of a c a t a l y t i c amount of a c i d to a f f o r d 49-55% y i e l d of octalone 234 on workup. To prepare the s u b s t a n t i a l amounts of octalone 234 required, the procedure of Marshall and Fanta was adopted and then modified s l i g h t l y - 56 -d u r i n g the course of r e p e a t i n g 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 of methyl v i n y l ketone observed d u r i n g i t s dropwise a d d i t i o n to the r e a c t i o n and the p r o h i b i t i v e l y l a r g e volumes of d i e t h y l ether-hexane s o l u t i o n r e q u i r e d f o r the c r y s t a l l i z a t i o n of the crude k e t o l 247. A Hershberg s t i r r e r rod on a h i g h torque s t i r r i n g motor overcame the f i r s t problem and the d i r e c t d e h y d r a t i o n of the k e t o l i n the r e a c t i o n v e s s e l w i t h 10% aqueous potassium hydroxide s o l v e d the second. In t h i s manner, the o c t a l o n e 234 was prepared i n 57% y i e l d d i r e c t l y or 75% y i e l d on the b a s i s of unrecovered 2-methylcyclohexanone. When Heathcock et a l . p u b l i s h e d t h e i r s y n t h e t i c procedure f o r 18 o c t a l o n e 234, i t s experimental s i m p l i c i t y encouraged us to apply i t . 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 o c t a l o n e were found to be contaminated w i t h 16% of a second component, 2-methyl-2(3-oxobutyl) -cyclohexanone (246). A s t r u c t u r a l assignment was made on the b a s i s of the s a t u r a t e d c a r b o n y l p r e s e n t i n the i n f r a r e d spectrum (1710 cm ^) and the downfield a c e t y l methyl (T 7 .80, s i n g l e t of three protons) i n the n u c l e a r magnetic resonance spectrum. T h i s i m p u r i t y 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 potassium hydroxide 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 procedure a c t u a l l y used 100 ml benzene i n the r e a c t i o n mixture for 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 omitted from r e f e r e n c e 100. Since 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° versus 7 9 - 8 0 ° ) , i t i s not s u r p r i s i n g that we have found the e l i m i n a t i o n o f benzene makes very l i t t l e d i f f e r e n c e 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 octalone 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 unaffected by the presence or absence of benzene as shown by conducting the r e a c t i o n s both ways. - 57 -O 2 4 6 3 2 4 9 2 4 8 246 and dehydrate the i n t e r m e d i a t e a l d o l product (247). At t h i s p o i n t , a s i d e - p r o d u c t that was shown to a r i s e from the a c i d - c a t a l y z e d c y c l i z a t i o n was i s o l a t e d i n the d i s t i l l a t i o n f o r e r u n of octalone 234. I t was i d e n t i f i e d 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 , the b r i d g e d ketone 248 that has been obtained by M a r s h a l l and Schaeffer (107) 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 with s u l f u r i c a c i d at 0-20° f o r 2 h . In both i n s t a n c e s , the i n t e r m e d i a t e dione 246 undergoes the a l t e r n a t i v e a l d o l condensation and d e h y d r a t i o n to a f f o r d 248 i n s t e a d of 234. The s p e c t r a l data recorded f o r compound 248 i s i n complete agreement w i t h that r e p o r t e d (107), and the compound was shown to be unaffected by the base treatment. The above r e s u l t s suggested that the a c i d - c a t a l y z e d procedure should 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 under b a s i c c o n d i t i o n s before workup. Upon r e p e a t i n g the method of Heathcock et a l . (100), a 0.5 molar e t h a n o l i c s o l u t i o n of sodium ethoxide was added before workup at the end of the r e a c t i o n p e r i o d , and the b a s i c s o l u t i o n was r e f l u x e d f o r an hour under a n i t r o g e n atmosphere. Workup then gave a 45% y i e l d of pure o c t a l o n e , a 60% o v e r a l l y i e l d based on the 25% 2-methylcyclohexanone r e c o v e r e d . A l i q u o t samples taken before and a f t e r the base treatment - 59 -were analyzed by gas chromatography to p r o v i d e the data i n F i g u r e 1. Ignoring the s t a r t i n g m a t e r i a l , 2-methylcyclohexanone at R^ (R^ = r e t e n t i o n time i s ^ 2 m i n ) , the product r a t i o of compound 248 (R,. ,.): 246 (R g ) :234 ( R 1 Q ) i s 7:14:75 under Heathcock's procedure ( i . e . (a) i n F i g u r e 1) becoming 7:0:87 a f t e r subsequent sodium ethoxide treatment ( i . e . (b) i n F i g u r e 1). Since Rj. _ i s the b r i d g e d ketone 248, a compound unaffected by the base treatment and t h e r e f o r e a u s e f u l i n t e r n a l s t a n d a r d , the t o t a l dione 246 p l u s octalone 234 present i n (a) and the t o t a l octalone 234 present i n (b) compare favourably as 89 versus 87. 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 terms that i n c r e a s i n g the amount of a c i d c a t a l y s t decreased the R^/R^Q r a t i o (246:234), but i n c r e a s e d ^ / ^ Q (248:234). In c o n t r a s t to t h i s a c i d -c a t a l y z e d work where the b r i d g e d ketone 248 had to be removed by c a r e f u l d i s t i l l a t i o n , M a r s h a l l and F a n t a ' s e x p e r i m e n t a l l y more arduous b a s e -c a t a l y z e d procedure afforded o c t a l o n e 234 free of i m p u r i t i e s . The p r e p a r a t i o n of the corresponding c r o s s - c o n j u g a t e d cyclohexanone (_B, R1 = R 2 = R 3 = H; 300) was r e p o r t e d i n the 1950 work (104) of Woodward and Singh u s i n g two methods. The sodium enolate of 2-methyl-cyclohexanone was condensed w i t h methyl e t h i n y l ketone i n an e x t e n s i o n of 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 foot 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° with a f l o w - r a t e of 97 ml/min hel ium c a r r i e r gas. Chromatographic samples were washed with a c i d and base and then d r i e d over anhydrous magnesium s u l f a t e before use. - 60 -The condensation of 2-formyl-2-methylcyclohexanone (241, = R 2 = H) w i t h acetone, adapted from the elegant method of Wilds and D j e r a s s i (105) f o r the s y n t h e s i s of the t e t r a c y c l i c ketone 251 from the t r i c y c l i ketone 250, a f f o r d e d compound 300 i n 62% y i e l d . Adopting the l a t t e r sequence, dry e t h y l formate was added under i t r o g e n 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 o l u t i o n of cyclohexanone to a f f o r d the d e s i r e d 2-hydroxymethylene-yclohexane (255) on workup (106). The s o l u b i l i t y of the sodium s a l - 61 -of a l l hydroxymethylene d e r i v a t i v e s (254) i n water makes t h e i r i s o l a t i o n v i a aqueous base s i m p l e , but a i r o x i d a t i o n and decomposition makes them d i f f i c u l t to s t o r e . Because of t h i s i n s t a b i l i t y , compound 255 was methylated by C l a i s e n ' s method (106) immediately a f t e r i t s d i s t i l l a -t i o n . A mixture of the C - m e t h y l a t i o n and O-methylat ion products^ 256 and 257, were obtained by r e f l u x i n g the f r e s h l y d i s t i l l e d 255 and methyl i o d i d e i n an acetone s l u r r y of potassium carbonate. A 3:1 r a t i o of 256:257 was obtained as determined by n . m . r . i n t e g r a t i o n of the downfield aldehyde p r o t o n of 256 at x 0.48 r e l a t i v e to the o l e f i n i c C-7 proton o f 257 at T 2 . 8 . The methylated product mixture was then condensed w i t h acetone to a f f o r d the d e s i r e d c r o s s - c o n j u g a t e d system i n 9% o v e r a l l y i e l d from cyclohexanone. The o r i g i n a l work by Wilds and D j e r a s s i r e v e a l e d that the C -methylated product was q u i t e s e n s i t i v e to cleavage with l o s s of the formyl group. While sodium ethoxide and aluminum _t-butoxide caused cleavage i n the attempted condensation w i t h acetone to p r o v i d e 251, p i p e r i d i n e w i t h a s l i g h t excess of a c e t i c a c i d gave y i e l d s of up to 40% of compound 251 (105). For the p r e p a r a t i o n of the c r o s s - c o n j u g a t e d dienone 300, the analogous r e a c t i o n was found to a f f o r d , i n our hands, a 32% y i e l d . The s p e c t r a l data of t h i s product f u l l y c o r r o b o r a t e d the s t r u c t u r a l assignment and the d i e n o n e ' s data i s d i s c u s s e d w i t h an a l t e r n a t e s y n t h e s i s that p r o v i d e d the pure dienone 300 i n over 30% o v e r a l l y i e l d from 2-methylcyclohexanone. - 62 -B. Octalone 235 ( 4 a , 8 - D i m e t h y l - 4 , 4 a , 5 , 6 , 7 , 8 - h e x a h y d r o - 2 ( 3 H ) -naphthalenone) In analogy with octalone 234, the 8a-methyl s u b s t i t u t e d octalone 235 has been prepared by condensing methyl v i n y l ketone w i t h 2 , 6 -dimethylcyclohexanone. U n f o r t u n a t e l y , M a r s h a l l and Fanta (99) found t h i s method p r o v i d e d an impure product i n low y i e l d (< 20%). A year l a t e r , M a r s h a l l and Schaeffer (107) 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 i n a s i x - s t e p sequence from 2,6-dimethylcyclohexanone to p r o v i d e the d e s i r e d t r a n s - 4 a , 8 q - d i m e t h y l o c t a l o n e 235 i n about 40% o v e r a l l y i e l d . The cyclohexanone 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 (259) and the Y~chlorocrotylcyclohexanone product (260) was brominated and dehydrobrominated to the cyclohexenone d e r i v a t i v e 261. T h i s product was C l 2 5 8 2 5 9 2 6 Q 2 6 1 2 6 2 2 6 3 2 3 5 63 -then h y d r o l y z e d to the unsaturated dione 262 which i n t u r n was hydrogenated to the dione 263 and c y c l i z e d with base to a f f o r d the o c t a l o n e 235. The i n t r o d u c t i o n of the cyclohexene double bond was necessary because h y d r o l y s i s o f the v i n y l c h l o r i n e of 260 immediately caused the a l t e r n a t i v e a c i d - c a t a l y z e d a l d o l c y c l i z a t i o n of the i n t e r -mediate dione 263 and dehydration under the r e a c t i o n c o n d i t i o n s to 264. Caine and T u l l e r (108) subsequently r e p o r t e d a sequence that used b a s i c r e a c t i o n c o n d i t i o n s to o b t a i n o c t a l o n e 235 from compound 260. Dehydrohalogenation of 260 w i t h sodium amide i n ammonia proceeded q u a n t i t a t i v e l y 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 of the t r i p l e bond w i t h sodium amide i n r e f l u x i n g toluene p r o v i d e d the t e r m i n a l a c e t y l e n e 266 i n 73% y i e l d . 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 methanol-water and m e r c u r i c s u l f a t e c a t a l y s t y i e l d e d 96% of the dione 263 which 4 i ° v 2 6 4 2 6 5 2 6 6 c y c l i z e d i n 73% y i e l d to the o c t a l o n e 235. The f i v e steps of Caine and T u l l e r ' s p r e p a r a t i o n afforded an o v e r a l l 35% y i e l d of 235 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 that Heathcock's a c i d - c a t a l y z e d Robinson a n n e l a t i o n procedure (100) c o u l d 19 p r o v i d e the d e s i r e d octalone 235. In F i g u r e 2, the gas chromatogram (a) i l l u s t r a t e s the very low y i e l d of o c t a l o n e 235 prepared by r e f l u x i n g - 64 -2 , 6 -dimethylcyclohexanone and methyl v i n y l ketone w i t h a c a t a l y t i c amount of s u l f u r i c a c i d . The d e s i r e d o c t a l o n e has a r e t e n t i o n time of approximately 14 minutes (R-j^) versus the b r i d g e d ketone ( 2 6 4 ) at and 2 , 6 - d i m e t h y l c y c l o h e x a n o n e ( 2 5 8 ) at R2« However, treatment f o r one hour w i t h a r e f l u x i n g 0 . 5 molar sodium ethoxide i n e t h a n o l s o l u t i o n caused a dramatic s h i f t to a more favourable s i t u a t i o n as i l l u s t r a t e d by (b) i n F i g u r e 2 . Upon workup, a c o n s i d e r a b l e amount of 2 , 6 - d i m e t h y l -cyclohexanone was recovered ( 4 6 - 6 4 % ) and both the u n d e s i r a b l e R^ component ( ^5% i n pure form) and octalone 235 ( 2 0 - 2 5 % ) were c l e a n l y separated by d i s t i l l a t i o n . The o c t a l o n e 2 3 5 a f f o r d e d by t h i s procedure was i d e n t i c a l by an a n a l y t i c a l i n f r a r e d comparison w i t h an a u t h e n t i c sample of o c t a l o n e 235 prepared by an a l t e r n a t e unambiguous route d e s c r i b e d subsequently. However, s i n c e the y i e l d of pure o c t a l o n e 2 3 5 from t h i s one-pot r e a c t i o n i s g r e a t e r than 40% based on unrecovered 2,6 -dime'thylcyclohexanone, the above procedure p r o v i d e s a very a t t r a c t i v e a l t e r n a t i v e to the s i x - and f i v e - s t e p l i t e r a t u r e sequence. The i m p u r i t y at R, c , being a v a i l a b l e 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 assigned the b r i d g e d ketone s t r u c t u r e 2 6 4 . The compound e x h i b i t e d the s p e c t r a l data p r e v i o u s l y r e p o r t e d f o r t h i s compound ( 1 0 7 ) and was very s i m i l a r to that observed e a r l i e r f o r the 1-desmethyl compound ( 2 4 8 ) . In the n . m . r . , the C - l t e r t i a r y methyl (T 8 . 9 ) i n 264 r e p l a c e d the C - l one proton resonance (T 7 . 3 ) i n 2 4 8 , but the J C 2 ( C H 3 ) - C 3 H = 1 ' 5 H Z > J C 2 ( C ^ - c V , = 2 ' 2 H z a n d ^ H - C ^ = 3 . 4 Hz were the same i n both compounds. The i n f r a r e d c a r b o n y l ( 1 7 2 0 cm--'-) and double bond ( 1 6 7 5 cm L ) a b s o r p t i o n s were i d e n t i c a l and both u l t r a v i o l e t spectrums e x h i b i t e d a weak 235 my shoulder 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 present i n chromatogram (a) of Figure 2 were i s o l a t e d by preparative gas chromatography and demonstrated to have nearly superimposable a n a l y t i c a l i n f r a r e d spectrum showing a 1710 cm ^ carbonyl 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 absorption below 220 my. Both n.m.r. spectrums showed an a c e t y l methyl (T 7.88 and 7.83 r e s p e c t i v e l y ) , a methyl doublet with J = 6.4 Hz (x 9.01 i n both spectra), a t e r t i a r y methyl (x 9.01 and 8.82 r e s p e c t i v e l y ) , and eleven other protons based on the i n t e g r a t i o n of the downfield a c e t y l methyl. Acid-catalyzed epimerization of e i t h e r pure compound with concentrated hydrochloric acid r e s u l t e d i n the growth of the other's t e r t i a r y methyl and a c e t y l methyl i n the n.m.r. spectrum u n t i l a 60:40 r a t i o was established, the same r a t i o as observed i n Figure 2 (a). The 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 chromatograph are s u r p r i s i n g since these two compounds are obviously the two methyl epimers of compound 263. The shorter retention time component was assigned the cis-2,6-dimethyl dione structure 263a and the longer retained component the trans-2,6-dimethyl structure 263b on the basis that the C - l carbonyl was exerting an a n i s o t r o p i c e f f e c t on the t e r t i a r y methyl. The e q u a t o r i a l C-2 methyl of 263a therefore 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 enol ized i n base to y i e l d 268. This intermediate i s protonated under the react ion condit ions to af ford the thermodynamically more stable 8a-methyl octalone. The st ructure and stereochemistry assigned to octalone 235 was confirmed by undertaking i t s synthesis by another approach. 2 6 7 2 6 8 2 3 5 The cross-conjugated cyclohexanone (B, = 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 for 300. Dry e thy l formate was added under nitrogen to a s lu r r y of a l coho l - f ree sodium methoxide i n a benzene so lu t ion 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 iodide i n r e f l u x i n g acetone so lu t ion 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 ind icates s i m i l a r d i f ferences 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 basis of aromatic solvent- induced s h i f t studies i n benzene on the mixture of isomers (110). - 68 -a s l u r r y of potassium carbonate. A 3:1 r a t i o of 271:272 was obtained as determined by n . m . r . i n t e g r a t i o n of the downfield aldehyde p r o t o n of 271 at T 0.30 and 0.52 i n r e l a t i o n to the o l e f i n i c C-7 proton of 272 at x 2.80. Of g r e a t e r i n t e r e s t i s the presence of the two aldehyde isomers, 271a and 271b (271a:271b r a t i o i s approximately 2:1) , which were assigned t h e i r s t e r e o c h e m i s t r y on the b a s i s of the a n i s o t r o p i c e f f e c t of the C - l c a r b o n y l on the t e r t i a r y methyl group. The major H epimer 271a shows x 0.52 ( s i n g l e t , I H , -CHO) and 8.78 ( s i n g l e t , 3H, t e r t i a r y methyl) s i g n a l s i n the n . m . r . w h i l e the other e x h i b i t s x 0.30 ( s i n g l e t , I H , -CHO) and 8.63 ( s i n g l e t , 3H, t e r t i a r y methyl) s i g n a l s . The methylated product mixture was condensed w i t h acetone i n a r e f l u x i n g s o l u t i o n that contained p i p e r i d i n e and a s l i g h t excess of a c e t i c a c i d . 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 c r o s s - c o n j u g a t e d system 301 i n 23% o v e r a l l y i e l d from 2-methylcyclohexanone. A n a l y t i c a l - 69 -samples were obtained by c r y s t a l l i z a t i o n from hexane and e x h i b i t e d p h y s i c a l and s p e c t r a l data which were i n good agreement w i t h that p r e v i o u s l y p u b l i s h e d (111). The s t e r e o c h e m i c a l r e l a t i o n s h i p between the methyl groups o f 301 has been proven by Bloom (112) to be t r a n s . T h e r e f o r e , s e l e c t i v e hydrogenation of only the d i s u b s t i t u t e d double bond of 301 under n e u t r a l 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 t r a n s - 4 a , 8 - d i m e t h y l octalone (235). T h i s s e l e c t i v e r e d u c t i o n was accomplished i n 99% y i e l d by u s i n g a benzene s o l u t i o n of the homogeneous hydrogenation c a t a l y s t t r i s ( t r i p h e n y l -phosphine)chlororhodium to hydrogenate the dienone 301 at atmospheric p r e s s u r e . 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 to that prepared by the a c i d - c a t a l y z e d 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 s y n t h e s i s of the d e s i r e d 8a-methyl o c t a l o n e 235, but the procedure lacked g e n e r a l i t y s i n c e other 8 a - s u b s t i t u t e d octalones (236 w i t h i t s 8a-acetoxy f o r example) c o u l d not be c o n v e n i e n t l y prepared t h i s way. In view of the o c t a l o n e 234 on hand and our d e s i r e to prepare a wider v a r i e t y of hydronaphthalenones s u b s t i t u t e d at the 8 - p o s i t i o n (8a-acetoxy or 8 a - a l k y l (^CH^)), c o n s i d e r a t i o n was g i v e n to methods of i n t r o d u c i n g s u b s t i t u e n t s y to a , 8 -unsaturated ketones. The V i l s m e i e r reagent, phosphoryl c h l o r i d e i n X OAc 278a 278 b - 70 -dime thylformamide, has been used to prepare the octalone 278a and the s t e r o i d 278b from t h e i r corresponding y-desmethyl compounds (50,114 ) . The conjugated enone 273 was converted to i t s e n o l ether 274 (R' = C H 3 or CR^CH^) and r e a c t e d w i t h the V i l s m e i e r reagent to y i e l d the s a l t 275 which, on h y d r i d e r e d u c t i o n (sodium b o r o h y d r i d e or l i t h i u m aluminum h y d r i d e ) , afforded the amine 276. 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 the e n o l ether 277 by h y d r o g e n o l y s i s and the d e s i r e d y - m e t h y l a,3 - u n s a t u r a t e d 276 277 278 ketone 278 was obtained by a c i d h y d r o l y s i s . While the octalone 278a was prepared from i t s p r e c u r s o r 273 (R = 5B-0Ac) i n 75% o v e r a l l y i e l d (50), and w h i l e such i n t e r m e d i a t e s as 275 have been used to o b t a i n other Y ~ s u b s t i t u e n t s ( f o r m y l , hydroxymethyl and methylene (114^)), another more g e n e r a l r e a c t i o n sequence that had been u t i l i z e d i n s t e r o i d chemistry appeared more a t t r a c t i v e . - 71 -K e t a l i z a t i o n and epoxidation of a,6-unsaturated ketones (273) r e a d i l y provide such 8,Y-epoxy s t e r o i d a l k e t a l s as 280 i n high y i e l d . In 1958, Campbell e_t a l . (115) reported the preparation of several 6a-methylandrostenones (278b, X = H, 6-OH f o r example) from t h e i r corresponding androst-4-en-3-ones (273) by cleaving the epoxide of 280 with methylmagnesium bromide, removing the k e t a l with aqueous a c i d and dehydrating and isomerizing to 278 with base. Zderic e_t a l . (116) have introduced a phenyl group i n an analogous manner to obtain an 80% y i e l d of the 66-phenyl d e r i v a t i v e of progesterone (281, C-17B-C(OCH2CH20)CH3) by adding phenylmagnesium bromide to the corresponding epoxy k e t a l 280. 2 7 3 279 281 2 8 2 2 7 8 - 72 -When the o c t a l o n e 234 was k e t a l i z e d with ethylene g l y c o l i n toluene c o n t a i n i n g a c a t a l y t i c amount of p - t o l u e n e s u l f o n i c a c i d , a 73% y i e l d of doubly d i s t i l l e d dioxolane 283 was o b t a i n e d . Gas chromatography and n . m . r . a n a l y s i s i n d i c a t e d 6% of the octalone was s t i l l p r e s e n t , an o b s e r v a t i o n that has been r e p o r t e d p r e v i o u s l y (117). The dioxolane methylene protons at x 6.03 ( s i n g l e t , 4H,-OCI^CH^O-) and the broadened s i g n a l at x 4.63 ( m u l t i p l e t , I H , =CH-) confirmed that 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 of the l a t t e r w i t h m - c h l o r o -perbenzoic a c i d i n dichloromethane 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 a ) then a f f o r d e d , a f t e r d i s t i l l a t i o n , an 87% y i e l d of a 40:60 mixture of the two epoxy k e t a l s (284). In view of the subsequently d i s c o v e r e d 2 3 4 2 8 3 2 8 4 a 2 8 4 b d i f f e r e n c e s i n r e a c t i v i t y of these two compounds, the major isomer, having s i g n a l s at x 8.92 ( s i n g l e t , 3H, t e r t i a r y methyl) and x 7.04 g ( m u l t i p l e t , I H , C H) i n the n . m . r . , was assigned the c i s - s t r u c t u r e 284b w h i l e the minor isomer, having s i g n a l s at x 8.87 ( s i n g l e t , 3H, t e r t i a r y g methyl) and x 7.17 ( m u l t i p l e t , I H , C H ) , was designated as the t r a n s -isomer 284a. In support of these assignments, the d e c a l i n s 285, R = H (118 a ) and 285, R = CH 2 0H, C ( C H 3 ) 2 0 H (118 b ) have been r e p o r t e d to y i e l d a 60:40 y i e l d of the analogous epoxides 286a and 286b w i t h the 286, R = H compounds having n . m . r . methyl resonances at 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 r i g o r o u s s t r u c t u r a l proof have shown that the trans-isomer 286"a predominates (118 ) . However, M a r s h a l l e_t a l . (117) found the h y d r o b o r a t i o n o f the k e t a l 283 fol lowed by o x i d a t i o n of the r e s u l t i n g organoborane with a l k a l i n e hydrogen peroxide p r o v i d e d only 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 expected on the s t e r i c grounds that the a x i a l oxygen of the k e t a l group i n 283 b l o c k e d the a - f a c e o f the m o l e c u l e . Therefore our observed 40:60 r a t i o of a : 8 e p o x i d a t i o n of the k e t a l 283 i s a c t u a l l y l e s s s t e r e o s e l e c t i v e w i t h r e s p e c t to the 8-isomer than might be expected (119). When the epoxide mixture 284a+b was t r e a t e d w i t h methylmagnesium bromide i n t e t r a h y d r o f u r a n or hexamethylphosphoramide under a n i t r o g e n atmosphere at 3 5 ° , the a-epoxide 284a was r a p i d l y c l e a v e d , but the 8-isomer was recovered unchanged a f t e r p e r i o d s of up to 60 h o u r s . T h i s was not completely unexpected s i n c e M a r s h a l l e_t a l . found that r e f l u x i n g a 60:40 mixture of 286a:286b (R = H) i n anhydrous t e t r a h y d r o -furan w i t h methylmagnesium bromide f o r 32 hours cleaved the trans-isomer In c o n t r a s t , 284a and 284b were r e a d i l y separated by g . l . c . u s i n g a 10 foot x 0.25 i n c h column packed with 20% SE 30 on 60/80 mesh Chromosorb W at 1 8 5 ° . 285 286q 286b - 74 -286a n e a r l y c o m p l e t e l y , but only c leaved t w o - t h i r d s of the c i s - i s o m e r (118). T h e i r work a l s o showed that w h i l e 85% of the t r a n s - i s o m e r c o u l d be accounted f o r by g . l . c . a n a l y s i s of the product m i x t u r e , only 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 . The i n t r o d u c -t i o n of the C-2 gem s u b s t i t u e n t s i n the k e t a l 284a must t h e r e f o r e make the a - f a c e s u f f i c i e n t l y s t e r i c a l l y hindered to prevent the a d d i t i o n of the G r i g n a r d reagent. In e x p e c t a t i o n that a l k y l l i t h i u m s would be b e t t e r n u c l e o p h i l e s (120), m e t h y l l i t h i u m a d d i t i o n to the epoxides 284a+b i n e t h y l ether was t r i e d a t 0° f o r 12 h o u r s , 20° f o r 12 hours and 35° f o r 24 h o u r s . At 0° o n e - t h i r d o f the ct-epoxide and a l l o f the 8-epoxide were recovered unchanged, w h i l e at 20° and 35° none of the a and a l l of the 6 were r e c o v e r e d . When 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 t e t r a h y d r o f u r a n f o r 2 h o u r s , a l l the * a - e p o x i d e , a s u b s t a n t i a l amount of the k e t a l and l i t t l e , i f any of the 0-epoxide were opened. By c o i n c i d e n c e , 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 and other organocopper reagents on cyclohexene oxide (122). The r e p o r t i n d i c a t e d that l i t h i u m d i a l k y l c u p r a t e s are more r e a c t i v e towards epoxides than the corresponding a l k y l l i t h i u m s and p o s s i b l y are s u p e r i o r to the a l k y l l i t h i u m s with r e s p e c t to y i e l d s of 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 . Since d i a l k y l c u p r a t e s are known - 75 -to be r e l a t i v e l y i n e r t to s a t u r a t e d c a r b o n y l s , l e t alone k e t a l s (123), 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 even the cx-epoxide was not c leaved over an 18 hour p e r i o d at room temperature w i t h a f i v e - f o l d excess of l i t h i u m d i m e t h y l c u p r a t e . C . Octalone 236 ( 8 a - A c e t o x y - 4 a - m e t h y l - 4 , 4 a , 5 ,6, 7 ,8-hexahydro-2(3H)-naphthalenone) The r e s i s t a n c e of the a-epoxide to n u c l e o p h i l i c a t t a c k had been so 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 i t was easy to be apprehensive about opening both 284a and 284b w i t h h y d r o x y l i c n u c l e o -p h i l e s . However, 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 monitored 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 that 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 k e t a l . 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 that the dioxolane grouping can be removed by the f o l l o w i n g fragmentation mechanism. 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 with the above Grignard 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 temperature. 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. 1 ii - 76 -under the same c o n d i t i o n s . 22 Since t h i s d i o l had p r e v i o u s l y been a c e t y l a t e d to the monoacetate 289 and dehydrated with concomitant 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 to a f f o r d 290 (125), there was some l i t e r a t u r e precedence f o r t r e a t i n g 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 acetone, a c e t i c anhydride i n p y r i d i n e and anhydrous hydrogen c h l o r i d e i n chloroform to p r o v i d e 236. The a d d i t i o n of a c i d c a t a l y s t (HCIO^) al lows 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 of the oxirane i n a t r a n s - d i a x i a l manner i s demonstrated very 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 with anhydrous hydrogen c h l o r i d e of 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-epoxide 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). ^CH 2OAc ...OH OH 2 8 7 a a-epoxide 288 B ii - 77 -2 8 4 g + b 2 9 2 2 3 6 When t h i s sequence was a p p l i e d to the epoxy k e t a l 284, the crude product of t h i s sequence (obtained i n 20% y i e l d o v e r a l l ) was found to be a mixture of the dione 294 and an a c e t o x y - s u b s t i t u t e d o c t a l o n e (236?). I n f r a r e d and n u c l e a r magnetic resonance s p e c t r a supported the s t r u c t u r a l assignments, but a c o n s i d e r a b l e amount of m a t e r i a l was l o s t i n the aqueous l a y e r of the workup of 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 r e a c t i o n . While g . l . c . m o n i t o r i n g of the d i o l 292 p r e p a r a t i o n was not f e a s i b l e because of the l a b i l e nature of 292, most o f the k e t a l (284) was shown by g . l . c . to be removed a f t e r the f i r s t hour of the twenty-hour h y d r o l y s i s r e a c t i o n . The dione 294 was r a t i o n a l i z e d to be the r e s u l t of d e h y d r a t i o n of the t e r t i a r y h y d r o x y l (C-8a) of 292, e n o l i z a t i o n of 293 to remove the 1 , 3 - d i a x i a l i n t e r a c t i o n , - 78 -292 293 294 and enolization to the dione 294 occurring much more readily than i n steroidal systems. The dione 294 was also prepared by a 20 min steam bath treatment of the epoxy ketal 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 ketal 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,8-unsaturated 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 direct epoxidation of 341 (i.e. deconjugated octalone 234) (155) failed since the competing Baeyer-Villiger reaction (128) led to a crude reaction product mixture that was predominantly lactones iL and i i . 341 2 9 1 i i i -- 79 -O 291 O having a B>Y_epoxy f u n c t i o n a l i t y . When the k e t a l of 284a+b was removed w i t h h y d r o c h l o r i c a c i d (.1 N 2 N) i n dioxane or acetone, some o f the dione 294 was a l s o produced, even a f t e r o n l y s h o r t p e r i o d s . A one hour treatment of 284 w i t h 1 ml of 1.5 N p e r c h l o r i c a c i d i n 40 ml acetone was found to be b e s t , but the subsequent treatment at room temperature w i t h a c e t i c anhydride i n p y r i d i n e was found to y i e l d a mixture of a c e t a t e - c o n t a i n i n g p r o d u c t s . S e v e r a l attempted m o d i f i c a t i o n s l e d to the same mixture of four r e a c t i o n p r o d u c t s . The work on t h i s approach was t h e r e f o r e d i s c o n t i n u e d . There i s l i t e r a t u r e precedence f o r i n t r o d u c i n g the y - a c e t o x y s u b s t i t u e n t through sequences that 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 of the e n o l a c e t a t e of the conjugated ketone (131^), y - b r o m i n a t i o n with N-bromosuccinimide (297), or y - h y d r o x y l a t i o n w i t h selenium d i o x i d e on a , 8 - u n s a t u r a t e d O COOH Br COOH 2 9 7 1Q6 2 9 6 O - 80 -ketones (296), or hydroxylation 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 autoxidation of 298 i n the presence of a l k a l i hydroxide, sodium isopropoxide, or other bases. The autoxidation even occurred i n aqueous piperidine, but at a much slower rate than i t did i n concentrated base. The influence of the 7a-substituent was demonstrated by the observation that the corresponding 76-compounds (307) provided only a small amount of 309 and none of the 25 expected 308. _ Santonin was synthesized v i a the sequence 296 -»• 297 106 (131) and A3-296 ->- 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 derivative was demonstrated by the destruction of the acetoxy substituent i n the readily available compound i_ (132) when hydroxyme'thylation was attempted on this ct-acetoxy ketone. An approach analogous to this one was considered i n one of the e a r l i e r santonin (106) syntheses (131 a). OAc OAc OAc L ii 302 The s t a b i l i t y of 299 to refluxing aqueous alcoholic potassium hydroxide ( i . e . to isomerization to the corresponding 2,8-dione) was rat i o n a l i z e d to be due to the deformation of ring B to a boat confirmation. The influence of C-7 stereochemistry was then related 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 -2 9 8 R = / 3 - H 3Q7 R = a — H 2 9 9 R = / 3 - H 2Q9_ 3 Q 8 R = a - H While the b a s i c c o n d i t i o n s that were employed i n the above r e a c t i o n (to both generate the enolate and then to reduce by h y d r o l y s i s the hydroperoxide i n t e r m e d i a t e ) p r e c l u d e d i t s being used i n a sequence l e a d i n g to the d e s i r e d o c t a l o n e 236, molecular oxygen has 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 , processes to prepare an i s o l a t a b l e y-hydroperoxide which, a f t e r m i l d r e d u c t i o n w i t h sodium i o d i d e or 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 the y-hydroxy-a,8-unsaturated ketone. The f i r s t of these oxygenation r e a c t i o n s uses the 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 w i t h ground s t a t e 3 -( t r i p l e t ) oxygen ( I ) i n a f r e e r a d i c a l process that probably i n v o l v e s 6 * the mesomeric r a d i c a l 311 (133,135,142) w h i l e the second u t i l i z e s e x c i t e d s t a t e ( s i n g l e t ) oxygen (^Z + or *A ) ^ on a 8 ,Y-unsaturated 26 These two metastable 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 occupied molecular ( 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 other v a c a n t . State Relative Energy (Kcal) O f'2 37 Configuration of the highest occupied orbitals - 82 -ketone in a concerted process that involves either a cis-"ene" (313a) or "perepoxide" (313b, peroxirane) transition state (136,143). These two processes are easily 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 solution of the norandrost-5,10-en-3-one 315 (X = -C=CH), after exposure to fluorescent light under an oxygen atmosphere, yielded 40% of the 103-hydroperoxy compound 316 (147) was later followed by a communication (136) that found the photosensitized irradiation of A free radical oxygenation process (J02) can be accomplished with oxygen and base (133), oxygen and peroxides (146), or oxygen in an unsensitized photolysis (135) while the excited singlet state oxygenation process ( I O 2 ) requires photo-oxygenation in the presence of a sensitizing dye (139,140), positive halogen compounds (hypo-chlorites, etc.) with hydrogen peroxide (•'•Ag only) (137,141), or a radiofrequency (6.7 Mc) discharge i n gaseous oxygen (138). - 83 -315 (X = H) i n p y r i d i n e afforded 45% of the corresponding 10B-hydroperoxy ketone 316. The f i r s t r e a c t i o n r e q u i r e s a free r a d i c a l c h a i n process i n v o l v i n g the g e n e r a t i o n of a mesomeric a l l y l i c r a d i c a l by a b s t r a c t i o n of the C-4 hydrogen w h i l e the second uses the p h o t o -1 28 e x c i t e d s i n g l e t s t a t e oxygen ( 0^). For reasons that w i l l be c o n s i d e r e d below, i t appears that 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 give d i s t i n g u i s h a b l e products i n a molecule where d i a s t e r e o i s o m e r s are p o s s i b l e when the oxygenated p o s i t i o n i s secondary r a t h e r than t e r t i a r y . H O X H O X 315 316 ^ 8 The nature of the "L02 s p e c i e s ( X Ag or X£g> or 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 , concerted processes w h i l e the -^Eg s t a t e should 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 with the l i f e t i m e of 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 that both -'•Eg and -^ Ag oxygen molecules 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 product 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 of 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 context of t h i s t h e s i s the symbol ^2 i s used without s p e c i f y i n g -*-Ae or -'-Eg s t a t e s . - 84 -In an e a r l y example o f the a u t o x i d a t i o n p r o c e s s , F i e s e r et a l . (146) found that c h o l e s t - 5 - e n - 3 - o n e i n a hexane s o l u t i o n at 25° combined w i t h molecular oxygen i n the presence of d i b e n z o y l peroxide (a r a d i c a l i n i t i a t o r ) to give 6(a p l u s 8 ) - h y d r o p e r o x i d e . A r e p o r t was made i n 1964 (147) that an attempted chromatography over s i l i c a g e l o f the 0 , y - s t e r o i d a l enone 317 y i e l d e d a mixture of the 6(ct p l u s 8 ) -hydroperoxides 318. Nickon and Mendelson then d i s c o v e r e d i n 1965 that c h o l e s t - 5 - e n - 3 - o n e photo-oxygenation (without a s e n s i t i z e r ) and r e d u c t i o n o f the photo-product w i t h sodium i o d i d e afforded a mixture of the 6(a p l u s B ) - a l c o h o l s . A c u r r e n t (1973) r e - e x a m i n a t i o n of OH OH 317 OOH 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 . (150 ) has r e s u l t e d i n the i s o l a t i o n of 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 from samples of c r y s t a l l i n e c h o l e s t e r o l s t o r e d at 70° i n a i r f o r one month. The i s o l a t i o n of the 68- but not the 6a-isomer (probably formed v i a A^-3-one) i n t h i s work suggests that a u t o x i d a t i o n i n i t i a l l y y i e l d s only the 68-hydroperoxide from t r i p l e t oxygen. I n t e r e s t i n g l y , Smith et a l . (150^) a l s o d i s c o v e r e d that secondary a l l y l i c hydroperoxides can be r e a d i l y epimerized ( i . e . 319 320). T h e r e f o r e , the e a r l i e r observed 6(a p l u s 8)-hydroperoxy mixtures could r e a d i l y be r a t i o n a l i z e d - 85 -AcO 319 3 2Q as occurr ing from epimerizat ion 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 st ructure 321) are completely oxidized i n 2 h at 30° 4 i n d i rec t sunl ight by an autoxidat ion process to give 6-hydroxy-A -3-ketones (322) (151) supports the above argument because the r a t i o general ly observed between the 68- and 6a-epimers was found to be at leas t e ight - ten to one. The cholest -5 -en -3 -one i s the only example of a photosensit ized oxygenation (^C^) studied to date where a B,Y -enone y ie lds a secondary hydroperoxy subst i tuted product. However, oxygenations of 8,Y~enones with s ing le 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 extensively studied general hydroperoxy-OH 321 R = alkyl 322 < - 86 -l a t i o n s of o l e f i n s . The f i e l d of oxygenation of monoolefins has been r e c e n t l y reviewed elsewhere (142-145) and only a summary of the p r i n c i p l e s i s c o n s i d e r e d h e r e . S i n g l e t oxygenation of the monoolefin i s always accompanied by the concommitant s h i f t of the double bond without the intermediacy of f r e e r a d i c a l s . An a n a l y s i s o f the r e a c t i o n products o f t e n shows that a h i g h degree o f both r e g i o - s e l e c t i v i t y and s t e r e o s e l e c t i v i t y i s e x h i b i t e d . In the case of (+)-limonene, the presence of o p t i c a l l y a c t i v e ( - ) - c i s - a n d ( + ) - t r a n s - a l c o h o l s 324 and 325 a long w i t h other compounds i n the r e a c t i o n mixture (324-329) was r e a d i l y understood i n terms of the concerted c i s - a t t a c k by ^O^ 29 on the t r i s u b s t i t u t e d double bond and the a l l y l i c hydrogen. Taking 326 327 328 329 2 9 The m e c h a n i s t i c d i f f e r e n c e s of a u t o x i d a t i o n ( 02) were i l l u s t r a t e d when the 3o2 oxygenation of 323 was found to y i e l d the racemates corresponding to 324 and 325 and none of the e x o c y c l i c (326, 327) p r o d u c t s . - 87 -into account the conformational analysis of (+)-limonene and assuming that the transition state for the cyclic product-forming step resembles starting olefin more than i t does the a l l y l i c hydroperoxide products, the product distribution of 324 (5%):325 (10%):326 (21%):327 (20%):328 (34%):329 (10%) was readily.rationalized. Reaction on the favoured conformation of 323 (E 330) gave ^0^ the choice of several quasi-axial (a') and quasi-equatorial (e 1) hydrogens. In the case of (+)-limonene, as is generally found, the predominant product at each position always favoured the a' hydrogen abstraction. 331 Conformationally r i g i d steroidal olefins provide even better examples of stereoselectivity since pronounced steric interactions are also exhibited during singlet oxygenation. In cholesterol (331, R = OH) there are two equatorial/quasi-equatorial hydrogens, '4a-H/78-H, and two axial/quasi-axial hydrogens, 48-H/7a-H. Since a cyclic step involving the 48 axial 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 is 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 stereospecificity 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 to 332 (95%-7-d) and cholesterol-7ct-d_ to 332 (8.5% 7-d_) . The i n e r t n e s s of the a l l y l i c 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 that c o p r o s t - 6 - e n e (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 hydrogen i n the ( n o n - f l e x i b l e ) B r i n g d i d not undergo oxygenation. S t e r i c b l o c k i n g 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 t h i s work. Since the preceding examples demonstrate that photo-oxygenation can be s u b s t a n t i a l l y blocked 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 s u b s t i t u e n t or when the a l l y l i c 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 (135), the r e p o r t that p h o t o s e n s i t i z e d oxygenation o f c h o l e s t - 5 - e n - 3 - o n e (334) y i e l d e d the 68-hydroperoxide as the major product (134) was s u r p r i s i n g . A r e i n v e s t i g a t i o n of the r e a c t i o n by Nickon and Mendelson (135) concluded that the expected product of ^0^ h y d r o p e r o x y l a t i o n , 335, was produced to the extent of ^35%. T h e i r attempted i s o l a t i o n of the corresponding 5 a - a l c o h o l (obtained a f t e r r e d u c t i o n ) by column chromatography r e s u l t e d i n a 27% y i e l d of the dehydrated compound c h o l e s t - 4 , 6 - d i e n e - 3 - o n e . However, 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 was i s o l a t e d i n 16% y i e l d - 89 -C H I 8 17 335 336 as the corresponding alcohol after reduction and was found to be a mixture of the 6a- and~6g-epimers. These C-6 oxygenated products were considered to be derived from the competing free-radical process 3 30 ( 0 2)• However more recently, Nakanishi et a l . (136) demonstrated (without bothering to refer to earlier work) that a concerted cyclo-addition at C-6 of cholest-5-en-3-one was occurring with excited singlet state oxygen. They employed stereospecifically deuterated 2 (90% 48- H) cholest-5-en-3-one (partial structure 337) and recovered the hydroperoxide 339 labelled with deuterium at C-4 (85%). Although ' 337 338 339 Nickon and coworkers had previously found examples of conventional-type autoxidation competing with the expected photosensitized pathway, in reactions on steroidal olefins (152). In at least one case with -k^, a free-radical inhibitor (2 ,6-di-_t-butylphenol) has been used to suppress radical reactions with while reactions were being studied. This technique does not appear to have been used in any photosensitized studies. - 90 -t h i s 1968 communication does not give many d e t a i l s and the f u l l paper has not yet appeared, a u t o x i d a t i o n would be expected to a b s t r a c t the q u a s i - a x i a l 46-hydrogen ( r i n g A i n c h a i r , see 331 where R i s = 0) and almost c e r t a i n l y give some ( a l l ? ) of the 68-hydroperoxide. With some c o n s i d e r a t i o n of 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 aspects of the p r e c e d i n g work, the y - a c e t y l a t i o n of o c t a l o n e 234 was undertaken by a sequence 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 y - h y d r o p e r o x y l a -31 t i o n of the corresponding 6,y-enone 341. This unconjugated o c t a l o n e 3 4 2 295 236 ~5J" While oxygenation of the corresponding enol ethers of conjugated ketones (151) appears to be the best 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 oxygenation appears to be the most u s e f u l x02 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 oxygena-t i o n has been used i n sesquiterpene work only on o l e f i n s ( J . A . M a r s h a l l and coworkers ( 1 1 8 a , 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 (136). - 91 -341, p r e v i o u s l y prepared from octalone 234 by Ringold and Malhotra through an acid-quenched e n o l i z a t i o n procedure, was i s o l a t e d i n h i g h y i e l d by f o l l o w i n g t h e i r method (155). The enolate anion of octalone 234 was generated w i t h potassium t^-butoxide i n _t-butanol and the corresponding anion 340 was t r e a t e d w i t h aqueous a c e t i c a c i d . As has been p r e v i o u s l y r e p o r t e d (155), the very h i g h c o n c e n t r a t i o n of enolate present i s i r r e v e r s i b l y protonated at C - l by the 10% aqueous a c e t i c a c i d to y i e l d 341. However, w h i l e the o r i g i n a l procedure was w r i t t e n f o r mg q u a n t i t i e s of o c t a l o n e 234 (a t y p i c a l example quoted would r e q u i r e <200 mg o c t a l o n e ) w i t h 10 e q u i v a l e n t s of base f o r 1.5 hours to o b t a i n 80% deconjugation ( i . e . the r a t i o of 234:341 i s 2 0 : 8 0 ) , 32 a modif ied form of t h e i r procedure was found to deconjugate up to 96% of o c t a l o n e 234 on l a r g e s c a l e . No attempt was made to determine the i s o l a b l e y i e l d of completely pure 8,Y~unsaturated ketone 341 because of the r e l a t i v e d i f f i c u l t y i n v o l v e d . The 96% pure compound was r e a d i l y i d e n t i f i e d as 341 by i t s s p e c t r a l d a t a . The deconjugation of 234 to 341 was accompanied by the removal of >90% of the 240 my u l t r a v i o l e t a b s o r p t i o n , a s h i f t i n the i n f r a r e d of the c a r b o n y l a b s o r p t i o n from 1670 to 1725 cm X , a n d the v i r t u a l removal of the T 4.29 (CXH) v i n y l a b s o r p t i o n of 234 w i t h the subsequent appearance of a q u a r t e t m u l t i p l e t centered at T 4.60 i n the n . m . r . In a d d i t i o n , the 32 Twenty grams (0.122 moles) of 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 ) that had reacted with 250 ml _t-butanol In 100 ml of diglyme. 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 of 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 with 500 ml of 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 organic 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 over magnesium s u l f a t e , and concentrated under reduced p r e s s u r e . - 92 -C°H of 341 would be expected to be coupled to the C-7 methylene and appear at % 4.6 x as i t d i d i n compound 283. Quite unexpectedly, i t was found that compound 341 was not isomerized on the gas chromatograph to 234 and t h e r e f o r e the r e l a t i v e amount of deconjugation 19 could be measured v e r y a c c u r a t e l y on a 20% SE 30 column at 185° because 234 and 341 e x h i b i t e d d i f f e r e n t r e t e n t i o n times under these c o n d i t i o n s . While even p u r i f i e d samples of 8 > Y - e n o n e s have been found to undergo p a r t i a l conjugation on s t a n d i n g at 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 , the deconjugated octalone 341 c o u l d be s t o r e d at 0° (where i t c r y s t a l l i z e d s lowly) without these s i d e r e a c t i o n s . Using the 8,Y - enone 341 now a v a i l a b l e , the c h o l e s t - 5 - e n - 3 - o n e oxygenation procedure 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 w i t h Rose Bengal was fol lowed (136). To monitor t h i s 3~3 Rose Bengal ( i ) i s 4 , 5 , 6 , 7 - t e t r a c h l o r o - 2 ' , 4 ' , 5 1 , 7 1 - t e t r a i i o d o f l u o r e s -c e i n potassium (or sodium) d e r i v a t i v e potassium (or sodium) s a l t (142). 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 Nickon ejt a l . have used a mixture 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). - 93 -p h o t o l y s i s of 0.2 molar octalone i n p y r i d i n e s o l u t i o n w i t h a 275 35 watt sunlamp b u l b , a l i q u o t s were removed and worked up for a n a l y s i s . Since the octalone 341 and y-hydroperoxide product 342 were not expected to be very s t a b l e , i t was not s u r p r i s i n g to f i n d that g . l . c . analyzed samples contained mainly a mixture of octalone 234, d e r i v e d from 341, and a longer r e t e n t i o n time component that was i d e n t i f i e d as the enedione 343, produced by thermal dehydration of 342. In an attempt to c l a r i f y the stereochemistry of the C-8 oxygenated product 344 j C H 3 342, the crude p h o t o l y s i s product was a c e t y l a t e d by treatment w i t h (a) a c e t i c anhydride i n p y r i d i n e at room temperature or (b) a c e t y l c h l o r i d e i n methylene c h l o r i d e added dropwise to a p y r i d i n e buffered methylene c h l o r i d e s o l u t i o n of crude product at 0 ° . In both cases, however, upon workup under n e u t r a l c o n d i t i o n s at room temperature, no acetoxy-or h y d r o p e r o x y - s u b s t i t u t e d compounds were found to be p r e s e n t . The n . m . r . 34 and g . l . c . a n a l y s i s confirmed that the enedione 343 was formed. O 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 very sharp downfield C TA resonance i n the n . m . r . of the crude product ' 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 (conj. C=0) and 1603 (conj. C=C ) c m - 1 ; 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 X | j|8" 251.5 my, e = 10,600). When the Brackman e_t a l . method (using 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 mixture of octalone 341 was r e c o v e r e d . However, as expected, 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 of 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 . - 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-7-hydroperoxy 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 in pyridine were 35 worked up, the crude product obtained was reduced with sodium iodide in ethanol (149), re-isolated as the alcohol, and acetylated with acetic anhydride i n pyridine. The i n i t i a l photolysis reaction was worked up after twelve hours of irradiation, 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% overall yield 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 irradiated for 36 h, reduced and acetylated. However, after d i s t i l l i n g 35 A petroleum ether:water partition removed the water soluble Rose Bengal dye and the organic solvents were removed below 40° under reduced pressure after drying the organic layer over magnesium sulfate. The g.l.c. analysis was routinely done at 185° on a 20% SE 30 column. 1 9 - 95 -octalone 236 from a fraction eluted with 60-80% benzene in petroleum ether off a s i l i c a gel column, only a 15% overall yield of pure y-acetoxy enone 236 was available from octalone 234. Also, while the spectral properties observed for this compound; ultraviolet 242 my (e = 15,400), infrared (film) 1760 (acetate carbonyl), 1670 (conj. carbonyl) and 1640 (conj. olefin) cm \ and n.m.r. x 4.28 (doublet, IH, C1^), 4.60 ( t r i p l e t , IH, C 8H), x 7.89 (singlet, 3H, 0=C-CH3) and x 8.94 (singlet, 3H, tertiary methyl), were those expected for 236 and were consistant with those reported for yacetoxy-a,8-unsaturated steroidal ketones, the subsequent elution of a much more polar conjugated ketone containing an acetoxy substituent made collaborative evidence for octalone 236 necessary. This was done by converting the f i r s t acetate eluted from the s i l i c a gel column to the enedione 343. A sample of this acetate, containing compound 248 as an internal standard, was reduced with excess lithium aluminum hydride i n ether for 1 h to yield a 1:2 ratio 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 in situ (158), then yielded a 1:2 ratio of the corresponding octalone 234 and enedione 343 i n over 95% yield based on the internal standard. The octalone 234 probably was produced in 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 addition to the unidentified very polar acetate, recovered octalone 234 (^ 12%), small amounts of the enedione 343 and the corresponding 2,8-diketone (294) were also 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 rat i o n a l i z e d 36 as the resu l t of photoreduction of octalone 234. Equally surprising was the absence of substantial amounts of the dienone 353, expected to result from the photoproduct 351. ° Authentic samples of the trans-decalone (349), prepared by Birch 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 cis:trans decalones, the same r a t i o obtained when octalone 234 was hydrogenated i n ethyl acetate under neutral conditions. While the closely related photo-reduction of a,B-cyclopropyl ketones w i l l be discussed subsequently, the above observed reduction of octalone 234 i n oxygenated pyridine (and oxygenated methanol) solutions i s unusual.(However see ref. 144). - 97 -3 4 9 a - H 3 5 J . R = 0 H 3 5 3 3 5 0 /3-H 3 5 2 R = H Persevering, the photosensitized (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 after 50 h i r r a d i a t i o n i n pyridine were observed by running the reaction for 86 h i n methanol. However, i n contrast to the aliquots taken from the pyridine reaction, the methanol 35 aliquots were found by g.l.c. analysis after workup to be a mixture of the enedione 343, the octalone 341 and a small amount of octalone 234. Washing these samples with aqueous bicarbonate l e f t them unchanged while the use of 4 N hydrochloric converted 341 to 234 as expected. When either the crude photolysis product obtained after 86 h or the corresponding sodium iodide reduction product were oxidized with chromium trioxide-pyridine complex i n methylene dichloride (185), the major product was found to be the enedione 343 accompanied by J / The r a t i o of deactivation to """02 consumed i n product formation i s denoted as 8 and i s a function of the substrate and the solvent (142). Since the 6 values of many steroids have been observed to be much larger i n alcohol solvents than i n pyridine, 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 pyridine. However, since Nickori and Mendelson (135) have reported using methanol i n place of ethanol i n the subsequent sodium iodide 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 permitting the immediate reduction of the crude hydroperoxide products. - 98 -octalone 234. However the i n f r a r e d spectra demonstrated an unoxidizable alcohol (or hydroperoxide) was present, suggesting the presence of 352 (or 351). Further g . l . c analysis work showed the photolysis samples and oxidized or reduced hydroperoxide samples contained the 38 dienone 353 i n a < 1:10 r a t i o to the enedione 343. In conclusion, while the preparation of the y-hydroxy octalone 295 was contaminated by only small amounts of the B-hydroxy d e r i v a t i v e , the product mixture and low y i e l d obtained upon a c e t y l a t i o n of 295 precluded employing t h i s sequence s y n t h e t i c a l l y . These unexpected and unsolved problems negated the o r i g i n a l work planned for octalone 236 but the synthetic necessity f o r such an approach, and the novel features of the 39 reactions employed, made the r e s u l t s obtained worthy of discussion. J O This analysis was performed with a 10 foot x 0.25 inch column packed with 20% FFAP on 60/80 mesh Chromosorb W at 220° and a flow-rate of 100 ml/min helium. Work on the dehydrogenation of octalone 234 had previously demonstrated that octalone 234 and 353 had the same rete n t i o n time on the 20% SE 30 column used for routine a n a l y s i s . The f a c i l e l o s s of the 8a substituent (hydroperoxy, hydroxy, peracetoxy, or acetoxy) prevented the i s o l a t i o n of these compounds. The dienone 353, i n comparison with octalone 234, exhibited a T 4.22 absorption i n the n.m.r. In addition, octalone 236 was found to decompose slowly i n s o l u t i o n (t-L/2 0 0 1 w e e k ) and more slowly when neat. While more than one product may be produced, the - acetate was not l o s t and g . l . c . behaviour and the very sharp c^H n.m.r. resonance suggested that dimerization at C-8 may be occurring. - 99 -D. Octalone 237_ (4a,8,8-Trimethyl-4,4a,5,6,7,8-hexahydro-2(3H)-naphthalenone). A consideration of the possible approaches to octalone 237 suggests e i t h e r elaboration of the gem-dimethyl substituted cyclohexanone 354 (R = CH^ or CN) to 237 or i n t r o d u c t i o n of gem-methyls i n t o 355 (R = CH,, H) by methylation followed by carbonyl t r a n s p o s i t i o n to 3 5 5 3 5 6 provide 237. While the former approach has been used to prepare the octalone 362 (160) v i a a sodium ethoxide-catalyzed Michael a d d i t i o n of methyl v i n y l ketone to the activ 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 also observed that the analogous methyl compound ( i . e . carboethoxy substituent replaced by methyl) did not react. Also of i n t e r e s t , the four-step conversion of 2,2-dimethyl-cyclohexanone (358) to the cyanoketone 363 i n 76% o v e r a l l y i e l d was followed by a reported 88% y i e l d of the octalone 364 obtained by condensing 363 with methyl v i n y l ketone (161). A hydrogenation, - 100 -k e t a l i z a t i o n , 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 fol lowed by k e t a l h y d r o l y s i s then afforded the t r i m e t h y l - t r a n s - d e c a l o n e 365 i n 70% o v e r a l l y i e l d from 364. The a l t e r n a t i v e approach of i n t r o d u c i n g the gem-dimethyl s u b s t i t u e n t s i n t o o c t a l o n e 355 has a l r e a d y been used on two occasions i n sesquiterpene s y n t h e s i s . Compound 356, the i n i t i a l product prepared by t h i s route was then converted to o c t a l o n e 237 by s u c c e s s i v e W o l f f - K i s h n e r - 101 -reduction and chromic acid oxidation reactions (162,163). The subsequent elaboration of 2_37 to (±)-widdrol (366) (162) and (±)-thujopsene (367) (163) required only two and four additional steps respectively. In the f i r s t synthesis, Enzell (162) prepared the gem-dimethyl octalone 356 40 from the corresponding 1-methyl octalone derivative 355 (R = CH^) by using Mukherjee and Dutta's procedure (164) of treating 355, R = CH^, with potassium _t-pentyloxide and methyl iodide, while i n the second synthesis, Dauben and Ashcraft (163) used octalone 355, R = H (= 234) and followed the steroid reaction method reported by Woodward et^ a l . (165) for 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 prerequisite 40 This compound was derived from 2-methylcyclohexanone and 2-chloroethyl ethyl 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 -octalone 234 was already at hand, t h i s l a s t synthetic route was chosen. Applying the "Woodward" methylation procedure, a one hour r e f l u x of a 1:3:6:63 mole r a t i o of ketone:potassium _t-butoxide:methyl i o d i d e : _t-butanol to 30 g of the octalone 234 afforded a 92% y i e l d of a colourless 41 o i l . A g . l . c . a n alysis and preparation of a n a l y t i c a l samples of product showed that t h i s o i l was 89% of the trimethyl octalone (356), 7% of the tetramethyl octalone (369) and 3.5% of a mixture of the 42 s t a r t i n g (234) and monomethylated (355) compounds. The extent 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 Ashcroft to provide 77.4% y i e l d of 95% pure 356. 42 19 This work required e i t h e r both 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° or, when only small amounts of 234 were present, a 10 foot x 0.25 inch column packed with 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 with a 1:6:13:64 mole r a t i o at room temperature overnight (Stork et a l . (166) procedure for the gem-dimethylation of i ) , a 94% y i e l d of OCH 3 crude product was obtained, but i t contained 30% overmethylated material. From t h i s and other o v e r a l k y l a t i o n reactions, preparative g . l . c . work with the Apiezon J column resu l t e d i n the i s o l a t i o n of the previously unreported compound ijL, i d e n t i f i e d from i t s spectroscopic data. 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 very s i m i l a r to that found for 356 and 369, but i t s n.m.r. absorptions were r e a d i l y assigned to the pentamethyl octalone 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 7H 2), 8.27 ( s i n g l e t , 2H, C 4H 2) and 28.73, 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 methyls). I r r a d i a t i o n 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) while i r r a d i a t i o n at T 7.96 collapsed the T 4.47 t r i p l e t to a s i n g l e t . - 103 -m e t h y l a t i o n was e a s i l y d i s c o v e r e d by observing the i n f r a r e d (1355, 1460 cm X r e g i o n ) and n . m . r . (x 8 . 7 - 9 . 2 ) s p e c t r a . The p h y s i c a l and chemical data obtained f o r the major product was i n complete agreement w i t h the data r e p o r t e d (162,163,167,168) f o r the compound 356. The n . m . r . d i f f e r e n c e s between 234 and 356 were p a r t i c u l a r l y u s e f u l evidence of the 356 369 s h i f t of the s i t e of 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 p r o t o n s i n g l e t of 234 being r e p l a c e d by a t r i p l e t (J = 3.7 Hz, AX^ system). The methyl s i n g l e t observed at T 8.74 i n 234 was r e p l a c e d by s i n g l e t s at x 8.78 (6H) and 9.01 (3H). Although these s i g n a l s have not been d e f i n i t e l y a s s i g n e d , the x 8.78 a b s o r p t i o n was t e n a t i v e l y i d e n t i f i e d w i t h the a x i a l methyls at C - l and C-4a of 356. This i s supported by __ The unconjugated monomethylated octalone i n t e r m e d i a t e 368 i s of mechanist ic 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. - 104 -the recent report that the T 8.78 (6H) and 9.01 (3H) signals observed i n chloroform are shifted to T 8.73 (6H) and 9.09 (3H) i n benzene (168). The minor (7%) product showed an additional methyl (doublet) absorption i n the n.m.r. When the reaction sequence was continued on the mixture, t h i s compound yielded 370 after carbonyl removal and 371 after a l l y l i c oxidation as an 8% impurity i n the reaction mixture. The n.m.r. spectrum of 371 was especially 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. This overalkylation problem was found to be more serious when 100 g quantities of octalone 234 were alkylated with a 1:3:6:60 mole r a t i o of ketone:base:methyl iodide :jt-butanol. Reactions on this 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 at 10-20° for 2 hours, the 94% y i e l d of colourless o i l recovered by d i s t i l l a t i o n was successfully fractionated on a spinning _ These large scale reactions were neutralized with hydrogen chloride rather than aqueous acid. I t was discovered that the crude product must be washed with aqueous sodium thiosulfate 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 thiosulfate to remove the free halogen liberated by a i r oxidation. 370 371 - 105 -band column under reduced p r e s s u r e to give a 74% y i e l d of 95% pure 356. E a r l i e r , 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, w h i l e Dauben et^  a_l. (163) had waited and p u r i f i e d the t r i m e t h y l conjugated o c t a l o n e 237 on a s p i n n i n g band column under reduced p r e s s u r e to a f f o r d 98% pure o c t a l o n e . T h i s l a t t e r group a l s o used r e c r y s t a l l i z a t i o n of the semicarbazone of 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 anhydride to r a i s e the y i e l d of pure 237. H An attempted p u r i f i c a t i o n of 356 v i a r e c r y s t a l l i z a t i o n of i t s semicarbazone (372) and then r e g e n e r a t i o n of the ketone w i t h p y r u v i c a c i d (170) proved u n s u c c e s s f u l . While f o r m y l a t i o n of 356, base e x t r a c t i o n of 373, and potassium carbonate h y d r o l y s i s to 356 removed the overmethylated compounds, t h i s procedure (171) d i d n o t , of c o u r s e , remove i n c o m p l e t e l y a l k y l a t e d m a t e r i a l . The s p i n n i n g band p u r i f i c a t i o n technique was found to be more e f f e c t i v e on the o c t a l i n mixture (357) than on the mixture corresponding to 356 or 237, but the time consumed by t h i s method along w i t h the tedious nature of s p i n n i n g band s e p a r a t i o n s l e d to the development of the modif ied route o u t l i n e d below. - 106 -The i n t r o d u c t i o n of a b l o c k i n g group allowed complete a l k y l a t i o n to be obtained without the problem o f o v e r a l k y l a t i o n . The ri -butylthiomethylene b l o c k i n g group was chosen because i t i s known that 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 conjugative or s t e r i c e f f e c t , and t h i s f u n c t i o n a l i t y i s s t a b l e to storage (172). Octalone 234 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 methanol-free sodium methoxide i n benzene to p r o v i d e the corresponding base s o l u b l e hydroxy-methylene compound 374 (64) i n 90% y i e l d . R e a c t i o n of 374 with n-butane^ t h i o l and p_-toluenesulfonic a c i d i n benzene afforded the d e s i r e d 3 - n -butyl thiomethylene d e r i v a t i v e 375 i n 91% y i e l d . A l k y l a t i o n of 375 w i t h methyl i o d i d e i n _t-butanol ( 1 : 4 . 2 : 9 . 5 : 6 9 mole r a t i o of ketone:base: methyl iodide:_t-butanol) gave a 90% y i e l d of the gem-dimethyl b l o c k e d octalone 376. The h y d r o l y s i s of the ri -butylthiomethylene f u n c t i o n a l i t y - 107 -of 376 was s u c c e s s f u l l y achieved w i t h some d i f f i c u l t y , y i e l d i n g 95% of 356 only a f t e r a n i n e t y - h o u r treatment w i t h potassium hydroxide i n r e f l u x i n g d i e t h y l e n e g l y c o l . However, the 70% o v e r a l l y i e l d of pure 356 from 234 made t h i s sequence very u s e f u l . Adopting Dauben and A s h c r a f t ' s experimental procedure f o r the p r e p a r a t i o n of o c t a l i n 357 from 356, the method developed by B a r t o n , Ives and Thomas (173) f o r the r e d u c t i o n of hindered ketones was used to o b t a i n a 92% y i e l d of pure o c t a l i n 357. E x p e r i m e n t a l l y , t h i s work i n v o l v e d the formation of the hydrazone d e r i v a t i v e of 356 w i t h a 170° r e f l u x i n g s o l u t i o n of anhydrous hydrazine i n a d i e t h y l e n e g l y c o l - s o d i u m g l y c o l a t e s o l u t i o n . The hydrazone was then decomposed to 357 by r a i s i n g the temperature to 210°. The much l e s s d a n g e r o u s ^ method of Nagata et a l . (174,175), u s i n g hydrazine 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 , and potassium h y d r o x i d e , 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 excessive foaming was observed d u r i n g the r e a c t i o n . An a l l y l i c o x i d a t i o n of 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 anhydride (162,163) then p r o v i d e d a 69% y i e l d of the d e s i r e d t r i m e t h y l octalone 237. T h i s compound was i d e n t i c a l to samples prepared by the d i r e c t a l k y l a t i o n route from octalone 234 b u t , u n l i k e the e a r l i e r p r o d u c t s , t h i s m a t e r i a l was not contaminated with 45 The danger of p r e p a r i n g the r e q u i r e d anhydrous hydrazine f o r the Barton e_t a l . method was "observed" d u r i n g the d i s t i l l a t i o n of hydrazine hydrate from sodium hydroxide when a 500 ml anhydrous hydrazine generator "detonated" i n a fume hood. The f a c t that the recommended procedure of p r e p a r i n g anhydrous hydrazine i n a n i t r o g e n atmosphere was being fol lowed (176) i l l u s t r a t e s the danger of having a leak i n a p o s i t i v e pressure 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 ox idat ion with chromium t r i o x i d e - p y r i d i n e complex i n methylene chlor ide (177) was employed. In our hands, a less than 50% y i e l d of octalone 237 with only a 5% recovery of o le f in ,coupled with the large volume of methylene chlor ide used? made the react ion impract ica l for large scale work. E. Octalone 238 and 239 (4a,5-Dimethyl -4,4a,5,6,7,8 -hexahydro-2(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 several routes, the s tereoselect ive synthesis of e i ther compound i s a formidable obstac le . The int roduct ion 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 un iversa l occurrence of t h i s re la t ionsh ip 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 recent ly (+)-eremophilenolide (377) (179a)), t r i c y c l i c a r i s to lane ( (+) -ar isto lone (378) (179b)), and t e t r a c y c l i c ishwarane ((+)-ishwarane (379) (179 )) c lasses of __ Caps id io l (x) , an ant i fungal compound whose structure was recent ly e lucidated by Stothers et a l . (178) i s a possib le exception. I t was assigned a trans v i c i n y l dimethyl re la t ionsh ip 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 chair conformation. OH i See Appendix I I , 'eremophilane approach' . - 109 -s e s q u i t e r p e n e s . 238/9 380/1 In the i n t e r e s t s of b r e v i t y , the work on the v i c i n y l methyl octalones can be considered 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 octalone 238/9 and the c l o s e l y r e l a t e d o c t a l o n e 380/1. The n o n - a n n e l a t i o n work i s 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 formic a c i d to p r o v i d e only 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 (180 a ) w h i l e the D i e l s - A l d e r r e a c t i o n of 385 and 386 was r e c e n t l y r e p o r t e d to y i e l d only the trans v i c i n y l compound - 110 -387 ( 1 8 0 b ) . 4 8 3 8 2 06 OCHO .-•OCHO 383 3 8 4 J 385 387 To date considerable success has been achieved i n stereoselectively preparing substituted octalones related to 380/1. The Michael addition of trans-3-penten-2-one (388) to derivatives of activated cyclohexanones (389 (181 a,183 b) 390 and 391 (181 b)) was found to lead to the c i s v i c i n y l 48 However, even more recently, a Diels-Alder reaction of the diene 1 with methyl acrylate ( i i ) was found to give the "masked" c i s v i c i n y l methyl compound i i i s tereoselectively. Elaboration of i i i to i v and the acid-catalyzed ring opening of the carbinol iy_'was then completed by the synthesis of (+)-nootkatone (v) (180°). O C H , C 0 2 C H 3 U R Y ^ O C H 3 JOT" LU R = C H , R ' = C 0 0 C H _ , i y R = - C H = C H 2 , R = C ( C H 3 ) 2 O H - I l l -product 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 (181°) and 394 (181 )) y i e l d e d predominantly the trans v i c i n y l dione 395. However, a much 394 more g e n e r a l route to s u b s t i t u t e d octalones that are r e l a t e d to 380/1 became a v a i l a b l e when i t was demonstrated that c r o s s - c o n j u g a t e d o c t a l o n e s s i m i l a r to 300 reacted w i t h l i t h i u m dimethylcuprate to a f f o r d the t r a n s product s t e r e o s e l e c t i v e l y (182 ) w h i l e 4-methyl s u b s t i t u t e d c r o s s -conjugated 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 to p r o v i d e a c i s v i c i n y l d i m e t h y l compound such as 397 (98, 181^, 1 8 2 ^ ' ° ) . In a d d i t i o n , XX) — 30Q 381 - 112 -the independent demonstration by two groups i n 1971 (183) that s o l v e n t 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 other p r e v i o u s approaches. T r a n s -3-penten-2-one and 2-methylcyclohexanone gave almost completely the c i s d i m e t h y l o c t a l o n e 380 (> 95% c i s ) i n dioxane w h i l e the trans (> 95% 381) was obtained w i t h dimethyl . s u l f o x i d e . In c o n t r a s t to the above, the methyl v i n y l ketone a n n e l a t i o n of 2,3-dimethylcyclohexanone has been r e p o r t e d by s e v e r a l groups to proceed i n only 15% y i e l d to a f f o r d a 3:2 c i s - . t r a n s (238:239) r a t i o (179 ,184). While 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 t h i s m i x t u r e , to i s o l a t e 398 by c r y s t a l l i z a t i o n and then dehydrohalogenate 398 399 to the octalone 399, the a t t e n t i o n of other s y n t h e t i c groups has turned to s t e r e o s e l e c t i v e l y a l k y l a t i n g d e r i v a t i v e s of 2 ,3-dimethylcyclohexane. A f t e r i t was d i s c o v e r e d that the a l k y l a t i o n of 2 , 3 - d i m e t h y 1 - 6 - n - b u t y l -- 113 -thiomethylenecyclohexanone (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 mixture of the corresponding c i s (403) and trans (404) d e r i v a t i v e s (185 ) , the a l k y l a t i o n of 400 with e t h y l 3-bromopropionate was found to a f f o r d approximately a 9:1 mixture of c i s (405) and trans (406) compounds (184 ) . Subsequently, the N-methylanil inomethylene d e r i v a t i v e of 2,3-dimethylcyclohexanone (401) was a l s o a l k y l a t e d w i t h 3-bromopropionate 4Q0 X= SBu n 405 X = SBu" 4 0 6 X = SBu n 4Q1 X=N(CH 3)C 6H 5 4 0 7 X = N(CHjC H, 4 0 8 X = N(CH J C H,. and found to p r o v i d e the c i s - 4 0 7 and trans-408 i n a r a t i o of >7:1 (184^). Even when the order of i n t r o d u c i n g a s u b s t i t u e n t at C-2 was reversed 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 blocked cyclohexanone, the c i s v i c i n y l methyl product was found to predominate. An 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 that 402 afforded only the d e s i r e d c i s product 410 when the b l o c k e d , i s o x a z o l e - s u b s t i t u t e d cyclohexanone was a l k y l a t e d w i t h methyl i o d i d e (185^). The h i g h degree of s e l e c t i v i t y observed f o r these c i s v i c i n y l methyl products permitted 405 and 407 - 114 -to be c o n v e r t e d , through 417, to 238 w h i l e 410 gave 411 and then 412. 417 411 238 R = H 412 R = COCH 3 The sequence that e l a b o r a t e d the n - b u t y l t h i o m e t h y l e n e blocked 2,3-dimethylcyclohexanone to octalone 238 i s o u t l i n e d on the f o l l o w i n g page. It was the i n i t i a l e x p e r i m e n t a l l y explored route because i t appeared to be the most e f f i c i e n t method a v a i l a b l e (186). At the o u t s e t , i t was hoped that a method could be found to produce the trans dimethyl o c t a l o n e (239) e f f i c i e n t l y through some parameter v a r i a t i o n s i n the a l k y l a t i o n step to enhance the r e l a t i v e y i e l d s of 418 and 420. In any event, i t was expected that a b e t t e r understanding of t h i s r e a c t i o n sequence would be o b t a i n e d . For the purposes of d i s c u s s i o n , t h i s work w i l l be considered i n three p a r t s - the c o n v e r s i o n of 2 , 3 -dimethylcyclohexanone, through i t s a l k y l a t e d blocked d e r i v a t i v e 415/6 and keto a c i d s 417/8 to a mixture of e n o l l a c t o n e s 419/420, the subsequent p r e p a r a t i o n of the corresponding i n d i v i d u a l e n o l l a c t o n e s 419 and 420, - 115 -4 J 4 X = C H 0 H 415. 3/Q-CH3 4T7 3/3-CH3 4 0 0 X = CHSBu 4J£.3a-CH 3 41S.3a-CH 3 and f i n a l l y , 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 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 permitted monoalkylat ion at the a ' p o s i t i o n when 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 the iv-butylthiomethylene f u n c t i o n a l i t y i n the p r e p a r a t i o n of o c t a l o n e 237 l e d to the use of t h i s b l o c k i n g group for 2 , 3 - d i m e t h y l -cyclohexanone. The ketone 413, obtained by o x i d i z i n g the a l c o h o l produced from hydrogenating 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_-toluenesulfonic 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 ethyl-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 hydrolysis of the n-butylthiomethylene and ethyl ester f u n c t i o n a l i t i e s with base i n refluxing aqueous diethylene g l y c o l proceeded i n 90% to afford a mixture of the keto acids 417 and 418. Enol lactone formation with sodium acetate i n acetic 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 cis:trans v i c i n y l methyl compounds re s u l t i n g from the a l k y l a t i o n reaction 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.) spectral data of t h i s mixture were found to be unsuitable for such an analysis. While the in d i v i d u a l keto acids showed small differences i n the n.m.r. spectra and while the corresponding methyl esters of 417 and 418 could be resolved by gas chromatography, the in d i v i d u a l enol lactones 419 and 420 were found to exhibit much more substantial a 49 differences i n their n.m.r. (184 ) and g.l.c. behaviour. These differences were then exploited 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 converting 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 difference i n the downfield v i n y l proton of the two enol lactones. The larger s h i f t difference between the t e r t i a r y methyl of 419 and 420, along with the absence of non-methyl resonances between x 8.7-9.4, permitted an accurate measurement of the cis:trans r a t i o to be made using double n.m.r. inte g r a l s . These integrals 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 (sin 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 (sin 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 hydrolysis and lactonization steps did 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 portion of th i s assumption was proven to be correct when the in 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 yields 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 also shown to leave the cis:trans 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 cis:trans 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 for 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 effect 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 control of stereochemistry. As expected, there were many examples of substantial s t e r i c hindrance on one side of the molecule leading to attack on the less hindered side (190 ) and one example of the a-substituent reversing 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 for substituted cyclohexanones i t appeared that the nature of the enolate substituent was of general importance. When the enolate Although a sim i l a r n.m.r. analysis (184 ) indicated a cis:trans r a t i o of approximately 9:1, the above would indicate that a r a t i o of approximately 8:2 or 4:1 would be a more accurate description. This ^ 4:1 r a t i o was the same as that previously reported for the a l k y l a t i o n of 400 with methallyl chloride (see 403/404) and confirms the observation made l a t e r that changing the halogen from Cl to Br does not affect the cis:trans r a t i o s i g n i f i c a n t l y . - 118 -s u b s t i t u e n t was hydrogen, approximately equal amounts of " a x i a l " and " e q u a t o r i a l " products were formed as, f o r example, when 421, R = H gave a 422a:422e r a t i o of 45:55 ( 1 9 1 a ) . An a l k y l s u b s t i t u e n t u s u a l l y l e d to 70-90% of the " a x i a l " product w i t h 421, R = CH, g i v i n g ^ 70% 422a w h i l e 423 y i e l d e d a 424a:424e r a t i o of 83:17 (191 ) . In an analogous manner, 425 R = D 426a 426e 427 R = Alkyl 428a the simple o c t a l o n e 425, which c o u l d be a l k y l a t e d r e g i o s e l e c t i v e l y by a r e d u c t i v e p r o c e s s , y i e l d e d a 40:60 mixture of the methyl decalones c 426a and 426e from m e t h y l a t i o n i n t e t r a h y d r o f u r a n (191 ) . The i n t r o d u c t i o n of a C - l a l k y l group was found to permit a s t e r e o s e l e c t i v e a x i a l a l k y l a t i o n to occur and has been explained i n terms of a - s i d e 1 2 a t t a c k c o n t r a c t i n g the C - l a l k y l to C-8a methylene d i h e d r a l angle (A ' s t r a i n ) i n the a l k y l a t i o n t r a n s i t i o n s t a t e (191 ) . In terms of changing the product s t e r e o c h e m i s t r y through the c h o i c e of r e a c t i o n parameters, the r e p o r t that m e t h y l a t i o n of the 10-nor s t e r o i d , 429, switched from a - 119 -r a t i o of 10:1 a-face alkylation:B-face 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. Preliminary 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 resulted i n l i t t l e or no change i n the cis:trans isomer r a t i o . This r a t i o was also independent of the extent of the reaction or the y i e l d obtained. Table I summarizes some of the results produced when two gram amounts of ketone 400 were enolized with d i f f e r e n t bases i n d i f f e r e n t solvents and alkylated with either 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 ignoring 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 li t h i u m _t-butoxide (51 + 1). * These runs paralleled 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 reaction, extending the reaction time to 5 h from 1 h raised the y i e l d from 30% to 80% o v e r a l l . However, the g.l.c. analysis s t i l l showed 50.3:49.7 cis:trans ratio' i n both cases. See experimental for other d e t a i l s on Table I. - 120 -TABLE I. STEREOCHEMISTRY OF THE ALKYLATION PRODUCTS OF THE BLOCKED KETONE 400. Base Employed Solvent System Alkylating Agent Enol Lactone Ratio 4 1 9 : 4 2 0 KOBu 1 B i f o H RBr 8 3 : 1 7 I I OH H 8 1 - 1 9 H T H F II 8 0 = 2 0 n HMPT II 9 0 - 1 0 NaOBu 1 Bi iOH RBr 7 5 = 2 5 LiOBu* BuOH RBr 50=50 M OH H 51 =49 II THF n 51 =49 11 HMPT 8 9 - 1 1 KOBu* BifOH RCl 8 6 M 4 LiOBu 1 Bu*OH RCl 51 : 4 9 The extension of t h i s work to other bases showed that even a weak potassium base l i k e potassium carbonate i n t - b u t a n o l provided a 84:16 r a t i o ( a l b e i t 10% o v e r a l l y i e l d ) w h i l e sodium methoxide i n t e t r a h y d r furan (THF) gave a 76:24 r a t i o . T h e r e f o r e , w h i l e potassium hydroxide i n _t-butanol and sodium methoxide i n _t-butanol, methanol, or benzene d i d not p r o v i d e any of the d e s i r e d product because of s i d e r e a c t i o n s , and while l i t h i u m carbonate d i d not appear to cause any a l k y l a t i o n - 121 -in _t-butanol, the stereochemistry of the a l k y l a t i o n of compound 400 appeared to be primarily dependent only on the a l k a l i metal cation (counterion) employed. The insignificance i n the choice of al k y l a t i n g agent was demonstrated by the observation that replacing the bromo-ester (RBr) with the chloro-ester (RC1) caused no change with l i t h i u m t-butoxide i n _t-butanol and only a minor difference with 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 was used i n place of the other solvents. The r e l a t i v e l y "free" nature of the enolate i n HMPT makes the enolate's behaviour independent of i t s counterion and leads to an interpretation 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 of solvent-separated ions (431) or contact ion pairs (432). The solvent-separated pair would be expected to be more reactive and could be represented as involving a mixture of the " h a l f - c h a i r " 431 432 Hexamethylphosphoric triamide (HMPT) i s a polar, aprotic 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 exceptionally good cation solvator and an exceptionally poor anion solvator (192) . Enolates i n protic solvents (Buc0H) generally favour C-alkylation but polar aprotic solvents l i k e HMPT enhance O-alkylation with the formation of enol ethers. The enol ether product of 400 would not i n t e r f e r with the cis:trans C-alkylation measurements but would lower the o v e r a l l y i e l d . - 122 -conformations 433a and 433b i n the t r a n s i t i o n s t a t e . L i t h i u m i s known to form more t i g h t l y a s s o c i a t e d i o n p a i r s than sodium or potassium i n most common p r o t i c or a p r o t i c s o l v e n t s (Bu tOH or 0H) (191^), but the 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 t r a n s i t i o n s t a t e . I f a p r o d u c t - l i k e t r a n s i t i o n s t a t e were i n v o l v e d with the l i t h i u m contact i o n p a i r s , t h e trans v i c i n y l methyl product r e s u l t i n g from the a l k y l a t i o n of the more favourable conformation 435a would be expected to dominate. Since t h i s i s c l e a r l y not the case f o r compound 400, and • s i n c e r e a c t a n t - l i k e t r a n s i t i o n s t a t e s have been found to be g e n e r a l l y a p p r o p r i a t e for C - a l k y l a t i o n r e a c t i o n s elsewhere (191^), the involvement of 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 conformations 434a and 434b by the aggregation of contact i o n p a i r s i s suggested. The involvement of 434a+b i n the t r a n s i t i o n s t a t e would lead to the observed 50:50 mixture of H H M BuSHC H H 433a 433 b BuSHC 434a 434 b - 123 -BuSHC BuSHC "H 435 b cis:trans products. When the enolate of 400 was shifted from contact ion pairs to solvent separated ions by HMPT or by the use of a potassium cation, the conformations 433a+b would become dominant. The a l k y l a t i o n of 433a gives a 1,3-interaction with the C-4 hydrogen on the a-face and a 1,2-eclipsing with the C-3 hydrogen on the B-face. If there i s any merit i n House's recent proposal (191^) that the dihedral 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 substituted enolates), 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 into 433a. Conformation 433b, which could readily reduce the C-6 blocking group, the C-l oxygen and C-2 methyl interaction by twisting 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 basis of the s t e r i c factor introduced by the pseudoaxially oriented methyl. In any case, while these observed changes i n stereochemistry with cation and solvent are of synthetic importance,the largest energy 53 difference between t r a n s i t i o n states i s quite small. 53 In going from l i t h i u m enolates i n ButOH (cis:trans i s 1:1) to those i n HMPT (cis:trans i s 9:1), the energy difference 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 cis/trans) (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 cation employed (194). The intramolecular a l k y l a t i o n of the n i t r i l e 436 with i t s a-haloketal substituent (X = Br, I) gave 95% c i s decalin 437 with potassium hexamethyldisilazane i n benzene, while the li 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 factor of the X anion a l k y l a t i o n was considered.to be the requirement of a more closely held t r a n s i t i o n state for a lith i u m cation i n benzene than for a potassium cation i n achieving the proper alignment of the departing halide, the al k y l a t i n g methylene, and.the t r i g o n a l nucleophilic centre. This work also reported that the use of the li t h i u m base i n tetrahydrofuran resulted i n loosening of the ion pair by cation solvation so that a 20:80 r a t i o of cis-437 to trans-437 resulted. The lack of a sim i l a r solvent effect i n Table I i s puzzling. Continuing the octalone preparation sequence, the c i s enol lactone could be re a d i l y c r y s t a l l i z e d from a hexane solution 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 elusive trans isomer required successive s i l i c a chromatographies of the enol lactone mixture, hydrolysis 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 acid (418) with subsequent dehydration to the enol lactone 420. Enol lactone 419 reacted with methyllithium at -25° i n - 125 -e t h y l ether to p r o v i d e intermediate 438a and the r e a c t i o n was quenched 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 440a v i a 439a. An immediate b a s e -c a t a l y z e d a l d o l condensation gave the d e s i r e d octalone 238 i n an o v e r a l l d i r e c t y i e l d from 419 of up to 78%. However, when the same experimental sequence was used on e n o l l a c t o n e 420^ only 30% octalone 239 was 238 *- or 239 419 3/3-CH3org 438_X = Li 440. 420 3a-CH 3orb 439 X = H i s o l a t e d . C o n s i d e r a b l y more unreacted trans e n o l l a c t o n e was recovered (19.4%, as the trans keto a c i d ) than had been the case of the c i s e n o l l a c t o n e (8-9%, as the c i s keto a c i d ) . The most reasonable e x p l a n a t i o n f o r these r e s u l t s suggested that the l i t h i u m adduct 438 was undergoing a spontaneous r i n g opening to 441 w i t h a subsequent r a p i d a d d i t i o n of 438 a 3/3-CH3 44j_ 442 438b 3a-CH 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. In the case of the c i s c c t t v i c i n y l methyl compounds, k^ > k^ while k^ = for the t r a n s . In the d i s t i l l a t i o n of o c t a l o n e 239, a c o n s i d e r a b l e amount of a s l i g h t l y h i g h e r b o i l i n g m a t e r i a l was i s o l a t e d . 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 w i t h those - 126 -expected for compound 443. 54 LiO OH 443 444. To gain a better understanding of the reaction, mixtures of enol lactones 419 and 420 were used to prepare a mixture of the corresponding octalones. The i n i t i a l rate of attack of methyllithium on either enol lactone to afford the methyl adduct 438 (k^) or the enolate 444 (k^,) was shown to be the same for 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 s t a r t i n g material. For example, when the keto acid mixture recovered from a reaction on a 59:41 r a t i o of cis:trans enol lactones was dehydrated, the enol lactone product analyzed for a 59:41 r a t i o of cis:trans 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 alcohol (443, i ) suggests that the hemiketal i i predominates. G.l.c. x^ work on t h i s compound also provided a compound tentatively i d e n t i f i e d as i i i . This ring-chain tautomerism has recently been reported (195) for 5-oxo-3,5--seco-A-norcholestan-3-o l , a compound analogous to i, R = H. i R = C H 3 IL R = C H 3 iii R = CH 3 - 127 -t c observed r a t i o s of octalones i s o l a t e d permitted an estimate of ^ 2 ^ 2 = 5 to 10 to be made."*"* Table II summarizes the r e s u l t s of optimizing the y i e l d of the c i s octalone (runs 1-4) and the work comparing c i s / t r a n s reactions (runs 5-9). T A B L E II. P R O D U C T D I S T R I B U T I O N O B T A I N E D B Y M E T H Y L L I T H I U M T R E A T M E N T O F E N O L L A C T O N E S . Experimental Ratio of C H ^ L i Run to Enol Lactone Enol Lactone 419 ; 4 2 0 Octalone Yield Octalone 2 3 8 : 2 3 9 Recovered Keto Acid l a 1 . 5 9 100=0 6 1 % 100--o 1 8 . 3 % 2 a 1 .69 100--0 6 7 . 7 1 0 0 = 0 1 3 . 4 % 3 1 .82 100=0 7 8 % 100=0 9 % 4 1.93 • 100=0 6 0 . 4 % 100=0 2 . 7 % 5 1.78 100=0 7 3 . 7 % 100=0 8 . 2 % 6 1.88 0=100 3 1 . 3 % OMOO 19.4 % 7 1.75 59=41 3 8 . 7 % 92=8 1 2 % 8 1.83 3 6 - - 6 4 2 5 . 6 % 7 2 = 2 8 1 3 % 9 1.83 84=16 5 8 % 9 5 = 5 8 % a 1 3 / 4 h at - 2 5 ° , otherwise 2 h a t - 2 5 ° 55 t c Estimate based on approximating ^/k^ by the product of the observed t r a n s / c i s enol lactone r a t i o and the r e s u l t i n g c i s / t r a n s octalone r a t i o . - 128 -To overcome 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 enol l a c t o n e 420, some c o n s i d e r a t i o n was given to u s i n g other p o s s i b l e methods. Corey and Chaykovsky (196) had used the m e t h y l s u l f i n y l carbanion with e s t e r s and l a c t o n e s to o b t a i n high y i e l d s of B-keto s u l f o x i d e s which were then d e s u l f u r i z e d w i t h aluminum amalgam to y i e l d the corresponding methyl ketones. Attempts to use t h i s method on the c o n v e r s i o n of the enol l a c t o n e 420 to 440b were u n s u c c e s s f u l , but c o n s i d e r a t i o n of the m o d i f i c a t i o n of the trans keto a c i d 418 l e d to Stork and C l a r k e ' s work (197) on the c o n v e r s i o n of the keto a c i d 445 to the b i c y c l i c enone 448 v i a the methyl ketone 447 i n the s y n t h e s i s of c e d r o l (450). In t h e i r 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 - 129 -only compound 449 by a process that was b e l i e v e d to be c a t a l y z e d by magnesium bromide. However, excess diazomethane w i t h the a c i d c h l o r i d e 446 y i e l d e d the diazoketone (446, X = C H ^ ) which was converted to the chloromethyl ketone (446, X = C ^ C l ) and then reduced w i t h z i n c dust i n a c e t i c a c i d to the methyl ketone 447. The remarkable 79% o v e r a l l y i e l d of 447 obtained from the sodium s a l t of the keto a c i d 445 gave t h i s sequence some appeal but the r e c e n t l y reported r e a c t i o n of a c i d c h l o r i d e s w i t h methyl cuprates to y i e l d methyl ketones appeared to be an even more a t t r a c t i v e and i n t e r e s t i n g a l t e r n a t i v e (198). Using e i t h e r a mixture of keto a c i d s 417+418 or a mixture of the sodium s a l t s of 417+418 i n a treatment with o x a l y l c h l o r i d e i n benzene at 0° gave a r e s i d u e that was i s o l a t e d under vacuum below room temperature and added to a 2 - f o l d excess of dimethylcuprate 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 both c a s e s , only a low y i e l d of a mixture of the d e s i r e d o c t a l o n e s and the c o r r e s p o n d -ing methyl e s t e r s of 417 and 418. Since there were two p o s s i b l e a l t e r n a t i v e routes to be e x p l o r e d , f u r t h e r approaches through the keto a c i d 418 to o c t a l o n e 239 were not c o n s i d e r e d . While the p h y s i c a l data obtained on the pure keto a c i d s (417 and 418), t h e i r methyl e s t e r s , the enol l a c t o n e s (419 and 420), and o c t a l o n e s (238 and 239) have not been d i s c u s s e d , the observed s p e c t r o s c o p i c data agreed w e l l w i t h that p u b l i s h e d (184) and, i n g e n e r a l , the a b s o r p t i o n s observed were those expected. The i n t e r e s t i n g exception was the proton magnetic resonance of the secondary methyl group that appears i n a l l of these compounds. In the case of the c i s octalone 238 and the trans keto a c i d 418 (or i t s corresponding methyl e s t e r ) , v i r t u a l c o u p l i n g - 130 -(199)"^ i s observed i n both the 60 MHz and 100 MHz secondary methyl resonance, while the other compounds i n the series show the expected methyl doublet. For example, the keto acid 418 exhibited an unresolved multiplet with l i n e shape 451a i n a 60 MHz spectrum and 451b i n a 100 MHz scan, while the corresponding c i s keto acid 417 showed the normal l i n e shape depicted i n 451c (60 MHz). A similar s h i f t of l i n e shape towards the expected doublet (451c) was observed for 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 close relationship 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 CJHCH3 and C^ H_2 being smaller than the i r coupling constant (JQ5\{-C6^) • Since the chemical s h i f t i s proportional 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 previously for octalone 238 and some of i t s derivatives (184 a). While the trans-fused decalone and l-hydroxy-A^-octalin derived from 238 exhibit v i r t u a l coupling i n their secondary methyl resonance, there was no such coupling evident i n the cis-fused decalone obtained from 238 or i n the trans-fused decalone obtained from 239. - 131 -se l e c t i v e l y to afford 452 (199), the question arose concerning the p o s s i b i l i t y of reducing a Wieland-Miescher ketone derivative regio-s e l e c t i v e l y and stereoselectively to octalone 238 or 239. Octalones 455 and 456 were prepared and th e i r respective hydrogenations were studied as both of these compounds were also of some interest i n several projected eremophilane syntheses. The Wieland-Miescher ketone (204, 202) was 204 452 455 Exocyclic 456 Endocyclic treated with 2,2-dimethoxypropane and a c a t a l y t i c amount of p_-toluene^ sulfonic acid to y i e l d i n 93% the enol ether 453 (200). The presence of one methoxyl function and two v i n y l protons by n.m.r. and a saturated carbonyl by infrared spectroscopy confirmed that a selective alkoxyl interchange had occurred. A W i t t i g reaction of methylenetriphenylphosphorane and compound 453 i n dimethyl sulfoxide (201) then produced a 93% y i e l d of the desired enol ether o l e f i n 454, readily i d e n t i f i e d by the replacement 204 453 454 - 132 -0 0' 0 455 456 H 457/458 of the saturated carbonyl i n the i n f r a r e d with a two v i n y l proton absorption at T 5.30 i n the n.m.r. A short treatment of compound 454 with methanolic hydrochloric acid gave the exocyclic o l e f i n i c octalone 455 i n 88%, while treatment of 454 with jD-toluenesulfonic acid i n r e f l u x i n g benzene or toluene y i e l d e d the endocyclic o l e f i n i c octalone 456 i n 80%. When the above reactions were c a r r i e d out with minimal workup of the intermediate steps, the Wieland-Miescher ketone afforded higher o v e r a l l y i e l d s of 455 (95%) and 456 ( 6 4 % ) . 5 7 Both of these "" A p r i v a t e communication (Geraghty, 186) indicated that an a l t e r n a t e route to compound 456 by a d d i t i o n of a methyl Grignard or methyllithium to the protected Wieland-Miescher ketone ( i ) and subsequent acid catalyzed dehydration proceeded i n poor y i e l d . In add i t i o n to considerable e n o l i z a t i o n of the carbonyl rather than the desired 1,2-addition of the methyl nucleophile, the bicyclic-6-hydroxy-a,8-enone precursor to 356, i i , once formed, has been shown re c e n t l y to undergo a rearrangement i n both acids and bases to i i i (203). 0 OH - 133 -compounds had a conjugated ketone chromophore, with compound 455 exhibiting an exocyclic methylene i n the n.m.r., while compound 456 indicated 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 regioselective for disubstituted 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 yielded a 55:45 mixture of cis-238:trans-239 (after an acid catalyzed removal of the methyl ether), while a s i m i l a r hydrogenation of compound 455 yielded a 75:25 r a t i o of 238:239 i n 98%. An attempted regioselective 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 with 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 also 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 successful, the stereoselectively available octalone 381 was transformed into octalone 239 by a route analogous to The reduction of 455 or 456 under dissolving metal (Birch) conditions gave the desired trans decalone derivatives and not the 204 -> 205 transformation indicated on page 43. The trans-fused derivative of 455 (i_, C9H3 at x 8.79 i n the n.m.r.) was hydrogenated with ( ( 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 Birch reduction of octalone 238 while i i i _ (C 9H 3 at x 8.83) was derived by a Birch reduction of octalone 239. H i i IL - 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 of h i n e s o l . In t h e i r work, the cross-conjugated dienone 459 was submitted to a conjugate a d d i t i o n of l i t h i u m dimethylcuprate to i n t r o d u c e a methyl i n t o the ' A ' r i n g . The enone 460 was then deconjugated to 461, the c a r b o n y l reduced and the h o m o a l l y l i c a l c o h o l product (462) a c e t y l a t e d and o x i d i z e d a l l y l i c a l l y to a f f o r d 464. A d e h y d r o a c e t y l a t i o n and s e l e c t i v e hydrogenation 459 460 : 461 X =0 462 X = a-H,/3-0H 463 X = a-H,/3-0Ac 464 465 466 then completed the ' A ' •> ' B ' r i n g t r a n s p o s i t i o n of the enone f u n c t i o n a l i t y . U s i n g the c r o s s - c o n j u g a t e d dienone 300 prepared as d e s c r i b e d e a r l i e r i n t h i s t h e s i s , a s t e r e o s p e c i f i c m e t h y l a t i o n was achieved with l i t h i u m 59 a dimethylcuprate to p r o v i d e an 87% y i e l d of compound 381 (182 ,204). In the absence of l a r g e s t e r i c f a c t o r s , cuprate a d d i t i o n s are 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 proven elsewhere (182a,204,205a), 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 a x i a l m e t h y l a t i o n occurs when compound 300 i s t r e a t e d with L i C u C C H ^ ^ - Compound 459, on the other hand, was found to give a 1:3 r a t i o of 4a:48 m e t h y l a t i o n (205). - 135 -300 381 467 The deconjugation of t h i s ketone by base e q u i l i b r a t i o n - a c i d quench (potassium _t-butoxide/acetic a c i d ) was accomplished by the procedure developed e a r l i e r for the corresponding 4-desmethyl compound (234), but i n t h i s case there was no measureable amount of o c t a l o n e 381 present a f t e r workup ( i . e . <1% 381 versus ^ 5% 234). The i n s t a b i l i t y of 8 , y - o c t a l o n e s n e c e s s i t a t e d the immediate r e d u c t i o n of compound 467 w i t h l i t h i u m aluminum h y d r i d e . The h o m o a l l y l i c a l c o h o l product was then a c e t y l a t e d w i t h a c e t i c anhydride and sodium a c e t a t e to a f f o r d a 76% o v e r a l l y i e l d of compound 469 from octalone 381. A t e n t a t i v e 468 R = H 4I0_ H i . A - ene 469 R = OCCH* 239 II 6 0 assignment of a 2:1 r a t i o of the a: 8 7-acetoxy s u b s t i t u e n t could be made on the b a s i s of the n . m . r . a b s o r p t i o n s of 469 , but these s p e c t r a l 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 mixtures (of 468, 469 and 470) were removed by the subsequent d e h y d r o a c e t y l a t i o n . The h o m o a l l y l i c 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 i n 80% y i e l d w i t h chromic anhydride i n a c e t i c a c i d by a procedure analogous to the one u t i l i z e d e a r l i e r on a t r i m e t h y l o c t a l i n (357, 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 ethanolic hydrochloric acid (149) was then accomplished cleanly i n 86% y i e l d to afford the desired dienone 471. This compound showed the required spectroscopic data, unencumbered by diastereoisomerism, having a conjugated dienone by infrared (1660, 1620, 1588 cm "S and three v i n y l protons (x 3.85, 3.88, 4.22), a t e r t i a r y methyl (x 8.75) and a doublet methyl (x 9.09) by n.m.r., but the observed MeOH extinction c o e f f i e i n t of e = 31,300 associated with the X my 282 max u l t r a v i o l e t absorption for 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 a,3-unsaturated and cross-conjugated ketones previously encountered (e = 10,000-15,000), the corresponding 5-desmethyl compound of 471 has been reported to have xEt0H 2 8 Q ^ ( e = 1 9 4 0 0 ) (206 a) and A E t 0 H 278 my (e = 26,800) (206 b), while max max the analogous A^'^-3-keto steroids have been shown to exhibit X E T ^ 284 my ° max (e = 28,000) (206°,135) absorptions i n the u l t r a v i o l e t , Spectroscopically, the chemical s h i f t changes observed for the downfield protons i n the n.m.r. are a useful feature of the above sequence, leaving no doubt that the enone f u n c t i o n a l i t y was transferred successfully. Of p a r t i c u l a r significance i s the movement of the v i n y l proton from a singlet at x 4.22 (381) to a multiplet at x 4.50 (467, 468, 469) and back to a singlet at x 4.15 (470) and 4.22 (471). The regioselective c a t a l y t i c hydrogenation of the disubstituted unsaturation of 471 with tris(triphenylphosphine)chlororhodium proved t h i s by y i e l d i n g octalone 239 (113). However, th i s selective reduction with a homogeneous catalyst proceeded so very slowly that a switch was made to a palladium catalyst. By using 0.005 N potassium hydroxide i n benzene-ethanol solution and pre-reducing the 5% palladium on carbon catalyst - 137 -(207), the dienone 471 was reduced rapidly i n 93% y i e l d to octalone 239. As expected, t h i s compound was physically and spectroscopically i d e n t i c a l with the one prepared e a r l i e r from enol lactone 420 but, i n contrast to the rhodium catalyst where careful monitoring was not required, care was required to avoid hydrogenation of 239 by palladium on carbon to a mixture of decalones. In conclusion therefore, while both c i s and trans octalones 238 and 239 could be prepared i n pure form from thei r respective enol lactones (419 and 420), the novel selective destruction 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 2 3 9 ^ 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 surprising since there i s one l i t e r a t u r e report- that the methyl cuprate addition to dieone 300 i s not as stereospecific as indicated i n footnote 59. Marshall and Warne (183^) found that the conjugate addition of lithium 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, this discrepancy requires an explanation. - 138 -F. 'Octalone' 240 (Androst-4-en-3-one) In considering the preparation of androst-4-en-3-one, two e q u a l l y inexpensive commercially a v a i l a b l e compounds, testosterone (472) anci 36-hydroxyandrost-5-en-17-one (473), appeared to be u s e f u l as p o s s i b l e precursors. The conversion of e i t h e r of these compounds i n t o 240 would require the reductive removal of the C-17 oxygen f u n c t i o n a l i t y 472 240 473 n e c e s s i t a t i n g C-3 carbonyl p r o t e c t i o n i n the case of 472 and, i n the 5 4 case of 473, subsequent C-3 oxidation with double bond (A -> A ) isomerism (228). Unforeseen d i f f i c u l t i e s with the r e d u c t i v e step i n the former sequence and with the o x i d a t i v e step i n the l a t t e r , r e s u l t e d i n further experimental work being undertaken to elaborate these problems and to formulate general methods f o r minimizing them. Since there i s a great deal 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 240 from 473, rather than from 472, t h i s approach and i t s oxidation problems w i l l be considered f i r s t . Androstenone 240 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 previously, 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 oxidation reactions. Shoppee and Krueger (208), and then Fetizon and Go l f i e r (209), reduced the carbonyl of 473 by the Huang-Minion modification (210) of the Wolff-Kishner reduction. Both groups then subsequently employed the Oppenauer oxidation (211) of androst-5-en-38-ol (474) to afford approximately 70% androstenone 240 from 473. More recently, Habermehl and Haaf (212) used a f i v e step 240 sequence to accomplish the same t r a n s f o r m a t i o n . The s t e r o i d 38-acetoxyandrost-5-en-17-one (475) was reduced v i a B a r t o n ' s v i n y l i o d i d e procedure f o r ketone removal (213). Formation of the hydrazone 476 was achieved under b a s i c 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 c a t a l y s t i n a r e f l u x i n g ethanol s o l u t i o n of h y d r a z i n e hydrate and the ketone 475. O x i d a t i o n with i o d i n e i n t r i e t h y l a m i n e - t e t r a h y d r o f u r a n s o l u t i o n X I 475 X = 0,R = Ac 477 - 140 -then provided the v i n y l i o d i d e 477 which f u r n i s h e d the d e s i r e d compound 474 on Raney n i c k e l r e d u c t i o n . However, the y i e l d of l e s s than 65% o v e r a l l does not compare favourably w i t h the 90% obtained by d i r e c t W o l f f - K i s h n e r r e d u c t i o n (208). A l l three groups of workers (208,209,212) converted the B,y-unsaturated a l c o h o l 474 to the a,B-unsaturated ketone 240 u s i n g 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 a l t e r n a t i v e d i d e x i s t . Studies by L.F. F i e s e r on both p a r t i a l (127) and exhaustive (214) dichromate 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 acid-benzene s o l u t i o n s showed that a complex product mixture was produced. In t h i s mixture, r a t h e r than the expected 3,y-unsaturated ketone 334 predominating, the enedione 480, cholest-4-ene-3,6-dione, was found to be the major 61 product. However, the dichromate o x i d a t i o n of the C-3 a l c o h o l i n the corresponding p r o t e c t e d 3,y-dibromo s t e r o i d 481 gave a n e a r l y q u a n t i t a t i v e (96%) y i e l d of the dibromo ketone 482. Thus F i e s e r (216) was able to r e p o r t the conversion of c h o l e s t e r o l (331) to cholestenone 478 i n 81% 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 the f o l l o w i n g sequence, A d i e t h y l ether s o l u t i o n of c h o l e s t e r o l was t r e a t e d w i t h an a c e t i c a c i d s o l u t i o n of bromine and the c r y s t a l l i n e dibromide 481 was o x i d i z e d 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 and immediately 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 ether 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 thermodynamically l e s s s t a b l e . 6B-oriented hyd 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 intermediacy 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 unconjugated ketone 334 was not isomerized i n a c e t i c acid-benzene f o r periods up to 20 hours and the r e a c t i o n mixture was found to be f r e e of even t r a c e amounts of the conjugated ketone 478 (215). - 141 -4 8 2 X = 0 unsaturated ketone 334. Isomerization of t h i s ketone to cholest-4-en-3-one (478) was accomplished e i t h e r by chromatography or by t r e a t -ment with mineral acid or base, with o x a l i c acid giving the best product. - 142 -Normally the yields reported for the Fieser or Oppenauer procedures approximate 70%. Since both methods require special precautions and workup conditions and take a day to complete, an easier alternative 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 quantitative i n 15 minutes, but the corresponding A^-3-ols are oxidized by manganese 4 dioxide i n refluxing solvents to a mixture of conjugated A -3-one and 4 6 A ' -dione products, with the l a t t e r predominating (217). In 1961, Rao (218) reported that Attenburrow's "active" manganese dioxide 4 afforded the conjugated A -3-one exclusively because of the rapid base isomerization of the 8,y-unsaturation to the r e l a t i v e l y stable conjugated compound. This work found such a low conversion rate, 6% i n eleven hours, that the method i s not of synthetic interest at this time. Three other pertinent l i t e r a t u r e procedures were available for the conversion of s t e r o i d a l A^ -3 - o l to the A^-3-one system. Djerassi and collaborators, i n 1956 (219), were interested 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 direct oxidation of the A^-3-ol precursors. They found the Jones procedure (220) of t i t r a t i n g the alcohol 483 (a-d.) i n an acetone solution with aqueous chromic-sulfuric acid oxidizing reagent afforded the unconjugated ketone 484 i n high y i e l d i f the reaction was carried out at 10° for two minutes (reported 89% of 484 when R' = C0CH.J . - 143 -483a R' = 0 (473) b R' = 0C0C 6H 5 c R' = COCH3 d. R' = COCH2OAc e-R/ = H 1 R' = C QH (331) O I f 484a R' = 0 b R' = 0C0C 6H 5 c. R' = COCH 3 d. R' = C0CH20Ac e R' f R' H C8H_!H4) Subsequently, i n 1956, Snatzke found that c h o l e s t e r o l (311) was 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 (334) w i t h a d i m e t h y l -formamide s o l u t i o n of chromic a c i d (221,222 ) . The s t e r o l (0.5 mM) i n dimethylformamide (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 concentrated s u l f u r i c a c i d (1-3 drops) i n d i m e t h y l -formamide (10 m l ) . As with the Jones reagent, t h i s work showed a - k e t o l s and k e t a l s were not cleaved d e s p i t e the use of s u l f u r i c - 144 -a c i d . A l s o , a l l y l i c o x i d a t i o n of A "'-sterols d i d not occur."*" In 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-ol -»- A^-3-one tr 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 best c o n d i t i o n s f o r androst-5-ene-3,17-dione (484a) p r e p a r a t i o n . In t h e i r survey of a v a i l a b l e procedures, the Jones o x i d a t i o n product was found to be contaminated w i t h s t a r t i n g m a t e r i a l (483a) and conjugated ketone w h i l e F i e s e r ' s dibromoketone intermediate underwent p h o t o l y t i c decompose i t i o n l e a d i n g to a lowered 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 modified form of P f i t z n e r and Moffat's procedure (224,222^) to 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-dicyclohexylcarbodiimide (DCC) and 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). By using a 1:1 benzene:dimethyl S u r p r i s i n g l y , no o x i d a t i o n of the unusually r e a c t i v e A" bond was reported i n e i t h e r case, but D j e r a s s i and coworkers, 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 at 5° produced i l , r a t h e r than i i i . A l l y l i c o x i d a t i o n of i v was excluded from the r e a c t i o n pathway when i t was found to be s t a b l e to 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 cleavage, to generate a 5a,6$-diol which dehydrated 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 of t r i c y c l i c o l e f i n i c bonds w i t h the Jones reagent were demonstrated (129^), - 145 -sulfoxide solution at 50°, compounds ^83a,e^,f_ yielded 60-70% of the corresponding 484 with some of the methylthiomethoxy ether (483, R = CH3-S-CH2-) as a byproduct. The recently reported d i f f i c u l t i e s i n the preparation of 6a-methylandrost-4-en-3-one (487) (225) from 38-hydroxy-6-methylandrost-5-en-17-one (485) are also p a r t i c u l a r l y informative. The Huang-Minion modification of the Wolff-Kishner reduction yielded 82% of the desired 8,y-unsaturated alcohol 486, but the subsequent Oppenauer 0 oxidation afforded only 40% 6a-methylandrost-4-en-3-one (487). In an attempt to oxidize the 8,y-unsaturated alcohol 486 d i r e c t l y to the corresponding ketone 488 for isomerization to the desired - 146 -ketone 487, the very m i l d S a r e t t o x i d a t i o n reagent (226 ) was employed. A p y r i d i n e s o l u t i o n of compound 486 was allowed to stand at room temperature f o r f o r t y hours i n the presence of an excess of d i p y r i d i n e chromium t r i o x i d e reagent. Chromatographic s e p a r a t i o n then afforded a 20% y i e l d of the 6 3 - h y d r o x y - 6 a - m e t h y l a n d r o s t - 4 - e n -3-one (489) . T h i s r e s u l t was completely unexpected s i n c e double bonds are not expected 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 noted, was p r e v i o u s l y r e p o r t e d to be e s s e n t i a l l y i n e r t towards them. • Apparently the modest e l e c t r o n donating power of these bonds u s u a l l y cannot compete w i t h the t r i v a l e n t n i t r o g e n f o r the chromic t r i o x i d e (226 ) . The i s o l a t i o n of products from the p y r i d i n e medium o f t e n presents t e c h n i c a l d i f f i c u l t i e s and Holum (226^), i n 1961, s t u d i e d acetone, dimethyl s u l f o x i d e , n i t r o b e n z e n e , nitromethane, e t h y l a c e t a t e , e t h y l bromide, chloroform and carbon d i s u l f i d e as a l t e r n a t i v e d i s p e r s i n g mediums to p y r i d i n e . U n f o r t u n a t e l y , even the best s o l v e n t , acetone, gave g r e a t l y reduced y i e l d s and i t was not u n t i l C o l l i n s , Hess, and Frank r e p o r t e d (227) i n 1968 that the anhydrous dipyr.idine-chromium(VI) oxide complex was moderately 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 , that 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 ) oxide 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 (226 a ) 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 leaved and i s o l a t e d double bonds are not isomerized s i n c e the medium i s b a s i c . Very prolonged exposure does lead 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 normally 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 ) . - 147 -p o s s i b l e . C o l l i n s ' coworkers i s o l a t e d a 64% y i e l d of c h o l e s t - 5 - e n -3-one (334) a f t e r c h o l e s t e r o l (331) was o x i d i z e d f o r t h i r t y minutes at 10 with a 6:1 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 detected i n the r e a c t i o n mixture but c h o l e s t - 4 - e n e - 3 , 6 - d i o n e (480 i n 10% y i e l d ) and ' c h o l e s t - 4 - e n - 3 - o l - 6 - o n e ' (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 s y n t h e t i c routes to v a r i o u s C - 1 7 - s u b s t i t u t e d A^-3-keto s t e r o i d s (229). In t h e i r hands the P f i t z n e r - M o f f a t t o x i d a t i o n of the B , y - u n s a t u r a t e d a l c o h o l s d i d not go to completion without s i d e r e a c t i o n s and the decomposition of the corresponding 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 dichloromethane ( C o l l i n s ) p r o v i d e d the most s a t i s f a c t o r y T h i s probably should 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 are "the major products obtained 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 ) oxide 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 thei r conjugated A -3-keto isomers. Current Synthetic Work Therefore, i n the interest of. obtaining high o v e r a l l yields of androstenone from the commercially available homoallylic alcohol precursor 473, Barton's Wolff-Kishner modifications (173) were used i n place of those of Huang-Minion and chromium t r i o x i d e oxidation procedures — Jones, C o l l i n s , Snatzke — were explored as a replacement for the Oppenauer oxidation. Treatment of 38-hydroxyandrost-5-en-17-one with a 180° refluxing diethylene g l y c o l solution of sodium glycolate and anhydrous hydrazine for 12 h, followed by 24 h at 210°, afforded the 8,y-unsaturated alcohol 474 i n 98% y i e l d a fter a short path 66 d i s t i l l a t i o n . Oxidation of 474 with 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 68 or n.m.r. The Jones oxidation method was quickly discarded because 65 66 67 68 This analysis, while undoubtedly true, i s misleading. Although there i s l i t t l e double bond isomerization reported i n t h e i r work, thei r results are based on the approximately < 50% y i e l d of isolated c r y s t a l l i z e d compounds and their analysis therefore excluded the production of at least 20% impurities that we have shown to be i n the reaction mixture. When th 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 ketol 473 (5.0 g) dropped to 78%. Using 2.00 M (50 ml) and 6 h @ 180°, 18 h @ 210° yielded 98% 474. As proven subsequently, compounds 474, 491 + 240, and 493 + 494 were eluted separately by g.l.c. (5' x k" 20% SE 30 columnl y) with base l i n e separation and thei r n.m.r. v i n y l proton differences (3.82 x for 493, 4.26 T for 492 and 240, and 4.64 x for 474 and 491) could then be exploited to measure the product r a t i o s i n mixtures. The closely related two phase oxidation procedure by Brown et a_l. (230) was also unsuccessful. A stoichiometric amount of sodium dichromate and s u l f u r i c acid i n water led to an attack on the d i e t h y l ether at room temperature while a 100% excess at 0° led, even after lh hours, to a mixture of s t a r t i n g material and compounds 240 + 493. Employing a 200% excess of aqueous chromic acid with an ether solution of alcohol 474 at 0° gave a 1:4 mixture of 240:493 after 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 reaction product, was cleanly isomerized on d i s t i l l a t i o n and alumina chromatography to 240. The more inter 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 fine yellow needles of 493 from methanol solutions. The structure of androst-4-ene-3,6-dione (493) was readily deduced from i t s spectral 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 half 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 with a 3.4 Hz width at half peak height. Also the u l t r a v i o l e t absorption for 493 exhibited X max 251 my (e = 10,600) with a s h i f t to X 372 my i n base, providing max 4 good agreement with values reported for other s t e r o i d a l A -3,6-diones 69 (151,157,231). The structure for the dione 494 was then confirmed to be androstane-3,6-dione by comparing i t with 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 structure proposed for the minor product was obtained by employing the procedure of Volger and Brackman (156 a) to prepare 493. Compound 240 was deconjugated to 491 with KOBut/HOAc (157) and then oxidized to 493 with a copper-catalyzed autoxidation i n a methanol-pyridine-trimethylamine solution. See also footnote 34, page 99. - 151 -above i s remarkably s i m i l a r to the mono-oxidation:overoxidation product r a t i o reported for cholesterol by C o l l i n s ejt a l . (227) — 64:18, better expressed as 78:22. 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 alcohol oxidation could be done s e l e c t i v e l y . Therefore, these results were greeted with some surprise ( d i s b e l i e f ) as both the ac i d i c and basic conditions yielded the same product mixture. Since the l i t t l e explored Snatzke method offered several interesting parameter variations while the C o l l i n s offered less experimental scope for such work, additional Snatzke reactions were performed on a model B,y-unsaturated alcohol. Snatzke Oxidations of Cholesterol Fieser's method (216) of purifying commercial cholesterol v i a debromination of the dibromide 481 as w e l l as his discussed procedure for 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 copper-catalyzed autoxidation. Volger and Brackman found B ,y-unsaturated ketones could be readily oxidized with a i r by using cupric complexes i n a l k a l i n e solution at 0° and their f i r s t reported example i n 1965 was a 75% y i e l d of 480 from 334. The dienolate anion (495) formation i s the rate determining step and electron transfer 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 ion. - 152 -£8H17 Usually, 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 rapidly with acetic acid (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 oxidized to the enedione with a i r and cupric acetate i n a methanol solution of pyridine-triethylamine for t h i r t y minutes. I t was this 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 with 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 extraction of their respective - 153 -potassium enolates (499, 231 ) from petroleum ether w i t h C l a i s e n ' s a l k a l i (aqueous potassium hydroxide i n methanol) (231 ) before being r e c r y s t a l l i z e d from methanol. With the p u r i f i e d c h o l e s t e r o l and expected products i n hand, a s e r i e s 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 analyzed and t a b u l a t e d . Table I l i a summarizes the r e s u l t s obtained 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 . In the standard o x i d a t i o n , c h o l e s t e r o l (1.0 mmole) i n a dimethylformamide s o l u t i o n (50 ml) was t r e a t e d f o r one hour at room temperature (23 ) i n a i r w i t h chromium t r i o x i d e (4.0 mmoles) and s u l f u r i c a c i d (1.8 mmole). R 0 42a I - 154 -Table Ilia Chromium Trioxide Oxidation of Cholesterol in Dimethylformamide Reaction - Changes0 Yield b « c Average Product Ratio 334 ;480 (% 331) 1 Standard Snatzke 88 % 73 : 27 (17%) 2 Nitrogen Atmosphere 89 % 80 : 20 (17%) 3 Reaction at 0° 60 : 40 (37%) 4 f|0 5 (2 mmoles) Added 73 % 57 : 43 (9%) 5 F|0 5(4 mmoles) Added 70 % 31 : 69 (9 % ) 6 No H 2S0 4 Used 82 % 76 :24 (79%) 7 H 2S0 4(Q9 mmoles) 90 % 83 ; 17 (31%) 1 H2S04(1.8 mmoles) 88 % 73 : 27 (17%) 8 H2S04(4.5 mmoles) 75 % 40 : 60 (3%) 9 H2S04(9.0 mmoles) 69 % 1 : 99 (1 %) 10 H2S04(18.0mmoles) 53 % 1 : 99 (1 %) 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 cholest-5 - e n - 3 - o n e (334) to cho les t -4 - en e - 3 , 6 - d io n e (480) . - 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 cholesterol oxidation products by substituting 1.0 mmole of cholest-5-en-3-one (344) or cholest-4-en-3-one (478) or cholest-4-ene-3,6-dione (480) for cholesterol (331) i n a Snatzke reaction. These experiments are essential for 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 reaction products' after a workup under neutral conditions. Although the conjugated enone 478 was demonstrated to be inert to a l l y l i c oxidation and although the i n i t i a l oxidation product of cholesterol, 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 trioxide,the 76% cholest-5-en-3-one isomerized i n the "standard Snatzke" went primarily (> 85%) to cholest-4-ene-3,6-dione. Under actual oxidation conditions t h i s conversion becomes e s s e n t i a l l y quantitative and cholest-4-en-3-one i s not found among the reaction products when neutral workup conditions are employed. Even when a two-fold excess of acid to oxidant was used i n a Snatzke oxidation of cholesterol, no cholest-4-en-3-one was produced. The short l i f e t i m e of the enol to a strong oxid i z i n g agent l i k e chromic acid i s completely understandable when one real i z e s that the enolate generated i n the 2+ 2+ Cu /O^ reaction (495) i s oxidized so quickly by Cu that the enolate cannot protonate at C-6 even though i t i s i n methanol. Similar reasoning Table HI b Snatzke Oxidations of Cholesterol Oxidation Products^ Compound 'Oxidation Conditions (% Mass Recovery)0 478: 480 (% 334) Cholest-5-en-3-one (334) Standard Snatzke (99%) b 14 : ; 86 (26%) II Standard without Cr0 3 (95%) b 100: 0 (21 %) II Inverse Snatzke (91 % ) b 13: 87 (45 %) Cholest-4-ene-3,6-dione (480) Standard(1.8 mmole H+) (82%) 7 6 % c 0: . 100 II " (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+) (83%) 83%° 95: 5 (9 mmole H+) (93%) 9 3 % c 95: . 5 Notes Non-acidic material isolated after oxalic acid isomerization except for 334 • Neutral workup employed ( NaHC03). cQuantitative measurement with internal standard. ^For details see Androstenone experimental ( c ) ( i ) . - 157 -explains why Fieser's work on the chromic acid oxidation of cholesterol i n acetic acid medium*'1 led only to the A^-3-one and A^-3,6-dione compounds. Table I l l b also demonstrates that cholest-4-ene-3,6-dione (480), unlike cholest-4-en-3-one, i s oxidized to a considerable extent as the amount of acid i s increased. The oxidation products of 480 were studied by Fieser and have been found to be a mixture of diacids and acid anhydrides (214). As an aid i n the product analysis for Table I l i a , and without introducing undue complications, the unconjugated enone product 334 was isomerized to the conjugated enone 478 with d i l u t e acid. The use of a c i d i c conditions i n the oxidation 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 ra 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 establish the product mole ra t i o s of cholest-5-en-3-one to cholest-4-ene-3,6-dione and the percentage of unreacted cholesterol. An in t e r n a l standard allowed a quantitative 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 solated non-acidic product and the weight assigned to 334, 480 and 331. This difference was mainly due to the non-inclusion of the very minor product 6-hydroxycholest-4-en-3-one, which i s isomerized to cholestane-3,6-dione, as wel l as material loss during sample handling. However, i n the case of an in e r t compound l i k e cholest-4-en-3-one, the mass recoveries and in t e r n a l standard analysis gave i d e n t i c a l results (Table I l l b ) . The reproduceability of i n d i v i d u a l experimental runs (Standard Snatzke was 73 - 3% of 334 for 6 experiments) was cert a i n l y - 158 -helped by the demonstration that the order of a d d i t i o n , the use of magnetic s t i r r i n g , the e x c l u s i o n of water and the use of an a i r or oxygen atmosphere were of no s i g n i f i c a n c e to the product mole r a t i o . The only three v a r i a b l e s found to be of any consequence were the amount of a c i d used, the temperature employed, and the presence or absence of an oxygen c o n t a i n i n g atmosphere. Decreasing the second parameter and i n c r e a s i n g the other two l e d to an undesired i n c r e a s e i n the enedione 480. A comparison of these r e s u l t s w i t h Snatzke's experimental (221) re v e a l s a fundamental "misunderstanding" i n h i s o r i g i n a l work. The o x i d a t i o n of c h o l e s t e r o l or any other a l c o h o l cannot be done w i t h a "few drops" or c a t a l y t i c amounts of s u l f u r i c a c i d . 7 ^ The Snatzke o x i d a t i o n , l i k e a l l other a c i d i c hexavalent chromium o x i d a t i o n s , f i t s the f o l l o w i n g s t o i c h i o m e t r i c equation (236 ). 2 C r 0 3 + 3 R 2 C H 0 H + 6 H + — ^ 3 R 2 C = 0 + 2 C r ? + + 6 H 2 0 ( a ) In agreement w i t h t h i s , the a l i q u o t s taken from a dimethylformamide s o l u t i o n of anhydrous chromium t r i o x i d e and 3-hydroxyandrost-5-ene Un f o r t u n a t e l y t h i s e r r o r has been transposed i n t o E n g l i s h through c i t a t i o n s of h i s work (226^ ) i n c l u d i n g a reference i n the organic chemist's B i b l e , F i e s e r ' s Reagents f o r Organic Synthesis (234a). A second i n t e r e s t i n g e r r o r i s the r e p o r t i n Augustine's book (222a) that c h o l e s t e r o l i s o x i d i z e d to 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) rep o r t that 3-hydroxy-A^-system cannot be o x i d i z e d to the ketone s a t i s f a c t o r i l y by Snatzke's method. The sad p a r t i s that they both are c i t i n g the 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 oxidation had occurred u n t i l small quantities of acid were introduced. As demonstrated by gas-liquid chromatography, the reaction ceased as the acid was consumed. However the oxidation went rapidly to completion after excess acid had been added. The same sequence of results i s reproduced i n Table I l i a when increasing amounts of s u l f u r i c acid (0.9 mmole -> 1.8 mmole -> 4.5 mmole) are considered. Important Parameters i n the Snatzke Oxidation While cholesterol oxidations have been studied for over a century, i t i s the very extensive studies of isopropanol oxidation that has led to mechanistic insights on the chromic acid oxidation. The oxidation of isopropanol by chromium(VI) i n aqueous acetic acid has been shown to follow equation (b) Rate of Oxidation- k1 [HCrO°] [(CH3)2CHOH] [H°] + kjHCrQj] [(CH^CHOH] [H*]2(b) requiring the two competing rate determining steps (e) and (f) R2CH0H + HCr04 + H® « [R2CH0-Cr03-H] + H20 (c) R2CH0 -Cr0 3H + H* [R 2CH0-Cr0 3H 2] (d) [R 2CH0-Cr0 3H] R2C = 0 + Cr l v • (e) [R 2CH0-Cr03H2] R 2 C=0 + Cr , v (f ) - 160 -i n one of two po s s i b l e t r a n s i t i o n states 500 or 501 (237 ). o. o 0 \ N f > ° \ S - R 2 R 2 C = 0 a ox xo Base + C r l v 500 501 X = Hor H 2 Stewart b c (237 ) and Wiberg (237 ) have discussed the r e l a t i v e merits of the two mechanisms and since has been found to be about t h i r t y times k^, the aqueous chromic acid oxidation appears to be predominantly second order i n a c i d . The Jones oxidation has also been studied (238 ) and i t has been found to follow f i r s t order k i n e t i c s i n chromium(VI), isopropanol and a c i d i t y . The authors favoured the c y c l i c t r a n s i t i o n state 501 i n t h i s case because proton trans f e r to an external base i n a l e s s polar solvent (acetone) should retard the r e a c t i o n rate and would not explain the observed rate enhancement. The s i g n i f i c a n t r o l e of acid i n chromate oxidations suggests that the phosphorus pentoxide employed i n Table I l i a i s serving as a source of phosphoric a c i d . The a d d i t i o n of the acid anhydride to a Snatzke rea c t i o n ensures that the water generated i n the rapid chromate ester formation step w i l l provide the a c i d i c protons required to catalyze the slower rate determining chromate ester decomposition. When a lower r e a c t i o n temperature was employed (0°), the rate of chromate ester decomposition was retarded r e l a t i v e to the rate of e n o l i z a t i o n of the 8,y-unsaturated ketone 334. Conversely, when the reaction temperature was raised to 37°, the enone (334) to enedione (480) product r a t i o became 84:16 i n a i r (90:10 i n nitrogen). - 161 -Unfortunately, at 57°, this r a t i o had dropped to 70:30 (82:18 i n nitrogen). Since two equivalents of acid are required to produce one mole of the enone 334 from cholesterol while s i x equivalents of acid are required to produce one mole of the enedione 480 by chromate oxidation of cholesterol, c o n t r o l l i n g the reaction temperature can be used to minimize the acid " c a t a l y s t " consumed i n the a l l y l i c C-6 hydroxy oxidation. 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 analysis of the stoichiometric equation (a) outlined i n (g), (h) and ( i ) below. In an a c i d i c hexavalent chromium oxidation, V up to two-thirds of the alcohol oxidation i s performed by a Cr species VI and one-third by a Cr species. R2CH0H + C r v , 0 3 R2C=0 + C r l v 0 2 + H 20 (g) H 20 + Cr0 2 + Cr0 3 —>» 2Cr v0 3H (h) 2(Cr03H + R 2CH0Ht3H + R 2C = 0 + Cr,u+- 3H20) (i ) 3R2CH0H + 2Cr03+6H+ 3R2C = 0 + 2Cr3 ++ 6H 20 (a) The result 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 active intermediate chromium species. Following this hypothesis, when the Snatzke i s done under IV V nitrogen, the stronger oxidant Cr and i t s derivative Cr are l e f t to perform oxidations. S ince these reactions are more rapid than the VI d parent Cr oxidations (236 ), this results i n the s u l f u r i c acid 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 enolization of the B,y-enone 334. A related oxygen effect has been reported by Wiberg and M i l l i n t h e i r work on the oxidation of benzaldehyde to benzoic acid (239). When th i s reaction was carried 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 possible. Repeating the reaction under nitrogen reduced the oxidant to 90% of t h e o r e t i c a l IV due to induced oxidation of the solvent by Cr Unfortunately the above interpretation f a i l s to explain why the amount of recovered cholesterol at a given reaction temperature i s independent of whether the reaction was done i n an a i r or nitrogen atmosphere. I t does not explain why employing excess s u l f u r i c acid (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 interpretation 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 electron transfer step. Even so, the majority (y 2/3) of the oxygen introduced at C-6 originates with the chromium t r i o x i d e and not with the molecular oxygen. Several additional observations were made of factors that have mechanistic rather than synthetic overtones. Using an extension of Table I l i a below, the results are l i s t e d from the Snatzke oxidation of cholesterol with 1.8 mmole of s u l f u r i c acid (the f i r s t two) and without s u l f u r i c acid (the l a s t s i x ) . The problem arises that i n the absence of acid and under normal reaction circumstances about 20% of the cholesterol i s oxidized. While hydration of hydroscopic chromium tri o x i d e yields chromic acid, H„Cr0., i t has already been demonstrated - 163 -that adding water has no e f f e c t 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 c h o l e s t e r o l i n the workup was shown not to be o c c u r r i n g s i n c e e n t r i e s s i x and twelve have the normal oxygen-nitrogen r a t i o changes and a blank run with c h o l e s t e r o l was recovered unchanged. The s u r p r i s i n g f e a t u r e i s that w h i l e these r e a c t i o n s c o n t a i n enough oxidant (4 mmoles) to r e a c t w i t h 6.0 mmole of a l c o h o l , even l e a v i n g r e a c t i o n s i x f o r Table III a Chromium Trioxide Oxidation of Cholesterol in Dimethylformamide Average Product Ratio Reaction - Changes 334 :480 (%331) 1 Standard Snatzke 73. :27 (17%) 11 Oxidant Doubled 63 :37 (6%) 6 NoH 2 S0 4 Used 76 : 24 (79%) 12 No H 2S0 4 >N 2 Atmosphere 87 ; 13 (82 %) 13 Volume Halved, NoH + ,N 2 86 ; 14 (69%) 14 No H +, Sodium Acetate (5.0 mmole) 0 •. 0 (100%) 15 Acetic Acid (17.5 mmole) 62 :38 (75%) 16 p-Toluenesulfonic Acid (2.0 mmole) 43 :57 (61 %) twenty-four hours i n a i r without added s u l f u r i c a c i d l e f t i t e s s e n t i a l l y unchanged (76:24 (74%) r a t i o a f t e r 24 h o u r s ) . T h i s " r e s i d u a l a c i d i t y " of the anhydrous chromium t r i o x i d e i s a l s o evident i n the r e s u l t s produced by doubling the oxidant (run 11) and by h a l v i n g the volume of dimethylformamide employed (run 13). When commercial chromium - 164 -t r i o x i d e was r e c r y s t a l l i z e d from d i s t i l l e d water and d r i e d under vacuum, r e s u l t s superimposeable with those found e a r l i e r were o b t a i n e d . That i s , run s i x changed from 76:24 (79%) w i t h commercial chromium t r i o x i d e to 77:23 (80%) with r e c r y s t a l l i z e d o x i d a n t . However, employing sodium a c e t a t e (5.0 mmole) as a weak base l e d to no o x i d a t i o n o c c u r r i n g (run 14) and even the a d d i t i o n of water (55 mmole) or a c e t i c a c i d (17.5 mmole) l e f t t h i s r e s u l t unchanged. The a d d i t i o n of s u l f u r i c a c i d (0.9 mmole) to the sodium a c e t a t e buffered s o l u t i o n r e s u l t e d i n ^ 40% of the c h o l e s t e r o l being o x i d i z e d . The most i n t e r e s t i n g aspect of employing sodium acetate was that i n the absence of a c i d only about 20% of the s t a r t i n g m a t e r i a l was i n i t i a l l y recovered by o r g a n i c e x t r a c t i o n of the quenched, s l i g h t l y b a s i c aqueous r e a c t i o n s o l u t i o n . I f e i t h e r a c e t i c or h y d r o c h l o r i c a c i d were used to a c i d i f y the aqueous l a y e r , the recovery jumped to over 75% i s o l a t e d c h o l e s t e r o l . T h i s i s c o n s i s t e n t w i t h the intermediacy of the monochromate e s t e r . T h i s e s t e r i s expected to be s o l u b l e i n b i c a r b o n a t e and to undergo a very r a p i d h y d r o l y s i s i n d i l u t e a c i d (242). While the e x t r a a c t i v i t y ( a c i d i t y ) of the chromium t r i o x i d e i s of no s y n t h e t i c consequence i t would i n f l u e n c e r a t e s t u d i e s and must be s u b t r a c t e d from the observed o x i d a t i o n r e s u l t s to permit comparisons, A c e t i c a c i d (17.5 mmole) and p - t o l u e n e s u l f o n i c a c i d (2.0 mmole) a c t u a l l y caused only < 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 15 and 16) w h i l e s u l f u r i c a c i d (0.9 mmole)led to 50% of the c h o l e s t e r o l being o x i d i z e d . In a d d i t i o n , the product r a t i o s for the monoprotic a c e t i c and p_-toluenesulfonic a c i d s were not as' favourable as that f o r - 165 -the b i p r o t i c s u l f u r i c . In retrospect, the s u l f u r i c acid results seemed almost anomalous especially when 2.0 mmoles of n i t r i c , p erchloric, 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%) respectively. 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 acid employed, equations (c) to (f) i n the Westheimer oxidation sequence must be replaced by (j) to (m). HCr04e + HA + H + HCr03A + H20 ( j ) R2CH0H + HCr0 3 A [R^CHO-CrC^-A] +• H 20 ( k) [R2CH0Cr02 A] R2C = 0 + Cr l v ( I) [R 2CH0Cr0 2AH+] R 2 C= 0 + Cr , v (m) Lee and Stewart have shown (241cl) that protonation of the acid chromate ion i n aqueous solutions i s accompanied by incorporation of the mineral acid anion into the chromium(VI) species. They have suggested that the oxidation of isopropanol i n moderately concentrated aqueous solutions of the mineral acid (HA) then proceeds by a c y c l i c , + 71 unimolecular decomposition of the chromate ester, R?CH0Cr0?AH (503). "The transfer 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 well as carbon-oxygen-chromium bonds, i . e . partly 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 state. The developing carbonyl group i n the electron-deficient t r a n s i t i o n state w i l l be s t a b i l i z e d by electron-donating substituents...Protonation of the chromate portion of the ester also increases the reaction rate. The conversion of ester to t r a n s i t i o n state i s thus aided by the combined po l a r i z i n g effects of an electron-donating aromatic ring and an electron-withdrawing metal cation."(241 ). - 166 -Since the t r a n s i t i o n s t a t e of chromate o x i d a t i o n s i s known to be e l e c t r o n d e f i c i e n t (241^), the i n c o r p o r a t e d conjugate base (A) w i l l Rp-C— 0V , 0 H / / \ 0 A 502 R — C-^0. OH k .A ••0 A . 503 R2C =0 HgCrOfc/S 0 a f f e c t the o x i d a t i o n r a t e markedly. In the Jones o x i d a t i o n employing chromic a c i d i n acetone, Lee et al_. (238 ) have shown that e l e c t r o n withdrawing l i g a n d s , l i k e n i t r a t e , enhance the r a t e w h i l e c h l o r i d e , an e l e c t r o n donating l i g a n d , r e t a r d s the o x i d a t i o n . From our r e s u l t s u s i n g dimethylformamide, the i n c o r p o r a t i o n of the conjugate base must a l s o be e s s e n t i a l 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 base i n c o r p o r a t e d must be of great s i g n i f i c a n c e i n the Snatzke o x i d a t i o n . While Lee and Johnson i n t h e i r study on the chromic a c i d o x i d a t i o n of i s o p r o p a n o l i n t r i f l u o r o a c e t i c a c i d (238^) could not d i s t i n g u i s h whether the conjugate.base group s h i f t e d the e s t e r formation (equation (k)) or e s t e r decomposition (equation (1)) r e a c t i o n s , the r e s u l t s on 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 that the e s t e r decomposition i s being a f f e c t e d . I t i s d i f f i c u l t to see how such strong a c i d s as s u l f u r i c and jD - t o l u e n e s u l f o n i c could give such d i f f e r e n t r e s u l t s i n equation ( k ) . I t i s q u i t e p o s s i b l e however that e l e c t r o n i c c o n s i d e r a t i o n s for b i s u l f a t e and t o s y l a t e would a f f e c t the r a t e of decomposition of 502. T h i s i d e a was strengthened when the r e s u l t s with p_-toluenesulfonic a c i d were found to be unchanged by the a d d i t i o n - 167 -o of 4 A molecular sieves 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 of hydroscopic reagents (molecular sieves, 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 carbodiimide) to the r e a c t i o n using s u l f u r i c acid was shown to have no e f f e c t on the r e s u l t s . While the a d d i t i o n 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 hydrate) did s h i f t these oxidations to completion and did suggest the intermediacy of a t r a n s i t i o n state l i k e 504, having both the favourable hydrogen bonding and the ,-Ht. R 0" *0 I II II R-C-0-Cr-0-S==0 I 8 + l l I 504 required protonation, the r e l a t i v e f a i l u r e of phosphoric acid (1.0 mmole H^PO^ afforded 77:23 (84%) terminated further 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 Oxidations of C h o l e s t e r o l Fortunately the methods that were devised to explore the Snatzke rea c t i o n r a p i d l y gave more general and s i g n i f i c a n t r e s u l t s when applied to the C o l l i n s oxidation. Table IVa displays the average r e s u l t produced from mul t i p l e runs by varying the oxidant mole r a t i o , the temperature, and the atmosphere employed i n a C o l l i n s r e a c t i o n . In a standard oxidation, c h o l e s t e r o l (1.0 mmole) i n dichloromethane s o l u t i o n (50 ml) was treated f o r t h i r t y minutes at room temperature (23 - 1°) with anhydrous chromium t r i o x i d e (2,4, or 6 mmoles) and p y r i d i n e (12 mmoles). - 168 -Table IVa Chromium irioxide-Pyridine Oxidation of Cholesterol in Dichloromethane ("Collins") Oxidant/Alcohol Average Product Ratio Reaction-Changes Mole 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 Atmosphere 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 Standard plus H20 (2.0 • mmole) 4 84 ;16 (79%) 9 H00(2.0mmole) + R 0.(6.0mmole) 4 91 : 9 (41%) 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 cho!est -4-ene-3,6-dione (480) . Table V demonstrates the r e l a t i v e s t a b i l i t y of the cholesterol oxidation products by substituting 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) for cholesterol (331) i n a C o l l i n s reaction at room temperature for one hour with a s i x - f o l d excess of oxidizing agent. These experiments i l l u s t r a t e that pyridine alone does not isomerize the unconjugated double bond of compound 334, that the conjugated ketone Table V Oxidations with Chromium Trioxide-Nitrogen Base Reagents. Compound0* Oxidation Conditions (%Mass Recovery)0 478:480 (% 334) Chotest-5-en-3-one (234J Standard Collins (70%) b(66) c 2 : 9 8 (15%) II Collins without Cr0 3 (99%) b - : - (100%) II Standard Corey (77 % ) b 5:95 (45%) Corey without Cr0 3 (94%) b 100:0 (98%) Cholest-4-ene-3,6-dione (42Q) Standard Collins (96%)(75%) c 0: 100 II Standard Corey (74%)(69%) c 0:100 Cholest-4-en-3-one (478) Standard Collins (92%)(85%) c 96: 4 II Standard Corey (85%)(78%) c 93 :7 Notes U .Non-acidic material isolated after oxalicacid isomerization except for 334 • b Neutral workup employed (NaHCO^. c Quantitative measurement with internal standard. ^ For details see Androstenone experimental (c.) (ii.).. - 170 -478 does not occur as a direct oxidation product of cholesterol and that cholest-4-ene-3,6-dione, the oxidation product of cholest-5-en-3-one, i s i t s e l f oxidized further. These are e s s e n t i a l l y the same observations as those made i n the Snatzke oxidations (Table I l l b ) As an aid to tabulating Table IVa, the reaction mixtures were once again isomerized with ox a l i c acid to establish the product mole r a t i o s of cholest-5-en-3-one to percentage of unreacted cholesterol, most s i g n i f i c a n t were the mole r a t i o temperature and atmosphere employed, present. At t h i s point, i t i s worthwhile cholest-4-ene-3,6-dione and the The variables found to be the of oxidant to alcohol, the and the amount of acid or base 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 "Stoichiometric analysis of the oxidation of 2-butanol at 25 using 2:1, 4:1, and 6:1 mole r a t i o s of complex to alcohol i n 6% complex solutions provided 56%, 79% and 98% end point conversions to 2-butanone, respectively (vpc analysis). This low oxidation e f f i c i e n c y i s undoubtedly due to the fact that reduced chromium products, as w e l l as alcohol, react with the reagent — no active complex remained i n solution following the oxidations even when the 6:1 r a t i o was used. Higher oxidizing 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 results for cholesterol are i n good agreement with the l i t e r a t u r e values for butanol as far as the oxidant mole rat 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 alcohol were found to provide a 49%, 84% and 97% end-point conversions of cholesterol. 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. This 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 of the hygroscopic nature of the dipyridine-chromium(VT) oxide. The hydrated 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 i s q u i t e u n r e a c t i v e as demonstrated by entry e i g h t of Table IVa. The h y d r o p h i l i c nature of the oxidant complex i s the main reason that i t i s no longer i s o l a t e d as suggested i n the procedure of C o l l i n s e_t a l . (227). The current procedure, suggested by R a t c l i f f e and Rodehorst (158), u t i l i z e s the i n s i t u p r e p a r a t i o n of the complex to minimize the handling d i f f i c u l t i e s . Two molar e q u i v a l e n t s of p y r i d i n e i n dichloromethane are added to one 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 red s o l u t i o n i s ready f o r use w i t h i n ten minutes. Since the problem now becomes one of having a weighed amount of anhydrous chromium t r i o x i d e (which i s i t s e l f hygroscopic) 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 are 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 commercial reagent grade chromium t r i o x i d e under vacuum and then c o o l i n g i n a n i t r o g e n atmosphere. The p y r i d i n e and dichloromethane are added by syringe and, a f t e r a few minutes, the a l c o h o l can be added as a 72 dichloromethane s o l u t i o n . Experiments show that f o r c h o l e s t e r o l a mole r a t i o of 8:1 of oxidant to a l c o h o l , r a t h e r than the normal 6:1 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 to go to completion 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) reported 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 oxidant 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 doing t h e i r r e l a t e d o x i d a t i o n work under an argon atmosphere. - 172 -The l i t e r a t u r e observations quoted above on the higher o x i d i z i n g e f f i c i e n c y of the C o l l i n s oxidant at lower temperature and on the use of phosphorus pentoxide appear to be m i s l e a d i n g . The o x i d i z i n g e f f i c i e n c y f o r a given mole r a t i o of oxidant to s t e r o l o b v i o u s l y drops as the temperature i s changed from 23 to 0 . That i s , employing a 4:1 r a t i o of complex to a l c o h o l changes the r e a c t i o n from being 83% o 6 complete at 23 to being 71% complete at 0 . On general p r i n c i p l e s , i t would be very s u r p r i s i n g i f higher o x i d i z i n g e f f i c i e n c i e s were obtained by lowering the temperature of 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 molecular oxygen than i t does on temperature, the l i t e r a t u r e observations 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 . Lowering the temperature then would give 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 completion because of the higher s o l u b i l i t y of oxygen at lower temperatures and the longer l i f e t i m e of the oxidant complex under these c o n d i t i o n s . The use by C o l l i n s et ail. of a suspension of phosphorus pentoxide to g i v e higher o x i d i z i n g e f f i c i e n c i e s suggests the a c i d anhydride prevents or reverses hydrate formation of the oxidant complex. From Table IVa, entry n i n e , i t i s c l e a r that using even a n i n e - f o l d excess of phosphorus pentoxide only regenerates (dehydrates) about one-half 3H 20 + P 2 0 5 - 2H 3 P0 4 - 173 -of the hydrated complex. As w i l l be demonstrated subsequently, the most important aspect of adding phosphorus pentoxide i s the a d d i t i o n of a good p r o t o n s o u r c e , as phosphoric a c i d , r a t h e r than the employment of phosphoric pentoxide as an e f f e c t i v e dehydrating reagent. A d i s c u s s i o n of a c i d parameter e f f e c t s w i l l f o l l o w that of the e f f e c t of bases, but f i r s t the favourable product s h i f t to c h o l e s t - 5 - e n - 3 - o n e i n Table IVa should be c o n s i d e r e d . The decrease i n c h o l e s t - 4 - e n e - 3 , 6 -dione produced by using a n i t r o g e n atmosphere suggests that about h a l f t h i s product o r i g i n a t e s from a u t o - o x i d a t i o n , as was observed i n the Snatzke o x i d a t i o n . The favourable m i n i m i z a t i o n of enedione p r o d u c t i o n at i c e bath temperatures i n d i c a t e s that i n the C o l l i n s o x i d a t i o n , u n l i k e i n the Snatzke, the r a t e of e n o l i z a t i o n of the unconjugated ketone compared to 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 i s diminished by lowering the temperature. The l a t t e r o b s e r v a t i o n p r o v i d e s experimental j u s t i f i c a t i o n f o r the procedure of Jones and Gordon (229) who o x i d i z e d v a r i o u s l y C-17 s u b s t i t u t e d A ^ - 3 - h y d r o x y s t e r o i d s at 0° w i t h d i p y r i d i n e chromium t r i o x i d e complex. However t h e i r work gives no i n d i c a t i o n that enedione formation i s suppressed at 0° and they are unaware that an e i g h t or ten:one mole r a t i o of o x i d a n t : s t e r o l i s r e q u i r e d to permit the r e a c t i o n to go to c o m p l e t i o n . Other Parameters i n the C o l l i n s O x i d a t i o n The parameter work f o r Table IVa was so encouraging that a set of experiments was performed to e s t a b l i s h the r o l e of p y r i d i n e i n the C o l l i n s o x i d a t i o n . The l i t e r a t u r e procedure of quenching the o x i d a t i o n r e a c t i o n with e t h e r and then working i t up was found to give anomalous - 174 -r e s u l t s at low p y r i d i n e c o n c e n t r a t i o n s . The reason f o r t h i s became evident when the r e s u l t s of performing a C o l l i n s ' o x i d a t i o n without any p y r i d i n e were c o n s i d e r e d . Using a 6:1 r a t i o of anhydrous chromium t r i o x i d e to c h o l e s t e r o l , without p y r i d i n e , gave a A^-3-one: 4 A - 3 , 6 - d i o n e (% c h o l e s t e r o l ) a n a l y s i s of 81:19 (43%) when the r e a c t i o n mixture was added to e t h y l ether 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 , d i l u t e h y d r o c h l o r i c a c i d (3 N) or aqueous sodium b i c a r b o n a t e , the product analyzed as - : - (100%). E v i d e n t l y , the lone p a i r e l e c t r o n s of oxygen i n d i e t h y l ether can serve the same f u n c t i o n as those of the n i t r o g e n i n 73 p y r i d i n e , a l b e i t s e v e r a l orders of magnitude l e s s e f f e c t i v e l y . As a r e s u l t of t h i s f i n d i n g , the r e a c t i o n s o l u t i o n s i n Table IVb were 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 s o l u t i o n s of sodium b i c a r b o n a t e fol lowed by washing the o r g a n i c l a y e r w i t h water and d i l u t e h y d r o c h l o r i c a c i d . Table IVb gives a p r o g r e s s i o n of e n d - p o i n t conversions s i m i l a r to those observed i n Table IVa when the 2:1, 4:1 and 6:1 mole r a t i o of complex ( t r i o x o b i s ( p y r i d i n e ) c h r o m i u m ) to s t e r o l are c o n s i d e r e d . A l s o the mass r e c o v e r i e s on workup f o r Table IVb were even higher than those observed f o r Table IVa, p r o v i d i n g ^ 90% y i e l d s . However the r e s u l t s t a b u l a t e d do not meet l i t e r a t u r e expectat ions when d i m i n i s h i n g amounts of p y r i d i n e are c o n s i d e r e d . I f the d i p y r i d i n e complex i s 73 . The p o i n t to be s t r e s s e d i s that while 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 , anything that 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 are 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 , reducing the p y r i d i n e below a two molar equ i v a l e n t should cause a dramatic f a l l i n the product y i e l d . However, Table IVb Pyridine Dependence of Collins Oxidation of Cholesterol Reaction0- (Base /Oxidant Oxidant/Alcohol Average Product Ratio0 Mole Ratio) Mole Ratio b 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 %) 5 No Pyridine 6 — ; — (100%) 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 a 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 ) t o cholest -4 -ene-3,6-d ione (480). - 176 -the l i s t e d r e s u l t s show there i s l i t t l e or no d i f f e r e n c e to employing one or two e q u i v a l e n t s of p y r i d i n e . When a r e a c t i o n c o n t a i n i n g a 1:1 r a t i o of p y r i d i n e : c h r o m i u m t r i o x i d e i s f i l t e r e d before the a d d i t i o n of the s t e r o l , the r e s u l t s were found to be u n a f f e c t e d . T h i s p a r t i c u l a r r e a c t i o n i s c o n s i s t e n t w i t h the intermediacy of the monopyridine complex and the r e s u l t s of Table IVb are i n agreement w i t h a monopyridine, r a t h e r than a d i p y r i d i n e , complex being r e s p o n s i b l e f o r the o x i d a t i o n . 7 ^ The hypothesis of a monopyridine complex was a l s o strengthened by s e v e r a l other f a c t s . The f i r s t of these was C o l l i n s ' own a n a l y s i s of the hydrated d i p y r i d i n e chromium t r i o x i d e complex to be C^Yl^Cr^^Oj. I f the " d i o l " water d i s p l a c e s a p y r i d i n e from each d i p y r i d i n e chromium(VI) complex (to form 505?), the t r a n s i t i o n s t a t e f o r the pyridine-chromium t r i o x i d e system and a secondary a l c o h o l , RR'CHOH, probably resembles 506a. An a l t e r n a t i v e 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 74 When 3B-hydroxyandrost-5-ene was o x i d i z e d w i t h a 6:1 mole r a t i o of 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 monitored by g . l . c , s i m i l a r r e s u l t s were observed. A f t e r t h i r t y minutes without 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 . A f t e r t h i r t y minutes with 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 with a 1:1 mole r a t i o of p y r i d i n e : C r O , afforded an 89:11 (7%) a n a l y s i s . R 505 506a - 177 -0 C r v - e f H I R' R 506b 0 508 s t r o n g b a s e s , even those which do no c o - o r d i n a t e chromium(VI), cause a s u b s t a n t i a l r e d u c t i o n i n the amount of o x i d a t i o n that o c c u r s . I f the h y d r o x y l proton was removed from 506b, the r e s u l t a n t dioxy d i a n i o n should a b s t r a c t a proton f a s t e r i n the d e p i c t e d t r a n s i t i o n s t a t e . In the case of t r a n s i t i o n s t a t e 506a a dioxy d i a n i o n would d i s c o u r a g e the d e p i c t e d c y c l i c concerted process because of i t s requirement f o r an e l e c t r o n d e f i c i e n t 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 the r a t e of o x i d a t i o n . In Table IVb there i s an i n d i c a t i o n that as the amount of p y r i d i n e i s i n c r e a s e d e i t h e r the y i e l d of enedione product r i s e s or the amount of recovered c h o l e s t e r o l i n c r e a s e s . T h i s amounts to the same t h i n g , that i s , that 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 decreases as more and more p y r i d i n e i s added. A more e x p l i c i t demonstration of t h i s was p r o v i d e d by performing C o l l i n s o x i d a t i o n s f o r s h o r t i n t e r v a l s and a n a l y z i n g the r e a c t i o n m i x t u r e . Below a r e the r e s u l t s obtained by d i s s o l v i n g c h o l e s t e r o l (1.0 mmole) i n dichloromethane (5 ml) and a second s o l v e n t (10 ml of " c o - s o l v e n t " ) , c o o l i n g to 0° and adding the s t e r o l to the l i s t e d oxidant (6.0 mmoles) i n dichloromethane (25 ml) at 0 ° . The analyses were determined f o r three minute r e a c t i o n p e r i o d s - 178 -and give the product r a t i o of c h o l e s t - 5 - 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 (480) w i t h the percentage of unreacted c h o l e s t e r o l (331) i n p a r e n t h e s i s . 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 that a c e t i c acid-chromium (VI) o x i d a t i o n s are much slower than d i p y r i d i n e -chromium(VI) o x i d a t i o n s i n the presence of a c e t i c a c i d . 7 ^ "Co-solvent" " Oxidant" "Analysis" Dichloromethane Cr03'(Pyridine)2 90:10 (35%) Pyridine Cr03(Pyridine)2 100: - (98%) Acetic Acid Cr03(Pyridine)2 93 : 7 (48%) Acetic Acid Cr0 3 100; - (92%) 75 S e v e r a l years before C o l l i n s et a l . employed dichloromethane, Stensio and Wachmeister (243^) found that a c e t i c a c i d was a u s e f u l s o l v e n t f o r 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 could be e a s i l y performed on e i t h e r a semimicro or p r e p a r a t i v e s c a l e . An example of the l a t t e r was Theander's work i n 1964 on the o x i d a t i o n of i + ( S a r e t t o x i d a t i o n f a i l e d ) ( 2 4 3 c ) . 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 procedure of employing a 1:3.5 r a t i o of a l c o h o l to oxidant 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 exception i s that 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 (242 a ) , ° s / y ° \ i R = 0 H , R ' = H RA_7 'X i i R , R ' = 0 R' 0 - j -- 179 -O b v i o u s l y , p y r i d i n e d r a m a t i c a l l y slows the r a t e of o x i d a t i o n 76 ' w h i l e a c e t i c a c i d has l i t t l e e f f e c t . C o l l i n s et a i . (227) have 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 i n the o x i d a t i o n of 2 - o c t a n o l i n dichloromethane ( C o l l i n s ) compared to i t s o x i d a t i o n i n p y r i d i n e ( S a r e t t ) f o r a one hour p e r i o d . The most r e a d i l y a v a i l a b l e e x p l a n a t i o n of t h i s behaviour employs the f a c t that the e q u i l i b r i u m 508 ( n )  507 . 517 represented by (n) l i e s f a r to the r i g h t . I f the a l c o h o l to be o x i d i z e d only r e a c t s w i t h the monopyridine complex (507), the r a t e of o x i d a t i o n c o u l d be s e v e r e l y r e t a r d e d . However, even i f the a l c o h o l can r e a c t with the d i p y r i d i n e complex 508, there i s a second and much b e t t e r reason f o r excess p y r i d i n e slowing down the o x i d a t i o n . When s m a l l q u a n t i t i e s of an amine base were i n t r o d u c e d to the s t e r o l being o x i d i z e d , the unexpected r e s u l t s l i s t e d i n Table IVc were o b t a i n e d . As the amount of t r i e t h y l a m i n e (pK + = 11.0) or d i i s o p r o p y l a m i n e (pK T 3 U + = 11.0) (233^) was i n c r e a s e d , the amount of Dei c h o l e s t e r o l 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, Stronger a c i d s may play a more s i g n i f i c a n t r o l e s i n c e protons are o b v i o u s l y important to the t r a n s i t i o n s t a t e 506a. Corey and Suggs (232^) have very r e c e n t l y demonstrated t h i s p o i n t with p y r i d i n i u m chlorochromate. T h i s reagent, formed with 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 four times as e f f i c i e n t as the d i p y r i d i n e complex. - 180 -Table IVc Influence of Amine Bases on the Collins Oxidation of Cholesterol. a Reaction—Base Oxidant/Alcohol Average Product Ratio (Base/Sterol Ratio) Mole 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 For details see Androstenone 240 experimental .section (ii) of (c) t h i s trend i s a l l wrong s i n c e Westheimer, i n 1951, r e p o r t e d that i the o x i d a t i o n of d i i s o p r o p y l chromate to acetone was c a t a l y z e d 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 of a 77 s m a l l amounts of p y r i d i n e or d i m e t h y l a n i l i n e (242 ) . The p o s s i b l e argument that the a l k y l amines are forming a n o n -r e a c t i v e complex i s untenable f o r s e v e r a l reasons. F i r s t , entry To the best of 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 p o s s i b l e l i t e r a t u r e precedent does e x i s t however. In the f i e l d of 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 eastern Europe and R u s s i a , has used such bases as g u a n i d i n e , cyclohexylamine, d i c y c l o h e x y l a m i n e , isobutylamine and hexanediamine to reduce c o r r o s i o n (245). - 181 -three f o r t r i e t h y l a m i n e should lead to no more than 50% recovered c h o l e s t e r o l , i n s t e a d of the 75% observed, i f an e q u i v a l e n t amount of chromium t r i o x i d e was t i e d up by the base. Second, the hindered 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 (pK B H + = 12.3) (244) leads to an even more i n e x p l i c a b l e r e s u l t . How can one m i l l i m o l e of 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 s i x m i l l i m o l e s of chromium(VI)? C o n s i d e r a t i o n of the c o l o u r changes that were observed i n a l l the r e a c t i o n s l i s t e d i n Table IVc i n d i c a t e s that chromate e s t e r formation i s t a k i n g p l a c e . Evidence was l a t e r obtained from a r e l a t e d o x i d a t i o n , C o r e y ' s method of employing d i m e t h y l p y r a z o l e i n p l a c e of p y r i d i n e , that chromate e s t e r formation i s almost complete even i n those cases where enough amine i s present to prevent any o x i d a t i o n from o c c u r r i n g . In any case, i t i s very d i f f i c u l t to see how the very f a s t chromate e s t e r formation step c o u l d be stopped by a base, e s p e c i a l l y by such a s t e r i c a l l y r e s t r i c t e d base as 1 ,8-bis(dimethylamino)naphthalene or " p r o t o n sponge". However the p o s t u l a t e d i n t e r m e d i a t e 506 i s capable of being completely deprotonated as the c o n c e n t r a t i o n of f r e e uncomplexed base r i s e s . As the amount of p r o t o n sponge i n c r e a s e s to about one e q u i v a l e n t of s t e r o l , the e q u i l i b r i u m 506 -> 509 i s s h i f t e d w e l l to the r i g h t . As the amount of a l k y l amine i s i n c r e a s e d to approximately f i v e 78 78 Besides having a remarkable b a s i c i t y , bis(dimethylamino)naphthalene, or " p r o t o n sponge", has been shown to be a very poor n u c l e o p h i l e . A l d e r et a l . (244) recovered i t unchanged a f t e r four days at r e f l u x w i t h e t h y l i o d i d e i n a c e t o n i t r i l e . For the purpose of Table IVc, proton 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 with chromium t r i o x i d e . Therefore the above q u e s t i o n should be rephrased to read "How does a very hindered 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 that can complex chromium(VI)?" - 182 -f >3NH f \=/ /V, / f \ = / e / v / o o - c ' °o o-c / / \ , K 3 N / \ H R R" R R' 506 509 equivalents, t h i s same s h i f t occurs. I t i s therefore not surprising that a weaker base l i k e pyridine can cause p a r t i a l deprotonation that leads to noticeable product changes when approximately t h i r t y or more excess equivalents of pyridine are employed. The preceding explanation indicates why the Sarett oxidation i s both catalyzed and poisoned by pyridine and why the oxidation rates are observed to be very slow i n the Sarett reaction. An experiment p a r t i c u l a r l y relevant to the topic of base-acid effects on the C o l l i n s oxidation was provided by g.l.c. monitoring of the oxidation of 33-hydroxyandrost-5-ene. When this 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 oxidation gave a 1:1 mixture of sta r t i n g material to cholest-5-en-3-one within f i f t e e n minutes. This r a t i o remained unchanged u n t i l acetic acid (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. - 183 -Corey O x i d a t i o n s of C h o l e s t e r o l At t h i s p o i n t , a s h o r t study of the g e n e r a l o x i d a t i v e method i n t r o d u c e d by Corey and F l e e t i n 1973 should be c o n s i d e r e d . They r e p o r t e d that a 1:1 complex of chromium t r i o x i d e — 3 , 5 - d i m e t h y l -p y r a z o l e i n dichloromethane serves as a s u i t a b l e reagent f o r o x i d i z i n g a l c o h o l s to c a r b o n y l compounds (232 ) . In one of t h e i r examples, a 2.5:1 mole r a t i o of complex to 4-_t-butylcyclohexanol was found to 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 a f t e r t h i r t y minutes at room temperature. T h i s reagent was consequently employed on c h o l e s t e r o l and the r e s u l t s were t a b u l a t e d i n Table V I . In the standard o x i d a t i o n , c h o l e s t e r o l Table VI Chromium Trioxide -Dimethylpyrazole Oxidation of Cholesterol in Dichloromethane ("Corey") Reaction-Changes Oxidant/Alcohol Mole Ratio 1 Standard 3 2 Standard 2 3 Standard .1 4 Reaction at 0° 3 5 Reaction under Nitrogen 3 6 Water(2mmole) Addition 3 7 1,8-Bis(dimethylamino)naphthalene(05 mmole) 3 8 Triethylamine (1.0 mmole) 3 Average Product Ratio 334; 480 (%331) 50 :50 (20%) 52 :48 (35%) 45 .55 (65%) 60 :40 (37%) 59 :41 (26%) 5 0 : 5 0 (25%) 38 :62 (90%) 40 :60 (49%) Notes a For details see Androstenone 240 experimental, section (ii) of (c). - 184 -(1.0 mmole) i n dichloromethane s o l u t i o n (50 ml) was t r e a t e d for t h i r t y minutes at room temperature w i t h the i n d i c a t e d amounts of oxidant (1 .0, 2 . 0 , or 3.0 mmoles). The r e s u l t s i n d i c a t e that the Corey procedure i s more comparable to the Snatzke o x i d a t i o n than to the C o l l i n s . 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 d i m e t h y l -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 e f f e c t on the e f f i c i e n c y or outcome of the o x i d a t i o n . A l s o w h i l e Table V , w i t h i t s synopsis .of the r e s u l t s of performing C o l l i n s and Corey r e a c t i o n s on Table V Oxidations with Chromium Trioxide-Nitrogen Base Reagents. Compound0" Oxidation Conditions (%Mass Recovery)0 478:480 (% 334) Cholest-5-en-3-one (334) Standard Collins (70%) b (66) c 2 : 98 (15 %) II Collins without C r 0 3 ( 9 9 % ) b - : - (100%) II Standard Corey (77 %) b 5 : 9 5 (45%) II Corey without CrOa ( 9 4 % ) b 1 0 0 : 0 (98 %) Cholest-4-ene-3,6-dione 14_8_Q.) Standard Collins (96%)(75%) c 0 : 100 II Standard Corey (74%) (69%) c 0 : 1 0 0 Cholest-4-en-3-one (478) Standard Collins (92%)(85%) c 9 6 : 4 II Standard Corey (85%)(78%) c 9 3 : 7 Notes Non-acidic materia! isolated after oxalic acid isomerization except for 334 . b Neutral workup employed (NaHC03). c Quantitative measurement with internal standard. ^ For details see Androstenone experimental (c) (ii). - 185 -c h o l e s t - 5 - e n - 3 - o n e , c h o l e s t - 4 - e n - 3 - o n e and c h o l e s t - 4 - e n e - 3 , 6 - d i o n e i l l u s t r a t e s that d i m e t h y l p y r a z o l e causes l i t t l e i s o m e r i z a t i o n of c h o l e s t - 5 - e n - 3 - o n e , the Corey o x i d a t i v e complex gives extensive o x i d a t i o n of both c h o l e s t - 5 - e n - 3 - o n e and c h o l e s t - 4 - e n e - 3 , 6 - d i o n e . D i m e t h y l -p y r a z o l e i s only a weak a c i d by e q u i l i b r i u m (o) below, but the oxidant complex , formulated as 512, should be a much b e t t e r proton source f o r 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 , C o r e y ' s 79 ' procedure can be d i s m i s s e d , s i n c e , from Table V I , the h i g h l y c o l o u r e d product mixture tends to be a 1:1 r a t i o of enone to enedione p l u s s u b s t a n t i a l amounts of recovered s t e r o l . However the r e s u l t s i n Table VI are very u s e f u l from a m e c h a n i s t i c v i e w p o i n t . Corey and F l e e t p o s t u l a t e d that the 3 , 5 - d i m e t h y l p y r a z o l e complex could be represented as 512. The o x i d a t i o n was thought to proceed by the c y c l i c , i n t r a -molecular course d e p i c t e d i n 513 a f t e r the oxidant 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 recent procedures 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 s a l t s ( 2 4 6 a ) , 1 - c h l o r o b e n z o t r i a z o l e (246^), the dimethyl s u l f o x i d e -c h l o r i n e complex (246 c ) and the dimethyl s u l f i d e - c h l o r i n e complex (246^). O x i d a t i o n s w i t h sulfoxonium s a l t s ( 2 4 6 e ) , s u l f u r t r i o x i d e (246^) or chromic a c i d i n dimethyl s u l f o x i d e at 70° (240) do not appear to compare favourably w i t h the C o l l i n s or Snatzke o x i d a t i o n s . - 186 -, N — C r — O H 513 512 R T h i s p o s t u l a t e d o x i d a t i v e mechanism appears untenable from the r e s u l t s i n Table V I . 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 , i f a n y t h i n g , enhance the formulated o x i d a t i o n , not r e s t r i c t i t . The behaviour of 1 ,8-bis(dimethylamino)naphthalene a l s o i s unaccountable on the b a s i s of 513 r e p r e s e n t i n g the t r a n s i t i o n s t a t e . How can o n e - h a l f m i l l i m o l e of proton sponge prevent one m i l l i m o l e of s t e r o l from b e i n g o x i d i z e d by three m i l l i m o l e s of oxidant? I f the c o n t r o l l i n g f a c t o r of the o x i d a t i o n i s the e l e c t r o n d e f i c i e n c y of the chromium i n the chromate e s t e r , the e q u i l i b r i u m represented by 514a and 514b may be the c r u c i a l i n t e r m e d i a t e . There are s e v e r a l examples known of the monohapto-pyrazole l i g a n d e x h i b i t i n g strong iminohydrogen bonding to the c o u n t e r i o n of t r a n s i t i o n metals (247). The oxidant complex 512 could serve as the proton source w h i l e the i n t r o d u c t i o n of f r e e bases would b u f f e r the r e a c t i o n medium. The f r e e amines would cause e i t h e r 514 a 514 b - 187 -m i n i m i z a t i o n of the c o n c e n t r a t i o n of 514 or shorten i t s l i f e t i m e s u f f i c i e n t l y to prevent the d e p i c t e d hydrogen s h i f t i n 515. In any case, the Corey d i p y r a z o l e r e a c t i o n , l i k e C o l l i n s d i p y r i d i n e o x i d a t i o n , 80 has a p r o t o n dependence i n the t r a n s i t i o n s t a t e . I n t e r e s t i n g r e s u l t s were p r o v i d e d by g . l . c . m o n i t o r i n g of amine blocked Corey o x i d a t i o n s of 33-hydroxyandrost-5-ene. Using only s h o r t exposures to workup c o n d i t i o n s , most of the s t e r o l was recovered as i t s chromate complex r a t h e r than as the f r e e a l c o h o l when e i t h e r a water quench or h y d r o c h l o r i c a c i d (3.0 N) quench was used. I f s a t u r a t e d b i c a r b o n a t e was used i n the workup, the free s t e r o l was r e c o v e r e d . Using an i n t e r n a l standard i n the o x i d a t i o n confirmed that at l e a s t 80% of the f r e e s t e r o l disappeared w i t h i n the f i r s t f i v e minutes. In the presence of an amine base, no r e a c t i o n products were observed, even a f t e r seven days, although most of the f r e e a l c o h o l had disappeared w i t h minutes of being added to the r e a c t i o n . T h i s suggests that a l c o h o l s r a p i d l y form chromate e s t e r s , even i n the The c y c l i c t r a n s i t i o n s t a t e employing a planar concerted r e a c t i o n i s c u r r e n t l y favoured (248) but the requirement that one of chromium's oxygens be protonated i s i g n o r e d . Our t r a n s i t i o n s t a t e 515 d i f f e r s from the suggested r e a c t i o n i n 513 i n that the p y r a z o l e n i t r o g e n " p r o t o n a t e s " the t r a n s i t i o n s t a t e r a t h e r than a b s t r a c t s the c a r b i n o l hydrogen. RR C = 0 515 - 188 -presence of l a r g e amounts of amine, and that these e s t e r s can be hydrolyzed on workup without any p e r c e p t i b l e s i d e r e a c t i o n s . C o n s i d e r a t i o n of the C o l l i n s and Corey o x i d a t i o n s i n more general terms leads d i r e c t l y to the concept of a monoamine-chromate e s t e r t r a n s i t i o n s t a t e . Since dimethylpyrazole (pK,,,,^ ^ 3) l e d to a Dn product d i s t r i b u t i o n so d i f f e r e n t to that of p y r i d i n e (pKg^+ = 5.25), the e f f e c t of other p y r i d i n e analogues was considered. Table V I I l i s t s the r e s u l t s of o x i d i z i n g c h o l e s t e r o l (1.0 mmole) w i t h anhydrous chromium t r i o x i d e (6.0 mmoles) and a p y r i d i n e d e r i v a t i v e (6.0 mmoles) f o r t h i r t y minutes at room temperature. While the r e s u l t s show l e s s v a r i a t i o n over a ApK .^4. of 2% u n i t s than was observed between p y r i d i n e Table VII Effect of pK B H+ on "Collins" Oxidation of Cholesterol-Average Product Ratio Reaction-Bases0 Base's pKBH+ 334:480 (%331) 1 Quinoline (516) 5.00 85:15 (34%) 2 Pyridine (51Z) 5.25 88:12 (3%) 3 4-Methylpyridine (518) . 6.02 75 :25 (2%) 4 2,4-Drmethylpyridine (519) 6.99 79 ;21 (3%) 5 2,4,6-Trimethylpyridine (520) 7.43 80:20 ( 31%) Notes0 For details see Androstenone 240 experimental, section (ii) of (c). - 189 -and d i m e t h y l p y r a z o l e , they demonstrate that the monopyridine complex a f f o r d s the most d e s i r a b l e product d i s t r i b u t i o n . While the a l k y l -p y r i d i n e complexes always formed completely w i t h i n t h i r t y minutes, they are not s t a b l e to s t o r a g e . The t r i m e t h y l p y r i d i n e complex l o s t ^50% of i t s a c t i v i t y a f t e r a one day p e r i o d , probably due to aldehyde formation (256). The q u i n o l i n e complex i s formed much more slowly than the others and i t was s t i r r e d f o r three hours before being employed. I t i s worth n o t i n g that N , N - d i m e t h y l a n i l i n e (521) ( p K B H + = 5.2) was found to be unable to complex chromium t r i o x i d e and to a f f o r d a - : - (100%) product a n a l y s i s when i t was employed under Table VII c o n d i t i o n s . While experimental work c o u l d , and s h o u l d , be extended to other amine bases, the o r i g i n a l o b j e c t i v e of undertaking a study of the C o l l i n s o x i d a t i o n has been accomplished. Table VII completes the work on circumventing the p r o d u c t i o n of the enedione product from the h o m o a l l y l i c a l c o h o l . While t h i s t a b l e r e p r e s e n t s the f i n a l parameter modications that were e x p e r i m e n t a l l y c o n s i d e r e d , i t a l s o leads d i r e c t l y i n t o a s h o r t but worthwhile d i g r e s s i o n . Having come t h i s f a r w i t h chromium t r i o x i d e o x i d a t i o n s and the i m p l i c a t i o n s of the p K ^ + of amines, p o s s i b l y the best footnote to t h i s d i s c u s s i o n i s a l i t e r a t u r e summary of some analogous work. 516 51Z R 2 = R 6 = R 4 = H 518 R 2 = R g = H , R 4 - C H 3 519 R 2= R 4 = C H 3 , R 6 = H 520 R2= R 4 = R 6 = C H 3 521 - 190 -Amino A l c o h o l O x i d a t i o n s I f the o r i g i n a l undertaking on the 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 s has l e d to anything of g e n e r a l s y n t h e t i c i n t e r e s t apart from a procedure f o r A^-3-keto s t e r o i d p r e p a r a t i o n s , i t i s an e x p l a n a t i o n of the d i f f i c u l t y i n o x i d i z i n g a l k a l o i d s . Often amino a l c o h o l i n t e r -mediates need to be converted to the corresponding c a r b o n y l c o n t a i n i n g amino a c i d s or a l k a l o i d s . The Oppenauer o x i d a t i o n i s u s u a l l y chosen f o r t h i s t r a n s f o r m a t i o n , but i t s u n r e l i a b i l i t y i s demonstrated by i t s f a i l u r e to o x i d i z e the b e n z y l i c a l c o h o l i n the amine 522 (249). In the case of the S a r e t t o x i d a t i o n , employing a 2.6:1 r a t i o of oxidant to a l c o h o l gave approximately 50% 523 a f t e r one day. The employment of chromate o x i d a t i o n s i s h i n d e r e d by s e v e r a l misconceptions of the 522 R1 = H, R2= OH 524 H, Rg= OH, R = C0CH 3 523.R 1 =R 2 = 0 525, R^R^O, R 3=C0CH 3 problems i n v o l v e d . The f i r s t of these i s that the b a s i c n i t r o g e n t i e s up the chromium t r i o x i d e and thereby prevents o x i d a t i o n . As demonstrated e a r l i e r by Table V i c , i t i s the b a s i c n i t r o g e n s that are not complexed to chromium that r e s u l t i n the o x i d a t i o n being r e t a r d e d . In any case, the l i t e r a t u r e s o l u t i o n to t h i s problem has been to employ the amide or lactam d e r i v a t i v e of the o r i g i n a l amino a l c h o l i n the chromium(VI) o x i d a t i o n . Examples of t h i s i n c l u d e the - 191 -primary amine d i o l i n t e r m e d i a t e , p r o t e c t e d as i t s amide 524, f o r the Jones or S a r e t t o x i d a t i o n s i n Wiesner's s y n t h e s i s of the C-18 diterpene a l k a l o i d 525 (250 ). The lactam f u n c t i o n a l i t y serves to d e a c t i v a t e the d i - and t r i - s u b s t i t u t e d n i t r o g e n s i n the work by S a l l e y (526 ->• 527) ( 2 5 0 b ) , Augustine (528 ->• 529) (250 b) and Wiesner (530 -+ 531) ( 2 5 0 d ) . 5 2 & R 1 = H , R 2 = 0 H 530 R T = H , R 2 = 0 H 5 2 9 R , = R 2 = 0 53L R 1 = R 2 = 0 The r a t i o n a l e given f o r d e a c t i v a t i n g the n i t r o g e n was not that i t removed the b a s i c i t y , but that "the lactam group pr o t e c t e d the n i t r o g e n from o x i d a t i o n " (250^). This b r i n g s forward the second misconception of the r e l a t i v e r a t e s of o x i d a t i o n . Amines are converted to amides or lactams by chromic a c i d (251) and although t h i s r e a c t i o n has been - 192 -known for some time, i t has only r e c e n t l y been used s y n t h e t i c a l l y . In 1974, Corey and Balanson, i n the t o t a l s y n t h e s i s of (±)-porantherine (532) (252), employed ten e q u i v a l e n t s of C o l l i n s reagent i n d i c h l o r o -methane f o r three days to a f f o r d 534 from 533 i n 80%. Since an a l c o h o l 532 533 R = CH 3 534 R = CHO o x i d a t i o n would be q u a n t i t a t i v e w i t h i n ten minutes under these c o n d i t i o n s , i t i s apparent that amine o x i d a t i o n s are many orders of magnitude slower than a l c o h o l o x i d a t i o n s . T h e r e f o r e , i t i s obvious that on the b a s i s of k i n e t i c r a t e s , a l c o h o l s should be s e l e c t i v e l y o x i d i z e d i n the presence of amines. The reason they are not i s due to the " p r o t o n sponge" problem. When a c e t i c a c i d was used e a r l i e r to overcome t h i s d i f f i c u l t y , the o x i d i z i n g a b i l i t y of the chromium t r i o x i d e reagent was found to be unimpaired by the presence of the amine. In l o o k i n g f o r l i t e r a t u r e c o n f i r m a t i o n of these i d e a s , the hexavalent chromium o x i d a t i o n s of the h y d r o x y l i n the secondary a b amine 535 (253 ) and the t e r t i a r y amine 537 (253 ) were of some i n t e r e s t , but were not completely p e r t i n e n t . A l l y l i c and b e n z y l i c - 193 -535 H,R2-R2= 0 OH 536 537 R1 = H, R2= OH 538 Rn = R2= 0 alcohols have a much lower a c t i v a t i o n energy for oxidation and their t r a n s i t i o n state requirements are quite d i f f e r e n t to those of al k a l o i d cycloneosamandione (541) by Schbpf and Miiller (257 ) involved the reoxidation of the unactivated d i o l derivative, neosamandiol (539), with chromium t r i o x i d e . An 88% y i e l d of cycloneosamandione was In the case of the indole alcohols 535 and 537, a Sarett oxidation only required ten minutes to provide 76% and 82% yields respectively of the 2-acyl a l k a l o i d 536, as i t s carbinolamine, and the N-acyl-indole 538. When the secondary amine of 535 was deactivated with the benzyl group (-CH^ C^ H,^ ) , the y i e l d went to 90%. The indole nitrogen has a very low b a s i c i t y (pKgH+ for indole i s ^-3) and when i t protonates i t i s at C-3 and not at the indole nitrogen (254) . Therefore the oxidation of i_ to j i i i n 70% by the Co l l i n s method (255) i s actually the oxidation of an a l l y l i c alcohol that contains a completely deactivated nitrogen base. unactivated alcohols. 81 However the elucidation of the salamander a H 2 - 194 -g ^ R ^ R ^ H 543 R1 = R2= H obtained by adding the t h e o r e t i c a l amount of 0.2 N aqueous chromium t r i o x i d e to a 3% s u l f u r i c a c i d s o l u t i o n of 539 on a steam b a t h . They a l s o found the r e o x i d a t i o n of the corresponding C-16 a l c o h o l (540) to cycloneosamandione was e s s e n t i a l l y quantitative by t h i s method. When Habermehl and Haaf l a t e r synthesized cycloneosamandione, they imployed the same o x i d a t i o n very s u c c e s s f u l l y (257^). They a l s o r e p o r t e d (257 ) a q u a n t i t a t i v e o x i d a t i o n i n converting the model compound 542 to 543 by t h i s same procedure. The 19-oxo-3-aza f u n c t i o n a l i t y cannot be i s o l a t e d as such since i t immediately forms the cyclocompound with the carbinolamine group. At t h i s d a t e , these p u b l i c a t i o n s appear to be the best (and only?) l i t e r a t u r e examples of amino a l c o h o l oxidations with chromium t r i o x i d e where a c i d was used to overcome the detrimental pK .^4. e f f e c t of the amine. - 195 -Synthetic Applications Putting mechanistic considerations aside and returning to the o r i g i n a l synthetic objective, androst-5-en-38-ol (474) was oxidized for t h i r t y minutes using an 8:1 mole r a t i o of oxidant to alcohol with monopyridine chromium(VI) oxide i n dichloromethane at 0° i n a nitrogen atmosphere. After a workup that included oxalic acid isomerization of the unconjugated ketone, the use of Claisen's a l k a l i to remove any enedione, and a short path d i s t i l l a t i o n , a 75% y i e l d of androst-4-en-3-one (240) was obtained. This represents a 73% o v e r a l l y i e l d of the 'octalone' 240 from 38-hydroxyandrost-5-en-17-one. If instead, the s t e r o l 474 was oxidized for f i f t e e n minutes with a 4:1 mole r a t i o of oxidant:alcohol using a 3:1 mole r a t i o of s u l f u r i c acid to chromium t r i o x i d e (acidic "Snatzke"), a 65% y i e l d of pure androst-4-ene-3,6-dione (493) was i s o l a t e d . While t h i s l a t t e r procedure has merit i n preparing enediones, the l i m i t e d a v a i l a b i l i t y 82 of the homoallylic alcohol precursors i n i t i a l l y appeared to r e s t r i c t the scope of the reaction. However, while the corresponding conjugated ketone was shown to be p r a c t i c a l l y i n e r t to the C o l l i n s and Snatzke oxidations, the B,Y _unsaturated ketone i s oxidized by either procedure to the enedione (Tables I l l b and V). Of more general significance, i t was found that the dienol ethers of conjugated ketones, but not the corresponding dienol acetates,were very readily converted to t h e i r respective enediones by either the C o l l i n s reagent or the Snatzke 82 Tsui and Just (258) have reported that epoxidation of homoallylic alcohols followed by a Sarett oxidation also leads to enediones. Both isomers of 5B,6B-epoxycholestan-3-ol were converted to the same A^-3,6-dione by an overnight Sarett oxidation. - 196 -reagent. For example, the C o l l i n s o x i d a t i o n of 601, the methyl d i e n o l ether of t e s t o s t e r o n e , d i d not g ive 602 but gave i n s t e a d the 601, R t= H R2= OH 0 544 602 R r R2- 0 e n e t r i o n e 544 as the major p r o d u c t . When compound 601 was o x i d i z e d 4 with the Snatzke reagent, i t was found that the A - 3 , 6 - d i o n e f u n c t i o n a l i t y was i n t r o d u c e d even f a s t e r than the C-17 c a r b o n y l and the e n e t r i o n e 544 was again the major p r o d u c t . 455 R l f R 2=CH 2 454 Ru R2= C H 2 547 R1 , R 2 =CH 2 238 R = H,R=CH 3 546 R1=H,R2=CH3 548 R,=H,Ra=CH3 Extending t h i s method,octalones 234, 455, and 238 were found to be converted q u a n t i t a t i v e l y to t h e i r r e s p e c t i v e enol ethers (545, 454, 546) by treatment w i t h 2,2-dimethoxypropane and p_-toluenesulfonic a c i d i n dimethylformamide (200) for four h o u r s . A Snatzke o x i d a t i o n then - 197 afforded the enedione d e r i v a t i v e s i n good y i e l d 83 A n d r o s t - 4 - e n - 3 -one (240) and c h o l e s t - 4 - e n - 3 - o n e (478) were a l s o converted to t h e i r 4 r e s p e c t i v e A - 3 , 6 - d i o n e d e r i v a t i v e s (493 and 480) by t h i s g e n e r a l procedure. 472 562 In a d d i t i o n to the o x i d a t i o n of d i e n o l ethers to enediones, the Snatzke method a l s o can be used to great advantage i n the o x i d a t i o n 84 of a l i p h a t i c a l c o h o l s . A Snatzke o x i d a t i o n with a 3:1 mole r a t i o 83 One a t t r a c t i v e a p p l i c a t i o n i s to use 547 as an i n t e r m e d i a t e i n the p r e p a r a t i o n of the sesquiterpene synthon JL. Taking 547 and s e s q u e n t i a l l y reducing the C - l double bond, i s o m e r i z i n g the other double bond w i t h H (exo-C-5 -> C-6,7) and e l i m i n a t i n g the s a t u r a t e d ketone would p r o v i d e jL. Compound 455 was p r e v i o u s l y prepared i n 95% o v e r a l l y i e l d by the sequence 240 453 -»- 454 455 (page 131). 84 T h i s was not optimized but the corresponding o x i d a t i o n by C o l l i n s method provided 98% of compound 562 from t e s t o s t e r o n e (472) u s i n g a 6:1 mole r a t i o of anhydrous oxidant to a l c o h o l ( o p t i m i z e d ) . - 198 -of oxidant to a l c o h o l afforded a 97% y i e l d of the enedione 562 from t e s t o s t e r o n e (472). The advantages of the u n d e r u t i l i z e d Snatzke procedure are even more apparent i n the o x i d a t i o n of primary a l c o h o l s to aldehydes. Using a 1:2:3 m i l l i m o l e r a t i o of alcohol:chromium t r i o x i d e : s u l f u r i c a c i d i n dimethylformamide (15 m l ) , octadecanol CH 3 (CH 2 ) 1 6 R 549 (549, R = CH2OH) could be o x i d i z e d to octadecanal (549, R = CHO) i n over 90% y i e l d . Commercial (hydrated) chromium t r i o x i d e was employed but l i t t l e s t e a r i c a c i d (549, R = COOH) was produced. The s i m p l i c i t y of the Snatzke r e a c t i o n i s a l s o a t t r a c t i v e . A f t e r a t h i r t y minute r e a c t i o n p e r i o d at room temperature, the o x i d a t i o n was quenched w i t h b i c a r b o n a t e and p a r t i t i o n e d between water and petroleum e t h e r . The d r i e d o r g a n i c l a y e r was concentrated to a f f o r d the aldehyde as a white s o l i d . T h i s corresponding C o l l i n s o x i d a t i o n of o c t a d e c a n o l would need three times as much oxidant and r e q u i r e anhydrous chromium t r i o x i d e . - 199 -Androstenone 240 from Testosterone (472) L i t e r a t u r e Precedence The s i m p l e s t and most obvious way of transforming t e s t o s t e r o n e to a n d r o s t - 4 - e n - 3 - o n e i s to p r o t e c t the C-3 carbonyl as i t s ethylene k e t a l , o x i d i z e the C-17 h y d r o x y l to a c a r b o n y l and then remove the l a t t e r f u n c t i o n a l i t y v i a a Wolff K i s h n e r r e d u c t i o n . T h i s sequence appeared to be p a r t i c u l a r l y a t t r a c t i v e s i n c e we had p r e v i o u s l y performed these r e a c t i o n s i n d i v i d u a l l y on other compounds i n a n e a r l y q u a n t i t a t i v e manner. A l s o , the l i t e r a t u r e precedent f o r s u c c e s s f u l l y reducing keto k e t a l s with hydrazine and base was e x c e l l e n t . U s u a l l y e i t h e r the method of Huang-Minion employing potassium hydroxide with 85% h y d r a z i n e hydrate (210), or that of Barton u t i l i z i n g sodium d i e t h y l e n e g l y c o l a t e w i t h anhydrous h y d r a z i n e (173), was f o l l o w e d . In 1962, Johnson and h i s coworkers (259) r e p o r t e d that the ethylene k e t a l group was s t a b l e to the Huang-Minion c o n d i t i o n s f o r the Wolff Kishner r e d u c t i o n . They achieved a 71% y i e l d of e p i m e r i c 551 from 550. Over the y e a r s , a l a r g e number of s u b s t i t u t e d b i c y c l o [ 4 . 4 . 0 ] d e c a n o n e k e t a l s have been reduced with h y d r a z i n e and then hydrolyzed on workup to p r o v i d e the corresponding decalones i n 60-80% (260). In the s t e r o i d - 200 -f i e l d , Nagata et a l (261°) obtained an 88% y i e l d of j>53 from 552 w h i l e Johnson et^  aL (261 b ) r e a l i z e d a more mediocre 63% 555 from 554. However the most encouraging l i t e r a t u r e precedent was the removal of C-17 h y d r o x y l by the sequence 556 through to 560. Jones and Zander 552 R = CH0 553 R=CH 3 HO' 554 R =CH = NH 555 R=CH 3 556 X=0 557 X=-0CH2CH20-R 2 R 1 558 R,= R2= 0, X=-0CH2CH20-559 R,= R2= H,X=-0CH2CH20-560 R,= R2= H,X=0 (262) s u c c e s s f u l l y removed the 178-hydroxyl from both A-homo-5a-a n d r o s t a n - 3 - and - 4 - o n e by p r o t e c t i n g the s a t u r a t e d c a r b o n y l , i n t r o d u c i n g and then removing a C-17 c a r b o n y l , and then r e g e n e r a t i n g the A - r i n g ketone. In the case of 3-keto a l c o h o l 556, the k e t a l 557 was obtained i n 86% by the Salmi procedure, the Moffat o x i d a t i o n with d i c y c l o h e x y l -carbodumide provided 90% 558 ,the Huang-Minion r e d u c t i o n y i e l d e d 89% - 201 -559 and an acid hydrolysis afforded 96% of the desired 3-keto steroid 560. The ov e r a l l y i e l d of A-homo-5a-androstan-3-one was 66% while an analogous sequence gave 45% A-homo-5ot-androstan-4-one o v e r a l l from 17 B-hydroxy-A-homo-5a-andros tan-4-one. Curr ent Synthetic Work. Therefore, while testosterone had not been previously u t i l i z e d as a precursor for androst-4-en-3-one, the required experimental manipulation seemed almost t r i v i a l . The Salmi dioxolanation procedure uses a water separating apparatus (Dean-Stark) (263 ) to p a r t i t i o n the water-benzene azeotrope produced by refluxing a benzene solution of p_-toluenesulf onic acid, ethylene g l y c o l and ketone. When testosterone (472) was subjected to th i s reaction, the product was found by n.m.r. 85 and infrared spectroscopy to be a mixture of the k e t a l 561 and recovered s t a r t i n g material. Even after prolonged periods with refluxing Dean and Christiansen (263 a) have postulated the sequence jL •+ v for unconjugated ketones being ketalized with ethylene g l y c o l . They have demonstrated that the A^-3-ketal (iv) i s isomerized by acid to i t s A -isomer. The A^-3-keto steroids usually, but not always (264), afford the unconjugated ketals when p-toluenesulfonic acid i s employed. The A^-3,3-eth.ylenedioxy product i s favoured by the employment of weaker organic acids ( o x a l i c , (COOH)2 or adipic ( 0 ^ ) 4 (COOH) 2) (263^) or small amounts of the much stronger p-toluene-sulfonic acid (263 a). 4 H + A 4-3-ketal iv v - 202 -benzene or t o l u e n e , the crude product contained 'v 20% t e s t o s t e r o n e . The o r i g i n a l work by Antonucci et a l (265 ) r e p o r t e d ^ 50% y i e l d of the k e t a l 561 a f t e r three and o n e - h a l f hours i n r e f l u x i n g benzene and, even twenty years ago, the s a t u r a t e d 3-keto s t e r o i d s , which afforded 4 >85% d i o x o l a n a t i o n , were c o n t r a s t e d to the A - 3 - k e t o s t e r o i d s , which afforded <65% conversions ( 2 6 6 a ) . ^ ^ Campbell et a l (265^) u t i l i z e d a vacuum d i s t i l l a t i o n of ethylene g l y c o l from a 90° s o l u t i o n of t e s t o s t e r o n e and c a t a l y i c p - t o l u e n e s u l f o n i c a c i d i n a l a r g e excess of ethylene g l y c o l to o b t a i n a 75% y i e l d of 561 that was 96% p u r e . L i s t o n and Toft (225) l a t e r employed t h i s vacuum d i s t i l l a t i o n method on 2a-methyl-t e s t o s t e r o n e to o b t a i n a 74% y i e l d of the corresponding A ^ - 3 , 3 - e t h y l e n e -dioxy d e r i v a t i v e . A p p l i c a t i o n of Campbell 's procedure to our work gave d i s a p p o i n t i n g r e s u l t s but f o r t u n a t e l y an even b e t t e r l i t e r a t u r e a l t e r n a t i v e was found. Dauben and cowo r k e r s (266 ) developed a method of p r e p a r i n g ethylenedioxy d e r i v a t i v e s by exchange d i o x o l a n a t i o n . In 86 The c o n t e n t i o n that the o i l y byproducts of the conjugated ketones were the r e s u l t of enol ether formation was i n v e s t i g a t e d . Close s c r u t i n y of the n . m . r . spectrum of the crude r e a c t i o n product showed l i t t l e enol ether was i n the m i x t u r e . E n o l ethers would be expected to s u r v i v e the b i c a r b o n a t e workup. - 203 -t h i s approach, the ethylene g l y c o l p ortion of simple 2 , 2 - d i a l k y l -1,3-dioxolanes i s transferred to the s t e r o i d a l ketones by acid t h i s technique, they k e t a l i z e d testosterone with 2-ethyl-2-methyl-l,3-dioxolane and obtained 75% y i e l d of the k e t a l 561. Of much greater s i g n i f i c a n c e was t h e i r observation that exchange k e t a l i z a t i o n , unlike d i r e c t k e t a l i z a t i o n , could introduce the ethylenedioxy f u n c t i o n a l i t y s e l e c t i v e l y at C-3 without a f f e c t i n g the C-17 carbonyl. That i s , that androst-4-ene-3,17-dione (562) could be d i r e c t l y converted to the desired monoketal 563 i n 74% y i e l d . Since t h i s compound (563) could be much more r e a d i l y c r y s t a l l i z e d from the enedione 562 than the k e t a l 561 could be from testosterone, and since the exchange k e t a l i z a t i o n was found to be a much cleaner r e a c t i o n , Dauben's approach was followed. D j e r a s s i and Gorman (266 b) extended Dauben's exchange dioxolanation re a c t i o n to 1,3-oxathiolanes (2,2-dimethyloxathiolane or c y c l i c ethylene hemithioketal of acetone, i_ Y=S) and 1,3-oxathianes (2,2-dimethyloxathiane or the c y c l i c trimethylene hemithioketal of acetone) and also demonstrated that c y c l i c t h i o k e t a l s would not undergo exchange. The generalized exchange rea c t i o n was formulated to proceed v i a the intermediacy of IJL, formed from the non v o l a t i l e ketone R 2 C = 0 and the 2 , 2 - d i a l k y l - l , 3-heterocycle i _ . By Dauben's procedure, 2-butanone i s usually d i s t i l l e d from the reac t i o n while i n D j e r a s s i ' s work the equilibrium s h i f t was accomplished by removing acetone. c a t a l y s i s i n a r e f l u x i n g i n e r t solvent or excess reagent. 87 Using R ? C = 0 y ii R*CCH II 0 (Y = 0,S R*= CH3,-CH2CH3) - 204 -As d i s c u s s e d e a r l i e r , t e s t o s t e r o n e (472) c o u l d be o x i d i z e d almost q u a n t i t a t i v e l y (98%) to the enedione 562 by a chromate o x i d a t i o n with the Snatzke or C o l l i n s reagent. The exchange d i o x o l a n a t i o n w i t h j>-t o l u e n e s u l f o n i c a c i d and p u r i f i e d 2 - e t h y l - 2 - m e t h y l - l , 3 - d i o x o l a n e i n r e f l u x i n g toluene afforded the expected monoketal, f r e e of b i s k e t a l and s t a r t i n g m a t e r i a l , i n 53% y i e l d . Based on the enedione recovered by a c i d h y d r o l y s i s of the c r y s t a l l i z a t i o n mother l i q u o r s , the y i e l d rose to 88% or 86% o v e r a l l from t e s t o s t e r o n e . T h i s compound was i d e n t i a l to the one obtained by o x i d i z i n g t e s t o s t e r o n e k e t a l (561) w i t h C o l l i n s reagent and e x h i b i t e d the l i t e r a t u r e p h y s i c a l and s p e c t r a l p r o p e r t i e s r e p o r t e d f o r 3 , 3 - e t h y l e n e d i o x y a n d r o s t - 5 - e n - 1 7 - o n e (563). The W o l f f - K i s h n e r r e d u c t i o n of compound 563 was accomplished u s i n g B a r t o n ' s procedure (173) w i t h anhydrous h y d r a z i n e and sodium d i e t h y l e n e g l y c o l a t e i n r e f l u x i n g d i e t h y l e n e g l y c o l . The hydrazone was formed at 170° i n the u s u a l way and then decomposed by h e a t i n g at 210° overnight ( fourteen h o u r s ) . A f t e r workup, a v i s c o u s o i l was recovered and shown to l a c k a c a r b o n y l a b s o r p t i o n i n i t s i n f r a r e d spectrum and to have a diminished ethylenedioxy a b s o r p t i o n i n i t s n . m . r . spectrum. - 205 -The removal of the ke t a l was accomplished by acid hydrolysis and the crude product was chromatographed on a c t i v i t y I I I alumina to afford androst-A-en-3-one (240). The y i e l d , hoever, was a dismal 15%I The reaction was therefore repeated employing the Huang-Minion method (210) with 85% hydrazine hydrate and potassium hydroxide i n refluxing diethylene g l y c o l . The prerequisite hydrazine was formed over a two hour period and then the reaction temperature was raised to 195° and l e f t r efluxing for eight hours. After workup, acid hydrolysis, and column chromatography, androstenone 240 was isolated i n 30% y i e l d . The ethylene k e t a l , contrary to " l i t e r a t u r e precedent", was obviously being destroyed under both the Huang-Minion and Barton reaction conditions. The other chromatographic fractions from both reactions were examined i n an attempt to understand what was occurring. The material isola t e d from the column before ketone 240 was eluted was demons'trated by n.m.r., infrared, and mass spectroscopy to be an isomeric mixture of two or more mono-olefins. Hydrogenation with tris(triphenylphosphine)-chlororhodium i n benzene (113) or palladium on charcoal i n perchloric-acetic acid (207) f a i l e d to saturate t h i s mixture. However a l l y l i c oxidation with C o l l i n s reagent (177) did afford up to 60% androst-4-en-3-one with a small amount of androst-4-ene-3,6-dione as a side product. Since no other ketone products were observed, these results suggested the mono-olefin mixture consisted of 3- and 4-androstenes. Dauben et_ a_l (177) have demonstrated that a l l y l i c oxidations with C o l l i n s reagent at a l l y l i c methine positions usually y i e l d the isomeric enone. - 206 -After some d i f f i c u l t y , the o l e f i n mixture was resolved by gas 19 l i q u i d chromatography into a 2:1:1 r a t i o of three components. The f i r s t and major one was assigned the structure 564 from the following observations. The infrared spectrum of th i s compound, with o l e f i n i c bands at 3020 and 681 cm \ corresponds very closely to that reported for 58-cholest-3-ene (3015, 679 cm"1) (152) but not at a l l to those reported for 5a-cholest-3-ene (3012 and 671 cm ^ ) , 5a-cholest-2-ene (3017 and 664 cm" 1), or cholest-4-ene (810 cm"1) (152,268). The n.m.r. spectra of 564 exhibits methyl singlets at x 9.04 and 9.29 and two downfield o l e f i n i c protons centered at x 4.34 and 4.67, the l a t t e r pair exhibiting a mutual coupling constant of 10 Hertz. Cholest-2-enes are known to show only a s i m p l i f i e d o l e f i n i c multiplet while cholest-3-enes have two unequivalent protons coupled by ^  10 Hertz (268). However, 5a-cholest-3-ene has been shown to have angular methyl resonances at x 9.26 and 9.34 (268), thereby eliminating 5a-androst-3-88 ene from consideration. The structure proposed on the basis of spectroscopic evidence was confirmed by the reduction of 564 to 58-androstane and the oxidation to androst-4-en-3-one (240). The hydrogenation was performed over platinum oxide catalyst to y i e l d the saturated hydrocarbon i n 98%. This product's physical properties gg Few members of the androstene family of o l e f i n s have been reported but consideration of the cholestene analogues i s h e l p f u l . For example, 5a-androst-2-ene exhibits C 1 9H 3 at x 9.23 and C 1 8H3 at 9.29 (270) while 5a-cholest-2-ene has i t s methyl resonances at 9.25 and 9.35 (268); androst-4-ene shows x 8.97 and 9.27 (see experimental) and cholest-4-ene i s reported to be 9.01 and 9.33 (268). Therefore 5a-cholest-3-ene, with x 9.26 and 9.34 (268), compares too unfavourably with the f i r s t component (x 9.04 and 9.29) to consider assigning i t the 5a-A^ structure. - 207 -correspond to 53-androstane' s, 565, with reported m.p. 78-79° and C-19 methyl resonance at x 9.08 by n.m.r., rather than those of 5a-androstane, m.p. 50-52° and C-19 methyl appearing at T 9.21 (269,271). The second component isolated by gas l i q u i d chromatography had an o l e f i n i c infrared absorption at 810 cm with l i t t l e or no absorption above 3000 cm \ and n.m.r. t e r t i a r y methyl resonances at T8.97 and 9.27. This spectroscopic data bore such a close analogy to that reported for cholest-4-ene that an authentic sample of androst-4-ene was immediately prepared from androst-4-en-3-one. Overnight treatment of ehohe 240 with 1,2-ethanedithiol and boron t r i f l u o r i d e etherate i n acetic acid (272) gave a quantitative y i e l d of 3,3-ethylenedithioandrost-4-ene (566). Desulfurization for twelve minutes EL with Raney n i c k e l i n ref l u x i n g ethanol (273 ) afforded an 80% y i e l d of the desired o l e f i n 567. This compound had the same spectroscopic properties as the second component of the o l e f i n mixture and enhanced the g.l.c. chromatogram of the second peak upon coinjection. Hauptmann (274) has shown that no rearrangement of the double bond i s involved i n a sequence of the type 240 ->• 566 -> 567. - 208 -240 The t h i r d component showed o l e f i n i c C-H bands at 3020 and 671 cm i n i t s i n f r a r e d spectrum and methyl s i n g l e t resonances at T 9.20 and 9.28 i n i t s n . m . r . spectrum. As f o r 564, a c l o s e analogy c o u l d be made between 568 and c h o l e s t - 3 - e n e , i n t h i s case 5 a - c h o l e s t - 3 - e n e . When t h i s t h i r d compound, 5 a - a n d r o s t - 3 - e n e , was hydrogenated i n e t h y l a c e t a t e over p l a t i n u m o x i d e , 5a-androstane (569) was the s i n g l e product i s o l a t e d i n 95% y i e l d (269). - 209 -Literature Revisited Determination of the structures of the Wolff-Kishner o l e f i n i c products permitted an assignment of a plausible reaction mechanism. If a base catalyzed fragmentation of the dioxolane group occurred as depicted i n the p a r t i a l structure 570 (121), the resu l t i n g unconjugated ketone 571 would be isomerized rapidly into conjugation and then reduced v i a the Wolff-Kishner reduction to a mixture of o l e f i n s . Conjugated ketones are known to give o l e f i n isomers (275) and when androst-4-ene-3,17-dione (562) was subjected to treatment with hydrazine and base by Barton's procedure, a 95% recovery of a 2:1:1 mixture of 3 4 5 5B-A -, A - and 5a-A -androstenes was obtained. Occasionally, the Wolff-Kishner reaction has been employed synt h e t i c a l l y to prepare o l e f i n s . For example, Nickon et a l (152) reduced cholest-4-en-3-one i n this way to obtain a mixture of cholest-4-ene and 5a- and 5B-cholest-3-ene. Djerassi and Fishman (276) have also reported that a Wolff-Kishner reduction of the steroid 572 afforded three isomeric o l e f i n s . In thei r reduction of 25£-spirost-4-en-3-one i n an autoclave at 200° for 16 hours with absolute ethanol and sodium ethoxide, they observed that the product r a t i o of - 210 -5B-A :A :5a-A was 2:1:1. However D j e r a s s i and Fishman found t h i s 89 r a t i o changed to 1:1:2 under the Huang-Minion conditions. In a l l these reactions, the o l e f i n mixture i s thought to r e s u l t from the rapid and i r r e v e r s i b l e solvent protonation of the a l l y l i c carbanion 576. The o r i g i n a l hydrazone 573 i s isomerized v i a the hydrazone anion (574) to the diimide anion 575 i n the rate determining step followed by rapid product formation (275). In working with the androstene isomers, we became aware of t h e i r s u s c e p t i b i l i t y to auto-oxidation. In the l i t e r a t u r e work above, the isomer r a t i o f o r the small scale Huang-Minion experiment was determined on ^25% product recovery while the large scale autoclave product r a t i o was for >40% i s o l a t i o n . Nickon e_t a l (152), without g i v i n g d e t a i l s , observed the product r a t i o changed when t r i e t h y l e n e g l y c o l was used i n place of diethylene g l y c o l . Szmant (275 a) has stressed the importance of solvent on the course of the Wolff-Kishner r e a c t i o n . In any event, our Wolff-Kishner reactions i n diethylene g l y c o l provided y i e l d s of up to 95% but g . l . c . showed only very minor r a t i o changes from 2:1:1. - 211 -R"" \ R N—NH 2 ET R' R" R"" , \ 6 R O N - N - H \ / C = C R" R'" R , U , H R C - N - N e w R" R" 573 574 575 Mil 576 577 578 While there appears to be no precedent for the Wolff-Kishner reaction affording o l e f i n i c products from the corresponding 8,Y -unsaturated ethylene k e t a l , there are a number of l i t e r a t u r e reports where these products must have' been overlooked. Liston and Howarth (277 ) found the Wolff-Kishner (Huang-Minion) reduction of 579, the 116-hydroxy analogue of 3,3-ethylenedioxyandrost-5-en-17-one, yielded 55% of the desired product 580. Since the hydrazone reduction proceeds nearly qu a n t i t a t i v e l y , about 40% of the st a r t i n g material (579) went 579 X = 0 581 X = 0 580 X = H 2 582 X= H 2 - 212 -3 4 unobserved i n t o o l e f i n i c (A + A ) products. The magnitude of t h i s problem i s even b e t t e r represented i n examples r e q u i r i n g the r e d u c t i o n of an 11-oxo f u n c t i o n a l i t y . The Huang-Minion procedure f a i l s completely to reduce t h i s s t e r i c a l l y hindered c a r b o n y l , but Barton's m o d i f i c a t i o n using anhydrous hydrazine u s u a l l y gives 90% y i e l d s . However, when Nagata e t a l reduced the 3 , 1 7 - b i s k e t a l 581 by Barton's procedure, the 11-deoxo compound 582 was obtained i n only 36% y i e l d (174). Although not reported as such, there i s no doubt that most of the 3,3-ethylenedioxy f u n c t i o n a l i t y was destroyed under the f o r c i n g r e a c t i o n c o n d i t i o n s . I n t e r e s t i n g l y , Nagata (174,175,277^) developed an a l t e r n a t i v e procedure using a mixture of hydrazine hydrate, hydrazine h y d r o c h l o r i d e and potassium hydroxide i n t r i e t h y l e n e g l y c o l to overcome Barton's requirement of using anhydrous hydrazine. This m o d i f i c a t i o n a f f o r d e d Nagata et a l (174) a 52% y i e l d of _582 from 581 and was a l s o found to provide a 40% y i e l d of 584 from 583 (277^). I t i s reasonable to expect a higher y i e l d of 582 by Nagata's m o d i f i c a t i o n s , r a t h e r than Barton's, because the base s t r e n g t h and base c o n c e n t r a t i o n are lower i n the former procedure. These same r e s u l t s have been i n t e r p r e t e d as showing that Nagata's procedure i s more vigorous than Barton's (275^) but a c t u a l l y i t i s q u i t e the opposite. I t i s evident, however, that c o n s i d e r a b l e dioxolane fragmentation i s o c c u r r i n g under both Nagata's 3 4 and Barton's r e a c t i o n procedures, even though no A" or A o l e f i n i c products were i s o l a t e d . - 213 -a OR o 583 X=CHO 561 R = H 584 X=CH3 585 R=S0 2 C 6 H 4 CH 3 586R=S0 2CH 3 Before c o n s i d e r i n g p o s s i b l e methods of overcoming the problem of p r o t e c t i n g ketones during the W o l f f - K i s h n e r r e d u c t i o n , a s l i g h t d i g r e s s i o n i s i n order to dea l w i t h a l t e r n a t i v e methods of removing the C-17 oxygen from t e s t o s t e r o n e and t e s t o s t e r o n e d e r i v a t i v e s . T o s y l a t e s , mesylates and i o d i d e s are known to be reduced to the hydrocarbon by the a c t i o n of l i t h i u m aluminum hydride i n many cases (273^). Therefore, the ethylene k e t a l of te s t o s t e r o n e was d i s s o l v e d i n dichloromethane and p y r i d i n e and t r e a t e d w i t h t o s y l c h l o r i d e to provide the t o s y l a t e 585 or w i t h mesyl c h l o r i d e to provide the mesylate 586. While the mesylate formation was complete at 0° i n s e v e r a l hours, the t o s y l a t e p r e p a r a t i o n was incomplete a f t e r s i x t y hours at room temperature and re q u i r e d e l e v a t e d temperatures to complete the e s t e r formation. Compounds 585 and 586 were then reduced w i t h l i t h i u m aluminum hydride i n r e f l u x i n g t e t r a h y d r o f u r a n f o r twelve hours. Both the t o s y l a t e and mesylate were found to be completely removed. Reagent a t t a c k had occurred to g i v e , not the d e s i r e d carbon-oxygen f i s s i o n at C-17, but complete oxygen-sulfur f i s s i o n to regenerate compound 561. A c i d - 214 -hydrolysis of t h i s product, followed by gas l i q u i d chromatographic analysis for androst-4-en-3-one, confirmed that l i t t l e , i f any, of the desired reduction has occurred. Attempts to displace the mesylate of 586 with iodide i n hexamethylphosphoramide were unsuccessful (278). 587 X = NNHS02C6H4CH3 588 X=H 2 589 X = NNHS02C6H4CH3 590 X=H 2 The deoxygenation of the C-17 postion was also attempted by reduction of the corresponding tosylhydrazone. C a g l i o t i and G r a s s e l l i (279) had reported that 17-oxo-steroids are reduced to the C-17 methylene compounds i n 60-70% (587 -> 588) by sodium borohydride i n dioxane. The same reaction f a i l s i n methanol and gives the A^^-androstene derivative with l i t h i u m aluminum (hydride. While thei r postulated intermediacy of an a l k y l diimide (RN=NH) makes th i s reaction a s i m i l a r , but milder, version of the Wolff-Kishner reaction, unresolved d i f f i c u l t i e s with the preparation of the hindered C-17 hydrazone i n the presence of 3,3-ethylenedioxy f u n c t i o n a l i t y (589) resulted i n abandonment of t h i s approach. - 215 -P r o t e c t i n g Group M o d i f i c a t i o n s Returning to the problem of ethylene k e t a l groups being l a b i l e to the W o l f f - K i s h n e r r e d u c t i o n , i t was thought that the fragmentation of the 1 , 3 - d i o x o l a n e c o u l d be circumvented by u s i n g a h e t e r e o c y c l i c r i n g that contained an a d d i t i o n a l carbon atom. For example, employing the 1 ,3-dioxane f u n c t i o n a l i t y i n p l a c e of the 1 , 3 - d i o x o l a n e should overcome the d e s t r u c t i o n of the masked c a r b o n y l at C - 3 . There are two l i t e r a t u r e examples of the 1 ,3-dioxane f u n c t i o n a l i t y s u r v i v i n g a W o l f f - K i s h n e r r e d u c t i o n . These compounds, 591 (259) and 592 (280), c o n t a i n i n g the 1,3-dioxane and 5 , 5 - d i m e t h y l - l , 3 - d i o x a n e masked ketones r e s p e c t i v e l y , were employed i n p l a c e of the corresponding ethylene k e t a l analogues only because the p r o p a n e d i o l s s e l e c t i v e l y k e t a l i z e d the d e s i r e d c a r b o n y l s . However, work by Newman (281) on k i n e t i c and e q u i l i b r i u m s t u d i e s for the formation and h y d r o l y s i s of c y c l i c k e t a l s has demonstrated that ketones r e a c t v e r y s l u g g i s h l y w i t h 1 , 3 - p r o p a n e d i o l to g i v e 1,3-dioxane d e r i v a t i v e s . In c o n t r a s t , ketones r e a c t w i t h 2 , 2 -d i a l k y l - 1 , 3 - p r o p a n e d i o l s even f a s t e r than they do w i t h ethylene g l y c o l . For t h i s r e a s o n , t e s t o s t e r o n e was k e t a l i z e d w i t h 2 , 2 - d i m e t h y l - l , 3 -p r o p a n e d i o l by the Salmi procedure u s i n g toluene as s o l v e n t and - 216 -jD - t o l u e n e s u l f o n i c a c i d as c a t a l y s t . C r y s t a l l i z a t i o n of the crude product from methanol, fol lowed by r e c r y s t a l l i z a t i o n of the i n i t i a l c r o p s , afforded the d e s i r e d s t e r o i d a l dioxane 593. The y i e l d , a f t e r X ,<H 593 X=a-H,/3-0H 524. X=0 595 X=H2 596 a l l o w i n g f o r a 76% recovery of t e s t o s t e r o n e by h y d r o l y s i s of the mother 90 l i q u o r s , was 87%. A C o l l i n s o x i d a t i o n of the k e t a l a l c o h o l 593 then 91 y i e l d e d 99% of the d e s i r e d k e t a l ketone 594. To check the r e l a t i v e s t a b i l i t y of the d i f f e r e n t C-3 p r o t e c t e d ketones, B a r t o n ' s m o d i f i c a t i o n of the W o l f f - K i s h n e r r e d u c t i o n was employed under s t a n d a r d i z e d c o n d i t i o n s . That i s , a twelve hour hydrazone formation p e r i o d at 180° w i t h anhydrous hydrazine and sodium d i e t h y l e n e g l y c o l a t e (1.45 N) was fol lowed by a twenty-four hour p e r i o d a t 210° f o r the hydrazone decomposit ion. Under these c o n d i t i o n s , the 3 , 3 - e t h y l e n e d i o x y d e r i v a t i v e of a n d r o s t - 4 - e n e - 3 , 1 7 - d i o n e and a n d r o s t - 4 -90 A chromatography of the mother l i q u o r s on t h i r t y times t h e i r weight of a c t i v i t y I I I alumina d i d not permit s e p a r a t i o n of the k e t a l 593 from t e s t o s t e r o n e (472). 91 Exchange k e t a l i z a t i o n was a l s o explored by p r e p a r i n g 2 - e t h y l - 2 , 5 , 5 -t r i m e t h y l - 1 , 3 - p r o p a n e d i o l (596) from 2-butanone and d i m e t h y l -p r o p a n e d i o l and r e a c t i n g i t with a n d r o s t - 4 - e n e - 3 , 1 7 - d i o n e . U n f o r t u n a t e l y , t h i s exchange r e a c t i o n f a i l e d , probably because of the s t e r i c l i m i t a t i o n s imposed by the gem-methyls of 596. - 217 -ene-3,17-dione i t s e l f provided 82% and 95% yi e l d s respectively of the 2:1:1 o l e f i n mixture. However, when the dioxane 594 was refluxed under these conditions, a nearly quantitative y i e l d of the" correspond-ing C-17 deoxy dioxane 595 was recovered with only a trace of o l e f i n compounds i n the product. Hydrolysis of this compound followed by product d i s t i l l a t i o n then afforded up to 93% androst-4-en-3-one o v e r a l l from compound 594. Since these forcing Wolff-Kishner conditions would remove a C - l l carbonyl, s i m i l a r high yields of masked carbonyl compounds should be obtained by u t i l i z i n g 1,3-dioxanes i n place of the 1,3-dioxolanes that have always been employed to date. In an attempt to f i n d other C-3 carbonyl derivatives that would survive the Wolff-Kishner reduction of a C-17 carbonyl, the 3,3-ethylenedithio, 3,3-trimethylenedithio and 3-methoxy derivatives of androst-4-ene-3,17-dione were prepared. Testosterone was reacted with 1,2-ethanedithiol, 1,3-propanedithiol and 2,2-dimethoxypropane and an acid catalyst to afford 597, 599 or 601 i n 99% y i e l d . A C o l l i n s oxidation of 597 gave 89% 598 while the same reaction on 599 and 601 did not give the expected products 600 and 602. The oxidation of the enol ether to an enedione, i n t h i s case androst-4-ene-3,6,17-trione, has already been mentioned. The desired compound 602 could be readily prepared by f i r s t oxidizing testosterone to androst-4-ene-3,17-dione (98%) and then s e l e c t i v e l y blocking the C-3 position with dimethoxy-propane (200) i n 99% y i e l d . U n t i l now, the physical constants of the ketals and thioketals have been so straightforward that d e t a i l s were l e f t to the experimental section. An exception should be made i n the - 218 -598 X = 0,/=2 602 X=0 599 X = a-H,/3-OH,r=3 600 X=0,x=3 case of the C o l l i n s product from 599. While the t h i o k e t a l a l c o h o l 597 had a C-4 o l e f i n i c s i n g l e t at x 4.51 and the t h i o k e t a l ketone 598 had one at x 4 . 5 0 , the t h i o k e t a l a l c o h o l 599 e x h i b i t e d a T 4.58 o l e f i n i c s i n g l e t that became a x 4.82 s i n g l e t i n the o x i d a t i o n p r o d u c t . A l s o , the h i g h r e s o l u t i o n mass spectrum showed a mass u n i t i n c r e a s e of fourteen u n i t s when 599 was o x i d i z e d i n s t e a d of the expected decrease of two mass u n i t s . Apparently one s u l f u r of the 1 , 3 - d i t h i a n e r i n g i n 600 i s being o x i d i z e d s e l e c t i v e l y to g i v e the s u l f i n y l d e r i v a t i v e 603. Since the o x i d a t i o n of t h i o k e t a l s w i t h p e r a c i d s and other oxidants fol lowed by h y d r o l y s i s i s a modern technique f o r r e g e n e r a t i n g a c a r b o n y l (282), C o l l i n s reagent may be u s e f u l i n s e l e c t i v e l y a t t a c k i n g d i t h i a n e s i n the presence of d i t h i o l a n e s . In any c a s e , by reducing the r e a c t i o n time and oxidant mole r a t i o , the C o l l i n s o x i d a t i o n of 599 p r o v i d e d compound 600 i n 85% y i e l d . The d e s i r e d product 600 e x h i b i t e d an o l e f i n i c s i n g l e t at x 4.56. - 219 -0 Of the three protecting groups considered, only the c y c l i c ethylene t h i o k e t a l has had i t s r e l a t i v e ' s t a b i l i t y ' to the Wolff-Kishner we l l documented. A 1,3-dithiolane masked carbonyl was considered by Fieser i n 1954 (272) to be expected to be stable to the Wolff-Kishner reduction. However Georgian .et _al, i n 1959 reported (283) that complete desulfurization occurred under the Huang-Minion reduction conditions. They also concluded that "Although a l k a l i was found not be necessary i n some cases, i t lowered the e f f e c t i v e temperature of the reaction considerably... The su l f u r was reduced completely to s u l f i d e , no mercaptan being generated i n the reaction. This fact plus the recognized s t a b i l i t y of thioketals to a l k a l i and the s i g n i f i c a n t l y lower reaction temperatures than those required i n the Wolff-Kishner reduction v i t i a t e an apparent r e l a t i o n -ship to the l a t t e r reaction." They then suggested, along with other applications, that this method would serve uniquely w e l l i n overcoming the migration of carbon bond unsaturation i n the reduction of a,8-unsaturated carbonyls. The publication by Georgian ert al_. subsequently realized synthetic importance i n the work of Corey et^ aj_ (284 ) on the t o t a l synthesis of longifolene (607). In t h i s synthesis, the Wolff-Kishner reduction of - 220 -604 f a i l e d to y i e l d 606 d i r e c t l y and the Raney ni c k e l desulfurization 604 605 606 X=0 607 X= CH2 of the monoethylene thiok e t a l 605 was unsuccessful. However, a combination of carbonyl reduction of 605 by lithi u m aluminum hydride and d i r e c t Wolff-Kishner reduction of the hydroxy thio k e t a l was followed by a chromic acid oxidation to afford the desired (i)-longicamphenylone (606). More recently, Becker and Loewenthal (284^) employed a Huang-Minion reduction to remove a thi o k e t a l i n the t o t a l synthesis of (±)-clovene (612). This "double" Wolff-Kishner, 609 -» 611, replaced the sequential desulf u r i z a t i o n (609 610) and reduction (610 •> 611) reactions. - 221 -The trimethylene thioketal or 1,3-dithiane appears to have been used only once previously i n connection with a Wol£f-Kishner reduction. In 1969, Marshall and Roebke reported (285) that the ketone 613 afforded mainly polymeric material under the Huang-Minion modification of the Wolff-Kishner. When the three androstenedione derivatives 598, 600 and 602 were subjected to the Wolff-Kishner reaction under standardized Barton 3 4 3 conditions, the f a m i l i a r 2:1:1 mixture of 5B-A :A :5a-A androstenes was recovered from each reaction. The results of a l l the Barton Wolff-Kishners are summarized i n Table V I I I . While the destruction of the 1,3-dithiolane was expected, the double bond isomerization was not. In a test for o l e f i n isomerization under the Wolff-Kishner conditions, p u r i f i e d androst-4-ene was subjected to a Barton modified Wolff-Kishner reduction. A 1:1 mixture of 5a- and 5B-androst-3-ene was also subjected to the same reaction. The recovery of unchanged ole f i n s i n both cases indicated bond isomerization was not occurring under the Wolff-Kishner reduction conditions. Treatment of these o l e f i n s with hydrochloric acid i n acetone under the k e t a l hydrolysis conditions also afforded un-isomerized o l e f i n s . - 222 -Table VIII Reduction of Androst-4-ene-3,17-dione and its C-3 Derivatives by the Barton Modification of the Wolff-Kishner Reduction 0 Compounds Reduced Androst-4-ene-3,17-dione (562) 3,3-Ethylenedioxy-androst-5-en-17-one (563) 3 - Methoxyandrosta • 3,5-dien-l7-one (602) 3,3-Ethylenedithio-androst-4-en-17-one (598) 3,3-Trimethylenedithio-androst-4-en-17-one (600) 3 , 3 - Trimethylenethiosulfinyl-androst-4-en-17-one (603) 3,3-(2,2-Dimethyltrimethylenedioxy)-androst-5-en-l7-one (594) Yield 95 % 82 % 79 % 86 % 76 % 78 % 92 % Hydrolysis Product Androstenes Androstenone (240) Note For details see Androstenone (240) experimental, section (d) (vi). k Androstenes were always in 2=1-1 ratio of 5/3-androst-3-ene:androst-4-ene: 5a -androst-3-ene, - 223 -The destruction of the 1,3-dithiane indicates the dithiolane reaction does not necessarily proceed v i a a process analogous to the 92 dioxolane fragmentation (570 -»- 571). While the methyl dienol ether 92 Besides hydrogenolysis, there are three k e t a l or thioketal destruction processes known. The f i r s t one i s the dioxolane fragmentation observed i n the Wolff-Kishner reduction and reported previously by Heathcock as occurring through the action of a l k y l l i t h i u m reagents on ethylene ketals (121). Ketone regeneration from ethylene hemi-thioketals by the action of Raney n i c k e l i n benzene has a closely related mechanism (286). The second process to give cleavage products i s caused by the action of lewis acids and hydride reagents. Ethylene ketals have been reported to be cleaved by diborane during synthetic operations such as the hydroboration of JL, where 40% keta l cleavage occurred (117). Brown et^ a l . have studied the lithium aluminum hydride-aluminum t r i c h l o r i d e cleavage of many acetals and ketals (287 a), including tetrahydropyranyl ethers ( i i ) . Both 1,3-dioxolanes (y = 2) and 1,3-dioxanes (y = 3) undergo reductive cleavage v i a the oxocarbonium ion ( i i i ) to afford hydroxy ethers. a i l 0 - R R=AlKyl 6-(ci-y - o e ill In 1974, t h i s same intermediate ( i i i , y = 2) was used i n an explanation of the reductive cleavage of acetals and ketals by borane (287^). The intermediate i i i (y = 2,3 and 0~ replaced by S~) bears a close analogy with the intermediate postulated for the regeneration of ketones from hemithioketals by the action of Raney n i c k e l i n hydroxylic solvents (286). The t h i r d process involves an oxidative cleavage that i s accomplished by a hydride transfer to the triphenylcarbonium ( t r i t y l ) cation. Both ethylene ketals and ethylene hemithioketals were completely removed but ethylene t h i o -ketals were found to be inert because of the high energy required for thiocarbonyl formation (288). - 224 -602 was unexpectedly hydrogenolyzed completely under the Barton modif ied W o l f f - K i s h n e r c o n d i t i o n s , there i s a r e p o r t by Gates and Tschudi (289) that e x t e n s i v e demethylation of 614 occurred under the Huang-Minion procedure. Since there was a q u e s t i o n as to whether i t was 0 the base or the h y d r a z i n e that l e d to the removal of the C-3 p r o t e c t i n g groups, compounds 563, 598 and 602 were subjected to a n e u t r a l W o l f f -Kishner r e d u c t i o n . In the absence of any base other than h y d r a z i n e , the ethylenedioxy f u n c t i o n a l i t y s u r v i v e d the Barton c o n d i t i o n s w h i l e the e t h y l e n e d i t h i o and d i e n o l methyl ether were d e s t r o y e d . However both the ethylenedioxy and e t h y l e n e d i t h i o f u n c t i o n a l i t i e s i n 590 and 566 were destroyed under the Barton b a s i c c o n d i t i o n s i n the absence of h y d r a z i n e . - 225 -The Dioxane Fragmentation I t would be a mistake to leave the impression that only e t h y l e n e -dioxy d e r i v a t i v e s of a , 8 - u n s a t u r a t e d 3-keto s t e r o i d s are destroyed i n the W o l f f - K i s h n e r r e d u c t i o n . I t would a l s o be a mistake to represent the base c a t a l y z e d fragmentation d i s c u s s e d e a r l i e r (dioxolane fragmentation, 570 •> 571) as the only process d e s t r o y i n g dioxolanes because some dioxane d e s t r u c t i o n has a l s o been observed. In pursuing the c o n v e r s i o n of t e s t o s t e r o n e to a n d r o s t - 4 - e n - 3 - o n e (240), i t was found that the k e t a l s of 1 , 3 - p r o p a n e d i o l , u n l i k e those of 2 , 2 - d i m e t h y l p r o p a n e d i o l , would undergo exchange k e t a l i z a t i o n . A scheme i n v o l v i n g exchange k e t a l i z a t i o n of t e s t o s t e r o n e w i t h 2 - e t h y l - 2 -m e t h y l - 1 , 3 - d i o x a n e (616) and the subsequent o x i d a t i o n (to 619), r e d u c t i o n (to 620), h y d r o l y s i s and d i s t i l l a t i o n was implemented. The 3 4 3 f i n a l product was found to be a 2:1:1 mixture of 58-A :A :5a-A s t e r o i d a l o l e f i n s . The tr imethylenedioxy compounds 618 and 619 c o u l d not be c r y s t a l l i z e d l i k e t h e i r gem-methyl analogues but the b i s k e t a l , 3 , 1 7 - b i s ( t r i m e t h y l e n e d i o x y ) a n d r o s t - 5 - e n e (621), obtained from a n d r o s t - 4 -e n e - 3 , 1 7 - d i o n e , was r e a d i l y p u r i f i e d by c r y s t a l l i z a t i o n . When t h i s - 226 -619 X = 0 621 6 2 0 X= H 2 compound was subjected to a Barton modified Wolff-Kishner both the 17-ketal and the 3-ketal were p a r t i a l l y destroyed. The recovered material after acid hydrolysis showed the presence of androst-4-en-3-one (^20%); A \ A^-androsten-17-ones (^30%); and A ^ , A^-androstenes (usual 2:1:1 r a t i o ) (^40%) with some androst-4-ene-3,17-dione ( 10%) 3 4 recovered. Authentic A , A -androsten-17-ones were prepared by a Barton Wolff-Kishner reduction of testosterone (472) i n 95% y i e l d followed by a subsequent C o l l i n s oxidation of 622 i n 96%. A Wolff-Kishner 3 4 3 reduction of 623 yielded the usual 2:1:1 r a t i o of 5g-A : A :5a-A -androstenes. 472 622 X = a - H , / 3 - 0 H 623 X = 0 - 227 -A f u l l understanding of the cleavage r e a c t i o n s would r e q u i r e the use of s u b s t i t u t e d d i o l s and the use of r e a c t i o n c o n d i t i o n s , such as ethanol i n an autoclave, that would a l l o w the d i o l fragment of the s u b s t i t u t e d dioxolane or dioxane to be i s o l a t e d . Pending the outcome of t h i s study, the fragmentation of the u n s u b s t i t u t e d dioxane ( t r i -methylenedioxy f u n c t i o n a l i t y ) has been assigned as depicted i n the p a r t i a l s t r u c t u r e 624 ->• 625. The i n t r o d u c t i o n of gem-methyls at C-5 of the dioxane (2,2-dimethyltrimethylenedioxy f u n c t i o n a l i t y ) prevents t h i s base c a t a l y z e d process from o c c u r r i n g . In any case, there i s no question that the s t a b i l i t y of the k e t a l s increases i n the order ethylene k e t a l < t r i m e t h y l e n e k e t a l < 2 , 2 - d i s u b s t i t u t e d trimethylene k e t a l . Any assessment of Wo l f f - K i s h n e r r e d u c t i o n procedures should emphasize that use of b a s i c c o n d i t i o n s during the hydrazone formation p e r i o d are unwise and unnecessary. In. a d d i t i o n , Barton's procedure, as i t now stands, i s very u n a t t r a c t i v e . The d i s t i l l a t i o n of excess hydrazine-water back i n t o the anhydrous hydrazine generator (173) when the r e a c t i o n temperature i s r a i s e d from 180° to 210° i s undesireable because s i d e products, and some of the d e s i r e d product, may be l o s t . - 228 -This may even be the reason fragmentation products have not been no t i c e d p r e v i o u s l y . From a p r a c t i c a l c o n s i d e r a t i o n of s a f e t y , the o r i g i n a l Barton p r e p a r a t i o n of a 180° b o i l i n g s o l u t i o n of anhydrous hydrazine i n b a s i c d i e t h y l e n e g l y c o l (173) i s extremely hazardous. A much b e t t e r method of accomplishing the same r e a c t i o n c o n d i t i o n s i s to add 8-10% anhydrous hydrazine, by volume, to a c o l d s o l u t i o n of the b a s i c ethylene g l y c o l s o l u t i o n along w i t h the compound to o be reduced. A m i c r o - d i s t i l l a t i o n condenser can then be used to c o l l e c t the s m a l l amount of excess hydrazine that d i s t i l l s as the temperature i s r a i s e d to 180°. The downward d i s t i l l a t i o n condenser i s then r o t a t e d u n t i l i t can serve as a r e f l u x condenser f o r the twelve hour p e r i o d of hydrazone formation. R o t a t i o n back to a downward d i s t i l l a t i o n p o s i t i o n permits the r e a c t i o n temperature to be r a i s e d to 210°. A f t e r the hydrazone decomposition i s complete, the l i q u i d that d i s t i l l e d i s included i n the workup. This procedure has been found to be a p p l i c a b l e to both l a r g e and s m a l l s c a l e r e a c t i o n s . The necessary anhydrous hydrazine can be prepared much more s a f e l y by an a z e o t r o p i c d i s t i l l a t i o n w i t h toluene o f f calcium oxide (174) than i t can be by the recommended three hour r e f l u x p e r i o d over sodium hydroxide. - 229 -EXPERIMENTAL General M e l t i n g p o i n t s , which were determined on a K o f l e r b l o c k , and b o i l i n g p o i n t s are uncorrected. O p t i c a l r o t a t i o n s were obtained at the sodium D l i n e using a Perkin-Elmer Model 141 Automatic P o l a r i m e t e r . U l t r a v i o l e t s p e c t r a were, unless otherwise noted, measured i n methanol s o l u t i o n w i t h a Cary, Model 14, or Model 15, spectrophotometer. R e f r a c t i v e i n d i c i e s were taken on an O f f i c i n e G a l i l e o Refractometer. Routine i n f r a r e d s p e c t r a were recorded on a Perkin-Elmer I n f r a c o r d Model 137 or a Perkin-Elmer Model 710 spectrophotometer w h i l e a n a l y t i c a l sample and comparison s p e c t r a were recorded on a Perkin-Elmer s p e c t r o -photometer, Model 457. Proton magnetic resonance (n.m.r.) s p e c t r a were, unless otherwise noted, recorded i n deuterochloroform s o l u t i o n on V a r i a n A s s o c i a t e s spectrometer A-60, T-60 and/or HA-100, Xl-100. L i n e p o s i t i o n s are given i n the T i e r s T s c a l e , w i t h t e t r a m e t h y l s i l a n e as i n t e r n a l standard; the m u l t i p l i c i t y , i n t e g r a t e d peak areas and proton assignments are i n d i c a t e d i n parentheses. G a s - l i q u i d chroma-tography ( g . l . c . ) was c a r r i e d out on e i t h e r an Aerograph Autoprep, - 230 -Model 700, or a Va r i a n Aerograph, Model 90-P. The f o l l o w i n g columns (10 f t x 1/4 i n , unless otherwise noted) were employed, w i t h the i n e r t supporting m a t e r i a l b e i n g , i n each case, 60/80 mesh Chromosorb W (unless otherwise noted): column A (5 f t x 1/4 i n ) , 20% SE-30; column B, 20% SE-30; column C (10 f t x 3/8 i n ) , 30% SE-30; column D, 20% FFAP; column E (10 f t x 3/8 i n ) , 30% FFAP; column F, 20% Apiezon J ; column G, 8% FFAP (60/80 mesh Chromosorb G). The s p e c i f i c column used, along w i t h the column temperature and c a r r i e r gas (helium) f l o w - r a t e ( i n ml/min) are i n d i c a t e d i n parentheses. Column chroma-tography was performed using n e u t r a l s i l i c a g e l (Camag or Macherey, Nagel and Co.) or n e u t r a l alumina (Camag or Macherey, Nagel and Co.). The alumina was d e a c t i v a t e d to Act. I l l by the a d d i t i o n of 6% water by weight. High r e s o l u t i o n mass s p e c t r a were recorded on an AEI, type MS-9, mass spectrometer by e i t h e r Mr G. Gunn or Dr. G. Eigendorf. Microanalyses were performed by Mr P. Borda, M i c r o a n a l y t i c a l Laboratory, U n i v e r s i t y of B r i t i s h Columbia, Vancouver. - 231 -4a-Methy1-4,4a,5,6,7,8-hexahydro-2(3H)-naphthalenone (234) (a) The octalone 234 was prepared by the procedure of Marshall and Fanta (99). The Michael condensation r e a c t i o n was done i n a flame-dried r e a c t i o n apparatus equipped with very e f f i c i e n t s t i r r i n g (Fisher Stedi-Speed apparatus on low range, Hershberg s t i r r i n g rod) under a nitrogen atmos-phere. External cooling with a thermostatically c o n t r o l l e d constant temperature bath was provided by a 1:1 methanol:water (volume r a t i o ) a i r - s t i r r e d bath s o l u t i o n maintained at -10° with an Eberbach apparatus. A s o l u t i o n of 18 ml of 3 N ethanolic sodium ethoxide, prepared from 1.25 g of sodium and 20 ml of ethanol, was added to 294 g (2.62 moles) of 2-methylcyclohexanone i n the r e a c t i o n f l a s k . Methyl v i n y l ketone was d i s t i l l e d j u s t before use and 180 g (2.57 moles) were added dropwise over a s i x hour i n t e r v a l with the r e a c t i o n conditions being maintained at -10° f o r an a d d i t i o n a l fourteen hours. Before the dehydration was s t a r t e d , a small sample was taken, dissolved i n ether, f i l t e r e d and evaporated to a small volume. A chloroform s o l u t i o n of the residue was washed with saturated sodium bicarbonate, dried over magnesium s u l f a t e and evaporated to a small volume again. Colourless c r y s t a l s were deposited from petroleum ether to provide 0.5 g of cis-10-methyl-2-decalon-9-ol (247), m.p. 121.5-122° ( l i t . (101) m.p. 120.8-121.4°). Infrared (KBr d i s c ) : 3350 (-0H); 1710 (C=0); 1050, 1035 cm"1 (C-0). Nuclear magnetic resonance: x 8.87 ( s i n g l e t , 3H, t e r t i a r y methyl), x 7.94 ( s i n g l e t , IH, -011, proton exchanged with D^O). The compound did not have u l t r a v i o l e t absorption i n the region 350-220 mp but i t did show end absorption (C=0) below 220 my. - 232 -A d i r e c t steam d i s t i l l a t i o n of the condensation r e a c t i o n mixture was accomplished by adding 1 1/3 1. of aqueous 10% potassium hydroxide to the two l i t e r r e a c t i o n f l a s k and d i s t i l l i n g steam through the s o l u t i o n f o r three hours. The cooled r e a c t i o n v e s s e l s o l u t i o n was sa t u r a t e d w i t h sodium c h l o r i d e and e x t r a c t e d w i t h d i e t h y l ether a f t e r n e u t r a l i z a t i o n w i t h 12 N h y d r o c h l o r i c a c i d . The steam d i s t i l l a t e was worked up i n an analogous manner and the combined organic e x t r a c t s were washed w i t h b r i n e and d r i e d over anhydrous sodium s u l f a t e and then evaporated under reduced pressure to provide % 300 ml of a red o i l . A d i s t i l l a t i o n of t h i s e x t r a c t gave 71.5 g (24%) of recovered 2-methylcyclohexanone (35-40° at 1 mm Hg) and 240.8 g (57%) of a c l e a r o i l , b.p. 113-115°/0.75 mm. A slow d i s t i l l a t i o n of the l a t t e r f r a c t i o n showed b.p. 73°/0.4 mm ( l i t . (99) b.p. of octalone 234 i s 70°/.3 mm and 82-83°/.7 mm) and a g . l . c . p r e p a r a t i o n of an a n a l y t i c a l sample (column C, 200°, 94) gave a c o l o u r l e s s 20 l i q u i d w i t h the p h y s i c a l p r o p e r t i e s expected f o r compound 234: n D 1.5249 ( l i t . n25 1.5230 (99)). U l t r a v i o l e t X 239 my, e = 14,400 D max ( l i t . 239 my, e = 14,400 (99)). I n f r a r e d ( f i l m ) : 1670 (con j . C=0), 1620 cm" 1 ( c o n j . C=C). N.m.r., x 4.29 ( s i n g l e t , IH, -C'H) and x 8.74 ( s i n g l e t , 3H, t e r t i a r y methyl). The 2,4-dinitrophenolhydrazone prepared (102) showed m.p. 170.5° ( l i t . (103) m.p. 169°). (b) The octalone 234 was a l s o prepared by the a c i d - c a t a l y z e d Robinson a n n e l a t i o n procedure of Heathcock et a l . (100). See (d) below as w e l l . A mixture of 56 g (0.5 moles) of 2-methylcyclohexanone, 44 g (0.63 moles) methyl v i n y l ketone and 0.4 ml cone, s u l f u r i c a c i d was r e f l u x e d under n i t r o g e n f o r 20 h. The cooled dark s o l u t i o n was d i l u t e d w i t h 100 ml petroleum ether (30-60°) and washed twice w i t h 50 ml p o r t i o n s of 5% - 233 -aqueous sodium hydroxide. A f t e r d r y i n g over anhydrous magnesium s u l f a t e , the dark red s o l u t i o n was concentrated under reduced pressure and d i s t i l l e d to provide 15.7 g (28%) of recovered 2-methylcyclohexanone and 44.3 g (54%) of a y e l l o w - t i n t e d o i l . R e d i s t i l l a t i o n of the l a t t e r f r a c t i o n at 130° on a water a s p i r a t o r a f f o r d e d 38.1 g (46%) of a c o l o u r l e s s o i l . A g . l . c . a n a l y s i s (column B, 185°, 86) of the d i s t i l l a t i o n f r a c t i o n s showed the d e s i r e d octalone (84%) was contaminated by a second component (16%) which could not be removed by d i s t i l l a t i o n . A g . l . c . i s o l a t e d (column C, 210°, 126) sample of t h i s s h o r t e r r e t e n t i o n time i m p u r i t y e x h i b i t e d i n f r a r e d of 1710 cm \ a s i g n i f i c a n t n.m.r. x 7.88 ( s i n g l e t , 3H, CH^CO) and x 8.95 ( s i n g l e t , 3H, t e r t i a r y methyl), and end ab s o r p t i o n (< 210 mp) i n the u l t r a v i o l e t . A one hour r e f l u x under a n i t r o g e n atmosphere i n a 400 ml ethanol s o l u t i o n of 5% potassium hydroxide removed the i m p u r i t y . This r e a c t i o n was worked up as i n (c) below and y i e l d e d octalone i d e n t i c a l to that reported i n ( a ) . (c) A mo d i