Open Collections

UBC Theses and Dissertations

UBC Theses Logo

UBC Theses and Dissertations

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

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

Notice for Google Chrome users:
If you are having trouble viewing or searching the PDF with Google Chrome, please download it here instead.

Item Metadata

Download

Media
831-UBC_1971_A1 P35_4.pdf [ 8.16MB ]
Metadata
JSON: 831-1.0060082.json
JSON-LD: 831-1.0060082-ld.json
RDF/XML (Pretty): 831-1.0060082-rdf.xml
RDF/JSON: 831-1.0060082-rdf.json
Turtle: 831-1.0060082-turtle.txt
N-Triples: 831-1.0060082-rdf-ntriples.txt
Original Record: 831-1.0060082-source.json
Full Text
831-1.0060082-fulltext.txt
Citation
831-1.0060082.ris

Full Text

APPROACHES TO THE SYNTHESIS OF CADINENE SESQUITERPENES AND THE BIRCH REDUCTION OF SOME 4-ALKYL-A1'9-2-OCTALONES BY WYNONA M. PHILLIPS B.Sc. (Hons.)> University of B r i t i s h Columbia, 1966 A THESIS SUBMITTED IN PARTIAL FULFILMENT OF . THE REQUIREMENTS FOR THE DEGREE'- OF DOCTOR OF PHILOSOPHY i n the Department of CHEMISTRY We accept t h i s thesis as conforming to the required standard THE UNIVERSITY OF BRITISH COLUMBIA, August, 1971 In present ing th i s thes i s in part i ak^fu 1 f i lment of the requirements for an advanced degree at the Un iver s i t y of B r i t i s h Columbia, I agree that the L ibrary sha l l make i t f r ee l y ava i l ab le for reference and study. I fu r ther agree that permission f o r extens ive copying of th i s thes i s f o r s cho la r l y purposes may be granted by the Head of my Department or by h i s representat ives . It is understood that copying or pub l i ca t i on o f th i s thes i s f o r f i nanc i a l gain sha l l not be allowed without my wr i t ten permiss ion. Department o f The Un ivers i ty of B r i t i s h Columbia Vancouver 8, Canada Date * /? 7/ ABSTRACT Part of t h i s thesis describes the i n v e s t i g a t i o n of several synthetic approaches to the cadinane group of sesquiterpenes. The f i r s t approach investigated the preparation of a possible key intermediate of type 118 using the known octalone 114 as s t a r t i n g material. However a l l attempts to obtain octalone 116, a necessary intermediate i n t h i s sequence were unsuccessful. This precluded further use of this approach. The second approach involved preparation of several cross-conjugated dienone systems (125, 133, 139 and 141) and the study of 1,4-conjugate addition of an a l k y l group by means of cuprous ion catalyzed Grignard reagents and l i t h i u m dialkylcuprate reagents. Use of reagents i n which the a l k y l group was methyl or primary e f f e c t e d the desired 1,4-conjugate addition. However when isopropylmagnesium bromide or l i t h i u m diisopropylcuprate reagents were t r i e d no addition products were detected. Evidence i s presented which indicates that e n o l i z a t i o n of the keto system was the main reaction pathway i n these cases. The f i n a l and most successful approach described i s the condensa-tion-annelation approach where condensation between a v i n y l ketone such as 144 and a substituted cyclohexanone de r i v a t i v e of type 143 was investigated. Octalones 162 were prepared by the enamine-annelation reaction employing v i n y l ketone 144 and the enamine of keto alcohol 158. The stereochemistry of octalones 162 was then established. The mixture of epimeric octalones 162 was degraded to decalones 165a and 165b. The stereochemistry of these decalones was unambiguously shown by a combination of chemical and spectroscopic methods. - i i i -Octalones (162a + 162c) were converted into t h i o k e t a l 166 by treatment with ethanedithiol and boron t r i f l u o r i d e etherate. Thioketal 166 was converted into alcohol 167 by desulphurization employing Raney n i c k e l . Treatment of alcohol 167 with chromium t r i o x i d e i n pyridine afforded octalone 168. Octalone 168 was converted i n t o (+)-cadinene dihydrochloride by treatment of the former with methyllithium followed by treatment of the resultant 3° alcohol with anhydrous hydrogen chloride i n ether. The Birch reduction of octalones of type 170 i s described. The octalones were prepared by 1,4-conjugate addition of l i t h i u m d i a l k y l -cuprate reagents to the cross-conjugated dienones of type 171. The preparation of the corresponding authentic c i s - and trans-fused decalones i s described. The r e s u l t s of Birch reduction of octalones 188 to 192 revealed a higher percentage of cis-fused decalone product 1 9 than normally obtained i n other substituted A ' -2-octalone systems. The r e s u l t s also indicated that as the bulk of the C. substituent was 4 increased the product r a t i o of cis-fused decalone to trans-fused decalone also increased. The substituent at the p o s i t i o n also effected the r a t i o of cis : t r a n s decalone obtained. Possible explanations for these r e s u l t s are presented. - i v -TABLE OF CONTENTS Page TITLE PAGE i ABSTRACT i i TABLE OF CONTENTS i v LIST OF FIGURES v i LIST OF TABLES v i i ACKNOWLEDGEMENTS v i i i INTRODUCTION 1 I. General 1 I I . Sesquiterpene Biosynthesis 4 II I . S t r u c t u r a l E l u c i d a t i o n and Stereochemical Studies 12 IV. Synthetic Approaches to the Cadinane-Type Sesquiterpenes 19 -V. Studies of the Birch Reduction of a,g-Unsaturated Ketones 32 DISCUSSION 39 I. General 39 II . Conjugate Addition Approach 40 I I I . Condensation-Annelation Approach 59 IV. Proof of the Stereochemistry of the Condensation Products 84 V. Synthesis, of Cadinene Dihydrochloride 96 1 9 VI. Studies on the Birch Reductions of A ' -2-0ctalone Systems 1 0 0 A. '•: General 100 B. Synthesis of A 1 , 9-2-Octalone Systems 101 C. Synthesis of trans-Fused Decalones 117 - v -Page D. Synthesis of cis-Fused Decalones 128 E. Lithium-Ammonia Reduction Studies 135 EXPERIMENTAL 147 BIBLIOGRAPHY 206 - v i -LIST OF FIGURES Figure Page 1 N.M.R. Spectrum of Octalone 155a 71 2 N.M.R. Spectrum of Octalone 155b 72 3 N.M.R. Spectrum of Octalone 157a 75 4 N.M.R. Spectrum of Octalone 157b 76 5 N.M.R. Spectrum of Octalones (162a + 162c) 82 6 N.M.R. Spectrum of Octalones (162b + 162d) 83 7 N.M.R. Spectrum of Decalone 165a 89 8 N.M.R. Spectrum of Decalone 165b 90 9 Connected Transitions for a Two-Spin System 92 10 . N.M.R. Spectrum of Octalone 190 H 4 11 N.M.R. Spectrum of Octalone 192 116 12 N.M.R. Spectrum of trans-Fused Decalone 209 124 13 N.M.R. Spectrum of trans-Fused Decalone 216 129 14 N.M.R. Spectrum of cis-Fused Decalone 219 132 15 N.M.R. Spectrum of cis-Fused Decalone 221 134 - v i i -LIST OF TABLES Table Page I Chemical Shifts and S p l i t t i n g s for Decalone 165a ... 92 II Chemical Shifts and S p l i t t i n g s for Decalone 165b ... 93 I I I Results Obtained from the Birch Reduction of Octalones 188-192 138 - v i i i -ACKNOWLEDGEMENTS I wish to express my sincere thanks to Dr. Edward Piers for his excellent guidance throughout the course of this research. I t has been a very rewarding experience working under his di r e c t i o n . My thanks are extended to a l l the members of Dr. Piers' research group for the i r many worthwhile discussions. I wish to thank Mr. C. Grant for performing the INDOR experiments and for many helpful discussions. The able typing of this thesis by Miss Diane Johnson i s greatly, appreciated. The f i n a n c i a l support from the National Research Council of Canada (1966-1970) i s gr a t e f u l l y acknowledged. I wish to thank my fianc£ for his encouragement throughout this study and for his help i n the preparation of this manuscript. Also I wish to thank Mr. Paul Worster for proof reading the entire thesis. - 1 -INTRODUCTION I. General Terpenoids are a class of naturally occurring compounds character-ized by a common building block, the isoprene unit (1). Terpenoids are subdivided according to the number of isoprene units embodied i n their structure. The group containing three such units, that i s f i f t e e n carbon atoms, are called sesquiterpenes. There i s an ever widening variety of compounds which f a l l into this class - at least forty different types to date (1). They may.be a c y c l i c , monocyclic, b i c y c l i c , t r i c y c l i c or t e t r a c y c l i c . Generally, each s k e l e t a l type can possess stereochemical variations, p o s i t i o n a l isomerism, as w e l l as a range of functional groups, such as, ketones, alcohols, lactones and oxides. The common biogenesis of terpenoids was postulated by Ruzicka, Eschenmoser and Heusser, i n 1953, as the Isoprene Rule C 2 ) • The l a t t e r was restated as the Biogenetic Isoprene Rule by Ruzicka, Eschenmoser, Jeger and Arigoni, i n 1955, to include compounds formed 1 - 2 -by the union of isoprene u n i t s f o l l o w e d by s k e l e t a l rearrangements (3). For example, t h i s r u l e allowed compounds such as eremophilene (2) to be f o r m a l l y c l a s s i f i e d as sesquiterpenes. Although sesquiterpenes have been recognized f o r over a century, i t has not been u n t i l recent years that meaningful s t r u c t u r a l e l u c i d a -t i o n has been c a r r i e d out. This i s mainly a t t r i b u t a b l e to the f a c t that sesquiterpenes u s u a l l y occur i n e s s e n t i a l o i l s as very complex mixtures. In past years f r a c t i o n a l d i s t i l l a t i o n was the only means used f o r s e p a r a t i o n . Hence, much work was c a r r i e d out w i t h substances which were not homogeneous and o f t e n erroneous conclusions r e s u l t e d . Only i n recent years w i t h the advent of separation techniques such as g a s - l i q u i d chromatography ( g . l . c . ) and t h i n l a y e r chromatography has separation of these complex mixtures been r e a l i z e d . One of the l a r g e s t groups of sesquiterpenes i s the cadinane c l a s s , which contains the b a s i c skeleton and numbering system shown i n _3. The 15 - 3 -basic cadinane class has been divided into four subgroups, d i f f e r i n g only i n the r e l a t i v e stereochemistry at C. , C, and C,. These c l a s s i f i c a -1 D / tions are exemplified by the following s t r u c t u r a l formulae: cadinane (4) , muurolane (5_) , bulgarane (6) and amorphane (7) (4) . t H 6 1_ Naturally occurring compounds belonging to the cadinane class occur as hydrocarbons, for example, 6-cadinene (8) (4,5,6), alcohols, for example, r-cadinol (9) (5,7), i n ring contracted and oxygenated forms, for example, oplopanone (10) (8,9) and t r i c y c l i c s t r u c t u r a l variants, for example, a-cubebene (11) (10). £ H - 4 -10 l l The work of n a t u r a l p r o d u c t c h e m i s t s i n s t r u c t u r a l e l u c i d a t i o n and s y n t h e s i s of t e r p e n o i d s i s e s s e n t i a l f o r a f i r m f o u n d a t i o n f o r more b i o l o g i c a l i n v e s t i g a t i o n s o f t e r p e n o i d s . Thus, t h e work d e s c r i b e d i n t h i s t h e s i s i s , i n p a r t , c o n c e r n e d w i t h g a i n i n g a g e n e r a l s y n t h e t i c e n t r y i n t o the c a d i n a n e c l a s s of s e s q u i t e r p e n e s . I I . S e s q u i t e r p e n e B i o s y n t h e s i s S e s q u i t e r p e n e s a r e b e l i e v e d t o be d e r i v e d by t h e u n i o n of t h r e e ; b i o l o g i c a l C,_ i s o p r e n o i d u n i t s , f o l l o w e d by a v a r i e t y o f c y c l i z a t i o n modes, w i t h o r w i t h o u t s k e l e t a l r e a r r a n g e m e n t s . I t i s g e n e r a l l y b e l i e v e d (1,11) t h a t the C,. u n i t a r i s e s from a c e t y l CoA (12) by t h r e e s u c c e s s i v e c o n d e n s a t i o n s ( C h a r t I , Route I ) t o a f f o r d 3-hydroxy-B-m e t h y l g l u t a r y l CoA ( 1 3 ) . An a l t e r n a t e mode o f c o n d e n s a t i o n o f a c e t y l CoA g i v e s r i s e t o a s t r a i g h t c h a i n d e r i v a t i v e JL4, w h i c h i s b e l i e v e d to be the p r e c u r s o r o f two groups of n a t u r a l p r o d u c t s , the a c e t o g e n i n s and the p h e n o l i c r e s i n s ( C h a r t I , Route I I ) . R e d u c t i o n of 3-hydroxy-B-methyl g l u t a r y l CoA (13) w i t h n i c o t i n a m i d e -a d e n i n e d i n u c l e o t i d e phosphate (NADPH) a f f o r d s m e v a l o n i c a c i d ( 1 5 ) . T h i s i n t e r m e d i a t e i s p h o s p h o r y l a t e d w i t h a d e n i n e t r i p h o s p h a t e (ATP) and - 6 -subsequently decarboxylates to form isopentenyl pyrophosphate (16). Isomerization of the terminal double bond of 16_ affords d i m e t h y l a l l y l pyrophosphate (17) , which upon condensation with 16_ affords geranyl pyrophosphate (18), the monoterpene precursor. Further condensation of geranyl pyrophosphate (18) with isopentenyl pyrophosphate y i e l d s f a r n e s y l pyrophosphate (19), the active precursor of the sesquiterpenes. It i s believed (12) that a l l sesquiterpenes can be formed from either trans- or c i s - f a r n e s y l pyrophosphate, (19) and (20) r e s p e c t i v e l y , by processes inv o l v i n g i n vivo transformations formally resembling c a t i o n i c a l l y induced transannular c y c l i z a t i o n s . I t i s understood of, course, that i n t h i s discussion the representation of formal charges i s only a convenient symbolism, as i n l i v i n g systems fa r n e s y l pyro-phosphate i s probably enzyme bound and the c y c l i z a t i o n s probably f u l l y or p a r t i a l l y concerted. In the representation shown i n Chart I I , the i n i t i a l step i s shown as the i o n i z a t i o n of the a l l y l i c pyrophosphate group from _19_ or 20. The c e n t r a l or terminal double bond can p a r t i c i p a t e with the r e s u l t i n g cation from c i s - f a r n e s y l pyrophosphate (20) to give r i s e to cations Z l to 2A_, while for s t e r i c reasons only the terminal double bond can i n t e r a c t with the cation from trans- farnesyl pyrophosphate giving r i s e to cations 25_ and 2^ 6. These r e s u l t i n g cations _21 to 26^  can undergo proton l o s s , i n t e r a c t i o n with nucleophiles or a series of further rearrangements. Germacrene D (27), a n a t u r a l l y occurring ten-membered carbocyclic r i n g compound, has recently been i s o l a t e d by Hirose et a l . (13) from the e s s e n t i a l o i l of PseudotsUga japonica. I t s presence has also been - 8 -noticed i n a variety of other essential o i l s (13). I t has been postulated that germacrene D (27) could be a c r u c i a l intermediate i n the biosynthesis of several cadinene compounds (13). While no in vivo experimental work has been done to v e r i f y i t s intermediacy i n biosynthesis, laboratory results strongly support this hypothesis (see Chart I I I ) . Germacrene D (27) , was smoothly converted into a mixture of y-muurolene (28), a-amorphane (29), 6-cadinene (8) and y-cadinene (30), thermally, on s i l i c a gel or by acid isomerization. From chemical and spectroscopic data, Hirose (13) proposed that the preferred conformation of germacrene D i s _3JL, where there are transannular interactions between the endocyclic double bonds. I t was suggested (13) that at least the y-isomers of the cadinane group most probably arise through this intermediate and the c y c l i z a t i o n was postulated as i n 32. 32 Several other postulates for the biosynthesis of cadinenes have been proposed and are represented diagrammatically i n Chart IV. Cation 21 was postulated to deprotonate with subsequent double bond isomeriza-tion to afford triene ^ 33, followed by c y c l i z a t i o n to afford cation 34. This cation could then be deprotonated to y i e l d , for example, 5-cadinene (81. - 9 -Chart I I I 31 - 10 -Chart IV - 11 -A second proposal involved cation 2_3, which could undergo a 1,3-hydride s h i f t to cation _35_, followed by c y c l i z a t i o n to y i e l d cation 36. Hydration of this cation from the ot-face would give r i s e to T-cadinol (9), while deprotonation from Cg or from would afford a-muurolene (37) or; 5-cadinene C8) , respectively. The other members of the cadinane family can be derived by analogous processes. For example, i f cation 23 were to undergo two 1,2-hydride s h i f t s and then followed through the above processes, the stereochemistry of the bulgarane (6) and amorphane (_7) groups would r e s u l t . These theoretical cyclizations have received some experimental support by Hirose and coworkers (4), who have a r t i f i c i a l l y generated some of the above cations i n the laboratory and have indeed isolated a mixture of cadinane-type sesquiterpenoids as the rearrangement products. 7 6 - 12 -III. S t r u c t u r a l E l u c i d a t i o n and Stereochemical Studies Since part of t h i s t h e s i s i s concerned w i t h g a i n i n g a s y n t h e t i c entry i n t o the cadinane c l a s s of sesquiterpenes, i t i s p e r t i n e n t to discuss the st u d i e s which l e d to the establishment of the s t r u c t u r e and stereochemistry of the cadinene group. Since p u b l i c a t i o n s d e a l i n g w i t h t h i s t o p i c are numerous and complex, i t i s necessary to l i m i t t h i s d i s c u s s i o n to s e v e r a l examples. Hence, only the establishment of s t r u c t u r e and stereochemistry of g-cadinene, using c l a s s i c a l methods, of a-cadinene, using modern chemical and spe c t r o s c o p i c methods, and of cadinene d i h y d r o c h l o r i d e , using a combination of methods, w i l l be discussed i n any d e t a i l . Semmler and St e n z e l (14), i n 1914, and Ruzicka and coworkers (15), i n 1924, proposed s t r u c t u r e 3^8 f o r cadinene. While the l o c a t i o n of the skeleton by dehydrogenation of cadinene to cadalene (39). Campbell and S o f f e r (16), i n 1942, proposed s t r u c t u r e 40_ f o r cadinene regenerated from cadinene d i h y d r o c h l o r i d e (41) . The l a t t e r double bonds remained u n c e r t a i n , Ruzicka confirmed the b a s i c carbon 40 41 - 13 -compound was f i r s t prepared i n 1840 by Soubeiran and C a p i t a i n e from cubeba o i l (17). From that time forward t h i s d e r i v a t i v e , along w i t h the corresponding dihydrobromide, have played a major r o l e i n i d e n t i f i -c a t i o n and i s o l a t i o n of cadinene compounds. These c r y s t a l l i n e d e r i v a t i v e s circumvented the major problem that plagued workers i n t h i s f i e l d , that i s , t h e i n s e p a r a b i l i t y of the s t r u c t u r a l l y s i m i l a r cadinene compounds. The s t r u c t u r e and stereochemistry of (-)-cadinene dihydrobromide was determined by Hanic i n 1958 (18). He c a r r i e d out an X-ray s t r u c t u r a l determination to confirm s t r u c t u r e 4_2 or i t s m i r r o r image f o r (-)-cadinene dihydrobromide. 42 The d i p o l e moment of t h i s compound was determined and found to be i n good accord w i t h s t r u c t u r e 42_ (19). The absolute c o n f i g u r a t i o n of'42 was then i n v e s t i g a t e d by Herout et a l . (19,20). The r e l a t i v e c o n f i g u r a t i o n at p o s i t i o n s 1, 6 and 7 i s maintained during formation of the d i h y d r o h a l i d e d e r i v a t i v e s ; hence, the determination of the absolute c o n f i g u r a t i o n of only one of these centers was necessary to f i x the absolute c o n f i g u r a t i o n of the n a t u r a l l y o c c u r r i n g cadinene compounds. (-)-Cadinene d i h y d r o c h l o r i d e was dehydrohalogenated w i t h g l a c i a l a c e t i c acid-sodium acetate to y i e l d a mixture of hydrocarbons w i t h 3-cadinene (40) predominating. This mixture was then subjected to o x i d a t i v e degradation to o b t a i n only s l i g h t l y racemized D-(+)-i s o p r o p y l s u c c i n i c a c i d (43). This f i x e s the absolute c o n f i g u r a t i o n at C - 14 -The o p t i c a l rotatory dispersion (o.r.d.) curve of a degradation product of a-cadinol was also investigated. The o.r.d. curve of the degradation product, decalone 44_, bore a mirror image r e l a t i o n s h i p to the o.r.d. curve of decalone _45, of known absolute configuration. These r e s u l t s are i n agreement with the assigned absolute configuration shown i n structure 42 for (-)-cadinene dihydrobromide. As mentioned e a r l i e r the major product from dehydrohalogenation of cadinene dihydrochloride was g-cadinene (40). Thus, t h i s hydrocarbon was the f i r s t cadinene compound to be r e a d i l y a v a i l a b l e for i n v e s t i g a t i o n . However "the very pure g-cadinene"(21) obtained as "regenerated cadinene" was shown to be a mixture with at l e a s t nine components (22). Campbell and Soffer (16) treated the diepoxide of regenerated cadinene with methylmagnesium iodide and subjected the resultant product to dehydrogenation, thus obtaining a 3% y i e l d of 2,7-dimethylcadalene (46) (see Chart V). Sutherland and collaborators (23) repeated t h i s epoxidation experiment and i s o l a t e d at l e a s t four d i f f e r e n t diepoxides. One of the diepoxides formed was then dehydrogenated on p a l l a d i s e d charcoal at 265° for 1 h to give a mixture of cadalene (39) , 2-hydroxycadalene (47) and 7-hydroxycadalene (48). - 15 -Chart V - 16 -Herout et a l . (22) reinvestigated t h e i r "very pure g-cadinene". By an elaborate combination of separation techniques they i s o l a t e d g-cadinene which formed one c r y s t a l l i n e diepoxide, i d e n t i c a l with the one which had been dehydrogenated by Sutherland. Herout then c a r r i e d out a hydroboration-oxidation of g-cadinene to obtain diketone ^9_, which upon deuterium exchange incorporated s i x deuterium atoms. Hence, a l l these r e s u l t s substantiate structure 40_ for g-cadinene. Naya and Kotake (24) using modern techniques elucidated the structure of the most recently i s o l a t e d cadinene, a-cadinene (50). Their work i s i n s t r i k i n g contrast to the inconsistencies and s t r u c t u r a l controversies of the e a r l i e r s t r u c t u r a l e l u c i d a t i o n s . The sesquiterpene, ^15^24' w a S i s ° l a t e d > i - n 1969, from Japanese hop (Humulus lupulus L.). The nuclear magnetic resonance (n.m.r.) spectrum of this compound gave evidence for an isopropyl group, x 9.22 and x 9.09 as a p a i r of three-proton doublets, two v i n y l methyl groups, x 8.35 as broad three-proton s i n g l e t s , and two v i n y l hydrogens, x 4.68 and x 4.48 as one-proton m u l t i p l e t s . The mass spectrum showed a molecular ion peak at m/e 2 0 4 , a base peak at m/e 105, and an abundant peak at m/e 161 (M-43). Upon p a r t i a l hydrogenation with platinum oxide i n methanol-ether a-cadinene (50) gave a sin g l e product, which was i d e n t i c a l with the dihydro compound prepared from y c a d i n e n e (31). Treatment of hydrocarbon 50 with dry hydrogen chloride i n ether afforded (-)-cadinene dihydro-chloride (41). The i n f r a r e d ( i . r . ) spectrum of a-cadinene was d i s t i n c t from that of g-cadinene. Therefore, the Japanese workers proposed structure 50 for a-cadinene. - 17 -In 1966, Westfelt (25) isolated ycadinene (31) from a high b o i l i n g fraction of Swedish sulfate turpentine. Bhattacharyya isolated the closely related Y 2 ~ c a d i n e n e (51) from Indian vetiver o i l (26). Herout and Santany (27) proposed structure j3 for 6-cadinene. After some controversy (28), Hirose et al.(4) and Dev et a l . (5), i n 1968, independently confirmed structure 8^  for 6-cadinene. A compound of structure .52 was mistakenly called 6-cadinene (28) but Sutherland et a l . (6) showed 5J2 to be a d i s t i n c t cadinene compound and named i t w-cadinene. Westfelt et a l . , i n 1964, (29) isolated e-cadinene (53) which was different from the previously isolated e-cadinene (21). Westfelt's d e f i n i t i v e work showed E-cadinene to have structure .53 and the previously isolated compound to be e-muurolene (54). - 18 -Two cadinols have been isolated to date. They are a-cadinol (55) and T-cadinol (9) (30,7). There have been at least eight publications dealing with the structure of 6-cadinol, with chemical and spectral evidence being put forward to support four different structures. This alcohol has been named 6-cadinol (5,31,30), abicaulol (32), cedrelanol (33), and (-)-torreyol (34). I t i s now becoming clear that this alcohol does not belong to the cadinane class but rather to the muurolane class (_5). Thus, 6-cadinol i s now proposed to possess structure 5_6_ (5). OH - 19 -IV« Synthetic Approaches to the Cadinane-type Sesquiterpenes At the time this work was undertaken there were no published syntheses of cadinene hydrocarbons. However recently several syntheses have been published. In 1960 Dev et al.(35,36) synthesized diketone 62^  for comparison with the ozonolysis product from e-cadinene (53). Their approach i s outlined i n Chart VI. The route involved the reduction of 4-isopropyl-6-methoxytetralone (57) with lithium aluminum hydride to give alcohol 58. Birch reduction of .58 with sodium i n l i q u i d ammonia containing ethanol as co-solvent and proton source proceeded i n 65% y i e l d to afford alcohol 59. This two-step sequence was necessary since Birch reduction of the s t a r t i n g tetralone _57_ resulted i n the formation 53 41 - 21 -of a major by-product, the hydrogenolysis product. Oppenhauer oxida-t i o n of 59_ afforded a mixture of octalone enol ethers j>0 and 6 1 . Octalone enol ether 6>0_ was isomerized to the f u l l y conjugated octalone enol ether 61_ when subjected to chromatography on basic alumina. Octalone enol ether ^60 was reduced with l i t h i u m i n l i q u i d ammonia, followed by treatment of the r e s u l t i n g product with aqueous hydrochloric a c i d to a f f o r d , i n 30% y i e l d , ( ± ) - 4 - i s o p r o p y l - t r a n s - d e c a l i n - l , 6 -dione ( 6 2 ) . The stereochemistry of t h i s product was predicted from mechanistic considerations of the Bi r c h reduction. The i n f r a r e d spectrum of dione 62^ was i d e n t i c a l with that of the ozonolysis product of e-cadinene ( 5 3 ) . Dione j52 was treated with excess methyllithium and the r e s u l t i n g g l y c o l treated with gaseous hydrogen chloride to af f o r d , i n 2 0% y i e l d , (±)-cadinene dihydrochloride ( 4 1 ) . The synthetic material was i d e n t i c a l ( i n f r a r e d spectrum, mixed melting point) with an authentic sample prepared from (±)-6-cadinene and anhydrous hydrogen chloride. More recent l y , Soffer and Gunay ( 3 7 , 3 8 ) prepared (+)-cadinene dihydrochloride s t a r t i n g from the monoterpenoid (-)-cryptone ( 6 3 ) . Their synthesis i s outlined i n Chart VII. The c r u c i a l step i n t h e i r synthesis involved the Diels-Alder addition of the dienophile, 2 -ethoxybutadiene - 1 , 3 ( 6 4 ) to (-)-cryptone. Addition of the dienophile from the side trans to the bulky isopropyl group afforded syn-cis-decalone enol ether _6_5. This was followed by acid hydrolysis of the decalone enol ether 6v5 and base-promoted epimerization of the c i s ri n g junction to the more stable ( + ) - 4 - i s o p r o p y l - t r a n s - d e c a l i n - l , 6 - d i o n e ( 6 2 ) . This compound was shown to be the enantiomer of the product of - 22 -Chart V I I - 23 -ozonolysis of e-cadinene. The o p t i c a l l y active diketone 62^ was treated with excess methyllithium and then dry hydrogen chloride to afford (+)-cadinene dihydrochloride, m.p. 116-117°. This product was i d e n t i c a l with an authentic sample obtained from reaction of (-)-y2 _ cadinene with hydrogen chloride. Within the past year several syntheses of cadinene hydrocarbons have been reported. In each case, either the decalone enol ether 65 or the decalone enol ether 66_ was used as the st a r t i n g material. Soffer and Burk (39), u t i l i z e d the cis-decalone enol ether 6j5 as thei r starting material. Treatment of the l a t t e r with either methyl-enetriphenylphosphorane or methyllithium afforded the corresponding trans-fused product. Hence, they proposed that f i r s t a fast reversible enolization-epimerization took place, followed by a nucleophilic attack on the carbonyl carbon. Therefore, they converted i n one step, the cis-decalone enol ether 65_ into the trans o l e f i n i c enol ether 67 employing methylenetriphenylphosphorane. Hydrolysis of the enol ether group was effected, i n 60% y i e l d , by treatment with 0.5 N hydrogen chloride i n 95% ethanol for 25 min at room temperature. The trans nature of the ring junction was shown by a strong positive Cotton effect i n the o.r.d. curve of the resulting product 6>8_. The o l e f i n i c ketone was converted i n 70% y i e l d into (+)-e-cadinene by a second Wittig reaction using methylenetriphenylphosphorane. The synthetic e-cadinene was i d e n t i c a l with the naturally occurring compound i n a l l respects. The synthetic (+)-e-cadinene was converted at low tempera-ture into (+)-cadinene dihydrochloride. This c r y s t a l l i n e derivative was obtained by a second pathway (see Chart V I I I ) . Methyllithium was - 24 -Chart V I I I 65 -25 -added to cis-decalone enol ether 6jj, followed by thorough extraction of the ether with sodium b i s u l f i t e solution yi e l d i n g d i r e c t l y the hydrolysis product 69_. Treatment of 69_ with methyllithium, followed by anhydrous hydrogen chloride afforded (+)-cadinene dihydrochloride. Ke l l y and Eber (40) u t i l i z e d the trans-decalone enol ether 6j) as st a r t i n g material for th e i r synthesis of Y2~cadinene. Their synthesis i s outlined i n Chart IX. Lithium aluminum hydride reduction of 66_ afforded, i n 73% y i e l d , alcohol 70. Hydrolysis of the enol ether group was effected i n 95% y i e l d by treatment of 70. with oxalic acid i n methanol. The resulting keto alcohol 71_ was converted into the d i o l 72 by the Grignard reaction, using methylmagnesium iodide. Selective dehydration of the t e r t i a r y alcohol was successfully carried out, i n 80% y i e l d , by s t i r r i n g with p_-toluenesulfonic acid i n benzene at 52° for 2 h. Sarett oxidation of the secondary alcohol of _73 gave a 65% y i e l d of octalone 7_4_. This compound was smoothly converted into y^-cadinene by reaction with methylenetriphenylphosphorane. Treatment of synthetic y^-cadinene with hydrogen chloride gave a 60% y i e l d of cadinene dihydrochloride. The spectral data of synthetic Y2~ c a c' :'- n e n e were i d e n t i c a l i n a l l respects with those of the naturally occurring compound. Vig and coworkers (41) recently synthesized (+)-y-cadinene by the method outline i n Chart X. The key step i n this synthesis involved 4 5 a Diels-Alder reaction which fixed the position of the A ' double bond. The sta r t i n g material for their synthesis was 2-isopropyl-4-carbethoxybutanal 75 prepared by the al k y l a t i o n of the piperidine enamine of isovalerald.ehyde with ethyl acrylate. Wittig reaction of - 27 -Chart X 1) MeOH-H„0-KOH I 2 ) Cu 76 80 81 - 28 -75 with methallylidenetriphenylphosphorane gave, i n 65% y i e l d , diene ester 76^ Formation of (3-keto-sulfoxide 810, followed by reduction with aluminum amalgam i n aqueous tetrahydrofuran converted diene ester 76_ i n compound 81, which was i d e n t i c a l with n a t u r a l l y occurring (+)-solanone (81). This conversion confirmed the structure of diene ester 76. The Di e l s - A l d e r addition of e t h y l acrylate to diene ester _76 afforded mainly l-methyl-4-carbethoxy-3-(isopropyl-3-carbethoxy-n.-propyl)-cyclohex-l-ene (77). This d i e s t e r 77_ was subjected to potassium t e r t -butoxide i n tert-butanol to a f f o r d , i n 65% y i e l d , the Dieckmann condensation product, keto ester 78^ . Hydrolysis of 78_ with aqueous methanolic potassium hydroxide, followed by decarboxylation over copper powder afforded octalone 79. This octalone was subjected to Wit t i g reaction with methylenetriphenylphosphonium iodide i n sodium hydride-dimethylsulfoxide to y i e l d , i n 75% y i e l d , (t)-y-cadinene (31). The synthetic material gave an i n f r a r e d spectrum i d e n t i c a l with that of the n a t u r a l l y occurring y-cadinene. Interesting s t r u c t u r a l variants of the cadinene skeleton are exemplified by a-cubebene (11) and g-cubebene (82). Recently two syntheses of these compounds have appeared i n the l i t e r a t u r e (42,43). Both syntheses employed as the key step the intramolecular c y c l i z a t i o n of an o l e f i n i c diazoketone to generate the t r i c y c l i c skeleton. The reaction sequence of Yoshikoshi and coworkers (42) i s outlined i n Chart XI. Treatment of (-)-trans-caran-2-one (83) with allylmagnesium bromide, followed by hydroboration-oxidation yielded 20% of c r y s t a l l i n e d i o l 84_. Oxidation with chromium t r i o x i d e i n pyridine afforded the - 29 -Chart XI 90 82 11 - 30 -spirolactone j8_5 i n quantitative y i e l d . Pyrolysis of lactone 85_ i n a sealed tube at 250° with a small amount of pyridine present afforded a 70% y i e l d of diene acid 86. The diazoketone '_87 was prepared from the acid 86_ by standard procedures. Treatment with copper powder i n refluxing cyclohexane gave a mixture of cyclopropyl ketones 88_, 8£ and £0 i n 11, 13 and 1% yields respectively, from spirolactone 85. Hydrogenation of ketone using tris(triphenylphosphine)chloro-rhodium as catalyst afforded ketone 9JL which was i d e n t i c a l with the ozonolysis product of g-cubebene. Treatment of this ketone 91. with methylenetriphenylphosphorane afforded synthetic g-cubebene (82) which was i d e n t i c a l i n a l l respects with the naturally occurring compound. Addition of methyllithium to ketone 9_1 resulted i n attack of the methyl group from the side opposite to the cyclopropane ring to afford cubebol (92). Dehydration of cubebol with thionyl chloride-pyridine yielded a-cubebene (11) and g-cubebene (82) i n a 7:2 r a t i o . The synthetic compounds were i d e n t i c a l i n every respect with the naturally occurring compounds. The synthesis of Piers and coworkers (43) i s outlined i n Chart X I I . Hydroxymethylene derivative S>4 was formed, i n 88% y i e l d , by condensation of commercial (i)-menthone and (+)-isomenthone with ethyl formate i n the presence of sodium methoxide i n benzene. Treatment of 94 with n-butanethiol i n the usual manner gave an 89% y i e l d of the n-butylthiomethylene derivative _95_. Reduction of 95_ with basic methanolic sodium borohydride afforded B-hydroxythioenol ether 9_6 i n quantitative y i e l d . Hydrolysis of 9j5 with 1% hydrochloric acid i n aqueous acetone afforded a mixture of thioenol ether 97_ and the desired a,g-unsaturated aldehyde '9_8, i n a r a t i o of 5:4, respectively. Sodium borohydride - 32 -reduction of aldehyde £8 provided, i n 91% y i e l d , a l c ohol 9£ and alcohol 99a, epimeric at the carbon bearing the isopropyl group. Preparation of the corresponding t r i m e t h y l s i l y l ether d e r i v a t i v e s , followed by preparative g . l . c . i s o l a t i o n afforded epimerically pure t r i m e t h y l s i l y l ether 100. The stereochemistry of th i s compound was demonstrated to be that shown i n structure 100 by an independent synthesis. The t r i m e t h y l s i l y l ether grouping was then hydrolyzed with hot 2% aqueous ethanol to regenerate, i n 98% y i e l d , alcohol £9. Treatment of £9 with phosphorus tribromide i n benzene-pyridine at 0° gave a 77% y i e l d of a l l y l i c bromide 101. The l a t t e r compound was then converted i n t o the corresponding W i t t i g reagent 102 by treatment with two equivalents of carbethoxymethylenetriphenyl-phosphorane i n r e f l u x i n g e t h y l acetate for 2.5 h. Hydrolysis of phosphorane 102 was achieved with 10% potassium hydroxide i n r e f l u x i n g methanol to affo r d , i n 69% y i e l d , o l e f i n i c carboxylic acid 103. This compound was converted i n the usual manner to the corresponding diazoketone, followed by c y c l i z a t i o n with cupric s u l f a t e i n r e f l u x i n g cyclohexane, to af f o r d i n a 5:3 r a t i o cyclopropyl ketones 91a and 9_1. W i t t i g reaction of 91. with methylenetriphenylphosphorane afforded a quantitative y i e l d of (+)-g-cubebene, possessing s p e c t r a l properties i d e n t i c a l with those of n a t u r a l l y occurring g-cubebene. V. Studies of the Birch Reduction of a,g-Unsaturated Ketones Since part of th i s thesis i s concerned with the stereochemistry of the Birch reduction of a,g-unsaturated ketones, i t i s appropriate to b r i e f l y review the theories which have been proposed on th i s subject. In 1954, Barton observed that i n Birch reductions where stereo-isomeric products were possible, the thermodynamically more stable product was almost always formed (44). To account f o r these r e s u l t s he proposed the formation of a t e t r a h e d r a l carbanion which was r e a d i l y capable of i n v e r s i o n (e.g., 104a —>• 104b). indicates an electron or electron p a i r H H 104a 104b The electron pair was assumed to have s p a t i a l requirements between that of a C-H and a C-C bond. Hence, the carbanion would assume i t s more stable configuration, which, upon protonation would a f f o r d the thermodynamically more stable product. Stork and Darling (45) questioned the v a l i d i t y of Barton's theory when they observed that i n several Birch reductions which they performed the products obtained were not only the less stable isomers but also that none of the more stable isomers could be detected. For example, 1 9 i n the B i r c h reduction of trans-7,10-dimethyl-A ' -2-octalone (105), they found e x c l u s i v e l y the trans-fused decalone product. Since i n t h i s case one of the conformations of the c i s enolate anion 106c i s of lower energy than the corresponding trans-intermediate 106a; Barton's theory would predict the cis-fused decalone as product. 0 ?and/or 105 106a 106b 106c - 34 -To account for this apparent anomaly, Stork and Darling (45) modified Barton's theory to include a stereoelectronic requirement. They stated that only t r a n s i t i o n states which maintained continuous overlap between the enolate system and the forming C-H bond at the (3-carbon were allowed. In the above example this requirement means that only t r a n s i t i o n states resembling 106a and 106b would be stereoelectronically allowed. Hence, of the two allowed t r a n s i t i o n states, the one resembling 106a i s of lower energy and protonation would lead to the trans-fused decalone. Robinson (46) continued the investigation with a study of the sodium-1 9 l i q u i d ammonia reductions of A ' -2-octalones and found that the observed ste r e o s e l e c t i v i t y was far greater than could be accounted for when only thermodynamic s t a b i l i t i e s of stereoelectronically allowed t r a n s i t i o n states were taken into account. In contrast to previous workers i n this area, Robinson maintained that the t r a n s i t i o n state for protonation would resemble the highly basic, anion intermediate 107 where the (3-carbon atom remained essent i a l l y t r i g o n a l . Robinson pointed out that i n the reduction of cycloalkyl halides, which have tetrahedral carbanion intermediates, the product. 107 - 35 -s t a b i l i t y does correlate with the observed s t e r e o s e l e c t i v i t y . Therefore, i f the Birch reduction did involve a tetrahedral carbanion as an intermediate, the same trend would be expected. Since this i s not the case, Robinson f e l t that the t r a n s i t i o n state for protonation should be si m i l a r to the conformation of the intermediate anion 107, i n which the g-carbon i s t r i g o n a l . In p a r t i c u l a r , he proposed three possible conformations for the t r a n s i t i o n state for protonation 107a, 107b and 107c. Considering angle and torsional s t r a i n , Robinson concluded that 107a would y i e l d the trans-decalone, that 107b would y i e l d the cis-decalone, and that 107c would generally involve too high an energy (large angle s t r a i n , lack of planarity of the conjugated system) to be a l i k e l y t r a n s i t i o n state. Further examination of 107a and 107b indicated, according to Robinson, that conformation 107a would be the only one i n which the three trigonal carbon atoms could be accommodated with minimal s t r a i n . Hence, for this reason, Robinson predicted a high proportion of trans-fused decalone products i n a l l 1 9 A ' -2-octalone reductions of the type studied. Johnson and coworkers (47) also Investigated the geometry of the @-carbon atom i n the protonation t r a n s i t i o n state. They studied (1 2) Birch reductions of compounds of type 108. Because of A ' s t r a i n 0 107a 107b 107c - 36 -R, 2 0 108 (48), R^ would be more stable i n the a x i a l o r i e n t a t i o n i n the cyclohex-enone r e l a t i v e to the alternate conformation with R^ equatorial. I f the g-carbon atom i s t r i g o n a l i n the t r a n s i t i o n state for protonation, Johnson postulated that the products should r e f l e c t the conformational composition of the s t a r t i n g m a t e r i a l , that i s to say the major product should be the 3,4-cis isomer. On the other hand, i f the t r a n s i t i o n state for protonation i s tetrahedral, the products should r e f l e c t the thermodynamic s t a b i l i t i e s of the carbanion intermediates 104a and 104b. The r e s u l t s obtained from t h e i r experiments indicated that the config-uration of the g-carbon i n the protonation t r a n s i t i o n state varied from tetrahedral for small R groups to t r i g o n a l when R^ was phenyl and capable of d e l o c a l i z i n g the negative charge. Thus, when R^ and were methyl groups the product consisted of trans- and cis-3,4-dimethylcyclo-104a 104b - 37 -hexanone i n a r a t i o of 84:16 respectively, while when R^  and were phenyl groups, 98% of the product was the 3,4-cis isomer. House and coworkers (49,50) i n an elegant series of experiments further investigated the nature of the pathway involved i n the Birch reduction of a,g-unsaturated ketones. Although their experiments w i l l not be discussed i n d e t a i l , i t i s pertinent to note the main conclusions resulting from t h e i r work. Using electron paramagnetic resonance (e.p.r.) studies,-House resolved several important mechanistic features of the Birch reduction of enones. F i r s t l y , he demonstrated an i n i t i a l rapid reversible electron addition to unreduced enones, while calcula-tions showed approximately 40-50% of the unpaired electron resided at the g-carbon atom. Furthermore, reduction of trans-enone 109a and c i s -enone 109b indicated that the i n i t i a l l y formed anion radicals were different but rapidly equilibrated to the more stable form. In the presence of proton donors or lithium cations the l i f e t i m e of t h i s anion radi c a l was substantially lowered. To explain this observation House proposed the formation of an 0-H bond i n the former case and a covalent Li-0 bond or tight ion pair i n the l a t t e r . Moreover, studies of polaro-graphic reduction potentials demonstrated that then and only then could a second electron be added to an a l i p h a t i c enone system; that i s 109a 109b - 38 -to say, f r e e d i a n i o n intermediates are g e n e r a l l y not formed. L a s t l y , by isotope s t u d i e s , House demonstrated that donation of a proton, not a hydrogen atom, was the n o n - r e v e r s i b l e step l e a d i n g to the f i n a l product. As f o r the nature of the geometry of the 8-carbon atom i n the intermediate anion, House favored a pyramidal c o n f i g u r a t i o n by analogy w i t h i s o e l e c t r o n i c enamines and a n i l i n e s . - 39 -DISCUSSION I. General As mentioned previously, the main purpose of the work described i n this thesis was to develop a general synthetic entry into the cadinane type of sesquiterpenes. On inspection of the general s t r u c t u r a l formula for the cadinenes, i t became obvious that the most important and d i f f i c u l t part of any synthetic approach would be the control of the r e l a t i v e stereochemistry at C. , C, and C . The f i r s t objective was, therefore, to synthesize a compound with fixed stereochemistry at these positions and with f u n c t i o n a l i t i e s i n both rings A and B which would allow elaboration to the cadinene compounds. Thus, a compound such as decalone 118 was envisaged as a possible key synthetic intermediate. 3 - 40 -0 ; H 118 I I . Conjugate A d d i t i o n Approach The s t a r t i n g m a t e r i a l which was i n i t i a l l y chosen f o r the synt h e s i s of the re q u i r e d c r u c i a l intermediate of type 118 was the well-known k e t a l octalone 114. This compound was prepared (see Chart X I I I ) by a combination of the procedures of Sa r e t t et a l . (51) and I r e l a n d et a l . (52). Thus, treatment of commercial f u r y l a c r y l i c a c i d (110) w i t h hydrogen c h l o r i d e i n methanol, followed by e s t e r i f i c a t i o n of the r e s u l t i n g product, using methanol i n the presence of a c a t a l y t i c amount of concentrated s u l p h u r i c a c i d a f f o r d e d , i n 84% y i e l d , dimethyl-a-ketopimelate (111). Treatment of the l a t t e r under the usual k e t a l i z a t i o n c o n d i t i o n s (p_-toluenesulfonic a c i d , ethylene g l y c o l ) r e s u l t e d i n a mixture of s t a r t i n g m a t e r i a l and dimethyl-y-ethylenedioxypimelate (112). I t was found that c a r e f u l f r a c t i o n a l d i s t i l l a t i o n s coupled w i t h repeated 114 - 41 -Chart XIII 0 '- H 121 - 42 -k e t a l i z a t i o n reactions were necessary to a f f o r d pure k e t a l d i e s t e r 112. By t h i s r e c y c l i z a t i o n procedure an o v e r a l l 44% y i e l d of k e t a l d i e s t e r 112 was r e a l i z e d . The s p e c t r a l data of compound 112 were i n complete accord with the assigned structure. In p a r t i c u l a r , the i n f r a r e d spectrum of compound 112 exhibited a strong absorption at 5.78 u due to the two ester carbonyls. The n.m.r. spectrum of 112 displayed sharp s i n g l e t s at T 6.05 and T 6.30 due to the k e t a l protons and methyl groups respectively. Treatment of k e t a l d i e s t e r 112 with sodium hydride i n r e f l u x i n g ether for f i v e days afforded, i n 80% y i e l d , the Dieckmann condensation product 113. The fact that the desired transformation had indeed taken place was shown by the s p e c t r a l data of the product 113. The in f r a r e d spectrum of 113 showed absorptions at 5.78, 5.81, 6.0 and 6.15 y while the n.m.r. spectrum exhibited a four-proton s i n g l e t at T 6.01 and a three-proton s i n g l e t at T 6.25 due to the k e t a l protons and the methyl group re s p e c t i v e l y . Condensation of compound 113 with l-diethylamino-3-pentanone methiodide i n the presence of sodium methoxide for three days at room temperature, followed by treatment with aqueous potassium hydroxide afforded, i n 64% y i e l d , the desired octalone 114. The l a t t e r again exhibited the expected s p e c t r a l properties. Of note was the appear-ance i n the i n f r a r e d spectrum of absorptions at 6.0 u and 6.2 y due to the a,8-unsaturated carbonyl group and the carbon-carbon double bond respectively. The u l t r a v i o l e t spectrum exhibited a maximum at 245 my. The n.m.r. spectrum of 114 displayed s i n g l e t s at x 6.09 and x 8.12 a t t r i b u t a b l e to the k e t a l protons and the v i n y l methyl group respectively. - 43 -Thus having octalone 114 readily available, i t was next planned to introduce the trans ring fusion by the well-documented lithium-l i q u i d ammonia reduction (45,46,48). Therefore, compound 114 was subjected to Birch reduction conditions with lithium i n l i q u i d ammonia for two hours. The reaction was then quenched with ammonium chloride and, after appropriate work-up, afforded the corresponding trans-fused decalone 115, i n 97% y i e l d . The fact that the desired reduction had indeed taken place was cl e a r l y shown by the spectral data of compound 115. The infrared spectrum of 115 exhibited an absorption at 5.85 u due to the saturated carbonyl. The n.m.r. spectrum exhibited a doublet at T 8.96 (J = 6 Hz) due to the secondary methyl group and a singlet at T 6.01 due to the ketal protons. The next steps i n the projected synthesis involved introduction 3 4 of the A ' -double bond into decalone 115, followed by cuprous ion catalyzed 1,4-conjugate addition of isopropylmagnesium halide to afford, presumably, a mixture of compounds of the cadinane (118) and bulgarane 3 A (117) s k e l e t a l types. However, introduction of the A ' -double bond 117 118 - 44 -proved e l u s i v e . Standard bromination-dehydrohalogenation techniques, employing a wide v a r i e t y of conditions, r e s u l t e d i n bad mixtures of products. A s p e c t r a l examination of the crude bromination product indicated that under a l l of the reaction conditions t r i e d , bromination was occurring not only on both sides of the keto group but also adjacent to the k e t a l f u n c t i o n a l i t y . Perhaps t h i s observation i s not e n t i r e l y unexpected, since the bromination of ketals i s a w e l l -established phenomenon (53,54). Hence, t h i s method was not s a t i s f a c t o r y for the preparation of octalone 116. Therefore, an alternate method 3 4 for introduction of the A ' -double bond was investigated. Edwards and coworkers (55) had reported that a-formyl ketones could be r e a d i l y dehydrogenated by high-potential quinones, such as 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ). Moreover, t h i s reaction had been widely used i n s t e r o i d chemistry. For example, a-formyl ketone 119 had been shown to undergo transformation to compound 120 upon treatment with one equivalent of DDQ i n dry dioxane for 1 to 10 minutes at room temperature (56). 119 - 45 -Therefore, i t was decided to make use of a s i m i l a r s e r i e s of reactions. Treatment of decalone 115 with e t h y l formate and sodium methoxide i n dry benzene gave r i s e to the corresponding c r y s t a l l i n e hydroxymethylene d e r i v a t i v e 121, i n 80% y i e l d . However, dehydrogenation of 121 with DDQ under the above conditions f a i l e d to y i e l d any of the desired product. This was not p a r t i c u l a r l y s u r p r i s i n g since the i n i t i a l l y formed oxidation product 122 would also be susceptible to further oxidation with DDQ. Hence, i t was proposed that a substituent other than hydrogen would be required at the C^Q p o s i t i o n to p r o h i b i t further oxidation. Since the C^^ p o s i t i o n i s unsubstituted i n sesquiterpenes possessing the cadinane skeleton, i t was e s s e n t i a l to block the p o s i t i o n with a group which could be r e a d i l y removed at a l a t e r stage i n the synthesis. The s t a r t i n g material which was chosen for preparation of a s u i t a b l e C substituted compound was the well-known octalone 123. This material - 46 -was prepared by condensation of the p r e v i o u s l y described keto e s t e r 113 w i t h e t h y l v i n y l ketone i n the presence of a c a t a l y t i c amount of t r i e t h y l a m i n e , to a f f o r d dione 124, i n 84% y i e l d (52). Sodium methoxide-123 124 ca t a l y z e d r i n g c l o s u r e of dione 124 a f f o r d e d , i n 97% y i e l d , octalone 123. The l a t t e r e x h i b i t e d the expected s p e c t r a l p r o p e r t i e s . In p a r t i c u l a r , 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 245 mp. The i n f r a r e d spectrum of 123 e x h i b i t e d absorptions at 5.8 u (est e r carbonyl),6.0 u (unsaturated ketone) and at 6.2 u (carbon-carbon double bond). The n.m.r. spectrum of 123 e x h i b i t e d assignable s i g n a l s at T 8.13 ( s i n g l e t , v i n y l methyl), T 6.30 ( s i n g l e t , methyl e s t e r ) and at x 6.08 ( s i n g l e t , k e t a l protons). Octalone 123 appeared to be p o t e n t i a l l y w e l l s u i t e d to the proposed r e a c t i o n sequence. F i r s t l y , i t had been shown that octalones of t h i s type d i r e c t l y underwent DDQ-promoted dehydrogenation to a f f o r d the corresponding cross-conjugated dienones i n good y i e l d (57). - 47 -Moreover, direct conjugate a l k y l a t i o n at on the proposed dienone 1 9 125 should presumably y i e l d the corresponding 4-alkyl-A ' -2-octalone. 1 9 Retention of the A ' -double bond at th i s stage was mandatory to permit subsequent easy removal of the C^Q carbomethoxy group by base-promoted hydrolysis and decarboxylation. Presumably this reaction would be accompanied by epimerization of the C^Q proton i n the resulting product. Furthermore, i t was proposed from conformational analysis that this epimerization would furnish predominantly the compound with the required stereochemistry for the cadinene compounds. Treatment of octalone 123 with one equivalent of DDQ (57) i n the presence of g l a c i a l acetic acid i n refluxing benzene for 36 h afforded, i n 80% y i e l d , dienone 125. The spectral properties of C0 2CH 3 C0 2CH 3 123 125 compound 125 were i n complete accord with the assigned structure. Thus, the u l t r a v i o l e t spectrum showed a maximum at 243 my, while the infrared spectrum showed absorptions at 5.82, 6.05, 6.15 and 6.25 p. The n.m.r. spectrum of 125 displayed a t y p i c a l AB pair of doublets at T 3.72 and T 3.28 (J = 10 Hz) for the protons at and respectively. In addition, there appeared a three-proton singlet at x 8.04 attributable to the v i n y l methyl, a three-proton singlet at x 6.30 due to the methyl ester and a four-proton singlet at x 6.02 due to the keta l protons. - 48 -The cuprous i o n c a t a l y z e d 1,4-conjugate a d d i t i o n of i s o p r o p y l -magnesium bromide to the cross-conjugated dienone 125 was attempted under a wide v a r i e t y of c o n d i t i o n s but only minor amounts of the d e s i r e d product could be detected. In a l l cases, at l e a s t 90% of the s t a r t i n g dienone 125 was recovered unchanged. This f a c t , coupled w i t h the observation that the r e a c t i o n mixture was a deep red c o l o r i n d i c a t e d that the Grignard reagent was a c t i n g as a base, causing formation of the h i g h l y conjugated enolate anion 126. This anion would, of course, be i n e r t w i t h respect to the d e s i r e d conjugate a d d i t i o n r e a c t i o n . McMurry (58), i n h i s paper on the s y n t h e s i s of s a t i v e n e , reported that a d d i t i o n of isopropylmagnesium bromide to decalone 127 r e s u l t e d i n the formation of only 5% of the d e s i r e d t e r t i a r y a l c o h o l 128. McMurry 126 / \ r o 0 127 128 - 49 -proposed that enolate formation was re s p o n s i b l e f o r the low y i e l d . However, he found that t h i s undesirable s i d e r e a c t i o n could be suppressed by c a r r y i n g out the r e a c t i o n at a lower temperature. Indeed, at a r e a c t i o n temperature of -50°, i t was p o s s i b l e to ob t a i n 50% of the des i r e d product. However, attempted a p p l i c a t i o n of t h i s p r i n c i p l e to our conjugate a d d i t i o n r e a c t i o n proved f r u i t l e s s , since v a r y i n g the r e a c t i o n temperature between 33° and -78° gave no s i g n i f i c a n t change i n the amount of product formed. To gain supporting evidence f o r the proposed enolate formation, copper s a l t c a t a l y z e d 1,4-conjugate a d d i t i o n of isopropylmagnesium bromide to dienone 129"*"was i n v e s t i g a t e d . Since both of the Y~P°sitions (with respect to the carbonyl group) i n dienone 129 are f u l l y s u b s t i t u t e d by a l k y l groups, no enolate formation i s p o s s i b l e . Indeed, treatment of dienone 129 w i t h isopropylmagnesium bromide i n the presence of c u p r i c acetate r e s u l t e d i n the i s o l a t i o n of two products i n the r a t i o of 3:2 r e s p e c t i v e l y . In con t r a s t to s i m i l a r Grignard a d d i t i o n s to dienone 125 no s t a r t i n g m a t e r i a l was recovered. 129 We thank Mr. Paul Worster f o r a sample of t h i s compound. - 50 -125 I t was shown that the major product of the copper s a l t c a t a l y z e d 1,4-conjugate a d d i t i o n of isopropylmagnesium bromide to dienone 129 was compound 130, the 1,4-addition product. The minor product e x h i b i t e d s p e c t r a l data i n accord w i t h e i t h e r s t r u c t u r e 131 or 132, presumably r e s u l t i n g from a c i d - c a t a l y z e d rearrangement (during work-up) of the i n i t i a l l y formed 1,2-addition product (59). A n a l y t i c a l samples of the major and minor products were c o l l e c t e d - 51 -by p r e p a r a t i v e g . l . c . The s p e c t r a l p r o p e r t i e s of compound 130 were i n f u l l accord w i t h the proposed s t r u c t u r e . Thus, the major product 130 gave an u l t r a v i o l e t maximum at 240 mu and a strong a,3-unsaturated carbonyl absorption at 6.0 u and carbon-carbon double bond absorption at 6.25 u i n the i n f r a r e d . The n.m.r. spectrum of compound 130 e x h i b i t e d a p a i r of three-proton doublets at T 9.35 and T 9.08 ( J = 7 Hz) due to the newly introduced i s o p r o p y l methyl groups, three three-proton s i n g l e t s at x 8.85, T 8.82, and x 8.61 due to the three t e r t i a r y methyl groups and a one-proton s i n g l e t at x 4.04 due to the o l e f i n i c proton. The n.m.r. spectrum of 130 a l s o provides evidence that the newly introduced isopropyl group i s i n the a x i a l o r i e n t a t i o n . The a x i a l proton exhibited a p a i r of doublets at x 7.39 and x,7.21 due to the A part of an ABX system, with J.„ = 18 Hz and J., R = 6 Hz, while r J AB AX the equatorial proton exhibited a p a i r of doublets at x 7.46 and x 7.65 due to the B part of the ABX system, with J = 18 Hz and J = A D B X 3 Hz (60). The small AX and BX coupling constants ind i c a t e that the C proton must be equatorial. This i s i n agreement with the expected introduction of the isopropyl group from the side opposite to the angular methyl group. This point w i l l be discussed l a t e r i n more d e t a i l . H H 0 130 - 52 -The minor product 131 or 132 e x h i b i t e d two weak absor p t i o n s , at 6.25 and 6.4 p i n the i n f r a r e d , t y p i c a l of the s t r e t c h i n g v i b r a t i o n s of an aromatic nucleus. The n.m.r. spectrum of the minor product e x h i b i t e d a s i x - p r o t o n doublet at T 8.80 (J = 6.5 Hz) due to the i s o p r o p y l methyl groups, a s i x - p r o t o n s i n g l e t at T 8.75 due to the gem-dimethyl groups a three-proton s i n g l e t at T 7.84 due to the aromatic methyl group and two broad one-proton s i n g l e t s at T 3.20 and x 3.00 due to the aromatic protons. Since the copper s a l t c a t a l y z e d 1,4-conjugate a d d i t i o n of i s o -propylmagnesium bromide to dienone 129 was s u c c e s s f u l , i t appeared even more l i k e l y that formation of enolate 126 was r e s p o n s i b l e f o r the f a i l u r e of the analogous a d d i t i o n s to dienone 125. In an attempt to circumvent t h i s d i f f i c u l t y , a d d i t i o n s to the corresponding dienone aldehyde 133 were proposed. I t was f e l t that even i f enolate formation i n v o l v i n g the carbonyl occurred, the aldehyde carbonyl could s t i l l provide s u f f i c i e n t a c t i v a t i o n to make conjugate a l k y l a t i o n at p o s s i b l e . To t h i s end, condensation of octalone 123 w i t h e t h y l formate 0 C0„CH 133 i n the presence of sodium methoxide i n benzene provided the 3-hydroxy-methylene d e r i v a t i v e 134 i n good y i e l d . - 53 -C0 2CH 3 0 C0 2CH 3 0 HOHG o- 0 123 / 134 0 II H-C 0 133 Dehydrogenation of the hydroxymethylene derivative 134 with DDQ (61) i n dioxane for 3.5 min afforded the corresponding 3-formyl cross-conjugated dienone 133 i n 43% y i e l d . The spectral data were i n complete agreement with the assigned structure. Of note was the appearance i n the infrared spectrum of absorptions at 5.75, 5.9, 6.08, 6.15 and 6.25 y due to the carbonyl groups and the carbon-carbon double bonds. In the n.m.r. spectrum of 133 there appeared one-proton singlets at x -0.25 and at x 2.55 due to the aldehydic proton and the o l e f i n i c proton respectively. Other pertinent n.m.r. signals for compound 133 appeared at x 7.97 (singlet, v i n y l methyl), x 6.25 (singlet, methyl ester) and x 5.98 (singlet, ketal protons). Compound 133 exhibited a maximum at 246 my i n the u l t r a v i o l e t spectrum. Unfortunately, copper s a l t catalyzed Grignard additions to 3-formyl - 5 4 -dienone 133 again f a i l e d to give s y n t h e t i c a l l y u s e f u l y i e l d s of a l k y l a t e d products. A s p e c t r a l examination of the crude r e a c t i o n mixture i n d i c a t e d that some c o n d i t i o n s t r i e d gave r i s e to bad mixtures of products w h i l e other c o n d i t i o n s r e s u l t e d i n recovery of unchanged s t a r t i n g m a t e r i a l . In view of the f a i l u r e of the copper s a l t c a t a l y z e d Grignard reagent to introduce the necessary i s o p r o p y l group v i a 1,4-conjugate a d d i t i o n to the above enone systems, the p o s s i b i l i t y of i n t r o d u c i n g the i s o p r o p y l group by means of l i t h i u m d i i s o p r o p y l c u p r a t e was next i n v e s t i -gated. At the time t h i s work was undertaken, Schudel et a l . (62) published a report concerning the sy n t h e s i s of a n a t u r a l l y o c c u r r i n g s e s q u i t e r p e n o i d , nootkatone. One of the key steps i n t h i s s y n t h e s i s i n v o l v e d the conjugate a d d i t i o n of a methyl group to cross-conjugated dienone 135, using l i t h i u m dimethylcuprate. 3 135 A s e r i e s of p r e l i m i n a r y r e a c t i o n s showed that l i t h i u m dimethyl-cuprate a l s o added a methyl group to the C^ p o s i t i o n of dienones 125 and 133. These r e s u l t s were p a r t i c u l a r l y encouraging and i t was decided to study analogous r e a c t i o n s employing l i t h i u m d i i s o p r o p y l c u p r a t e . However, cuprate a d d i t i o n r e a c t i o n s u s u a l l y r e q u i r e quenching w i t h a c i d . In order to study the r e a c t i o n i n some d e t a i l i t was therefore - 55 -133 desirable to work with a more readily available model system (lacking the k e t a l group). The sequence used for preparation of the model compounds i s outlined i n Chart XIV. Octalone 138 was prepared by the procedure of Meyer et a l . (63). Thus, condensation of l-diethylamino-3-pentanone methiodide with 2-carbethoxycyclohexanone (136) i n ethanol i n the presence of a c a t a l y t i c amount of sodium ethoxide afforded, i n 83% y i e l d , dione 137. The l a t t e r compound exhibited the expected spectral data. In p a r t i c u l a r , the infrared spectrum exhibited a strong absorption at 5.8 u due to the carbonyl groups. The n.m.r. spectrum H of 137 displayed signals at T 8.97 ( t r i p l e t , CH„CH C- , J = 7 Hz), at 0 x 8.72 ( t r i p l e t , CH_3CH20- , J = 7 Hz), at x 7.59 (quartet, -CH^-C-, J = 7 Hz) and at x 5.8 (quartet, -CH--0-, J = 7 Hz). - 56 -Chart XIV I ~ + 140 141 - 57 -i Sodium ethoxide-catalyzed ring closure of dione 137 afforded octalone 138, i n 96% y i e l d . The fact that the expected ring closure had taken place was shown by the spectral data of product 138. Of note was the appearance i n the infrared spectrum of absorptions at 5.8 u (ester carbonyl), 6.0 u (a,{^-unsaturated ketone) and at 6.2 u (carbon-carbon double bond). The u l t r a v i o l e t spectrum exhibited a maximum at 247 my. In the n.m.r. spectrum of 138 were signals due to the ethyl ester as a three-proton t r i p l e t at x 8.72 (J = 7 Hz) and as a two-proton quartet at x 5.72 (J = 7 Hz) and a signal due to the v i n y l methyl group as a three-proton singlet at x 8.12. Treatment of octalone 138 with DDQ (57) i n the presence of g l a c i a l acetic acid i n refluxing benzene for 70 h afforded dienone 139, i n 76% y i e l d . The fact that the expected dehydrogenation had taken place was shown by the spectral data of the product 139. In pa r t i c u l a r the infrared spectrum of 139 exhibited absorptions at 5.8, 6.05, 6.12 and 6.23 y. The n.m.r. spectrum of 139 displayed a t y p i c a l AB pair of doublets at x 3.77 and x 3.33 (J = 10 Hz) for the C_ and C. o l e f i n i c 3 4 protons, respectively. Other assignable signals i n the n.m.r. spectrum appeared at x 8.79 ( t r i p l e t , methyl of ester), x 5.85 (quartet, methylene of ester) and at x 8.05 (singlet, v i n y l methyl). Condensation of octalone 138 with ethyl formate i n the presence of sodium methoxide afforded the corresponding 3-hydroxymethylene , derivative 140, i n 83% y i e l d . Dehydrogenation of the hydroxymethylene derivative 140 with DDQ (61) i n dioxane for 3.5 min afforded the corresponding 3-formyl cross-conjugated dienone 141 i n 65% y i e l d . The spectral data of dienone 141 were i n complete accord with the assigned - 58 -0 CO„CH0CH 3 141 s t r u c t u r e . Of note was the appearance i n the n.m.r. spectrum of 141 of two one-proton s i n g l e t s at x -0.25 and at x 2.55 due to the aldehydic proton and the o l e f i n i c proton, r e s p e c t i v e l y . Other p e r t i n e n t n.m.r. s i g n a l s appeared at x 8.75 ( t r i p l e t , -C02CH2CH_3, J = 7 Hz), at x 7.97 ( s i n g l e t , v i n y l methyl) and at x 5.82 (qu a r t e t , -C02CH_2CH3, J = 7 Hz). 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 247 my. The i n f r a r e d spectrum of 141 showed absorptions at 5.8, 5.9, 6.1, and 6.2 y. With the model compounds 139 and 141 r e a d i l y a v a i l a b l e , the i n v e s t i g a t i o n of l i t h i u m d i i s o p r o p y l c u p r a t e a d d i t i o n s was c a r r i e d out. The conjugate a d d i t i o n r e a c t i o n s were attempted under a wide v a r i e t y of con d i t i o n s i n c l u d i n g a wide temperature range, a v a r i e t y of s o l v e n t s , a v a r i e t y of copper s a l t s and a v a r i e t y of a d d i t i v e s s i m i l a r to those used to enhance the n u c l e o p h i l i c i t y of Grignard reagents - amines, l i t h i u m h a l i d e s and hexamethylphosphoramide (64,65,66). However, w h i l e a l l these c o n d i t i o n s r e a d i l y converted 2-cyclohexenone i n t o 3-iso-propylcyclohexanone, the m a t e r i a l obtained from compounds 139 and 141 i n e x p l i c a b l y showed no signs of the de s i r e d conjugate a d d i t i o n products. - 59 -I I I . Condensation-Annelation Approach In view of the f a i l u r e of the approach inv o l v i n g introduction of the necessary isopropyl group v i a 1,4-conjugate addition to an enone system, an alternate method f or the preparation of an intermediate of type 142 was investigated. The c r u c i a l proposed reaction i n t h i s new approach was the Robinson annelation reaction of an appropriately substituted cyclohexanone of type 143 with a v i n y l ketone such as 144. 11 ll R_ = OH, OCC,H,., 0CCH o; R = H R 2,R 3 = -0-CH2-CH2-0-, H 2 Hence, the f i r s t synthetic objective was the preparation of v i n y l ketone 144. V i n y l ketone 144 was prepared by two d i f f e r e n t routes which are outline i n Chart XV. The general synthetic procedure used i n the f i r s t route was analogous to that used by House and coworkers i n the preparation of - 60 -Chart XV Route I CH 3CH 2CC1 + CH 2N 2 CH3CH2CCH N 2 145 0 II CH 3CH 2CCR 2-P(C 6H 5) 3 CH 3CH 2CCH 2Br 147 Br 0 II CH 3CH 2CCH=P(C 6H 5) 3 148 146 144 Route I I 0 t 0 II (CH 30) 2PCH 2COCH 3 + 149 0C1L 150 - 61 -trans-3-penten-2-one (152) (67). This route i n v o l v e d the W i t t i g r e a c t i o n 152 between a s u b s t i t u t e d phosphorane and an appropriate aldehyde or ketone. For the p r e p a r a t i o n of 144, the two necessary reactants would be the a c y l a t e d phosphorane 148 and isobutyraldehyde. The s t a r t i n g m a t e r i a l used f o r the p r e p a r a t i o n of phosphorane 148, bromomethyl e t h y l ketone (146), was prepared by a procedure analogous to that of Catch et a l . (68). Thus, p r o p i o n y l c h l o r i d e was reacted w i t h e t h e r e a l diazomethane at 0° f o r 30 min to y i e l d diazomethyl e t h y l ketone (145). The l a t t e r was not p u r i f i e d but was immediately converted, i n 70% y i e l d (from p r o p i o n y l c h l o r i d e ) , i n t o bromomethyl e t h y l ketone (146) by r e a c t i o n w i t h anhydrous hydrogen bromide at 0° f o r 30 minutes. Treatment of bromoketone 146 w i t h triphenylphosphine i n benzene aff o r d e d the corresponding a c y l phosphonium bromide 147 i n 85% y i e l d . The l a t t e r , compound 147, was converted i n t o - 62 -phosphorane 148 i n 64% y i e l d , by treatment w i t h aqueous sodium hydroxide f o r 2 hours. An a n a l y t i c a l sample of 148 e x h i b i t e d s p e c t r a l data i n complete accord w i t h the assigned s t r u c t u r e . In p a r t i c u l a r , i n the n.m.r. spectrum of 148, the o l e f i n i c proton was evident as a one-proton s i n g l e t at T 1.0, the phenyl protons were present as an unresolved f i f t e e n - p r o t o n m u l t i p l e t at x 2.50, w h i l e the e t h y l group e x h i b i t e d a two-proton quartet at T 7.66 and a three-proton t r i p l e t at T 8.85 ( J = 7 Hz). The u l t r a v i o l e t spectrum e x h i b i t e d three maxima at 268, 275 and 288 my. The i n f r a r e d spectrum of compound 148 e x h i b i t e d absorptions at 6.60, 6.98, 7.16, and 9.07 y. W i t t i g r e a c t i o n of phosphorane 148 w i t h isobutyraldehyde i n r e f l u x i n g methylene c h l o r i d e f o r 12 h a f f o r d e d , i n 63% y i e l d , t rans-6-methyl-hept-4-en-3-one (144). S p e c t r a l data f o r t h i s compound were i n complete accord w i t h the assigned s t r u c t u r e . In p a r t i c u l a r , the i n f r a r e d spectrum e x h i b i t e d absorptions at 5.98 and 6.14 y due to the carbonyl group and carbon-carbon double bond, r e s p e c t i v e l y . The n.m.r. spectrum of 144 e x h i b i t e d a s i x - p r o t o n doublet at x 8.90 ( J = 7 Hz) f o r the and Cg protons, a three-proton t r i p l e t at x 8.95 and a two-proton quartet at x 7.45 ( J = 7 Hz) f o r the methyl and methylene protons of the e t h y l group and two one-proton doublet of doublets at x 3.98 and x 3.20 f o r the C. and CL o l e f i n i c protons, r e s p e c t i v e l y . The coupling constants - 63 -revealed a t r a n s - o l e f i n i c coupling of 16 Hz for the and C,. hydrogens, a coupling of 6 Hz for the C,. and hydrogens and a long-range coupling of 1.5 Hz for the and hydrogens. It i s interesting to note that d i s t i l l a t i o n of v i n y l ketone 144 at temperatures above 75° resulted i n a d i s t i l l a t e which showed a n.m.r. spectrum quite different from that discussed above. This was due to the presence, i n the d i s t i l l a t e , of s i g n i f i c a n t amounts of the corresponding 3,y-unsaturated ketone, 6-methylhept-5-en-3-one (144a). Thus careful thermal control had to be maintained both i n d i s t i l l a t i o n s and i n the subsequent Robinson annelation reactions employing the v i n y l ketone 144. Since the ov e r a l l y i e l d of the above sequence was not p a r t i c u l a r l y high (23%) and large scale preparation of anhydrous diazomethane proved very laborious, an alternate approach to the synthesis of 6-methylhept-4-en-3-one (144) was investigated (see Chart XV, Route I I ) . This route involved an i n i t i a l Wittig reaction, employing sodium hydride i n DMSO, of isobutyraldehyde with trimethylphosphonoacetate (149) to afford, i n 65% y i e l d , the trans o l e f i n i c ester 150 (69). This compound exhibited the expected spectral properties. Of pertinence were the absorptions i n the infrared spectrum, at 5.8 u (carbonyl group) and at 144 144a - 64 -r^ 3 2 ° ^ O C H : 150 6.05 u (carbon-carbon double bond). The n.m.r. spectrum of 150 dis p l a y e d a s i x - p r o t o n doublet at T 8.95 ( J = 7 Hz) f o r the secondary methyl groups, a three-proton s i n g l e t at T 6.30 f o r the methyl e s t e r group and two one-proton doublet of doublets at x 4.25 and T 3.05 f o r the and protons r e s p e c t i v e l y . The t r a n s - o l e f i n i c c o u p l i n g constant f o r the and hydrogens was 16 Hz, wh i l e the coupling constant f o r the C„ and C. protons was 7 Hz. 3 4 Hy d r o l y s i s of the o l e f i n i c e s t e r 150 w i t h potassium carbonate i n aqueous methanol a f f o r d e d , i n 82% y i e l d , the a,g-unsaturated a c i d 151. This compound e x h i b i t e d the expected s p e c t r a l c h a r a c t e r i s t i c s . 2 0 ^ OH 151 Of note was the appearance, i n the i n f r a r e d spectrum, of the cha r a c t e r -i s t i c a bsorption bands f o r a c a r b o x y l i c a c i d , at 3.1-4.0 u and at 5.9 u and a carbon-carbon double bond absorption at 6.05 u. The n.m.r. spectrum of 151, which exhibited.no s i g n a l due to the methyl e s t e r , - 65 -e x h i b i t e d a o n e - p r o t o n s i n g l e t a t T -2.15 f o r t h e a c i d p r o t o n , two one-p r o t o n d o u b l e t o f d o u b l e t s a t T 2.9 and x 4.2 f o r the and p r o t o n s r e s p e c t i v e l y (J^ ^ = 15.5 Hz, ^ = 6.5 Hz, J £ 4 = and a s i x - p r o t o n d o u b l e t a t T 8.95 ( J = 6.5 Hz) f o r t h e s e c o n d a r y m e t h y l g r o u p s . The n e x t phase i n t h e p r o j e c t e d s y n t h e s i s was t o c o n v e r t a c i d 151 i n t o t h e c o r r e s p o n d i n g a c i d c h l o r i d e , f o l l o w e d by t r e a t m e n t w i t h d i e t h y l cadmium. However, a l l a t t e m p t s t o p r e p a r e t h e a c i d c h l o r i d e o f 151 r e s u l t e d i n s u b s t a n t i a l i s o m e r i z a t i o n o f t h e c a r b o n - c a r b o n d o u b l e bond t o t h e g , y - p o s i t i o n . Due t o t h i s u n d e s i r a b l e bond i s o m e r i z a t i o n a n o t h e r a p p r o a c h was i n v e s t i g a t e d . T h i s a p p r o a c h i n v o l v e d t r e a t m e n t of c a r b o x y l i c a c i d 151 w i t h f r e s h l y p r e p a r e d e t h y l l i t h i u m a t -78° f o r 2 h, f o l l o w e d by r a p i d low t e m p e r a t u r e q u e n c h i n g w i t h aqueous h y d r o c h l o r i c a c i d . I t s h o u l d be n o t e d t h a t t h e s u c c e s s o f t h i s r e a c t i o n depended, t o a l a r g e e x t e n t , upon a j u d i c i o u s c h o i c e o f r e a c t i o n t e m p e r a t u r e , r e a c t a n t c o n c e n t r a t i o n and r e a c t i o n t i m e . That i s , use o f r e a c t i o n t e m p e r a t u r e s g r e a t e r t h a n -40°, b r use o f l o n g e r r e a c t i o n t i m e s , r e s u l t e d i n the f o r m a t i o n o f a c o n s i d e r a b l e amount o f a l c o h o l - c o n t a i n i n g p r o d u c t . On .the o t h e r hand, m i l d e r r e a c t i o n c o n d i t i o n s (more d i l u t e s o l u t i o n s , s h o r t e r r e a c t i o n t i m e s ) r e s u l t e d i n the r e c o v e r y o f f a i r l y c o p i o u s amounts o f s t a r t i n g m a t e r i a l . However, i n o r d e r t o e l i m i n a t e the f o r m a t i o n o f a l c o h o l - c o n t a i n i n g p r o d u c t s , i t was n e c e s s a r y t o t o l e r a t e t h e r e c o v e r y o f some s t a r t i n g m a t e r i a l . I t was f o u n d t h a t . r e c y c l i n g the r e c o v e r e d s t a r t i n g m a t e r i a l s e v e r a l t i m e s a f f o r d e d , i n 92% y i e l d , t r a n s - 6 - m e t h y l h e p t - 4 - e n - 3 - o n e ( 1 4 4 ) . The l a t t e r compound - 66 -e x h i b i t e d s p e c t r a l p r o p e r t i e s which were i d e n t i c a l i n every respect w i t h those of compound 144 p r e v i o u s l y prepared. The above described s y n t h e s i s has s e v e r a l advantages over the previous p r e p a r a t i o n of compound 144. The o v e r a l l y i e l d of the conversion of isobutyraldehyde i n t o 144 v i a the route j u s t described was 50%, obviously a considerable improvement over the f i r s t route C 2 3 % ) . A d d i t i o n a l l y , each of the steps was r e a d i l y adaptable to r e l a t i v e l y l a r g e s c a l e , t h e r e f o r e a l l o w i n g p r e p a r a t i o n of moderately large amounts of v i n y l ketone 144. With the v i n y l ketone 144 now r e a d i l y a v a i l a b l e , i t remained to synthesize the appropriate cyclohexanone compounds of type 143. The keto e s t e r 113 was r e a d i l y a v a i l a b l e by the p r e v i o u s l y discussed s y n t h e t i c method. I t was t h e r e f o r e decided to employ t h i s compound i n the Robinson an n e l a t i o n r e a c t i o n . 113 - 67 -I t i s pertinent to note that Rapson (70) had reported good y i e l d s of base-catalyzed condensation products using the analogous 2-carb-ethoxycyclohexanone (136) and several v i n y l ketones for example, ethylidene acetone (152) and p_-methoxystyryl methyl ketone (153). 153 R = p-MeOC,H -Thus, employing the reaction conditions described by Rapson (70) keto ester 113 was reacted with the v i n y l ketone 144 i n the presence of potassium ethoxide. However, none of the desired octalone could be 144 113 detected although a good recovery of s t a r t i n g material was r e a l i z e d . Keto ester 113 was then treated with v i n y l ketone 144 employing a wide v a r i e t y of base-catalyzed condensation conditions. Again only s t a r t i n g material could be i s o l a t e d from the reaction mixtures. It was f e l t that the k e t a l f u n c t i o n a l i t y might be s t e r i c a l l y hindering approach of v i n y l ketone 144 to the carbanionic s i t e of - 68 -the' enolate anion derived from the keto e s t e r 113. To t e s t t h i s p o s s i b i l i t y an u n s u b s t i t u t e d cyclohexanone d e r i v a t i v e was employed. Thus, the hydroxymethylene of cyclohexanone was prepared i n the usual manner (sodium methoxide, e t h y l formate)(71) and t r e a t e d w i t h the v i n y l ketone 144 under a wide v a r i e t y of base-catalyzed condensa-t i o n c o n d i t i o n s . Again no product could be i s o l a t e d , and i n each case a good recovery of s t a r t i n g m a t e r i a l was r e a l i z e d . In view of the above f a i l u r e s of the base-promoted Robinson a n n e l a t i o n r e a c t i o n , another p o s s i b l e route was i n v e s t i g a t e d . Stork et a l . (72) had reported the f a c i l e condensation of the p y r r o l i d i n e enamine of cyclohexanone w i t h methyl v i n y l ketone to a f f o r d , i n 83% y i e l d , octalone 154. Hence, i t was decided to attempt a s i m i l a r condensation employing the v i n y l ketone 144. Thus, the p y r r o l i d i n e enamine of cyclohexanone and v i n y l ketone 144 were s t i r r e d together at 60° f o r 40 h. Dry dioxane was then added and the s o l u t i o n r e f l u x e d f o r an a d d i t i o n a l 12 h. Subsequent h y d r o l y s i s of the crude r e a c t i o n mixture w i t h hot aqueous a c e t i c a c i d -sodium acetate s o l u t i o n a f f o r d e d , i n 83% y i e l d , octalone 155. H 154 - 69 -H 0 + G N 0 144 155 G.l.c. analysis of octalone 155 indicated the presence of two components i n the r a t i o of 7:3, r e s p e c t i v e l y , i t was proposed that these two components were epimeric at C^ Q. Treatment of octalone 155 under base-catalyzed epimerization conditions (sodium methoxide, methanol) resulted i n the recovery of the same two components, i n the r a t i o of 3:1, r e s p e c t i v e l y . Upon examination of the non-bonded i n t e r a c t i o n s present i n 155a and 155b, i t i s evident that 155a i s the more stable isomer. The two 2 skew in t e r a c t i o n s between the isopropyl group and the and sp centers, present i n 155b, but absent i n 155a, are mainly responsible for t h i s r e l a t i v e s t a b i l i t y . Hence, i t was proposed that octalone 155a was the major component and octalone 155b was the minor component. 0 155a 155b - 70 -Y 0 0 155a 155b These compounds were i s o l a t e d by p r e p a r a t i v e g . l . c . and showed the expected s p e c t r a l p r o p e r t i e s . The major epimer e x h i b i t e d , i n the i n f r a r e d spectrum, absorptions at 6.0 u and 6.15 u due to the carbonyl and carbon-carbon double bond r e s p e c t i v e l y . In the n.m.r. spectrum (see Figure 1) the major epimer e x h i b i t e d s i g n a l s at T 9.21 and T 9.11 as three-proton doublets ( J = 7 Hz)due to the i s o p r o p y l methyl groups and at T 8.26 as a three-proton s i n g l e t due to the v i n y l methyl group. S i m i l a r l y the minor isomer e x h i b i t e d , i n the i n f r a r e d spectrum, absorptions at 6.0 and 6.1 u and i n the n.m.r. spectrum (see Figure 2 ) , s i g n a l s at T 9.11 as a s i x - p r o t o n doublet ( J = 6 Hz) f o r the i s o p r o p y l methyl groups and at T 8.26 as a three-proton s i n g l e t f o r the v i n y l methyl group. Both epimers e x h i b i t e d a maximum i n the u l t r a v i o l e t spectrum at 249 mu". Having r e a l i z e d i n c o r p o r a t i o n of an i s o p r o p y l group i n t o the p o s i t i o n of a simple octalone, i t was next planned to prepare a compound w i t h f u n c t i o n a l i t y i n the B r i n g which would a l l o w e l a b o r a t i o n to the cadinane s k e l e t o n . Thus, h y d r o l y s i s and deca r b o x y l a t i o n of keto e s t e r 113 employing aqueous potassium hydroxide, r e s u l t e d i n a 66% y i e l d of 4-ethylenedioxycyclohexanone 156. This compound e x h i b i t e d s p e c t r a l - 72 t o r 3 CM s 9 a a__o_ - 73 -113 156 p r o p e r t i e s i n complete accord w i t h the assigned s t r u c t u r e . Of note was the appearance i n the i n f r a r e d spectrum of a carbonyl absorption at 5.85 u and the appearance, i n the n.m.r. spectrum, of s i g n a l s at T 5.84 ( s i n g l e t , k e t a l protons) and at x 7.17-8.00 (unresolved m u l t i p l e t , r i n g p rotons). Treatment of the p y r r o l i d i n e enamine of ketone 156 w i t h v i n y l ketone 144 under the p r e v i o u s l y described c o n d i t i o n s a f f o r d e d , i n only 8% y i e l d , octalone 157. Attempts to improve the y i e l d of t h i s r e a c t i o n by v a r y i n g the r e a c t i o n c o n d i t i o n s were uns u c c e s s f u l . Octalone 157, a f t e r e p i m e r i z a t i o n , was shown to be a mixture of octalones 157a and 157b i n a r a t i o of 4:1 r e s p e c t i v e l y . 144 157 - 74 -157a 157b These compounds were i s o l a t e d by p r e p a r a t i v e g . l . c . and e x h i b i t e d the expected s p e c t r a l p r o p e r t i e s . Using the same reasoning as above the major epimer was po s t u l a t e d to be 157a. The, l a t t e r e x h i b i t e d a strong 157a 157b ahsorption at 6.05 y i n the i n f r a r e d spectrum and s i g n a l s i n the n.m.r. spectrum (see Figure 3) at - x 9.18 and x 9.08 ( p a i r of doublets, i s o p r o p y l methyl groups, J = 6.5 Hz), at x 8.23 ( s i n g l e t , v i n y l methyl group) and at x 6.06 ( s i n g l e t , k e t a l p rotons). S i m i l a r l y , the minor epimer e x h i b i t e d a strong absorption at 6.01 y (carbonyl) and a weak absorption at 6.15 y (carbon-carbon double bond) i n the i n f r a r e d . The n.m.r. spectrum of 157b (see Figure 4) e x h i b i t e d s i g n a l s at x 9.08 and x 9.06 ( p a i r of doublets, i s o p r o p y l methyl groups, J = 6.0 Hz), at x 8.23 ( s i n g l e t , v i n y l methyl) and at x 6.06 ( s i n g l e t , k e t a l protons). I t was f e l t that the k e t a l f u n c t i o n a l i t y could be s t e r i c a l l y Figure 4. N.M.R. Spectrum of Octalone 157b. - 77 -h i n d e r i n g approach of the v i n y l ketone 144 to the a-carbon of the enamine of 156, thus accounting f o r the low y i e l d of octalone 157. I t was t h e r e f o r e decided to replace the k e t a l group by the s t e r i c a l l y l e s s demanding a l c o h o l f u n c t i o n a l i t y . To t h i s end, i t was necessary to synthesize 4-hydroxycyclohexanone (158). Q u i n t o l (159) was converted i n t o keto a l c o h o l 158 by a procedure s i m i l a r to that described by Jones and Sondheimer (73). Thus, r e a c t i o n of one equivalent of benzoyl c h l o r i d e w i t h q u i n t o l i n a chloroform-pyridine s o l u t i o n a f f o r d e d , i n 62% y i e l d , q u i n t o l mono-benzoate (160). Oxidation of 160 w i t h chromium t r i o x i d e i n g l a c i a l a c e t i c a c i d a f f o r d e d , i n 87% y i e l d , 4-benzoyloxycyclohexanone (161). 0 II - 78 -T r a n s e s t e r i f i c a t i o n of 161 w i t h methanol i n the presence of a c a t a l y t i c amount of sodium methoxide a f f o r d e d , i n 74% y i e l d 4-hydroxycyclohexanone Now w i t h 4-hydroxycyclohexanone r e a d i l y a v a i l a b l e i t remained to i n v e s t i g a t e the c r u c i a l enamine-annelation r e a c t i o n . Thus, condensa-t i o n of the p y r r o l i d i n e enamine of 4-hydroxycyclohexanone w i t h v i n y l ketone 144 was attempted under a v a r i e t y of c o n d i t i o n s , w i t h a 40% y i e l d of octalone 162 f i n a l l y r e a l i z e d . The optimum c o n d i t i o n s found were as f o l l o w s . The enamine of 158 was s t i r r e d w i t h the v i n y l ketone 144 f o r 36 h at 50°. A l i q u o t samples were taken at r e g u l a r i n t e r v a l s and more v i n y l ketone was added when the i n f r a r e d spectrum of the m a t e r i a l obtained from the a l i q u o t showed the presence of enamine and saturated carbonyl compounds, but the absence of any a,3-unsaturated ca r b o n y l - c o n t a i n i n g compounds. The crude r e a c t i o n mixture was then hydrolyzed w i t h hot a c e t i c acid-sodium acetate s o l u t i o n to a f f o r d octalone 162. (158). 162 144 - 79 -162 Since octalone 162 has three asymmetric centers (C^, and C^), the product obtained from the above condensation could c o n s i s t of one or more of four d i f f e r e n t diastereomers. These, along w i t h the c o r r e s -ponding conformational diagrams are l i s t e d below. - 80 -A n a l y s i s of the condensation product by a combination of g . l . c . and s p e c t r a l methods revealed the presence of a l l four octalones 162a, 162b, 162c and 162d. Again i t was f e l t that a f t e r base-catalyzed e p i m e r i z a t i o n the octalones possessing an e q u a t o r i a l i s o p r o p y l group would predominate over the octalones possessing an a x i a l i s o p r o p y l group. Octalone 162 was t h e r e f o r e subjected to e p i m e r i z a t i o n c o n d i t i o n s (sodium methoxide, methanol) to e s t a b l i s h the f o l l o w i n g e q u i l i b r i a : 162c 162d A f t e r t h i s base-catalyzed e p i m e r i z a t i o n of the crude octalone 162, g . l . c . a n a l y s i s of the product e x h i b i t e d two peaks i n the r a t i o of 7:3, r e s p e c t i v e l y . I t was subsequently shown t h a t the m a t e r i a l g i v i n g r i s e to the major peak c o n s i s t e d of a mixture of products 162a and 162c, while the m a t e r i a l g i v i n g r i s e to the minor peak c o n s i s t e d of a 2 mixture of products 162b and 162d. 2 To avoid confusion i n the subsequent d i s c u s s i o n 162a plus 162c w i l l be t r e a t e d as one product and r e f e r r e d to as the major conden-s a t i o n product, while 162b plus 162d w i l l be t r e a t e d as one product and r e f e r r e d to as the minor condensation product. - 81 -This was shown as described below. The major and minor condensa-tio n products were i s o l a t e d by preparative g . l . c . and exhibited s p e c t r a l properties i n complete accord with the assigned structures. The major condensation product (162a + 162c) exhibited absorptions i n the in f r a r e d spectrum at 2.75 and 2.9 u due to the alcohol f u n c t i o n a l i t y and at 6.05 y due to the a,^-unsaturated carbonyl group. The n.m.r. spectrum of the major condensation product (see Figure 5) displayed signals at x 9.16 and x 9.07 as two three-proton doublets (J = 6.5 Hz) due to the isopropyl methyl groups, at x 8.23 as a three-proton s i n g l e t due to the v i n y l methyl group and at x 6.15 and x 5.82 as mult i p l e t s 3 ( t o t a l l i n g one proton) f o r the protons adjacent to the alcohol groups. The u l t r a v i o l e t spectrum exhibited a maximum at 248 my. The minor condensation product (162b plus162d) exhibited absorptions, i n the inf r a r e d spectrum, at 2.75 and 2.9 y due to the alcohol function-a l i t y , at 6.05 y due to the a,B-unsaturated carbonyl group and at 6.15 y due to the carbon-carbon double bond. The n.m.r. spectrum of this material (see Figure 6) displayed two three-proton doublets at x 9.07 and x 9.04 due to the isopropyl methyl groups (J = 6.5 Hz), at x 8.26 as a three-proton s i n g l e t due to the v i n y l methyl group and at x 6.10 and x 5.78 as unresolved m u l t i p l e t s ( t o t a l l i n g one proton) for the proton 4 adjacent to the alcohol group. The u l t r a v i o l e t spectrum exhibited a maximum at 247 my. 3 Integration of the n.m.r. spectrum indicated that the octalone 162c with an a x i a l alcohol group and the octalone 162a with an equatorial alcohol group were present i n the r a t i o of approximately 3:2, resp e c t i v e l y . 4 Integration of the signals at x 6.10 and x 5.78 indicated that octalone 162b and 162d were present i n a r a t i o of approximately 1:1. 3 - 4 5 6 7 8 9 10 T Figure 6. N.M.R. Spectrum of Octalones (162b + ,162d). • - 84 -A d d i t i o n a l supporting evidence for the nature of the major condensa-t i o n product was obtained as follows: a sample of the major condensation product was c o l l e c t e d by preparative g . l . c . and subjected to Sarett oxidation (74). Thus, oxidation of the major condensation product (162a plus 162c) afforded, i n 94% y i e l d , compound 163 which was shown to be homogeneous by g.l . c . and s p e c t r a l analysis. This demonstrated 162a 162c 163 that the two components of the major condensation product did i n fac t d i f f e r only i n the stereochemistry of the C,-hydroxyl group. o The s p e c t r a l properties of dione 163 were i n complete accord with the assigned structure. The u l t r a v i o l e t spectrum exhibited a maximum at X 247 my. The i n f r a r e d spectrum exhibited absorptions at max 5.85 y (saturated carbonyl group), at 6.05y (a, 6-unsaturated carbonyl group) and at 6.15 y (carbon-carbon double bond). The n.m.r. spectrum of 163 displayed two three-proton doublets at T 9.20 and T 9.07 due to the isopropyl methyl groups (J = 6.5 Hz) and a three-proton s i n g l e t at x 8.12 due to the v i n y l methyl group. IV. Proof of the Stereochemistry of the Condensation Products Having c l e a r l y shown that the proposed Stork enamine-annelation was a f e a s i b l e process, i t was necessary to unequivocally determine the - 85 -re l a t i v e stereochemistry at C, and C,„ of the major and minor condensa-4 10 J tion products. In order to accomplish t h i s objective, i t was planned to convert octalones 162 into the corresponding simple decalone derivatives, unsubstituted at Cg. I t was then hoped that careful spectral studies would unambiguously define the r e l a t i v e stereochemistry at C^  and C^Q. With this objective i n mind, i t was proposed that the next two necessary steps - namely removal of the C^-hydroxyl group and saturation of the conjugated carbon-carbon double bond - could be conveniently carried out i n one main operation. It has been well documented that a,8-unsaturated ketones undergo stereoselective lithium-ammonia reduction, affording the corresponding saturated ketones (45,46,48). Furthermore, i t has been shown that mesylate groups can be hydrogenolyzed under lithium-ammonia reduction conditions (75). Hence, i t appeared that Birch reduction would be the appropriate reaction for degrading octalone 162. Treatment of octalone 162 with methanesulfonyl chloride i n pyridine afforded, i n 85% y i e l d , the corresponding methanesulfonate derivative 164. Evidence that this transformation had indeed taken place was shown i n the infrared spectrum of 164. I t exhibited absorptions at 7.45 and 8.55 u for the methanesulfonate group but no absorptions for the hydroxyl 162 - 86 -group present i n the s t a r t i n g m a t e r i a l . Treatment of 164 w i t h l i t h i u m i n l i q u i d ammonia, c o n t a i n i n g ethanol as co-solvent and proton source, followed by o x i d a t i o n of the r e s u l t i n g crude a l c o h o l s w i t h Jones reagent (76) a f f o r d e d , i n 85% y i e l d , two epimeric decalones 165a and 165b^ i n a r a t i o of 7:3, r e s p e c t i v e l y . | H | H ^ 165a 165b As p r e v i o u s l y described, base-catalyzed e p i m e r i z a t i o n of octalone 155 afforded octalones 155a and 155b i n the r a t i o of 3:1, r e s p e c t i v e l y . 155 155a 155b The f a c t that 165b d i d conta i n a c i s r i n g j u n c t i o n was subsequently unambiguously shown (see p. 95). - 87 -B i r c h r e d u c t i o n of t h i s e q u i l i b r i u m mixture would be expected to y i e l d decalones 165a and 165b i n the r a t i o of 3:1 r e s p e c t i v e l y . As expected B i r c h r eduction of a 3:1 mixture of octalones 155a and 155b w i t h l i t h i u m i n l i q u i d ammonia, followed by quenching w i t h ammonium c h l o r i d e a f f o r d e d , i n 78% y i e l d , a mixture of decalones 165a and 165b i n the r a t i o of 3:1 r e s p e c t i v e l y . The s p e c t r a l p r o p e r t i e s and g . l . c . r e t e n t i o n times of the major and minor products formed from B i r c h r e d u c t i o n of octalone 155 were i d e n t i c a l i n every respect w i t h those of the major and minor products formed from the r e d u c t i o n - o x i d a t i o n of mesylate 164 (obtained from octalone 162). The above r e s u l t s provided confirmatory evidence that the major condensation product of octalone 162 d i d indeed c o n s i s t of octalones 162a and 162c w h i l e the minor condensation product of octalone 162 c o n s i s t e d of octalones 162b and 162d. 162b 162d - 88 -To ensure that no epimerization was taking place p r i o r to reduction i n the lithium-ammonia-ethanol conditions pure octalone 155a was is o l a t e d by preparative g . l . c . and subjected to these conditions. Reduction of octalone 155a with l i t h i u m i n l i q u i d ammonia containing ethanol as co-solvent and proton source, followed by Jones oxidation (76) of the crude product afforded, i n 91% y i e l d , only decalone 165a. 155a 165a This c o n t r o l experiment demonstrated that the mesylate (164) of octalone 162 did not undergo epimerization p r i o r to reduction. That i s to say, the r a t i o s of the reduction products, decalones 165a and 165b, did indeed r e f l e c t the o r i g i n a l composition of octalone 162. The s p e c t r a l properties of the decalones 165a and 165b were i n complete agreement with the assigned structures. Thus, the infrared, spectrum of decalone 165a exhibited an absorption at 5.85 u due to the carbonyl group. In the n.m.r. spectrum of 165a (see Figure 7) signals were evident for the isopropyl methyl groups at x 9.23 and x 9.13 as two three-proton doublets (J = 7 Hz) and for the secondary methyl at x 8.99 as a three-proton doublet (J = 6.5 Hz). S i m i l a r l y , decalone 165b exhibited i n the i n f r a r e d spectrum, an absorption at 5.85 y (carbonyl group). The n.m.r. spectrum of 165b (see Figure 8) displayed two three-proton doublets at T 9.13 and T 9.09 a t t r i b u t a b l e to the isopropyl methyl groups (J = 6 Hz) and a three-proton doublet at T 9.02 for the C - 91 -methyl group (J = 6.5 Hz). That the stereochemistry of the two decalones 165a and 165b was as shown below was subsequently confirmed by internuclear double resonance (INDOR) studies (77,78). Since the re s u l t s obtained from the 165a 165b INDOR experiments played a c r u c i a l r o l e i n the assignment of the stereo-chemistry of the two decalones 165a and 165b, i t i s pertinent to b r i e f l y discuss t h i s technique. This experiment i s performed using a perturbing energy beam of lower power than that used i n eit h e r spin-decoupling (79) or s p i n - t i c k l i n g experiments (80). The observing frequency i s centered exactly on a si n g l e sharp s p e c t r a l l i n e . Then the perturbing energy beam i s swept through the spectrum. This energy beam i s ju s t powerful enough to s h i f t energy l e v e l populations. In order to i l l u s t r a t e t h i s technique, consider a two spin system for which a diagrammatic representation of the connected t r a n s i t i o n s i s given i n Figure 9. It should be emphasized that t h i s i s not meant to be a precise energy l e v e l diagram but i s purely a convenient q u a l i t a -t i v e representation to aid i n p r e d i c t i n g r e s u l t s . Now i f t r a n s i t i o n 1 i s monitored and the perturbing energy beam coincides with the frequency of t r a n s i t i o n 4, l e v e l A w i l l be depopulated and the i n t e n s i t y of the monitored s i g n a l w i l l decrease. Conversely, when the perturbing ( + l / 2 , - l / 2 ) B CC-1/2,+1/2) Figure 9 energy beam coincides with the frequency of t r a n s i t i o n 2, l e v e l B w i l l be depopulated and the i n t e n s i t y of the monitored s i g n a l w i l l increase. Hence, t h i s technique gives r i s e to a spectrum possessing a f l a t baseline except when the perturbing frequency coincides with a t r a n s i t i o n connected to the t r a n s i t i o n being monitored. This technique therefore permits determin-ation of the p o s i t i o n and coupling constants of protons whose signals might otherwise be obscured by the methylene envelope. This technique appeared p a r t i c u l a r l y a t t r a c t i v e because observation of a s p e c t r a l l i n e due to one of the protons at i n decalones 165a and 165b would allow determination of the C^-C^ proton coupling constants and thus provide information on the stereochemistry of the isop r o p y l group. The r e s u l t s obtained from the INDOR spectrums of decalone 165a and decalone 165b are shown i n Table I and Table II res p e c t i v e l y . Table I. Chemical S h i f t s and S p l i t t i n g s f o r Decalone 165a P r o t o n Measured C h e m i c a l S h i f t ( i n Hz from CHC1 3) P r o t o n s Measure S p l i t t i n g s (Hz) 3e 495.8 H„ —H„ 3e 3a 12.7 H 3 a 523.2 H_ -H. 3e 4a 3.8 H 4 580.4 H_ —H. 3a 4a 12.7 H l 517.5 H 1 - ( C H 3 ) 1 6.4 - 93 -Table I I . Chemical S h i f t s and S p l i t t i n g s f o r Decalone 165b Proton Measured Chemical S h i f t ( i n Hz from CHC13) Protons Measured S p l i t t i n g s (Hz) 3e 481.7 H, -H_ 3e 3a 13.0 H 3 a 515.7 H, -H. 3e 4a 3.9 H l 463.1 H 3 a " H 4 a H 1 - ( C H 3 ) 1 13.0 6.4 I t should be noted that the observed s p l i t t i n g s are not corrected f o r higher order e f f e c t s but are almost c e r t a i n l y w i t h i n experimental e r r o r of the true coupling constants. The observed s p l i t t i n g s f o r decalone 165a are i n complete accord w i t h the stereochemistry as depicted i n s t r u c t u r e 165a. 165a H The s p l i t t i n g s observed were 12.7 Hz due to the coupling between the geminal C 3 a x i a l and C 3 e q u a t o r i a l protons, 12.7 Hz due to the d i a x i a l coupling between the C 3 a x i a l and C^ a x i a l protons and 3.8 Hz due to the coupling between the C 3 e q u a t o r i a l and the C^ a x i a l protons These s p l i t t i n g s are i n accord w i t h those p r e d i c t e d f o r compound 165a - 94 -from the Karplus curve (81). Hence, these s p l i t t i n g s confirm that the isopropyl group at i s indeed i n the equatorial o r i e n t a t i o n as shown i n 165a. The s p l i t t i n g s f or the minor product of the Birch reduction of octalone 155 or mesylate 164, s u r p r i s i n g l y p a r a l l e l e d those of the major product, decalone 165a, (discussed above). This indicated that contrary to a l l expectations the minor product obtained from these Birch reductions was not the trans-fused decalone 165c . 165c The INDOR spectrum of decalone 165c would be expected to reveal two small s p l i t t i n g s - one for the diequatorial coupling between the equatorial and equatorial protons and one for the axial-equatorial coupling between the a x i a l and equatorial protons. To explain the observed s p l i t t i n g s i t was necessary to postulate that the Birch reduction had proceeded anomalously to produce the cis-fused decalone 165b. 165b - 95 -This compound would be expected to exhibit two large s p l i t t i n g s - one due to the geminal coupling between the a x i a l and equatorial protons and one due to the d i a x i a l coupling between the a x i a l and a x i a l protons and one small s p l i t t i n g due to the coupling between the equatorial and a x i a l protons. These predictions are i n complete accord with the observed s p l i t t i n g s of 13.0 Hz, 13.0 Hz and 3.9 Hz. This evidence combined with the following chemical evidence confirmed that the minor product from the B i r c h reduction of e i t h e r octalone 155 or mesylate 164 possessed the stereochemistry depicted i n structure 165b. In order to obtain further chemical evidence that decalone 165b was the correct structure f or the minor product obtained from the Birch reduction of mesylate 164 i t was next planned to synthesize this decalone i n another way. Examination of a molecular model of octalone 155b showed that the double bond was very hindered to attack from the B-side by the a x i a l isopropyl group. Hence, hydrogenation of octalone 155b would be expected to y i e l d only the cis-fused decalone as product. Hydrogenation of octalone 155b 0 155b 165b less hindered side i n the presence of a c a t a l y t i c amount of palladium on charcoal, followed by epimerization (sodium methoxide, methanol) of the a-methyl group .in the product, afforded only decalone 165b. This decalone was i d e n t i c a l i n a l l respects with decalone 165b obtained from the - 96 -lithium-ammonia r e d u c t i o n of octalone 155b or mesylate 164. This confirms that the B i r c h r e d u c t i o n of octalone 155b and mesylate 164 had indeed proceeded to give the c i s - f u s e d decalone 165b. The B i r c h r e d u c t i o n r e s u l t s w i l l be discussed i n d e t a i l l a t e r i n t h i s t h e s i s . V. Synthesis of Cadinene Di h y d r o c h l o r i d e With c o n f i r m a t i o n that the r e l a t i v e stereochemistry at C, and C, „ 4 10 of the major c o n s t i t u e n t of octalone 162 was that r e q u i r e d f o r the cadinane s k e l e t o n , i t was next planned to convert t h i s octalone i n t o cadinane d e r i v a t i v e s . The major c o n s t i t u e n t s of octalone 162, octalones 162a plus 162c, were i s o l a t e d by p r e p a r a t i v e g . l . c . and c a r r i e d through the sequence o u t l i n e d i n Chart XVI. Thus, treatment of octalone 162a plus 162c w i t h e t h a n e d i t h i o l i n the presence of boron t r i f l u o r i d e etherate a f f o r d e d , a f t e r r e c r y s t a l l i z a t i o n , a 66% y i e l d of the corresponding t h i o k e t a l 166. The f a c t that the d e s i r e d t r a n s f o r m a t i o n had indeed occurred was shown by the s p e c t r a l data of compound 166. The i n f r a r e d spectrum of compound 166 e x h i b i t e d absorptions at 3.0 u due to the a l c o h o l f u n c t i o n a l i t y , 6.1 u due to the carbon-carbon double bond but no a b s o r p t i o n at 6.0 u (carbonyl group). The n.m.r. spectrum of 166 e x h i b i t e d two three-proton doublets at x 9.21 and x 9.02 a t t r i b u t a b l e to the i s o p r o p y l methyl groups, a one-proton s i n g l e t at x 8.57 due to the hydroxyl proton (exchanged, on deuterium oxide a d d i t i o n ) , a three-proton s i n g l e t at x 8.07 due to the v i n y l methyl, a four-proton s i n g l e t at x 6.67 due to the protons of the t h i o k e t a l group and one m u l t i p l e t ( l e s s than one proton) at x 5.85 due to the e q u a t o r i a l proton adjacent to the hydroxyl group. D e s u l p h u r i z a t i o n of 166 w i t h Raney n i c k e l i n Chart XVI - 98 -r e f l u x i n g ethanol afforded, i n 77% y i e l d , o l e f i n i c alcohol 167. The spe c t r a l data of compound 167 f u l l y substantiated the assigned structure. In p a r t i c u l a r , the n.m.r. spectrum exhibited assignable signals at x 9.23 and T 9.09 (pair of doublets, isopropyl methyl groups, J = 6.5 Hz), at T 8.40 ( s i n g l e t , v i n y l methyl) at x 8.22 ( s i n g l e t , hydroxyl proton, exchanged on addition of deuterium oxide) and at x 6.36 and x 5.85 (multiplets, CHOH) but no s i g n a l for the k e t a l group. Oxidation of 167 with chromium t r i o x i d e i n pyridine afforded, i n 89% y i e l d , the corresponding ketone 168. Confirmation that the expected oxidation had i n f a c t taken place was given by the absorption i n the i n f r a r e d spectrum of 168 at 5.85 u due to a saturated carbonyl but no absorption c h a r a c t e r i s t i c of a hydroxyl group. The n.m.r. spectrum of 168 displayed signals at x 9.21 and x 9.05 (pair of doublets, isopropyl methyl groups, J = 6.5 Hz), and at x 8.36 ( s i n g l e t , v i n y l methyl). Treatment of ketone 168 with methyllithium resulted i n the forma-tio n of alcohol 169 i n 91% y i e l d . An a n a l y t i c a l sample of alcohol 169 was i s o l a t e d by preparative g . l . c . The sp e c t r a l data were i n complete agreement with the assigned structure. In p a r t i c u l a r , the i n f r a r e d exhibited absorptions at 3.0 u(hydroxyl group) and at 6.1 u (carbon-carbon double bond). The n.m.r. spectrum of 169 exhibited assignable signals at x 9.21 and x 9.07 (pair of doublets, isopropyl methyl groups, J = 6.5 Hz), at x 8.81 ( s i n g l e t , t e r t i a r y methyl group) and at x 8.37 (s i n g l e t , v i n y l methyl group). Alcohol 169 was converted into (+)-cadinene dihydrochloride (41) i n 80% y i e l d , by treatment with anhydrous hydrogen chloride i n anhydrous - 99 -ether at 0°. The r e c r y s t a l l i z e d material exhibited an i n f r a r e d spectrum which was i d e n t i c a l with that of authentic (+)-cadinene dihydrochloride.^ The melting point of the synthetic material showed no depression on admixture with the authentic material. Since the stereochemistry of a cadinene dihydrohalide d e r i v a t i v e had been unambiguously shown by X-ray s t r u c t u r a l determination (18) t h i s conversion of alcohol 169 into cadinene dihydrochloride confirmed that a l l of the previously described stereochemical work was correct. That i s to say, the major condensation product, a f t e r epimerization, of the enamine-annelation reactions did indeed possess the stereochemistry necessary for the synthesis of the cadinane sesquiterpenes. Hence, the enamine-annelation approach i s p a r t i c u l a r l y a t t r a c t i v e , since i n one step i t y i e l d s a compound possessing a l l the s k e l e t a l features required for elaboration to the cadinane compounds. This permits the synthetic sequence to be kept r e l a t i v e l y simple and short. However, t h i s sequence does possess several disadvantages. One serious complication i s the production of c l o s e l y r e l a t e d epimeric products, requiring preparative g . l . c . p u r i f i c a t i o n at the i n i t i a l stages of the sequence. In addition, t h i s approach does not make allowance for the r e g i o s e l e c t i v e introduction of the required double bond into the B r i n g . This l a t t e r disadvantage coupled with the f a c t that authentic samples of the cadinene hydrocarbons were not a v a i l a b l e hindered attempts to obtain and i d e n t i f y to- and 6-cadinene, (52) and (8) r e s p e c t i v e l y , by dehydration of alcohol 169. However, i f the above mentioned disadvantages could be 6 We thank M.D. Sutherland for a generous sample of (+)-cadinene dihydrochloride. - 100 -e f f e c t i v e l y overcome, t h i s s y n t h e t i c sequence would provide an e f f i c i e n t entry i n t o the cadinane type of sesquiterpenes. 1 9 VI. Studies on the B i r c h Reductions of A ' -2-0ctalone Systems A. General Although a number of t h e o r i e s have been proposed to e x p l a i n the 1 9 stereochemistry of the products of B i r c h r e d u c t i o n of A ' -2-octalone systems, research to date has f a i l e d to adequately e x p l a i n the product s e l e c t i v i t y observed i n these reductions (48). G e n e r a l l y , l i t h i u m -1 9 ammonia reductions of A ' -2-octalones proceed to y i e l d a high p r o p o r t i o n (^98%) of the corresponding trans-fused decalone. As p r e v i o u s l y discussed, lithium-ammonia r e d u c t i o n of octalone 155b proceeded anomalously to a f f o r d s t e r e o s e l e c t i v e l y , the c i s - f u s e d decalone 165b; w h i l e s i m i l a r 0 I • = H 155b 165b redu c t i o n of the corresponding C^ e q u a t o r i a l l y s u b s t i t u t e d octalone 155a proceeded normally to a f f o r d the trans-fused decalone 165a. z H 155a 165a - 101 -Since an explanation f o r the anomalous r e s u l t obtained i n the B i r c h r e d u c t i o n of octalone 155b was not obvious, i t was decided to extend the i n v e s t i g a t i o n to i n c l u d e lithium-ammonia reductions of analogous octalone systems of type 170. I t was thus hoped that these r e s u l t s would a s s i s t i n c l a r i f y i n g some of the f a c t o r s governing the stereochemical outcome of B i r c h reductions of t h i s type of octalone. 1 9 B. Synthesis of A ' -2-0ctalone Systems The f i r s t o b j e c t i v e was, t h e r e f o r e , to synthesize octalones of type 170. I t was decided that of the number of p o s s i b l e routes which might be employed i n the c o n s t r u c t i o n of these o c t a l o n e s , the scheme i n v o l v i n g 1,4-conjugate a d d i t i o n of l i t h i u m d i a l k y l c u p r a t e s to c r o s s -conjugated dienones of type 171 was both a t t r a c t i v e and general. - 102 -It i s obvious that i n dienones of type 171, R^ can not be hydrogen. Furthermore syntheses of octalones of type 170 with R^ = H generally are ambiguous with respect to the r e l a t i v e stereochemistry at and C. . For these reasons a methyl group was chosen as the C. bridgehead l u 1 u substituent i n contrast to the hydrogen substituent present i n the compound o r i g i n a l l y studied, octalone 155b. The s t a r t i n g materials which were chosen f or the synthesis of octalones of type 170 were the two well-known octalones 172 and 173 (see Chart XVII). These octalones were prepared by the l i t e r a t u r e procedure of Marshall and Fanta (82). Thus,condensation of 2-methylcyclohexanone with methyl v i n y l ketone at -10° i n the presence of a c a t a l y t i c amount of sodium ethoxide afforded the c i s - k e t o l 174. The l a t t e r was subjected to potassium hydroxide-catalyzed dehydration to af f o r d , i n 48% y i e l d , 10-methyl-A 1' 9-2-octalone (172). S i m i l a r l y , condensation of 2-methylcyclohexanone with e t h y l v i n y l ketone, followed by base-catalyzed dehydration of the intermediate k e t o l afforded, i n 60% y i e l d , 1,10-dimethyl-A 1' 9-2-octalone (173) (83). Treatment of octalone 1721 with DDQ (84) i n the presence of benzoic acid i n r e f l u x i n g anhydrous benzene for 48 h afforded a mixture of the desired cross-conjugated dienone 175 plus trienone 176, i n a r a t i o of 88:12 res p e c t i v e l y . Hydrogenation of t h i s mixture (175 +176) under c a r e f u l l y c o n t r o l l e d b a s ic conditions i n the presence of a c a t a l y t i c amount of palladium on charcoal afforded, i n 70% y i e l d (from octalone 172), cross-conjugated dienone 175 (85). Dehydrogenation of octalone 173 with DDQ i n the presence of g l a c i a l a c e t i c acid i n . r e f l u x i n g anhydrous benzene f o r 60 h afforded, i n 84% y i e l d , the corresponding cross-conjugated, dienone 177 (57). The - 103 -177 173 - 104 -s p e c t r a l data of dienone 177 f u l l y corroborated the s t r u c t u r a l a s s i g n -ment. In p a r t i c u l a r the i n f r a r e d spectrum e x h i b i t e d absorptions at 6.01, 6.12 and 6.21 y. The n.m.r. spectrum of 177 d i s p l a y e d a t y p i c a l AB p a i r of doublets at T 3.80 and T 3.31 (J = 10 Hz) due to the and o l e f i n i c protons. Other assignable s i g n a l s i n the n.m.r. spectrum appeared at T 8.78 ( s i n g l e t , t e r t i a r y methyl) and at T 8.12 ( s i n g l e t , v i n y l methyl). 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. I t was next planned to i n v e s t i g a t e the 1,4-conjugate a d d i t i o n s of the appropriate l i t h i u m d i a l k y l c u p r a t e reagents to the now r e a d i l y a v a i l a b l e cross-conjugated dienones 175 and 177. Since the conjugate a d d i t i o n of l i t h i u m d i a l k y l c u p r a t e reagents i s c r u c i a l to the remaining s y n t h e s i s , i t would be advantageous to di g r e s s to consider the nature of the pathway of 1,4-conjugate a d d i t i o n s of cuprate reagents to enone systems. The proposed mechanism (65,67,86) f o r 1,4-conjugate a d d i t i o n of l i t h i u m d i a l k y l c u p r a t e reagents i s as f o l l o w s : While e x t r a p o l a t i o n s of the stereochemical r e s u l t s obtained i n cuprous i o n ca t a l y z e d 1,4-conjugate a d d i t i o n of Grignard reagents to enone systems, to the product stereochemistry of the analogous l i t h i u m - 105 -dialkylcuprate reactions must be done with caution, there are many analogies i n the l i t e r a t u r e where conjugate a l k y l a t i o n by a copper s a l t catalyzed Grignard reagent and the analogous cuprate reagent proceed to y i e l d products with the same stereochemistry. With t h i s precaution i n mind, i t i s pertinent to discuss the elegant work of Marshall and Andersen (87) who studied the cuprous ion catalyzed conjugate addition of several Grignard reagents to l,l-dimethyl-trans-3-octal-2-one (178). B r i e f l y , these workers proposed that the conjugate addition of an a l k y l group, by means of cuprous ion catalyzed Grignard reagents, to an octalone of type 178 must, for s t e r e o e l e c t r o n i c reasons, take place v i a the c h a i r - l i k e t r a n s i t i o n state 179a and/or the boat-like t r a n s i t i o n state 179b. Marshall and Andersen's experiments showed that, i n the 179b 181 R = CH 182 R = C,H_ o 5 184 R = (CH 3) 2CH-- 106 -absence of l a r g e s t e r i c f a c t o r s the former t r a n s i t i o n s t a t e 179a was favored over the l a t t e r t r a n s i t i o n s t a t e 179b. Hence, the a d d i t i o n of methylmagnesium i o d i d e to octalone 178 produced decalone 180 as the major conjugate a d d i t i o n product, w h i l e decalone 181 was formed i n minor amounts. However, as the bulk of the Grignard reagent was increased, s t e r i c hindrance to a x i a l a t t a c k v i a t r a n s i t i o n s t a t e 179a al s o increased. When phenylmagnesium bromide was employed as the Grignard reagent the only product formed was 182 (attack v i a t r a n s i t i o n s t a t e 179b). F i n a l l y , i n the case of isopropylmagnesium bromide s t e r i c hindrance to a x i a l approach i n t r i n s i c i n t r a n s i t i o n s t a t e 179a was approximately balanced by the unfavorable nature of the b o a t - l i k e t r a n s i t i o n s t a t e 179b. Consequently the two products 183 and 184 were formed i n approximately equal amounts. I f one now considers the conjugate a d d i t i o n of l i t h i u m d i a l k y l -cuprate reagents to dienones 175 and 177, by analogy w i t h the above p r i n c i p l e s t r a n s i t i o n s t a t e s 185a and 185b can be proposed. I t i s immediately obvious that the important f a c t o r s i n these t r a n s i t i o n s t a t e s 185a and 185b are the presence of the angular methyl group at C^Q and the absence of the C^ hydrogen (removing one s y n - a x i a l R-H i n t e r a c t i o n i n t r a n s i t i o n s t a t e 185a). - 107 -Molecular models i n d i c a t e that i f s t e r e o e l e c t r o n i c c o n t r o l i s to be maintained i n t r a n s i t i o n s t a t e 185b, then the incoming a l k y l group must approach the molecule i n such a way that i t i s n e a r l y e c l i p s e d w i t h the C^Q angular methyl group. The r e s u l t i n g s t e r i c and t o r s i o n a l s t r a i n (88,89) should be the dominant f a c t o r and should ensure that t r a n s i t i o n s t a t e 185a i s favored over t r a n s i t i o n s t a t e 185b. Hence, i t was f u l l y expected that the i n t r o d u c t i o n of an a l k y l group i n the l i t h i u m d i a l k y l c u p r a t e conjugate a d d i t i o n r e a c t i o n s would be h i g h l y - 108 -s t e r e o s e l e c t i v e and furthermore i t was p r e d i c t e d that the product should contain the stereochemistry depicted i n 186 . In a l l cases stu d i e d R R' 186 the l i t h i u m d i a l k y l c u p r a t e a d d i t i o n s were h i g h l y s t e r e o s e l e c t i v e as a n a l y s i s by a combination of g . l . c . and s p e c t r a l methods of the r e a c t i o n product revealed the presence of only one of the two p o s s i b l e epimeric compounds. I t should be noted that i n the p r e v i o u s l y discussed systematic study of conjugate a d d i t i o n s of l i t h i u m d i a l k y l c u p r a t e reagents to cross-conjugated dienone systems s e v e r a l important experimental requirements were worked out. I t should be pointed out that House and coworkers (65,67) had done a d e t a i l e d study of the p r o p e r t i e s of l i t h i u m dimethylcuprate but at the time t h i s work was underway no analogous in f o r m a t i o n was a v a i l a b l e f o r l i t h i u m d i v i n y l - or l i t h i u m d i i s o p r o p y l c u p r a t e . I n i t i a l l y a procedure analogous to that used by House et a l . (65) f o r the p r e p a r a t i o n of l i t h i u m dimethylcuprate was employed i n the pr e p a r a t i o n of l i t h i u m d i v i n y l - or l i t h i u m d i i s o p r o p y l -cuprate. Thus, two equivalents of the a l k y l l i t h i u m reagent were added to one equivalent of cuprous i o d i d e i n ether at 0°. I t was found that a d d i t i o n of cross-conjugated dienones of type 171 to s o l u t i o n s of l i t h i u m d i v i n y l c u p r a t e or l i t h i u m d i i s o p r o p y l c u p r a t e , prepared i n the - 109 -above manner gave r i s e to only poor y i e l d s of conjugate addition products i n the former case and only recovered s t a r t i n g material or polymeric material i n the l a t t e r case. In an attempt to enhance the r e a c t i v i t y to 1,4-conjugate addition of l i t h i u m diisopropylcuprate so l u t i o n s , reactions were t r i e d i n the presence of various a d d i t i v e s . Indeed f a i r y i e l d s of conjugate addition products could be r e a l i z e d i f anhydrous li t h i u m bromide was present i n the reaction mixture. Repetition of the reactions at various temperatures revealed that better y i e l d s of conjugate addition products were obtained i f these reactions were run at -78°. However, y i e l d s obtained i n these reactions were only moderate when compared with the y i e l d s obtained i n the analogous l i t h i u m dimethylcuprate reactions (62). Hence, another method of preparing the cuprate reagents was investigated. In t h i s approach the ether-soluble copper (I) iodide-tri-n-butylphosphine complex prepared by the method of Kaufman et a l . (90) was employed instead of cuprous iodide. The r e s u l t i n g organocopper I solutions were homogeneous i n contrast to the c o l l o i d a l appearance of those previously prepared. Lithium diisopropylcuprate prepared with the phosphine complex again required the addition of anhydrous l i t h i u m bromide before 1,4-conjugate addition to cross-conjugated dienones would occur. While use of the phosphine complex i n preparation of these reagents gave r i s e to better y i e l d s of 1,4-conjugate addition products i t also complicated the i s o l a t i o n procedures. It was found that f r a c t i o n a l d i s t i l l a t i o n s of the crude reaction mixtures, followed by chromatography of the low b o i l i n g f r a c t i o n s on s i l i c a gel allowed i s o l a t i o n of the desired product. This p u r i f i c a t i o n procedure was - 110 -used i n a l l the f o l l o w i n g r e a c t i o n s employing l i t h i u m d i v i n y l c u p r a t e and l i t h i u m d i i s o p r o p y l c u p r a t e . In an attempt to optimize the y i e l d s of conjugate a d d i t i o n products, the v a r i a b l e parameters of r e a c t i o n time, temperature, c o n c e n t r a t i o n , and quenching procedures were next i n v e s t i g a t e d . Again i t was found that use of low temperatures (-78°) improved the y i e l d s . Y i e l d s obtained upon varying the r e a c t i o n time from 4 h to 36 h appeared to be i n v a r i a n t although use of r e a c t i o n times shorter than 4 h g e n e r a l l y r e s u l t e d i n some recovered s t a r t i n g m a t e r i a l . The r e a c t i o n s were quenched by dropwise a d d i t i o n of the r e a c t i o n mixture to a r a p i d l y s t i r r e d s o l u t i o n of aqueous a c i d . The product y i e l d s were found to be s u b s t a n t i a l l y lower i f t h i s quenching procedure was not employed. A f t e r attempting the a d d i t i o n s under a v a r i e t y of con-c e n t r a t i o n s i t was found that optimum y i e l d s were obtained when the s o l u t i o n was between 0.01 and 0.005 molar i n the organocopper I reagent. The l i t h i u m d i a l k y l c u p r a t e conjugate a d d i t i o n r e a c t i o n s were next attempted employing the optimum co n d i t i o n s l i s t e d above. Thus, an e t h e r e a l s o l u t i o n of dienone 175 was added to a s o l u t i o n of l i t h i u m dimethylcuprate and s t i r r e d at 0° f o r 2 h. A f t e r the appropriate workup the crude product was p u r i f i e d by d i s t i l l a t i o n , followed by chromato-graphy of the d i s t i l l a t e on s i l i c a g e l , to a f f o r d , i n 82% y i e l d , octalone 188 . That the d e s i r e d t ransformation had taken place was shown c l e a r l y 175 188 - I l l -by the s p e c t r a l data of compound 188 (91). In p a r t i c u l a r the i n f r a r e d spectrum of octalone 188 showed a carbonyl absorption at 6.0 y and a carbon-carbon double bond absorption at 6.15 y. The n.m.r. spectrum of 188 e x h i b i t e d a three-proton doublet at T 9.02 (J = 7 Hz) a t t r i b u t a b l e to the newly introduced methyl group, a three-proton s i n g l e t at x 8.74 due to the t e r t i a r y methyl group and a one-proton s i n g l e t at x 4.30 due to the v i n y l hydrogen. There were no s i g n a l s due to the and o l e f i n i c protons present i n the s t a r t i n g m a t e r i a l . The u l t r a v i o l e t spectrum of 188 e x h i b i t e d a maximum at 239 my. Treatment of dienone 175 w i t h l i t h i u m d i v i n y l c u p r a t e f o r 4 h at -78°, followed by appropriate workup and p u r i f i c a t i o n , afforded octalone 194 i n 73% y i e l d . That the v i n y l group had been introduced at the C. 175 194 p o s i t i o n of dienone 175 was c l e a r l y shown by the s p e c t r a l data of the product. The n.m.r. spectrum of 194 d i s p l a y e d s i g n a l s due to the v i n y l group as an unresolved m u l t i p l e t (x 3.89-5.13) a s i g n a l due to the t e r t i a r y methyl group as a three-proton s i n g l e t at x 8.72 and a s i g n a l due to the v i n y l proton at C - l as a one-proton s i n g l e t at x 4.25. The i n f r a r e d spectrum of 194 e x h i b i t e d absorptions at 6.0 y and 10.9 y due to the a,8-unsaturata.d carbonyl group and the v i n y l group r e s p e c t i v e l y . Octalone 194 proved to be q u i t e unstable and hence the v i n y l group was - 112 -immediately transformed to the d e s i r e d e t h y l group. Since i t was feared that standard hydrogenation procedures might r e s u l t i n considerable r e d u c t i o n of the e n d o c y c l i c double bond t r i s (triphenylphosphine) chlororhodium (92), a s e l e c t i v e c a t a l y s t f o r hydrogenation of unhindered double bonds, was employed. Hydrogenation of octalone 194 at atmospheric pressure and room temperature, employing the above c a t a l y s t a f f o r d e d as the major product octalone 189, w i t h a minor amount of the f u l l y s aturated cis-decalone 193 al s o being formed. The minor component was X \ \ 194 189 193 r e a d i l y separated from the octalone by chromatography on s i l i c a g e l . The f a c t that the simple hydrogenation had indeed taken place was shown by the s p e c t r a l data of octalone 189. In p a r t i c u l a r , the i n f r a r e d spectrum w h i l e s t i l l e x h i b i t i n g an absorption at 6.0 u f o r the a,3-unsaturated c a r b o n y l , no longer e x h i b i t e d an absorption at 10.9 u fo r the v i n y l group. Octalone 189 e x h i b i t e d a maximum i n the u l t r a v i o l e t spectrum at 239 mu. The n.m.r. spectrum of octalone 189 no longer e x h i b i t e d the complex s i g n a l s f o r the protons of the v i n y l group but e x h i b i t e d a three-proton t r i p l e t at x 9.07 ( J = 6.5 Hz) f o r the primary methyl group, a three-proton s i n g l e t at x 8.75 f o r the t e r t i a r y methyl group and a one-proton s i n g l e t at x 4.21 f o r the o l e f i n i c proton. The s p e c t r a l data f o r the c i s - f u s e d decalone 193 w i l l be - 113 -discussed l a t e r . Treatment of dienone 175 with l i t h i u m diisopropylcuprate for 5.75 h at -78°, followed by the appropriate workup and p u r i f i c a t i o n afforded octalone 190 i n 95% y i e l d . The fac t that the addition of an 175 190 isopropyl group to of dienone 175 had indeed taken place was shown by the s p e c t r a l data of octalone 190. The u l t r a v i o l e t spectrum exhibited a maximum at 240 my. The i n f r a r e d spectrum exhibited sharp absorptions at 6.0 y(carbonyl) and at 6.16 y (carbon-carbon double bond). The n.m.r. spectrum of octalone 190 (see Figure 10) displayed two three-proton doublets at x 9.20 and x 9.05 (J = 6.5 Hz), due to the newly introduced secondary methyl groups, a three-proton s i n g l e t at f 8.74, due to the t e r t i a r y methyl group and a one-proton s i n g l e t at T 4.22, due to the o l e f i n i c hydrogen. The synthesis of the desired octalones was then continued by 1,4-conjugate additions of organocopper (I) reagents to the dimethyl dienone 177. Hence, treatment of dienone 177 with l i t h i u m dimethyl-cuprate f o r 1 h at 0°, followed by quenching with d i l u t e hydrochloric acid, afforded octalone 191 i n 92% y i e l d . An a n a l y t i c a l sample of octalone 191 exhibited the expected s p e c t r a l properties. In the in f r a r e d spectrum of 191 two sharp absorptions appeared at 6.0 and . 6.2 y due to the carbonyl group and the carbon-carbon double bond - 115 -0 0 177 191 r e s p e c t i v e l y . The n.m.r. spectrum of 191 e x h i b i t e d s i g n a l s at x 9.04 as a three-proton doublet ( J = 6.5 Hz) due to the newly introduced secondary methyl group. Other assignable s i g n a l s i n the n.m.,r. spectrum appeared at x 8.74 and x 8.25 as two three-proton s i n g l e t s a t t r i b u t a b l e to the t e r t i a r y methyl group and the v i n y l methyl group r e s p e c t i v e l y . Octalone 191 e x h i b i t e d a maximum at 249 my i n the u l t r a v i o l e t spectrum. Treatment of dienone 177 w i t h excess l i t h i u m d i i s o p r o p y l c u p r a t e at -78° af f o r d e d , a f t e r p u r i f i c a t i o n , octalone 192 i n 95% y i e l d . The conjugate a d d i t i o n product gave an u l t r a v i o l e t maximum at 249 my, and a strong carbonyl absorption at 6.0 y and carbon-carbon double bond absorption at 6.2 y i n the i n f r a r e d . The n.m.r. spectrum of 192 (see Figure 11) showed two three-proton doublets at x 9.23 and x 9.04 177 192 - 117 -(J = .7 Hz) f o r the isopropyl methyl groups, a three-proton s i n g l e t at x 8.73 for the t e r t i a r y methyl group and a three-proton s i n g l e t at x 8.22 for the v i n y l methyl group. C. Synthesis of trans-Fused Decalones Having r e a l i z e d e f f i c i e n t synthesis of the desired octalones of type 170, i t was next planned to unambiguously synthesize the correspond-ing c i s - and trans-fused decalones of type 195 and 196 r e s p e c t i v e l y . These decalones would then serve as authentic samples for d i r e c t comparison with the products expected from the B i r c h reduction of octalones 188 to 192. 170 195 196 The key intermediates i n the proposed syntheses of the trans-fused decalones of type 196 were envisaged as octalones 197 and 198 (see Chart XVIII). I t was proposed that these octalones could be r e a d i l y elaborated to the desired trans-fused decalones of type 196 by 1,4-conjugate addition of the appropriate organocopper (I) species to the a,g-unsaturated carbonyl system. Using the same reasoning as before (see p. 107) the a l k y l group would be expected to be introduced trans to the angular methyl group to give the stereochemistry depicted i n structure 196. - 118 -- 119 -The s t a r t i n g m a t e r i a l s chosen f o r the s y n t h e s i s of octalones 197 and 198 were the p r e v i o u s l y discussed octalones 172 and 173. I t i s w e l l documented (45,46,48) that lithium-ammonia reductions of simple octalones such as 172 and 173 s t e r e o s e l e c t i v e l y y i e l d the trans-fused decalones as products, w i t h l e s s than 2% of the corresponding c i s isomer being detected. Thus, lithium-ammonia r e d u c t i o n of octalone 172 w i t h ethanol (93) as co-solvent and proton source, followed by Jones o x i d a t i o n (76) of the r e s u l t i n g mixture of a l c o h o l s 199, gave, i n 62% y i e l d , the known decalone 200 (93,94). Treatment of the l a t t e r w i t h bromine i n g l a c i a l a c e t i c a c i d a f f o r d e d , a f t e r r e c r y s t a l l i z a t i o n , a 60% y i e l d of bromo-ketone 201 (93). Dehydrohalogenation of bromoketone 201 w i t h anhydrous l i t h i u m bromide i n hot hexamethylphosphoramide, a f f o r d e d , i n a 76% y i e l d , the d e s i r e d octalone 197 (95). S i m i l a r l y lithium-ammonia r e d u c t i o n of octalone 173 i n the presence of ethanol, followed by Jones o x i d a t i o n (76) of the r e s u l t i n g a l c o h o l s 202, afforded i n 70% y i e l d decalone 203 (84). As expected t h i s decalone e x h i b i t e d a strong carbonyl absorption at 5.85 U i n the i n f r a r e d . D i r e c t bromination of decalone 203 by a procedure s i m i l a r to that described above afforded an inseparable mixture of the two p o s s i b l e mono-bromoketones. In an attempt to circumvent t h i s d i f f i c u l t y decalone 203 was t r e a t e d w i t h isopropenyl acetate i n the presence of a c a t a l y t i c amount of concentrated s u l p h u r i c a c i d to a f f o r d a mixture of enol acetates 204 and 204a i n the r a t i o of 85:15 r e s p e c t i v e l y . The crude enol acetates were p u r i f i e d by chromatography on A c t i v i t y I I I n e u t r a l alumina. The p u r i f i e d m a t e r i a l e x h i b i t e d the expected s p e c t r a l p r o p e r t i e s . In p a r t i c u l a r , the i n f r a r e d spectrum e x h i b i t e d absorptions - 120 -at 5.7 and 5.95 y due to the acetate carbonyl and the carbon-carbon double bond respectively. Treatment of a mixture of enol acetates 204 and 204a with a sodium acetate buffered s o l u t i o n of bromine i n g l a c i a l a c e t i c acid for 1 h afforded, a f t e r several r e c r y s t a l l i z a t i o n s , the highly c r y s t a l l i n e bromoketone 205 i n 84% y i e l d . This compound exhibited the expected s p e c t r a l data. Of note was the carbonyl absorption i n the i n f r a r e d spectrum at 5.8 y and the signals i n the n.m.r. spectrum of 205 due to the proton adjacent to the bromine at T 5.13 as the X portion of an ABX system with the observed s p l i t t i n g s of 14 Hz and 6 Hz. Other assignable s i g n a l s i n the n.m.r. spectrum appeared at T 8.99 as a three-proton doublet (J = 6.5 Hz) due to the secondary methyl group and at x 8.84 as a three-proton s i n g l e t due to the t e r t i a r y methyl group. Bromoketone 205, when dehydrobrominated by treatment with a mixture of anhydrous l i t h i u m bromide i n hot hexamethyl-phosphoramide, afforded the desired octalone 198 i n 76% y i e l d . The l a t t e r compound, which was i s o l a t e d by chromatography on s i l i c a g e l , exhibited a maximum at 229 my i n the u l t r a v i o l e t spectrum. The other s p e c t r a l properties also corroborated the assigned structure. Of note was the appearance i n the i n f r a r e d spectrum of absorptions at 6.0 y Ca,3-unsaturated carbonyl) and at 6.15 y (carbon-carbon double bond). The n.m.r. spectrum of 198 exhibited signals at x 8.93 as a three-proton s i n g l e t f o r the t e r t i a r y methyl group, at T 8.92 as a three-proton doublet-CJ = 7 Hz) for the secondary methyl group, and at T 4.19 and x 3.35 as two one-proton doublets (J = 9 Hz) for the and o l e f i n i c protons respectively. Having achieved the synthesis of the two required intermediates 197 - 121 -and 198, i t was next planned to investigate the 1,4-conjugate addition reactions of the appropriate organocopper I species to these i n t e r -mediates. Thus, treatment of octalone 197 with l i t h i u m dimethylcuprate at 0° for 2 h afforded, i n 98% y i e l d , the known dimethyl decalone 206 (96). It was shown by INDOR studies that the stereochemistry of this-conjugate addition product was as depicted by structure 206. The s p l i t t i n g s that were observed for compound.206 are l i s t e d below. I t should be noted that these s p l i t t i n g s are not corrected f o r higher order e f f e c t s but are almost c e r t a i n l y very close i n value to the true coupling constants. Thus J . _ = 14.5 Hz, J . , =6.2 Hz, J„ , 3a,3e 3a,4e 3e,4e 1.4 Hz, J_ . = 0.5 Hz and J. ,_TT . =7.3 Hz. These observed 3a,(CH 3) 4 a 4 e ^ C H 3 ) 4 a s p l i t t i n g s are those expected for a compound possessing an a x i a l methyl group at C^. Treatment of octalone 197 with l i t h i u m divinylcuprate at -78° f o r - 122 -4 h followed by the usual workup and p u r i f i c a t i o n , afforded decalone 207 i n 73% y i e l d . Compound 207 e x h i b i t e d the expected s p e c t r a l 197 207 p r o p e r t i e s . Of pertinence were the absorptions i n the i n f r a r e d spectrum at 5.85 u (carbonyl) and 6.15, 10.9 u ( v i n y l group). The n.m.r. spectrum of 207 e x h i b i t e d s i g n a l s due to the v i n y l protons (T 4.0-5.2) as an unresolved m u l t i p l e t and a s i g n a l due to the t e r t i a r y methyl group at x 8.88. Hydrogenation of decalone 207 i n the presence of a c a t a l y t i c amount of palladium on charcoal a f f o r d e d , i n 98% y i e l d , the corresponding saturated decalone 208. Absence of s i g n a l s i n the 207 i n f r a r e d and n.m.r. sp e c t r a due to the v i n y l group confirmed that the expected transformation had taken place. Treatment of octalone 197 w i t h l i t h i u m d i i s o p r o p y l c u p r a t e at -78° f o r 4 h a f f o r d e d , i n 72% y i e l d , the c r y s t a l l i n e decalone 209. - 123 -197 209 Decalone 209 was i d e n t i c a l ( i n f r a r e d and n.m.r. s p e c t r a , g . l . c . r e t e n t i o n times, m.p.) w i t h the compound prepared by P i e r s et a l . (97,98) (see Figure 12 f o r the n.m.r. spectrum of decalone 209). These workers unambiguously demonstrated that the stereochemistry of t h e i r compound was as shown i n s t r u c t u r e 209. The sequence used by these workers to confirm the stereochemistry of decalone 209 i s shown below. 212 211 - 125 -212 213 214 B r i e f l y , decalone 210 (formed by cuprous i o n c a t a l y z e d 1,4-conjugate a d d i t i o n of isopropenylmagnesium bromide to octalone 197) was hydrogenated to a f f o r d decalone 209. K e t a l i z a t i o n of decalone 210, followed by o z o n o l y s i s of the is o p r o p e n y l double bond and chromatography (alumina) of the r e s u l t i n g product, a f f o r d e d a mixture of dione 211 and keto k e t a l 212. The l a t t e r compound remained unchanged when subjected to e p i m e r i z a t i o n c o n d i t i o n s . From examination of molecular models of 212 and 212a the more s t a b l e epimer and hence the one expected to predominate a f t e r e p i m e r i z a t i o n was p r e d i c t e d to be 212. This p r e d i c t i o n was based on the r e l i e f of the 1 , 3 - d i a x i a l i n t e r a c t i o n between the a c e t y l group and the a x i a l oxygen of the k e t a l group i n going from compound 212a to the e q u a t o r i a l epimer 212. Reaction of 212 w i t h methylenetriphenylphosphorane, followed by successive h y d r o l y s i s and - 126 -hydrogenation of the r e s u l t i n g product 213 afforded decalone 214. The l a t t e r compound was d i s t i n c t l y d i f f e r e n t from decalone 209. The stereochemistry of decalone 209 was therefore completely defined. Treatment of octalone 198 with l i t h i u m dimethylcuprate at 0° for 2 h afforded, i n 93% y i e l d decalone 215. The s p e c t r a l properties of the l a t t e r , were i n complete accord with the assigned structure and stereochemistry. Of note was the appearance i n the i n f r a r e d spectrum 198 215 of 215 of a strong carbonyl absorption at 5.87 y. The n.m.r. spectrum of 215 exhibited signals at x 9.18 and x 9.12 as two three-proton doublets (J = 6.5 Hz) due to the secondary methyl groups, at x 8.89 as a three-proton s i n g l e t due to the t e r t i a r y methyl group, and at x 7.97 and x 7.21 as two one-proton doublet of doublets due to the equatorial and C„ a x i a l protons re s p e c t i v e l y (J„ „ =14 Hz). The coupling constants confirm the assigned stereochemistry. The C equatorial proton 215 - 127 -coupled w i t h the e q u a t o r i a l proton w i t h a coupling constant of 2.2 Hz, wh i l e the a x i a l proton coupled w i t h the e q u a t o r i a l proton w i t h a coupling constant of 6 Hz. These coupling constants together w i t h the absence of a l a r g e d i a x i a l coupling constant ( J - 14 Hz) confirmed the a x i a l o r i e n t a t i o n of the newly introduced methyl group at C^. Treatment of octalone 198 w i t h l i t h i u m d i i s o p r o p y l c u p r a t e at -78° f o r 4 h a f f o r d e d , i n 84% y i e l d , the trans-fused decalone 216. The 198 216 s p e c t r a l data of the l a t t e r compound confirmed the assigned s t r u c t u r e and stereochemistry. Of p a r t i c u l a r importance was the absorption at 5.85 u i n the i n f r a r e d spectrum due to the saturated carbonyl and s i g n a l s i n the n.m.r. spectrum at T 9.21, and T 9.09 as two three-proton doublets (J = 6.5 Hz) due to the i s o p r o p y l methyl groups, at x 9.00 as a three-proton doublet (J = 6 Hz) due to the secondary methyl group and at x 8.87 as a three-proton s i n g l e t due to the t e r t i a r y methyl group. A well-known technique used i n n.m.r. spectroscopy to separate otherwise i n d i s t i n g u i s h a b l e s i g n a l s i s solvent-induced chemical s h i f t s (99,100). Connolly and McCrindle (101) have proposed an e m p i r i c a l r u l e to p r e d i c t the e f f e c t of solvent change on the chemical s h i f t of the protons adjacent to the carbonyl group i n c y c l i c ketones. This - 128 -r u l e s t a t e d that when a plane i s drawn through the carbonyl carbon at r i g h t angles to the bonds, the protons i n f r o n t of the plane are s h i f t e d downfield r e l a t i v e to the protons behind the plane, when the n.m.r. solvent i s changed from deuterochloroform to benzene (see s t r u c t u r e 217). Indeed, f o r compound 216, changing the n.m.r. solvent from 217 deuterochloroform to benzene r e s u l t e d i n a s i m p l i f i c a t i o n of the n.m.r. spectrum (see Figure 13) i n the region T 7.40 to x 7.90. A p p l i c a t i o n of the above r u l e allowed assignment of the downfield doublet of doublets at x 7.56 to the e q u a t o r i a l proton and the doublet of doublets at x 7.74 to the a x i a l C„ proton J . „ = 15.5 Hz. The 3 3a,3e coupling constants thus obtained confirmed the assigned stereochemistry of C^. The coupling constant between the a x i a l proton and the e q u a t o r i a l proton was 7.6 Hz w h i l e the coupling constant between the e q u a t o r i a l and the e q u a t o r i a l proton was 2.4 Hz. Both these values are p r e d i c t e d f o r compound 216 from examination of the Karplus curve (81). D. Synthesis of cis-Fused Decalones Having r e a l i z e d the e f f i c i e n t s y n t h e s i s of the r e q u i r e d a u t h e n t i c trans-fused decalones, i t was next planned to unambiguously synthesize i Figure 13.. N.M.R. Spectrum of trans-Fused Decalone 216. - 130 -the corresponding cis-fused decalones. Lowenthal (102) demonstrated 4 that the hydrogenation of A -3-keto steroids and related materials i n basic media produced almost exclusively the c i s A/B ring-fused product. Since octalones 188 to 192 were readily available i t was f e l t that hydrogenation under basic conditions of these octalones should furnish the required cis-fused decalones. Thus octalones 188 to 192 were hydrogenated at atmospheric pressure and room temperature i n the presence of 0.3 N ethanolic potassium hydroxide to y i e l d the corresponding cis-fused decalones shown below. 218 193 219 220 221 These hydrogenations a l l proceeded i n better than 95% y i e l d . In a l l cases, g.l.c. analysis of the product revealed the presence of a maximum of 6% of a minor component, which i n each case, was shown by g.l.c. retention times to be the corresponding trans-fused decalone. A n a l y t i c a l samples of the major products, the cis-fused decalones 193, 218-221, were isolated by preparative g.l.c. The spectral data of a l l - 131 -these compounds were i n complete accord w i t h the proposed s t r u c t u r e s . In each case, the i n f r a r e d spectrum e x h i b i t e d an absorption at 5.85 u due to the saturat e d carbonyl group. The n.m.r. spectrum of decalone 218 d i s p l a y e d a three-proton doublet at T 9.10 ( J = 6.5 Hz) a t t r i b u t a b l e to the secondary methyl group and a three-proton s i n g l e t at x 8.95 due to the t e r t i a r y methyl group. The only assignable s i g n a l i n the n.m.r. spectrum of decalone 193 appeared at x 8.90 ( s i n g l e t , t e r t i a r y methyl). The n.m.r. spectrum of decalone 219 (see Figure 14) d i s p l a y e d s i g n a l s at x 9.19 and x 9.10 as two three-proton doublets ( J = 6.5 Hz) due to the secondary methyl groups and at x 8.88 as a three-proton s i n g l e t due to the t e r t i a r y methyl group. The n.m.r. spectrum of decalone 220 e x h i b i t e d s i g n a l s at x 9.08 and x 9.01 as two three-proton overlapping doublets ( J = 6.5 Hz) due to the secondary methyl groups, at x 8.92 as a three-proton s i n g l e t due to the t e r t i a r y methyl group, at x 7.35 as a one-proton se x t e t due to the C proton (J., , . * U T i-> v \ -? QC 1 la,(CH„) 1 = 6 Hz, J.. _ = 13 Hz), at x 7.85 J l e xa,ya as the B p o r t i o n of an ABX system due to the e q u a t o r i a l proton and at x 7.64 as the A p o r t i o n of an ABX system due to the C^ a x i a l proton ( J . = 13 Hz). The coupling constants derived from the m u l t i p l e t s at x 7.85 and x 7.64 allowed c o n f i r m a t i o n of the s t e r e o -chemistry at C^. The coupling constant f o r the a x i a l - C o a x i a l protons was 14.4 Hz, w h i l e the coupling constant f o r the C^ e q u a t o r i a l -Co a x i a l protons was 3.6 Hz. These values corroborate the assigned stereochemistry f o r cis-decalone 220. F i g u r e 14. N.M.R. Spectrum of c i s - F u s e d Decalone 219. - 133 -The n.m.r. spectrum f o r the c i s - f u s e d decalone 221 (see Figure 15) e x h i b i t e d s i g n a l s at T 9.19 and x 9.11 as two three-proton doublets (J = 6.5 Hz) due to the i s o p r o p y l methyl groups, at x 9.01 as a three-proton doublet ( J = 6 Hz) due to the secondary methyl group, at x 8.89 as a three-proton s i n g l e t due to the t e r t i a r y methyl group, at x 7.86 as the B p o r t i o n of an ABX system due to the C, e q u a t o r i a l proton (J „ = 14 Hz, J„ . = 3.6 Hz), at x 7.63 •j J a , J 6 3 e , 4 a as the A p o r t i o n of an ABX system due to the C„ a x i a l proton ( J 0 , r J 3 r 3a,4a 14.3 Hz) and at x 7.30 as a one-proton s e x t e t due to the C. proton by the s i g n a l s f o r the a x i a l and e q u a t o r i a l protons and the s i g n a l f o r the proton confirm that the stereochemistry i s as depicted i n s t r u c t u r e 221. - 135 -E. Lithium-Ammonia Reduction Studies As p r e v i o u s l y d i s c u s s e d , a study of the l i t h i u m - l i q u i d ammonia re a c t i o n s of octalones of type 170 was undertaken because of the analogy of these compounds to octalone 155b, which under l i t h i u m - l i q u i d ammonia re d u c t i o n c o n d i t i o n s proceeded s t e r e o s e l e c t i v e l y to a f f o r d R„ 3 170 the c i s - f u s e d decalone 165b. I t was hoped that the a d d i t i o n a l i n f o r m a t i o n 155b obtained from the B i r c h reductions of octalones of type 170 would a i d i n c l a r i f y i n g some of the f a c t o r s a f f e c t i n g the stereochemical outcome 1 9 of the B i r c h r e d u c t i o n of A ' -2-octalone systems i n general. As mentioned e a r l i e r octalones 188 to 192.had been synthesized and had been shown to be: homogeneous by g . l . c . In a d d i t i o n , the a u t h e n t i c c i s - and trans-fused decalones corresponding to the above octalones were now r e a d i l y a v a i l a b l e (by the syntheses described above) f o r comparison w i t h the products obtained from the B i r c h reductions of octalones 188 to 192. In each case, g a s - l i q u i d chromatographic c o n d i t i o n s were found - 136 -191 192 i n which the octalone, the corresponding c i s - f u s e d decalone and the corresponding trans-fused decalone e x h i b i t e d d i s t i n c t r e t e n t i o n times on g . l . c . c o - i n j e c t i o n . Hence, i t was a n t i c i p a t e d that the product mixtures from B i r c h r e d u c t i o n of octalones 188 to 192 would be r e a d i l y analyzable by g . l . c . As p r e v i o u s l y noted by other workers (49) l i t h i u m - l i q u i d ammonia re d u c t i o n s , i n the absence of proton donors, g e n e r a l l y l e a d to the recovery of some s t a r t i n g m a t e r i a l . Presumably t h i s i s because some of the unreduced enone acts as a proton source and r e a c t s w i t h a base (e.g. amide ion) to form the corresponding enolate anion, which i s then i n e r t to the described r e d u c t i o n (49). However, i n the present case recovered s t a r t i n g m a t e r i a l posed no problem to the a n a l y s i s of the product mixtures. Furthermore, the y i e l d s of the B i r c h r e d u c t i o n - 137 -products were higher when the a d d i t i o n a l o x i d a t i o n step could be omitted. Hence, the f o l l o w i n g c o n d i t i o n s were chosen f o r the B i r c h reductions. Octalones 188 to 192 were reacted w i t h l i t h i u m i n anhydrous l i q u i d ammonia f o r 2 h , and the r e a c t i o n s were quenched by a d d i t i o n of ammonium c h l o r i d e as the proton source. Each r e d u c t i o n was repeated at l e a s t twice w h i l e the m a j o r i t y of the reductions were performed f i v e times. The r e s u l t s ( y i e l d s and product composition) f o r the l i t h i u m - l i q u i d ammonia reductions were averaged over the v a r i o u s runs and are recorded i n Table I I I . 7 In each case, g . l . c . a n a l y s i s of the crude r e d u c t i o n product revealed some recovered o c t a l o n e , along w i t h the corresponding t r a n s -and c i s - f u s e d decalones. The t r a n s - and c i s - f u s e d decalones were i s o l a t e d by p r e p a r a t i v e g . l . c . and shown to be i d e n t i c a l ( i n f r a r e d and n.m.r. s p e c t r a , g . l . c . r e t e n t i o n times) w i t h the corresponding a u t h e n t i c t r a n s - and c i s - f u s e d decalones p r e v i o u s l y prepared. The percent composition of the crude r e d u c t i o n product was determined by i n t e g r a t i o n ( d i s c i n t e g r a t o r ) of the g . l . c . t r a c e of the product mixture. I t was found that the molar response f a c t o r was the same f o r each p a i r of c i s - and trans-fused decalones. This i s expected as molecules of s i m i l a r molecular complexity g e n e r a l l y have i d e n t i c a l response f a c t o r s (103). This f a c t o r was determined by weighing samples of the authentic c i s - and trans-fused decalones and combining them so 7 The percent composition r e s u l t s were found to be re p r o d u c i b l e to w i t h i n + 2% f o r each of the c i s - and trans-fused decalones l i s t e d i n Table I I I . - 138 -that the r a t i o represented by t h e i r admixture would be very s i m i l a r to the observed r a t i o i n the B i r c h r e d u c t i o n product. The mixture of known composition was then i n j e c t e d i n t o the g . l . c . The r a t i o of c i s -to t r a n s - f u s e d decalone was then c a l c u l a t e d by i n t e g r a t i o n of the g . l . c . t r a c e and found to be w i t h i n experimental e r r o r of the known r a t i o . ; Table I I I . R e s u lts Obtained from the B i r c h Reduction of Octalones 188 to 192 Octalone % Y i e l d t r a n s : c i s r a t i o % Recovered Observed s t a r t i n g m a t e r i a l s t e r e o s e l e c t i v i t y -RT l n c i s / t r a n s decalone Kcal/mole 188 93 87:13 2 0.91 189 94 75:25 13 0.52 190 98 69:31 14 0.38 191 90 82:18 8 0.72 192 . 98 65:35 7 0.29 Before d i s c u s s i n g the r e s u l t s of the B i r c h reductions of octalones 188 to 192 i t would be advantageous to d i g r e s s to consider the nature 1 9 of the pathway of l i t h i u m - l i q u i d ammonia reductions of A ' -2-octalone systems. The mechanism r e c e n t l y proposed by House et a l . (49) f o r d i s s o l v i n g metal reductions i s summarized i n Chart XIX. This mechanism i n v o l v e s an i n i t i a l r a p i d r e v e r s i b l e a d d i t i o n of an e l e c t r o n to the unreduced enone, followed by subsequent formation of a t i g h t i o n p a i r - 139 -Chart XIX w i t h the l i t h i u m c a t i o n (or of the corresponding enol by p r o t o n a t i o n i n the presence of a proton source). The second e l e c t r o n i s then added i n a r e v e r s i b l e step followed by a n o n - r e v e r s i b l e product determining p r o t o n a t i o n . The t r a n s i t i o n s t a t e f o r p r o t o n a t i o n can, t h e r e f o r e , be assumed to l i e between the intermediate 222 and the f i n a l protonated product, that i s , i n the present case, the corresponding l i t h i u m enolate of the decalone. As p r e v i o u s l y discussed the nature of the geometry of the g-carbon atom i n the t r a n s i t i o n s t a t e f o r p r o t o n a t i o n i n lithium-ammonia reductions i s u n c e r t a i n . Various workers have proposed that the geometry of the 3 -carbon atom i n the t r a n s i t i o n s t a t e f o r p r o t o n a t i o n 2 3 could be t r i g o n a l (sp h y b r i d i z e d ) , pyramidal (sp h y b r i d i z e d ) or a - 140 -geometry somewhere between these two extremes. In the absence of any experimental data to d i s t i n g u i s h between the v a r i o u s geometries of the g-carbon atom, t h i s d i s c u s s i o n w i l l consider s e v e r a l of the p o s s i b i l i t i e s . An examination of the r e s u l t s i n Table I I I revealed that as the bulk of the a l k y l group i n c r e a s e d , the percentage of c i s - f u s e d decalone product was increased. Furthermore, the r e s u l t s f o r octalone 192 ( l i s t e d i n Table I I I ) compared w i t h the r e s u l t s f o r octalone 155b revealed that the angular methyl group had a l a r g e e f f e c t on the stereochemical outcome of the lithium-ammonia r e d u c t i o n of octalone 192. As p r e v i o u s l y discussed i n the i n t r o d u c t i o n , many workers (44,45,50) have proposed a pyramidal c o n f i g u r a t i o n f o r the geometry of the g-carbon atom i n the t r a n s i t i o n s t a t e f o r p r o t o n a t i o n . This proposal has been modified to i n c l u d e a s t e r e o e l e c t r o n i c requirement (45). Bearing i n mind t h i s s t e r e o e l e c t r o n i c requirement, the product determining p r o t o n a t i o n of the intermediate carbanion 222 could t h e o r e t i c a l l y proceed through one or both of two p o s s i b l e t r a n s i t i o n s t a t e s , one resembling the pyramidal carbanion intermediate 223, which would give r i s e to the trans-fused decalone product and the other resembling the R. ; i - 141 -pyramidal carbanion intermediate 224, which would give r i s e to a c i s -fused decalone product. G e n e r a l l y a t r a n s i t i o n s t a t e f o r p r o t o n a t i o n resembling 223 i s favored as i t i s of lower energy than 224, thus accounting f o r the general predominance of the trans-fused products. However, the lithium-ammonia reductions of octalones 188 to 192 should be e x c e p t i o n a l as the s t e r e o e l e c t r o n i c a l l y allowed t r a n s i t i o n s t a t e s l e a d i n g to the t r a n s - and c i s - f u s e d decalones are e s s e n t i a l l y e q u i v a l e n t i n energy or that l e a d i n g to the c i s product i s s l i g h t l y favored. At the present time experimental conformational energy values are not a v a i l a b l e f o r the conformations of A ^ - o c t a l i n d e r i v a t i v e s . Hence, only r a t h e r q u a l i t a t i v e estimates f o r the r e l a t i v e energies of 223 and 224 can be made by conventional conformational a n a l y s i s . A q u a l i t a t i v e examination of the non-bonded i n t e r a c t i o n s present i n 223 and 224 revealed that these two intermediates should be of approximately the same energy. That i s , the unfavorable nature of the c i s - l i k e t r a n s i t i o n s t a t e plus the skew R-CH^ i n t e r a c t i o n present i n 224 are 2 approximately comparable w i t h the skew R-sp i n t e r a c t i o n plus the developing syn a x i a l R-H i n t e r a c t i o n between the incoming proton and the a x i a l R group i n the t r a n s i t i o n s t a t e f o r p r o t o n a t i o n resembling 223. Thus on the b a s i s of a pyramidal t r a n s i t i o n s t a t e f o r p r o t o n a t i o n , an approximately 50:50 mixture of products would be expected. An examination of the r e s u l t s i n Table I I I revealed a s t e r e o -s e l e c t i v i t y higher than would be expected by the above q u a l i t a t i v e energy approximations on the t r a n s i t i o n s t a t e s resembling 223 and 224. However, t h i s trend seems to be i n l i n e w i t h the e m p i r i c a l trend that the c i s / t r a n s product r a t i o i s g e n e r a l l y l e s s than would be expected on the - 142 -b a s i s of the conformational energies i n v o l v e d (46). Since immediate explanations f o r the e f f e c t of the bulk of the a l k y l group and f o r the e f f e c t of the angular methyl group on the c i s / t r a n s product r a t i o s are not obvious, the f o l l o w i n g d i s c u s s i o n w i l l examine s e v e r a l p l a u s i b l e f a c t o r s which might be d i r e c t i n g the r e a c t i o n pathway. F i r s t l y the e f f e c t of the angular methyl group on the stereochemical outcome of the lithium-ammonia reductions w i l l be discussed i n terms of a pyramidal t r a n s i t i o n s t a t e . As mentioned above, a s t r i k i n g d i f f e r e n c e i n product s t e r e o s e l e c t i v i t y was evident on comparison of the products obtained from the B i r c h r e d u c t i o n of octalones 155b and 192. 155b 192 Changing the C ^ s u b s t i t u e n t from a hydrogen to a methyl group e f f e c t e d a change from the s t e r e o s e l e c t i v e production of the c i s - f u s e d decalone product i n the case of octalone 155b, to the production of a 35:65 r a t i o of c i s - f u s e d to trans-fused decalone products i n the case of octalone 192. Examination of molecular models of the p o s s i b l e pyramidal carbanion intermediates - 225, p r o t o n a t i o n of which would lead to the trans-fused decalone, and 226 , p r o t o n a t i o n of which would lead to the cis-fused decalone - revealed the i n t r o d u c t i o n of one s e r i o u s i n t e r a c t i o n i n 226 when R was changed from a hydrogen to a methyl group. (That i s , - 143 -H *v OLi H OLi 225 226 when R i n 226 i s a methyl group, a gauche i n t e r a c t i o n between the angular methyl s u b s t i t u e n t and the i s o p r o p y l group i s present, whereas when R i n 226 i s a hydrogen, t h i s gauche i n t e r a c t i o n i s absent.) This gauche i n t e r a c t i o n would, t h e r e f o r e , make the t r a n s i t i o n s t a t e resembling the intermediate carbanion 226 l e s s f a vorable when R i s a methyl group than when R i s a hydrogen. There i s a l s o the added p o s s i b i l i t y that the methyl group i n 226 (R = CH^) might be a f f o r d i n g a s m a l l amount of s t e r i c hindrance to the incoming pr o t o n a t i n g species i n the t r a n s i t i o n s t a t e l e a d i n g to the c i s product which would be absent when R ( i n 226) i s a hydrogen. I t f o l l o w s that l e s s c i s - f u s e d decalone should be formed on lithium-ammonia r e d u c t i o n of octalone 192 than on reduction of octalone 155b. As reported above t h i s was found to be the case. As the bulk of the C. a l k y l s u b s t i t u e n t increases the H R 1 H R "2 OLi R OLi 2 223 224 - 144 -2 non-bonded interaction i n 223 between the a l k y l group and the sp center and the a l k y l group and the incoming protonating species would be expected to increasingly make conformation 224, i n which the a l k y l group i s equatorial, more favorable r e l a t i v e to conformation 223. This could p a r t i a l l y account for the increase i n the amount of cis-fused product as the bulk of the a l k y l group increases. As discussed previously, Robinson proposed that the 3-carbon atom was t r i g o n a l , or very nearly t r i g o n a l , i n the t r a n s i t i o n state for protonation. In addition he proposed that the reduction could proceed v i a one or both of two possible t r a n s i t i o n states, 107a which would lead predominantly to the trans-fused decalone and 107b which would give r i s e predominantly to the cis-fused decalone. Other possible t r a n s i t i o n states were also considered but were predicted to be of very high energy and therefore were not considered further (46). Robinson stated 0 that there would be less angle and torsional s t r a i n involved i n a t r a n s i t i o n state resembling 107a than there would be i n one resembling 107b. I f we consider octalones 155b and 188 to 192, i t i s possible that the s t a b i l i t y gained by changing the a l k y l group from an a x i a l orientation i n 227 (analogous to 107a) to an"equatorial-like" orientation i n 228 - 145 -( a n a l o g o u s t o 107b) w o u l d a t l e a s t p a r t i a l l y o f f s e t t h e a n g l e and R. 1 R i R R, 2 227 R, 2 228 t o r s i o n a l s t r a i n i n t r i n s i c i n c o n f o r m a t i o n 228. T h i s w o u l d r e s u l t i n a l o w e r i n g o f t h e energy o f t h e t r a n s i t i o n s t a t e r e s e m b l i n g 228 r e l a t i v e t o t h a t r e s e m b l i n g 227. R o b i n s o n ' s t h e o r y would t h u s p r e d i c t a h i g h e r p r o p o r t i o n o f c i s - f u s e d d e c a l o n e i n t h e p r e s e n t examples r e l a t i v e t o t h a t n o r m a l l y f o u n d . However, i n c o n t r a s t t o o c t a l o n e 155b, o c t a l o n e s 188 t o 192 p o s s e s s an added d e s t a b i l i z i n g i n t e r a c t i o n i n c o n f o r m a t i o n 228. I n t h e c a s e o f o c t a l o n e s 188 t o 192 t h e s t a b i l i z a -t i o n a r i s i n g f rom c h a n g i n g t h e a l k y l group from t h e a x i a l o r i e n t a t i o n t o t h e " e q u a t o r i a l - l i k e " o r i e n t a t i o n (227 ->• 228) w o u l d t h u s be p a r t i a l l y o f f s e t by t h e i n c r e a s i n g skew i n t e r a c t i o n between t h e e q u a t o r i a l a l k y l group and the C ^Q m e t h y l group ( i n 2 28) . Hence, i n t h e s e o c t a l o n e s 188 t o 192 t h e amount of c i s - f u s e d d e c a l o n e formed on l i t h i u m - a m m o n i a r e d u c t i o n w o u l d be p r e d i c t e d t o be l e s s t h a n i n t h e c a s e o f o c t a l o n e 155b where t h e r e i s no d e v e l o p i n g i n t e r a c t i o n between t h e C ^Q hydrogen and a l k y l group. As t h e b u l k o f t h e a l k y l group i n c r e a s e s i t i s p r o b a b l e t h a t t h e s t a b i l i z a t i o n a r i s i n g f rom c h a n g i n g t h e a l k y l group from t h e a x i a l o r i e n t a t i o n t o t h e " e q u a t o r i a l - l i k e " o r i e n t a t i o n would a l s o i n c r e a s e . T h i s i n c r e a s e d s t a b i l i z a t i o n w o u l d make t h e t r a n s i t i o n s t a t e r e s e m b l i n g - 146 -228 i n c r e a s i n g l y more favored, and could thus account f o r the observed f a c t that as the a l k y l group increases i n s i z e , the amount of c i s -decalone obtained i n the r e d u c t i o n a l s o i n c r e a s e s . I t i s a l s o p o s s i b l e that i n the t r a n s i t i o n s t a t e l e a d i n g to the trans-fused decalone there i s an i n c r e a s i n g degree of s t e r i c hindrance to p r o t o n a t i o n as the bulk of the s u b s t i t u e n t i n c r e a s e s . This would make pr o t o n a t i o n of 228 more l i k e l y as the b u l k of the s u b s t i t u e n t i n c r e a s e s . The e f f e c t of the a l k y l s u b s t i t u e n t on the s t e r e o -chemistry of lithium-ammonia reductions has both p r a c t i c a l and t h e o r e t i c a l i n t e r e s t . The B i r c h r e d u c t i o n of octalones 188 to 192 revealed a higher per-centage of c i s - f u s e d decalone product than normally o b t a i n i n other substitutEd 1.9 A ' -2-octalone systems. Although use of a t r a n s i t i o n s t a t e model possess-ing a pyramidal 3-carbon atom along w i t h crude estimates of conformational energies would p r e d i c t a higher percentage of c i s - f u s e d decalone than observed, use of a t r a n s i t i o n s t a t e model possessing a t r i g o n a l 3-carbon atom would give r i s e to q u a l i t a t i v e p r e d i c t i o n s i n accord w i t h the observed r e s u l t s . The magnitude of the e f f e c t of changing the s u b s t i t u e n t from a hydrogen to a methyl group was not expected a p r i o r i . However, i n r e t r o s p e c t the r e s u l t s can at l e a s t q u a l i t a t i v e l y be accounted f o r (see above). F i n a l l y the f a c t that the r e d u c t i o n of octalone 155b l e d s t e r e o -s e l e c t i v e l y to a c i s - f u s e d decalone has obvious s y n t h e t i c a p p l i c a t i o n s . For example, use of t h i s observation could provide a s y n t h e t i c entry i n t o the amorphane c l a s s of sesquiterpenes. - 147 -EXPERIMENTAL General M e l t i n g p o i n t s , which were determined on a Fisher-Johns m e l t i n g po i n t apparatus, and b o i l i n g p o i n t s are uncorrected. Routine i n f r a r e d spectra were recorded on a Perkin-Elmer I n f r a c o r d model 137 or a Perkin-Elmer I n f r a r e d Spectrophotometer model 710, w h i l e comparison sp e c t r a were recorded on Perkin-Elmer spectrophotometers model 421 or model 457. U l t r a v i o l e t s p e c t r a were, unless otherwise noted, measured i n methanol s o l u t i o n on a Unicam, SP. 800, spectrophotometer. N.m.r. spect r a were, unless otherwise noted, recorded i n deuterochloroform s o l u t i o n on Varian Associates spectrometers, models A-60, T-60 and/or HA-100, XL-100. Line p o s i t i o n s are given i n the T i e r s x s c a l e , w i t h t e t r a m e t h y l s i l a n e as i n t e r n a l standard; the m u l t i p l i c i t y , i n t e g r a t e d peak areas and proton assignments are i n d i c a t e d i n parentheses. Gas-l i q u i d chromatography ( g . l . c . ) was c a r r i e d out on e i t h e r an Aerograph Autoprep, model 700 or a Varian Aerograph, model 90-P. The f o l l o w i n g columns (10 f t x 1/4 i n unless otherwise noted) were employed, w i t h the i n e r t supporting m a t e r i a l being 60/80 mesh Chromosorb W (unless otherwise noted): column A,3% SE-30; column B, 15% QF-1; column C } (10 f t x 3/8 i n ) 20% SE-30; column D, 20% FFAP; column E, 8% FFAP (60/80 mesh Chromosorb G); column F, 20% Carbowax 20 M; column G (10 f t x 3/8 i n . ) 30% Carbowax 20 M; column H, 20% SE-30. The - 148 -s p e c i f i c column used, along w i t h the column temperature and c a r r i e r gas (helium) f l o w - r a t e ( i n ml/min) are i n d i c a t e d i n parentheses. High r e s o l u t i o n mass spectra were recorded on an AEI, type MS-9, mass spectrometer. Microanalyses were performed by Mr. P. Borda, M i c r o a n a l y t i c a l Laboratory, U n i v e r s i t y of B r i t i s h Columbia, Vancouver. Pr e p a r a t i o n of Dimethyl a-ketopimelate (111) The procedure used was that of Lukes, Poos and S a r e t t (51). Through a s o l u t i o n of 100 g (0.725 mole) of commercial f u r y l a c r y l i c a c i d (110) i n 400 ml of methanol was passed hydrogen c h l o r i d e u n t i l the s o l u t i o n reached the b o i l i n g p o i n t . The gas flow was reduced and the s o l u t i o n was maintained at the b o i l i n g p o i n t f o r 4 h. Then the s o l u t i o n was concentrated on the r o t a r y evaporator to one-fourth the volume. > One l i t r e of benzene was added to the residue and d i s t i l l a t i o n continued at atmospheric pressure u n t i l the vapour temperature reached 80°. Then the remaining benzene was removed under reduced pressure. To the residue was added 350 ml of methanol and o n e - t h i r d ml of 95% s u l p h u r i c a c i d and the mixture r e f l u x e d overnight. The methanol was then removed under reduced pressure and the residue d i s s o l v e d i n 650 ml of benzene. The benzene s o l u t i o n was washed s u c c e s s i v e l y w i t h water, 1 N sodium carbonate s o l u t i o n ( u n t i l b a s i c ) , water and b r i n e and d r i e d over anhydrous magnesium s u l f a t e . The concentrated benzene e x t r a c t was d i s t i l l e d i n vacuo, b.p. 110-115° at 0.65 mm; l i t . (51) b.p. 90-93° at 0.1 mm, to a f f o r d 122 g (84%) of dimethyl a-ketopimelate (111), m.p. 49-50°; l i t . (51) m.p. 49-50°. I n f r a r e d ( C H C l J , X 5.8, 6.97, 8.5 u; n.m.r., 3 max T 7.29 ( m u l t i p l e t , 8 H, -CH^CH^) , 6.33 ( s i n g l e t , 6 H, C0 2CH 3). - 149 -Pr e p a r a t i o n of Dimethyl-Y-ethylenedioxypimelate (112) The procedure used was analogous to that of Lukes, Poos and S a r e t t (51). In a 1.0 1 f l a s k , equipped w i t h a Dean-Stark water separator, was placed 120 g (0.59 mole) of keto d i e s t e r 111, 41.5 g (0.64 mole) of ethylene g l y c o l and 220 mg of p_-toluenesulfonic a c i d i n 600 ml of dry benzene. The mixture was r e f l u x e d u n t i l the c a l c u l a t e d amount of water had been c o l l e c t e d . The cooled s o l u t i o n was washed s u c c e s s i v e l y w i t h saturated sodium bicarbonate s o l u t i o n , water and b r i n e , and d r i e d over anhydrous magnesium s u l f a t e . The concentrated residue was d i s t i l l e d through a Vigreux column s e v e r a l times to a f f o r d 34 g (23%) of dimethyl-y-ethylenedioxypimelate (112) , which was greater than 97% pure by g . l . c . (column A, 220°, 85), b.p. 115-120° at 0.6 mm; l i t . (51) b.p. 96-98° at 0.08mm, n D 1.4504; l i t . (51) n^ 1.4501. I n f r a r e d ( f i l m ) , X 5.77, 7.0 u ; n.m.r., x 6.30 ( s i n g l e t , 6 H, C0 oCH.), 6.04 ( s i n g l e t , TD3X Z. j 4 H, k e t a l protons). I t should be noted that a f t e r d i s t i l l a t i o n a s u b s t a n t i a l amount of high b o i l i n g m a t e r i a l was recovered. This m a t e r i a l was subjected to m e t h a n o l - s u l f u r i c a c i d treatment which regenerated keto d i e s t e r 111. I t was there f o r e f e l t that t h i s m a t e r i a l had t r a n s e s t e r i f i e d under the k e t a l i z a t i o n c o n d i t i o n s . R e c y c l i z a t i o n of recovered keto d i e s t e r 111 s e v e r a l times r a i s e d the o v e r a l l y i e l d of t h i s r e a c t i o n to 44%. Prepa r a t i o n of Keto E s t e r 113 The procedure employed was that of Lukes, Poos and Sarett (51). - 150 -A s o l u t i o n of 58 g (0.24 mole) of k e t a l d i e s t e r 112 and 5.7 g (0.24 mole) of sodium hydride i n 350 ml dry ether was r e f l u x e d w i t h e f f i c i e n t s t i r r i n g f o r 5 days under a n i t r o g e n atmosphere. At the end of t h i s time 20 ml of g l a c i a l a c e t i c a c i d and 20 ml of water were added s u c c e s s i v e l y . The ether l a y e r was washed w i t h 1 N sodium carbonate s o l u t i o n , water and b r i n e and d r i e d over anhydrous magnesium s u l f a t e . The ether l a y e r was concentrated and the residue d i s t i l l e d to a f f o r d a c o l o r l e s s o i l which c r y s t a l l i z e d on standing, b.p. 124° at 0.35 mm. R e c r y s t a l l i z a t i o n from methanol a f f o r d e d 40.5 g (80%) of keto e s t e r 113, m.p. 60-61°; l i t . (51) m.p. 60-61°. I n f r a r e d (CHCl.), X 5.75, 5.85, 3 max 6.03, 6.20 y; n.m.r., x 6.23 ( s i n g l e t , 3H, C02CH_3) , 5.97 ( s i n g l e t , 4H, k e t a l protons). P r e p a r a t i o n of Octalone 114 The procedure used was s i m i l a r to that of I r e l a n d et a l . (52). A s o l u t i o n of 14.6 g (68 mmoles) of keto ester 113 and 4.0 g (73 mmoles) of sodium methoxide i n 120 ml of anhydrous methanol was s t i r r e d at room temperature under a n i t r o g e n atmosphere. To t h i s s o l u t i o n was added 30.8 g (102 mmoles) of l-diethylamino-3-pentanone methiodide i n 80 ml of anhydrous methanol and the r e a c t i o n allowed to s t i r f o r 3 days. At the end of t h i s p e r i o d , the methanol was removed i n vacuo and 1 g of potassium hydroxide i n 200 ml of water was added. An a d d i t i o n a l 9 g of potassium hydroxide i n 150 ml of water was added dropwise over 3 h and the s o l u t i o n r e f l u x e d f o r an a d d i t i o n a l 5 h. The cooled r e a c t i o n mixture was thoroughly e x t r a c t e d w i t h ether and the combined ether e x t r a c t s were washed w i t h water and b r i n e and d r i e d over - 151 -anhydrous sodium s u l f a t e . The ether e x t r a c t was concentrated and d i s t i l l e d , b.p. 117-120° at 0.1 mm, to a f f o r d a c o l o r l e s s o i l which c r y s t a l l i z e d on standing. R e c r y s t a l l i z a t i o n from petroleum ether (30-60°) affo r d e d 9.5 g (64%) of the d e s i r e d octalone 114, m.p. 61-62°; l i t . (52) m.p. 61-63°. U l t r a v i o l e t , X 245 mu (e = 14,400); i n f r a r e d max ^ ' ( n u j o l ) , X 6.03, 6.24 u; n.m.r., T 8.13 ( s i n g l e t , 3H, v i n y l methyl), H13.X 6.08 ( s i n g l e t , 4H, k e t a l p r otons). Reduction of Octalone 114 To 150 ml of l i q u i d ammonia ( f r e s h l y d i s t i l l e d from sodium metal) was added 108 mg of f i n e l y cut l i t h i u m w i r e . A f t e r a l l the l i t h i u m had d i s s o l v e d 500 mg (2.24 mmoles) of octalone 114 d i s s o l v e d i n 25 ml of dry ether was added dropwise over 0.5 h. The s o l u t i o n was allowed to s t i r f o r an a d d i t i o n a l 2 h and then the blue c o l o r was discharged by a d d i t i o n of ammonium c h l o r i d e . The l i q u i d ammonia was allowed to evaporate and the residue d i l u t e d w i t h water. The aqueous s o l u t i o n was thoroughly e x t r a c t e d w i t h ether. The combined ether e x t r a c t s were washed w i t h water and b r i n e and d r i e d over anhydrous sodium s u l f a t e . The ether e x t r a c t was concentrated and the residue d i s t i l l e d (b.p. 120° at 2 mm) to a f f o r d 491 mg (97%) of the d e s i r e d decalone 115. G.l.c. a n a l y s i s of the r e a c t i o n product (column B, 195°, 85) revealed approximately 10% of recovered s t a r t i n g m a t e r i a l p l u s the d e s i r e d decalone 115. An a n a l y t i c a l sample of the l a t t e r was c o l l e c t e d by p r e p a r a t i v e g . l . c . 25 (column C, 200°, 110) and e x h i b i t e d the f o l l o w i n g s p e c t r a l data: n^ 1.4954; i n f r a r e d ( f i l m ) , X 5.85 u ; n.m.r., x 8.96 (doublet, 3H, ' max secondary methyl group, J = 6 Hz), 6.01 ( s i n g l e t , 4H, k e t a l protons). - 152 -Mol. Wt. Calcd. f o r C23 H20°3 : 224.141. Found (high r e s o l u t i o n mass spectrometry): 224.138. Pre p a r a t i o n of Hydroxymethylene D e r i v a t i v e 121 To an i c e - c o l d s o l u t i o n of 4 g (18 mmoles) of decalone 115, 1.95 g of sodium methoxide i n 20 ml of dry benzene was added 3 ml of e t h y l formate. The r e a c t i o n mixture was allowed to s t i r at room temperature under n i t r o g e n f o r 14 h. At the end of t h i s time i c e water was added and the benzene l a y e r separated. The aqueous l a y e r was a c i d i f i e d w i t h g l a c i a l a c e t i c a c i d and thoroughly e x t r a c t e d w i t h ether. The combined ether e x t r a c t s were washed w i t h water and b r i n e and d r i e d over anhydrous sodium s u l f a t e . The ether e x t r a c t was concentrated to a f f o r d 3.7 g (80%) of the d e s i r e d hydroxymethylene d e r i v a t i v e 121. I n f r a r e d ( f i l m ) , X 6.1, 6.4 t i . Due to the i n s t a b i l i t y of t h i s compound i t was max J . v o x i d i z e d immediately without f u r t h e r c h a r a c t e r i z a t i o n . P r e p a r a t i o n of Dione 124 This compound was prepared by the procedure of I r e l a n d et a l . (52). A s o l u t i o n c o n t a i n i n g 25 g (0.127 mole) of keto e s t e r 113, 16.8 g (0.2 mole) of e t h y l v i n y l ketone, 5 ml of triethylamine i n 250 ml of methanol was allowed to stand f o r 48 h at room temperature under an atmosphere of n i t r o g e n . The methanol was then removed i n vacuo. The residue c r y s t a l l i z e d on standing. R e c r y s t a l l i z a t i o n from methanol afforded 29.1 g (84%) of dione 124, m.p. 83-85°; l i t . (52) m.p. 83-85°. Dione 124 e x h i b i t e d the f o l l o w i n g s p e c t r a l p r o p e r t i e s . I n f r a r e d ( n u j o l ) , 0 X 5. 85p; n.m.r., T 8.97 ( t r i p l e t , 3H, CH0CH_C-, J = 7 Hz), 6.30 ( s i n g l e t , max . > *- > » _3 2 - 153 -3H, methyl e s t e r ) , 6.08 ( s i n g l e t , AH, k e t a l p r otons). P r e p a r a t i o n of Octalone 123 The procedure used to prepare t h i s compound was that of I r e l a n d et a l . (52). A suspension of 10 g (0.034 mole) of dione 124 i n 75 ml of absolute methanol c o n t a i n i n g 1 g of sodium metal was warmed i n a n i t r o g e n atmosphere at 40° f o r 1 h. This s o l u t i o n was then r e f l u x e d f o r 2 h. At the end of t h i s time 3.1 g (0.05 mole) of g l a c i a l a c e t i c a c i d was added slow l y at 15°. The r e a c t i o n mixture was then f i l t e r e d . The f i l t r a t e was concentrated under reduced pressure. The residue was e x t r a c t e d w i t h benzene. The benzene e x t r a c t was then washed w i t h water, sodium bicarbonate s o l u t i o n ( u n t i l n e u t r a l ) , water and b r i n e and d r i e d over anhydrous sodium s u l f a t e . The benzene e x t r a c t was concentrated and the residue c r y s t a l l i z e d on standing. These c r y s t a l s were combined w i t h those obtained from the f i r s t f i l t r a t i o n . R e c r y s t a l l i z a t i o n of octalone 123 from methanol-water afforded 9.02 g (97%), m.p. 102-103°; l i t . (52) m.p. 101.5-103°. I n f r a r e d (CHC1-), A 5.8, 6.0, 6.2 u; 3 max n.m.r., x 8.13 ( s i n g l e t , 3H, v i n y l methyl), 6.30 ( s i n g l e t , 3H, methyl e s t e r ) , 6.08 ( s i n g l e t , 4H, k e t a l p r o t o n s ) ; u l t r a v i o l e t , ^ m a x 247 my (e = 13,000). Pr e p a r a t i o n of Dienone 125 A s o l u t i o n of 5 g (18 mmoles) of octalone 114, 4.4 g (19 mmoles) of DDQ, 6.2 ml of g l a c i a l a c e t i c a c i d i n 100 ml of anhydrous benzene was r e f l u x e d f o r 36 h under n i t r o g e n . At the end of t h i s time, the cooled - 154 -r e a c t i o n mixture was f i l t e r e d and concentrated i n vacuo. The residue was taken up i n ether and washed w i t h water, saturated sodium bicarbonate s o l u t i o n , water and b r i n e and d r i e d over anhydrous magnesium s u l f a t e . The d r i e d e x t r a c t was concentrated to a f f o r d 4 g (80%) of a white c r y s t a l l i n e s o l i d . An a n a l y t i c a l sample was prepared by r e c r y s t a l l i z a t i o n from e t h y l acetate-petroleum ether (30-60°) to a f f o r d white needles, m.p. 143-144°. This sample e x h i b i t e d u l t r a v i o l e t , A m a x 243 my (e = 10,300); i n f r a r e d ( n u j o l ) , X 5.82, 6.05, 6.15, 6.25 y; n.m.r., T 8.04 ( s i n g l e t , m 3.x 3H, v i n y l methyl), 6.30 ( s i n g l e t , 3H, C0 2CH 3), 6.02 ( s i n g l e t , 4H, k e t a l p r o t o n s ) , 3.72, 3.28 ( p a i r of doublets, 2H, and protons r e s p e c t i v e l y , J = 10 Hz). Anal. Calcd. f o r C - J f f - o 0 c : C, 64.74; H, 6.52. Found: C, 64.84; I J l o _> H, 6.49. Isopropylmagnesium Bromide A d d i t i o n to Dienone 129 To an i c e - c o l d suspension of 326 mg of magnesium f i l i n g s i n 12 ml anhydrous tetrahydrofuran (THF) was added 1.55 ml of i s o p r o p y l bromide. A f t e r a l l the magnesium had reacted 12 mg of cuprous c h l o r i d e was added and the s o l u t i o n placed i n an e x t e r n a l i c e bath. To t h i s s o l u t i o n 190 mg of dienone 129 i n 4 ml of anhydrous ether was added dropwise over 15 min and the s o l u t i o n allowed to s t i r f o r an a d d i t i o n a l 2 h. The r e a c t i o n mixture was poured i n t o a r a p i d l y s t i r r e d 1 N h y d r o c h l o r i c a c i d s o l u t i o n . The ether l a y e r was separated and washed w i t h water and b r i n e and d r i e d over anhydrous magnesium s u l f a t e . The ether e x t r a c t was concentrated i n vacuo to a f f o r d 207 mg of a yellow o i l . A n a l y s i s of the product by g . l . c . revealed two major products i n the - 155 -r a t i o of 2:3 r e s p e c t i v e l y , (column B, 180°, 85). The minor product (131 or 132) exhibited i n f r a r e d ( f i l m ) , X 3.45, 6.25 (w), 6.4 (w) y; D13X n.m.r., T 8.80 (doublet, 3H, secondary methyls, J = 6.5 Hz), 8.75 ( s i n g l e t , 6H, t e r t i a r y methyls), 7.84 ( s i n g l e t , 3H, v i n y l methyl), 3.20, 3.00 (broad s i n g l e t s , 2H, phenyl protons). Anal. Calcd. f or C ^ H ^ : C, 88.82; H, 11.18. Found: C, 88.70; H, 11.07. The major product exhibited i n f r a r e d ( f i l m ) , X 6.0, 6.25 u; max K u l t r a v i o l e t , X 240 my ( e=13,000); n.m.r., T 9.35, 9.08 (pair of doublets, 6H, secondary methyls, J = 7 Hz), 8.85, 8.82 ( s i n g l e t s , 6H, gem-dimethyl groups), 8.61 ( s i n g l e t , 3H, C^Q t e r t i a r y methyl), 7.39, 7.21 (pair of doublets, IH, C„ proton, J , , =18 Hz, J . = 6 Hz), 7.46, 7.65 (pair of doublets, IH, C proton, J =18 Hz, J , = 3 Hz), 4.04 ( s i n g l e t , IH, C proton). Anal. Calcd. for C 1 6 H 2 6 0 : c» 81.99; H, 11.18. Found: C, 81.89; H, 11.09. Preparation of Hydroxymethylene Derivative 134 To an i c e - c o l d s o l u t i o n of 1.75 g (6.25 mmoles) of octalone 123, 0.756 g of sodium methoxide i n 17.5 ml of dry benzene was added 463 mg of e t h y l formate. The reaction mixture was allowed to s t i r at room temperature under nitrogen for 14 h. At the end of t h i s time i c e water was added and the benzene layer separated. The aqueous layer was a c i d i f i e d with g l a c i a l a c e t i c a c i d and thoroughly extracted with ether. The combined ether extracts were washed with water and brine and dried over anhydrous sodium s u l f a t e . The ether extract was concentrated to - 156 -a f f o r d 1.34 g (70%) of the d e s i r e d hydroxymethylene d e r i v a t i v e 134. I n f r a r e d ( f i l m ) , X 5.8, 6.1,6.4 u. Due to the i n s t a b i l i t y of t h i s max compound i t was o x i d i z e d immediately without f u r t h e r c h a r a c t e r i z a t i o n . Dehydrogenation of Hydroxymethylene D e r i v a t i v e 134 To 700 mg (2.26 mmoles) of hydroxymethylene d e r i v a t i v e 134 d i s s o l v e d i n 10 ml of anhydrous dioxane was added 570 mg (2.5 mmoles) of DDQ i n 10 ml of anhydrous dioxane. The r e a c t i o n was allowed to s t i r r a p i d l y f o r 3.5 min. At the end of t h i s time, methylene c h l o r i d e was added to quench the r e a c t i o n . The s o l u t i o n was f i l t e r e d and the f i l t r a t e washed w i t h water, 2% sodium hydroxide s o l u t i o n ( u n t i l b a s i c ) , water ( u n t i l n e u t r a l ) and b r i n e and d r i e d over anhydrous sodium s u l f a t e . The organic e x t r a c t was then concentrated and the residue c r y s t a l l i z e d on standing. R e c r y s t a l l i z a t i o n from n-hexane-ether a f f o r d e d 292 mg (43%) of pale yellow c r y s t a l s , m.p. 142-144°. I n f r a r e d ( n u j o l ) , ^ m a x 5.75, 5.9, 6.08, 6.15, 6.25 y; n.m.r., x 7.97 ( s i n g l e t , 3H, v i n y l methyl), 6.25 ( s i n g l e t , 3H, C02CH_3) , 5.98 ( s i n g l e t , 4H, k e t a l p r o t o n s ) , 2.55 ( s i n g l e t , IH, v i n y l proton), -0.25 ( s i n g l e t , IH, aldehydic H); u l t r a v i o l e t , X 246 my (e=14,700). max Anal. Calcd. f o r C 1 6 H 1 8 ° 6 : C, 62.74; H, 5.92. Found: C, 62.81; H, 5.97. P r e p a r a t i o n of Dione 137 To a s o l u t i o n of 60 g of l-N,N-diethylamino-3-pentanone i n 250 ml of dry benzene at 0° was added over 2 h 60 g of freshly d i s t i l l e d methyl i o d i d e . The r e s u l t i n g s o l u t i o n was allowed to s t i r at 0° f o r an - 157 -a d d i t i o n a l 15 h. At the end of t h i s time the benzene and excess methyl i o d i d e were removed i n vacuo and 200 ml of anhydrous ethanol were added. A s o l u t i o n of 60 g of 2-carbethoxycyclohexanone and 20 g of sodium ethoxide i n 900 ml of anhydrous ethanol was cooled to 0°. To t h i s s o l u t i o n was added dropwise over 2 h the above 1-diethylamino-3-pentanone methiodide s o l u t i o n . The r e a c t i o n mixture was allowed to s t i r f o r an a d d i t i o n a l 4 h at 0° and r e f l u x e d f o r 0.5 h. At the end of t h i s p e r i o d , most of the ethanol was removed on the r o t a r y evaporator and the residue d i l u t e d w i t h water. The aqueous l a y e r was thoroughly e x t r a c t e d w i t h ether. The combined ether e x t r a c t s were washed w i t h water, d i l u t e h y d r o c h l o r i c a c i d , water and b r i n e and d r i e d over anhydrous sodium s u l f a t e . The ether e x t r a c t was concentrated and the residue d i s t i l l e d to a f f o r d 64.8 g (83%) of a pale yellow o i l , b.p. 130-135° at 0.9 mm. G.l.c. a n a l y s i s (column D, 200°, 75) e x h i b i t e d one peak only. I n f r a r e d ( f i l m ) , X m 5.8 u; n.m.r., x 8.97 ( t r i p l e t , 3H, CH CH J ! , J = 7 Hz), 8.72 ( t r i p l e t , 3H, CH CH -0, J = 7 Hz), 7.59 ( q u a r t e t , 0 : 2H, CH2C, J = 7 Hz), 5.8 (quart e t , 2H, -CH2-0-, J = 7 Hz). Pr e p a r a t i o n of Octalone 138 To a s o l u t i o n of 530 mg of sodium d i s s o l v e d i n 35 ml of dry ethanol was added 5 g of dione 137. This s o l u t i o n was allowed to s t i r at 40° f o r 2 h, under a n i t r o g e n atmosphere. At the end of t h i s p e r i o d , the ethanol was removed i n vacuo and the residue d i l u t e d w i t h water. The aqueous s o l u t i o n was thoroughly e x t r a c t e d w i t h ether. The ether l a y e r was washed w i t h water and b r i n e and d r i e d over anhydrous magnesium s u l f a t e . The ether e x t r a c t was concentrated and the residue d i s t i l l e d to a f f o r d 4.2 g (96%) of the d e s i r e d octalone 138, b.p. 135° at 0.2 mm; - 158 -l i t . (105) b.p. 135-136° at 0.2 mm. U l t r a v i o l e t , X 247 my (e 13,000); r max i n f r a r e d ( f i l m ) , X 5.8, 6.0, 6.2 y; n.m.r., T 8.72 ( t r i p l e t , 3H, IU3.X CH_3CH2-0, J = 7 Hz) , 8.12 ( s i n g l e t , 3H, v i n y l methyl), 5.72 (qu a r t e t , 2H, CH 3-CH 2-0-, J = 7 Hz). Dehydrogenation of Octalone 138 A s o l u t i o n of 3.2 g (13.6 mmoles) of octalone 138, 4.8 g (21 mmoles) of DDQ, 6.4 ml of g l a c i a l a c e t i c a c i d i n 128 ml of anhydrous benzene was r e f l u x e d under n i t r o g e n f o r 70 h. At the end of t h i s time the cooled r e a c t i o n mixture was f i l t e r e d , and concentrated i n vacuo. The residue was taken up i n ether and washed t h r i c e w i t h water, w i t h saturated sodium bicarbonate s o l u t i o n , w i t h water and w i t h b r i n e and d r i e d over anhydrous magnesium s u l f a t e . The concentrated e x t r a c t was d i s t i l l e d , b.p. 120° at 0.2 mm, to a f f o r d 2.4 g (76%) of dienone 139, which c r y s t a l l i z e d on standi n g , m.p. 55-57°. U l t r a v i o l e t , ^ m a x 245 my (e = 9,680), sh 265 my (e = 6,700); i n f r a r e d (CHC1 3), X m a x 5.8, 6.05, 6.12, 6.23 y; n.m.r., T 8.79 ( t r i p l e t , 3H, C0 2CH 2CH 3, J = 7 Hz), 8.05 ( s i n g l e t , 3H, v i n y l methyl), 5.85 (qu a r t e t , 2H, -CH 2-0, J = 7 Hz), 3.77, 3.33 ( p a i r of doublets, 2H, C 3 and protons r e s p e c t i v e l y , J = 10 Hz). Anal. Calcd. f o r C ^ H ^ O ^ C, 71.77; H, 7.74. Found: C, 71.61; H, 7.91. Pr e p a r a t i o n of Hydroxymethylene D e r i v a t i v e 140 To a s o l u t i o n of 4 g (17.1 mmoles) of octalone 138 and 1.84 g (34.1 mmoles) of sodium methoxide d i s s o l v e d i n 20 ml of dry benzene, - 159 -at 0°, was added 3.15 ml (39 mmoles) of e t h y l formate. The r e a c t i o n v e s s e l was then put under a n i t r o g e n atmosphere and s t i r r i n g continued at room temperature f o r 24 h. At the end of t h i s time, i c e water was added and the benzene l a y e r separated. The aqueous l a y e r was n e u t r a l i z e d w i t h d i l u t e h y d r o c h l o r i c a c i d and the s o l u t i o n thoroughly e x t r a c t e d w i t h ether. The combined ether e x t r a c t s were washed w i t h water and br i n e and d r i e d over anhydrous sodium s u l f a t e . The ether l a y e r was concentrated i n vacuo to a f f o r d 3.7 g (83%) of an orange colored o i l . I n f r a r e d ( f i l m ) , \ 5.8, 6.1, 6.4 u; n.m.r., T 8.82 ( t r i p l e t , 3H, TIlcLX CH 3CH 20 2C, J = 7 Hz), 8.09 ( s i n g l e t , 3H, v i n y l methyl), 5.89 (quart e t , 2H, CH 2-0, J = 7 H z ) , 2.65 ( s i n g l e t , IH, =CH0H). Pr e p a r a t i o n of 3-Formyl Dienone 141 To a s o l u t i o n of 2.6 g (0.01 mole) of hydroxymethylene d e r i v a t i v e 140 i n 20 ml of dry dioxane was added 2.3 g (0.01 mole) of DDQ i n 20 ml of dry dioxane. The s o l u t i o n was allowed to s t i r w i t h a r a p i d flow of n i t r o g e n passing through the s o l u t i o n f o r 3.5 min. The r e a c t i o n mixture was then d i l u t e d w i t h methylene c h l o r i d e and f i l t e r e d through a column of n e u t r a l alumina. The f i l t r a t e was concentrated and d i s t i l l e d , b.p. 200° at 0.1 mm, to a f f o r d 1.68 g (65%) of a l i q u i d which c r y s t a l l i z e d on standing. R e c r y s t a l l i z a t i o n from n-hexane-ether afforded an a n a l y t i c a l sample, m.p. 46-48°, which gave the f o l l o w i n g s p e c t r a l data: u l t r a v i o l e t , x 247 m,, ( P = 8,270): i n f r a r e d max ( n u j o l ) , x 5.8, 5.9, 6.1, 6.2 y; n.m.r., x 8.75 ( t r i p l e t , 3H, TUclX C0 2CH 2CH 3, J = 7 Hz), 7.97 ( s i n g l e t , 3H, v i n y l methyl), 5.82 ( q u a r t e t , 2H, -CH 2-0, J = 7 Hz), 2.55 ( s i n g l e t , IH, v i n y l hydrogen), -0.25 ( s i n g l e t , IH, aldehydic H). - 160 -Anal. Calcd. f o r C._H_o0.: C, 68.69; H, 6.92. Found: C, 68.52; • 15 18 4 H, 7.09. P r e p a r a t i o n of Bromomethyl e t h y l Ketone (146) A procedure s i m i l a r to that of Catch et a l . was used (68). To an i c e - c o l d e t h e r e a l s o l u t i o n of 12 g (0.3 mole) of anhydrous diazomethane was added 14 g (0.15 mole) of f r e s h l y d i s t i l l e d p r o p i o n y l c h l o r i d e . This s o l u t i o n was allowed to s t i r f o r 30 min at 0°. Then anhydrous hydrogen bromide was bubbled through the s o l u t i o n and the s o l u t i o n maintained at 0° f o r an a d d i t i o n a l 30 min. The e t h e r e a l s o l u t i o n was then washed w i t h water, 5% sodium bicarbonate s o l u t i o n and b r i n e and d r i e d over anhydrous magnesium s u l f a t e . Removal of the solvent and d i s t i l l a t i o n of the o i l y residue under reduced pressure afforded 15.8 g (70%) of bromomethyl e t h y l ketone (146), b.p. 48° at ? n 10 mm; l i t . (68) b.p. 154-155°; n~ 1.4673. I n f r a r e d ( f i l m ) , X D max 5.85 u; n.m.r., x 8.88 ( t r i p l e t , 3H, CH 3-, J = 6.5 Hz), 7.27 (q u a r t e t , 2H, CH 3-CH 2-, J = 6.5 Hz), 6.06 ( s i n g l e t , 2H, -CH - B r ) . P r e p a r a t i o n of A c y l Phosphonium S a l t 147 To a s o l u t i o n of 20 g of triphenylphosphine i n 20 ml anhydrous benzene was added 15 g of bromomethyl e t h y l ketone. The r e a c t i o n mixture was allowed to stand overnight at room temperature. The p r e c i p i t a t e d phosphonium s a l t (147) was then c o l l e c t e d by s u c t i o n f i l t r a t i o n . R e c r y s t a l l i z a t i o n from methanol gave 33.6 g (82%) of white needles, m.p. 253-255°. An a n a l y t i c a l sample gave i n f r a r e d ( n u j o l ) , X 5.85, 6.90, 7.00, 9.05 y; n.m.r., x 9.08 ( t r i p l e t , 3H, CH -, J = - 161 -6.5 Hz), 6.97 ( q u a r t e t , 2H, -CH2~c\ J = 6.5 Hz), 4.03 (doublet, 2H, -CH 2 J = 11 Hz), 2.30 (unresolved m u l t i p l e t , 15H, ( C g H ^ ) . Anal. Calcd. f o r C^H^OPBr: C, 63.93; H, 5.37; Br, 19.33. Found: C, 63.65; H, 5.61; Br, 19.21. P r e p a r a t i o n of A c y l Phosphorane 148 To a s o l u t i o n of 34 g of sodium hydroxide i n 330 ml of water was added 33.5 g of the a c y l phosphonium s a l t 147 and allowed to s t i r f o r 2 h. The product was c o l l e c t e d by s u c t i o n f i l t r a t i o n , a i r - d r i e d and r e c r y s t a l l i z e d from e t h y l acetate-petroleum ether (30-60°) to a f f o r d 17.3 g (64%) of the a c y l phosphorane 148, m.p. 224-226°. I n f r a r e d (CHC1J, X 6.60, 6.98, 7.16, 9.07 y; n.m.r., T 8.85 ( t r i p l e t , 3H, CH„, J = 7 Hz), 7.66 (quarte t , 2H, -CH -C, 3=1 Hz), 2.50 (unresolved Pi m u l t i p l e t , 15 H, phenyl p r o t o n s ) , 1.0 ( s i n g l e t , IH, =CHC-); u l t r a v i o l e t , X 268 my (e = 6,600), 275 my (e = 6,200), 288 my (e = 5,500). IU9.X Anal. Calcd. f o r C^H^PO: C, 79.49; H, 6.37. Found: C, 79.22; H, 6.38. Pr e p a r a t i o n of trans-6-methylhept-4-en-3-one (144) To a s o l u t i o n c o n s i s t i n g of 11.3 g (0.034 mole) of a c y l phosphorane 148 i n 50 ml of methylene c h l o r i d e was added 7 ml (0.085 mole) of isobutyraldehyde and the s o l u t i o n r e f l u x e d overnight. The solvent was removed by c a r e f u l d i s t i l l a t i o n through a Vigreux column and the residue d i l u t e d w i t h 40 ml of n-pentane. The s o l u t i o n was f i l t e r e d to c o l l e c t the triphenylphosphine oxide and the f i l t r a t e concentrated as above. The concentrated f i l t r a t e was then f r a c t i o n a l l y d i s t i l l e d - 162 -to a f f o r d 4.28 g (63%) of a c o l o r l e s s o i l , b.p. 54° at 10 mm; l i t . (104) b.p. 55-58° at 10 mm. An a n a l y t i c a l sample of the unsaturated ketone was c o l l e c t e d by pr e p a r a t i v e g . l . c . (column D, 200°, 100). I n f r a r e d ( f i l m ) , X 5.98, 6.14 y; n.m.r., x 8.90 (doublet, 6H, C-CH , J = 7 Hz), nicix si 8.95 ( t r i p l e t , 3H, CH^-CH^, J = 7 Hz) , 7.45 (qu a r t e t , 2H, -CH_2-C, J = 7 Hz), 3.98 (doublet of doublets, IH, C. proton, J . c = 16 Hz, J . , = 4 4,5 4,6 1.5 Hz), 3.20 (doublet of doublets, IH, C 5 proton, 5 = 16 Hz, ^ 5 6 = 6 Hz); u l t r a v i o l e t , X 221 my (since i t was not p o s s i b l e to o b t a i n max r v i n y l ketone 144 without i t s (3,Y-isomer a q u a n t i t a t i v e u l t r a v i o l e t 25 spectrum was not r u n ) , n^ 1.4425. Anal. Calcd. f o r CgH^O: C, 76.19; H, 11.11. Found: C, 76.10; H, 11.12. Pr e p a r a t i o n of O l e f i n i c E s t e r 150 A s t i r r e d suspension of 4.3 g of a 56% sodium hydride d i s p e r s i o n i n m i n eral o i l i n 50 ml of dimethyl sulphoxide (DMSO) was slowly heated under a n i t r o g e n atmosphere to 75° and maintained at that temperature u n t i l a l l f r o t h i n g had ceased (y 45 min). The s o l u t i o n was cooled to room temperature and a s o l u t i o n of 18.2 g of trimethylphosphonoacetate (149) i n 30 ml of DMSO was added. The s o l u t i o n was allowed to s t i r f o r 10 min and then dropwise a d d i t i o n of 5.76 g of isobutyraldehyde i n 30 ml of DMSO was begun. The r e a c t i o n was very exothermic. A f t e r the a d d i t i o n was complete the r e a c t i o n mixture was allowed to s t i r f o r an a d d i t i o n a l hour. Water was added to the cooled r e a c t i o n mixture and i t was thoroughly e x t r a c t e d w i t h petroleum ether (30-60°). The - 163 -combined petroleum ether e x t r a c t s were washed t h r i c e w i t h water, b r i n e and d r i e d over anhydrous magnesium s u l f a t e . The solvent was removed at atmospheric pressure and the r e s i d u a l o i l d i s t i l l e d at a s p i r a t o r pressure (10 mm) to a f f o r d 6.5 g (65%) of a c l e a r c o l o r l e s s o i l , b.p. 65° at 10 mm; l i t . ( 1 0 6 ) b.p. 145-148° at 640 mm; n^ 5 1.4309; 25 l i t . (106) n^ 1.4302. This product e x h i b i t e d i n f r a r e d ( f i l m ) , \ D r max 5.8, 6.05 u; n.m.r., T 8.95 (doublet, 6H, gem-dimethyl groups, J = 7 Hz), CH3 CH 3 7.50 ( m u l t i p l e t , IH, \ / ), 6.30 ( s i n g l e t , 3H, methyl e s t e r ) , —L>—ri 4.25 (doublet of doublets, IH, proton, J 2 3 = 16 Hz, ^ = 1 Hz), 3.05 (doublet of doublets, IH, proton, 3 = 16 Hz, ^ = 7 Hz); u l t r a v i o l e t , \ 227 mu (e = 5,600). max ' ' Pr e p a r a t i o n of O l e f i n i c A c i d 151 To a s t i r r e d s o l u t i o n of 34 g of potassium carbonate d i s s o l v e d i n 200 ml of methanol-water was added 23 g of unsaturated e s t e r 150. The r e a c t i o n mixture was s t i r r e d at r e f l u x f o r 3 h. Most of the methanol was then removed under reduced pressure and water added to the residue. This aqueous s o l u t i o n was thoroughly e x t r a c t e d w i t h ether. The e t h e r e a l l a y e r was washed w i t h water and w i t h b r i n e and d r i e d over anhydrous magnesium s u l f a t e . The concentrated e x t r a c t a f f o r d e d 2 g of s t a r t i n g e s t e r 150. The aqueous l a y e r was a c i d i f i e d w i t h d i l u t e h y d r o c h l o r i c a c i d and thoroughly e x t r a c t e d w i t h ether. The ether e x t r a c t was washed w i t h water and b r i n e and d r i e d over anhydrous magnesium s u l f a t e . Removal of the solvent and vacuum d i s t i l l a t i o n afforded 15 g (82%) of a c o l o r l e s s o i l , b.p. 75° at 0.6 mm; l i t . (106) b.p. 99-110° - 164 -at 10 mm; 1.4454. This unsaturated a c i d 151 e x h i b i t e d i n f r a r e d ( f i l m ) , X 3.1-4.0, 5.9, 6.1 u; n.m.r., x 8.95 (doublet, 6H, gem-in 3.x dimethyl groups, J = 6.5 Hz), 7.25-7.8 ( m u l t i p l e t , IH, p r o t o n ) , 4.2 (doublet of doublets, IH, C 2 proton, J 2 3 = 1 5 , 5 H z ' J 2 4 = 1 , 5 H z ^ ' 2.9 (doublet of doublets, IH, C 3 proton, J 2 3 = 1 5 , 5 H z ' J 3 4 = 6 , 5 H z ^ » -2.15 ( s i n g l e t , IH, C0„H); u l t r a v i o l e t , X 217 my (e =3634). Z ITlcLX Anal. Calcd. f o r C,H1r.0o: C, 63.14; H, 8.83. Found: C, 62.85; 6 10 2 H, 8.76. P r e p a r a t i o n of E t h y l l i t h i u m To 600 ml of anhydrous ether under n i t r o g e n was added 25.8 g of f i n e l y cut l i t h i u m w i r e . To the s t i r r e d mixture was added dropwise a s o l u t i o n of 120 ml of e t h y l bromide ( d i s t i l l e d from calcium hydride) i n 300 ml of anhydrous ether. During the a d d i t i o n the r e a c t i o n mixture was kept at -10° by an e x t e r n a l dry ice-acetone c o o l i n g bath. A f t e r the a d d i t i o n was complete the s o l u t i o n was warmed to 0° f o r 1 h, f i l t e r e d and used immediately. P r e p a r a t i o n of trans-6-methylhept-4-ene-3-one (144) A s o l u t i o n of 32 g of unsaturated a c i d 151 i n 540 ml of anhydrous ether was' cooled to -78° by an e x t e r n a l dry ice-acetone bath. To t h i s s o l u t i o n 600 ml of the p r e v i o u s l y prepared e t h y l l i t h i u m s o l u t i o n was added dropwise. A f t e r the a d d i t i o n was complete, the r e s u l t i n g white s l u r r y was allowed to s t i r f o r an a d d i t i o n a l hour. Then the c o o l i n g bath was removed and the s t i r r i n g continued u n t i l a c l e a r s o l u t i o n r e s u l t e d . - 165 -I t was then poured i n t o a s t i r r e d and cooled 1 N h y d r o c h l o r i c a c i d s o l u t i o n . The r e s u l t i n g s o l u t i o n was thoroughly e x t r a c t e d w i t h ether. The ether l a y e r was washed w i t h d i l u t e ammonium hydroxide, water and b r i n e and dried over anhydrous magnesium s u l f a t e . The solvent was then c a r e f u l l y removed by d i s t i l l a t i o n through a Vigreux column at atmospheric pressure. The residue was f r a c t i o n a l l y d i s t i l l e d to give 17 g (92%, based on recovered s t a r t i n g m a t e r i a l ) of unsaturated ketone b.p. 54° at 10 mm. This product gave i n f r a r e d , n.m.r. and u l t r a v i o l e t s p e c t r a which were superimposable w i t h those obtained f o r trans-6-methyl-hept-4-ene-3-one (144) by the previous p r e p a r a t i o n . P r e p a r a t i o n of Octalone 155 The enamine of cyclohexanone was prepared by the method of Stork et a l . (66). A s o l u t i o n of 6 g of f r e s h l y d i s t i l l e d cyclohexanone and 9 g of p y r r o l i d i n e i n 20 ml of benzene were r e f l u x e d under a Dean-Stark water separator u n t i l no f u r t h e r s e p a r a t i o n of water occurred (approximately 3 h). The excess p y r r o l i d i n e and benzene were removed on a r o t a r y evaporator and the residue d i s t i l l e d under vacuum to a f f o r d 6 g (79%) of the p y r r o l i d i n e enamine of cyclohexanone, b.p. 60-70° at 0.6 mm; l i t . (66) b.p./105-107° at 13 mm. I n f r a r e d ( f i l m ) , X 6.1 y. max A s o l u t i o n of 6 g (0.02 mole) of the p y r r o l i d i n e enamine of cyclohexanone and 2.6 g (0.02 mole) of trans-6-methylhept-4-en-3-one (144) were s t i r r e d together under n i t r o g e n at 60° f o r 40 h. Then 12 ml of anhydrous dioxane was added and the r e a c t i o n mixture r e f l u x e d - 166 -overnight. To the reaction mixture was added 1 ml g l a c i a l a c e t i c a c i d , 2 ml water and 0.5 g anhydrous sodium acetate and r e f l u x maintained for 4 h. The cooled reaction mixture was d i l u t e d with water and the r e s u l t i n g s o l u t i o n thoroughly extracted with ether. The combined ether extracts were washed with water, d i l u t e hydrochloric acid, water and brine before being dried over anhydrous magnesium s u l f a t e . The solvent was removed and the residue d i s t i l l e d under vacuum to a f f o r d 3.5 g (83%) of a pale yellow o i l , b.p. 100° at 0.2 mm. This was shown by g . l . c . to contain a 70:30 mixture of octalone 155a and 155b, r e s p e c t i v e l y . A n a l y t i c a l samples of these two components were co l l e c t e d by preparative g . l . c . (column E, 200°, 86) and exhibited the following s p e c t r a l p r o p e r t i e s : Major epimer: Infrared ( f i l m ) , ^ m a x 6.0, 6.15 y; n.m.r., T 9.21, 9.11 (pair of doublets, 6H, isopropyl methyl groups, J = 7 Hz), 8.26 ( s i n g l e t , 3H, v i n y l methyl); u l t r a v i o l e t , A 249 my (E = 13,600). Mol. Wt. Calcd. for C1A^22°'' 2 0 6 • 1 6 7 • Found (high r e s o l u t i o n mass spectrometry): 206.166. Minor epimer: Infrared ( f i l m ) , A 6.0, 6.1 y; n.m.r., x 9.11 max ' (doublet, 6H, isopropyl methyl groups, J = 6 Hz), 8.26 ( s i n g l e t , 3H, v i n y l methyl); u l t r a v i o l e t ^ m a K 249 my (e = 13,400). Mol. Wt. Calcd. for C 1 ^ H 2 2 0 : 206.167. Found (high r e s o l u t i o n mass spectrometry): 206.166. Preparation of 4-ethylenedioxycyclohexanone (156) A s o l u t i o n of 3 g (14 mmoles) of keto ester 113, 1.5 g of potassium hydroxide and 30 ml of 1:1 methanol-water was refluxed for - 167 -4 h. At the end of t h i s time the methanol was removed i n vacuo. The aqueous l a y e r was a c i d i f i e d w i t h g l a c i a l a c e t i c a c i d and thoroughly e x t r a c t e d w i t h ether. The combined ether e x t r a c t s were washed w i t h water, saturated sodium bicarbonate s o l u t i o n , water and b r i n e and d r i e d over anhydrous magnesium s u l f a t e . The ether l a y e r was concentrated and the residue c r y s t a l l i z e d on standing. R e c r y s t a l l i z a t i o n from n-hexane afforded 1.5 g (66%) of white p l a t e s , m.p. 69-70°. I n f r a r e d ( n u j o l ) , X m a x 3.45, 5.85 ,:y; n.m.r., T 7.17-8.00 (unresolved m u l t i p l e t , 8H, r i n g p r o t o n s ) , 5.84 ( s i n g l e t , 4H, k e t a l p r o t o n s ) . P r e p a r a t i o n of Octalone 157 The enamine of keto k e t a l 156 was prepared by the method of Stork et a l . (66). A s o l u t i o n of 1 g of keto k e t a l 156 and 0.5 g of f r e s h l y d i s t i l l e d p y r r o l i d i n e i n 10 ml of anhydrous benzene were r e f l u x e d under a Dean-Stark water separator u n t i l no f u r t h e r s e p a r a t i o n of water occurred. The excess p y r r o l i d i n e and benzene were removed on the r o t a r y evaporator and the residue d i s t i l l e d under vacuum to y i e l d 1 g (86%) of a c o l o r l e s s o i l , b.p. 128-138° at 0.3 mm; l i t . (66) b.p. 110-120° at 0.1-0.15 mm. I n f r a r e d ( f i l m ) , X 6.1 u. max A s o l u t i o n of 1 g of the p r e v i o u s l y prepared p y r r o l i d i n e enamine of 156, 500 mg of v i n y l ketone 144 i n 4 ml of dry dioxane were r e f l u x e d together f o r 48 h. Then 1.1 ml of the f o l l o w i n g s o l u t i o n was added: 1 ml a c e t i c a c i d , 2 ml water and 0.5 g sodium acetate. These reagents were r e f l u x e d together f o r 1.5 h. The cooled r e a c t i o n mixture was then d i l u t e d w i t h water and thoroughly e x t r a c t e d w i t h ether. - 168 -The combined ether e x t r a c t s were washed w i t h water, sodium carbonate s o l u -t i o n , water and b r i n e and d r i e d over anhydrous magnesium s u l f a t e . The concentrated ether e x t r a c t was d i s t i l l e d to a f f o r d 121 mg (8%) b.p. 150° at 0.1 mm, of a vi s c o u s o i l . G.l.c. a n a l y s i s (column E, 180°, 85) revealed two components i n the r a t i o 1:4 r e s p e c t i v e l y . A n a l y t i c a l samples were c o l l e c t e d by p r e p a r a t i v e g . l . c . using the above c o n d i t i o n s . The minor isomer, octalone 157a, e x h i b i t e d the f o l l o w i n g s p e c t r a : u l t r a v i o l e t , X 243 mu (e =13,000): i n f r a r e d max ( f i l m ) , A 6.05 u; ri.m.r., x 9.18, 9.08 ( p a i r of doublets, 6H, max r i s o p r o p y l methyl groups, J = 6.5 Hz), 8.23 (singlet-, 3H, v i n y l methyl), 6.06 ( s i n g l e t , 4H, k e t a l p rotons). Mol. Wt. Calcd. f o r c l 6 H 2 4 ° 3 : 264.172. Found (high r e s o l u t i o n mass spectrometry): 264.172. The major isomer, octalone 157b, e x h i b i t e d the f o l l o w i n g s p e c t r a : u l t r a v i o l e t , A 243 mp (e = 18,900); i n f r a r e d ( f i l m ) , A 6.01, 6.15 u; max max n.m.r., x 9.08, 9.06 ( p a i r of doublets, 6H, i s o p r o p y l methyl groups, J = 6.0 Hz), 8.23 ( s i n g l e t , 3H, v i n y l methyl), 6.06 ( s i n g l e t , 4H, k e t a l protons). Mol. Wt. Calcd. f o r C,,H..0_: 264.172. Found (high r e s o l u t i o n 16 24 3 mass spectrometry): 264.172. Pr e p a r a t i o n of Q u i n t o l Monobenzoate (160) This compound was prepared using the procedure of Jones and Sondheimer (73). To a s o l u t i o n of 125 g (1.0 mole) of q u i n t o l (159) d i s s o l v e d i n a mixture of 355 ml of anhydrous chloroform and 292 ml of anhydrous - 169 -p y r i d i n e , was added dropwise over 5 h 148 g (1.04 mole) of benzoyl c h l o r i d e i n 307 ml of anhydrous chloroform. The temperature was kept at 0° during the a d d i t i o n by an e x t e r n a l i c e bath. A f t e r standing at room temperature f o r 2 days, the chloroform s o l u t i o n was thoroughly washed w i t h water, d i l u t e s u l p h u r i c a c i d , water and b r i n e and d r i e d over anhydrous magnesium s u l f a t e . A f t e r removal of the solvent the o i l y residue was f r a c t i o n a l l y d i s t i l l e d to a f f o r d 140 g (62%) of q u i n t o l monobenzoate 160, b.p. 160-165° at 0.3 mm; l i t . (73) b.p. 175-178° at 0.2 mm. The product e x h i b i t e d i n f r a r e d ( f i l m ) , A 2.93, 5.85, max 6.3, 6.35 u; n.m.r.,x 1.95-2.55 (unresolved m u l t i p l e t , 5H, phenyl pro t o n s ) , 4.95 (broad s i n g l e t , IH, -CH-Oc'cglL.) , 6.25 (broad s i n g l e t , IH, -CH-OH), 6.64 ( s i n g l e t , IH, exchangeable, OH), 8.20 ( m u l t i p l e t , 8H, remaining r i n g p rotons). P r e p a r a t i o n of 4-Benzoyloxycyclohexanone (161) To a cooled and s t i r r e d s o l u t i o n of 50 g of q u i n t o l monobenzoate (160) i n 85 ml of g l a c i a l a c e t i c a c i d was added 22 g of chromium t r i o x i d e i n 12.5 ml of water and 50 ml of g l a c i a l a c e t i c a c i d . The temperature was maintained below 35° during the a d d i t i o n and then at room temperature f o r an a d d i t i o n a l 12 h. A f t e r t h i s p e r i o d ether was added and the s o l u t i o n thoroughly washed w i t h water, d i l u t e sodium hydroxide s o l u t i o n , water and b r i n e and d r i e d over anhydrous magnesium s u l f a t e . Removal of the solvent a f f o r d e d 48 g of a white c r y s t a l l i n e product. R e c r y s t a l l i z a t i o n from ether-petroleum ether (30-60°) gave 42 g (87%) of the keto ester 161 m.p. 59-61°; l i t . (73) m.p., 62°. The keto e s t e r 161 e x h i b i t e d i n f r a r e d ( n u j o l ) , X 5.85, 6.25, 6.3 u; - 170 -n.m.r., T 1.95-2.55 (unresolved m u l t i p l e t , 5H, phenyl p r o t o n s ) , 4.55 (broad s i n g l e t , IH, CH-oiicgH ) , 7.50 (unresolved m u l t i p l e t , 8H, remaining r i n g p rotons). P r e p a r a t i o n of 4-Hydroxycyclohexanone (158) This compound was prepared by a procedure analogous to Jones and Sondheimer (73). A s o l u t i o n of 80 g of 4-benzoyloxycyclohexanone (161) i n 320 ml of dry methanol, c o n t a i n i n g 0.8 g of sodium metal, was r e f l u x e d f o r 18 h. To the cooled r e a c t i o n mixture water and dry i c e were added. A f t e r the s o l u t i o n became homogeneous, the methanol was removed on the r o t a r y evaporator. To t h i s v i s c o u s s o l u t i o n , water and ether were added. The s o l u t i o n was thoroughly e x t r a c t e d w i t h ether to remove the methyl benzoate. The aqueous l a y e r was then c a r e f u l l y d i s t i l l e d to give 30.6 g (74%) of a c l e a r c o l o r l e s s o i l , b.p. 92° at 1.1 mm; l i t . (73), b.p. 83-85 at 0.6 mm. The product was shown to be homogeneous by g . l . c . a n a l y s i s (column F, 180°, 85). The a l c o h o l e x h i b i t e d i n f r a r e d OH ( f i l m ) , X 2.95, 5.85 y; n.m.r., x 5.85 ( m u l t i p l e t , IH, C ) , 6.25 max ( s i n g l e t , IH, exchangeable on D^ O a d d i t i o n , OH). P r e p a r a t i o n of Octalone 162 A s o l u t i o n of 18 g (0.16 mole) of 4-hydroxycyclohexanone (158) and 20.7 ml of p y r r o l i d i n e i n 234 ml of benzene were r e f l u x e d under a Dean-Stark water separator u n t i l no f u r t h e r s e p a r a t i o n of water occurred (approximately 3 h ) . The benzene and excess p y r r o l i d i n e were removed under vacuum (0.1 mm) to y i e l d a white c r y s t a l l i n e enamine. - 171 -I n f r a r e d ( n u j o l ) , A 3.0, 6.1 u. To the above enamine under • max ^ n i t r o g e n was added 13.5 g (0.1 mole) of trans-6-methylhept-4-en-3-one (144). These reagents were s t i r r e d together at 50° f o r 17 h. At t h i s time the i n f r a r e d spectrum of the enamine mixture e x h i b i t e d absorptions f o r the s t a r t i n g enamine, the enamine of the octalone 162 but no v i n y l ketone. Hence, an a d d i t i o n a l 5 g of v i n y l ketone 144 was added and s t i r r i n g continued f o r an a d d i t i o n a l 19 h. Dry dioxane was then added and the s o l u t i o n r e f l u x e d f o r 16 h. To t h i s r e a c t i o n mixture was added the h y d r o l y s i s s o l u t i o n , c o n s i s t i n g of 5 g anhydrous sodium a c e t a t e , 10 ml g l a c i a l a c e t i c a c i d and 20 ml of water and the s o l u t i o n r e f l u x e d f o r 4 h. The cooled r e a c t i o n mixture was then d i l u t e d w i t h water and thoroughly e x t r a c t e d w i t h ether. The combined ether e x t r a c t s were washed s u c c e s s i v e l y w i t h water, d i l u t e h y d r o c h l o r i c a c i d , water and b r i n e and d r i e d over anhydrous magnesium s u l f a t e . The ether was removed under reduced pressure and the o i l y r e sidue d i s t i l l e d to a f f o r d 14 g (40%) of the d e s i r e d octalone 162, b.p. 200° at 0.1 mm. This was shown by g . l . c . a n a l y s i s (column G, 215°, 170) to be a 3:2 mixture of octalone (162a p l u s 162c) and octalone (162b plus 162d), r e s p e c t i v e l y . These two components were i s o l a t e d by g . l . c . and then d i s t i l l e d to give the f o l l o w i n g s p e c t r a l data: Major epimer octalones 162a + 162c: I n f r a r e d ( C H C l n ) , A 2.75, 2.9, J r 3 max 6.05 u; n.m.r., x 9.16, 9.07 ( p a i r of doublets, 6H, i s o p r o p y l methyl groups, J = 6.5 Hz), 8.23 ( s i n g l e t , 3H, v i n y l methyl), 6.15, 5.82 OH (unresolved m u l t i p l e t s , IH, C ); u l t r a v i o l e t , A 248 mu (e = \ -rj m 3.x n 10,900). Mol- Wt. Calcd. f o r C 1 4 H 2 2 ° 2 : 2 2 2 • 1 6 2 • Found (high r e s o l u t i o n - 172 -mass spectrometry): 222.162. Minor epimer octalones 162b + 162d: I n f r a r e d (CHC1J , A 2.75, 2.9, 3 max 6.05, 6.15 y; n.m.r., T 9.07, 9.04 ( p a i r of doublets, 6H, i s o p r o p y l methyl groups, J = 6 Hz), 8.26 ( s i n g l e t , 3H, v i n y l methyl group), 6.10, OH 5.78 (unresolved m u l t i p l e t , IH, C ); u l t r a v i o l e t , A 247 my (E = n 9,272). Mol. Wt. Calcd. f o r C X 4 H 2 2 0 2 : 2 2 2 • 1 6 2 • Found (high r e s o l u t i o n mass spectrometry): 222.162. E p i m e r i z a t i o n of Octalone 162 To a s o l u t i o n of 100 mg of sodium metal d i s s o l v e d i n 20 ml of methanol was added 2 g of the 3:2 epimeric mixture of octalones 162. The s o l u t i o n was r e f l u x e d under n i t r o g e n f o r 12 h. Then most of the methanol was removed at a s p i r a t o r pressure and water added. The r e s u l t i n g s o l u t i o n was thoroughly e x t r a c t e d w i t h ether. The combined ether e x t r a c t s were washed w i t h water, d i l u t e h y d r o c h l o r i c a c i d , water and b r i n e and d r i e d over anhydrous magnesium s u l f a t e . The d r i e d e t h e r e a l e x t r a c t was concentrated and d i s t i l l e d under vacuum to a f f o r d 1.8 g (90%) of a pale y e l l o w o i l , b.p. 200° at 0.1 mm. G.l.c. a n a l y s i s (column G, 215°, 170) showed the epimers to now be i n the r a t i o of 7:3. These two components were i s o l a t e d by g . l . c . and e x h i b i t e d g . l . c . r e t e n t i o n times, i n f r a r e d , n.m.r. and u l t r a v i o l e t s p e c t r a i d e n t i c a l w i t h the two s t a r t i n g epimers. - 173 -Preparation of Dione 163 A s o l u t i o n of 60 mg of chromium t r i o x i d e i n 1.5 ml of methylene chloride containing 0.09 ml pyridine was allowed to s t i r at room temperature f o r 15 min. To t h i s s o l u t i o n was added 30 mg of octalones 162a + 162c i n 0.5 ml methylene chloride and the s o l u t i o n allowed to s t i r for 25 min at room temperature. At the end of t h i s time the reaction mixture was d i l u t e d with 8 ml of ether. The ether layer was washed twice with water and brine and dried over anhydrous magnesium s u l f a t e . The concentrated residue afforded 28 mg (94%) of dione 163, o m.p. 108-110. This compound exhibited one peak on g . l . c . analysis (column E, 180°, 86); i n f r a r e d (CHC1„), X 5.85, 6.05, 6.15 u; n.m.r., x 9.20, 9.07 (pair of doublets, 6H, isopropyl methyl groups, J = 6.5 Hz), 8.12(singlet, 3H, v i n y l methyl); u l t r a v i o l e t , X 247 mp max (e = 13,000). Anal. Calcd. for C ^ H ^ O ^ C, 76.33; H, 9.15. Found: C, 76.28; H, 9.18. Preparation of Methanesulfonate Derivative 164 To a s o l u t i o n of 200 mg of octalone 162 i n 5 ml of dry pyrid i n e , at 0°, was added 0.1 ml of methanesulfonyl chloride. The reaction mixture was then allowed to s t i r at room temperature for 3.5 h. Ice was added and the so l u t i o n allowed to s t i r f o r an a d d i t i o n a l 10 min. The s o l u t i o n was then thoroughly extracted with ether. The combined ether extracts were washed with water, d i l u t e s u l f u r i c acid ( u n t i l a c i d i c ) , aqueous sodium bicarbonate ( u n t i l n e u t r a l ) , and brine and dried over anhydrous magnesium s u l f a t e . Removal of the solvent i n vacuo - 174 -a f f o r d e d 250 mg (85%) of an o i l y methanesulfonate d e r i v a t i v e 164. I n f r a r e d ( f i l m ) , X 6.0, 7.45, 8.55 y. max Reduction of Octalone 155 To 150 ml of l i q u i d ammonia ( d i s t i l l e d from sodium metal) was added 200 mg of f i n e l y cut l i t h i u m w i r e . A f t e r the l i t h i u m had d i s s o l v e d 450 mg of octalone 155 d i s s o l v e d i n 25 ml of anhydrous ether was added dropwise over 0.5 h. The r e a c t i o n mixture was allowed to s t i r f o r an a d d i t i o n a l 1.5 h, and then ammonium c h l o r i d e added to discharge the blue c o l o r . A f t e r a l l the ammonia had evaporated water was added and t h i s aqueous s o l u t i o n thoroughly e x t r a c t e d w i t h ether. The combined ether e x t r a c t s were washed s u c c e s s i v e l y w i t h water, d i l u t e h y d r o c h l o r i c a c i d , water and b r i n e and d r i e d over anhydrous magnesium s u l f a t e . The ether was removed i n vacuo and the o i l y r esidue vacuum d i s t i l l e d to a f f o r d 350 mg (78%) of a pale y e l l o w o i l , b.p. 125° at 0.6 mm. This e x h i b i t e d two components i n a 3:1 r a t i o on g . l . c . a n a l y s i s (column F, 215°, 110). A n a l y t i c a l samples of these two components were c o l l e c t e d by g . l . c . and e x h i b i t e d the f o l l o w i n g s p e c t r a l p r o p e r t i e s : Major component (decalone 165a): I n f r a r e d ( f i l m ) , ^ m a x 3.42, 3.51, 5.85 n.m.r., T 9.23, 9.13 ( p a i r of doublets, 6H, i s o p r o p y l methyl groups, J = 7 Hz), 8.99 (doublet, 3H, secondary methyl, J = 6.5 Hz). Anal. Calcd. f o r C^H^O: C, 80.71; H, 11.61. Found: C, 80.48; H, 11.31. Minor component (decalone 165b): I n f r a r e d ( f i l m ) , ^ m a x 3.45, 5.85 y; n.m.r., T 9.13, 9.09 ( p a i r of doublets, 6H, i s o p r o p y l methyl groups j J = 6 Hz), 9.02 (doublet, 3H, secondary methyl, J = 6.5 Hz). - 175 -Mol. Wt. Calcd. f o r C^H^O: 208.183- Found (high r e s o l u t i o n mass spectrometry): 208.182. Reduction of Methanesulfonate D e r i v a t i v e 164 A s o l u t i o n of 280 mg of the methanesulfonate d e r i v a t i v e 164 i n 1.8 ml of absolute ethanol was added dropwise to a s o l u t i o n of 1.35 g of l i t h i u m d i s s o l v e d i n 50 ml of l i q u i d ammonia ( d i s t i l l e d from sodium metal) at -7 8°. The mixture was s t i r r e d at -78° f o r 1 h then f o r 1.5 h at -33°. The r e a c t i o n was quenched by c a r e f u l a d d i t i o n of ethanol. The l i q u i d ammonia was then allowed to evaporate and water added. This aqueous s o l u t i o n was thoroughly e x t r a c t e d w i t h ether. The combined ether e x t r a c t s were washed w i t h water and b r i n e and d r i e d over anhydrous magnesium s u l f a t e . The s o l v e n t was removed i n vacuo and the residue vacuum d i s t i l l e d to a f f o r d 160 mg (98%) of a mixture of a l c o h o l - c o n t a i n i n g products, b.p. 120° at 0.25 mm. I n f r a r e d ( f i l m ) , X 3.0 u. This product was immediately d i s s o l v e d i n 12 ml of acetone max e r J ( d i s t i l l e d from potassium permanganate) and 0.8 ml of a standard chromic a c i d s o l u t i o n (76) was added dropwise u n t i l the orange c o l o r p e r s i s t e d . The orange c o l o r was then discharged by a d d i t i o n of isopropanol and most of the acetone removed on the r o t a r y evaporator. The residue was then d i l u t e d w i t h water and the s o l u t i o n thorougly e x t r a c t e d w i t h ether. The combined ether e x t r a c t s were washed w i t h water and b r i n e and d r i e d over anhydrous magnesium s u l f a t e . The solvent was removed i n , vacuo and vacuum d i s t i l l a t i o n of the residue afforded 136 mg (85%) of the decalones 165a and 165b, b.p. 125° at 0.6mm. Decalones 165a and 165b were shown by g . l . c . a n a l y s i s (column F, 215°, 110) to be i n the r a t i o - 176 -of 70:30. A n a l y t i c a l samples of these two products were c o l l e c t e d and shown to have i d e n t i c a l g . l . c . r e t e n t i o n times, i n f r a r e d and n.m.r. spect r a w i t h the two products from the B i r c h r e d u c t i o n of octalones 155a and 155b. B i r c h Reduction of Octalone 155a To a s o l u t i o n of 35 mg of l i t h i u m metal i n 100 ml of l i q u i d ammonia ( f r e s h l y d i s t i l l e d from sodium metal) was added over 15 min 103 mg (0.5 mmole) of octalone 155a i n 5 ml of anhydrous ether c o n t a i n i n g 0.094 ml of anhydrous ethanol. The r e a c t i o n mixture was allowed to s t i r f o r 2 h. The r e a c t i o n was then quenched by c a r e f u l a d d i t i o n of excess ethanol, and the ammonia allowed to evaporate. The r e s i d u a l m a t e r i a l was d i l u t e d w i t h s a t u r a t e d b r i n e and e x t r a c t e d three times w i t h ether. The ether was removed at a s p i r a t o r pressure and the crude m a t e r i a l o x i d i z e d by Jones reagent as described above. This procedure afforded 94.6 mg (91%) of decalone 165a. A n a l y s i s of the product by g . l . c . (column F, 215°, 110) revealed the presence of only one component. The s p e c t r a l data of t h i s product (n.m.r., i . r . , g . l . c . r e t e n t i o n time) were i d e n t i c a l w i t h those of decalone 165a p r e v i o u s l y prepared. Hydrogenation of Octalone 155b A s o l u t i o n of 100 mg of octalone 155b [ i s o l a t e d by p r e p a r a t i v e g . l . c . (column F, 180°, 110)] d i s s o l v e d i n 10 ml of f r e s h l y d i s t i l l e d e t h y l acetate was hydrogenated at atmospheric pressure and room temperature over 10 mg of 10% palladium on c h a r c o a l . A f t e r f i l t r a t i o n - 177 ~ and removal of the solvent the residue was vacuum d i s t i l l e d to a f f o r d 96 mg (92%) of a c o l o r l e s s o i l , b.p. 125° at 0.6mm. This m a t e r i a l was subjected to the p r e v i o u s l y described sodium methoxide e p i m e r i z a t i o n c o n d i t i o n s to epimerize the a-methyl group. The r e s u l t i n g product was shown to contain 98% of one component by g . l . c . a n a l y s i s (column F, 180°, 100). An a n a l y t i c a l sample gave i n f r a r e d and n.m.r. sp e c t r a that were superimposable w i t h those of the minor isomer of the B i r c h r e d u c t i o n of octalone 155 or mesylate 164. Pre p a r a t i o n of T h i o k e t a l 166 The major epimer of octalone 162 was c o l l e c t e d by p r e p a r a t i v e g . l . c . (column G, 230°, 110). To a 3.6 g sample of octalones 162a and 162c was added 3.0 ml of e t h a n e d i t h i o l . This s o l u t i o n was cooled to 0° and 1.4 ml of boron t r i f l u o r i d e etherate was added. The s o l u t i o n was allowed to warm to room temperature and allowed to s t i r f o r 1 h. The s o l u t i o n was then d i l u t e d w i t h water and thoroughly e x t r a c t e d w i t h chloroform. The chloroform e x t r a c t s were combined and washed w i t h water and b r i n e and d r i e d over anhydrous magnesium s u l f a t e . The concentrated e x t r a c t gave 5.2 g of crude t h i o k e t a l . This m a t e r i a l was then f i l t e r e d through a 20 g bed of Woelm a c t i v i t y I n e u t r a l alumina. The concentrated f i l t r a t e c r y s t a l l i z e d on standing. I t was r e c r y s t a l l i z e d from ether to a f f o r d 3.2 g (66%) of white r e c t a n g u l a r c r y s t a l s , m.p. 109-110°. An a n a l y t i c a l sample e x h i b i t e d the f o l l o w i n g s p e c t r a l p r o p e r t i e s : i n f r a r e d ( n u j o l ) , ^ m a x 3.0, 6.1 u; n.m.r., x 9.21, 9.02 (p a i r of doublets, 6H, i s o p r o p y l methyl groups, 3 = 1 Hz), 8.57 ( s i n g l e t , IH, exchanges on D„0 a d d i t i o n , C-OH), 8.07 ( s i n g l e t , 3H, v i n y l methyl), - 178 -6.67 ( s i n g l e t , 4H, t h i o k e t a l p r o t o n s ) , 5.86 (unresolved m u l t i p l e t , IH, CHOH ( e q u a t o r i a l ) ) . Mol. Wt. Calcd. f o r C ^ H ^ O S ^ 298.142. Found (high r e s o l u t i o n mass spectrometry): 298.144. Pr e p a r a t i o n of A l c o h o l 167 To a s o l u t i o n of 700 mg (1.44 mmoles) of t h i o k e t a l 166 i n 100 ml of absolute ethanol was added 10 g of commercial Raney n i c k e l . The s o l u t i o n was r e f l u x e d f o r 5 h. The s o l u t i o n was then cooled and the Raney n i c k e l removed by s u c t i o n f i l t r a t i o n through a bed of C e l i t e . The f i l t r a t e was concentrated and the r e s i d u a l o i l vacuum d i s t i l l e d to a f f o r d 350 mg (77%) of a viscous c o l o r l e s s a l c o h o l 167, b.p. 120° at 0.25 mm. On g . l . c . a n a l y s i s (column F, 215°, 110) t h i s product e x h i b i t e d one major peak along w i t h t r a c e amounts of u n i d e n t i f i e d components. An a n a l y t i c a l sample of the major component was c o l l e c t e d by p r e p a r a t i v e g . l . c . (column G, 215°, 110) and e x h i b i t e d i n f r a r e d ( f i l m ) , X 3.0, 6.0 u; n.m.r., x 9.23, 9.09 ( p a i r of doublets, 6H, IT13.X i s o p r o p y l methyl groups, J = 6.5 Hz), 8.40 ( s i n g l e t , 3H, v i n y l methyl), 7.52 ( s i n g l e t , IH, exchanges on D 20 a d d i t i o n , hydroxyl p r o t o n ) , 6.36, 5.85 (unresolved m u l t i p l e t s , t o t a l l i n g IH, CHOH). Mol. Wt. Calcd. f o r C^H^O: 208.183. Found (high r e s o l u t i o n mass spectrometry): 208.183. Pr e p a r a t i o n of Octalone 168 To an i c e - c o l d s o l u t i o n of 720 mg of chromium t r i o x i d e d i s s o l v e d i n 18 ml of anhydrous p y r i d i n e was added 350 mg of a l c o h o l 167 i n 9 ml - 179 -of anhydrous p y r i d i n e . The s o l u t i o n was allowed to s t i r at room tempera-ture f o r 40 h. The r e a c t i o n mixture was then poured i n t o s t i r r e d anhydrous ether. C e l i t e was then added and the mixture f i l t e r e d . The f i l t r a t e was thoroughly washed w i t h water and b r i n e and d r i e d over anhydrous magnesium s u l f a t e . A f t e r removal of the solvent the o i l y residue was d i s t i l l e d under vacuum to y i e l d 307 mg (89%) of a c o l o r l e s s o i l , b.p. 130° at 0.35 mm. This product was shown to be homogeneous by g . l . c . (column F, 180°, 85). An a n a l y t i c a l sample e x h i b i t e d i n f r a r e d ( f i l m ) , \ 5.85 u; n.m.r., T 9.21, 9.05 ( p a i r of doublets, 6H, max r i s o p r o p y l methyl groups, J = 6.5 Hz), 8.36 ( s i n g l e t , 3H, v i n y l methyl). Mol. Wt. Calcd. f o r C^H^O: 206.167. Found (high r e s o l u t i o n mass spectrometry): 206.168. P r e p a r a t i o n of A l c o h o l 169 A s o l u t i o n of 230 mg (1.06 mmoles) of octalone 168 d i s s o l v e d i n 30 ml of anhydrous ether was cooled to 0°. To t h i s s o l u t i o n was added, dropwise, 2 ml of 2.16 M m e t h y l l i t h i u m (4.32 mmoles). A f t e r the a d d i t i o n was complete the s o l u t i o n was allowed to s t i r f o r 2 h at room temperature. I t was then poured onto a mixture of i c e and water. The ether l a y e r was separated and washed w i t h water and b r i n e and d r i e d over anhydrous magnesium s u l f a t e . The solvent was removed at a s p i r a t o r pressure and the o i l y residue vacuum d i s t i l l e d to a f f o r d 224 mg (91%) of a viscous o i l , b.p. 130° at 0.25 mm. This o i l was shown to contain one major component along w i t h t r a c e amounts of u n i d e n t i f i e d m a t e r i a l on g . l . c . a n a l y s i s (column G, 200°, 110). The major component was g . l . c . i s o l a t e d and shown to be a white c r y s t a l l i n e - 180 -substance, m.p. 79-80°. I n f r a r e d ( n u i o l ) , A 3.0, 6.1 y; n.m.r., x J ' max ' ' 9.21, 9.07 ( p a i r of doublets, 6H, i s o p r o p y l methyl groups, J = 6.5 Hz), 8.81 ( s i n g l e t , 3H, t e r t i a r y methyl group), 8.37 ( s i n g l e t , 3H, v i n y l methyl). Mol. Wt. Calcd. f o r C H^O: 222.198. Found (high r e s o l u t i o n mass spectrometry): 222.198. Pr e p a r a t i o n of Cadinene D i h y d r o c h l o r i d e 4J_ A s o l u t i o n of 100 mg of c r y s t a l l i n e g . l . c . i s o l a t e d a l c o h o l 169 i n 10 ml of anhydrous ether was cooled to 0° and dry hydrogen c h l o r i d e gas passed i n . At the end of 15 min, the gas flow vas stopped and the s o l u t i o n s t i r r e d f o r an a d d i t i o n a l hour. The ether was then removed under vacuum and the residue c r y s t a l l i z e d to a f f o r d 100 mg (80%) of compound 41. An a n a l y t i c a l sample was r e c r y s t a l l i z e d from n-hexane-methanol to a f f o r d white c r y s t a l s , m.p. 104.5-106°. This sample showed no depression of m e l t i n g p o i n t on admixture w i t h an auth e n t i c sample of cadinene d i h y d r o c h l o r i d e and i t s i n f r a r e d spectrum was superimposable w i t h that of the au t h e n t i c sample. I n f r a r e d ( n u j o l ) , X 3.45, 6.95, 8.75, 11.75 y. max Anal. Calcd. f o r C 1 5 H 2 6 C 1 2 : C, 65.01; H, 9.39. Found: C, 64.75; H, 9.52. Pr e p a r a t i o n of Octalone 172 This compound was prepared by the procedure of M a r s h a l l and Fanta (82). - 181 -A so l u t i o n of 56 g (0.5 mole) of 2-methylcyclohexanone and 3 ml of 3 N ethanolic sodium ethoxide were placed under nitrogen i n a flame-dried f l a s k equipped with a dropping funnel and mechanical s t i r r e r . The rea c t i o n vessel and contents were then cooled to -10° by a thermostatically c o n t r o l l e d constant temperature bath. To the reaction mixture was added 35 g (0.5 mole) of methyl v i n y l ketone over a 6 h period. The reaction mixture was then allowed to s t i r f o r an a d d i t i o n a l 6 h. The intermediate k e t o l 174 was then dehydrated by the addition of 400 ml of 15% potassium hydroxide and the r e s u l t i n g octalone 172 removed from the reaction mixture by continuous steam d i s t i l l a t i o n . The steam d i s t i l l a t e was saturated with sodium chloride and extracted with ether. The ether extracts were dried over anhydrous magnesium s u l f a t e and then concentrated. The residue was d i s t i l l e d under reduced pressure to a f f o r d 39.3 g (48%) of octalone 172, b.p. 73° at 0.4 mm; l i t . (82) b.p. 82-83° at 0.7 mm. An a n a l y t i c a l 20 sample c o l l e c t e d by g . l . c . (column H, 200°, 85), exhibited n Q 1.5249; 25 l i t . (82) n n 1.5230. U l t r a v i o l e t , X 239 mu (e = 14,400); i n f r a r e d D max ( f i l m ) , X 5.96, 6.17 u; n.m.r., x 8.74 ( s i n g l e t , 3H, t e r t i a r y methyl), TT13.X 4.29 ( s i n g l e t , IH, v i n y l proton). Preparation of Dienone 175 To a s o l u t i o n of 20.4 g (90 mmoles) of 2,3-dichloro-5,6-dicyano-benzoquinone and 1 g of benzoic acid i n 150 ml dry benzene was added 10 g (61 mmoles) of octalone 172. This s o l u t i o n was refluxed under - 182 -ni t r o g e n f o r a 48 h pe r i o d . To the cooled r e a c t i o n mixture was added w i t h s t i r r i n g 150 ml of methylene c h l o r i d e and C e l i t e . A f t e r f i l t r a -t i o n , the s o l u t i o n was passed through a 100 g bed of Woelm a c t i v i t y I I I n e u t r a l alumina. An a d d i t i o n a l 400 ml of methylene c h l o r i d e was passed through the alumina and the combined e l u t a n t s f l a s k evaporated and vacuum d i s t i l l e d to y i e l d 7.1 g (72%) of a yellow o i l , b.p. 110-115° at 0.5 mm; l i t . (84) b.p. 129° at 4 mm. The d i s t i l l e d product was subjected to g . l . c . a n a l y s i s (column H, 200°, 85) and showed 88% dienone and 12% trien o n e . An a n a l y t i c a l sample of dienone was c o l l e c t e d by p r e p a r a t i v e g . l . c . (column C, 200°, 110) which e x h i b i t e d 21 1 n„ 1.5470; i n f r a r e d ( f i l m ) , X 6.0, 6.15, 6.2 u; n.m.r., T 8.74 D ' max ' ' ' ' ( s i n g l e t , 3H, t e r t i a r y methyl), 3.94 ( s i n g l e t , IH, p r o t o n ) , 3.31, 3.84 ( p a i r of doublets, 2H, and protons r e s p e c t i v e l y , J = 9 Hz); u l t r a v i o l e t , X 240 my (e = 10,500). max Hydrogenation of Dienones 175 + 176 A suspension of 300 mg of 5% palladium on charcoal i n 200 ml of 0.005 N e t h a n o l i c potassium hydroxide was placed i n an atmospheric pressure hydrogenation apparatus at room temperature and allowed to e q u i l i b r a t e f o r 1.5 h. A s o l u t i o n of dienones 175 + 176 was then introduced by syringe. A f t e r 45 min the re q u i r e d amount of hydrogen had been absorbed. The r e a c t i o n mixture was f i l t e r e d through a bed of C e l i t e and the f i l t r a t e concentrated i n vacuo. The residue was chromatogrammed on 1 kg of Woelm a c t i v i t y I I I n e u t r a l alumina. The f r a c t i o n s e l u t e d w i t h 90% benzene-petroleum ether (30-60°) afforded 14.3 g (70%) of the de s i r e d dienone 175. G.l.c. a n a l y s i s (column C, - 183 -200°, 110) revealed the presence of up to 3% i m p u r i t i e s . P r e p a r a t i o n of Octalone 173 This compound was prepared by the procedure of M a r s h a l l and Fanta (82). To a flame-dried f l a s k under n i t r o g e n was added 56 g of 2-methyl-cyclohexanone and 3 ml of 3 N e t h a n o l i c sodium ethoxide. The r e s u l t i n g y ellow s o l u t i o n was cooled to -10°. Over a p e r i o d of 6 h, 42 g of e t h y l v i n y l ketone was added. The viscous r e a c t i o n mixture was allowed to s t i r f o r an a d d i t i o n a l 6 h. At the end of t h i s p e r i o d , 400 ml of 15% potassium hydroxide was added and the s o l u t i o n subjected to con-tinuous steam d i s t i l l a t i o n . The 4 1. of steam d i s t i l l a t e c o l l e c t e d , were thoroughly e x t r a c t e d w i t h ether. The combined e t h e r e a l e x t r a c t s were washed w i t h b r i n e and d r i e d over anhydrous magnesium s u l f a t e . The ether was removed at a s p i r a t o r pressure and the residue d i s t i l l e d under vacuum to a f f o r d two d i s t i n c t f r a c t i o n s . The f i r s t f r a c t i o n contained 11 g of s t a r t i n g material,2-methylcyclohexanone, b.p. 36-42° at 2.5 mm, w h i l e the second f r a c t i o n contained 53 g (60%) of the desi r e d octalone 173, b.p. 96-100° at 0.6 mm; l i t . (57) b.p. 74-78° at 0.4 mm. An a n a l y t i c a l sample was c o l l e c t e d by p r e p a r a t i v e g . l . c . 22 (column H, 200°, 85) and e x h i b i t e d n 1.5439, i n f r a r e d ( f i l m ) , X D max 6.0, 6.2 y; n.m.r., x 8.77 ( s i n g l e t , 3H, t e r t i a r y methyl), 8.22 ( s i n g l e t , 3H, v i n y l methyl); u l t r a v i o l e t , X 246 my (e = 15,500). Pr e p a r a t i o n of Dienone 177 This compound was prepared by a procedure s i m i l a r to that used by Kropp (57). - 184 -To a s o l u t i o n of 7.7 g (33 mmoles) of 2,3-dichloro-5,6-dicyano-benzoquinone and 25 ml g l a c i a l a c e t i c acid i n 250 ml anhydrous benzene was added 4 g (22 mmoles) of octalone 173. This s o l u t i o n was allowed to r e f l u x f or 60 h under nitrogen. Then the reaction mixture was cooled, f i l t e r e d , concentrated and ether added. The ethereal layer was washed successively with water, 10% sodium bicarbonate s o l u t i o n , water and saturated brine and dried over anhydrous magnesium s u l f a t e . The concentrated extract was d i s t i l l e d at 154° at 0.2 mm to a f f o r d 25 6.5 g (84%) of a pale yellow o i l ; n^ 1.5234. The product was greater than 95% pure by g . l . c . analysis (column B,180°, 80). The dienone exhibited u l t r a v i o l e t , A 240 mu (e = 10,500); i n f r a r e d ( f i l m ) , A ' max max 6.0, 6.15, 6.2 u; n.m.r., x 8.78 ( s i n g l e t , 3H, t e r t i a r y methyl), 8.12 ( s i n g l e t , 3H, v i n y l methyl), 3.80, 3.31 (AB quartet, 2H, C 3 and C^ protons r e s p e c t i v e l y , J = 10 Hz). Preparation of Tri-n-butylphosphine Copper I Iodide The procedure employed i s that of Kaufman et a l . (90). A suspension of 13.15 g of cuprous iodide, 130 g of potassium iodide, 10.15 g of tri-n-butylphosphine and 100 ml of water were shaken together u n t i l the i n i t i a l l y formed greasy p r e c i p i t a t e became c r y s t a l l i n e . The p r e c i p i t a t e was f i l t e r e d and r e c r y s t a l l i z e d from isopropanol-ethanol to afford 17.6 g (89%) of white c r y s t a l l i n e complex, m.p. 74.5-75.5°; l i t . (90) m.p. 75°. - 185 -Preparation of Octalone 188 To an i c e - c o l d s l u r r y of 6.84 g of cuprous iodide i n 150 ml of anhydrous ether was added 34.3 ml of 2.1 M methyllithium i n ether s o l u t i o n . To the r e s u l t i n g c l e a r s o l u t i o n was added, dropwise over 1 h, 1 g (6.2 mmoles) of dienone 175. The r e s u l t i n g thick yellow s o l u t i o n was immediately quenched by addition to a saturated ammonium chloride s o l u t i o n . The ammonium chloride s o l u t i o n was thoroughly extracted with ether. The ether extract was washed with water, d i l u t e ammonium hydroxide, water and brine and dried over anhydrous magnesium s u l f a t e . The ether extract was concentrated and d i s t i l l e d (b.p. 124° at 0.3 mm). The d i s t i l l a t e was chromatogrammed on 40 g of MN s i l i c a gel and the fra c t i o n s eluted with 15% ether-petroleum ether (30-60°) afforded 900 mg (82%) of a clear c o l o r l e s s o i l . This o i l showed a single peak on analysis by g . l . c . (column E, 190°, 86). The product exhibited i n f r a r e d ( f i l m ) , A 6.0, 6.15 u; n.m.r., x 9.02 (doublet, 3H, max secondary methyl, J = 7 Hz), 8.74 ( s i n g l e t , 3H, t e r t i a r y methyl), 4.30 ( s i n g l e t , IH, v i n y l H); u l t r a v i o l e t , A 239 my (e = 14,000). max Preparation of Octalone 191 The cross-conjugate addition to dienone 177 by l i t h i u m dimethyl-cuprate was ca r r i e d out by a procedure i d e n t i c a l to the above. From 1 g of dienone 177 a f t e r d i s t i l l a t i o n , b.p. 125° at 0.3 mm, was obtained l;.g (92%) of octalone 191. This product was shown to be homogeneous by g . l . c . (column E, 200°, 86). Infrared (film),'-A TTlciX 6.0, 6.2 u; n.m.r., x 9.04 (doublet, 3H, secondary methyl, J = 6.5 Hz), - 186 -8.74 ( s i n g l e t , 3H, t e r t i a r y methyl), 8.25 (doublet, 3H, v i n y l methyl, J = 1 Hz); u l t r a v i o l e t , X 249 my (e = 13,800). max This compound was f u r t h e r c h a r a c t e r i z e d as a red 2 , 4 - d i n i t r o p h e n y l -hydrazone, r e c r y s t a l l i z e d from et h a n o l , m.p. 174-175°. Anal. Calcd. f o r C ^ H ^ N ^ : C, 61.28; H, 6.50; N, 15.04. Found: C, 60.98; H, 6.42; N, 15.11. Pr e p a r a t i o n of Octalone 194 A s o l u t i o n of 15 g of t r i - n - b u t y l p h o s p h i n e copper (I) i o d i d e i n ' 150 ml of anhydrous ether was cooled to -78° by an e x t e r n a l dry i c e -acetone bath. To t h i s c o l o r l e s s s o l u t i o n was added by syringe 22.8 ml of 3.2 M v i n y l l i t h i u m i n t e t r a h y d r o f u r a n . To the r e s u l t i n g pale green s o l u t i o n was added over 1 h, 1 g (6.1 mmoles) of dienone 175 i n 50 ml of anhydrous ether. The r e s u l t i n g t h i c k y e l l o w s o l u t i o n was allowed to s t i r f o r an a d d i t i o n a l 4 h. At the end of t h i s time the r e a c t i o n mixture was allowed to warm to room temperature and was quenched by pouring onto 250 ml of 10% h y d r o c h l o r i c a c i d . The aqueous s o l u t i o n was thoroughly e x t r a c t e d w i t h ether. The combined ether e x t r a c t s were washed w i t h water, d i l u t e ammonium hydroxide, water and b r i n e and d r i e d over anhydrous magnesium s u l f a t e . A f t e r removal of the s o l v e n t , the product was roughly separated from the h i g h b o i l i n g m a t e r i a l by c o l l e c t i n g a l l m a t e r i a l w i t h a b o i l i n g p o i n t l e s s than 130° at 0.2 mm. The d i s t i l l a t e was then chromatogrammed on 100 g of MN s i l i c a g e l . The f r a c t i o n s e l u t e d w i t h 10% ether-petroleum ether (30-60°) afforded 870 mg (73%) of octalone 194. On a n a l y s i s by g . l . c . t h i s m a t e r i a l e x h i b i t e d only one peak (column E, 195°, 100). A l l - 187 -traces of solvent were removed on the vacuum pump 0.1 mm) to a f f o r d an a n a l y t i c a l sample. I n f r a r e d ( f i l m ) , X 6.0, 6.2, 10.9 u; max n.m.r., T 8.72 ( s i n g l e t , 3H, t e r t i a r y methyl), 3.89-5.13 (unresolved m u l t i p l e t , 3H, v i n y l p r o t o n s ) , 4.25 ( s i n g l e t , IH, v i n y l proton). Due to i t s i n s t a b i l i t y t h i s compound was not c h a r a c t e r i z e d f u r t h e r but immediately hydrogenated. Hydrogenation of Octalone 194 The hydrogenation of octalone 194 was c a r r i e d out i n benzene (50 ml) at room temperature and atmospheric pressure using t r i s ( t r i -phenylphosphine)chlororhodium (120 mg) as c a t a l y s t . At the end of the hydrogen uptake the r e a c t i o n mixture was f i l t e r e d through a column of Woelm a c t i v i t y I I I n e u t r a l alumina (20 g) and e l u t e d w i t h an a d d i t i o n a l 100 ml of benzene. From 708 mg (3.73 mmoles) of octalone 194 was obtained a f t e r d i s t i l l a t i o n 650 mg of a c l e a r c o l o r -l e s s o i l . A n a l y s i s of t h i s product by g . l . c . (column E, 180°, 100) showed that i t c o n s i s t e d of 10% decalone 193 and 90% octalone 189. The mixture was chromatogrammed on a 50 g MN s i l i c a g e l column. The f r a c t i o n s e l u t e d w i t h 8% ether-petroleum ether (30-60°) contained 57 mg of cls-decalone 193. The f r a c t i o n s e l u t e d w i t h 15% ether-petroleum ether (30-60°) contained 413 mg (58%) of the d e s i r e d octalone 189. An a n a l y t i c a l sample of octalone 189 e x h i b i t e d the f o l l o w i n g s p e c t r a l p r o p e r t i e s : i n f r a r e d ( f i l m ) , ^ m a x 6.0, 6.2 u; n.m.r., x 9.07 ( t r i p l e t , 3H, CH2CH_3, J = 4 Hz), 8.73 ( s i n g l e t , 3H, t e r t i a r y methyl), 4.21 (broad s i n g l e t , IH, v i n y l H); u l t r a v i o l e t , X 239 mu (e = 11,000). TT13.X This compound was further characterized as a red 2,4-dinitrophenyl-- 188 -hydrazone d e r i v a t i v e , r e c r y s t a l l i z e d from e t h a n o l , m.p. 118-120°. Anal. Calcd. f o r C ^ H ^ N ^ : C, 61.28; H, 6.50; N, 15.04. Found: C, 61.07; H, 6.42; N, 15.05. Pr e p a r a t i o n of Octalone 190 A s o l u t i o n of 15 g (38 mmoles) of t r i - n - b u t y l p h o s p h i n e copper (I) i o d i d e , 0.5 g anhydrous l i t h i u m bromide i n 150 ml of anhydrous ether was cooled to -78° w i t h an e x t e r n a l dry ice-acetone bath. Then 39 ml (73 mmoles) of 1.86 M i s o p r o p y l l i t h i u m i n n-pentane was added, forming f i r s t a dark red and then a pale aqua s o l u t i o n . To t h i s complex was added 1 g (6.1 mmoles) of dienone 175 i n 50 ml of anhydrous ether over a 0.75 h p e r i o d . The dark red r e a c t i o n mixture was allowed to s t i r f o r an a d d i t i o n a l 5 h p e r i o d . The r e a c t i o n was then allowed to s l o w l y warm to room temperature. This r e s u l t e d i n the formation of a copper m i r r o r on the w a l l s of the r e a c t i o n v e s s e l . The r e a c t i o n mixture was t r a n s f e r r e d under n i t r o g e n to a dropping funnel and s l o w l y added to a r a p i d l y s t i r r e d s o l u t i o n of 10% h y d r o c h l o r i c a c i d . The aqueous l a y e r was separated and twice e x t r a c t e d w i t h ether. The combined e t h e r e a l e x t r a c t s were washed s u c c e s s i v e l y w i t h water, d i l u t e ammonium hydroxide, water and sa t u r a t e d b r i n e and d r i e d over anhydrous magnesium s u l f a t e . A f t e r removal of the s o l v e n t , the residue was d i s t i l l e d and the d i s t i l l a t e chromatogrammed on 25 g of MN s i l i c a g e l . The f r a c t i o n s e l u t e d w i t h 20% ether-petroleum ether (30-60°) afforded 395 mg (95%) of octalone 190. This sample e x h i b i t e d one component by g . l . c . (column E, 180°, 86). I n f r a r e d ( f i l m ) , A 6.0, 6.15 y; J max n.m.r., T 9.2, 9.05 ( p a i r of doublets, 6H, i s o p r o p y l methyl groups, - 189 -J = 6.5 Hz), 8.74 ( s i n g l e t , 3H, t e r t i a r y methyl), 4.22 (broad s i n g l e t , IH, v i n y l H); u l t r a v i o l e t , X 240 my (e = 9,370). max ' This compound was c h a r a c t e r i z e d as i t s 2,4-dinitrophenylhydrazone d e r i v a t i v e , r e c r y s t a l l i z e d from et h a n o l , m.p. 153-155°. Anal. Calcd. f o r c 2o H26 N4°4 : C ' 6 2 ' 1 6 ' H» 6 l 7 8 ; N> 1 4 - 5 0 - Found: C, 62.01; H, 6.80; N, 14.40. Pr e p a r a t i o n of Octalone 192 The cross-conjugate a d d i t i o n to dienone 177 by l i t h i u m d i i s o p r o p y l c u p r a t e was c a r r i e d out by a procedure i d e n t i c a l to that described above. From 2 g of dienone 177, a f t e r chromatography on 140 g of MN s i l i c a g e l , the f r a c t i o n s e l u t e d w i t h 15% ether-petroleum ether (30-60°) afforded 2.38 g (95%) of octalone 192. A l l t r a c e s of s o l v e n t were removed on the vacuum pump (0.1 mm) to a f f o r d an a n a l y t i c a l sample which e x h i b i t e d the f o l l o w i n g s p e c t r a l p r o p e r t i e s : one component on g . l . c . (column E, 190°, 86); i n f r a r e d ( f i l m ) , X 6.0, 6.2 y; n.m.r., THcSX x 9.23, 9.04 ( p a i r of doublets, 6H, i s o p r o p y l methyl groups, J = 7 Hz), 8.73 ( s i n g l e t , 3H, t e r t i a r y m e t h y l), 8.22 ( s i n g l e t , 3H, v i n y l methyl); u l t r a v i o l e t X 249 my (G = 14,000). max ' This compound was f u r t h e r c h a r a c t e r i z e d as a red 2 , 4 - d i n i t r o p h e n y l -hydrazone d e r i v a t i v e , r e c r y s t a l l i z e d from et h a n o l , m.p. 134-135°. Anal. Calcd. f o r C o lH. oN.0.: C, 62.98; H, 7.05; N, 13.99. Found: 21 28 4' 4 C, 63.13; H, 6.90; N, 13.76. - 190 -P r e p a r a t i o n of Decalone 200 To 800 ml 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 4 g of l i t h i u m . A f t e r the l i t h i u m had d i s s o l v e d 10 g (61 mmoles) of octalone 172 i n 80 ml of anhydrous ether was added dropwise. A f t e r 1 h, 11 ml of anhydrous ethanol was added and the r e a c t i o n mixture was allowed to s t i r f o r an a d d i t i o n a l 1.5 h. The r e a c t i o n was quenched w i t h excess ethanol and the l i q u i d ammonia was allowed to evaporate. A f t e r removal of most of the e t h a n o l , b r i n e was added and the r e s u l t i n g s o l u t i o n thoroughly e x t r a c t e d w i t h ether. The combined ether e x t r a c t s were washed w i t h water and b r i n e and d r i e d over anhydrous magnesium s u l f a t e . The ether was removed at a s p i r a t o r pressure and the r e s u l t i n g m a t e r i a l c r y s t a l l i z e d to a f f o r d 7.7 g of d e c a l o l . The crude d e c a l o l was immediately o x i d i z e d to the d e s i r e d decalone 200. To a s o l u t i o n of 7.7 g (46 mmoles) of d e c a l o l i n 177 ml acetone at 0° was added dropwise a standard s o l u t i o n of chromic a c i d (76) u n t i l the orange c o l o r p e r s i s t e d . Isopropanol was then added to destroy the excess o x i d i z i n g agent and the solvent was removed under reduced pressure. Water was added to the r e s i d u e and i t was thoroughly e x t r a c t e d w i t h ether. The combined ether e x t r a c t s were washed w i t h water and b r i n e and d r i e d over anhydrous magnesium s u l f a t e and concentrated i n vacuo. Vacuum d i s t i l l a t i o n of the o i l y residue a f f o r d e d 6.5 g (88%) of the d e s i r e d decalone 200, b.p. 80-82° at 0.8 mm; l i t . (93) b.p. 69° 20 at 0.1 mm; n D 1.4943. The decalone 200 e x h i b i t e d i n f r a r e d ( f i l m ) , X 5.85 u; n.m.r., T 8.95 ( s i n g l e t , 3H, t e r t i a r y methyl), max - 191 -Bromination of Decalone 200 To a s o l u t i o n of 8.7 g (0.052 mole) of trans-fused decalone 200 d i s s o l v e d i n 100 ml of g l a c i a l a c e t i c a c i d was added, dropwise over 1 h, 8.4 g (0.052 mole) of bromine i n 100 ml g l a c i a l a c e t i c a c i d . A f t e r the a d d i t i o n was complete, the r e a c t i o n was allowed to s t i r f o r an a d d i t i o n a l 15 min and then i c e was added. The major part of the water and g l a c i a l a c e t i c a c i d was then removed at a s p i r a t o r pressure. The r e s i d u e was d i s s o l v e d i n ether and washed twice w i t h water, twice w i t h 5% sodium bicarbonate s o l u t i o n , once w i t h water and b r i n e and d r i e d over anhydrous magnesium s u l f a t e . The solvent was removed to a f f o r d 13.1 g of a c r y s t a l l i n e bromoketone 201. This m a t e r i a l was r e c r y s t a l l i z e d from petroleum ether (65-110°) to a f f o r d 7.7 g (60%) of a white c r y s t a l l i n e bromoketone, m.p. 100-102°; l i t . (93) m.p., 101-102°. The bromoketone 201 e x h i b i t e d i n f r a r e d (KBr), X 5.78 u; n.m.r., max x 8.86 ( s i n g l e t , 3H, t e r t i a r y CH 3), 5.32 (X p o r t i o n of an ABX system, IH, -HcHBr, J . v = 12 Hz, = 6 Hz). — A X B X Dehydrohalogenation of Bromoketone 201 A s o l u t i o n of 7.7 g of bromoketone 201 and 3 g of anhydrous l i t h i u m bromide d i s s o l v e d i n 75 ml of hexamethylphosphoramide was heated at 120° f o r 3 h under n i t r o g e n . The cooled r e a c t i o n mixture was d i l u t e d w i t h water and thoroughly e x t r a c t e d w i t h ether. The combined e t h e r e a l e x t r a c t s were washed t h r i c e w i t h water, once w i t h b r i n e and d r i e d over anhydrous magnesium s u l f a t e . A f t e r removal of the ether the residue was chromatogrammed on 100 g of MN s i l i c a g e l . The - 192 -f r a c t i o n s eluted with 10% ether-benzene afforded 3.9 g of octalone 197 (76%) which exhibited one peak only on g . l . c . (column E, 180°, 86). The compound was placed on the vacuum pump (a, 0.1 mm) to remove any traces of solvent to a f f o r d an a n a l y t i c a l sample. This sample gave the following s p e c t r a l data: i n f r a r e d ( f i l m ) , X 5.95, 6.15 u: n.m.r., max T 8.96 ( s i n g l e t , 3H, t e r t i a r y methyl), 4.24, 3.33 (pair of doublets, 2H, ft ft CCH=CH and CCH=CH re s p e c t i v e l y , J = 9.8 Hz); u l t r a v i o l e t , X 229 mu — max 20 (e = 9,200); n^ 1.5088. Birch Reduction of Octalone 173 To a s o l u t i o n of 4 g of l i t h i u m metal dissolved i n 1 l i t r e l i q u i d ammonia ( d i s t i l l e d from sodium metal) was added, dropwise over 0.75 h, 10 g (0.056 mole) of octalone 173 dissolved i n 80 ml of anhydrous ether. The reaction was allowed to s t i r f o r 1 h a f t e r addition was complete. Then 11 ml of anhydrous ethanol was added and s t i r r i n g continued f o r an a d d i t i o n a l hour. The reaction was then quenched by c a r e f u l addition of excess ethanol and the l i q u i d ammonia allowed to evaporate. The r e s i d u a l material was n e u t r a l i z e d with 10% hydrochloric acid and extracted t h r i c e with ether. The combined ether extracts were then washed with water, 5% sodium bicarbonate s o l u t i o n and saturated brine and dried over anhydrous magnesium s u l f a t e . The ether was removed at aspirator pressure to afford 8.9 g of crude d e c a l o l . Without further p u r i f i c a t i o n the crude decalol was oxidized with a standard chromic acid s o l u t i o n (76). To a s o l u t i o n of 8.9 g (56 mmoles) of decalol i n 150 ml acetone at 0° was added dropwise a standard s o l u t i o n of chromic acid u n t i l the - 193 -orange c o l o r p e r s i s t e d . Isopropanol was then added to destroy the excess o x i d i z i n g agent and the solvent was removed under reduced pressure. Water was added to the residue and i t was thoroughly e x t r a c t e d w i t h ether. The combined ether e x t r a c t s were washed w i t h water and b r i n e and d r i e d over anhydrous magnesium s u l f a t e and concentrated i n vacuo. Vacuum d i s t i l l a t i o n of the o i l y r esidue a f f o r d e d 7.1 g (81%) of decalone 203, b.p. 89° at 1.5 mm; l i t . (84) 99° at 3 mm. The decalone e x h i b i t e d i n f r a r e d ( f i l m ) , X 5.85 u; n.m.r., T 8.98 (doublet, max 3H, secondary methyl, J = 6.5 Hz), 8.84 ( s i n g l e t , 3H, t e r t i a r y methyl). P r e p a r a t i o n of Enol Acetate 204 To a s o l u t i o n of 7.9 g (44 mmoles) of decalone 203 d i s s o l v e d i n 50 ml of i s o p r o p e n y l acetate was added 0.1 ml of 98% s u l f u r i c a c i d . This mixture was r e f l u x e d f o r 2.5 h under a n i t r o g e n atmosphere. At the end of t h i s time most of the i s o p r o p e n y l acetate was removed on the r o t a r y evaporator. The residue was d i s s o l v e d i n ether and washed s u c c e s s i v e l y w i t h water, 5% sodium bicarbonate s o l u t i o n , water and s a t u r a t e d b r i n e and d r i e d over anhydrous magnesium s u l f a t e . A f t e r removal of the ether the product was chromatogrammed on 150 g of .Woelm a c t i v i t y I I I n e u t r a l alumina. The f r a c t i o n s e l u t e d w i t h benzene gave 9.5 g of an 85:15 mixture of enol a c e t a t e s , w i t h enol acetate 204 predominating. The mixture e x h i b i t e d i n f r a r e d ( f i l m ) , ^ m a % 5.7, 5.95 u. P r e p a r a t i o n of Bromoketone 205 To a s o l u t i o n of 9.5 g of enol acetates 204 and 204a and 10 g of anhydrous sodium acetate d i s s o l v e d i n 100 ml of g l a c i a l a c e t i c a c i d was - 194 -added during 1 h, 7.2 g of bromine i n 50 ml of g l a c i a l a c e t i c a c i d . A f t e r the a d d i t i o n was complete, the " r e a c t i o n was allowed to s t i r f o r an a d d i t i o n a l 15 min. The g l a c i a l a c e t i c a c i d was then removed i n vacuo and the residue d i s s o l v e d i n water and thoroughly e x t r a c t e d w i t h ether. The combined e t h e r e a l e x t r a c t s were washed s u c c e s s i v e l y w i t h water, t h r i c e w i t h 5% sodium bicarbonate s o l u t i o n , water and b r i n e and d r i e d over anhydrous magnesium s u l f a t e . A f t e r removal of the solvent the residue c r y s t a l l i z e d and was r e c r y s t a l l i z e d from petroleum ether (30-60°) to a f f o r d 4.7 g of a white c r y s t a l l i n e bromo-ketone 205, m.p. 67-69°. Concentration of the mother l i q u o r s gave an a d d i t i o n a l 4.5 g (84%) c r y s t a l l i n e bromoketone, m.p. 69-70°. The c r y s t a l l i n e bromoketone 205 e x h i b i t e d i n f r a r e d (CHC1„), X J. 3 max 5.8 u; n.m.r., T 8.99 (doublet, 3H, secondary methyl, J = 6.5 Hz), 8.84 ( s i n g l e t , 3H, t e r t i a r y methyl), 5.13 (X p o r t i o n of ABX system, IH, EcH Br, J . V = 14 Hz, J „ V = 6 Hz). — A A £>A Anal. Calcd. f o r C 1 2 H i g 0 B r : C, 55.60; H, 7.34; Br, 30.89. Found: C, 55.59; H, 7.26; Br, 30.86. P r e p a r a t i o n of Octalone 198 A s o l u t i o n of 4 g (15 mmoles) of c r y s t a l l i n e bromoketone 205 and 1.5 g of anhydrous l i t h i u m bromide d i s s o l v e d i n 35 ml of hexamethyl-phosphoramide was heated to 120° f o r 3 h under n i t r o g e n . At the end of t h i s time the s o l u t i o n was d i l u t e d w i t h water and thoroughly e x t r a c t e d w i t h ether. The combined ether e x t r a c t s were washed t h r i c e w i t h water and once w i t h saturated b r i n e and d r i e d over anhydrous magnesium s u l f a t e . The so l v e n t was removed at a s p i r a t o r pressure to - 195 -y i e l d the crude octalone 198. The l a t t e r was chromatogrammed on 100 g of s i l i c a g e l to a f f o r d , w i t h benzene as e l u t a n t , 2.1 g of octalone 198 (76%). This was shown to be a mixture of octalone 198 and octalone 173 by g . l . c . (column E, 185°, 86). The mixture of octalones (4 g) was separated on 150 g of MN s i l i c a g e l . The f r a c t i o n s e l u t e d w i t h 3% ether-benzene gave 3.8 g of octalone 198 w h i l e the f r a c t i o n s e l u t e d w i t h &% ether-benzene gave 100 mg of octalone 173. An a n a l y t i c a l sample of the major product was c o l l e c t e d by p r e p a r a t i v e g . l . c . (column E, 185°, 86) and e x h i b i t e d : i n f r a r e d ( f i l m ) , X 6.0, 6.15 u: n.m.r., max x 8.93 ( s i n g l e t , 3H, t e r t i a r y methyl), 8.92 (doublet, 3H, secondary methyl, J = 7 Hz) , 4.19, 3.35 ( p a i r of doublets, 2H, CCH=CH and (lcH=CH r e s p e c t i v e l y , J = 9 Hz); u l t r a v i o l e t , X 229 mu (e = 9,200). max This compound was f u r t h e r c h a r a c t e r i z e d as a red 2 , 4 - d i n i t r o -phenylhydrazone d e r i v a t i v e , r e c r y s t a l l i z e d from e t h a n o l , m.p. 198-199°. Anal. Calcd. f o r C 1 8 H 2 2 N 4 ° 4 : C,-60.32; H, 6.19; N, 15.63. Found: C, 60.51; H, 6.11; N, 15.73. P r e p a r a t i o n of Decalone 206 To an i c e - c o l d s l u r r y of 2.3 g cuprous i o d i d e i n 67 ml anhydrous ether under n i t r o g e n , was added 11.4 ml of 2.1 N m e t h y l l i t h i u m s o l u t i o n . To the r e s u l t i n g c l e a r s o l u t i o n was added, dropwise over 0.5 h, 328 mg (2 mmoles) of octalone 197 i n 40 ml of anhydrous ether. The r e a c t i o n was allowed to s t i r f o r an a d d i t i o n a l 1.5 h. Then i t was poured slowly i n t o a s t i r r e d 10% aqueous h y d r o c h l o r i c a c i d s o l u t i o n . The l a y e r s were separated and the aqueous l a y e r e x t r a c t e d twice w i t h ether. The combined e t h e r e a l e x t r a c t s were washed w i t h water and b r i n e and - 196 -d r i e d over anhydrous magnesium s u l f a t e . The concentrated e t h e r e a l e x t r a c t was d i s t i l l e d b.p. 110° at 0.2 mm; l i t . (96) b.p. 133-137° at 9 mm.to a f f o r d 345 mg (98%) of a c l e a r o i l . This o i l e x h i b i t e d , one peak on g . l . c . (column E, 190°, 100); i n f r a r e d ( f i l m ) , A 3.45, max 5.85 u; n.m.r., T 9.08 (doublet, 3H, secondary methyl, J =6.5 Hz), 8.87 ( s i n g l e t , 3H, t e r t i a r y methyl). P r e p a r a t i o n of Decalone 207 A s o l u t i o n of tr i - n - b u t y l p h o s p h i n e copper (I) i o d i d e (4 g) i n anhydrous ether (50 ml) was cooled to -78° by an e x t e r n a l dry i c e -acetone c o o l i n g bath. A s o l u t i o n of 3.1 M v i n y l l i t h i u m i n tetrahydro furan (6.4 ml) was added dropwise u n t i l the i n i t i a l l y formed red s o l u t i o n became c o l o r l e s s . To t h i s s o l u t i o n was added, dropwise over 0.5 h, 328 mg (2 mmoles) of octalone 197 i n 50 ml anhydrous ether. The r e s u l t i n g brown s o l u t i o n was allowed to s t i r f o r an a d d i t i o n a l 5 h at -78° and then allowed to warm slowly to room temperature. The r e a c t i o n mixture was then added dropwise w i t h s t i r r i n g to 100 ml of 10% h y d r o c h l o r i c a c i d . The l a y e r s were separated and the aqueous l a y e r e x t r a c t e d twice w i t h ether. The combined e t h e r e a l e x t r a c t s were washed w i t h d i l u t e ammonium hydroxide, water and b r i n e and d r i e d over anhydrous magnesium s u l f a t e . The ether was removed at a s p i r a t o r pressure to a f f o r d 4.6 g of a viscous yellow o i l . This m a t e r i a l was subjected to column chromatography on 50 g of MN s i l i c a g e l . The f r a c t i o n s e l u t e d w i t h 15% ether-petroleum ether (30-60°) contained 280 (73%) of the d e s i r e d decalone 207. This m a t e r i a l was d i s t i l l e d , b.p. - 197 -130° at 0.15 mm, to a f f o r d an o i l which e x h i b i t e d one peak only on g . l . c . a n a l y s i s (column E, 190°, 100). An a n a l y t i c a l sample of t h i s m a t e r i a l e x h i b i t e d the f o l l o w i n g s p e c t r a l p r o p e r t i e s : i n f r a r e d ( f i l m ) , A 5.85, 6.1, 10.9 u; n.m.r., T 8.88 ( s i n g l e t , 3H, t e r t i a r y methyl), IT13.X 4.0-5.2 (unresolved m u l t i p l e t , 3H, v i n y l group). This compound was f u r t h e r c h a r a c t e r i z e d as a dark red 2,4-dinitrophenylhydrazone d e r i v a -t i v e , m.p. 186°, r e c r y s t a l l i z e d from ethanol. Anal. Calcd. f o r C 1 f tH o /N.0.: C, 61.28: H, 6.50; N, 15.04. Found: 19 24 4 4 C, 60.98; H, 6.41; N, 14.94. Hydrogenation of Decalone 207 The hydrogenation of the v i n y l s u b s t i t u t e d decalone 207 was done at atmospheric pressure and room temperature using 10% palladium on charcoal as c a t a l y s t and absolute ethanol as so l v e n t . From 675 mg (3.5 mmoles) of decalone 207 was obtained 670 mg (98%) of e t h y l s u b s t i t u t e d decalone 208. The product e x h i b i t e d one component by g . l . c . (column E, 180°, 86). I n f r a r e d ( f i l m ) , A 5.85 u; n.m.r., x 8.88 max ( s i n g l e t , 3H, t e r t i a r y methyl). This compound was f u r t h e r c h a r a c t e r i z e d as a pa l e orange 2,4-dinitrophenylhydrazone d e r i v a t i v e , r e c r y s t a l l i z e d from ethanol, m.p. 192-193°. Anal. Calcd. f o r C. ftH~-N.0. : C, 60.95; H, 7.00; N, 14.96. Found: 19 26 4 4 C, 60.74; H, 6.89; N, 14.92. Pr e p a r a t i o n of Decalone 209 To a s o l u t i o n of 4 g of tr i - n - b u t y l p h o s p h i n e copper (I) i o d i d e i n - 198 -60 ml of anhydrous ether at -78° was added 11 ml of 1.86 M i s o p r o p y l -l i t h i u m i n n-pentane. To the r e s u l t i n g aqua s o l u t i o n was added, drop-wise over 0.5 h, 328 mg (2 mmoles) of octalone 197 i n 10 ml of anhydrous ether. A f t e r the a d d i t i o n was complete the dark red r e a c t i o n mixture was allowed to s t i r f o r an a d d i t i o n a l 3 h and then quenched by dropwise a d d i t i o n to 50 ml of 10% h y d r o c h l o r i c a c i d s o l u t i o n . The r e s u l t i n g s o l u t i o n was thoroughly e x t r a c t e d w i t h ether. The combined ether e x t r a c t s were washed w i t h water, d i l u t e ammonium hydroxide, water and b r i n e and d r i e d over anhydrous magnesium s u l f a t e . The concentrated ether e x t r a c t was d i s t i l l e d under vacuum 0.1 mm) and a l l m a t e r i a l b o i l i n g at l e s s than 150° was c o l l e c t e d . The d i s t i l l a t e was chromatogrammed on 35 g of MN s i l i c a g e l . The f r a c t i o n s e l u t e d w i t h 20% ether-petroleum ether (30-60°) affo r d e d 297 mg of trans-decalone 209 (72%). A n a l y s i s of the product by g . l . c . demonstrated the presence of only one component. The decalone 209 c r y s t a l l i z e d on standing. R e c r y s t a l l i z a t i o n from ri-hexane gave an a n a l y t i c a l sample, m.p. 49-50°; l i t . (97,98) m.p. 49-50°. This compound gave the f o l l o w i n g s p e c t r a l p r o p e r t i e s : i n f r a r e d (CHC1„) , A 5.87 u: n.m.r., x 9.08, 3 max 9.17 ( p a i r of doublets, 6H, secondary methyls, J = 6.8 Hz), 8.89 ( s i n g l e t , 3H, t e r t i a r y methyl). P r e p a r a t i o n of Decalone 215 To an i c e - c o l d s l u r r y of 1.36 g (7.3 mmoles) of cuprous i o d i d e i n 15 ml anhydrous ether was added 6.8 ml (14 mmoles) of 2.1 M m e t h y l l i t h i u m s o l u t i o n i n ether. To t h i s c l e a r s o l u t i o n was added, dropwise over 1 h, 200 mg (1.2 mmoles) of octalone 198 i n 10 ml of anhydrous ether. A f t e r - 199 -the a d d i t i o n was complete, the yellow r e a c t i o n mixture was allowed to s t i r f o r an a d d i t i o n a l 1.5 h and then quenched by a d d i t i o n to 30 ml of 5% h y d r o c h l o r i c a c i d s o l u t i o n . The r e s u l t i n g mixture was then thoroughly e x t r a c t e d w i t h ether. The combined ether e x t r a c t s were washed w i t h water, d i l u t e ammonium hydroxide and water and d r i e d over anhydrous magnesium s u l f a t e . A f t e r removal of the e t h e r , the residue was chromatogrammed on 20 g of MN s i l i c a g e l . The f r a c t i o n s e l u t e d w i t h 5% ether-petroleum ether (30-60°) affo r d e d 189 mg (93%) of trans-decalone 215. The product e x h i b i t e d on g . l . c . (column E, 220°, 86), one major product w i t h ^3% of a s h o r t e r r e t e n t i o n time i m p u r i t y . An a n a l y t i c a l sample c o l l e c t e d by p r e p a r a t i v e g . l . c . (column E, 190°, 86) e x h i b i t e d : i n f r a r e d ( f i l m ) , X 5.85 u; n.m.r., x 9.1, 9.02 max ( p a i r of doublets, 6H, secondary methyls, 3 = 7 Hz), 8.77 ( s i n g l e t , 3H, t e r t i a r y methyl), 7.97 (doublet of doublets, IH, H^, J ^ e ^ - 2.2 Hz, J 0 „ = 14 Hz), 7.21 (doublet of doublets, IH, H„ , J„ . = 14 Hz, 3a,3e 3a 3a,3e J„ . = 6 Hz). This compound was f u r t h e r c h a r a c t e r i z e d as an orange 3a,4e r ° 2,4-dinitrophenylhydrazone d e r i v a t i v e , r e c r y s t a l l i z e d from e t h a n o l , m.p. 167-168°. Anal. Calcd. f o r C H ^ N ^ : C, 60.95; H, 7.00; N, 14.96. Found: C, 60.66; H, 6.87; N, 15.06. Pr e p a r a t i o n of Decalone 216 To a s t i r r e d s o l u t i o n of 4 g (10.1 mmoles) of t r i - n - b u t y l p h o s p h i n e copper (I) i o d i d e i n 50 ml anhydrous ether at -78° was added 11 ml of 1.86 M (20.2 mmoles) of i s o p r o p y l l i t h i u m i n ri-pentane. To the r e s u l t i n g - 200 -blue s o l u t i o n was added, dropwise over 0.5 h, 356 mg (2.1 mmoles) of octalone 198 i n 20 ml anhydrous ether. The s o l u t i o n was allowed to s t i r f o r an a d d i t i o n a l 3 h and then quenched by dropwise a d d i t i o n to 100 ml of 10% h y d r o c h l o r i c a c i d . The r e s u l t i n g s o l u t i o n was then thoroughly e x t r a c t e d w i t h ether. The combined ether e x t r a c t s were washed w i t h water, d i l u t e ammonium hydroxide, water and b r i n e and d r i e d over anhydrous magnesium s u l f a t e . The residue a f t e r c o n c e n t r a t i o n was hot-box d i s t i l l e d (b.p. 120° at 0.3 mm) and the d i s t i l l a t e chromatogrammed on 20 g of MN s i l i c a g e l . The t h i r d and f o u r t h f r a c t i o n s e l u t e d w i t h benzene afforded 262 mg (84%) of trans-decalone 216. This product e x h i b i t e d one peak by g . l . c . (column E, 198°, 86). The product gave i n f r a r e d ( f i l m ) , X 5.85 u; n.m.r., x 9.21, 9.09 ( p a i r of & ' max r doublets, 6H, i s o p r o p y l methyls, J = 6.5 Hz), 9.00 (doublet, 3H, secondary methyl, J = 6 Hz), 8.87 ( s i n g l e t , 3H, t e r t i a r y methyl); n.m.r., (benzene), 7.74 (doublet of doublets, IH, H , J = Ja j a , j e 15.5 Hz, J = 7.6 Hz), 7.56 (doublet of doublets, IH, H , J ~ , = Ja,4-e Je J a , Je 15.5 Hz, J„ . = 2.4 Hz). The product was f u r t h e r c h a r a c t e r i z e d as a 3e,4e yellow 2,4-dinitrophenylhydrazone d e r i v a t i v e , r e c r y s t a l l i z e d from et h a n o l , m.p. 145-146°. Anal. Calcd. f o r C ^ H ^ N ^ : C, 62.67; H, 7.51; N, 13.92. Found: C, 62.55; H, 7.50; N, 13.73. Hydrogenation of Octalone 188 A suspension of 20 mg of 10% palladium on charcoal i n 15 ml of 0.3 N e t h a n o l i c sodium hydroxide s o l u t i o n was e q u i l i b r a t e d f o r 1 h i n an atmospheric pressure hydrogenation apparatus at room temperature. - 201 -A f t e r t h i s p e r i o d 122 mg (0.68 mmole) of octalone 188 i n 10 ml ethanol was added by sy r i n g e . A f t e r the c a l c u l a t e d amount of hydrogen had been absorbed, the mixture was f i l t e r e d and the f i l t r a t e concentrated. The residue was d i l u t e d w i t h water and then thoroughly e x t r a c t e d w i t h ether. The combined ether e x t r a c t s were washed s u c c e s s i v e l y w i t h 5% h y d r o c h l o r i c a c i d , 5% sodium bicarbonate s o l u t i o n , water and b r i n e and d r i e d over anhydrous magnesium s u l f a t e . The r e s i d u e , a f t e r removal of the s o l v e n t , was d i s t i l l e d , b.p. 110° at 0.2 mm, to a f f o r d 119 mg (97%) of c i s - f u s e d decalone 218. This sample was shown to be homogeneous by g . l . c . (column E, 190°, 86). Decalone 218 e x h i b i t e d i n f r a r e d ( f i l m ) , X 5.85 u; n.m.r., x 9.10 (doublet, 3H, secondary max methyl, J = 7 Hz), 8.95 ( s i n g l e t , 3H, t e r t i a r y methyl). This compound was f u r t h e r c h a r a c t e r i z e d as a y e l l o w 2,4-dinitrophenylhydrazone d e r i v a t i v e , r e c r y s t a l l i z e d from e t h a n o l , m.p. 161-162°. Anal. Calcd. f o r C, oH o /N.0.: C, 59.99; H, 6.71; N, 15.55. Found: 18 24 4 4 C, 59.99; H, 6.80; N, 15.46. Hydrogenation of Octalone 189 The hydrogenation was c a r r i e d out as above. From 100 mg of octalone 189 was obtained 96 mg of cis-decalone 193. The product e x h i b i t e d one major peak by g . l . c . w i t h approximately 3% of a sh o r t e r r e t e n t i o n time i m p u r i t y (column E, 180°, 86). An a n a l y t i c a l sample was c o l l e c t e d by p r e p a r a t i v e g . l . c . aid e x h i b i t e d : i n f r a r e d ( f i l m ) , X 5.85 u; n.m.r., x 8.90 ( s i n g l e t , IH, t e r t i a r y methyl). This max compound was f u r t h e r c h a r a c t e r i z e d as a yellow 2,4-dinitrophenylhydrazone d e r i v a t i v e , r e c r y s t a l l i z e d from e t h a n o l , m.p. 174°. - 202 Anal. Calcd. f o r C, „H„.N.0.: C, 60.95; H, 7.00; N, 14.96. Found: 19 26 4 4 C, 60.81; H, 6.85; N, 14.88. Hydrogenation of Octalone 190 The octalone 190 was hydrogenated as above. From 100 mg of octalone 190 was obtained 96 mg of cis-decalone 219 (96%). The decalone e x h i b i t e d one major peak on g . l . c . (column E, 190°, 86) w i t h a 5% im p u r i t y of i d e n t i c a l r e t e n t i o n time to the trans-decalone 209. An a n a l y t i c a l sample of cis-decalone 219 was c o l l e c t e d by p r e p a r a t i v e g . l . c . (column E, 190°, 86). I n f r a r e d ( f i l m ) , X 5.85 u; n.m.r., max T 9.19, 9.10 (p a i r of doublets, 6H, i s o p r o p y l methyls, J = 6.5 Hz), 8.88 ( s i n g l e t , 3H, t e r t i a r y methyl). This compound was f u r t h e r c h a r a c t e r i z e d as an orange 2,4-dinitrophenylhydrazone d e r i v a t i v e , r e c r y s t a l l i z e d from e t h a n o l , m.p. 180-181°. Anal. Calcd. f o r C 2 0 H 2 8 N 4 ° 4 : C ' 6 1* 8 4> H> 1-21'•> N> 14.42. Found: C, 61.86; H, 7.35; N, 14.30. Hydrogenation of Octalone 191 The m a t e r i a l was hydrogenated by a procedure i d e n t i c a l to that described above. From 130 mg of octalone 191 was obtained 125 mg (95%) of a c o l o r l e s s o i l , b.p. 115° at 0.2 mm. This product e x h i b i t e d one peak by g . l . c . (column E, 180°, 86). I n f r a r e d ( f i l m ) , X 5.85 u; max n.m.r., x 9.08, 9.01 ( p a i r of doublets, 6H, secondary methyls, J = 6.5 Hz), 8.92 ( s i n g l e t , 3H, t e r t i a r y methyl), 7.85 (doublet of doublets, IH, H , J o D o = 13 Hz, J 0 . = 3.6 Hz), 7.64 (doublet of doublets, IH, H., , J e>3a 3e,4a ' 3a J„ „ = 13 Hz, J . . =14.4 Hz), 7.35 (sextet, IH, H, , J . . = 13 Hz, 3a,3e 3a,4a l a la, 9 a - 2 0 3 -J\J / ™ T \ = 6 Hz). The decalone 2 2 0 was further characterized as H l a ' ( C V l e i t s 2,4-dinitrophenylhydrazone d e r i v a t i v e , r e c r y s t a l l i z e d from ethanol, m.p., 2 1 3 - 2 1 4 ° . Anal. Calcd. f o r C 1 9 H 2 6 N 4 ° 4 : C> 6 n - 9 5 5 H » 7 - 0 0 ; N > 1 4 . 9 6 . Found: C, 6 0 . 8 5 ; H, 7.08; N, 1 4 . 9 3 . Hydrogenation of Octalone 192 Octalone 192 was hydrogenated by a procedure i d e n t i c a l to that used f or octalone 188. From 100 mg (0.45 mmoles) of octalone 192 was obtained 96 mg (95%) of cis-decalone 221. This product exhibited one component on g . l . c . (column E, 180°, 86). Infrared ( f i l m ) , A 5.85 y; n.m.r., T 9.19, max 9.11 (pair of doublets, 6H, isopropyl methyls, J = 6.5 Hz), 9.01 (doublet, 3H, secondary methyl, J = 6 Hz), 8.89 ( s i n g l e t , 3H, t e r t i a r y methyl), 7.86 (multiplet, IH, H J =14 Hz, J = 3.6 Hz), 7.63 (multiplet,IH, H , J , = 14 Hz, J , . = 14.3 Hz), 8.30 (multiplet, IH, H J = 13 Hz, J (CH ) = 6 Hz). This ' l a 3 l e cis-decalone was characterized further as i t s 2,4-dinitrophenylhydrazone d e r i v a t i v e , m.p. 188-189° from ethanol. Anal. Calcd. for C-H-.N.O. : C, 62.67; H, 7.51; N, 13.92. Found: 21 30 4 4 C, 62.46; H, 7.28; N, 14.01. Birch Reductions General: Each Birch reduction was repeated at le a s t twice while the majority of the reductions were performed f i v e times. The r e s u l t s (yields and - 204 -product composition) are l i s t e d i n Table I I I . These r e s u l t s are the average of the v a r i o u s runs. In each case, g a s - l i q u i d chromatographic Table I I I . R e s u l t s Obtained from the B i r c h Reduction of Octalones 188 to 192. Octalone % Y i e l d t r a n s : c i s R a tio % Recovered s t a r t i n g m a t e r i a l 188 93 87:13 2 189 94 75:25 13 190 98 69:31 14 191 90 82:18 8 192 98 65:35 7 c o n d i t i o n s were found i n which the o c t a l o n e , the corresponding c i s -fused decalone and the corresponding trans-fused decalone e x h i b i t e d d i s t i n c t r e t e n t i o n times on g . l . c . c o - i n j e c t i o n , (column E, 160-190°, 86). In each case, the c i s - f u s e d and trans-fused decalones were c o l l e c t e d by p r e p a r a t i v e g . l . c . and the i n f r a r e d and n.m.r. s p e c t r a were i d e n t i c a l w i t h those of the aut h e n t i c c i s - f u s e d and trans-fused decalones p r e v i o u s l y prepared. Sample Procedure: Reduction of Octalone 188 To 60 ml of l i q u i d ammonia ( f r e s h l y d i s t i l l e d from sodium metal) was added 55 mg of f i n e l y cut l i t h i u m w i r e . A f t e r a l l the l i t h i u m had d i s s o l v e d , 100 mg of octalone 188 i n 10 ml of anhydrous ether was added - 205 -dropwise over 0.5 h to the blue ammonia s o l u t i o n . A f t e r the a d d i t i o n was complete, the r e a c t i o n mixture was allowed to s t i r f o r an a d d i t i o n a l 2 h. The blue c o l o r was then discharged by c a r e f u l a d d i t i o n of ammonium c h l o r i d e . A f t e r the l i q u i d ammonia had evaporated d i l u t e h y d r o c h l o r i c a c i d was added u n t i l the s o l u t i o n became n e u t r a l . This s o l u t i o n was d i l u t e d w i t h water and thoroughly e x t r a c t e d w i t h ether. The combined ether e x t r a c t s were washed w i t h water and b r i n e and d r i e d over anhydrous magnesium s u l f a t e . A f t e r removal of the e t h e r , the residue was vacuum d i s t i l l e d , b.p. 110° at 0.2 mm, to a f f o r d 94 mg (93%) of c i s - and trans-fused decalones and s t a r t i n g m a t e r i a l . The product proved to bean 87:13 mixture of t r a n s : c i s decalone by g . l . c . a n a l y s i s (column E, 180°, 86). The percent composition was determined by i n t e g r a t i o n ( d i s c i n t e g r a t o r ) of the g . l . c . t r a c e of the crude re d u c t i o n product. Samples of c i s - f u s e d decalone 218 and trans-fused decalone 206 were then weighed out and combined to a f f o r d an a u t h e n t i c mixture of known composition approximating that observed i n the B i r c h reduction of octalone 188. I n j e c t i o n of t h i s a u t h e n t i c mixture i n t o the g . l . c . (column E, 180°, 86) f o l l o w e d by i n t e g r a t i o n of the g . l . c . trace confirmed that no compensation was r e q u i r e d ( i . e . the molar response f a c t o r s of decalones 218 and 206 were i d e n t i c a l ) . - 206 -BIBLIOGRAPHY 1. G. Ourisson, S. M u n a r a l l i , and C. Ehret. " I n t e r n a t i o n a l Tables of Selected Constants, V o l . 15, Data R e l a t i v e to Sesquiterpenoids", Pergamon Press, New York, 1966. 2. L. Ruzicka, A. Eschenmoser, and H. Heusser. E x p e r i e n t i a , 9_, 357 (1953), 3. L. Ruzicka, A. Eschenmoser, 0. Jeger, and A. A r i g o n i . Helv. Chim. Ac t a . , 38, 1890 (1955). 4. Y. Ohta, K. Ohara, and Y. Hiros e . Tetrahedron L e t t e r s , 4181 (1968). 5. B.A. Nagasampagi, L. Yankov, and Sukh Dev. i b i d . , 1913 (1968). 6. D.W. Co n n e l l , R.P. Hildebrand, and M.D. Sutherland, i b i d . , 519 (1968). 7. Y.S. Cheng, Y.J. Kuo, Y.T. L i n . Chem. Comm., 565 (1967). 8. K. Takeda, H. Minato, and M. Ishikawa. i b i d . , 79 (1965). 9. K. Takeda, H. Minato, and M. Ishikawa. Tetrahedron, Suppl. No. 7, 219 (1966). 10. Y. Ohta, T. Sakai, and Y. Hiros e . Tetrahedron L e t t e r s , 6365 (1965). 11. J.B. Hendrickson. Tetrahedron, ]_, 82 (1959). 12. W. Parker, J.S. Roberts, and R. Ramage. Quart. Rev., 21, 331 (1967). 13. K. Yoshihara, Y. Ohta, T. Sakai and Y. Hiros e . Tetrahedron L e t t e r s , 2263 (1969). 14. F.W. Semmler and H. St e n z e l . B e r . , 4 7 , 2555 (1914). 15. L. Ruzicka and M. S t o l l . Helv. Chim. Ac t a , ]_, 84 (1924). 16. W.P. Campbell and M.D. So f f e r . J . Am. Chem. Soc.,64, 417 (1942). 17. E. Soubeiran and H. Ca p i t a i n e . L e i b i g s Ann.,34, 323 (1840). 18. F. Hanic. Chem. L i s t y , 52^, 165 (1958). 19. V. Herout and V. Sykora. Tetrahedron, 4_, 246 (1958). 20. V. Herout and V. Sykora. Chem. and Ind., 130 (1958). 21. V. Herout and V. Sykora. C o l l . Czech. Chem. Comm., 23, 2181 (1958). 22. V. Herout, A. Banassek, and M. Romanuk. i b i d . , 31, 3012 (1966). - 207 -23. M.J. Gallagher, R.P. Hildebrand, and M.D. Sutherland. Tetrahedron  L e t t e r s , 3715 (1964). 24. Y. Naya and M. Kotake. B u l l . Chem. Soc. (Japan), 4^ 2, 1468 (1969). 25. L. We s t f e l t . Acta Chem. Scand., 20, 2841 (1966). 26. C C . Kartha, P.S. K a l s i , A.M. Shaligram, K.K. Ch a a k r a v a r t i , and S.C. Bhattacharyya. Tetrahedron, 19, 241 (1963). 27. V. Herout and F. Santany. C o l l . Czech. Chem. Comm., 19, 118 (1954). 28. R. Vlahov, M. Holub, and V. Herout. i b i d . , 32, 822 (1967). 29. L. W e s t f e l t . Acta Chem. Scand., 18, 572 (1964). 30. 0. M o t l , V. Sykora, V. Herout, and F. Sorm. C o l l . Czech. Chem. Comm., 23, 1297 (1958). 31. R.R. Smolders. Can. J . Chem.,45, 889 (1967). 32. W.G. Dauben, B. Weinstein, P. Lim, and A. Anderson. Tetrahedron, 15, 217; (1961). 33. R.R. Smolders. Can. J . Chem., 42, 2836 (1964). 34. L. We s t f e l t . Acta. Chem. Scand. , 20, 2893 (1966). 35. M.V.R. Rao, G.S.K. Rao, and S. Dev. Tetrahedron L e t t e r s , (27), 27 (1960). 36. M.V.R.K. Rao, G.S.K. Rao, and S. Dev. Tetrahedron, 22., 1977 (1966). 37. M.D. S o f f e r , G.E. Gunay, 0. Korman, and M. Adams. Tetrahedron L e t t e r s , 389 (1963). 38. M.D. S o f f e r and G.E. Gunay. i b i d . , 1355 (1965). 39. M.D. S o f f e r and L.A. Burk. i b i d . , 211 (1970). 40. R.B. K e l l y and J . Eber. Can. J . Chem., 48, 2246 (1970). 41. O.P. V i g , O.P. Chugh, and K.L. Matta. Indian J . Chem., 8, 29 (1970). 42. A. Tanaka, H. Uda, and A. Yo s h i k o s h i . Chem. Comm., 308 (1969). 43. E. P i e r s , R.W. B r i t t o n , and W. de Waal. Can. J . Chem. 49, 12 (1971). 44. D.H.R. Barton and CH. Robinson. J . Chem. S o c , 3045 (1954). 45. G. Stork and S.D. D a r l i n g . J . Am. Chem. Soc., 86, 1761 (1964). - 208 -46. M.J.T. Robinson. Tetrahedron, 21, 2475 (1965). 47. S.K. Malhotra, D.F. Moakley and F. Johnson. Tetrahedron L e t t e r s , 1089 (1967). 48. F. Johnson. Chem. Rev., 68, 375 (1968). 49. K.W. Bowers, R.W. Giese, J . Grimshaw, H.O. House, N.H. Kolodny, K. Kronberger, and D.K. Roe. J . Am. Chem. Soc.,92, 2783 (1970). 50. H.O. House, R.W. Giese, K. Konberger, J.P. Kaplan, and J.F. Simeone. J . Am. Chem. Soc., 92, 2800 (1970). 51. R.M. Lukes, G.I. Poos, and L.H. S a r e t t . J . Am. Chem. S o c , 74, 1401 (1952). 52. R.F. Church, R.E. I r e l a n d , and D.R. Shridhar. J . Org. Chem., 27, 707 (1962). 53. A.A. Amos and P. Z i e g l e r . Can. J . Chem., 37, 345 (1959). 54. A. Marquet, M. D v o l a i t z k y , H.B. Kagan, L. Mamlok, C. Ouannes, and J . Jacques. B u l l . Soc. Chim. France, 1822 (1961). 55. J.A. Edwards, M.C. Calzada, L.C. Ibanez, M.E. Cabezas R i v e r a , R. Urquiza, L. Cardona, J.C. Orr, and A. Bowers. J . Org. Chem., 29_, 3481 (1964). ~~ 56. D. Walker and J.D. Hi e b e r t . Chem. Rev., 67, 153 (1967). 57. P.J. Kropp. J . Org. Chem., 29, 3110 (1964). 58. J.E. McMurry. J . Am. Chem. S o c , 90, 6821 (1968). 59. L.J. Chinn. J . Org. Chem., 27, 2703 (1962). 60. E.D. Becker. "High R e s o l u t i o n N.M.R.", Academic P r e s s , Inc., New York and London (1969), p. 149-163. 61. D. Caine and J.F. DeBardeleben, J r . Tetrahedron L e t t e r s , 4583 (1965) 62. M. Pesaro, G. Bozzato, and P. Schudel. Chem. Comm., 1152 (1968). 63. W.L. Meyer and A.S. Levinson. J . Org. Chem., 28, 2184 (1963). 64. G. Fraenkel, S.H. E l l i s , and D.T. Dix. J . Am. Chem. Soc.,87, 1406 (1965). 65. H.O. House and W.F. F i s c h e r , J r . J..Org. Chem., 33, 949 (1968). 66. G. Stork, M. Gregson, and P.A. Grieco. Tetrahedron L e t t e r s , 1391 (1969). - 209 -67. H.O. House, W.L. Respess, and G.M. Whitesides. J . Org. Chem., 31, 3128 (1966). 68. J.R. Catch, D.F. E l l i o t t , D.H. Hey, and E.R.H. Jones. J . Chem. Soc., 278 (1947). 69. W.S. Wadsworth and W.D. Emmons. J . Am. Chem. Soc., 83, 1733 (1961). 70. W.S. Rapson. J . Chem. Soc., 1626 (1936). 71. W.S. Johnson and H. Po s v i c . J . Am. Chem. Soc. , 69, 1361 (1947). 72. G. Stork, A. B r i z z o l a r a , H. Landesman, J . Szmuszkovicz, and R. T e r r e l l . i b i d . , 8 5 , 207 (1963). 73. E.R. Jones and F. Sondheimer. J . Chem. Soc. 43, 615 (1949). 74. G . l . Poos, G.E. A r t h , R.E. B e y l e r , and L.H. S a r e t t . J . Am. Chem. Soc., 75, 422 (1953). 75. J.A. M a r s h a l l and H. Roebke. J . Org. Chem., 34, 4190 (1969). 76. K. Bowden, I.M. H e i l b r o n , E.R.H. Jones, and B.C.L. Weedon. J . Chem. Soc., 39 (1946). 77. E.B. Baker. J . Chem. Phys.,37, 911 (1962). 78. E.B. Baker, i b i d . , 4 5 , 609 (1966). 79. J.D. Baldeschwieler and E.W. Ran d a l l . Chem. Rev.,63, 81 (1963). 80. R. Freeman and W.A. Anderson. J . Chem. Phys.,37, 2053 (1962). 81. N.S. Bhacca and D.H. W i l l i a m s . " A p p l i c a t i o n s of Nuclear Magnetic Resonance Spectroscopy i n Organic Chemistry", Holden-Day, Inc., San Francisco (1964), p. 50. 82. J.A. M a r s h a l l and W.I. Fanta. J . Org. Chem., 29, 2501 (1964). 83. F.D. Gunstone and R.M. Heggie. J . Chem. S o c , 1437 (1952). 84. M. Yanagita and R. F u t a k i . J . Org. Chem.,21, 949 (1956). 85. P.M. Worster and E. P i e r s , unpublished work. 86. H.O. House, R.A. Latham, and CD. S l a t e r . J . Org. Chem. , 31, 2667 (1966). 87. J.A. M a r s h a l l and N.H. Andersen, i b i d . , 31, 667 (1966). 88. M. Cherest, H. F e l k i n , and N. Prudent. Tetrahedron L e t t e r s , 2199 (1968). - 210 -89. M. Cherest and H. F e l k i n . i b i d . , 2205 (1968). 90. G.B. Kaufman and L.A. Teter. Inorg. Syn. , ]_, 9 (1963). 91. T.M. Warne, J r . , Ph.D. Thesis, Northwestern U n i v e r s i t y , June 1970, p. 40. 92. J.A. Osborn, E.F. J a r d i n e , J.F. Young and G. Wil k i n s o n . J . Chem. Soc. [A], 1711 (1966). 93. J.A. M a r s h a l l , N. Cohen, and K.R. Arenson. J . Org. Chem., 30, 762 (1965). 94. R.B. Woodward, F. Sondheimer, 0. Taub, K. Heusler, and W.M. McLamore. J . Am. Chem. Soc. , 74, 4223 (1952). 95. E.J. Corey and A.G. Hartmann. i b i d . , 87, 5736 (1956). 96. R.M. Coates and J.E. Shaw. i b i d . , 92, 5657 (1970). 97. E. P i e r s , W. de Waal and R.W. B r i t t o n . Chem. Comm., 188 (1968). 98. E. P i e r s , W. de Waal and R.W. B r i t t o n . Can. J . Chem., 47, 4299 (1969). 99. A.A. Bothner-By and R.E. G l i c k . J . Chem. Phys.,26, 1651 (1957). 100. L.W. Reeves and W.G. Schneider. Can. J . Chem., 35 ( 1 ) , 1651 (1957). 101. J.D. Connolly and R. McCrindle. Chem. and Ind., 379 (1965). 102. H.J.E. Lowenthal. Tetrahedron, 6_, 269 (1959). 103. G.G.S. Dutton, K.B. Gibney, G.D. Jensen, and P.E. Reid. J . Chromatog., 36, 152 (1968). 104. O.P. V i g , S.D. Sharma, S. Chander, and I. Raj. Indian J . Chem., 4_, 275 (1966). 105. F.J. M c Q u i l l i n and R. Robinson. J . Chem. Soc., 586 (1941). 106. J.B.. Rogan. J . Org. Chem. , 27, 3910 (1962). 

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}]}"
                            data-media="{[{embed.selectedMedia}]}"
                            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:
https://iiif.library.ubc.ca/presentation/dsp.831.1-0060082/manifest

Comment

Related Items