Open Collections

UBC Theses and Dissertations

UBC Theses Logo

UBC Theses and Dissertations

Studies related to the synthesis of guaiane-type sesquiterpenes Cheng, Kin-Fai 1969

Your browser doesn't seem to have a PDF viewer, please download the PDF to view this item.

Item Metadata

Download

Media
831-UBC_1969_A1 C43.pdf [ 6.35MB ]
Metadata
JSON: 831-1.0061888.json
JSON-LD: 831-1.0061888-ld.json
RDF/XML (Pretty): 831-1.0061888-rdf.xml
RDF/JSON: 831-1.0061888-rdf.json
Turtle: 831-1.0061888-turtle.txt
N-Triples: 831-1.0061888-rdf-ntriples.txt
Original Record: 831-1.0061888-source.json
Full Text
831-1.0061888-fulltext.txt
Citation
831-1.0061888.ris

Full Text

5cn _ STUDIES RELATED TO THE SYNTHESIS OF GUAIANE-TYPE SESQUITERPENES by KIN-FAI CHENG B.Sc. ( S p e c i a l Honours), U n i v e r s i t y of Hong Kong, 1965 A THESIS SUBMITTED IN PARTIAL FULFILMENT OF THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY i n the Department of Chemistry We accept t h i s t h e s i s as conforming to the re q u i r e d standard THE UNIVERSITY OF BRITISH COLUMBIA J u l y , 1969 In p r e s e n t i n g t h i s t h e s i s i n p a r t i a l f u l f i l m e n t of the r e q u i r e m e n t s f o r an advanced degree a t the U n i v e r s i t y of B r i t i s h C olumbia, I a g r e e t h a t the L i b r a r y s h a l l make i t f r e e l y a v a i l a b l e f o r r e f e r e n c e and Study. I f u r t h e r agree t h a t p e r m i s s i o n f o r e x t e n s i v e c o p y i n g o f t h i s t h e s i s f o r s c h o l a r l y purposes may be g r a n t e d 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 u n d e r s t o o d t h a t c o p y i n g o r p u b l i c a t i o n o f t h i s thes.is f o r f i n a n c i a l g a i n s h a l l not be a l l o w e d w i t h o u t my w r i t t e n p e r m i s s i o n . Department The U n i v e r s i t y o f B r i t i s h Columbia Vancouver 8, Canada ABSTRACT An e f f i c i e n t , 8-step s y n t h e s i s of (+)-a-cyperone 168 from (-)-a-santonin 107 i s described. E p i m e r i z a t i o n of 107 followed by hydrogenolysis of the r e s u l t i n g product 174 gave the a c i d 175, which was e s t e r i f i e d by treatment with diazomethane. Conversion of the r e s u l t i n g keto e s t e r 176 i n t o the s u b s t i t u t e d octalone 184 was achieved by hydrogenation of the former i n the presence of the homogeneous c a t a l y s t t r i s ( t r i p h e n y l p h o s p h i n e ) -chlororhodium. Lithium aluminum hydride r e d u c t i o n of 184, followed' by o x i d a t i o n of the product w i t h 2,3-dichloro-5,6-dicyanobenzoquinone gave keto a l c o h o l 189. P y r o l y s i s of the corresponding keto carbonate 191 afforded (+)-a-cyperone 168 i n good y i e l d . Photochemical rearrangement of a number of cross-conjugated dienones (192, 193, 200, and 176) i n t o hydroguaiazulene d e r i v a t i v e s (194, 195, 195, and 221, r e s p e c t i v e l y ) by the i r r a d i a t i o n of the former compounds i n 45% aqueous a c e t i c a c i d i s a l s o described. Conversion of 194 i n t o 5-epi-a-bulnesene 216 was achieved by the f o l l o w i n g sequence. B i r c h r e d u c t i o n of 194, followed by chromium t r i o x i d e - p y r i d i n e o x i d a t i o n of the r e s u l t i n g product afforded ketone 201. The stereochemistry of the l a t t e r was e s t a b l i s h e d by means of o p t i c a l r o t a t o r y d i s p e r s i o n ( o . r . d . ) . Wolff- , Kishner r e d u c t i o n of 201 and subsequent dehydration gave 5-epi-a-bulnesene 216. In a s i m i l a r r e a c t i o n sequence, 195 was converted i n t o 4-epi-a-bulnesene 218. Conversion of compound 221 i n t o a-bulnesene 1_ was accomplished, accord-ing t o the f o l l o w i n g scheme. S t e r e o s e l e c t i v e c a t a l y t i c hydrogenation of the acetate d e r i v a t i v e of 221 gave 223 as the only product. The stereochemistry of the latter was established by an o . r . d . study and by chemical evidence. Sodium borohydride reduction of 223, followed by tosylation of the resulting product, gave a mixture of the o l e f i n 230 and the tosylate 229. Hydrogenation of the former in the presence of the homogeneous catalyst, tris(triphenylphosphine)chlororhodium, followed by lithium aluminum hydride reduction, gave the diol 235. The same diol was also-obtained by lithium aluminum hydride reduction of the tosylate 229. Successive treat-ment of the diol 253 with methyl chloroformate and thionyl chloride in pyridine afforded the monocarbonate 255. Pyrolysis of 255 gave a-bulnesene 7_. The described stereoselective synthesis of the sesquiterpene a-bulnesene 1_ f u l l y corroborates the structure and stereochemistry assigned to this compound and indicates a general approach to the synthesis of guaiane-type sesquiterpenes. - i v -TABLE OF CONTENTS Page TITLE PAGE i ABSTRACT i i TABLE OF CONTENTS i v LIST OF FIGURES ; v ACKNOWLEDGEMENTS v i INTRODUCTION 1 I. General 1 I I . Sesquiterpene B i o s y n t h e s i s 4 .....III. S t r u c t u r e and Stereochemistry o f a-Bulnesene 9 IV. Other S y n t h e t i c Approaches to Guaiane-type Sesquiterpenes 17 DISCUSSION 39 I. General Approach ' 39 I I . Synthesis of 5-Epi-a-bulnesene and 4-Epi-a-bulnesene .... 45 A. Synthesis o f (+)-a-Cyperone and (-)-7-Epi-a-cyperone by Robinson Annelation 45 B. Conversion of (-)-a-Santonin i n t o (+)-a-Cyperone .... 50 C. Conversion of (+)-a-Cyperone and (-)-7-Epi-a-cyperone i n t o the.Hydroguaiazulene D e r i v a t i v e s 68 D. E l a b o r a t i o n of the Hydroguaiazulene D e r i v a t i v e s to 5-Epi-a-bulnesene and 4-Epi-a-bulnesene 80 I I I . Synthesis o f a-Bulnesene 100 EXPERIMENTAL 122 BIBLIOGRAPHY 159 - V -LIST OF FIGURES Figure Page 1 N.M.R. Spectrum o f Compound 185 58 2 N.M.R. Spectrum of Compound 186 . 59 3 N.M.R. Spectrum of Compound 187 62 4 N.M.R. Spectrum o f Compound 188 63 5 The P y r o l y s i s Apparatus 66 6 N.M.R. Spectrum o f Compound 194 .71 7 N.M.R. Spectrum o f Compound 195 73 8 O.R.D. Curves of Compounds 143, 194 and 19S_ 75 9 O.R.D. Curves of Compounds 20l_ and 204 89 10 N.M.R. Spectrum of 5-Epi-a-bulnesene 92 11 N.M.R. Spectrum of 4-Epi-a-bulnesene .95 12 N.M.R. Spectrum o f Compound 219_ 96 13 I n f r a r e d Spectrum of•5-Epi-a-bulnesene 97 14 I n f r a r e d Spectrum of 4-Epi-a-bulnesene 98 15 I n f r a r e d Spectrum o f Authentic a-Bulnesene 99 16 N.M.R. Spectrum o f Compound 222 104 17 N.M.R. Spectrum o f Compound 221 105 18 N.M.R. Spectrum of Compound 229_ I l l 19 N.M.R. Spectrum o f Compound 230 113 20 N.M.R. Spectrum o f Compound 232 116 21 I n f r a r e d Spectrum of Synt h e t i c and Authentic a-Bulnesene. 119 22 N.M.R. Spectrum of Sy n t h e t i c a-Bulnesene 120 - v i -ACKNOWLEDGEMENTS I wish to express my s i n c e r e thanks to Dr. E. P i e r s f o r the opportunity o f working with him and f o r h i s e x c e l l e n t guidance and i n v a l u a b l e suggestions throughout the course of my research and the pr e p a r a t i o n of t h i s t h e s i s . I am indebted to Mr. Ronald W. B r i t t o n f o r proof-reading the e n t i r e t h e s i s , t o Miss Y.H. Wong f o r her a s s i s t a n c e i n the pr e p a r a t i o n of the t h e s i s at various stages, and a l s o to Miss Diane Johnson f o r her most p r o f i c i e n t t y p i n g . Numerous d i s c u s s i o n s w i t h other members of the group have been most b e n e f i c i a l and v a l u a b l e . To them I extend my thanks and best wishes. Receipt o f a s c h o l a r s h i p from the Canadian Commonwealth Sc h o l a r s h i p and F e l l o w s h i p Committee i s g r a t e f u l l y acknowledged. INTRODUCTION I. General The sesquiterpenes are n a t u r a l l y - o c c u r r i n g i s o p r e n o i d compounds normally c o n t a i n i n g f i f t e e n carbon atoms. They are b i o g e n e t i c a l l y r e l a t e d and are considered to be b u i l t up by the union of three isoprene u n i t s 1_ w i t h or without carbon s k e l e t a l rearrangement during the course of t h e i r b i o s y n t h e s i s (1,2). 1 Although sesquiterpenes have been known as c o n s t i t u e n t s o f e s s e n t i a l o i l s f o r more than a century, i t i s only i n comparatively recent times that-the chemistry of these compounds has been i n v e s t i g a t e d i n d e t a i l . The delay i n the i n v e s t i g a t i o n of these compounds has mostly been caused by the f a c t that i n the e s s e n t i a l o i l s , they u s u a l l y occur as a very complicated mixture. Thus the i s o l a t i o n of pure, homogeneous compounds i s u s u a l l y q u i t e d i f f i c u l t and, u n t i l r e c e n t l y , was o f t e n not f e a s i b l e at a l l . However, i n the l a s t two decades, a p p l i c a t i o n of new se p a r a t i o n techniques ( t . l , c , g . l . c , e t c . ) , along w i t h modern spectroscopic methods has g r e a t l y f a c i l i t a t e d - 2 -t h i s type of work and, at the present time, the s t r u c t u r e and stereochemistry of a large number of sesquiterpenes have been e s t a b l i s h e d . The r e s u l t s o f these i n v e s t i g a t i o n s have revealed a very great s t r u c t u r a l v a r i a b i l i t y - over f o r t y d i f f e r e n t s e s q u i t e r p e n i c s k e l e t a l types are known ( 3 ) . They may occur as a c y c l i c , monocyclic, b i c y c l i c , t r i c y c l i c or t e t r a c y c l i c hydrocarbons, a l c o h o l s , ketones, oxides or l a c t o n e s . I t i s i n t e r e s t i n g to note that some sesquiterpenes have r a t h e r unusual s t r u c t u r e s . For example, acorone 2_, i s o l a t e d from Acorus calamus (4,5,6) has a spirane carbon s k e l e t o n , while a-humulene _ (7) and g-caryophyllene 4 (8) c o n t a i n medium-sized c a r b o c y c l i c r i n g s . Indeed, the l a t t e r two sesquiterpene hydro-carbons were the f i r s t known n a t u r a l l y - o c c u r r i n g compounds having a medium-s i z e d c a r b o c y c l i c r i n g i n the molecule. -2 3 4 One large group of sesquiterpenes i s the guaiane c l a s s which possesses the b a s i c carbon s k e l e t o n 5_, as e x a m p l i f i e d by g u a i o l _ and a-bulnesene 7. The numbering system of t h i s c l a s s of sesquiterpenes i s as shown i n 5_. 12 6 7 - 3 -Sesquiterpenes with carbon skeletons _ or 9_, such as aromadendrene 1_0 or cyperene 1_1 respectively, are also c lass i f ied as guaiane sesquiterpenes, because of the obvious structural s i m i l a r i t i e s . Biogenetically, skeletons _ and 9_ can be envisioned to have arisen from 5_ by appropriate ring closure of the C-7 isopropyl side chain in 5_. Thus, carbon-carbon bond formation between C-6 and C - l l would produce _ , whereas carbon-carbon bond formation between C - l and C - l l would give _ . In contrast to the large amount of work which has been concerned with the structural elucidation of the guaiane sesquiterpenes, very few reports had been concerned with the synthesis of these compounds (9,10,11) at the time when the present work was begun. Therefore, the work reported in this thesis was to investigate a general synthetic entry into the guaiane class of sesquiterpenes and in part icular , to synthesize a member of this-group, a-bulnesene 1_ (formerly called 6-guaiene), a C 1 5 H 2 4 hydrocarbon isolated from Pogostemon patchouly (12), Bulnesia sarmienti (13) and Acorus calamus (14). - 4 -I I . Sesquiterpene B i o s y n t h e s i s Although much e f f o r t has been devoted to the s t r u c t u r a l e l u c i d a t i o n of sesquiterpenes (15,16,17,18), the study of t h e i r b i o s y n t h e s i s has been very l i m i t e d . I t i s g e n e r a l l y b e l i e v e d (1,19) that sesquiterpenes are d e r i v e d from f a r n e s y l pyrophosphate _0 and a recent review (20) summarizes w e l l the current s t a t e of the hypothesis. The b i o s y n t h e s i s of f a r n e s y l pyrophosphate from a c e t y l CoA 1_2, v i a mevalonic a c i d 1_5 (21) , has found experimental v e r i f i c a t i o n (18,22,23); and can be summarized as shown i n Chart I. The successive s e l f condensation of three molecules of a c e t y l CoA 1_2 a f f o r d s g-hydroxy-g-methyl g l u t a r y l CoA _4. Reduction w i t h nicotinamide-adenine d i n u c l e o t i d e phosphate (NADPH) gives mevalonic a c i d 1_5 which upon phosphoryla-t i o n w i t h adenine triphosphate (ATP) and subsequent d e c a r b o x y l a t i o n , g i v e s 3 A -isopentenylpyrophosphate 17_. I s o m e r i z a t i o n of t e r m i n a l double bond of 17_ r e s u l t s i n the formation of d i m e t h y a l l y l pyrophosphate 1_ which on condensa-t i o n w i t h 1_7 gives geranyl pyrophosphate _9. Condensation of geranyl-3 pyrophosphate 19_ w i t h A -isopenteryl pyrophosphate _7 y i e l d s f a r n e s y l pyro-phosphate 2_. The carbon skeletons of v i r t u a l l y a l l the sesquiterpenes can be obtained by a s u i t a b l e c y c l i z a t i o n of e i t h e r c i s - f a r n e s y l pyrophosphate 2__ or _t r a n s - f a r n e s y l pyrophosphate 22_ as i n d i c a t e d i n Chart I I (19) . The i n i t i a l step i n these c y c l i z a t i o n s can be considered as i o n i z a t i o n of the a l l y l i c pyrophosphate anion f o l l o w e d by the p a r t i c i p a t i o n of e i t h e r the c e n t r a l or t e r m i n a l double bonds le a d i n g to c a t i o n s _3 to _8. I t should be noted, of course, t h a t the r e p r e s e n t a t i o n of a formal charge on these ions i s only a convenient symbolism, s i n c e the b i o s y n t h e t i c c y c l i z a t i o n s : are e n z y m a t i c a l l y c o n t r o l l e d and probably occur v i a a p a r t i a l l y or f u l l y - 5 -- 6 -Chart I I - 7 -concerted process. According to Hendrickson1s scheme (19), an anti-Markownikoff. cyclization of cation 27, conformationally represented as 29, would generate the guaiane skeleton 50_. Recently, Moss and coworkers (24), in the studies of later stages of santonin biosynthesis, found that 11,12-dihydrocostunolide 3J_ was incorporated into santonin 3_2. This provides the f i r s t piece of evidence that a germacrane derivative is a precursor in sesquiterpene biosynthesis. While there i s , up to now, no experimental work reported to verify germacrane derivatives as intermediate precursors in the biosynthesis of guaiane-type sesquiterpenes, there are chemical analogies supporting this postulate. Thus, dihydroparthenolide 33, upon treatment with boron t r i f l u o r i d e in ether or upon ultraviolet i r radiat ion, was found to be readily rearranged to a guaianolide 34_ (25) . Lithium aluminum hydride reduction of the rearranged product 3_4 gave alcohol 35_. - 8 -33 34 35 Sutherland and coworkers (26) showed that epoxide 37, obtained by epoxida-tion of germacrene 36, cyclises with aqueous acid to form d i o l 38_ and alcohol 39. The formation of the bicyclo[5,3,0]ring system was the result of an anti-Markownikoff opening of the epoxide, with simultaneous or subsequent Markownikoff addition to the Rouble bond. If the cyclization of 3_7 had s t r i c t l y followed the Markownikoff rule , then a strained bicyclo[6,2 ,C o -ring system would have resulted. On the other hand, formation of the thermo-- 9 -dynamically more s t a b l e d e c a l i n system would r e q u i r e two anti-Markownikoff a d d i t i o n s ; thus i t appears that there i s a balance between s t e r i c and e l e c t r o n i c e f f e c t s . The stereochemistry of the c y c l i z a t i o n products can be accounted f o r by adoption of the "crown" conformation of epoxide 40 which has been e s t a b l i s h e d f o r the t r i e n e 36 by X-ray a n a l y s i s (27). This r e s u l t could imply that epoxides may be i n v o l v e d i n the b i o s y n t h e s i s of guaiane d e r i v a t i v e s . I t should be r e a l i z e d t h a t although the above proposed b i o s y n t h e t i c pathway f o r sesquiterpenes i s very elegant and h i g h l y probable, i t does not exclude other p o s s i b l e pathways. In f a c t , there i s precedence (28);for the occurrence of more than one b i o s y n t h e t i c pathway to a n a t u r a l product. I I I . S t r u c t u r e and Stereochemistry of q-bulnesene Since the work described i n t h i s t h e s i s was concerned w i t h the stereo-s e l e c t i v e s y n t h e s i s o f a-bulnesene 7_, i t i s p e r t i n e n t to d i s c u s s the st u d i e s which l e d to the establishment o f the s t r u c t u r e and stereochemistry o f t h i s compound. The s t r u c t u r e and stereochemistry of a-bulnesene 1_ was e s t a b l i s h e d by an i n d i r e c t c o r r e l a t i o n w i t h g u a i o l (S. 7 6 - 1 0 -In 1960, D j e r a s s i and coworkers (29) e s t a b l i s h e d the absolute stereo-chemistry at C-4 of g u a i o l _ by c o r r e l a t i n g the l a t t e r compound, v i a (+)-dih y d r o g u a i o l 43, w i t h bishomonepetalinic a c i d 45_ which was prepared from a nepetalinic a c i d 4_6 of known absolute stereochemistry. C a t a l y t i c hydrogena-t i o n of g u a i o l _ w i t h Raney n i c k e l under high pressure (30,31) gave two isomeric d i h y d r o g u a i o l s , the c r y s t a l l i n e l e v o r o t a t o r y compound _0 and the o i l y d e x t r o r o t a t o r y isomer 4_3. Each of these isomeric d i h y d r o g u a i o l s was c o n v e r t e d t o a b i s h o m o n e p e t a l l i c a c i d as shown i n chart I I I . The bishomo-H 45 nepetallinic acid 4_5 derived from (+)-dihydroguaiol _3 was in a l l respects identical with that synthesized, as shown in Chart IV, from nepetalinic acid 46 (32), of known absolute stereochemistry. Thus, the absolute Chart IV configuration at C - l , C-4 and C-5 of (+)-dihydroguaiol 43 were established. On the assumption that hydrogenation of the double bond of guaiol _ did not involve i n i t i a l double bond migration and that i t proceeded by cis-addition of hydrogen, then the crystal l ine (-)-dihydroguaiol 40_ possess the stereo-chemistry shown. The absolute stereochemistry of guaiol _ at C-4 and C-10 was also established independently at the same time by Minato and coworkers.(33,34) who correlated guaiol _ with (+)-methylglutaric acid 47_ and with (-)-y-methylbutyrolactone 4_ as shown in Chart V. The a-methylglutaric acid 47 obtained was dextrorotatory and was identical with the synthetic (+)-a-_ The abolute configuration at C-10 of (+)-dihydroguaiol 43_ could not be determined, since the stereochemistry of nepetalinic acid at that center was not known. - 12 -Chart V - 13 -m e t h y l g l u t a r i c a c i d (35) whose absolute c o n f i g u r a t i o n at C-2 had been e s t a b l i s h e d p r e v i o u s l y (36) to be S. The y-methylbutyrolactone _8 obtained was l e v o r o t a t o r y and was i d e n t i c a l w i t h s y n t h e t i c (-)-y-methylbutyrolactone (37) whose absolute c o n f i g u r a t i o n at C-4 a l s o had been e s t a b l i s h e d p r e v i o u s l y (37,38) to be S. Thus C-4 and C-10 methyl groups i n g u a i o l both possess the g - c o n f i g u r a t i o n as shown i n The absolute stereochemistry at C-7 i n g u a i o l was e s t a b l i s h e d by Minato (39,40) by c o r r e l a t i o n of g u a i o l w i t h ( - ) - a - i s o p r o p y l - y - a c e t o b u t y r i c a c i d 4_9 of known stereochemistry (41). The degradation scheme by which g u a i o l _ was converted to the keto a c i d 49_ i s o u t l i n e d i n Chart V I . Now, (-) - a - i s o p r o p y l - y - a c e t o b u t y r i c a c i d 49_ had been converted t o (-) - a - i s o p r o p y l -g l u t a r i c a c i d S0_ (42) and the absolute c o n f i g u r a t i o n o f the l a t t e r had been e s t a b l i s h e d to be S(41). Thus the C-7 s i d e - c h a i n i n g u a i o l (5 i s B-oriented as shown. Combining the r e s u l t s o f D j e r a s s i e t . a l . and Minato e t . a l . , the absolute stereochemistry of (-)-dihydroguaiol 40_ and g u a i o l (5 was completely e s t a b l i s h e d . OH 40 6 51 Chart VI - 15 -The stereochemistry o f b u l n e s o l 51_ was e s t a b l i s h e d by Sorm and coworkers (43) by c o r r e l a t i o n w i t h (-)-dihydroguaiol 40. Thus, c a t a l y t i c hydrogenation of b u l n e s o l 5_1 af f o r d e d a dihydrobulnesol which was i d e n t i c a l w i t h (-)-dih y d r o g u a i o l 40. Hence, the absolute c o n f i g u r a t i o n s at C-4, C-5, and C-7 of b u l n e s o l are the same as i n (-)-dihydroguaiol. The l o c a t i o n of the double bond i n b u l n e s o l was shown to be between C-l and C-10 by chemical degradation s t u d i e s o u t l i n e d i n Chart V I I . Thus, o z o n o l y s i s o f b u l n e s o l 51 and subsequent hydrogenation of the r e s u l t i n g ozonide on p a l l a d i z e d charcoal l e d t o the enol ether 5_2. On o z o n o l y s i s and subsequent h y d r o l y s i s , the ether 5_ affo r d e d a c e t i c a c i d . The product of o z o n o l y s i s 53_ when o x i d i z e d with potassium permanganate i n a c e t i c a c i d , gave keto-lactone 54_. I t fo l l o w s from these r e s u l t s that the l o c a t i o n of the double bond of b u l n e s o l i s as shown i n 51. F i n a l l y , the stereochemistry and s t r u c t u r e o f a-bulnesene was e s t a b l i s h e d by Bates and S l a g e l (44) by p y r o l y s i s o f b u l n e s y l acetate 5_, which gave 7% g-bulnesene 56 and 84% a-bulnesene 7. The a-bulnesene thus obtained was i d e n t i c a l w i t h the n a t u r a l l y o c c u r r i n g compound, 6-guaiene. Thus t h i s conversion of b u l n e s y l acetate 5_5 to a-bulnesene 1_ completed the determination of the s t r u c t u r e and stereochemistry of the l a t t e r compound. 55 56 7 - 16 -5_3 54 + HOAc Chart VII - 17 -IV. Other Synthetic Approaches to Guaiane-type Sesquiterpenes Although the number of known, naturally occurring guaiane-type sesquiterpenes has increased rapidly over the past few years (3,45,46), re lat ively few reports have been concerned with the total synthesis of these compounds. At the beginning of our work in 1966, the only compound reported to have been successively synthesized was patchouli alcohol _7 (10,11). Recently, several reports have appeared concerning the synthesis of:these guaianes. Thus, cyperene 11_ and i ts derivatives patchoulenone 58, cyperotundone _9 (47); (-)-aromadendrene _94 (48); a c h i l l i n 60 and desacetoxy-matricarin 61 (49), and bulnesol 51 (50) have been successfully synthesized. HO : - 18 -II.ml OH 61 0 51 The preparation of patchouli alcohol 5_7 by Buchi and coworkers in 1962 (10,11) constituted the f i r s t successful total synthesis of a guaiane sesquiterpene. The synthesis involved the elaboration of homocamphor 62 (51) to give a-patchoulene 75, which had been previously converted (52) to patchouli alcohol 79_. The synthetic sequence is outlined in Chart VIII. Treatment of (-)-homocamphor 62_ with allylmagnesium chloride gave the unsaturated alcohol 6_ which upon successive hydroboration and oxidation with Jones reagent, gave lactone (3_. The cyclopentenone 65_ was then formed under acidic conditions. However, in this dehydration-cyclization process, racemisation of the product occurred and, in order to avoid t h i s , a different route to the cyclopentenone 65_ was adopted. Selective dehydration of the readily obtainable d i o l 66 gave the primary alcohol (57. Oxidation, followed by cyclisation via the acid chloride 68, gave the desired cyclo-pentenone 65_ without racemisation. 3-Patchoulene 6£ was then obtained by subjection of 65 to the Wittig reaction (with methylenetriphenylphosphorane) followed by selective hydrogenation of the resulting diene. Although patchouli alcohol is s t r i c t l y speaking not a guaiane, i t is thought to be related to the guaianes biogenetically. See ref . (20). * * - 19 -Chart VIII - 20 -Chart VIII (cont'd) - 21 -Acid-catalyzed rearrangement of the epoxide 7__ of 3-patchoulene 69 gave the unsaturated alcohol 71, containing the a-patchoulene skeleton. The fact that only one o l e f i n isomer was obtained, was explained in terms of the proposed mechanism as depicted in 80, in which the abstraction of the secondary proton is assisted by intramolecular attack of f luoride. It then F 2 B — F 80 remained to eliminate the hydroxyl group without simultaneous return to the skeleton of 8-patchoulene. This was achieved by treatment of the d i o l 12_ (obtained by hydroboration of 71) with acetic anhydride in pyridine, result -ing in acetylation of the secondary alcohol and in elimination of the tertiary alcohol, to form the monoacetate 73. Hydrogenation of 7_3, followed by pyrolysis of the saturated acetate 74_ gave a-patchoulene 75. a-Patchoulene 75_ had earl ier been converted into patchouli alcohol 79_ in the following way (52). Oxidation of a-patchoulene 7_ with peracetic acid gave the trans-diol 76 which was selectively mono-acetylated with acetic anhydride in pyridine to give the monoacetate 77_. Pyrolysis of the monoacetate 77, followed by catalytic hydrogenation of the resulting a l l y l i c alcohol 7_ gave patchouli alcohol which, at the time of completion of the synthesis, was formulated as 79_. . - 22 -However, a subsequent determination o f the s t r u c t u r e of p a t c h o u l i a l c o h o l by X-ray c r y s t a l l o g r a p h y (53) demonstrated that the c o r r e c t s t r u c t u r e of, t h i s compound i s 5_7. Therefore, p y r o l y s i s of p a t c h o u l i a l c o h o l acetate OHj: OAc^ .1 81 to give a-patchoulene 7_5 was accompanied by a s k e l e t a l rearrangement; and, more s u r p r i s i n g l y , the conversion of a-patchoulene i n t o p a t c h o u l i a l c o h o l , i . e . , _5 to 7_9 proceeded,at some stage, with the reverse s k e l e t a l rearrange-ment. i In terms of the new s t r u c t u r e of p a t c h o u l i a l c o h o l 57, the correspond-ing acetate 81 could not e l i m i n a t e a c e t i c a c i d without invoking rearrangement because the r e s u l t i n g o l e f i n would v i o l a t e Bredt's r u l e (54). Therefore, Buchi and coworkers proposed that the formation of a-patchoulene 75 by p y r o l y s i s of p a t c h o u l i a l c o h o l acetate 81_ occurred v i a the f o l l o w i n g mechanism: - 23 -The skeletal rearrangement which took place during the conversion of a-patchoulene into patchouli alcohol was found to occur during the epoxidation of the double bond of a-patchoulene. The non-isolated $-epoxide 82_ rearranged to the 1,3-glycol 83 by a stereochemically favourable process as shown. The conversion More recently, Danishefsky and Dumas (55) reported the total synthesis of patchouli alcohol 5_7 employing an entirely different approach. In this 57 Chart IX - 25 -synthesis, which is summarized in Chart IX, no skeletal rearrangement occurred. Reaction of the dienone 84_ with methyl vinyl ketone afforded the adduct _5 which was saturated by hydrogenation to 8_. Reaction of the saturated d i -ketone 86_ with vinyl lithium provided the alcohol 87, which was converted into the chloride 88_. Solvolysis of 88, followed by hydrogenation gave an epimeric mixture of keto-alcohols from which 89_ was isolated. Treatment of 89 with phosphorus tribromide gave bromoketone 9_0 which, upon reductive cyclization with sodium metal in tetrahydrofuran gave patchouli alcohol 57. Ito and coworkers synthesized cyperotundone 5_9 and i t s cogeners, patchoulenone _8 and cyperene 1__ (47). They employed as their starting material the o l e f i n i c acetate 73 which was obtained from (-)-homocamphor 6_ as previously described by Buchi and coworkers (10,11) (see page 18). Compound 73 was converted to cyperene 1_ by successive subjection of the former to lithium aluminum hydride reduction, Jones oxidation, and f i n a l l y , Wolff-Kishner reduction (Chart X). Cyperotundone 59_ and patchoulenone 58 were obtained by oxidation of cyperene 1__ with _t-butyl chromate. A l l the three compounds 11, 58, and 5_9 thereby obtained were identical with the respective naturally occurring sesquiterpenes isolated from cyperus rotundus (56,57,58). The configuration at C-10 in the ketone 92 was established by the fact that the n.m.r. signal due to the C-10 methyl was essentially unchanged on passing from carbon tetrachloride to benzene solution, indicating that the methyl group adjacent to the carbonyl was equatorially oriented (59a). This was further supported by the conversion of this ketone _ _ by lithium aluminum hydride reduction to a new alcohol 93_ differ ing from the alcohol 91_. Detailed n.m.r. analysis of the C-9 proton of the alcohol 9_ revealed that - 26 -0 58 59 Chart X both hydroxy1 and C-10 methyl groups were equatorially oriented. This required the latter compound to have the stereochemistry as depicted i n 93. Buchi and colleagues (48) reported in 1966 the total synthesis of (-)-aromadendrene 9_4, which is enantiomeric to the naturally-occurring (+)-aromadendrene _0. The key step in the preparation of the aromadendrene - 27 -94 10 skel e t o n was based on an e a r l i e r reported f a c i l e s t e r e o s p e c i f i c rearrangement of a s u b s t i t u t e d bicyclo[4,4,0]decane to a bicyclo[5,3,0]decane (60). This l a t t e r conversion i n v o l v e d a base-promoted pinacol-pinacolone-type rearrangement of a v i c i n a l c i s - g l y c o l monotosylate. Thus, when 10-methyl-d e c a l - l , 9 - d i o l - l - t o s y l a t e 95 was t r e a t e d with potassium t-butoxide i n t-butanol or with alumina, 10-methylbicyclo[5,3,0]-decan-l-one 96 was formed. 95 96 The t r a n s i t i o n s t a t e f o r t h i s rearrangement demands that the migrating bond and the C-0 bond to the t o s y l a t e be a n t i c o p l a n a r . This s t e r e o e l e c t r o n i c requirement together w i t h the concerted mechanism of the rearrangement f i x e s the stereochemistry at the bridgehead of the product. The s y n t h e t i c sequence used by Buchi and coworkers i n the synthesis of (-)-aromadendrene 9_4 i s summarized i n Chart XI. A d d i t i o n o f hydrogen - 28 -Chart XI - 29 -bromide to (-)-perillaldehyde 9_ followed by treatment of the bromide 9_8 with potassium t-butoxide in t-butyl alcohol yielded the b i c y c l i c aldehyde 99. Treatment of 99_ with methylenetriphenylphosphorane gave the diene 100 which upon reaction with acrolein gave a mixture of adducts containing 75% of the aldehyde 101 and 15% of the epimer 102. Conversion of the aldehyde 101 into the t r i c y c l i c hydrocarbon 103 was achieved by consecutive treatment of the former with lithium aluminum hydride, methanesulfonyl chloride, and lithium aluminum hydride. Oxidation of 103 with osmium tetroxide yielded d i o l 104 which was converted to the tosylate 105. The tosylate 105,, when allowed to remain in contact with activated alumina or when treated with potassium t-butoxide in t-butyl alcohol, rearranged to give 106. Wittig reaction of ketone 106 with methylenetriphenylphosphorane gave (-)-aromaden-drene 94 which was identical with naturally-occurring (+)-aromadendrene 10, but with opposite specific rotation. White and Marx (49) synthesized two guaianolides, a c h i l l i n 6_ and desacetoxymatricarin 61_. The starting material, O-acetylisophotosantonic 0 0 60 61 lactone 108, was obtained by photochemical rearrangement of (-)-a-santonin 107 in aqueous acid, a reaction f i r s t performed by Barton and coworkers in 1957 (61). This type of photochemical rearrangement was found, in subsequent - 30 -Chart XII - 31 -studies, to be a general one f o r a compound possessing a cross-conjugated cy c l o -hexadienone chromophore. The stereochemistry and mechanism.of t h i s rearrange-ment w i l l be discussed i n more d e t a i l l a t e r i n t h i s thesis (see page 44 ). C a t a l y t i c hydrogenation of O-acetylisophotosantonic lactone 108 (Chart XII) gave the dihydro d e r i v a t i v e 109 with the stereochemistry at C-4 as shown. Although 109 was thermodynamically less stable than i t s epimer 110, i t gave only two alcohols 111 and 112 when i t was reduced with sodium boro-hydride. Treatment of 111 with methanesulfonyl c h l o r i d e i n pyridine at room temperature res u l t e d i n elimination, forming the o l e f i n 114. Desacetoxy-matrican 61_ was then obtained by oxidation of 114 with t-butyl chromate, followed by elimination of a c e t i c acid from the oxidation product 115. On the other hand, a c h i l l i n (5_0 was formed by epimerization (at C - l l ) of 114 with potassium tert-butoxide, followed by oxidation of the product 116 with t-butyl chromate. The elegant synthesis of (i)-bulnesol by Marshall and Partridge (50) i n 1968 provided another synthetic approach to the guaiane-type sesquiterpenes. The key reaction i n which the basic guaiane skeleton was formed, was based on the f i n d i n g that s o l v o l y s i s of a b i c y c l o [ 4 , 3 , l ] d e c y l mesylate 117 with a c e t i c ac i d at 120° s t e r e o s p e c i f i c a l l y produced the corresponding bicyclo[5,3,0]-decene system 119 (62). It was therefore apparent that with s u i t a b l e substituents (R,R* and R") c e r t a i n guaiane-type sesquiterpenes could be obtained. The f i r s t phase of Marshall's synthesis of (i ) - b u l n e s o l was the construction of a system l i k e 117 with R,R'=CH3 and R"=CH20Ac. This was achieved by the r e a c t i o n sequence outlined i n Chart XIII. Keto ester 120 - 32 -117 was converted to mesylate 121 by consecutive treatment of 120 with ethylene glycol in the presence of acid, lithium aluminum hydride, and methanesulfonyl chloride. Treatment of 121 with sodium p-chlorophenoxide, followed by acid hydrolysis yielded 4-(p-chlorophenoxymethyl)-cyclohexanone 122. Ring expansion with ethyl diazoacetate-boron t r i f l u o r i d e etherate yielded the keto ester 123 which was converted to the diketo ester 124 by condensation of the former with methyl vinyl ketone. The diketo ester 124 cyclised upon treatment with sulphuric acid-acetic acid (4:1), affording the b i c y c l o [ 4 , 3 , l ] -decenone ester 125 which was hydrolyzed to the keto acid 126. The keto acid 126 was converted into the alcohol 127 by successive subjection (of 126) to lithium aluminum hydride reduction, tosylation, and lithium aluminum hydride - 33 -r-OH F . h+ I- OH o. o 2. LAH 3. MsCl-py COOEt 120 1 . C l 2. H 30 CH2OMs 121 COOEt 0 Cl<f>-0-CH COOEt 123 p-Cl<j)-0-CH, z 122 COOR HoS0^-H0Ac 2 4 Cl<J>-0-C 124 Cl(f)-0-CH H Cl<|>-0-CH 127 COOR 1. LAH 2. TsCl 3. LAH Cl<j>-0-CH, 125 R 126 R Et H Chart X I I I - 34 -Chart X I I I (cont'd) - 35 -r e d u c t i o n . Removal of the p-chlorophenyl group was e f f e c t e d w i t h l i t h i u m i n ammonia-ethanol followed by a c i d c a t a l y s e d h y d r o l y s i s of the r e s u l t i n g enol ether. The stereochemistry of the r e s u l t i n g d i o l 128, and hence the s t e r e o -chemistry of a l c o h o l 127, was a s c e r t a i n e d as f o l l o w s . Jones o x i d a t i o n of 128, f o l l o w e d by treatment of the r e s u l t i n g keto a c i d 129 w i t h sodium borohydride, gave the lactone 130. Reduction of the l a t t e r w i t h l i t h i u m aluminum hydride regenerated the same d i o l 128. Upon treatment of 128 w i t h a c e t i c anhydride i n p y r i d i n e , monoacetate 131 was obtained, which gave e s s e n t i a l l y a s i n g l e dihydro isomer 132 on hydrogenation over platinum. The stereochemistry assigned to the C-4 methyl group was based upon an a n a l y s i s of the molecular model of 131 and upon the n.m.r. cou p l i n g constant a n a l y s i s o f the product 132. A molecular model of 131 showed that the 1,3-d i a x i a l arrangement r e q u i r e d of the four carbon bridge e f f e c t i v e l y b l o c k s the bottom face of the cyclohexene double bond. Therefore, a d s o r p t i o n of hydrogen on the r e l a t i v e l y more a c c e s s i b l e top face i s favoured. The coupling constant of C-4 methyl of 132 was observed to be 5.5 Hz, i n d i c a t i n g that the methyl group on the cyclohexane r i n g was probably e q u a t o r i a l (62). The a l c o h o l 132 was then converted to mesylate 133, which had the c o r r e c t t r a n s , coplanar arrangement needed f o r rearrangement t o the corresponding hydroazulene s k e l e t o n . /Thus, the f i r s t phase of the s y n t h e s i s was completed. The second phase of the synthesis i n v o l v e d the rearrangement of 133 to the corresponding hydroazulene skeleton and the m o d i f i c a t i o n of the s i d e chain at C-7 t o an isopropanol group. This was s u c c e s s f u l l y accomplished according to the scheme o u t l i n e d i n Chart XIV. The mesylate 133, upon 1 Chart XIV - 37 -r e f l u x i n g i n a c e t i c a c i d c o n t a i n i n g sodium a c e t a t e , rearranged to the b i c y c l o -[5,3,0]-decene d e r i v a t i v e 134. Lithium aluminum hydride r e d u c t i o n of the l a t t e r gave the a l c o h o l 155, which, upon o x i d a t i o n with Jones reagent, f o l l o w e d by e s t e r i f i c a t i o n w i t h diazomethane a f f o r d e d the methyl e s t e r 136. E p i m e r i z a t i o n of the e s t e r s i d e chain of 136 w i t h methanolic sodium methoxide produced an epimeric mixture of e s t e r s 136 and 137, i n a r a t i o of 3:7 r e s p e c t i v e l y . Separation of the epimers by gas chromatography, followed by r e a c t i o n of the more s t a b l e epimer 137 w i t h m e t h y l l i t h i u m , gave (±)-bulnesol The above d i s c u s s i o n has o u t l i n e d the reported t o t a l s y n t h e s i s o f n a t u r a l l y - o c c u r r i n g guaiane-type sesquiterpenes. However, i t i s p e r t i n e n t t o note that very r e c e n t l y , Heathcock and R a t c l i f f e (63) have i n p r e l i m i n a r y form reported another s y n t h e t i c pathway which could give entry i n t o the same system. This approach i n v o l v e d a s o l v o l y t i c rearrangement of 9-methyl-trans-d e c a l i n - l - t o s y l a t e 138. Thus when 138 was r e f l u x e d i n anhydrous a c e t i c a c i d c o n t a i n i n g two equivalents of potassium acetate, the major product i s o l a t e d was compound 139. On the other hand, the c i s - f u s e d keto e s t e r 140 gave only 51. OTs 0 5 IO"- 4 H 3 ,2 0 139 Hi OTs H I H 138 140 a very small amount of a hydroazulene compound. In the trans-fused keto ester 138, the r i g i d conformation requires that the tosylate group occupy an equatorial position and assures an anti-coplanar disposition of the C9-C10 bond and the tosylate group. Thus bond migration can occur concomitantly with ionization. Although thus far no synthesis has been reported employing this approach, i t i s apparent that this provides another promising method for guaiane-type sesquiterpene synthesis. DISCUSSION I. General Approach The main purpose of the work described in this thesis was to develop a general synthetic entry into the guaiane-type sesquiterpenes. Of'the number of possible routes which might be employed in the construction of the guaiane system, as represented, for example, by a-bulnesene 1_, we chose the scheme which would involve a photochemical rearrangement of a cross-conjugated dienone in aqueous acid. This can be i l l u s t r a t e d , in general term, by the 7 conversion of 141 into 142. OH hv 0 : 0' R 141 142 - 40 -The l i g h t - i n d u c e d rearrangement of the cross-conjugated cyclohexadienone chromophore was noted i n the l i t e r a t u r e (64) as e a r l y as 1830. Around the t u r n of the century (65), a number of I t a l i a n workers devoted considerable e f f o r t to a study of the photochemistry of the n a t u r a l l y o c c u r r i n g s e s q u i -terpene (-)-a-santonin 107, but i t was not u n t i l the l a s t decade that c o r r e c t s t r u c t u r e s were e l u c i d a t e d f o r the various photoproducts. In 1957, Barton and colleagues (61,66) found that i r r a d i a t i o n o f (-)-a-santonin 107 i n 45% aqueous a c e t i c a c i d produced, as the major product, isophotosantonic lactone 143. The stereochemistry of compound 143 was c o n c l u s i v e l y e s t a b l i s h e d by X-ray c r y s t a l l o g r a p h y (67,68). The same observation was reported independently at the same time by A r i g o n i and coworkers (69). Subsequent i n v e s t i g a t i o n of the photochemical rearrangement o f various cross-conjugated cyclohexadienone systems 144 employing a number of d i f f e r e n t solvent systems and v a r y i n g the d u r a t i o n of i r r a d i a t i o n , showed that a number of d i f f e r e n t photoproducts, 145 to 150, could be formed i n t h i s type of r e a c t i o n . These are l i s t e d i n Chart XV. The photochemistry of cyclohexadienones has been reviewed p a r t i a l l y or t o t a l l y i n a number of recent a r t i c l e s (8-12). The p r i n c i p a l course of photochemical rearrangement of the cross-conjugated - 41 -149 R 150 Chart XV cyclohexadienone 144 in aqueous acidic media is the formation of either a 5/7-fused hydroxy ketone 147 or a spiro[4 ;5] hydroxy ketone 146 or a mixture of 147 and 146. The type of hydroxy ketone photoproduct formed influenced mainly by the presence or absence of substituents at the C-2 + and/or C-4 positions. Thus, the formation of a 5/7-fused hydroxy ketone 147 as the major product in aqueous acidic media is general for dienones of type 144, which have a methyl substituent (or, presumably, another electron-donating substituent) at the C-4 position. For example, photolysis of 151 (75,76) and 155 (77) gave r ise to 152 and 154 respectively. 153 154 On the other hand, the 2-methyl dienone 155 gave almost exclusively the spiro hydroxy ketone 156 with the formaton of no detectable amount of the alternative 5/7-fused hydroxy ketone (78). t Steroidal-type numbering. - 43 -OH 155 156 Dienone 157, which has no substituent on either C-2 or C-4, gave, upon irradiation in aqueous acidic medium, the 5/7-fused hydroxy ketone 158 and the spiro hydroxy ketone 159 in approximately equal amounts (79). 157 158 159 The presence of electron-withdrawing substituents at the C-2 position also results in a preferred rearrangement to the 5/7-fused system. Thus, i rradiation of the 2-carboxy dienone 160 in aqueous acetic acid gave hydroxy ketone 161 in good yie ld (80). H00< 160 161 - 44 -It i s generally believed that the formation of hydroxy ketones from the eross-conjugated dienones of type 162 involves the intermediate 163 (79,81,82,83). Both the structural and the stereochemical features of the 163 165 Chart XVI two types of photoproducts 164 and 165, as well as the marked substituent effects on the course of the rearrangement can be understood i n terms of this intermediate 163. The nucleophilic attack by solvent on the intermediate 163 at C-10 from the front side and cleavage of C1-C10 bond (path A in Chart XVI) accounts for the formation of the spiro product 164. Alternately, nucleophilic attack by solvent on intermediate 163 at C-10 from the back side and cleavage of C10-C5 bond (path B in Chart XVI) would give r ise to a 5/7-fused product 165, with stereochemistry as shown. These two modes of nucleophilic attack by - 45 -solvent, i n the absence of a substituent in ring A and i n the absence of any-obvious steric hindrance, could occur with equal f a c i l i t y , thus giving r i se to the spiro and 5/7-fused compounds in approximately equal amounts. However, the presence of a methyl group in ring A would, due to the electron-releasing inductive effect of the methyl group, localize the positive charge at the substituted posit ion. Thus, the C-4 methyl dienone 162 (R' = H, R" = CHg) would give the intermediate 163 (R' = H, R" = CH^) which would then undergo preferential cleavage of the C10-C5 bond (path B). Similarly , the C-2 methyl dienone 1_32 (R* = C H 3 > R" = H) would afford the intermediate 163 (R' = CH^, R" = H) which would then undergo preferential cleavage of the C1-C10 bond (path A). Furthermore, the presence of an electron-withdrawing substituent (e.g. -COOH) at the C-2 posit ion, would destablize the positive charge at the C-2 position of the intermediate 163 and would therefore result in a preferred rearrangement to the 5/7-fused system. II. Synthesis of 5-Epi-a-bulnesene 216 and 4-Epi-a-bulnesene 218 A. Synthesis of (+)-a-Cyperone 168 and (-)-7-Epi-a-cyperone 169 by Robinson Annelation In applying the above general approach (involving the photochemical rearrangement of a cross-conjugated cyclohexadienone system) to the synthesis of a-bulnesene 7_, i t became necessary to prepare compound of the type 141, where R is either an isopropenyl group or a functionality which can be readily converted into an isopropenyl side chain. I n i t i a l l y , we chose. - 46 -\ 141 7 compounds 166 and 167 as the systems to be subjected to photochemical rearrangement. Thus the f i r s t phase of the projected synthesis of a-bulnesene 7_ was the preparation of compounds 166 and 167. Compounds 166 and 167 166 167 could be obtained by dehydrogenation of (+)-a-cyperone 168, a naturally-occurring sesquiterpene, and i t s epimer (-)-7-epi-q-cyperone 169, respectively. The starting materials for the present synthesis, (+)-a-cyperone 168 and i t s epimer 169, were prepared by a procedure similar to that reported by ^ Howe and McQuillin (84) named this compound (-)-6-epi-a-cyperone. However, i t is now general practice to number eudesmane-type sesquiterpenes according to the steroid numbering system, as indicated in formula 169. - 47 -168 169 Howe and McQuillin (84). Thus, commercial 1-carvone 170, upon reduction with zinc and sodium hydroxide in ethanol (85), gave, after steam d i s t i l l a -t ion , (+)-dihydrocarvone 171. 170 171 Condensation of (+)-dihydrocarvone 171 with l-diethylamino-3-pentanone methiodide i n the presence of sodium amide (Robinson Annelation) (84) afforded mainly ketol 172, accompanied by an epimeric mixture of (+)-a- . 172 - 48 -cyperone 168 and (-)-7-epi-a-cyperone 169. The ketol 172 was separated from the mixture of the epimeric cyperones, 168 and 169, by fractional c rys ta l l iza t ion . Recrystallization of ketol 172 from n-hexane afforded a colourless crystal l ine material, the spectral data of which was in complete agreement with the structure 172. Thus, the infrared spectrum showed a, strong saturated carbonyl absorption at 5.92 u , a hydroxyl absorption at 2.96 ]i and isopropenyl double bond absorptions at 6.14 u and 11.28 u. ;The nuclear magnetic resonance (n.m.r.) spectrum exhibited signals at x 5.35 (unresolved multiplet , ^ C = C 1 2 H 2 ) , x 8.33 (doublet, - C 1 4 H 3 , J = 1 Hz),, ;x 8.77 (singlet, - C 1 5 H 3 ) , and x 8.97 (doublet, - C 1 3 H 3 , J = 6.5 Hz). The pure crystal l ine ketol 172 was dehydrated to 169 by treatment of the former with alcoholic potassium hydroxide. The spectral properties of the product were in agreement with structure 169. Of particular pertinence were the ultraviolet spectrum (^max 250 my) and infrared spectrum, which exhibited a strong absorption at 6.05 u due to the a,6-unsaturated carbonyl group. 12 The n.m.r. spectrum showed signals at x 5.21 and x 5.37 ( ^:C=C H^), x 8.21 and x 8.30 (two vinyl methyls) and x 8.79 (angular methyl). Separation of epimeric mixture of (+)-a-cyperone 168 and (-)-7-epi-a-cyperone 169 by gas-l iquid chromatography (g . l . c . ) or fractional d i s t i l l a t i o n through a spinning band column was unsatisfactory. Therefore, the separation procedure of Howe and McQuillin (84) was adopted. To that end, the epimeric mixture of compounds 168 and 169 was converted, by treatment with hydrpxyl-amine hydrochloride in refluxing methanol, into the corresponding oxime derivative. Upon cooling, the oxime derivative of (+)-a-cyperone 173 ; crystal l ized from the reaction mixture. Purif icat ion of this compound was - 49 -173 e f f e c t e d by r e c r y s t a l l i z a t i o n from methanol. The pure oxime was hydrolyzed by o x a l i c a c i d i n aqueous methanol i n the presence of l i g h t petroleum ether. Continuous e x t r a c t i o n of the hydrolyzed product i n t o petroleum ether avoided acid-induced i s o m e r i z a t i o n of the ter m i n a l o l e f i n i c double bond. P u r i f i c a -t i o n of the crude h y d r o l y s i s product by d i s t i l l a t i o n gave pure (+)-a-cyperone 168, which gave the f o l l o w i n g s p e c t r a l data. The i n f r a r e d spectrum showed a strong absorption at 6.00 y, due to the a,3-unsaturated carbonyl group and absorptions at 6.22 u and 11.20 u, due to the isopropenyl ^ . 1 2 double bond. The n.m.r. spectrum showed s i g n a l s at x 5.23 ( „C=C H^), x 8.23 (two v i n y l m ethyls), and x 8.78 (angular methyl). The i n f r a r e d and n.m.r. sp e c t r a were i d e n t i c a l w i t h those obtained from an authe n t i c sample t of (+)-a-cyperone. The condensation of (+)-dihydrocarvone 171 with l-diethylamino-3- • pentanone methiodide, as reported by Howe and M c Q u i l l i n (84), provided an e f f i c i e n t means to prepare (-)-7-epi-a-cyperone 169. However, t h i s method was not s a t i s f a c t o r y f o r the p r e p a r a t i o n of (+)-a-cyperone 168 i n large We are very g r a t e f u l to Dr. Sukh Dev f o r a generous sample o f n a t u r a l (+)-a-cyperone. - 50 -quantities because of the poor yield of the latter compound (the isolated yield of 168 reported by Howe and McQuillin was approximately 4%) and because of the d i f f i c u l t y in separating (+)-a-cyperone 168 from i t s epimer 169. Therefore, we investigated an alternate method for the preparation of (+)-a-cyperone 168. This was accomplished by a successful conversion of the well-known and readily available sesquiterpene, (-)-a-santonin 107 into (+)-a-cyperone 168. 0 107 168 B. Conversion of (-)-a-Santonin 107 into (+)-a-Cyperone 168 (-)-a-Santonin 1_7_, of known absolute stereochemistry (86,87), was converted into i ts C-6 epimer 174 by a procedure similar to that described by Ishikawa (88). Thus, a solution of (-)-a-santonin 107 in anhydrous 107 174 - 51 -dimethyl formamide c o n t a i n i n g 5% anhydrous hydrogen c h l o r i d e was heated to 85-90° f o r 3.5 hours and then allowed to stand at room temperature overnight. P u r i f i c a t i o n o f the crude product by column chromatography on alumina a f f o r d e d , i n 63% y i e l d , the c r y s t a l l i n e (-)-6-epi-q-santonin 174. The s p e c t r a l data of t h i s compound was i n complete accord w i t h s t r u c t u r e 174. A comparison o f the n.m.r. spectrum of the s t a r t i n g m a t e r i a l 107 w i t h t h a t of the product 174 was p a r t i c u l a r l y i n s t r u c t i v e . Thus, the C-6 proton o f (-)-a-santonin 107 appeared as a doublet (J = 9 Hz) at T 5.16, w h i l e the C-6 proton of (-)-6-epi-a-santonin 174 appeared as a doublet (J = 4.5 Hz) at T 4.46. Both the chemical s h i f t d i f f e r e n c e and coupling constants were c o n s i s t e n t with the conversion (107 i n t o 174). Treatment of compound 174 with z i n c dust i n g l a c i a l a c e t i c acid-methanol, e s s e n t i a l l y by the procedure of Nakazaki and Naemura (89), r e s u l t e d in; the re d u c t i v e cleavage of the lactone r i n g and a f f o r d e d , i n 85% y i e l d , the keto a c i d 175 as a viscous yellow o i l . Although the l a t t e r was not p u r i f i e d f u r t h e r , the s p e c t r a l data of the crude m a t e r i a l was i n complete agreement w i t h s t r u c t u r e 175. Thus, the u l t r a v i o l e t spectrum e x h i b i t e d a maximum at 240 my, w h i l e the i n f r a r e d spectrum showed a.very broad absorption at C00H 175 - 52 -2.95-3.95 u and a peak at 5.85 u , both attributed to the carboxyl group. The absorption due to the unsaturated ketone carbonyl was found at 6.05 u . The n.m.r. spectrum exhibited a typical AB pair of doublets for the protons at C - l and C-2: x 3.32 (doublet, «C H) and x 3.79 (doublet, ^-C H, 2 = 10 Hz). In addition, there appeared three 3-proton signals at x 8.14 (singlet, - C 1 4 H 3 ) , x 8.78 (doublet, - C 1 3 H 3 , J n 1 3 = 7 Hz), and x 8.82 (singlet, - C 1 5 H 3 ) . The keto acid 175 was further characterized as i t s crystal l ine cyclohexylamine sal t , m.p. 1 2 2 - 1 2 4 ° . The crude carboxylic acid 175 was converted into the corresponding methyl ester 176 by treating the former compound with excess ethereal diazomethane at 0 ° . The crude material was purif ied by d i s t i l l a t i o n under reduced pressure, affording a 76% yield of the keto ester 176 as a clear 011 which exhibited the expected spectral characteristics. Of note was the C00CH3 176 appearance, in the n.m.r. spectrum, of a strong singlet at x 6.32, due to the -C00CH3 grouping. At this point in the synthetic sequence, the selective removal of the C1-C2 o l e f i n i c double bond of the keto ester 176 was desired. In this connection, i t is pertinent to point out that the catalytic hydrogenation of (-)-a-santonin 107 and i t s derivatives has been studied i n some detail by - 53 -Cocker and coworkers (90,91) and by Yanagita and colleagues (92,93). These workers found that the catalytic hydrogenation of (-)-a-santonin 107 over Adam's catalyst, even when stopped after the absorption of one mole of hydrogen, gave, along with some starting material, a tetrahydro-ketone 177, as the only product. Therefore, i t appeared unlikely that the use of the 177 usual heterogeneous catalytic hydrogenation would effect complete selective removal of the C1-C2 double bond in the presence of the C4-C5 double bond of the ester 176. At that time, however, there appeared reports (94,95,96) 1 4 that hydrogenation of a number of A ' -3-keto steroids in the presence of the novel hydrogenation catalyst, tris(triphenylphosphine)chlororhodium 178 (97), resulted i n a highly selective reduction of the C1-C2 double bond. For example, Djerassi and Gutzwiller (96) found that hydrogenation 1 4 of A ' -androstadiene-3,17-dione 179 in the presence of the soluble • 4 catalyst gave, in 75-85% y i e l d , the A -3-ketone 180 as the only product. - 54 -Since the homogeneous catalyst, tris(triphenylphosphine)chlororhodium 178, played a rather crucial role in various stages of our synthetic work, i t is pertinent to discuss very b r i e f l y the mechanism of hydrogenations involving this compound as catalyst. Wilkinson and coworkers (98) proposed that the i n i t i a l step involved the dissociation of the complex 178 in solution to give a solvated species, RhCl(Ph 3P) 2(S) 181) (where S = solvent). The latter takes up molecular hydrogen forming a dihydrido-complex, RhCl(Ph 3P) 2(S)H 2 182. Coordination of the o lef in to the rhodium by displacement of solvent forms an intermediate species, RhCl(Ph 3 P) 2 H 2 (olefin) 183. The olef in is then reduced by a stereospecific, intramolecular c i s -transfer of the bound hydrogen to the o l e f i n . S H2 RhCl(Ph 3P) 3 RhCl(Ph 3P) 2(S) —-_- RhCl (Ph3P) 2 (S)H2 178 181 A \ olef in paraffin + RhCl(Ph3P) (S) — — ' RhCl (PhjP),,*!., (olefin) Cl 183 Hydrogenation, at room temperature and atmospheric pressure, of a benzene solution of the keto ester 176 and tris(triphenylphosphine)chloro-rhodium 178, gave, in 96% y i e l d , the desired product 184. - 55 -176 184 The s p e c t r a l p r o p e r t i e s of the product were i n complete agreement with the s t r u c t u r a l assignment. Thus, the i n f r a r e d spectrum e x h i b i t e d the e s t e r carbonyl absorption at 5.84 y, the a,3-unsaturated carbonyl a b s o r p t i o n at 6.07 u and the o l e f i n i c a bsorption at 6.24 u. The n.m.r. spectrum, which showed no s i g n a l s due to o l e f i n i c protons, e x h i b i t e d p e r t i n e n t s i g n a l s at x 6.34 ( s i n g l e t , -C00CH 3), T 8.27 (doublet, -C 1 4H 3, J = 1 Hz), x 8.80 ( s i n g l e t , -C 1 5H„), and x 8.81 (doublet, -C 1 3H 3, J n _ 3 = 7 Hz). I t i s r e l e v a n t to mention that the keto e s t e r 184 had been p r e v i o u s l y prepared (99) by d i r e c t lithium-ammonia r e d u c t i o n of (-)-a-santonin 107, followed by treatment o f the crude product with diazomethane. However, t h i s method, i n a d d i t i o n to being experimentally l a b o r i o u s to c a r r y out on a large s c a l e , gave, i n our hands, a mixture of compounds co n t a i n i n g three components, as i n d i c a t e d by g a s - l i q u i d chromatographic a n a l y s i s . Reduction of the keto e s t e r 184 with l i t h i u m aluminum hydride i n ether afforded i n 97% y i e l d a c r y s t a l l i n e m a t e r i a l . Examination of the l a t t e r by t h i n - l a y e r chromatography i n d i c a t e d that i t was a mixture of two compounds. Indeed, i t was subsequently shown (see below, page 56 ) that t h i s was an epimeric mixture (at C-3) of two d i o l s , the major component - 56 -(80%) 185 having a 3 B(pseudoequatorial) hydroxyl group and the minor component (20%) 186 having a 3<*(pseudoaxial) hydroxyl group. Careful column chromatography of the crystal l ine material on ac t ivi ty II alumina effected separation of the two components. The d i o l 185 which 25 was eluted f i r s t showed m.p. 1 2 7 . 5 - 1 2 9 ° and [a]^ + 1 3 ° , while the more 25 polar d i o l 18_ exhibited m.p. 115-116° and [ a ] Q + 1 0 5 ° . The spectral, data (infrared and n.m.r.) for each compound f u l l y corroborated the respective structural proposals. However, since the configurational assignments at C-3 were based entirely upon the n.m.r. spectra, these w i l l be discussed in some d e t a i l . - 57 -The n.m.r. spectrum of the 33-alcohol 185 ( f i g u r e 1) e x h i b i t e d the C-3 proton as a d i s t o r t e d , unsymmetrical t r i p l e t (overlapped p a i r of d o u b l e t s ) , w i t h the center peak at x 6.01, the low f i e l d peak at x 5.95, and the high f i e l d peak at x 6.08. The t o t a l width at h a l f - h e i g h t of the s i g n a l was 15 Hz. The unsymmetrical nature of t h i s t r i p l e t w i l l be commented upon l a t e r (see page 58 ). I t i s a l s o i n t e r e s t i n g to note that the methylene protons at C-12 of compound 185 appeared as a septet (AB pa r t of an ABX system) centered at x 6.46. However, the magnetic nonequivalence of methylene protons immediately adjacent to an assymmetric center i s a common phenomenon (100a), and t h i s t h e r e f o r e deserves no f u r t h e r comment. Other p e r t i n e n t 14 15 s i g n a l s appeared at x 8.31 ( s i n g l e t , -C H^), x 8.95 ( s i n g l e t , -C H^), and x 9.06 (doublet, -C 1 3H 3, J = 6.5 Hz). In the n.m.r. spectrum of the 3a-alcohol 186 ( f i g u r e 2 ) , the C-3 proton was present as a broad, unresolved peak centered at x 6.12, with a width at h a l f - h e i g h t of approximately 7 Hz. Other assignable s i g n a l s were s i m i l a r i n chemical s h i f t and m u l t i p l i c i t y to the corresponding resonances of the 3g-alcohol 185. On a f i r s t - o r d e r b a s i s , the C-2 and C-3 protons of each of the d i o l s 185 and lj_6 would be assigned as an A(-C 2H )B(-C 2H ) +X(-C 3H) system. The (X)H \ (B)H (X)H OH z / \ 185 186 t a = a x i a l (or p s e u d o a x i a l ) , e = e q u a t o r i a l (or pseudoequatorial). Figure 2. N.M.R. Spectrum of Compound 186 - 60 -coupling of X i n an ABX system i s the sum of the two coup l i n g s , + J ^ -For the 3 B-alcohol 185, the sum J + J should be approximately 12-15 Hz, wh i l e f o r the 3ct-alcohol 186, the sum J _ + J„ „ should be —•— Aa.fjQ /e,^e approximately 5-8 Hz (16b). As noted above, the t o t a l width at h a l f -height of the ;C H resonance of compound 185 was found to be 15 Hz, which i s c l e a r l y i n good agreement w i t h a compound having a 3 3 - c o n f i g u r a t i o n of 3 the hydroxy1 group. Furthermore, the width at h a l f - h e i g h t o f the H s i g n a l f o r the d i o l 186 was, as noted above, approximately 7 Hz, i n d i c a t i n g c l e a r l y that t h i s compound has the hydroxyl group at C-3 i n the a - c o n f i g u r a t i o n . 3 The f a c t that the "t h r e e " l i n e s of the ~C H resonance of the 36-alcohol 185 were not symmetrical may r e f l e c t the f a c t t h a t the system i s not merely an ABX system, but i s r a t h e r an ABXC(-C 1H )D(-C 1H ) system. However, t h i s does not i n v a l i d a t e the above q u a l i t a t i v e argument. Each of the d i o l s 185 and 186 was converted, by treatment with a c e t i c anhydride i n p y r i d i n e , into the corresponding d i a c e t a t e 187 and 188, r e s p e c t i v e l y . The i n f r a r e d and n.m.r. spectra o f these compounds completely H3CC0 187 188 CH2OCCH3 - 61 -corroborated the above s t r u c t u r a l assignments. In the n.m.r. spectrum o f d i a c e t a t e 187 ( f i g u r e 3 ) , the C-3 proton again appeared as an unsymmetrical t r i p l e t , w i t h i n d i v i d u a l peaks at x 4.70, x 4.76 and x 4.83 and a width at h a l f - h e i g h t of 15 Hz. Furth e r , an oct e t centered at x 6.02 could be assigned t o the methylene protons at C-12. Thus, a c e t y l a t i o n of the hydroxyl groups produced the expected paramagnetic s h i f t s (100b,59c) of the .^C H 12 and resonance, s i n c e , r e l a t i v e to the corresponding s i g n a l s i n the d i o l 185, the H resonance was moved downfield by 1.25 ppm and the 12 H^ resonance was moved downfield by 0.44 p.p.m. S i m i l a r l y , the n.m.r. spectrum of the d i a c e t a t e 188 ( f i g u r e 4) e x h i b i t e d a broad s i g n a l at x 4.90 (>C3H, width at h a l f - h e i g h t = 7.5 Hz), and an o c t e t centered at x 6.00 O C 1 2 H 2 ) . The c r y s t a l l i n e epimeric mixture of d i o l s 185 and 186 was converted i n t o the k e t o - a l c o h o l 189 by s e l e c t i v e o x i d a t i o n of the a l l y l i c a l c o h o l f u n c t i o n w i t h 2,3-dichloro-5,6-dicyanobenzoquinone (101) i n dry dioxane at room temperature f o r 4 hours. In order to e f f e c t only o x i d a t i o n of the CH20H 189 Figure 3. N.M.R. Spectrum of Compound 187. Figure 4. N.M.R. Spectrum of Compound 188. - 64 -a l l y l i c a l c o h o l at C-3, i t was important to choose proper r e a c t i o n c o n d i t i o n s . Thus, i f the r e a c t i o n was allowed to proceed u n t i l a l l of the s t a r t i n g m a t e r i a l had r e a c t e d , a s i g n i f i c a n t amount of o x i d a t i o n of the primary a l c o h o l group t o the corresponding aldehyde occurred as i n d i c a t e d by the appearance of an absorption at 5.80 u i n the i n f r a r e d spectrum. Therefore, c o n d i t i o n s were adopted which gave only the keto a l c o h o l 189, along w i t h s t a r t i n g m a t e r i a l 185 and 186. The d e s i r e d product 189 was r e a d i l y obtained by column chromatography of the mixture, and the recovered d i o l s 185 and 186 were then subjected to a second o x i d a t i o n r e a c t i o n . The i n f r a r e d spectrum of the c r y s t a l l i n e keto a l c o h o l 189 showed, i n a d d i t i o n to the a,g-unsaturated carbonyl a b s o r p t i o n at 6.09 u, hydroxyl and o l e f i n i c absorptions at 3.00 u and 6.27 u, r e s p e c t i v e l y . The n.m.r. 12 spectrum e x h i b i t e d s i g n a l s at T 6.28-6.62 ( o c t e t , >C H ), T 8.26 (broad J = 6.5 Hz). Treatment of keto a l c o h o l 189 w i t h f r e s h l y d i s t i l l e d e t h y l c h l o r o -formate i n p y r i d i n e at 0° gave, i n 75% y i e l d , the corresponding keto carbon-ate 190. The l a t t e r was p u r i f i e d by d i s t i l l a t i o n under reduced pressure 0 CH 0C0CH2CH 190 t This compound was p r e v i o u s l y reported as an o i l ( r e f . 99) - 65 -and exhibited the expected spectral characteristics. Of note was the appearance of a strong carbonyl absorption at 5.18 y in the infrared spectrum, and the presence of a t r i p l e t at x 8.76 (J = 7.1 Hz) and a quartet centered at T 5.95 (J = 7.1 Hz), in n.m.r. spectrum, due to the 9 -0C0CH2CH3 group. Compound 190 was pyrolyzed at approximately 400° in a ver t ical pyrex glass column packed with glass helices (figure 5). During the pyrolysis , nitrogen was slowly passed through the column. Pyrolytic elimination of ethanol and carbon dioxide from 190 (102) resulted in the formation of (+)-a-cyperone 168) (path A in chart XVII). Alternatively, pyrolytic elimination of ethylene and carbon dioxide from 190 gave keto alcohol 189 (path B i n chart XVII). Thus, the crude material obtained from the pyrolysis of 190 consisted of a mixture of (+)-<x-cyperone 168 and the keto alcohol 189. The two components were separated by column chromatography on , alumina. (+)-a-Cyperone 168, obtained in 61% y i e l d , was identical in every respect (infrared, n .m.r . , optical rotation, gas-l iquid chromatographic retention times) with an authentic sample of the sesquiterpene. The keto alcohol 189, obtained in 32% y i e l d , was identical (infrared, n.m.r. and m.p.) with compound 189 previously prepared. In order to avoid this undesirable formation of compound 189 during pyrolysis , the keto alcohol 189 was converted into the corresponding methyl carbonate 191 by treatment of the former with methyl chlorofofmate in dry pyridine. An analytical sample of the methyl carbonate 191 exhibited the expected spectral properties. In the n.m.r. spectrum of 191, a three-proton sharp singlet appeared at x 6.28 (-0CH 3). Other assignable signals were similar in chemical shif t and mul t ip l i c i ty to the corresponding ethyl carbonate 190. - 66 -— vert ical furnace glass helices ice bath Figure 5. The pyrolysis apparatus - 67 -H "-CH2 6. ..6 191 Chart XVII - 68 -Pyrolysis of compound 191 under conditions identical with those used for compound 190 gave, as expected, only one product, the desired (+)-a-cyperone 168 in 84% y i e l d . The above described synthesis of (+)-a-cyperone 168 has several advantages over the previously reported (84) preparation of this compound. Although the former was somewhat lengthy (eight steps), the overall y ie ld of (+)-a-cyperone 168, based on (-)-a-santonin 107, was approximately 20%. Additionally, each of the steps was readily adaptable to relat ively large scale, and the preparation of moderately large amounts of pure (+)-a-cyperone 168 was, therefore, easily accomplished. C. Conversion of (+)-a-Cyperone 168 and (-)-7-Epi-a-cyperone 169 into the Respective Hydroguaiazulene Derivatives 194 and 195 Having realized eff ic ient syntheses of both (+)-a-cyperone 168 and i t s epimer, (-)-7-epi-a-cyperone 169, we next planned to convert these compounds into hydroguaiazulene derivatives. To that end, both (+)-a-cyperone 168 and (-)-7-epi-a-cyperone 169 were converted separately into the corresponding 1,2-dehydro derivatives 192 and 195, respectively. Thus, treatment of compound 168 with 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ) (101) in refluxing dioxane for 45 hours gave, in 73% y i e l d , 1,2-dehydro-(+)-a-cyperone 192. The dehydro derivative, was purified by column 0 0 168 192 - 69 -169 193 chromatography on act ivi ty II alumina, affording a colourless o i l which showed the expected spectral properties. The ultraviolet spectrum showed a maximum at 240 my and the infrared spectrum exhibited a conjugated carbonyl absorption at 6.03 y and o lef inic absorptions at 6.15 y and 6.25 y. The n.m.r. spectrum showed a typical AB pair of doublets for the protons at C - l and C-2: T 3.22 (doublet, ^ C 1 H ) and T 3.87 (doublet, ^ C 2 H , J__ 2 = 10 Hz). In addition, there appeared a broad 2-proton signal at x 5.18 ( X!=C 1 2 H 2 ) and three 3-proton signals, at x 8.07 (singlet, - C 1 4 H 3 ) , x 8.21 13 15 (poorly resolved multiplet , -C H^), and x 8.74 (singlet, -C H^). ; Similarly , 1,2-dehydro-(-)-7-epi-a-cyperone 193 was obtained by; reacting (-)-7-epi-a-cyperone 169 with 2,3-dichloro-5,6-dicyanobenzoquinone in refluxing dioxane. In this case, the product 193 was obtained only in low yie ld (25%, based on unrecovered starting material). However, the spectral properties of 193, which were very similar to those of compound 192, were in complete agreement with the assigned structure. Irradiation of 1,2-dehydro-(+)-a-cyperone 192 in 45% aqueous acetic acid at room temperature for approximately one hour, using a Hanovia 450 W - 70 -high-pressure mercury lamp and a pyrex f i l t e r , gave, after appropriate work-up, a high yie ld of a crude gummy product. Chromatography of this crude material on Woelm neutral s i l i c a gel or Woelm neutral ac t ivi ty III alumina produced a nicely crystal l ine substance to which structure 194 was assigned. 192 194 This crystal l ine material exhibited spectral characteristics which were in complete agreement with the proposed structure 194. Thus, the ultraviolet spectrum showed a maximum at 244 my, and the infrared spectrum exhibited the expected absorption for the hydroxyl group at 2.96 y, the conjugated cyclopentenone carbonyl at 6.01 y, and the isopropenyl group at 6.19 y and .11.21 y. Furthermore, the n.m.r. spectrum (figure 6), showed a broad 12 2-proton signal at x 5.28 ( >C=C H^), and a sharp 3-proton singlet at x 9.08 ( - C 1 5 H j ) . The two 3-proton signals arising from the v i n y l i c methyl groups 13 appeared as broad, unresolved multiplets at x 8.24 (-C H^) and x 8.31. ( - C 1 4 H 3 ) . These latter assignments were confirmed by a frequency-swept decoupling experiment in which the o l e f i n i c protons at C-12 were strongly irradiated, thus eliminating the a l l y l i c coupling between these protons and those of C-13, and causing the unresolved multiplet at x 8.24 to collapse to a sharp singlet . Figure 6. N.M.R. Spectrum of Compound 194. - 72 -The cross-conjugated dienone, 1,2-dehydro-(-)-7-epi-a-cyperone 193, was subjected to photochemical rearrangement under conditions similar to those used for compound 192. Chromatography of the crude product on Woelm neutral s i l i c a gel or Woelm neutral ac t ivi ty III alumina gave, in good y i e l d , a highly crystal l ine material to which structure 195 was assigned. The 193 195 spectral properties of this crystall ine material were similar to those of compound 194 (the n.m.r. spectrum of 195 is shown in figure 7), and f u l l y corroborated the structure 195. It is pertinent to comment b r i e f l y on the stereochemistry of the rearrangement products 194 and 195. The absolute configuration at a l l of the asymmetric centers of (+)-a-cyperone 168 and i t s epimer 169 are known (86) and, because of the known stereospecific nature of the photochemical rearrangement of cross-conjugated cyclohexadienones (87), compounds 19.4 and 195 should.have possessed the absolute stereochemistry shown. This conclusion, of course, assumed that no epimerization at C - l had taken place in the acidic reaction media after completion of the rearrangement reactions, or during work-up and purif icat ion of the products. Examples of epimeriza-tion at C - l of similar , although by no means ident ica l , systems are known Figure 7. N.M.R. Spectrum of Compound 195. - 74 -(103,104). We have therefore obtained independent evidence that structures 194 and 195 do, in fact , correctly represent the stereochemistry of these compounds, by measuring their optical rotatory dispersion (o.r .d. ) curves. These curves were then compared with that of isophotosantonic lactone 143, of known absolute stereochemistry (67,68,87). 143 i Compound 194 showed a positive Cotton effect curve, $2gg+16000, $242^' $2_6~24000, which was nearly superimposable on that of isophotosantonic lactone 143 (figure 8). Compound 195, on the other hand, exhibited a negative Cotton effect curve which bore a mirror image relationship to those.of compounds 194 and 143. Since the five-membered cyclopentenone ring of each of these substances is essentially planar, the configuration at C - l should, in each case, largely determine the sign of the Cotton effect curve. The octant projections (105) of compounds 194, 195, and 143 can be represented as shown in 194a, 195a arid 143a, respectively. Therefore, with respect to the configuration at C - l , compound 195 must bear an antipodal relationship to compounds 194 and 143. - 75 -+ 2 0 0 -~ ~ i 1 1 i 1 2 0 0 2 5 0 3 0 0 3 5 0 m 1^ Figure 8. O.R.D. Curves of Compounds 1_4_ ( ), 194 (---) and 195 (•••••)• - 76 -15 t 194a 7 + 143a Although the preparation of the substituted hydroguaiazulene 194 from (+)-a-cyperone 168 could be realized in reasonable y ie ld (overall yield 57%), the preparation of the corresponding derivative 195 from (-)-7-epi-a-cyperone 169 could be achieved in only poor y ie ld (approximately 15%). The chief reason for the inefficiency of the latter conversion was - 77 -the poor y ie ld of the dehydrogenation reaction of (-)-7-epi-a-cyperone 169 with 2,3-dichloro-5,6-dicyanobenzoquinone (101). Attempts to improve the yie ld of this reaction by varying the reaction conditions were unsuccessful. Thus, an alternative route for the conversion of compound 169 into compound 195 was sought. Caine and DeBardeleben (106) had reported that reaction of the hydroxy-methylene derivative 196 with 2,3-dichloro-5,6-dicyanobenzoquinone gave, in very good yield (76%), the dienone aldehyde 197. Moreover, Caine and coworkers (80) had also shown that the corresponding dienone carboxylic acid derivative 160, which could easily be obtained by oxidation of 197, gave, upon irradiat ion in aqueous acidic medium, the substituted hydroazulene 161, in 65% y i e l d . Therefore, we decided to use a similar series of reactions 161 160 - 78 -for the conversion of compound 169 into compound 195. Condensation of (-)-7-epi-a-cyperone 169 with ethyl formate i n the presence of sodium methoxide in benzene provided the 2-hydroxymethylene derivative 198 in good y i e l d . Purif icat ion of the crude product by 169 198 d i s t i l l a t i o n under reduced pressure afforded a clear o i l which exhibited the expected spectral properties. The ultraviolet spectrum showed maxima at 263 my and 310 my. A dramatic change in the ultraviolet spectrum was observed by the addition of a trace of sodium hydroxide. In this case, the maxima appeared at 260 my and 360 my. The same observation with similar hydroxy-methylene derivatives had been reported (106,107). The n.m.r. spectrum :of 198_ exhibited signals at x 2.68 (broad signal , =CH0H), x 5.20 and x 5.38 12 14 (two broad singlets, X=C H 2 ) , x 8.14 (poorly resolved doublet, -C H 3 > 13 J = 1 Hz), x 8.29 (unresolved multiplet , -C H 3 ) , and x 8.94 (singlet, - C 1 5 H 3 ) -Dehydrogenation of the hydroxymethylene derivative 198 with 2,3-dichloro-5,6-dicyanobenzoquinone (101) i n dioxane for 10 minutes afforded the corresponding 2-formyl cross-conjugated dienone 199 in 79% y i e l d . Again, the spectral data were in complete agreement with the assigned structure. Of note was the appearance, in the n.m.r. spectrum, of a singlet at x -0.27 - 79 -(-CHO) and a singlet at x 2.55 (^C*H). The other assignable signals were similar i n chemical shif t and mul t ipl ic i ty to the corresponding resonances of 198. Conversion of the formyl compound 199 into the corresponding carboxylic acid 200 was achieved by s i lver oxide oxidation (108). The carboxylic acid 200 was a nicely crystal l ine substance and exhibited the expected spectral 199 200 properties. Of note was the change in chemical shift in the n.m.r. spectrum of C - l proton from T 2.55 in the aldehyde 199 to x 1.92 i n the product 200. Irradiation of the carboxylic acid 200 in 45% aqueous acetic acid under conditions similar to those used for compounds 166 and 167, gave, after the appropriate work-up, a high yield of a crude product. Pur i f i ca -tion of this crude material by chromatography on Woelm neutral alumina afforded a highly crystal l ine compound. The latter was identical (infrared, n.m.r. and m.p.) with compound 195 previously prepared. - 80 -The overall y i e l d of the conversion of 169 into 195 v ia the route just described was 32%, obviously a considerable improvement over the f i r s t route. D. Elaboration of the Hydroguaiazulene Derivatives 194 and 195 to 5 -Epi-a-bulnesene _2JL6 and 4-Epi-a-bulnesene 218, Respectively The next phase i n the projected synthesis of a-bulnesene 7_ was concerned with the modification of compounds 194 and 195 which already possessed the required carbon skeleton for a-bulnesene. This modification would include, in each case, the removal of the C4-C5 double bond, removal of the carbonyl function at C-3, and the introduction of the C1-C10 double bond. One obvious method for the removal of the C4-C5 double bond would involve Birch reduction (109) of compounds 194 and 195. Even though, at the outset, i t was f e l t that this method would lead to stereochemical d i f f i c u l t i e s with respect to the C4 and/or C5 positions of the products (see below), i t was nevertheless decided to study the lithium-ammonia reduction of 194 and 195. In part icular , this study was undertaken because very l i t t l e was known regarding the stereochemical outcome of the Birch reduction of systems such as 194 and 195. Also, subsequent modification - 81 -of the products would, presumably, eventually lead to a-bulnesene-type molecules, and the synthetic sequences would therefore provide models for subsequent projected work for the synthesis of a-bulnesene _7_ i t s e l f . It i s well known that Birch reduction (109) can selectively reduce a double bond conjugated to a carbonyl group, in the presence of an isolated double bond. Therefore compound 194 was subjected to Birch reduction with lithium in l iquid ammonia for two hours. The reaction was then quenched with ammonium chloride and, after appropriate work-up, afforded a crude sol id product. The infrared spectrum of the lat ter , which showed no peaks due to an unsaturated carbonyl group, had an absorption at 5.81 u, indicating the presence of a cyclopentanone carbonyl group, and at 3.10 u, due to a hydroxyl group. However, examination of this material by thin-layer chromatography indicated that i t was a mixture of two components. It was fe l t that the reduction product was a mixture of the desired saturated keto alcohol 201 and the undesired d i o l 202. The stereochemistry at 0 4 and C-5 in 201 and 202 w i l l be commented upon later (see below). Attempts to avoid the formation of the d i o l 202 in the Birch reduction were unsuccessful. However, the diol 202 could easily be converted into the keto alcohol 201 by oxidation of the former with chromium trioxide in pyridine (110). 201 202 - 82 -Therefore, in order to avoid any p o s s i b i l i t y for incomplete reduction, compound 194 was completely converted into the diol 202 by quenching the Birch reduction reaction with methanol. The crude product, which was a semi-crystalline material, exhibited, i n the infrared spectrum, a strong hydroxyl absorption at 3.10 y and no absorption i n the carbonyl region. This crude diol 202 was then oxidized with chromium trioxide in pyridine (110) at room temperature to the corresponding keto alcohol 201 which crystal l ized from ether at 0 ° , giving f ine , needle-like crystals . The spectral data obtained from the latter was in complete agreement with structure 201. Thus, the infrared spectrum exhibited a hydroxyl absorption at 2.81 y, a cyclopentanone carbonyl absorption at 5.81 u, and isopropenyl double bond absorptions at 6.12 y and 11.15 y. The n.m.r. spectrum 12 showed signals at T 5.33 (unresolved multiplet , "C=C H^), T 8.30 (poorly 13 15 resolved doublet, -C H^, J = 1 Hz), x 8.82 (sharp singlet , -C H 3 ) , and T 8.95 (doublet, - C 1 4 H 3 , J = 6.5 Hz). In a sequence of reactions similar to that described above, compound 195 was reduced with lithium-ammonia-methanol to give diol 203. The spectral properties, which were very similar to those of compound 202, were in complete agreement with structure 203. - 83 -Compound 203 was subjected to chromium trioxide-pyridine oxidation under conditions very similar to those used for compound 202. The crude product, which resisted c rys ta l l iza t ion , was purif ied by d i s t i l l a t i o n under reduced pressure. The spectral data were similar to those obtained from compound 201, and f u l l y corroborated the structural assignment, 204. 201 The stereochemistry at C-4 and C-5 of the Birch reduction products 201 and 204 was determined by measuring the optical rotatory dispersion (o.r .d. ) curves of these compounds. Reduction of the a,g-unsaturated ketone 194 with lithium-ammonia-methanol, as described above, followed by oxidation of the resulting diol with chromium trioxide in pyridine, could, theoretically , lead to the formation of four possible stereoisomers, 201, 205, 206, and 207. It i s 201 205 - 84 -207 well documented (49,87,111), however, that a 5/7-fused ring system of the type 205 or 206, with a C-4 methyl group trans to the C-5 hydrogen, is thermodynamically unstable. For example, compound 208, when treated with 1% ethanolic potassium hydroxide, readily undergoes epimerization to the more stable epimer 209 (87). Molecular models clearly show that in compounds 0 0 208 209 of the type 205 or 206, the C-4 methyl group is nearly eclipsed with C-6, and the above-mentioned i n s t a b i l i t y can therefore readily be attributed to the resulting steric interaction. In view of the above s t a b i l i t y relationships, one would expect that protonation of the two (theoretically)possible epimeric (at C-5) enolates 210 and 211, i n i t i a l l y formed in the Birch reduction, would result in the - 85 -formation of the thermodynamically more stable isomers 201 and 207 respectively. Therefore, compounds 205 and 206 could be eliminated from 211 207 consideration as possible products from the Birch reduction of 194, and i t was now only necessary to distinguish between the two remaining p o s s i b i l i t i e s , namely 201 and 207. The two isomers 201 and 207 could be distinguished unambiguously by measuring their optical rotatory dispersion curves. It is well known that in the optical rotatory dispersion curves of compounds such as 201 and 207, the sign and amplitude of the Cotton effect depends strongly on the conformation of the cyclopentanone ring (112). Therefore, i t is - 86 -necessary to consider carefully this point. The cyclopentanone ring i n the trans-fused compound 201 is very r i g i d and the octant projection of compound 201 is as shown in 201a. Applying the octant rule (105), compound 201 should 201a show a strong negative Cotton effect curve, since C - l , C-5, and the C-4 methyl group are a l l i n negative octants. The cyclopentanone ring in the cis-fused compound 207 is re la t ively f l e x i b l e . . Sasaki and Eguchi (113) studied a similar 5/7 cis-fused ring system and suggested three possible basic conformations which, in our case, can be represented by 207a, 207b and 207c. Conformation 207a has a very + i H I I I 207a f l a t half-chair or an almost planar cyclopentanone r ing . In this conforma-t ion , the effect of the cyclopentanone ring on the Cotton effect should be very small, since C - l and C-5 l i e almost in a plane. Therefore the chief - 87 -contribution to the Cotton effect should be due to the C-4 methyl group, and a positive Cotton effect curve would be expected. Conformation 207b has a + + 207b half-chair cyclopentanone r ing , which causes C - l and C-5 to l i e in negative octants, and the C-4 methyl group to l i e in a positive octant. The overall Cotton effect would therefore be expected to be weakly positive or weakly negative, depending upon the combined contribution to the Cotton effect of C - l and C-5 relative to the contribution of the C-4 methyl group. H 207c In the conformation 207c, C - l , C-5, and the C-4 methyl group a l l l i e in the positive octants and thus a strong positive Cotton effect curve would be expected. The optical rotatory dispersion curve of the compound obtained from Birch reduction of 194 showed a strong negative Cotton effect curve, - 88 -a = -160 (figure 9) . Clearly this result was consistent only with the reduction product having the structure 201. It ;is pertinent, to point out that compound 110 was reported (113) to have a weakly positive Cotton effect curve with a = +25. 0 110 Using arguments similar to those employed above, the a,B-unsaturated ketone 195, upon Birch reduction, would be expected to give one of the two possible epimers (at C-5) 204 or 212. Compound 212 would be expected to 195 204 212 show a weakly posit ive, a weakly negative or a strongly negative Cotton effect curve, depending upon the predominant conformation of the relat ively f lexible cis-fused cyclopentanone r ing . On the other hand, compound 204 would be expected to show a strong positive Cotton effect curve. The optical - 89 -I o o - 1 — i 1 — — 1 1 1 2 0 0 250 3 0 0 350 4 0 0 mjuu Figure 9. O.R.D. Curves of Compounds 201 and 204 - 90 -rotatory dispersion curve of the compound obtained from the Birch reduction of compound 195 exhibited a strongly positive Cotton effect curve, a = +147 (figure 9). Thus the stereochemistry of the product was correctly assigned as represented by 204. It is relevant to mention that dihydro-torilolone 213 (104) and dihydrogeigerin 214 (114) both exhibited positive Cotton effect curves. The molecular amplitude for the latter compound was reported to be +56. The work described above had clearly indicated that, insofar as the synthesis of a-bulnesene 7_ was concerned, the Birch reduction of the keto alcohols 194 and 195 had given products (201 and 204, respectively) with the incorrect stereochemistry at C-5 and C-4, respectively. However, in order to f u l l y corroborate t h i s , and to provide model studies for the projected synthesis of a a-bulnesene 1_, i t was decided to convert the keto alcohols 201 and 204 into a-bulnesene-type compounds. ; Huang-Minion reduction (115) of keto alcohol 201 was accomplished by treating the latter with excess hydrazine hydrate and base in refluxing aqueous diethylene g lycol . Purification of the crude product by recrysta l l iza-tion afforded colourless needle-like crystals , the spectral properties of which were in complete accord with structure 215. Of note was the lack, in 213 214 - 91 -201 215 the infrared spectrum, of a cyclopentanone carbonyl absorption at 5.81 y. Also, in the n.m.r. spectrum, the doublet (T 9.05) due to the C-4 methyl group was moved upfield by 0.1 p .p .m. , relative to the corresponding signal (x 8.95) in compound 201. Dehydration of alcohol 215 with thionyl chloride in pyridine at 0° afforded a mixture of d e f i n e s , the major component (78%) of which was isolated by preparative gas-l iquid chromatography. The spectral data of this component was in f u l l accord with the assigned structure 216, 5-epi-a-bulnesene. Thus, the infrared spectrum exhibited absorptions at 6.11 y and 11.00 y, due to the terminal methylene of the isopropenyl group. The n.m.r. 12 spectrum (figure 10) showed signals at x 5.34 (unresolved multiplet , ^C=C H„) , 216 - 93 -13 15 T 8.28 (unresolved multiplet , -C H^), T 8.33 (unresolved multiplet , -C H^), 14 i 9.05 (doublet, -C H^, J = 5.5 Hz). Compound 216 showed a positive plain o . r . d . curve. In a sequence of reactions similar to that described above, keto alcohol 204 was converted into 4-epi-a-bulnesene 218. Thus compound 204 was subjected to Huang-Minion reduction (115), to give the alcohol 217., The spectral data of the latter were very similar to those of compound 215, and were in complete agreement with the assigned structure. 204 217 Thionyl chloride-pyridine dehydration of 217 gave essentially two products in approximately .equal amounts. These were separated and purified by means of preparative g . l . c . The component of shorter retention time exhibited spectral properties consistent with structure 218, 4-epi-a-bulnesene. 218 - 94 -Thus, the infrared spectrum showed strong absorptions at 6.11 u and 11.32 u. The n.m.r. spectrum (figure 11) had signals at x 5.38 (unresolved multiplet , - C = C 1 2 H 2 ) , x 8.31 (poorly resolved doublet, - C 1 3 H 3 , J = 1.5 Hz), x 8.34 (poorly resolved m u l t i p l e t , - C 1 5 H 3 ) , x 8.99 (doublet, - C 1 4 H 3 , J = 6 Hz). The 13 15 chemical shifts assigned to the v i n y l i c methyl groups (-C H 3 and -C H 3) were confirmed by a frequency-swept decoupling experiment in which the o l e f i n i c protons at C-l2 were strongly irradiated, whereupon the multiplet a t x 8.31 collapsed to a strong, sharp singlet . Compound 218 showed a negative p l a i n o . r . d . curve. The second component isolated from the dehydration mixture had spectral characteristics consistent with structure 219. Thus, the infrared spectrum showed absorptions at 6.11 u and 11.33 u due to the isopropenyl group., The i I 219 n.m.r. spectrum (figure 12) showed, in addition to three 3-proton signals, at x 8.32 (unresolved multiplet , two vinyl methyl groups) and x 9.06 (doublet, - C 1 4 H 3 , J = 6 Hz), a broad t r i p l e t at x 4.45 ( ^ C 9 H , J = 7 Hz). The infrared spectra of 5-epi-a-bulnesene 216 (figure 13) and 4-epi-a-bulnesene 218 (figure 14) were different from the corresponding spectrum of a-bulnesene 7_ (figure 15) obtained by dehydration (thionyl chloride-pyridine) - 95 -. . . . I . . . . I . . . . I . . . . I . . . . . ^ . . . I . . . . . . . . . I . . . . . . . . . I . . . . I . . . . I . . . . I . . . . I . . . . I . I • 1 2 3 4 5 6 7 8 9 10T Figure 12. N.M.R. Spectrum of Compound 219. TO c 3 l-i Q O r+ O H i O l I cn i s I c I— (D </) 0 3 fl> K ) t—» ON ,2000 1900 1800 1700 1600 1500 1400 1300 1200 1100 1000 900 800 700 L6 Figure 14. Infrared Spectrum of 4-Epi-a-bulnesene 218. - 100 -* of authentic bulnesol 5_1 . Furthermore, the g . l . c . retention times of both 5-epi-a-bulnesene 215 and 4-epi-a-bulnesene 218 were different from those of a-bulnesene 7. . 51 7 III. Synthesis of a-Bulnesene 7_ The synthetic sequence involved in the conversion of compounds 194 and 195 into 5-epi-a-bulnesene 216 and 4-epi-a-bulnesene 218, respectively, revealed the fact that lithium-ammonia reduction of the C4-C5 double bonds of * We are very grateful to Professor G. Chiurdoglu for a generous sample of authentic bulnesol. - 101 -195 218 194 and 195 stereoselectively gave products possessing a cis stereochemistry with respect to the C-4 methyl group and the C-5 hydrogen. Obviously, this was undesirable insofar as the synthesis of a-bulnesene was concerned, since, in a-bulnesene 7_, the C-4 methyl group is trans to the C-5 hydrogen. In this connection, i t is pertinent to point out that Barton e t . a l . . (87) and White e t . a l . (49) reported that catalytic hydrogenation of compounds 108 and 143 gave compounds 109 and. 208, respectively, as the only products. Therefore, one solution to the stereochemical problem involved in the removal of the C4-C5 double bond of compound 194 would be to reduce this double bond by catalytic hydrogenation. It was obvious, however, that, selective catalytic hydrogenation of C4-C5 double bond would be impossible - 102 -143 R = H 208 R = H in the presence of the terminal double bond present in the C-7 isopropenyl side chain. It was therefore necessary to modify the C-7 side chain in such a way that the isopropenyl group could be generated at a later stage in the synthesis. We chose the keto diester 220 as the appropriate inter-mediate for this purpose. 220 C00CH3 The keto diester 220 was obtained from the previously prepared keto ester 176 (see page 52 ). Photolysis of the latter in 45% aqueous acetic acid, under conditions similar to those used for compound 192 (see page 69 )_ gave a crude photolysis product which, upon purif icat ion by means of column chromatography on alumina, afforded, in addition to the desired compound 221 - 103 -(79% y i e l d ) , a small amount (10%) of the spiro compound 222. The spectral properties of these compounds were in complete accord with the assigned structures. Thus, the infrared spectrum of the spiro compound exhibited a hydroxyl absorption at 2.95 y, an ester carbonyl absorption at 5.94 y and < an a,g-unsaturated carbonyl absorption at 6.32 y. The n.m.r. spectrum (figure 16) showed a typical AB pair of doublets for the protons at C - l and C-2: x 2.30 (doublet, ^ ^ H ) and T 3.87 (doublet, ^ C 2 H , J = 6 Hz). Other 4 signals appeared at T 6.40 (singlet, -C00CH 3), T 7.36 (quartet, $C H, J = , 13 14 7.5 Hz), x 8.87 (doublet, -C H J = 6.75 Hz), T 8.90 (doublet, -C H 3 , J = 7.5 Hz), and T 8.96 (singlet, - C 1 5 H 3 ) . The desired 5/7-fused compound 221 also showed the expected spectral characteristics. The infrared spectrum showed a hydroxyl absorption at 2.93 y. The absorptions due to the ester carbonyl and a,3-unsaturated carbonyl were found at 5.82 y and 5.95 y, respectively. The n.m.r. spectrum (figure 17) showed signals at T 6.37 (singlet, -C00CH ) , T 8.37 (doublet, - C 1 4 H 3 , J = 1 Hz), T 8.83 (doublet, - C 1 3 H 3 , J = 7 Hz), and T 9.13 (singlet, - C 1 5 H 3 ) . The optical rotatory dispersion curve of this compound showed a strong positive Cotton effect curve (a .= +364) which was superimposable on the o . r . d . curve of isophotosantonic lactone 143, of known absolute. Figure 17. N.M.R. Spectrum of Compound 221 - 106 -stereochemistry (67,68,87). Therefore, the stereochemistry at C - l of compound 221 was f u l l y corroborated. 0 143 Acetylation of compound 221 with hot acetic anhydride and sodium acetate gave the keto diester 220 which showed the expected spectral characteristics. Of note was the appearance, in the n.m.r. spectrum, of a strong singlet at T 8.04, due to the acetyl methyl group. Catalytic hydrogenation of the acetate 220 with 10% palladium on charcoal in 95% ethanol at room temperature and atmospheric pressure afforded the saturated keto diester 223 in 85% y i e l d . Since compound 223 was thermodynamically unstable, i t was subjected to further reaction without puri f ica t ion . However, the spectral properties of this crude product were in f u l l accord with the structure assigned. Thus, the infrared spectrum - 107 -showed a strong absorption at 5.80 u, due to the saturated carbonyl groups. The n.m.r. spectrum exhibited five 3-proton signals, at T 6.44 (singlet, -C00CH 3), T 8.00 (singlet, -C0CH 3), T 8 . 5 5 (singlet, - C 1 5 H 3 ) , T 8.96 and T 9.05 (doublets, J = 7 Hz, 6 Hz, respectively, secondary methyls). The stereochemistry of the hydrogenation product 225, with respect to the C-4 methyl group and the C-5 hydrogen, was based p a r t i a l l y upon analogy. As noted before, catalytic hydrogenation of systems similar to that of compound 220, gave, in each case, only one compound, with the C-4 methyl group g-oriented and the C-5 hydrogen a-oriented (see page 101 ). In addition we obtained independent evidence that structure 225 does, in fact , correctly represent the stereochemistry of the hydrogenation product, by measuring i t s o . r . d . curve. Hydrogenation of the C4-C5 double bond of compound 220 could, theoreti-c a l l y , give r ise to four possible stereoisomers 225, 224, 225 and 226.* Compounds 224 and 225 would, presumably, result from cis addition of hydrogen (from the a and the g-side, respectively), followed by epimerization at C-4. - 108 -0 H 225 0=3 226 Applying the octant rule (105) and considering also the various possible conformations of the cyclopentanone ring of the cis-fused systems 223 and 224 (113), the sign and magnitude of the o . r . d . curve of each of these compounds could be predicted (for an analogous detailed analysis, see page 86 ). Compound 223 would be expected to show a strongly negative or weakly negative or weakly positive Cotton effect curve, depending upon the preferred conformation of the relat ively f lexible cis-fused cyclopentanone r ing. Compound 224 would be expected to show a strongly positive or weakly positive or weakly negative Cotton effect curve, again depending upon the. preferred conformation of the five-membered r ing . Compound 225, which is . conformationally r i g i d with respect to the cyclopentanone r ing , would be expected to show a strongly negative Cotton effect curve. F i n a l l y , compound 226 would be expected to show either a weakly positive or a weakly negative Cotton effect curve. The o . r . d . curve of the compound obtained from hydro-genation of 220 showed a strongly negative Cotton effect , a = -232. Therefore only compounds 223 and 225 were consistent with this observation. The two isomers 225 and 225 could be distinguished by subjecting the hydrogenation product to conditions (1% methanolic potassium hydroxide) - 109 -which would cause expimerization at the C-4 posi t ion, adjacent to the cyclo-pentanone carbonyl. If the hydrogenation product had structure 225, one would expect no epimerization to take place, since compound 225, possessing cis stereochemistry with respect tolthe C-4 methyl group and the C-5 hydrogen, should be thermodynamically much more stable than the epimer 226 (see page 84 ). On the other hand, compound 223, having trans stereochemistry with respect to the C-4 methyl group and the C-5 hydrogen, should be thermodynamic cal ly less stable than the corresponding epimer 224. Therefore, i f the hydrogenation product had structure 223, one would expect that treatment of this product with methanolic hydroxide ion would result in par t ia l or complete epimerization to give compound 224 (for an analogous example,, see page 84 )• This epimerization (223 —> 224) would be accompanied by a change in the magnitude (and, possible, the sign) of the Cotton effect curve. A small sample of the product obtained from the hydrogenation of 220 was treated with 1% methanolic potassium hydroxide at room temperature. Purification of the crude product by column chromatography on alumina gave a clear o i l which was shown by analytical data and by n.m.r. spectrum to consist largely of a compound epimeric with the starting material. A small amount of the latter was also present. The o . r . d . curve of this material showed a weakly negative Cotton effect curve, a = -17.4. This result f u l l y supported the proposal that the structure and stereochemistry of the product obtained from the hydrogenation of compound 220 Was correctly represented by 223. Reduction of the crude ketone 223 with sodium borohydride in methanol gave a mixture of epimeric alcohols 227 and 228. An analytical sample of the - 110 -mixture of the two epimers, obtained by d i s t i l l a t i o n of the crude material under reduced pressure, gave the expected spectral characteristics. The epimeric mixture of the alcohols 227 and 228, upon treatment with £ - to luenesulfonyl chloride in dry pyridine gave the tosylate 229 in 20% yie ld and the o l e f i n 230 in 55% y i e l d . The tosylate, which was isolated from the crude product mixture by means of column chromatography, was unstable and decomposed upon prolonged standing at room temperature or upon warming to 35-40° in vacuum. However, the spectral data obtained from the freshly isolated material was in complete accord with structure 229. The n.m.r. spectrum (figure 18) exhibited an AB pair of doublets for the aromatic protons: T 2.24 (doublet, H & and H & 1 ) T 2.70 (doublet, H^ and H ^ , , Figure 18. N.M.R. Spectrum of Compound 229. - 112 -3 J = 8 Hz). In addition, there appeared a multiplet at T 5.60 ( >C H), and six 3-proton signals, at x 7.60 (singlet, aromatic methyl), x 8.05 (singlet, -C0CH 3), x 8.64 (singlet, - C 1 5 H 3 ) , x 8.97 and x 9.23 (two doublets,secondary methyls, J = 6.9 Hz, 6.8 Hz, respectively). The spectral properties of the o l e f i n , which was also isolated by column chromatography, were in complete agreement with structure 230. Of particular pertinence was the appearance, in the n.m.r. spectrum (figure 19) of an o l e f i n i c resonance signal at x 4.77 (broad signal , width 3 at half-height = 7 Hz, _ .^C H). Other assignable signals were at x 6.38 (singlet, -C00CH 3), x8.02 (singlet, -C0CH 3),x 8.37 (doublet, - C 1 4 H 3 , J = 1.5 Hz), x 8.55 (singlet, - C 1 5 H 3 ) , and x 8.95 (doublet, - C 1 3 H 3 > J = 7 Hz). The chemical shifts assigned to _?.C3H and -C^H^ were confirmed by a frequency-swept decoupling experiment i n which the proton at C-3 was strongly irradiated, thus eliminating a l l y l i c coupling between ^ C 3 H and - C ^ H . ^ , and causing the signal at x 8.37 to sharpen. The o l e f i n 230 can be thought to arise by the base-promoted trans elimination of £ - t o l u e n e s u l f o n i c acid from the i n i t i a l l y formed B-tosylate 231. This elimination would alleviate the steric interaction between the TsO C00CH 231 - 114 -tosylate group and the C-4 methyl group. It should be noted that an observation similar to the one above had been made by White and Marx (49). Thus, these workers found that reduction of ketone 109 with sodium boro-hydride gave two alcohols, one 111 of which gave, upon treatment with methanesulfonyl chloride and pyridine, the unsaturated compound 114. The 109 111 114 formation of the o lef in 230 as the major product from the tosylation of the epimeric mixture of alcohols 227 and 228 reflected the fact that compound 227 (B-alcohol) was the major component in the epimeric mixture. Although hydrogenation of o l e f i n 230 over Adam's catalyst gave a product consisting of a mixture of epimers, hydrogenation of 230 i n benzene in the presence of the homogeneous catalyst tris(triphenylphosphine)chlororhodium (94-98) was completely stereoselective and afforded, in 85% y i e l d , the diester 232. The infrared spectrum of compound 232 showed an ester carbonyl - 115 -absorption at 5.84 u . The n.m.r. spectrum (figure 20) showed five 3-proton signals, at T 6.37 (singlet, -COOCHp, T 8.01 (singlet, -C0CH 3), T 8.57 15 (singlet, -C H 3 ) , T 8.94 and 9.11 (two doublets, secondary methyls, J = 7 Hz, 6.4 Hz, respectively). Even though the spectral data agreed well with the structure 232, and even though i t was f e l t that the hydrogenation of the o l e f i n 230 would take place preferentially from the a-side of the molecule, i t should be noted that the configuration at C-4 of the product 232 was somewhat uncertain at this stage. However, the homogeneity of this diester 232 was ascertained by thin-layer chromatography and by the n.m.r. spectrum, which clearly showed that only two methyl doublets (r 8.94 and r 9.11) were present in the molecule. . The stereochemistry at C-4 in the diester 232,was ascertained by conver-sion of this compound, by lithium aluminum hydride reduction, into the crystall ine d i o l 233. The same crystal l ine diol 233, was also obtained by lithium aluminum hydride reduction of the diester tosylate 229. Since the stereochemistry at C-4 of the latter compound was known (see page 110), this - 117 -clearly established that the diester 232 had the assigned stereochemistry with respect to this center. The n.m.r. spectrum of the d i o l 233 showed signals at x 6.27-6.72 12 15 (septet, -C H_2OH, AB part of a ABX system), x 8.85 (singlet, -C H^), x 9.10 and x 9.19 (two doublets, secondary methyls, J = 6.3 Hz, 6.8 Hz, respectively). Treatment of the diol 233 with methyl chloroformate in dry pyridine gave the corresponding monocarbonate 234. The spectral properties of the monocarbonate f u l l y corroborated the structural assignment. Thus, the infrared spectrum showed a strong hydroxyl absorption at 2.94 y and an absorption due to the ester carbonyl at 5.76 y. The n.m.r. spectrum showed 12 an octet at x 5.81-6.19 (>C H 2 , AB part of an ABX system), a singlet at x 6.25 (-0CH 3), a singlet at x 8.85 ( - C 1 5 H 3 ) , and two coincident doublets at x 9.12 ( - C 1 3 H 3 and - C 1 4 H 3 , J = 6.5 Hz). Dehydration of the monocarbonate 254 with thionyl chloride in pyridine afforded the olef in 235,'which was contaminated with a small amount of two double-bond isomers. Compound 235 exhibited the expected spectral characteristics. Of note was the lack, in infrared spectrum, of a hydroxyl - 118 -0 II CH OCOCH 235 absorption; and the appearance, in n.m.r. spectrum, of a strong vinyl methyl signal at x 8.39. Pyrolysis of the unsaturated monocarbonate 235 under conditions similar to those used for compound 190 (see page 65 ) gave a mixture of o lef ins , the major component of which exhibited a gas-l iquid chromatographic retention time identical with that of a-bulnesene 1_. Isolation of this component by preparative g . l . c . gave pure a-bulnesene _ which showed the following spectral properties. The infrared spectrum (figure 21) showed strong absorptions at 6.11 y and 11.38 y, due to the isopropenyl group. The n.m.r. spectrum (figure 22) showed signals at T 5.37 (unresolved multiplet , 1 1 IT >C=C H 9 ) , T 8.31 (unresolved multiplet , -C H_), x 8.34 (unresolved 7 - 121 -multiplet , - C 1 5 H _ ) , and-x.-9.il (doublet, - C 1 4 H 3 , J = 6.5 Hz). The a-bulnesene thus prepared exhibited spectra (infrared, n.m.r.) and gas-liquid chromatographic retention times identical with those of authentic a-bulnesene, obtained by dehydration (thionyl chloride in pyridine) of authentic bulnesol 51_. It should be noted that synthetic and authentic a-bulnesene also gave identical negative plain optical rotatory dispersion curves, thereby corroborating the proposed absolute configuration of the latter compound. EXPERIMENTAL Melting points, which were determined on a Kofler block, and boil ing points are uncorrected. The infrared spectra were recorded on either a Perkin-Elmer Infracord model 137, a Perkin-Elmer model 21 or a Perkin-Elmer model 421 spectrophotometer. The latter instrument was employed for a l l comparison spectra. Ultraviolet spectra were measured i n methanol solution on either a Cary 14 spectrophotometer or a Perkin-Elmer model 202 u l t r a v i o l e t - v i s i b l e spectrophotometer. Nuclear magnetic resonance (n.m.r.) spectra were taken in deuteriochloroform solution on either a JEOLCO C-60H spectrometer, a Varian Associates model A-60 spectrometer, or a Varian Associates model HA-100 spectrometer, decoupling experiments being performed with the latter instrument. Line positions are given in the Tiers x scale, with tetramethylsilane as an internal standard; the multi -p l i c i t y , integrated peak areas, and proton assignments are indicated in parentheses. The optical rotatory dispersion measurements were performed on a JASCO model ORD/UV-5 instrument. Mass spectra were recorded on an AEI, type MS-9, mass spectrometer. Gas-liquid chromatography (g . l . c . ) was carried out on an Aerograph Autoprep, model 700. The following columns (10 f t x 1/4 in . ) were employed, with the inert , supporting material being 60/80 mesh Chromosorb W in each case: column A, 20% FAAP; column B, 20% - 123 -SE 30; column C, 20% carbowax; column D, 30% SE 30; column E 20% Apiezon J . The specific column used, along with the column temperature, are indicated in parentheses. The carrier gas (helium) flow-rate was 90-100 ml/min i n each case. S i l i c a gel G and Woelm neutral alumina containing 2% by weight of .a fluorescent indicator (electronic phosphor) were used for thin-layer chromatoplates. Aqueous potassium permanganate solution 10% was used as a spraying reagent. Column chromatography was preformed using neutral Woelm s l i c a gel or neutral Woelm alumina. The latter was deactivated as required by addition of the correct amount of water. In cases where basic Shawinigan alumina was used, 10% aqueous acetic acid was used for deactivation. Microanalyses were performed by Mr. P. Borda, Microanalytical Laboratory, University of Bri t ish Columbia, Vancouver. (+)-Dihydrocarvone 171 The procedure employed was similar to that reported by Yoshida (85). To a solution of 1-carvone 170 (10 g) in 375 ml of ethanol was added zinc dust (75 g) and a solution of sodium hydroxide (37.5 g) in 150 ml water. The resulting mixture was heated under reflux for 5 h with vigorous s t i r r i n g . The ethanol was d i s t i l l e d off and the residue was subjected to steam d i s t i l l a t i o n . The d i s t i l l a t e was extracted thoroughly with ethyl ether. The extract was dried over anhydrous sodium sulfate. Removal of solvent, followed by d i s t i l l a t i o n , under reduced pressure, of the residual o i l , gave 16 g (53%) of (+)-dihydrocarvone 171 as a colourless o i l , b .p . 67-68° at 2 mm; l i t . b . p . 100-104° at 12 mm (85). Infrared (f i lm), \ 5.85, 6.-10, r max ' ' 11.20 y; n.m-.r., T 5.30 (unresolved multiplet , >C=CH ), 8.26 (singlet, 3H, - 124 -vinyl methyl), 8.95 (doublet, 3H, secondary methyl, J = 6.5 Hz). Preparation of (-)-7-Epi-a-cyperone 169 and (+)-a-Cyperone 168 by Robinson Annelation The procedure employed was similar to that give by Howe and McQuillin (84). To a solution of (+)-dihydrocarvone 171 (45 g) in 400 ml of anhydrous ethyl ether was added commercial sodium amide (13 g). To this mixture was added slowly a solution of l-diethylamino-3-pentanone methiodide (86 g), [prepared by reaction of l-diethylamino-3-pentanone (45 g) with methyl iodide (41 g)] in 90 ml of dry pyridine. The reaction mixture was s t i r red at 0° for 6 h and then refluxed for 5.5 h. Water (200 ml) was then added and the mixture was extracted with ether. The ether extract was washed with water and dried over anhydrous sodium sulfate. Removal of the solvent, afforded a reddish-brown o i l which was subjected to fractional d i s t i l l a t i o n under reduced pressure. The i n i t i a l fractions (10 g, b .p . 85-100° at 0.7 mm) consisted largely of the starting material, (+)-dihydro-carvone 171. The later fractions (44 g, b . p . 130-160° at 0.75 mm) consisted of an o i l which s o l i d i f i e d on standing. Recrystallization of the above solidified material from n-hexane gave the pure ketol 172 (16 g), m.p. 1 0 7 - 1 0 8 ° ; l i t . m.p. 106° (84). Infrared (CHC1 ), X 2.96, 5.92, 6.14, 11.28 y; n .m.r . , x 5.35 (unresolved multiplet , 2H, >C=C 1 2H 2), 8.33 (doublet, 3H, - C 1 4 H 3 > J = 1 Hz), 8.77 (singlet, 3H, - C 1 5 H 3 ) , 8.97 (doublet, 3H, - C 1 3 H 3 , J = 6.5 Hz). The ketol 172 (8.25 g) was dissolved in 85 ml of 10% ethanolic potassium hydroxide and the resulting solution was heated under reflux in a nitrogen atmosphere for 9.5 h. The cooled solution was diluted with water (40 ml) - 125 -and neutralized with 3 N hydrochloric acid. The resulting mixture was extracted with ether. The extract was dried over anhydrous sodium sulfate. Removal of the solvent, followed by d i s t i l l a t i o n of the residual o i l under reduced pressure, gave 7.5 g (90%) of (-)-7-epi-a-cyperone 169, b .p . 115-120° at 0.3 mm; l i t . b .p . 102-104° at 0.25 mm (84). Ul t raviolet , X 250 my; r v J '• max infrared (f i lm), X 6.05, 6.24, 11.25 y; n .m.r . , T 5.21 and 5.37 (two v • max v broad signals, 2H, >C=CH.2), 8.21 and 8.30 (two poorly resolved multiplets, 6H, v inyl methyls), 8.79 (singlet, 3H, angular methyl). The o i l (26 g) obtained from the mother liquors of the recrystal l izat ion of ketol 172 contained, as shown by i ts infrared spectrum, a small amount of the ketol 172, as well as the a,^-unsaturated ketones 168 and 169. A solution of this material in 10% ethanolic potassium hydroxide was refluxed for 8 h. The work-up procedure was the same as that described above in the dehydration of ketol 172. Purif icat ion of the crude product by d i s t i l l a t i o n gave an epimeric mixture (16 g) of (+)-a-cyperone 168 and (-)-7-epi-a-cyperone 169, in a ratio of approximately 1:2, respectively. A portion of the above epimeric mixture (9.2 g) was treated with hydroxy1-amine hydrochloride (3.15 g) and sodium acetate (2.9 g) in 85 ml of methanol and the solution was refluxed for 4 h. The solution was concentrated somewhat by d i s t i l l i n g off approximately 40 ml methanol. Upon cooling, a white sol id precipitated from the solution. Recrystallization of this so l id material from methanol gave 2.5 g of (+)-a-cyperone oxime 173, as a colourless needles, m.p. 1 5 3 ° ; l i t . m.p. 1 5 0 . 5 ° (84). A solution of the pure oxime (2.5 g) in a mixture of methanol (100 ml) and petroleum ether (b.p. 8 0 - 1 0 0 ° ; 45 ml) was refluxed for 23 h with oxalic acid (5.3 g) and 40% aqueous formaldehyde (26 ml). Water was added and the aqueous layer was - 126 -extracted thoroughly with ether. The combined extracts were washed with water and dried over anhydrous sodium sulfate. Purif icat ion of the crude product by d i s t i l l a t i o n under reduced pressure gave (+)-a-cyperone 168 (2.0 g), b .p . 120-125 at 0.3 mm; l i t . b .p . 96 -97° at 0.2 mm (84). Ultra-v i o l e t , X 250 mp; infrared (f i lm), X 6.0, 6.22, 11.2 y; n .m.r . , x 5.23 max max 12 (unresolved multiplet , 2H, >^C=C H^)^ 8.23 (unresolved multiplet , 6H, two vinyl methyls), 8.78 (singlet, 3H, angular methyl).' This compound was identical with authentic (+)-a-cyperone, a sample of which was obtained from Dr. Sukh Dev. (-)-Epi-a-santonin 174 This compound was prepared by a procedure similar to that described by Ishikawa (88). • • (-)-a-Santonin 107 (100 g) was dissolved in 1 l i t e r of anhydrous dimethyl-formamide containing 5% anhydrous hydrogen chloride. The resulting solution was heated to 85 -90° for 3.5 h, and then allowed to stand at room tempera-ture overnight. The solution was diluted with 750 ml of water, and then extracted thoroughly with chloroform. The combined extracts were washed thrice with saturated brine,once with saturated sodium bicarbonate solution, once with water, and then evaporated under reduced pressure. Removal of the dimethylformamide remaining in the residual material was effected by d i s t i l -lation under reduced pressure at 5 0 ° , and the viscous red o i l thus.obtained was purif ied by column chromatography on 750 g of ac t ivi ty II Shawinigan alumina. Elution with 3 l i t e r s of benzene gave a crystal l ine sol id which, upon recrystal l izat ion from ethyl acetate, afforded 63 g (63%) of l ight -yellow blocks. Recrystallization of a small amount of this material gave an analytical sample of (-)-6-epi-q-santonin 174, m.p. 1 0 3 - 1 0 4 ° ; [a]j;3 -308° - 127 -(c, 0.9 i n methanol); l i t . m.p. 1 0 2 - 1 0 5 ° , [ a ] p ° -311 (c, 1.5 i n ethanol) (89). Ul t raviolet , X 246 my (e = 14,100); infrared (nujol), X 5.68, iricix ni3.x 6.04, 6.19, 6.25 y; n .m.r . , T 3.26 (doublet, IH, ^C^H) , 3.80 (doublet, IH, ^ C 2 H , J_ 2 = 1 0 H z)> 4 - 4 6 (doublet, IH, ^ C 6 H , J & y = 4.5 Hz), 7.45 (quartet IH, ^ C 1 1 H , J n 1 3 = 8 Hz), 7.96 (singlet, 3H, - C 1 4 H 3 ) , 8.62 (doublet, 3H, - C 1 3 H 3 , J n 1 3 = 8 Hz), 8.72 (singlet, 3H, - C 1 5 H 3 ) ; optical rotatory dispersion, [$] 2 y 4 -14,160 (trough), |>]_52 °> [^228 + 1 7 > 3 1 0 (P e a k ) (c> 0.08 in methanol). Preparation of Keto Acid 175 This compound was prepared by a procedure similar to that used by Nakazaki and Naemura (89) for the hydrogenolysis of (-)-6-epi-g-santonin. To a solution of (-)-6-epi-a-santonin 174 (21 g) in 500 ml of methanol was added 25 ml of glacial acetic acid and 50 g of zinc dust. The resulting mixture was refluxed gently for 15 min under an atmosphere of nitrogen, cooled, and f i l t e r e d . The f i l t r a t e was evaporated under reduced pressure to a volumn of approximately 250 ml. Addition of ethyl ether (100 ml) caused the formation of a white precipitate, which was removed by f i l t r a t i o n , The f i l t r a t e was made basic by addition of saturated sodium bicarbonate solution and extracted thoroughly with ether. The aqueous layer was ac idif ied with 2 N hydrochloric acid and the resulting mixture was extracted thrice with ether. The combined ether extracts were washed with water and dried over anhydrous sodium sulfate. Removal of solvent gave 18 g (85%) of a viscous yellow o i l . This crude keto acid 175 was not purif ied further, but exhibited the following expected spectral properties: u l t rav io le t , ^ m a x 240 my; infrared (f i lm), X 2.95-3.95 (very broad), 5.85, 6.05, 6.24 y; - 128 -n .m.r . , T 3.32 (doublet, IH, ^ H ) , 3.79 (doublet, IH, ^ C 2 H , J1 2 = 10 Hz), 8.14 (singlet, 3H, - C 1 4 H 3 ) , 8.78 (doublet, 3H, - C 1 3 H 3 , J n 1 3 = 9 Hz), 8.82 (singlet, 3H, - C 1 5 H 3 ) . A 0.5 g sample of the keto acid 175 was dissolved i n ether and treated with an equivalent amount of cyclohexylamine. The precipitated salt was collected by f i l t r a t i o n and recrystall ized twice from acetone, giving, 0.55 g o f colourless crystals , m.p. 1 2 2 - 1 2 4 ° ; u l t ravio le t , X 241 (e = 9,800) Anal. Calcd. for C ^ H ^ C ^ N : C, 72.62; H, 9.51; N, 4.04. Found:, C, 72.48; H, 9.72; N, 4.15. Preparation of Keto Ester 176 The crude keto acid 175 (50 g) obtained as described above, was esteri-fied by treatment with excess ethereal diazomethane at 0 ° . The crude material was puri f ied by d i s t i l l a t i o n under reduced pressure, affording 40 g (76%) of keto ester 176 as a clear, pale yellow o i l , b . p . 164-167° at o n o ? 0.25 mm, 1.5252,' [ a ] " -99° (c, 0.8 in methanol). Ultraviolet , X m a x 240 my.( e = 10,900); infrared (fi lm), X 5.84, 6.08, 6.18, 6.24 y; n.m.r. T 3.32 (doublet, IH, .^C 1 H), 3.82 (doublet, IH, ^ C 2 H , J = 10 Hz), 6.32 (singlet, 3H, -C00CH 3), 8.12 (singlet, 3H, - C 1 4 H 3 ) , 8.78 (doublet, 3H, - C 1 3 H 3 , J 1 1 1 3 = 7 Hz), 8.79 (singlet, 3H, - C 1 5 H 3 ) ; optical rotatory dispersion, [$]_g2 -8,800 (trough), [^H2 0, t * ] 2 , ^ +18,680 (peak) (c, 0.013 in methanol). Anal. Calcd. for C ^ H ^ O , : C, 73.25; H, 8.45; mol. wt., 262. Found: C, 73.21; H, 8.55; mol. wt., 262 (mass spectrometry). - 129 -Preparation of Keto Ester 184 To a solution of compound 176 (12 g) in 200 ml of dry benzene was added a solution of 2.4 g of tris(triphenylphosphine)chlororhodium (94-98) i n 250 ml of dry benzene. The resulting solution was subjected to hydrogenation at room temperature and atmospheric pressure. After one equivalent of hydrogen had been absorbed (approximately 9 h) the rate of hydrogenation decreased markedly. The solution was f i l t e r e d through a column of 450 g of ac t ivi ty II Shawinigan alumina, and the column was washed with 2 l i t e r s of ether. Evaporation of the combined f i l t r a t e and washings afforded a reddish-brown o i l which, upon d i s t i l l a t i o n under reduced pressure, gave 11.6 g (96%) 20 of keto ester 184 as a clear, colourless o i l , b .p. 150° at 0.1 mm, n^ 1.5138, [a]D +115° (c, 0.2 in methanol); l i t . b . p . 135-140° (bath temperature) at 0.1 mm, [a]D +90° (c, 1.04 in CHC13) (99). Ultraviolet , X m a x 248 (e = 14,400); infrared (f i lm), A 5.84, 6.07, 6.24 p; n .m.r . , T 6.34 (singlet, 3H, max 14 15 -C00CH 3), 8.27 (doublet, 3H, -C H J = 1 Hz), 8.80 (singlet, 3H, -C ^ RJ, 13 8.81 (doublet, 3H, -C H 3 > J ^ j 3 = 7 Hz); optical rotatory dispersion [ $ ] ^ 4 +22,470 (peak), {§]fu 0, [ S ] 2 ^ -17,020 (trough) (c, 0.008 in: methanol). , Anal. Calcd. for C.^H-.O • C, 72.69; H, 9.15; mol. wt.,264. Found: C, 72.80; H, 8.82; mol. wt. , 264 (mass spectrometry). Lithium Aluminum Hydride Reduction of Keto Ester 184 To a st irred mixture of lithium aluminum hydride (7.0 g) in 700 ml of anhydrous ether was added slowly a solution of keto ester 184 (11.0 g) in 300 ml of anhydrous ether. The resulting mixture was refluxed under an - 130 -atmosphere of dry nitrogen for 4 h, and then cooled to 0 ° . After the excess lithium aluminum hydride had been destroyed by dropwise addition of 50 ml of acetone, ice-cold water (300 ml) was added and the resulting mixture was st i rred for 30 min and then f i l t e r e d . The inorganic salts were washed thoroughly with ether. The organic and aqueous layers of the f i l t r a t e were separated, and the aqueous layer was extracted twice with ether. After the combined ether layer and washings had been dried (anhydrous sodium sulfate) , the solvent was removed under reduced pressure, giving 9.6 g (97%) of a white crystall ine s o l i d . Examination of this material by thin-layer chromotography (Woelm neutral alumina plates, developed with 2:1 ethyl, acetate-chloroform) indicated that i t was a mixture of two compounds. . A 1.0 g sample of the crystal l ine material was subjected to column chromatography on act ivi ty II Shawinigan alumina (50 g). Elution with 300 ml of benzene, 150 ml of 1:1 benzene-chloroform and 150 ml of chloroform gave 680 mg of the diol 185. Recrystallization from methanol-ether gave 25 material with m.p. 1 2 7 . 5 - 1 2 9 ° , [aj^ +13° (c, 0.8 in methanol); infrared (KBr), A 3.08, 6.12 y; n .m.r . , T 5.90-6.12 (unsymmetrical t r i p l e t with peaks at x 5.95, 6.01, and 6.08, IH, $C 3 H, total width at half-height. = : 15 Hz), 6.27-6.70 (septet, 2H, >C 1 2HAHg with H^ at x 6.43 and Hg at x 6.56, J . _ = 10.5 Hz, J . = 6.4 Hz, J . „ = 7.1 Hz), 8.31 (broad singlet , 3H, A, D A, II ts, II - C 1 4 H 3 ) , 8.95 (singlet, 3H, - C 1 5 H 3 ) , 9.06 (doublet, 3H, - C 1 3 H 3 , J n 1 3 = 6.5 Hz). Anal. Calcd. for C l r H o ^ 0 „ : C, 75.58; H, 10.99; mol. wt. , 238. Found: lb zo 2 C, 75.52; H, 10.85; mol. wt., 238 (mass spectrometry). Further elution in the above chromatography with 150 ml of chloroform and 200 ml of ethyl acetate gave 160 mg of d i o l 186 as a white s o l i d . - 131 -Rec r y s t a l l i z a t i o n from methanol-ether afforded colourless needles, m.p. 115-116°, [ a ] 2 5 +105°(c, 0.2 i n methanol); infrared (KBr), X 3.11, 6.10 y; L) max n.m.r., x 6.12 (broad s i g n a l , IH, H, width at half-height = 7 Hz), 12 6.24-6.63 (septet, 2H, .>C H^ Hg with H^ at x 6.37 and Kfi at T 6.48, J A fi = 10.8 Hz, J. „ = 5.9 Hz, J D = 6.5 Hz), 8.26 (broad s i n g l e t , 3H, -C 1 4H_), A,11 B, II 5 9.02 (singlet, 3H, -C 1 5H 3), 9.08 (doublet, 3H, -C 1 3H 3 > J n ^ = 6.5 Hz). Anal. Calcd. for C1rH„-0,,: C, 75.58; H, 10.99; mol. wt., 238. Found: I D / D Z C, 75.37; H, 11.06; mol. wt., 238 (mass spectrometry). Preparation of Diacetate 187 A solution of d i o l 185 (300 mg) and freshly d i s t i l l e d acetic anhydride (0.5 ml) i n 2 ml of dry pyridine was allowed to stand at 0° for 15 h. Water (10 ml) was added and the resulting mixture was extracted thoroughly with chloroform. The combined extracts were washed twice with 2 N hydrochloric acid, thrice with water, and dried over anhydrous magnesium sulfate. Removal of the solvent gave a yellow o i l which was pu r i f i e d by chromatography on 15 g of a c t i v i t y II Shawinigan alumina. Elution with 50 ml of 1:1 petroleum ether (b.p. 30-60°)-benzene afforded 360 mg of diacetate 187 as a 25 pale-yellow o i l , n^ 1.4946. Infrared ( f i l m ) , ^ m a x 5.81, 8.08, 9.90 y; n.m.r. x 4.65-4.87 (unsymmetrical t r i p l e t with peaks at x 4.70, 4.76, and 4.83, IH, ^C 3H, t o t a l width at half-height = 15 Hz), 5.84-6.20 (octet, 2H, >C 1 2H AH g with H. at x 5.94 and H D at x 6.05, J. = 11.0 Hz, J. „ = 6.0 Hz, J . = A D A , D A,11 D , l l 6.3 Hz), 7.96 and 7.97 (two si n g l e t s , 6H, two -C0CH3), 8.43 (singlet, 3H, -C 1 4H 3), 8.92 (singlet, 3H, -C 1 5H 3), 9.06 (doublet, 3H, -C 1 3H 3, J n J 3 = 7.0 Hz) Anal. Calcd. for C l gH 0 : C, 70.80; H, 9.38. Found: C, 71.00; H, 9.51. Preparation of Diacetate 188 The diol 186 was converted into the corresponding diacetate 188 by a procedure identical with that described above. From 120 mg of 186 there was 25 obtained 127 mg of 188, as a clear o i l , n^ 1.4918: infrared (fi lm), X 6 ' ' D max 5.82, 8.06, 9.71, 9.90 y ; n .m.r . , T 4.90 (broad signal , 1H,^C 3H, width at half-height=7.5 Hz), 5.81-6.17 (octet, 2H, >C 1 2 H.H D with H. at T 5.93 and A D A H„ at x 6.02, J . = 11 Hz, J . . . = 5.8 Hz, J n n i = 6.9 Hz), 7.96 (singlet, a A , rs A , 11 15,11 6H, two -C0CH 3), 8.40 (singlet, 3H, - C 1 4 H 3 ) , 9.01 (singlet, 3H, - C 1 5 H 3 ) , 9.06 (doublet, 3H, - C 1 3 H 3 , J u ^ = 7 Hz). Anal. Calcd. for C i g H 3 Q 0 4 : C, 70.80; H, 9.38. Found: C, 70.62; H, 9.12 Preparation of Keto Alcohol 189 To a solution of 8.8 g of the mixture of diols 185 and 186 (see page 55 ) in 1 l i t e r of dry dioxane was added 2,3-dichloro-5,6-dicyanobenzo-quinone (lOg) in 500 ml of dry dioxane. The resulting solution was st irred at room temperature for 4 h, and f i l t e r e d . The f i l t r a t e was diluted with 1 l i t e r of ether and then passed through a column of 200 g of Act ivi ty II Shawinigan alumina. The column was washed with 2 l i t e r s of ether and 1 l i t e r of chloroform, and the total eluant was evaporated under reduced pressure. The residual orange gummy material was subjected to column chromatography on act ivi ty II Shawinigan alumina (550 g). Elution with 3 l i t e r s of benzene gave 4.6 g. of keto alcohol 189 as an o i l y , semicrystalline material. Crystal l izat ion of a small sample from ether at 0° gave colourless plates, 20 m.p. 70.5-71 , [a],. +97 (c, 0.26 in methanol). Ultraviolet , X 249 my r- D max (e =• 13,600); infrared (nujol), X 3.00, 6.09, 6.27, 9.78 y; n.m.r. , , ./>;;/ •' < - 133 -T 6.28-6.62 (octet, 2H, > C 1 2 H A H n with H at r 6.41 and H_ at T 6.49, A D A D J A D = 10.3 Hz, J . . . = J D = 6.0 Hz), 7.32 (broad singlet , IH, -OH), A , D A , 11 D , J. 1 8.26 (broad singlet , 3H, - C 1 4 H 3 ) , 8.83 (singlet, 3H, - C 1 5 H 3 ) , 9.06 (doublet, 13 23 3H, -C H 3 , ^ 3 = 6.5 Hz); optical rotatory dispersion, [^^G^ +21,300 (peak), [$] 24 8 °> [^227 _ 9 ' 7 2 0 ( t r o u g h ) (c> ° - 0 1 in methanol). Anal. Calcd. for ci5^24°2: c> 76.20; H, 10.23; mol. wt, , 236. Found: C,'76.19; H, 10.03; mol. wt., 236 (mass spectrometry). , Continued elution i n the above chromatography with 1.5 liters of 1:1 benzene-chloroform and 1 l i t e r of chloroform gave 2.5 g of d i o l 185, as shown by m.p. , and by i t s infrared spectrum. F i n a l l y , elution with 2 l i t e r s of chloroform and 1 l i t e r of ethyl acetate afforded 0.6 g of d i o l 186, again identif ied by m.p. and infrared spectrum. Thus, in the above oxidation, the y i e l d of keto alcohol 189, based on unrecovered starting material,, was 81%. Preparation of Keto Carbonate 190 A solution of keto alcohol 189 (13.9 g) in 310 ml of dry pyridine was cooled to 0 ° , and freshly d i s t i l l e d ethyl formate (134 ml) was added dropwise, over a period of 3 h. The reactants were allowed to stand at room temperature, under an atmosphere of nitrogen, for 20 h, during which time a white precipitate had formed. The reaction mixture was poured into cold (0° ) 50% aqueous acetic acid (600 ml) and the resulting mixture was extracted thoroughly with ether. The combined ether extracts were washed several times with water and evaporated. The residue was dissolved in benzene and the resulting solution was dried over anhydrous sodium sulfate. Removal of the benzene gave a clear o i l which, upon d i s t i l l a t i o n under reduced pressure, afforded 13.4 g (75%) of the keto carbonate 190 as a clear, pale - 134 -20 23 yellow l i q u i d , b .p . 166° at 0.25 mm, n Q 1.5078, [a] +75° (c, 0.25 in methanol). Ul t raviolet , X 249my ( e = 13,600); infrared (f i lm), X H13-X IflELX 5.81, 6.06, 6.25, 8.01, 9.98 y; n .m.r . , T 5.73-6.12 (complex pattern of l ines , 4H, ^ C 1 2 H A H g and -0CH_2CH3), 8.31 (broad singlet , 3H, - C 1 4 H 3 ) , 8.76 ( t r ip le t , 3H, -OCH 2 C_ 3 , J = 7.1 Hz), 8.86 (singlet, 3H, - C 1 5 H 3 ) , 9.03 13 27 (doublet, 3H, -C H 3 , ^ 3 = 6.7 Hz); optical rotatory dispersion, [$]2g^ +23,950 (peak), OI ^ Q °> [^226 -14,010 (trough) (c, 0.008 in methanol). Anal. Calcd. for C 1 Q H ' 0 . : C, .70.1-0; H, 9.15. Found: C, 69.87; H, 18 zo 4 8.98. Preparation of Keto Carbonate 191 This compound was prepared by reaction of keto alcohol 189 with methyl chloroformate, using a procedure identical with that described above. The crude product obtained from 8.5 g of keto alcohol 189 was purif ied by d i s t i l l a t i o n under reduced pressure and gave 8.5 g (81%) of a pale-yellqw o i l (b.p. 154° at 0.03 mm) which crystal l ized on standing. Recrystallization of a small sample from ether-petroleum ether (b.p. 3 0 - 6 0 ° ) gave colourless blocks, m.p. 5 1 . 5 - 5 2 ° , [ a ] 2 3 +98° (c, 0.8 i n methanol). Ul t raviolet , X D v ' max 249 my (e= 13,700); infrared (nujol), X 5.78, 6.05, 6.26, 7.92 y; • UlcLX 12 n .m.r . , x 5.75-6.09 (octet, 2H,>C H^Hg with H^ at T 5.84 and Hg at T .5.90, J A _ = 10.5 Hz, J A , , = 6.3 Hz, J D = 6.0 Hz), 6.28 (singlet, 3H, -0CH_), A,D A,11 D , 1 1 J 8.28 (broad singlet , 3H, - C 1 4 H 3 ) , 8.82 (singlet, 3H, - C 1 5 H 3 ) , 9.01 (doublet, 3H, - C 1 3 H 3 , J n 1 3 = 7.0 Hz). Anal. Calcd. for C . _ H o . 0 . : C, 69.36; H, 8.90. Found: C, 69.52; 1/ Z D 4 H, 8.68. - 135 -Preparation of (+)-a-Cyperone 168 by Pyrolysis of Keto Carbonate 190. Compound 190 (2.80 g) was introduced dropwise onto a ver t ica l pyrex glass column (1.5 cm x 40 cm) packed with glass helices and heated to approximately 400° by a vert ical furnace. During the pyrolysis , nitrogen was passed slowly through the column from the top to the bottom, and the pyrolysate was collected i n a receiving tube cooled in an ice-water bath. The contact time of pyrolysis was approximately 2 min. When the ester 190 had been subjected to this procedure, the product s t i l l contained some starting material and i t was therefore necessary to pass the f i r s t pyrolysate through the heated column a second time. The crude product (2.10 g) thus obtained was subjected to column chromatography on 150 g of ac t iv i ty II Shawinigan alumina. Elution with 400 ml of petroleum ether (b.p. 3 0 - 6 0 ° ) , 1200 ml of 1:1 petroleum ether-benzene, 800 ml of benzene, and 60 ml of 1:1 benzene-chloroform gave 1.2 g (61%) of (+)-a-cyperone 168, which was identical (infrared, n .m.r . , optical rotation, gas-l iquid chromatographic retention time on two different columns: A, 2 0 8 ° ; B, 190°) with an authentic.sample. Further elution with 1 l i t e r of chloroform gave 0.7 g (32%) of the keto alcohol 189, identif ied by m.p., mixture m.p., and infrared comparison with compound 189 prepared previously (see page 132 ). Preparation of (+)-a-Cyperone 168 by Pyrolysis of Keto Carbonate 191 Compound 191 was subjected to pyrolysis under conditions identical with those described above for the pyrolysis of 190. The crude pyrolysate obtained from 7.4 g of 191 gave, upon d i s t i l l a t i o n under reduced pressure, 4.6 g (84%) of pure (+)-a-cyperone 168, b .p. 101° at 0.04 mm. - 136 -I, 2-Dehydro-(+)-a-cyperone 192 To a solution of (+)-a-cyperone 168 (1.10 g) in 170 ml of p u r i f i e d , dry dioxane (116) was added 2,3-dichloro-5,6-dicyanobenzoquinone (101) (1.37 g), and the resulting solution was refluxed under an atmosphere of nitrogen for 45 h. The reaction mixture was then cooled and f i l t e r e d . The f i l t r a t e was evaporated under reduced pressure to give a dark-brown o i l , which was subjected to chromatography on 100 g of act ivi ty II Shawinigan alumina. Elution with 200 ml of 1:1 benzene-n-pentane gave 390 mg (35%) of starting material, as shown by thin-layer chromatography (Woelm neutral alumina plates, developed with 2:1 benzene-chloroform) and by i t s infrared spectrum. Further elution with 800 ml of 1:1 benzene-n-pentane gave 520 mg (73%, based on unrecovered starting material) of pure 1,2-dehydro-(+)-a-cyperone 20 192 as a clear, colourless o i l n D 1.5449. Ultraviolet , X f f l a x 240 my (e = II , 500). Infrared (f i lm), X 6.03, 6.15, 6.25, 11.29 and 12.06 y ; . nictx n.m.r . , T 3.22 (doublet, 1H,>C 1 H), T 3.87 (doublet, 1H, ^ C 2 H , ^ 2 = 10 Hz), 5.18 (broad signal , 2H, >C=C 1 2H 2), 8.07 (singlet, 3H, - C 1 4 H 3 ) , 8.21 (poorly resolved multiplet , 3H, - C 1 3 H 3 ) , 8.74 (singlet, 3H, - C 1 5 H 3 ) . Anal. Calcd. for C ^ H ^ O : C, 83.28; H, 9.32; mol. wt.,216. Found: C, 83.42; H, 9.33; mol. wt. , 216 (mass spectrometry). 1,2-Dehydro-(-)-7-epi-a-cyperone 193 This compound was obtained from (-)-7-epi-a-cyperone 169 by a procedure identical with that described above. The crude gummy product obtained from the reaction of 6.40 g of 169 with 8.20 g of 2,3-dichloro-5,6-dicyanobenzo-quinone in 310 ml of dry, purif ied dioxane was again purif ied by chromatography on act ivi ty II Shawinigan alumina (400 g). Elution with 750 ml of 1:1 - 137 -benzene-_-hexane gave 2.82 g (44%) of starting material, as shown by thin-layer chromatography (Woelm neutral alumina plates, developed with 2:1 benzene-chloroform) and by infrared spectrum. Further elution with 3.5 l i t e r s of 1:1 benzene-n-hexane gave 900 mg (25%, based on unrecovered starting material) of l ,2Tdehydro-(-)-7-epi-a-cyperone 193 as a clear,; 20 colourless o i l , n^ 1.5485. Ultraviolet , X 241 my (e = 10,500): ' D max f v. infrared (f i lm), X 6.04, 6.18, 6.27, 11.27, 12.02 u; n .m.r . , x 3.28 nicix (doublet, IH, Z C*H), 3.81 (doublet, IH,J>C2H, ^ 2 = 10 Hz), 5.22 and 5.33 (two broad signals, 2H, ^C=C 1 2 H 2 ) , 8.03 (broad singlet , 3H, - C 1 4 H 3 ) , 8.28 13 15 (poorly resolved multiplet , 3H, -C H 3 ) , 8.74 (singlet, 3H, -C H 3 ) . Anal. Calcd. for C ^ H ^ O : C, 83.28; H, 9.32; mol. wt., 216. Found: C, 83.15; H, 9.25; mol. wt. , 216 (mass spectrometry). Preparation of Hydroguaiazulene Derivative 194 by Irradiation of 1,2-Dehydro-(+)-a-cyperone 192. The irradiation of 192 was carried out with a Hanovia 450 W high-pressure mercury lamp, in an apparatus similar to that described by Kropp and Erman (79), except that the lamp was housed in a quartz water-jacketed immersion well . A solution of 1,2-dehydro-(+)-a-cyperone 192 (400 mg) in 350 ml of 45% aqueous acetic acid was irradiated, using a pyrex f i l t e r , for 55 min.. During the i r radia t ion , the solution was vigorously st irred with a stream of^nitrogen and the temperature was kept near 25° by adjusting the rate of flow of cold water through the quartz water-jacket. After completion of the photolysis, the solvent was removed under reduced pressure, the temperature being kept below 5 0 ° . The crude gummy residue was dissolved in chloroform, and the resulting solution was washed twice with saturated sodium bicarbonate - 138 -solution and once with cold water, and dried over anhydrous sodium sulfate. F i l t r a t i o n and evaporation of the solvent gave a crude brown o i l which was subjected to column chromatography on 30 g of neutral Woelm s i l i c a g e l . Elution with 100 ml of 1:1 benzene-petroleum ether (b.p. 3 0 - 6 0 ° ) gave 90 mg (22%) of starting material, as shown by infrared analysis. Continued elution with 150 ml of benzene, 250 ml of 1:1 benzene-chloroform, and f i n a l l y with 1 l i t e r of chloroform gave 256 mg (76% based on unrecovered 192) of the crystall ine hydroguaiazulene derivative 194. Recrystallization from chloroform-petroleum ether (b.p. 3 0 - 6 0 ° ) gave an analytical sample, m.p. 1 7 5 - 1 7 7 ° . Ul t raviolet , X m a x 244 my (e = 15,700); infrared (KBr disk) , 12 A 2.96, 6.01, 6.19, 11.21 y; n .m.r . , x 5.28 (broad signal , 2H, ^C=C H ), ITlcLX c, 13 14 8.24 and 8.31 (two poorly resolved multiplets, 6H, -C H^ and -C H^, respectively) , 9.08 (singlet, 3H, - C ^ H ^ ) . The chemical shifts assigned to 13 14 -C and -C H^ were confirmed by a frequency-swept decoupling experiment. in which the protons at C-12 were strongly irradiated, thus eliminating the a l l y l 13 12 coupling between -C H and =C H_, and causing the unresolved multiplet at T. 8.24 to collapse to a sharp, strong singlet . Optical rotatory dispersion, [*]^ Q +16,600 (peak), [ * ] ^ j Q 0 , [*]^ & -24,000 (trough) (c, 0.009 in methanol). Anal. Calcd. for C 1 5 H 2 2 0 2 : C, 76.88; H, 9.46; mol. wt. , 234. Found: C, 77.11; H, 9.66; mol. wt. , 234 (mass spectrometry). Preparation of Hydroguaiazulene Derivative 195 by Irradiation of 1,2-Dehydro-(-)-7-epi-a-cyperone 193 The irradiation of compound 193 was carried out under conditions very similar to those employed for the irradiat ion of compound 192. The crude - 139 -product obtained from the irradiation of 800 mg of 193 in 350 ml of 45% aqueous acetic acid was purif ied by column chromatography on neutral Woelm s i l i c a gel (30 g). Elution with 200 ml of 1:1 benzene-petroleum ether (b.p. 3 0 - 6 0 ° ) gave 180 mg (22%) of starting material 193. Further elution with 150 ml of benzene, 100 ml of 1:1 benzene-chloroform, and 1.5 l i t e r s of chloroform gave 474 mg (71%, based on unrecovered 193) of crystal l ine hydroguaiazulene derivative 195. Recrystallization from chloroform-petroleum ether (b.p. 3 0 - 6 0 ° ) gave colourless needles, m.p. 1 5 2 . 5 - 1 5 3 . 5 ° . Ul t raviolet , X • 6 > f >. m a x 243 my (e = 13,700); infrared (KBr disk) , X 2.90, 5.98, 6.20, 11.04 y; H13-X 12 n.m.r . , T 5.27 and 5.40 (two broad signals, 2H, >C=C H ), 8.26 and 8.34 13 14 (two poorly resolved multiplets, 6H, -C and -C H^, respectively) , 8.96 15 (sharp singlet , 3H, -C H^). Again, the chemical shifts assigned to the 13 14 v i n y l i c methyl groups (-C and -C H^) were confirmed by a frequency-swept decoupling experiment in which the olef inic protons at C-12 were strongly irradiated, whereupon the unresolved multiplet at T 8.26 collapsed to a 25 strong, sharp singlet . Optical rotatory dispersion, [ $ ] o c o -10,900 (trough), ^ 2 4 2 ° ' f^215 + 2 5 > 1 0 0 (peak) (c, 0.009 in methanol). Anal. Calcd. for C 1 5 H 2 2 Q 2 : C ' 7 6 - 8 8 > H> 9 - 4 6 ' m o 1 - w t - » 2 3 4 - Found: C, 76.64; H, 9.56; mol. wt., 234 (mass spectrometry). 2-Hydroxymethylene-(-)-7-epi-a-cyperone 198 This compound was prepared by a procedure similar to that described by Sorm e t . a l . (117). To a st irred slurry of sodium methoxide (23.5 g) in 60 ml of dry benzene was added a solution of ethyl formate (14.9 g) in 60 ml of dry benzene. The resulting mixture was cooled to 0° and then a solution of (-)-7-- 140 -epi-a-cyperone 193 (14.5 g) in 120 ml of dry benzene was added dropwise, over a period of 1 h in an atmosphere of nitrogen. The mixture was allowed to warm to room temperature and st irred for another 48 h. A yellow precipitate was formed. Water was added, the mixture was thoroughly shaken, and the layers were separated. The organic layer was extracted with 500 ml of 7% aqueous sodium hydroxide. The combined aqueous layer and; alkaline extract were cooled, ac idif ied with 6 N hydrochloric acid, and thoroughly extracted with ethyl ether. The combined ether extracts were dried over anhydrous magnesium sulfate. Removal of solvent gave 14.5 g . (86%) of the crude hydroxymethylene derivative 198 as a brown o i l . D i s t i l -lation under reduced pressure, of a small amount of this material gave an analytical sample as a clear, pale-yellow o i l , b .p . 140-150° (bath tempera-ture) at 0.015 mm, n 2 0 1.5589, [a]p 5 - 5 0 ° ( c , 0.5 in methanol). Ultraviolet X 263 my (e = 8,480), 310 my (E = 5,770), X M e ° H + N a ° H 260 my (e = 9,800), ITlcLX nicix 360 my ( e = 9,970); infrared (f i lm), X 3.48, 5.84, 6.13, 11.15 y; n .m.r . , x 2.68 (broad signal , IH, -CHOH), 5.20 and 5.38 (two broad signals, 2H, ^C=C 1 2 H 2 ) , 8.14 (poorly resolved doublet, 3H, - C 1 4 H 3 , J = 1 Hz), 8.29 (unresolved multiplet , 3H, - C 1 3 H 3 ) , 8.94 (singlet, 3H, - C 1 5 H 3 ) . Anal. Calcd. for C ^ H o „ 0 _ : C, 78.00; H, 9.00; mol. wt. , 246. Found: 16 ZZ Z C, 78.09; H, 9.01; mol. wt. , 246 (mass spectrometry). 1,2-Dehydro-2-formyl-(-)-7-epi-a-cyperone 199 To a solution of the crude hydroxymethylene derivative 198 (21 g) in 200 ml dry dioxane was added, in one portion, a solution of 21.6 g of 2,3-dichloro-5,6-dicyanobenzoquinone i n dry dioxane (250 ml). The mixture was s t i r red , under an atmosphere of nitrogen, at room temperature for 10 min. - 141 -The mixture was f i l t e r e d and the f i l t r a t e was diluted with 1 l i t e r benzene. The resulting solution was f i l t e r e d through a column of ac t iv i ty III Woelm neutral alumina (200 g). The column was washed with 2 l i t e r s of benzene and 3 l i t e r s of chloroform. Removal of the solvent from the combined eluant gave 16.5 g (79%) of the crude keto aldehyde 199, as a brown o i l . Pur i f i ca -tion of a small amount of the crude product by d i s t i l l a t i o n under reduced pressure gave an analytical sample of aldehyde 199 as a clear yellow viscous 20 23 o i l , b . p . 150° (bath temperature) at 0.02 mm, n Q 1.5567, [a]Q +30° (c, 1.0 in methanol). Ultraviolet , A 239 my (e = 8,850), 280 my (e = 6,200) (shoulder); infrared (f i lm) , A 3.51, 5.90, 6.10, 7.82, 7.98, 8.10, 11.13 y; IT13.X n.m.r . , T -0.27 (singlet, IH, -CHO), 2.55 (singlet, IH, ^ C 1 H ) , 5.25 and 5.43 (two broad signals, 2H, >C=C 1 2H 2), 8.02 (doublet, 3H, - C 1 4 H 3 > - J = 1.3 Hz), 8.30 (unresolved multiplet , 3H, - C 1 3 H 3 ) , 8.68 (singlet, 3H, - C 1 5 H 3 ) . 13 14 The chemical shifts assigned to -C H 3 and -C H 3 were confirmed by a i 12 frequency-swept decoupling experiment in which one of the protons of =C at T5.25, was strongly irradiated, thus eliminating part of the a l l y l i c 13 12 coupling between -C and =C H^, and causing the unresolved multiplet at T 8.30 to sharpen to a broad singlet . Anal. Calcd. for C ^ H ^ C " : C, 78.65; H, 8.26; mol. wt., 244. Found: lo 2U 2 C, 78.39; H, 8.49; mol. wt., 244 (mass spectrometry). 1,2-Dehydro-2-carboxy-(-)-7-epi-a-cyperone 200 To a st irred solution of the aldehyde derivative 199 (16 g) in 18 ml of 95% aqueous ethanol was added a solution of s i lver nitrate (24.6 g) in 126 ml water, followed by the dropwise addition of a solution of sodium hydroxide (11.2 g) in 300 ml water. After the addition was complete (1.5 h), - 142 -the mixture was st i rred at room temperature for 4 h. The mixture was f i l t e r e d and the residue was washed with 200ml of saturated sodium bicarbonate solution. The combined f i l t r a t e and washings were ac idif ied with 6 N hydrochloric acid and then made alkaline with sodium carbonate solution. The mixture was f i l t e r e d and the f i l t r a t e was ac idif ied with 4 N hydrochloric acid. The resulting mixture was extracted thoroughly with ether, and the combined ether extracts were evaporated. The residual material was dissolved in benzene and the^resulting solution was dried over anhydrous sodium sulfate. Removal of >h'e solvent gave 13.2 g (77%) of a light-yellow crystal l ine s o l i d . Recrystallization of a small amount of this material from ether gave an s analytical sample of the carboxylic acid derivative 200, m.p. 102.5-104 , [ a ] 2 3 +93 .2° (c, 0.25 i n methanol). Ultraviolet , X m a x 203 my (e= 19,600), 246 my (e = 7,950); infrared (CHC1_), X 5.77, 6.07, 6.33, 11.02 y; n.m.r. o max 1 12 T 1.92 (singlet, IH, * C H ) , 5.28 and 5.52 (two broad signals, 2H,>.C=C H 2 ) , 14 8.01 (poorly resolved doublet, 3H, -C H j , J = 1 Hz), 8.31 (broad singlet , 3H, - C 1 3 H 3 ) , 8.64 (singlet, 3H, - C 1 5 H 3 ) . Anal. Calcd. for C.^H-.O • C, 73.79; H, 7.75; mol. wt., 260. Found: lo ZU J C, 73.59; H, 7.92; mol. wt. , 260 (mass spectrometry). Preparation of Hydroguaiazulene Derivative 195 by Irradiation of 1,2-Dehydro-2-carboxy-(-)-7-epi-a-cyperone 200 The irradiation of compound 200 was carried out under conditions very similar to those employed for compound 192 (see page 137 ) . The crude product obtained from the irradiat ion of 12.5 g of 200 in 2.6 l i t e r s of 45% aqueous acetic a c i d , s o l i d i f i e d on standing. Crystal l izat ion of this sol id - 143 -material from chloroform-petroleum ether (b.p. 3 0 - 6 0 ° ) afforded 7.5 g (60%) of the hydroguaiazulene derivative 195 which was identical (infrared, n .m.r . , m.p.) with the compound obtained previously by irradiation of compound 193 (see page 136). Preparation of Diol 202 To a solution of lithium (1.5 g) in 1 l i t e r of l i q u i d ammonia (which had been d i s t i l l e d from sodium metal), was added a solution of compound 194 (1.0 g) i n 50 ml of ether. The mixture was st irred for 1.5 h and then the reaction was quenched by cautious addition of methanol. After the ammonia had evaporated, the residue was diluted with water. The resulting mixture was extracted with ether. The ether extract was washed with water and dried over anhydrous sodium sulfate. Removal of solvent yielded a white sol id mass (0.9 g). This crude diol 202 was not purif ied further, but exhibited the following expected spectral properties: infrared (nujol), X 3.10,. 6.10, 11.31 y ; n .m.r . , T 5.35 (unresolved multiplet , 2H, ^C=C 1 2 H 2 ) , 6.49 ; (multiplet, IH, ^ C 3 H ) , 8.33 (unresolved multiplet , 3H, - C 1 3 H 3 ) , 8.47 (broad singlet , -OH), 8.88 (singlet, 3H, - C 1 5 H 3 ) , 9.00 (doublet, 3H, - C 1 4 H 3 , J = 5 Hz). Preparation of Keto Alcohol 201 To a slurry of chromium trioxide (7.2 g) in pyridine (120 ml) at 0° was added, in one portion, a solution of the diol 202 (3.6 g) in 60 ml of pyridine. The mixture was st irred at room temperature for 22 h, and then poured into 500. ml of cold water. The resulting mixture was extracted with ether (1.5 l i ters ) and the combined ether extracts were evaporated. The - 144 -residual material was dissolved in benzene and the resulting solution was washed thoroughly with water and then dried over anhydrous sodium sulfate. Removal of solvent under reduced pressure gave 3.2 g of viscous yellow o i l . . A small amount of this crude product was purif ied by column chromatography on act ivity III neutral Woelm alumina (70 g). Elution with 450 ml 1:1 chloroform-benzene gave the keto alcohol 201 as a white s o l i d . Recrystalliza-tion from ether-petroleum ether (b.p. 3 0 - 6 0 ° ) afforded colourless needles, m p. 5 8 . 5 - 5 9 ° . Infrared (CHC1_), A 2.81, 3.45, 5.81, 6.12, 11.15 u; n .m.r . , 12 T 5.33 (unresolved multiplet , width at half-height = 4 Hz, 2H, >C=C H 2) , 13 8.30 (poorly resolved doublet, 3H, -C H^, J = 1 Hz), 8.82 (sharp singlet , 3H, - C 1 5 H 3 ) , 8.95 (doublet, 3H, - C 1 4 H 3 , J = 6.5 Hz); optical rotatory dispersion, [ $ ] ^ 3 -6,135 (trough), [ S ] 2 ^ 0, +10,050 (peak) (c, 0.035 in methanol). Anal. Calcd. for C ^ H^Cy C, 76.23; H, 10.24; mol. wt. , 236. Found: C, 76.11; H, 10.23; mol. wt., 236 (mass spectrometry). Preparation of Diol 203 This compound was obtained from compound 195 by a procedure identical with that described for the conversion of 194 into 202 (see page 143). From 7.0 g of 195 there was obtained 7.9 g of 203 as a crude yellow s o l i d . Two recrystall izations of a small sample of this material from 10:1 n-hexane-ether at 0° afforded colourless needles, m.p. 1 5 3 - 1 5 5 ° . Infrared (nujol), A 3.00, 6.10, 11.30 u; n .m.r . , x 5.32 (unresolved multiplet , 2H, IHciX >C=C 1 2H 2), 6.45 (multiplet, IH, £ C 3 H ) , 8.28 (unresolved multiplet , 3H, - C 1 3 H 3 ) , 8.88 (singlet, 3H, - C 1 5 H 3 ) , 9.02 (doublet, 3H, - C 1 4 H 3 , J = 5 Hz). . Anal. Calcd. for C i r H O i l 0 o : C, 75.57; H, 10.99. Found: C, 75.45; H, lb lo I 11.07. - 145 -Preparation of Keto Alcohol 204 This compound was obtained from compound 203 by a procedure identical with that described for the oxidation of compound 202 (see page 143 ). From 7.9 g of crude d i o l 203 there was obtained 5.3 g of crude product as a light-brown o i l . A small sample of the crude product, upon d i s t i l l a t i o n under reduced pressure in a hot box, gave a pale-yellow o i l which s o l i d i f i e d on standing. Recrystallization from ether-petroleum ether (b.p. 3 0 - 6 0 ° ) at 0° gave fine needles, m.p. 6 4 . 5 - 6 5 ° , [ c t ] D +38.2 (c, 0.2 i n methanol). Infrared (CHC1_), X 2.96, 3.46, 5.82, 6.11, 11.15 u; n .m.r . , T5.32 (broad o max 12 signal , width at half-height = 6.5 Hz, 2H, >C=C H 2 ) , 8.29 (poorly resolved doublet, 3H, - C 1 3 H 3 , J = 1 Hz), 8.85 (singlet, 3H, - C 1 5 H 3 ) , 8.95 (doublet, 3H, - C 1 4 H 3 , J = 6.5 Hz); optical rotatory dispersion, t^ 1]^^ + 6 » 9 3 0 (peak), [$] 2 g 5 0, [^27! -7,780 (trough) (c, 0.036 in methanol). Anal. Calcd. for C 1 5 H 2 4 ° 2 : C> 76.23; H, 10.24; mol. wt. , 236. Found: C, 76.00; H, 10.31; mol. wt., 236 (mass spectrometry). Preparation of Alcohol 215 This compound was prepared by Huang-Minion reduction (115) of compound 201. To a solution of compound 201 (2.3 g) in i50 ml of purif ied diethylene glycol was added potassium hydroxide powder (3.1 g) and 85% hydrazine hydrate (70 ml). After refluxing at 155° for 2 h, hydrazine was d i s t i l l e d from the reaction mixture u n t i l the reaction temperature reached 2 0 5 ° . The reaction mixture was then refluxed at 205-210° for 5 h. The cooled reaction mixture was diluted with 300 ml of water and extracted several times with benzene. The combined extracts were washed several times with water, once - 146 -with saturated brine and then dried over anhydrous sodium sulfate. Removal of solvent afforded 1.93 g (89%) of a pale-yellow, viscous o i l . A small amount of this crude product was purif ied by thin-layer chromatography (Woelm neutral alumina plates developed with 2:1 chloroform-ethyl acetate) whereby a pale yellow sol id was obtained. Recrystallization from n-hexane at 0° , 27 o gave colourless needles, m.p. 5 4 . 5 - 5 5 ° , [a]D +34 .7° (c, 0.35 in methanol). Infrared (CHC1,), X 3.47, 6.12, 11.3 y; n .m.r . , T 5.35 (unresolved multiplet , o nicix width at half-height = 5.5 Hz, 2H, i C = C 1 2 H 2 ) , 8.33 (poorly resolved doublet, 3H, - C 1 3 H 3 , J.= 1 Hz), 8.88 (singlet, 3H, - C 1 5 H 3 ) , 9.05 (doublet, 3H, - C 1 4 H 3 , J = 6 Hz). Anal. Calcd. for C 1 c H o , 0 : C, 81.01; H, 11.78; mol. wt. , 222. Found: C, 80.86; H, 11.76; mol. wt. , 222 (mass spectrometry). Preparation of Alcohol 217 This compound was obtained from keto alcohol 204 by a procedure identical with that described above for the preparation of 215. From 3.0 g of keto alcohol 204 there was obtained 2.5 g (90%) of crude product as a viscous yellow o i l which, upon d i s t i l l a t i o n under reduced pressure, gave a 2 2 o 23 clear, colourless o i l , [a]D - 3 0 . 6 ° ( c , 0.8 in methanol), n p 1.6875. Infrared (f i lm), X 2.99, 3.43, 6.11, 11.14 y; n .m.r . , x 5.37 (unresolved v • max 12 multiplet , width at half-height = 8 Hz, 2H, >C=C H_2), 8.30 (poorly resolved doublet, 3H, - C 1 3 H 3 , J = 1 Hz), 8.88 (singlet, 3H, - C 1 5 H 3 ) , 9.05 (doublet, 3H, - C 1 4 H 3 , J = 6 Hz). Anal. Calcd. for C 1 c H o , 0 : C, 81.01; H, 11.78; mol. wt. , 222. Found: I D Z D C, 80.88; H, 12.09; mol. wt. , 222 (mass spectrometry). - 147 -5-Epi-a-bulnesene 216 To a solution of alcohol 215 ( 7 8 O mg) in 40 ml of dry pyridine at 0° was added dropwise 1.5 ml of purif ied thionyl chloride. The mixture was st irred at 0° for f i f teen minutes, and then evaporated under vacuum at room temperature. Water was added to the residue and the resulting mixture was extracted thoroughly with benzene. The extract was washed thrice with water, once with brine and then dried over anhydrous sodium sulfate. Removal of solvent afforded 600 mg of crude product as light-brown o i l which was shown by gas- l iquid chromatographic analysis (column C, 167°) to be approxi-mately 80% pure. An analytical sample of the major component, 5-epi-a-bulnesene 216, was collected by preparative g . l . c . (column C, 167°) and exhibited a positive plain optical rotatory dispersion curve. Infrared (fi lm), A 3.42, 6.11, 6.88, 7.26, 11.00 \i; n .m.r . , T 5.34 (broad signal , width IT13-X 12 at half-height = 10 Hz, 2H, >C=C H 2 ) , 8.28 (unresolved multiplet , 3H, - C 1 3 H 3 ) , 8.33 (unresolved multiplet , 3H, - C 1 5 H 3 ) , 9.05 (doublet, 3H, - C U H 3 , 13 15 J = 5.5 Hz). The chemical shifts assigned to -C H 3 and -C H 3 were confirmed by a frequency-swept decoupling experiment in which the protons at C-12 were strongly irradiated, thus eliminating the a l l y l i c coupling 13 12 between -C H 3 and =C H^, and causing the unresolved multiplet at x 8.28 to collapse to a sharp singlet . The infrared and n.m.r. spectra of 5-epi-d-bulnesene 216 were clearly different from the corresponding spectra of a-bulnesene 7_. Also, the g . l . c . retention times (column B, 180°) of the two compounds were different . Mol. Wt. Calcd. for C ^ H ^ : 204.188. Found: 204.187 (high-resolution mass spectrometry). - 148 -4-Epi-a-bulnesene 218 This compound was obtained by dehydration (thionyl chloride in pyridine) of alcohol 217, employing a procedure identical with that described above for the preparation of 5-epi-a-bulnesene 216. From 420 mg of compound 217 there was obtained 350 mg of crude product as a light-brown o i l which was shown by gas-l iquid chromatographic analysis (column D, 170°) to consist of two components in approximately equal amounts. An analytical sample of each of these components was obtained by preparative g . l . c . (column D, 1 7 0 ° ) . The component of shorter retention time was 4-epi-a-bulnesene 218 and exhibited the following spectral data: infrared (f i lm), ^ m a x 3.46, 6.11, 6.94, 7.28, 11.32 y; n .m.r . , x 5.38 (unresolved multiplet , 2H, 5C=C 1 2 H 2 ) , 8.31 13 (poorly resolved doublet, 3H, -C Hg, J = 1.5 Hz), 8.34 (poorly resolved multiplet , 3H, - C 1 5 H 3 ) , 8.99 (doublet, 3H, - C 1 4 H 3 , J = 6 Hz). Again,, the 13 15 chemical shifts assigned to the v i n y l i c methyl groups (-C H 3 and -C H 3) were confirmed by a frequency-swept decoupling experiment in which the o lef inic protons at C-12 were strongly irradiated, whereupon the multiplet at x 8.31 collapsed to a strong, sharp singlet . This compound showed a negative plain optical rotatory dispersion curve. The infrared and n.m.r. spectra of 4-epi-a-bulnesene 218 were clearly different from the corresponding spectra of a-bulnesene 7_. Also, the g . l . c . retention times (column B, 175°) of the two compounds were different . Mol. Wt. Calcd. for C ^ H ^ : 204.188. Found: 204.187 (high-resolution mass spectrometry). The second component isoalted was compound 219 and exhibited the, following spectral data: infrared (fi lm), X 3.43, 6.11, 6.90, 7.27, 11.33 y; n .m.r . , - 149 -9 x 4.45 (poorly resolved t r i p l e t , IH, H, J = 7 Hz), 5.40 (unresolved 12 multiplet , 2H, >C=C H^), 8.32 (unresolved multiplet , 6H, two vinyl methyls), 9.06 (doublet, 3H, - C 1 4 H 3 , J = 6 Hz). Preparation of a-Bulnesene 1_ by Dehydration of Bulnesol 5_1_ The dehydration of bulnesol 5_1 was carried out under conditions identical with those described above for the dehydration of alcohol 215 (see page 147 ). From 66 mg of bulnesol 51_ there was obtained 50 mg of crude product as a brown o i l . An analytical sample of a-bulnesene 7_ was obtained from the crude product by means of preparative g . l . c . (column C, 1 7 5 ° ) . Infrared (f i lm), X 3.42, 6.10, 7.04, 7.39, 11.38 y; n .m.r . , T 5.37 (unresolved ; IH3-X multiplet , 2H, >C=C 1 2 H 2 ) , 8.31 (doublet, 3H, - C 1 3 H 3 , J = 1 Hz), 8.34 (unresolved multiplet , 3H, - C 1 5 H 3 ) , 9.11 (doublet, 3H, - C 1 4 H 3 > J = 6.5;Hz). 13 Again, the chemical shifts assigned to the v i n y l i c methyl groups (-C H 3 and T C ^ H J ) were confirmed by a frequency-swept decoupling experiment in which the o l e f i n i c protons at C-12 were strongly irradiated, whereupon the doublet at T 8.31 collapsed to a strong, sharp singlet . a-Bulnesene 7_ exhibited a negative plain optical rotatory dispersion curve. Preparation of Hydroguaiazulene Derivative 221 by Irradiation of Compound 176 The irradiation of compound 176 was carried out under conditions very similar to those employed for compound 192 (see page 137 ). The crude gummy product obtained from the i rradiat ion of 34 g of 176 in 4.5 l i t e r s of 45% aqueous acetic acid,was purif ied by column chromatography on ac t ivi ty III neutral Woelm alumina (1,100 g). Elution with 2 l i t e r s of benzene gave 10.8 g (32%) of starting material 176. Continued elution with 2 l i t e r s of - 150 -1:1 benzene-chloroform gave 2.7 g (8.2%) of the spiro compound 222 which, upon d i s t i l l a t i o n under reduced pressure, afforded a viscous pale yellow o i l , b .p . 170° (bath temperature) at 0.2 mm. Infrared (fi lm), A m a x 2.95, 3.47, 5.94, 6.32 y; n .m.r . , x 2.30 (doublet, l H ^ C " ^ ) , 3.87 (doublet, IH, ^ C 2 H , J1 2= 6 Hz), 6.40 (singlet, 3H, -C00CH 3), 7.36 (quartet, IH, ^ C 4 H , J 4 1 4 = 7.5 Hz), 8.87 (doublet, 3H, - C 1 3 H 3 , J n 1 3 = 6.75 Hz), 8.90 (doublet, 3H, - C 1 4 H 3 , J 4 1 4 = 7.5 Hz), 8.96 (singlet, 3H, - C 1 5 H 3 ) . Anal. Calcd. for C ^ H ^ O ^ C, 68.54; H, 8.63; mol. wt. , 280. Found: C, 68.34; H, 8.49; mol. wt., 280 (mass spectrometry). Further elution with 2 l i t e r s of 1:1 benzene-chloroform and 3 l i t e r s chloroform gave 18.3 g (79% based on unrecovered 176) of hydroguaiazulene derivative 221 as a viscous yellow o i l which, upon d i s t i l l a t i o n under reduced pressure, afforded a clear, pale-yellow viscous o i l , b .p . 175° (bath temperature) at 0.2 mm, [a]Q +88 .5° (c, 0.1 in methanol). Ul t raviolet , A m a x 243 my (e = 13,760); infrared (f i lm), X 2.93, 3.45, 5.82, 5.95, 6.16 y; IQclX n.m.r . , x 6.37 (singlet, 3H, -C00CH 3), 6.83 (very broad signal , width at half-height = 10 Hz, IH, ^ C * H ) , 8.37 (poorly resolved doublet, 3H, - C 1 4 H 3 , J = 1 Hz), 8.83 (doublet, 3H, - C 1 3 H 3 , J n 1 3 = 7 Hz), 9.13 (singlet, 3H, 15 28 28 -C H 3 ) ; optical rotatory dispersion, [$1254 +16,310 (peak), [ $ ] 2 4 Q ^> 28 [ $ ] 2 ° 2 -20,100 (trough) (c, 0.01 in methanol). Anal. Calcd. for C ^ H - . O • C, 68.54; H, 8.63; mol. wt., 280. Found: 16 z4 4 C, 68.42; H, 8.45; mol. wt. , 280 (mass spectrometry). Preparation of Keto Diester 220 A solution of the alcohol 221 (19 g) in 170 ml of acetic anhydride containing 11 g of sodium acetate was warmed at 90 -95° for 60 h, under an - 151 -atmosphere of dry nitrogen. The mixture was diluted with cold water (250 ml) and benzene (200 ml). The mixture was st irred at room temperature for 1 h, and the layers separated. The aqueous layer was extracted with benzene. The combined extracts were washed thoroughly with water and once with saturated brine and then dried over anhydrous sodium sulfate. Removal of solvent under reduced pressure gave a light-brown o i l which was purif ied by column chromato-graphy on act ivi ty III neutral.Woelm alumina (400 g). Elution with 2.5 l i t e r s of benzene and 1 l i t e r of 1:1 chloroform-benzene gave 15.5 g (70%) of the keto diester 220. Removal of a l l traces of solvent by warming at 50-60° under vacuum for several days afforded an analytical sample of 220,, 19 o as a clear, pale-yellow o i l , [ a ] D +27.5 (c, 1.0 in chloroform). Ultraviolet , X 241 my (E = 14,400); infrared (fi lm), X 3.45, 5.87, 5.93, 6.15. y; max ma.x n.m.r . , T 5.93 (broad signal , width at half-height = 10 Hz, IH, TC^H ) , 7.61 (doublet, 2H, > C 2 H 2 , 2 = 4 Hz), 8.04 (singlet, 3H, -COCRj), 8.34 (poorly resolved doublet, 3H, - C 1 4 H 3 , J = 1.5 Hz), 8.82 (doublet, 3H, - C 1 3 H 3 , J n 1 3 = 7 Hz), 8.96 (singlet, 3H, - C 1 5 H 3 ) . The chemical shifts assigned to T.C 1H 2 and >C H 2 were confirmed by frequency-swept decoupling experiments. F i r s t l y the proton at C - l was strongly irradiated, thus eliminating coupling between 1 2 7 C H and >C H 2 , and causing the doublet at T 7.61 to collapse to a singlet . Further, when protons at C-14 were strongly irradiated, thus eliminating the 1 14 homoallylic coupling between-p-C H and -C H 3 , the broad signal at T 5.93: sharpened to a poorly resolved t r i p l e t with 2 = 4 Hz. Anal. Calcd. for C 1 o H o , 0 , _ : C, 67.06; H, 8.13. Found: C, 67.01; H, io zo b 8.14. - 152 -Preparation of Keto Diester 223 A solution of the unsaturated keto diester 220 (12.4 g) in 250 ml 95% aqueous ethanol was hydrogenated at room temperature and atmospheric pressure over 10% palladium-on-charcoal (4 g) for 40 h. F i l t r a t i o n and removal of solvent afforded 10.5 g (85%) of the saturated keto diester 223 as a clear, colourless o i l . This crude product was not purif ied further, but exhibited the following expected spectral properties: infrared (f i lm), X 5.80 u ; n .m.r . , T 6.44 (singlet, 3H, -C00CH 3), 8.00 (singlet, 3H, -C0CH 3), 8.55 (singlet, 3H, - C 1 5 H 3 ) , 8.96 and 9.05 (doublets, 6H, secondary methyls, 27 J = 7 Hz, 6 Hz, respectively) ; optical rotatory dispersion, [ ^ ^ ^ n -11,960 (trough), 0 ] 2 9 6 °» [^275 + 1 1 » 2 3 0 (P e a k ) Cc» 0-026 i n methanol) . ; -Anal. Calcd. for C l o H _ o 0 • C, 66.64; H, 8.70. Found: C, 66.87; H, 8.83. Epimerization of Keto Diester 223 A small amount of compound 223 (0.8 g) was treated with 1% methanolic potassium hydroxide at room temperature for 2 h. The methanol was replaced by benzene and the benzene solution was washed twice with water, once with saturated brine and then dried over anhydrous sodium sulfate. The crude product was purif ied by column chromatography on act ivi ty III Woelm neutral alumina (85 g). Elution with 500 ml benzene gave a clear o i l which upon removal of solvent by warming the o i l at 40-50° under vacuum for 2 days , gave an analytical sample of an epimeric mixture of 223 and 224, with the latter predominating. Infrared (fi lm), X 5.81 u; n .m.r . , T 6.34 (singlet, mux 3H, -C00CH 3), 7.93 and 8.00 (two singlets , 3H, -C0CH3 of 223 and 224, respectively), 8.51 and 8.60 (two singlets , 3H, - C 1 5 H 3 of 223 and 224 - 153 -respectively), 8.95 and 9.04 (overlapping doublets, 6H, secondary methyls of 27 27 223 and 224); optical rotatory dispersion, [ $ ] 3 1 2 -1240 (trough), [*] 2 9Q ° » 27 [$]2y2 +504 (peak) (c, 0.16 in methanol). Anal. Calcd. for C , o H o o 0 _ : C, 66.64; H, 8.70. Found: C, 66.79; H, 8.63. Sodium Borohydride Reduction of Keto Diester 223 To a solution of the crude keto diester 223 (10.5 g) in 400 ml of anhydrous methanol at 0° was added sodium borohydride (6 g). The resulting mixture was st irred at 0° for 2.5 h under an atmosphere of nitrogen. The reaction was quenched by cautious addition of water and the mixture was st irred for an additional 30 min. The methanol was evaporated under reduced pressure and the remaining aqueous layer was extracted with benzene. The benzene extract was washed with water and dried over anhydrous sodium sulfate. Removal of the solvent under reduced pressure, gave 10.2 g (96%) of a mixture of the epimeric alcohols 227 and 228, as a very viscous colourless o i l . An analytical sample was obtained by d i s t i l l a t i o n under reduced pressure, b .p . 130-140° (bath temperature) at 0.2 mm. Infrared (fi lm), A m a x 2.96, 3.50, 5.87 u ; n .m.r .* , T 6.32 (singlet, 3H, -C00CH3), 7.47 (singlet, IH, OH), 8.00 (singlet, 3H, -COCti^), 8.54 (singlet, 3H, - C 1 5 H 3 ) , 8.94 and 9.04 (two doublets, 6H, secondary methyls, J = 6.5 Hz, 7 Hz, respectively). Anal. Calcd. for C l o H „ - 0 r : C, 66.23; H, 9.26. Found: C, 66.24; H, 9.36. The n.m.r. signals of the epimeric mixture of alcohols 227 and 228 reported herein are that corresponding to the major component 227 (see page 114). - 154 -Tosylation of the Mixture of Epimeric Alcohols 227 and 228 To a solution of the mixture of epimeric alcohols 227 and 228 (2 g) in 30 ml of dry pyridine was added 2 g of p-toluenesulfonyl chloride. The solution was st irred at room temperature under an atmosphere of nitrogen for 65 h. The solution was diluted with water (50 ml) and the resulting mixture was extracted with benzene. The benzene extract was washed twice with water, twice with sodium bicarbonate solution and twice with saturated brine and then dried over anhydrous magnesium sulfate. Removal of solvent gave a l ight -brown o i l which was subjected to column chromatography on act ivi ty III neutral Woelm alumina (100 g). Elution with 200 ml benzene afforded 1.04 g (55%) of the olef in 230. Removal of the last traces of solvent from this material by warming the o i l at 50° under vacuum for two days afforded a clear, 23 pale-yellow o i l , [al,, +74.5° (c, 0.4 in methanol). Infrared (film), X ' L J D max 3.47, 5.84 y; n .m. r . , x 4.77 (broad signal , width at half-height = 7 H z , ; l H , ^ C 3 H ) , 6.38 (singlet, 3H, -C00CH 3), 8.02 (singlet, 3H, -C0CH 3), 8.37 (poorly resolved doublet, 3H, - C 1 4 H 3 , J = 1.5 Hz), 8.55 (singlet, 3H, - C 1 5 H 3 ) , 13 8.95 (doublet, 3H, -C H 3 , J n 1 3 = ? Hz). The chemical shifts assigned to ^ C 3 H and - C ^ 4 ^ were confirmed by frequency-swept decoupling experiment in which the proton at C-3 was strongly irradiated, thus eliminating the *3 a l l y l i c coupling between ^ C 3 H and - C 1 4 H , and causing the signal at x 8.37 to sharpen. Anal. Calcd. for C 1 o H o o 0 . : C, 70.10; H, 9.15. Found: C, 70.39(; H, 9.28. l o Ao 4 Further elution with 300 ml of 1:4 chloroform-benzene gave 0.6 g (20%) of the tosylate 229 as a clear, colourless viscous o i l which was unstable and. decomposed upon standing at room temperature for a few days or upon warming to 35° under vacuum. However, the spectral data obtained were in - 155 -complete accord with the structure 229. Infrared (film), X 3.48, 5.85, _ max 6.29, 6.92, 7.42, 8.07, 8.54, 15.05 y; n.m.r., T 2.24 (doublet, 2H, aromatic protons meta to the methyl group, J = 8 .Hz), 2.70 (doublet, 2H, aromatic \ 3 protons ortho to the methyl group, J = 8 Hz), 5.60 (multiplet, IH, H), 7.60 (singlet, 3H, Ar-CH3), 8.05 (singlet, 3H, -C0CH3), 8.64 (singlet, 3H, 15 -C H3), 8.97 and 9.23 (two doublets, 6H, secondary methyls, J = 6.9 Hz,, 6.8 Hz, respectively). The instability of this compound precluded the acquisition of satis-factory analytical data. Preparation of Diester 232 To a solution of the olefin 230 (400 mg) in 40 ml of dry benzene was added a solution of 160 mg of tris(triphenylphosphine)chlororhodium (94-98) in 20 ml of dry benzene. The resulting solution was subjected to hydrogena-tion at room temperature and atmospheric pressure for 10 h. The benzene was removed under reduced pressure and ether was added to the residue. The resulting mixture was filtered through a column of activity III Woelm neutral alumina (20 g), and the column was washed with 300 ml of ether. Evaporation of the combined filtrate and washings afforded a light-brown oil which, upon distillation under reduced pressure, gave 330 mg (84%) of diester 232 as a viscous, pale-yellow o i l , b.p. 130° (bath temperature) at 0.2 mm, [ a ] 2 3 -18.8° (c, 0.7 in methanol). Infrared (film), X 3.47, D max 5.84, 6.88, 7.32, 8.02, 8.64, 9.17 y; n.m.r., T 6.37 (singlet, 3H, -C00CH3), 8.01 (singlet, 3H, -C0CH3), 8.57 (singlet, 3H, -C 1 5H 3), 8.94 and 9.11 (two doublets, 6H, secondary methyls, J = 7 Hz, 6.4 Hz, respectively). Anal. Calcd. for C,QH 0: C, 69.64; H, 9.74. Found: C, 69.39; H, 9.73. - 156 -Preparation of Diol 253 (a) From Diester 232 To a solution of diester 232 (600 mg) in 25 ml of anhydrous ether was added 200 mg of lithium aluminum hydride powder. The resulting mixture was refluxed under an atmosphere of nitrogen for 4 h ; and then cooled to 0 ° . Excess lithium aluminum hydride was destroyed by dropwise addition of water. The resulting mixture was f i l t e r e d and the f i l t r a t e was extracted with benzene. After the extract had been dried over anhydrous sodium sulfate, the solvent was removed under reduced pressure, giving 430 mg (92%) of a viscous o i l which s o l i d i f i e d upon standing at 0 ° . Recrystallization from 22 o ether at 0° gave colourless crystals , m.p. 1 0 0 - 1 0 2 ° , [OOQ - 3 2 . 5 ° ( C , 0.6 in methanol). Infrared (CHC1,), X 2.80, 2.90, 6.87, 7.28, 9.83 u; n .m.r . , o IHclX x 6.37-6.72 (septet, 2H, ^ C^H^Hg with at x 6.48 and H g at x 6.62, J A „ = 10.8 Hz, J A = 7.3 Hz and J D = 6.5 Hz), 7.86 (singlet, 2H, OH), A, D A,II D , XX 8.85 (singlet, 3H, - C 1 5 H 3 ) , 9.10 and 9.19 (two doublets, 6H, secondary methyls, J = 6.3 Hz, 6.8 Hz, respectively). Anal. Calcd. for C . _ H _ o 0 . : C, 74.95; H, 11.74. Found: C, 75.14; H, 1 b lo I 11.68. (b) From Diester Tosylate 229 A solution of the diester tosylate 229 (150 mg) in 10 ml of a 1.3 molar solution of lithium aluminum hydride in tetrahydrofuran was refluxed under an atmosphere of nitrogen for 20 h , and then cooled to 0 ° . The work-up procedure was similar to that described above and 50 mg (65%) of crude product was obtained. This crude material, upon recrystal l izat ion from , ether at 0 ° , gave a colourless crystall ine compound which was identical - 157 -(infrared, n .m.r . , m.p.) with the diol 235 obtained from lithium aluminum hydride reduction of compound 232. Preparation of Monocarbonate 234 This compound was.prepared by reaction of d i o l 233 with methyl chloro-formate, using a procedure identical with that employed for the preparation of compound 191 (see page 134). From 490 mg of d i o l 233 there was obtained 450 mg (74%) of monocarbonate 234 which, upon d i s t i l l a t i o n under reduced pressure gave a clear o i l , b .p . 135-140° (bath temperature) at 0.15 mm, r ,B [oj -20.7 (c, 0.5 i n methanol). Infrared (f i lm), X 2.94, 3.48, 5.76 u; j) ma.x n.m.r . , T 5.81-6.19 (octet, 2H, > C 1 2 H A H n with H. at T 5.91 and H n at x 6.09, A B A B J . D = 10.5 Hz, J . = 6.1 Hz, J D i n = 7.5 Hz), 6.25 (singlet, 3H, -0CH„), A, D A,II D , 1 I o 8.07 (singlet, IH, -OH), 8.85 (singlet, 3H, - C 1 5 H 3 ) , 9.12 (two coincident doublets, 6H, secondary methyls, J = 6.5 Hz). Anal. Calcd. for C^ll^O^: C, 68.42; H, 10.13; mol. wt., 298. Found: C, 68.51; H, 10.09; mol. wt., 298 (mass spectrometry). Synthetic a-Bulnesene 7_ This compound was obtained by dehydration (thionyl chloride in pyridine) of compound 234, using a procedure very similar to that employed for the preparation of compound 216 (see page 147 ). From 400 mg of compound 234, there was obtained 300 mg (75%) of the unsaturated monocarbonate 235 as a clear reddish brown o i l . The crude material, which was not purif ied further, was shown (by n.m.r.) to be contaminated with small amounts of two double-bond isomers. However, this crude material exhibited the following expected spectral properties: infrared (fi lm), X 3.50, 5.76 u; n .m.r . , - 158 -T 5.82-6.27 (octet, 2H, > C 1 2 H 2 ) , 6.29 (singlet, 3H, -OCHj), 8.39 (unresolved multiplet , 3H, - C 1 5 H 3 ) , 9.14 (two coincident doublets, 6H, secondary methyls, J = 7 Hz). This crude dehydration product (300 mg) was subjected to pyrolysis under conditions very similar to that employed in the pyrolysis of compound 190. An analytical sample of a-bulnesene 7_, obtained from the crude . pyrolysate, by preparative g . l . c . (column E, 1 7 0 ° ) , was identical (infrared, n.m.r. and g . l . c . retention times: column E, 1 7 0 ° ; column B, 1 7 0 ° , column A, 175°) with authentic a-bulnesene obtained by dehydration (thionyl chloride in pyridine) of authentic bulnesol 5_1 (see page 149 ). The synthetic a-bulnesene showed a plain negative Cotton effect curve, super-imposable on that of authentic a-bulnesene. - 159 -BIBLIOGRAPHY 1. L. Ruzicka, A. Eschenmoser, and H. Heusser. Experientia 9_, 357 (1953). 2. L. Ruzicka, A. Eschenmoser, 0. Jeger, and D. Arigoni . Helv. Chim. Acta. 38, 1890 (1955). 3. G. Ourisson, S. Munaralli , and C. Ehret. "International Tables of Selected Constants, V o l . 15, Data Relative to Sesquiterpenoids", Pergamon Press, New York, 1966. 4. F. Sorm and V. Herout. C o l l . Czech. Chem. Comm. 13, 177 (1948). 5. F. Sorm, V. Herout, J . P l iva , and V.V. Sykora. C o l l . Czech. Chem. Comm. 23, 1072 (1958). 6. F. Sorm, V. Herout, A. Reiser, and V.V. Sykora. C o l l . Czech. Chem. Comm. 24, 1306 (1958). 7. F. Sorm, V. Herout, L. Dolejs, V. Jarolim, L. Novotny, and M. S t r e i b l . C o l l . Czech. Chem. Comm. 19_, 570 (1954). 8. F. Sorm, L. Dolejs, and J . Pl iva . C o l l . Czech. Chem. Comm. 15_, 186 (1950). 9. G. Buchi and H . J . E . Loewenthal. Proc. Chem. Soc. 280 (1962). 10. G. Buchi and W.D. MacLeod, J r . J . Am. Chem. Soc. 8£ , 3205 (1962). 11. G. Buchi, W.D. MacLeod, J r . , and J . Padilla 0. J . Am. Chem. Soc. 8(5, 4438'(1964). 12. F. Sorm, L. Dolejs, 0. Knessel, and L. P l iva . C o l l . Czech. Chem. Comm. 15_, 82 (1950). 13. R.B. Bates and R.C. Slagel. Chem. and Ind. (London), 1715 (1962). 14. F. Sorm, V. Herout, J . P l iva , M. Holub, V. Sykora, J . Mlezvia, M. S t r e i b l , and B. Schneider. C o l l . Czech. Chem. Comm. 18_, 512 (1953). 15.. J . L . Simonsen and D.H.R. Barton. The Terpenes. Cambridge University press. V o l . III. 1952 (Addenda in v o l . V, 1957). 16. D.H.R. Barton and P. de Mayo. Quart. Rev. 11_, 189 (1957). 17. T . G . Halsall and D.W. Theobald. Quart. Rev. 16, 1011 (1962). 18. R.B. Clayton. Quart. Rev. 19_, 201 (1965). 19. J .B . Hendrickson. Tetrahedron 7_, 82 (1959). 20. W. Parker, J . S . Roberts, and R. Ramage. Quart. Rev. 2_1, 331 (1967). - 160 -21. D.E. Wolf, C.H. Hoffman, P.E. Aldr ich , H.R. Skeggs, L.D. Wright, and K. Folkers. J . Am. Chem. Soc. 78, 4499 (1956). 22. B.W. Agranoff, H. Eggerer, U. Henning, and F. Lynen. J . Am. Chem. Soc, 81, 1254 (1959). 23. G.J . Popjak and J.W. Cornforth. Biochem. J . 101, 553 (1966). 24. D.H.R. Barton, G.P. Moss, and J . A . Whittle. J . Chem. Soc. (C) 1813 (1968). 25. T.R. Govindochari, B.S. Joshi , and V.N. Kamat. Tetrahedron 21_, 1509 (1965). 26. J .K . Sutherland and E.D. Brown. Chem. Comm. 1060 (1968). 27. F.A. Allen and D. Rogers. Chem. Comm. 588 (1967). 28. I.D. Frantz, jun. and G.J . Schroepfer, jun. Ann. Rev. Biochem. 36, 691 (1967). 29. C. Djerassi, E . J . Eisenbraun, T. George, and B. Biniker. J . Am. Chem. Soc. 82, 3648 (I960). 30. P.A. Plattner and L. Lemay. Helv. Chim.Acta 23, 879 (1940). 31. H. Minato, T. Terasawa, C. Yanaihara, and K. Takeda. Chem. Pharm. B u l l . (Japan) 13, 942 (1965). 32. S.M. McElvain and E . J . Eisenbraun. J . Am. Chem. Soc. 77_, 1599 (1955). 33. H. Minato and K. Takeda. Tetrahedron Letters 22_, 33 (1960). 34. H. Minato and K. Takeda. Chem. Pharm. B u l l . (Japan) 8_, 619 (1961). 35. E. Berner and R. Leonardsen. Liebegs Ann. 538, 1 (1939). 36. E . J . Eisenbraun and S.M. McElvain. J . Am. Chem. Soc. 77_, 3385 (1955). 37. P.A. Levene and H.L. Haller . J . B i o l . Chem. 6£ , 165 (1926). 38. P.A. Levene and H.L. Haller . J . B i o l . Chem. 77, 555 (1928). 39. H. Minato. Tetrahedron Letters 8_, 280 (1961). 40. H. Minato. Tetrahedron 18, 365 (1962). 41. A. Fredga. Acta. Chem. Scand. 1_, 371 (1947). 42. 0. Wallach. Ann. 379, 182 (1911). - 161 -43. F. Sorm, L. Dolejs, and A. Mironov. Tetrahedron Letters 11_, 18 (1960). 44. R.B. Bates and R.C. Slagel . J . Am. Chem. Soc. 84_, 1307 (1962). 45. T. Nozoe and S. Ito in Progress in the Chemistry of Organic Natural Products. Vol . XIX. Edited by L. Zechmeister. Springer-Verlag, Vienna. 1962. p. 52. 46. F. Sorm and L. Dolejs in Guaianolides and Germacranolides. Edition Scientifiques Herman, Paris, and Holden-Day, San Francisco. 1966. 47. H. Hikino, K. Ito, K. Aota, and T. Takemoto. Chem. Pharm. B u l l . (Japan) 16^  43 (1968). 48. G. Buchi, W. Hofheinz, and J . V . Pauls te i l i s . J . Am. Chem. Soc. 88_, 4113 (1966). 49. E.H. White and J . Marx. J . Am. Chem. Soc. 89, 5511 (1967). 50. J . A . Marshall and J . J . Partridge. J . Am. Chem. Soc. 90_, 1090 (1968). 51. G. Komppa. Ann. 307, 209 (1909). 52. G. Buchi, R.E. Erickson, and N. Wakabayashi. J . Am. Chem. Soc. 83_ 927 (1961). 53. G. Buchi, M. Dobler, J . D . Dunitz, B. Gubler, H.P. Weber, and J . Padil la 0. Proc. Chem. S o c , 383 (1963). 54. J . Bredt, H. Thanet, and J . Schmitz. Ann. 437, 1 (1924). 55. S. Danishefsky and D. Dumas. Chem. Comm. 1287 (1968). 56. F. Sorm, V. Herout, B. Tr ivedi , and 0. Motl. Chem. and Ind. (London) 1284 (1963). 57. F. sorm, V. Herout, B. T r i v e d i , and 0. Motl . C o l l . Czech. Chem. Comm. 29, 1675 (1964). 58. F. Sorm, V. Herout, B. Tr ivedi , and 0. Motl. Tetrahedron Letters, 1197 (1964). 59. N.S. Bhacca and D.H. Williams. Application of NMR Spectroscopy in Organic Chemistry. Holden-Day, San Francisco.I960. a)p.159 b)p.49 c)p.77. 60. K.M. Harmon, A.B. Harmon, and F .E . Cummings. J . Am. Chem. Soc 83, 3911 (1961) and references therein. 61. D.H.R. Barton, P. deMayo, and M. Shafig. J . Chem. S o c , 929 (1957). 62. J . A . Marshall and J . J . Partridge. Tetrahedron Letters, 2545 (1966). - 162 -63. C. Heathcock and R. Ratc l i f fe . Chem. Comm. 691 (1968). 64. Kahler. Arch. Pharm. 34, 318 (1830). 65. J . L . Simonsen and D.H.R. Barton. The Terpenes. Cambridge University Press. Vol . I l l , 1952. p. 292. 66. D.H.R. Barton, P. de Mayo, and M. Shafig. Proc. Chem. S o c , 205 (1957). 67. J .D.M. Asher and G.A. Sim. Proc. Chem. S o c , 111 (1962). 68. J .D.M. Asher and G.A. Sim. Proc. Chem. S o c , 1584 (1965). 69. D. Arigoni , 0. Jeger, H. Bosshard, G. Buchi, and L . J . Krebraum. Helv. Chim. Acta 40, 1732 (1957). 70. P. de Mayo in Advances in Organic Chemistry: Methods and Results. Vol, II. Edited by R.A. Raphael, E .C. Taylor, and H. Wynberg. Wiley-Interscience, New York, 1960. p. 367. 71. P. de Mayo and S.T. Reid. Quart.Rev. 15_, 393 (1961). 72. O.L. Chapman. Advances in Photochemistry 1_, 323 (1963). 73. K. Schaffner. Advances in Photochemistry 4_, 81 (1966). 74. P .J . Wagner. Advances in Photochemistry 5_, 21 (1968). 75. P .J ; Kropp. J . Org. Chem. 29, 3110 (1964). 76. D. Caine and J . B . Dawson. J . Org. Chem. 29, 3108 (1964). 77. K. Weinberg, E .C. Utzinger, D. Arigoni , and 0. Jeger. Helv. Chim. Acta 43, 236 (1960). 78. P .J . Kropp. J . Am. Chem. Soc. 86, 4053 (1964). 79. P .J . Kropp and W.F. Erman. J . Am. Chem. Soc. 85_, 2456 (1963). 80. D. Caine, J . F . DeBardeleben J r . , and J .B . Dawson. Tetrahedron Letters, 3627 (1966). 81. H.E. Zimmerman and D.J . Schuster. J . Am. Chem. Soc. 84_, 4527 (1962). 82. H.E. Zimmerman. Tetrahedron 19, suppl. 2, 393 (1963). 83. C. Ganter, E .C. Utzinger, K. Schaffner, D. Arigoni , and 0. Jeger. Helv. Chim Acta 45, 2403 (1962). 84. R. Howe and J . F . McQuill in. J . Chem. Soc 2423 (1955). - 163 -85. M. Yoshida. Chem. Pharm. B u l l . Tokyo 3_, 215 (1955). 86. W. Cocker and T . B . H . McMurry. Tetrahedron 8^ , 181 (1961). 87. D.H.R. Barton, J . E . D . Levisal les , and J . T . Pinhey. J . Chem. S o c , 3472 (1962). 88. H. Ishikawa. J . Pharm. Soc. Japan 76, 504 (1956). 89. M. Nakazaki and K. Naemura. B u l l . Chem. Soc. Japan 37_, 1842 (1964). 90. W. Cocker, H. Gobinsingh, and T . B . H . McMurry. J . Chem. S o c , 1432 (1962). 91. W. Cocker, B. Donnelly, H. Gobinsingh, and T . B . H . McMurry. J . Chem. S o c , 1262 (1963) and references therein. 92. M. Yanagita and A. Tahara. J . Org. Chem. 20_, 959 (1955). 93. M. Yanagita and 0. Ogura. J . Org. Chem. 22, 1092 (1957). 94. A . J . Birch and K.A.M. Walker. J . Chem. Soc. (C), 1894 (1966). 95. A . J . Birch and K.A.M. Walker. Tetrahedron Letters, 1935 (1967) and references therein. 96. C. Djerassi and J . Gutzwiller. J . Am. Chem. Soc. 88, 4537 (1966). 97. F.A. Jardine and G. Wilkinson. J . Chem. Soc. (C), 270 (1967) and references therein. 98. J . A . Osborn, F . J . Jardine, J . F . Young, and G. Wilkinson. J . Chem. Soc. (A), 1711 (1966). 99. H. Bruderer, D. Arigoni , and 0. Jeger. Helv. Chim. Acta 39_, 858 (1956). 100. L.M. Jackman. Applications of Nuclear Magnetic Resonance Spectroscopy in Organic Chemistry. The Pergamon Press, L t d . , Oxford. 1959. (a) p. 99, (b) p. 55. 101. D. Walker and J . D . Hiebert. Chem. Rev. 67_, 153 (1967). 102. E .L . E l i e l , N.L. Al l inger , S.J . Argyal, and G.A. Morrison. Conforma-tional Analysis. Interscience Publishers, New York. 1965. p. 102. 103. R.E. Carbett and H. Young. Australian J . Chem. 16, 250 (1963). 104. M. Nakazaki, H. Chikamatsu, and M. Maeda. Tetrahedron Letters, 4499 (1966). - 164 -105. W. M o f f i t t , R.B. Woodward, A. Moscowitz, W. Klyne, and C. Djerassi . J . Am. Chem. Soc. 83, 4013 (1961). 106. D. Caine and J . F . DeBardeleben, J r . Tetrahedron Letters, 4583 (1965). 107. J . A . Edwards, M.C. Calzada, A. Bowers, J . C . Orr, L. Cardona, R. Urquiza, and M.E.C. Rivera. J . Org. Chem. 29_, 3481 (1964). 108. K . J . Clark, G. I . Fray, R.H. Jaeger, and R. Robinson. Tetrahedron 6, 217 (1959). 109. A . J . Birch and H. Smith. Quart. Rev. 12_, 17 (1958). 110. J .R. Holum. J . Org. Chem. 26, 4814 (1961). 111. D.H.R. Barton, J . T . Pinhey, and R.J . Wells. J . Chem. S o c , 2518 (1964) 112. P. Crabbe. Optical Rotatory Dispersion and Circular Dichroism in Organic Chemistry. Holden-Day, Inc. , San Francisco, p. 90 (1965). 113. T. Sasaki and S. Eguchi. B u l l . Chem. Soc. Japan 41, 2453 (1968). 114. C. Djerassi , J . Osiecki , and W. Herz. J . Org. Chem. 2_2, 1361 (1957). 115. Huang-Minion. J . Am. Chem. Soc. 68, 2487 (1946). 116. K.B. Wiberg. Laboratory Technique in Organic Chemistry. McGraw-Hill Book Co . , Inc . , New York. 1960. p. 245. 117. V. Sykora, J . Cerny, V. Herout, and F. Sorm. C o l l . Czech. Chem. Comm. 19, 566 (1954). 

Cite

Citation Scheme:

        

Citations by CSL (citeproc-js)

Usage Statistics

Share

Embed

Customize your widget with the following options, then copy and paste the code below into the HTML of your page to embed this item in your website.
                        
                            <div id="ubcOpenCollectionsWidgetDisplay">
                            <script id="ubcOpenCollectionsWidget"
                            src="{[{embed.src}]}"
                            data-item="{[{embed.item}]}"
                            data-collection="{[{embed.collection}]}"
                            data-metadata="{[{embed.showMetadata}]}"
                            data-width="{[{embed.width}]}"
                            async >
                            </script>
                            </div>
                        
                    
IIIF logo Our image viewer uses the IIIF 2.0 standard. To load this item in other compatible viewers, use this url:
http://iiif.library.ubc.ca/presentation/dsp.831.1-0061888/manifest

Comment

Related Items