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Studies related to the veratrum alkaloids : the total synthesis of C-nor-D-homo steriod analogue Torupka, J. Edward 1968

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STUDIES RELATED TO THE VERATRUM ALKALOIDS. THE TOTAL SYNTHESIS OF C-NOR-D-HOMO STEROID ANALOGUES by J. EDWARD TORUPKA B . S c , The U n i v e r s i t y o f B r i t i s h Columbia, 1965 A THESIS SUBMITTED IN PARTIAL FULFILMENT OF THE REQUIREMENTS FOR THE DEGREE OF • MASTER OF SCIENCE in the Department of Chemistry We accept t h i s t h e s i s as conforming to the re q u i r e d standard THE UNIVERSITY OF BRITISH COLUMBIA March, 1968 In presenting th is thesis in pa r t ia l fu l f i lment of the requirements for an advanced degree at the Univers i ty of B r i t i sh Columbia, I agree that the Library sha l l make i t f ree ly ava i lab le for reference and Study. I further agree that permission for extensive copying of th is thesis for scholar ly purposes may be granted by the Head of my Department or by hiJs representat ives. It is understood that copying or publ icat ion of th is thesis for f inanc ia l gain shal l not be allowed without my wri t ten permission. r l • h Department of Ly^U^^iAhj/Uj The Univers i ty of B r i t i sh Columbia Vancouver 8, Canada Date /j,(Lh^Jl 5c3 . 1^1(0$. ABSTRACT The t o t a l synthesis of trans-syn-cis-C-nor-2-methoxy-8, ll-dihydroxy-10a-methyl-4b,5,6,6a,7,8,9,10,10a,10b,ll-undecahydro chrysene (87) i s described. This compound has been synthesized from the C-nor-D-homo hydroxy aldehyde (67) v i a the o l e f i n (71) by oxidative hydroboration. This sequence has the advantage of giving a much higher overall y i e l d of (87). The conversion of the said compound (87), to the a-methyl ketone (74), a relay compound which has been used to synthesize verarine (76) i s now nearing completion. 88 Contrary to previous speculations , pyrolidene enamine methylation of model compounds (77,78) did not prove as f r u i t f u l as methylation of trapped enolates (figure 13). i i i TABLE OF CONTENTS Page TITLE PAGE i ABSTRACT . . . . . ... . . . . . . . '. ii TABLE OF CONTENTS. i i i LIST OF FIGURES v ACKNOWLEDGEMENT. v i INTRODUCTION ;. 1 DISCUSSION . . . . . . . . . . . . . . . . . . . . . . . . 22 A. The Birch Reduction .22 1. Trans-anti-trans Isomer 27 2. Trans-anti-cis Isomer 28 3. Trans-Anti-Trans Isomer with Axial Acetate. 29 4. Anomalous Isomer Mixture . . . 31 5. Trans-anti-trans Olefin Mixture 32 B. The t-Butyl Chromate Reaction . 33 C. Sodium Borohydride Reduction 35 1. Normal Reduction . . 35 2. Sodium Borohydride Reduction with Hydrolysis . . . 36 3. Lead Tetra-acetate Oxidationof the Diol . . . . . . . . . .37 D. Phosphorus Pentoxide Dehydration Reaction. 38 E. Osmium Tetroxide Hydroxylation . 38 1. Oxidation. . 38 2. Acetylation 41 F. Cleavage of the Diol 41 G. Aldol Condensation 42 H. Acetylation of the Diol Aldehyde . . .44 i v I . Deformylation . . 44 J. C a t a l y t i c Hydrogenation 50 K. Birch Reduction . . . . . . . . . . . 51 L. Hydroboration 51 M. Birch Reduction and Isomerization 51 1. Birch Reduction of the Anisole Ring (a) The trans-anti-trans compound 53 (b) The trans-anti-cis compound 54 2 . Enol Ether Hydrolysis and Isomerization (a) The trans-anti-trans compound 54 (b) The trans-anti-cis methyl ether cleavage and isomerization.55 3. Birch Reduction Hydrolysis and Isomerization of the C-nor-D-homo Trans-Acetate (72) 55 N. Methylation 1. Studies on D-homo Compounds (a) 56 (b) The enamine alk y l a t i o n 57 (c) Enolate trapping and methylation (A) The trans-anti-cis isomer 57 (B) The trans-anti-trans isomer 58 CONCLUSION 60 EXPERIMENTAL 61 BIBLIOGRAPHY. . 97 V L I S T OF F I G U R E S Figure Page I 7 • 2 . . 9 3 11 4 13 5 . . . . . . 14 6 15 7 17 8 18 9 19 10 20 II 23 12 . 24 13 25 14 26 15 47 16 49 ACKNOWLEDGEMENTS I am indebted to Dr. J.P. Kutney for his encouragement, super-v i s i o n , and expert guidance, without which so many try i n g problems would not have been solved so e a s i l y . These years i n his laboratory w i l l always be a source of i n s p i r a t i o n . My thanks go also to Dr. W.A.C. Gladstone with whom I had the great pleasure to collaborate on this problem. I would also wish to express my sincere thanks to Smith M i l l e r § Patch Inc. and the National Research Council of Canada for t h e i r f i n a n c i a l support of t h i s project. INTRODUCTION 1 Recently, greater attention has been devoted to the study of steroids with unnatural stereochemistry as well as those with expanded or contracted ring systems. The ring expanded steroids are referred to by the p r e f i x "homo" while those with ring contraction are denoted by "nor". The impetus for such interest was given by recent reports which show that such unnatural steroid molecules can have b i o l o g i c a l properties markedly d i f f e r e n t from the common steroids. For example, a large number of papers * report alterations i n b i o l o g i c a l a c t i v i t y for compounds which have C-18 or C-19 methyl groups removed from the steroid molecule. Another excellent example i s given by the work of W.S. Johnson and his collaborators ^>9»10^ ^ a v e synthesized several D-homo steroids. The (+)-D-homo-18-norandrostane-3,17-dione, compound (8), has been found to be as androgenically active as (+) androstane-3,17-dione. The synthesis 12 13 of B-nor steroids ' , though more demanding sy n t h e t i c a l l y , has also been reported. F i n a l l y , i t i s interesting to note that 9a, 106 progesterone 14 i s approximately f i v e times as active as a progestational agent In the majority of the above cases, naturally occurring steroids have been used as star t i n g materials. Although these were the l o g i c a l s t a r t i n g materials, they offered certain l i m i t a t i o n s i n synthesizing the steroid analogues of interest i n our studies. These studies were concerned with chemical structure and b i o l o g i c a l a c t i v i t y . For t h i s reason we i n i t i a t e d investigations toward the t o t a l synthesis of steroid analogues. The sequence chosen to r e a l i z e the said analogues, was one i n which the introduction of substituents was re a d i l y achieved. By vi r t u e of t h i s ready s u b s t i t u t i o n , convenient a l t e r a t i o n of the steroid skeleton could be achieved i n the analogues. These alterations would not be ea s i l y 2 possible i f natural steroids were used as starting materials. E s s e n t i a l l y , we were interested i n developing a t o t a l synthesis of the modified C-nor, D-homo type steroid skeleton. This steroid skeleton i s known to be present i n the naturally occurring Veratrum alk a l o i d s . Jervine (1) and cevadine (2) are examples of the two major families of the Veratrum^ group. It was f e l t that, by construction of appropriate C-nor, D-homo steroid intermediates, subsequent extension to the Veratrum series would be possible. The Veratrum Alkaloids are a group of steroid alkaloids which occur i n the plants of the t r i b e Veratreae. This t r i b e i s part of the subfamily Melanthioideae of the family Lileaceae. Sometimes the subfamily i s treated as a separate family the Melanthioideae or the Colchicaceae. The genera which have been investigated are the following: Veratrum ( f a l s e hellebore ), Zygadenus (death camus), Schoenocaulon (Sabadilla), Stenanthium, Amianthium (crow poison), Melanthium (bunch flowers), and F r i t i l l a r i a . The. species of the f i r s t three genera have received the most attention. Kupchan, Zimmerman and Alfonso*'' have recently reviewed the occurrence and structure of alkaloids isolated from Verat reae, the c l a s s i c a l botanical taxonomy of the Veratreae, and the implications of al k a l o i d occurrence -and structure to the taxonomy of Veratreae. This review does not cover the work done on the F r i t i l l a r i a genus. 3 Veratrum and related plants have been used medicinally for hundreds of years. Galenical preparations were used i n the middle ages for purposes of sorcery and mystical r i t e s . Subsequently the crude extracts have been used i n the treatment of fevers, as local c o u n t e r - i r r i t a n t s , as cardiac 16 17 t o x i c s , and as insecticides ' . The use of Veratrum to control hyper-tension, at least i n the United States, dates from the report of Baker 18 i n 1859 . During the late t h i r t i e s , p u r i f i e d a l k a l o i d preparations 19 20 responsible for hypotensive a c t i v i t y of Veratrum were made available ' The group of alkaloids responsible for hypotensive a c t i v i t y are the esters of the ceveratrum series. Cevadine (2) i s an example of this family of compounds. These compounds have a heptacyclic skeleton and are highly oxygenated, usually containing up to 9 oxygen atoms. These compounds have never been found as glycosides but exist as benzoic, acetic, and other 21-25 short chain a l i p h a t i c acid esters. Imperialine (3) and Verticine 26 27 ("peimine") (4) ' are closely related to these compounds, but in contrast 23-25 occur naturally as g-D-glucosides, edpetiline (5) and peiminoside , 26 28 (6) . Kupchan published a review on the hypotensive Veratrum ester 29-33 alkaloids. More recently, a series of papers on the structure a c t i v i t y relationships i n a series of protovertine (7) esters have appeared. The R=H, 4 4 r / 0 - C H z o -CH 4 I HO-CH I H C — O H HO - C H , R= •c, C H ,6 I HC-OH I I .c most recent review on Veratrum Alkaloids by Kupchan and By is now in publication, Jervine may be cited as an example pf the other family of Veratrum alkaloids. This family is referred to as the Jervaratrum series. Only 2 to 3 oxygen atoms are generally present in this family's molecules. These compounds which occur as free amines 'or esters show very l i t t l e 34 hypotensive effect . One of the most recent reviews of Veratrum alkaloid chemistry is by 35 Narayanan . Since then several new alkaloids have been isolated and 21,22 characterized. Yunsov and Muriddinov showed that:raddeanine (3) from F r i t i l l a r i a eduardi was identical with sipeimine- and imperialine. . 22 These authors also report five new alkaloids, isolated from F r i t i l l a r i a sewerzoni; Korseverine (^yH^O^N), alginidine (^yH^O^N), korseverinine (C 2 ?H 4 30N) , korseveridue (C^H^O^J, and korseveramine (C^H^O.^) . The 36 structure of a new alkaloid ester (8) was proposed by Yagi and Kawasaki but no formal name was given. 5 This compound (8) possessed the molecular formula C^H^OgN and was iso l a t e d from V. grandiflorum. (Maxim.) Loesener f i l . Kupchan and co-37 workers determined the structure of sabadine (9) ("neosabadine", C 2 7H 4 50 ?N) , and i t s 3-acetate (10) ("sabatine", C^H^OgN). Tomko and 38 Bendik postulated the structure of the jerveratrum a l k a l o i d , verakamine, (11) (C 2 ?H 4 50 2N). OH Ho and collaborators obtained evidence permitting assignment of structure (4) for verti c i n e (C^H^C^N) , the major a l k a l o i d of F r i t i l l a r i a  v e r t i c i l l a t a ver Thunbergu Baker. Verticine was also shown to be i d e n t i c a l with peimine. Since Fukuda, who named the pure a l k a l o i d v e r t i c i n e , was the f i r s t to suggest a name, the authors chose the former name over the 6 23 l a t t e r . In 1963> Yunusov isola t e a from Petilium eduardi the following a l k a l o i d s : peimisine edpelitidine ( C 2 N C ^ ) , edpetiline, and three unnamed compounds (mp 247-51°, 269-71°, and 228-31°). Acid hydrolysis of edpetiline produced D-glucose and imperialine. Recently Yunusov 24 and collaborators synthesized edpetiline from imperialine and t e t r a -O-acetyl-a-D-glucopyranosyl bromide. In 1964, Masamune and co-workers is o l a t e d a new a l k a l o i d , 11-de-oxojervine, (12) (C^yH^C^N) > from the roots of V. album L. var. glandiflorum Maxim. I t was found to be i d e n t i c a l 40 41 with one of the Wolff-Kishner reduction products of jervine. Tomko has iso l a t e d a number of alkaloids from Veratrum album subsp. Lobelium (BERNH.) Suessenguth including: veralinine (C^H^ON) , veraminine, verorine (C2yH,_9QN) , and veralkamine (C^H^CvN) . The structure (13) was proposed for verarine. Also i n 1964, the i s o l a t i o n of a new ester a l k a l o i d G was 43 reported by A.G. Smith , from the plant Amianthium muscaetoxicum Gray. 44 45 Communications by Wintersteiner and Masamune i n 1962 presented the elucidation of isojervine (14) an isomer of jervine formed i n high y i e l d when jervine was treated with hydrochloric acid-methanol solution. figure 1 8 The f i n a l "detailed" papers on the structure of isoj.ervine have 46 47 48 been published by three groups; Dauben , Wintersteiner and Masamune and t h e i r respective collaborators. A l l three groups reached the same conclusion. Isojervine derivatives have also been studied by Wintersteiner 49 and Moore . . The stereochemistry of these compounds has been studied by various groups. Mitsuhashi and Shinusu^^'^* synthesized the C-nor-D-homo derivative (16) from hecogenin (15) (figure 1) and obtained evidence for the 9a configuration of jervine (1) and veratramine (18) (Figure 1). Si m i l a r l y jervine and veratramine have been converted to a common in t e r -mediate (17) or the acetate (19) proving that they have some structural aspects i n common. Nuclear magnetic resonance and chemical evidence from Johnson's 52 53 laboratory ' has substantiated the forementioned proposals. He also accepts Mitsuhashi's"^ evidence for the existence of the B/C trans ring fusion. On the other hand, the configuration of C-9 was i n doubt since the biogenesis of veratramine could involve a 11-keto veratramine i n t e r -mediate which would render the C-9 position epimerizable. Nuclear magnetic 9 figure 2 10 resonance spectroscopy (nmr) showed that the C-19 methyl protons of the derivative (20) figure 1) of 11-keto veratramine and of the diketone(21) (figure 1) resonate at exactly the same position (T8.18). Further evidence 54 55 for the 9a configuration was provided by Mitsuhashi and Masamune Mitsuhashi synthesized the C-nor-D-homo compound (22) (figure 2) from hecogenin (15) , while Masamune synthesized (22) (figure 2) from veratramine (18). These endeavors had now established the C-9 configuration beyond doubt. In the case of jervine (1) Masamune^ transormed both jervine and veratramine into compound (22) (figure 2). Jervine and veratramine have also been converted to a common intermediate with an aromatic "D" ring (23). I t i s now known that 11-deoxy-jervine (12) has the 9a configuration since i t was transformed into compound (24) (figure 2) which i s a degrada-tion product of veratramine. 56 57 W.S. Johnson and co-workers ' were the f i r s t to report on the degradation of veratramine to compound (22) which was an intermediate i n the degradation to compound (25, figure 2). The reactions leading to (22) were also t r i e d on compounds with a 5,6-double bond but the yields >• were somewhat lower. Compound (25) could have been used to determine the stereochemistry of some of our C-nor-D-homo compounds. Recently published reports by Johns****'"^' and Mitsuhashi^ indicate the synthesis of etiojervane derivatives from hecogenin, a readily available sapogenin. "Etiojervane" i s a name which i s applied to the system, 17a-methyl-C-nor-D-homo-18-nor-5a,13a-androstane (26). Johns' sequence i s i l l u s t r a t e d in figures 3 and 4. The work of Johns i s pertinent to our synthesis, since our i n i t i a l goal i s to synthesize compound (33; figure 4) 11 figure 3 12 (figure 5). The a v a i l a b i l i t y of t h i s compound from hecogenin w i i l thus allow us to confirm the stereochemistry of our t o t a l l y synthetic C-nor-D-homo molecules. Mitsuhashi's work' i s very s i m i l a r to that of Johns'. The exception i s that in the Japanese paper, compound (28) instead of (27) (figure 3) was used to synthesize the C-nor-D-homd compound (32) (figure 4). This conversion was studied extensively and (29) was found to be one of the intermediates. Mitsuhashi's more recent researches^ described the synthesis of (33) v i a compound (34) (figure 4). In the above papers there i s an error which has been corrected by 62 Coxon i n some recent work. Coxon gives physical as well as chemical evidence to indicate that the double bond was at the 13,17a position not at the 17,17a position as previously state'd. He also gave proof that the configuration of the C-13 position i n (30) (figure 3) i s a. Et i o -jervine derivatives have been synthesized from jervine by Kupchan and his c o l l a b o r a t o r s ^ ' ^ . Some of these compounds are useful as relay substances i n a subsequent synthesis of jervine since they possess an oxygen function at C - l l obtained by degradation of naturally occuring steroids to etiojervane derivatives. I would now l i k e to turn to the t o t a l synthesis of these compounds. The only published attempts at w 26 13 figure 4 figure 5 figure 6 16 the t o t a l synthesis of these compounds up to 1966 have been by R.A. 65 66 67 52 53 Barnes ' ' and W.S. Johnson ' (figure 6). Barnes attempted "he t o t a l synthesis of etiojervane derivatives by several sequences none i f which has yet been successful. The more successful hydrochrysene approach i s already known from the previous elegant t o t a l syntheses of various 68 - 7 3 steroids . More recently t h i s elegant and powerful sequence has been directed at the t o t a l synthesis of veratramine (figure 6). Very recently Masamune^^ and Johnson*^ have published a t o t a l synthesis of veratramine. It i s quite questionable whether Masamune's sequence constitutes an acceptable t o t a l synthesis since the last two reactions i n his sequence 157 proceed with yields of 2% and 1% respectively. Concurrently Johnson has published a t o t a l synthesis of Jervine v i a the hydrochrysene approach. This sequence does not lend i t s e l f to convergence as well as the sequence developed i n our laboratories. 76—79 Several years ago investigations i n t h i s laboratory and indepen-74 75 dently by Nagata and collaborators ' provided a synthetic sequence to the t e t r a c y c l i c ketone (36) (figure 7). The ketol (35) i s a v e r s a t i l e derivative since i t not only provides entry into the cis-syn-cis series, 80 81 but also has enabled Roller and Inaba to successfully convert i t into B-nor-D-homo steroids derivatives (figures 8,9,10). This thesis presents work directed toward the t o t a l synthesis of C-nor-D-homo-intermediates which are useful intermediate compounds for the t o t a l synthesis of Veratrum alkaloids. The Ketone (36) i s u t i l i z e d as the s t a r t i n g material. I n i t i a l l y the "hydrochrysene method" i s 17 figure 7 18 figure 8 19 figure 9 figure 10 21 u t i l i z e d to obtain the necessary hydrochrysene derivatives. Modifica-tions of conditions and experimental technique given by Johnson were found to be essential due to differences i n chemical r e a c t i v i t y between his compounds and ours. These differences i n chemical r e a c t i v i t y were dictated largely by the difference i n position of the methoxy group on the aromatic ring. 22 DISCUSSION The differences i n the two series of Veratrum alka l o i d s , represented by jervine and veratramine are of p a r t i c u l a r interest. The major feature of the jervine series i s that these derivatives possess a ketonic function i n the C-ring whereas none occurs i n the veratramine compounds. An a t t r a c t i v e p o s s i b i l i t y exists for developing a synthetic sequence lead-ing to the two series of C-nor-D-homo derivatives. In the case of the jervine family, the carbonyl group would be retained while for the synthesis of veratramine i t would be e a s i l y removed during the Birch reduction of the D-ring. With t h i s goal i n mind, the synthesis of the C-nor-D-homo compound (40) was developed. The compounds and reactions 40 36 they undergo are outlined i n figures 11, 12 and 13. The t e t r a c y c l i c ketone (36) w i l l be considered as the s t a r t i n g material for t h i s synthetic sequence. This compound was prepared from g-naphthol i n large quantities by a well known series of reactions (figure 14). Although these reactions were repeated many times they w i l l not be discussed here since no modifica-77 82 tions nor new techniques were introduced ' A. THE BIRCH REDUCTION As mentioned before, the stereochemistry of jervine containing the 23 figure 11 figure 12 25 figure 13 26 figure 14 27 modified s t e r o i d "backbone" (1), has been shown to be trans-anti-trans. For t h i s reason Birch reduction was chosen over the other available methods since the application of t h i s reaction to hydrochrysene analogues, 70 has been studied i n considerable d e t a i l by Johnson . This reaction has the d i s t i n c t advantage of producing compounds which are i n general thermo-dynamically most stable. These considerations were discussed as well as 70 studied extensively by Johnson and co-worders . The re s u l t i n g molecules i n both hydrochrysene series would be expected to have the required trans-anti-trans stereochemistry after Birch reduction. Four new asymmetric centres would be formed as a result of t h i s reaction. The subjection of the t e t r a c y c l i c ketone (36) to the reaction conditions perfected by Johnson for the hydrochrysene series containing e f f e c t i v e l y a m-methostyrene system, gave the desired reduction product i n very poor y i e l d . In order to avoid the formation of the side products resulting from a reduction of 83 the aromatic r i n g , many modifications of the Johnson conditions were t r i e d with l i t t l e success. F i n a l l y a substantial improvement of y i e l d was obtained when the reduction was carried out i n an amine solvent (see below). 1. Trans-anti-trans Isomer When a solution of the ketone (36) i n tetrahydrofuran was treated with sodium i n l i q u i d ammonia i n the presence of a n i l i n e , a good y i e l d of the desired reduction product was obtained. Usually i n t h i s reaction the product consisted of a mixture of alcohol and carbonyl compounds i but the l a t t e r could be e a s i l y reduced to the required alcohol with sodium borohydride. The u l t r a v i o l e t spectra of the trans-anti-trans ketone (41) and alcohol (42) were i d e n t i c a l with the spectrum of 1,2,3,4-tetrahydro-6-methoxy naphthalene (43), (figure 11). The ketone absorption was lso detected b infra-red spectroscopy and i t s conversi  from the 28 ketone with a saturated carbonyl peak at 1700 cm to the alcohol with a hydroxyl absorption at 3450 cm * was e a s i l y observed. The nmr spectra of these reduction products were quite t y p i c a l . In considering the alcohol (42a) i t was noted that the hydroxyl group absorbed at T7.63 and disappeared on equilibration with D^O. The a x i a l proton geminal to the hydroxyl group was observed as a broad multiplet centered at T6.37. This observed broadness confirms the expectation that the proton i n question i s indeed a x i a l . The methyl group absorbed at x9.17. In the aromatic region, the O C H 2 R=H, 42a R=Ac,42b • C-l proton was seen as a doublet at x3.45 with the usual meta coupling constant J = 3 cps. The quartet for the C-3 proton appeared at x3.35 with coupling constant J = 8 cps. The doublet for the'C-4 proton was observed at T2.84. NO evidence of para coupling was observed i n any of the compounds prepared, however for compounds with C-12 keto groups, the C-l proton w^as observed at lower f i e l d than the C-3 and C-4 protons. , 2. Trans-anti-cis Isomer Several of the side products were isolat e d from the acetate mother liquors and shown to be stereoisomers of the above compound (42b). One of these (44b), mp. 135 - 138°C analyzed for ^22^30^3' ^ a c* a t wi- n maximum in the u l t r a v i o l e t (X 280, 287 my) which i s t y p i c a l for the anisole A max J r . chromophore. The infrared spectrum showed an acetate carbonyl at 1720 cm ^ The nmr spectrum was very interesting and showed; an angular methyl group at 29 a very high field (x9.65). This could be considered as evidence that a cis B/C ring fusion existed in this molecule (see later). The C-8 proton appeared as a broad multiplet at T 5 . J indicating that this proton which is geminal to the acetate was in the aicial orientation. From the above evidence this compound was established as trans-anti-cis-2-methoxy-88-acetoxy-10a-methyl-4b,5,6,6a,7,8,9,10,10a,10b,11,12, dodecahydrochrysene. (44 OCH, R=H, 44a R=Ac, 44b 3. Trans-Antj-Trans Isomer with Axial Acetate Another compound (45b) (mp 154-156°C) which could be completely characterized contained an axial hydroxyl group. Its ultraviolet spectrum (A m a x 278, 286 my) was superimposable on the authentic trans-anti-trans alcohol (42a). From high resolution mass spectrometry the molecular formula of the acetate derivative (4 5b) was determined to be. C^HjnOy This result established beyond doubt that this compound is indeed isomeric with the trans-anti-trans acetate (42b). The nmr spectrum showed an angular methyl group resonating at T9.19, a normal region for the B/C trans ring fusion. This conclusion was warranted by a previous detailed 83 87 study in this laboratory ' where i t had been shown that cis fusion, particularly in the B/C ring, shifts the C-lOa methyl group to a much higher field due to its shielding by the aromatic ring of this molecule. Further, inspection of the low field region yields some interesting informa-tion. In the spectrum of this stereoisomer, the proton geminal to the hydroxyl appears as a relatively narrow multiplet compared to the same 30 proton i n the t r a n s - a n t i - t r a n s a l c o h o l (42a). This m u l t i p l e t i s centred at T6.37. The width at h a l f height f o r the former i s 8 cps while f o r the l a t t e r (47a) i t i s 24 cps. The f i r s t c o n c l u s i o n which can be drawn i s tha t the stereochemistry at C-8 of the compound i n question i s d i f f e r e n t from that o f the major product (42a). The broad m u l t i p l e t observed f o r the l a t t e r compound (42a) i s t y p i c a l of an a x i a l proton s i n c e i t i s able to couple w i t h two other a x i a l protons at C-7 and C-9. The c o u p l i n g constant, J , i s w e l l e s t a b l i s h e d as being i n the order o f 8-10 cps thus g i v i n g r i s e cL j ct t o the observed broad s p l i t t i n g p a t t e r n . The coupling constants, J , and J g g J are both small (3-5 cps), and i t i s e a s i l y deduced that as i n the case under d i s c u s s i o n , the C-8 e q u a t o r i a l proton would be observed as a 0CH3 R=H, 45a R=Ac, 45b narrow m u l t i p l e t . On t h i s b a s i s , s t r u c t u r e 45a i s assigned t o t h i s compound. Confirmation o f the assignment i s obtained from nmr data on the acetate d e r i v a t i v e o f t h i s compound. The acetate, mp 138-139.5°C, was obtained i n the usual manner. T h i s compound had the c h a r a c t e r i s t i c a n i s o l e u l t r a v i o l e t spectrum (X 278, r max 286 my) while the i n f r a r e d , as expected, showed a strong carbonyl absorption at 1710 cm * due t o the acetate absorption. The nmr spectrum i n d i c a t e d a new low f i e l d s i g n a l (T4.98 f o r the proton geminal t o the acetate f u n c t i o n . This s h i f t (from T6.37 t o T 4 . 9 8 ) i s normally observed upon a c e t y l a t i o n o f secondary a l c o h o l groups. In a d d i t i o n , t h i s downfield s h i f t c o r r e l a t e s very w e l l w i t h the s h i f t observed upon a c e t y l a t i o n o f the t r a n s - a n t i - t r a n s 31 alcohol (42a). F i n a l l y , as i s indicated by the spectrum, the geminal proton i s once more a narrow multiplet (7 cps at h a l f height), whereas in- the trans-anti-trans acetate, the low f i e l d multiplet remains broad (24 cps at h a l f width). From the above evidence the assignment of stereo-chemistry to the structure of this Birch reduction by-product may be conclusively established as trans-anti-trans-2-methoxy-8a-hydroxy-10a-methyl-4b,5,6,6a,7,8,9,10,10a,10b,11,12,-dodecahydrochrysene. 4. Anomalous Isomer Mixture The next compound isolat e d from the reduction was acetylated to give a crystalline s o l i d , mp 134.5-136°C, with molecular formula C 22 H30°3 e s t a ' : ) l i s n e ^ by elemental analysis as well as high resolution mass spectrometry. This compound i s therefore another stereoisomer of the trans-anti-trans acetate (42b). Thin layer chromatography on t h i s substance showed only one spot when eluted with 10% ethyl acetate i n chloroform (R^ 0.52). U l t r a v i o l e t spectroscopy produced the expected anisole spectrum (A f f l a x 278, 286 my). While i n the infrared region, the major bands were noted at 1717 cm * and 1245 cm - 1. The nmr data consisted of the following signals: T9.03 and T8.86 (singlets, t o t a l area = 3H), x6.22 (singlet, 3H), T5.2 (IH, multiplet of 32 cps i n width) a multiplet centred at T3.15 for the aromatic protons. Form the above nmr data i t was concluded for several reasons, that t h i s material was a mixture of two compounds. F i r s t l y , the two methyl singlets had unequal integral values. Secondly, the proton multiplet (T5.2) geminal to the acetate group was much broader (32 cps) than that of the trans-anti-trans compounds (24 cps). F i n a l l y , t h i s multiplet possessed more s p l i t t i n g than was allowable for the exi s t i n g number of coupling protons (at least nine signals were counted versus fiv e i n the 32 trans-anti-trans case). No further e f f o r t was made to separate these stereoisomers. 5. Trans-anti-trans Olefin Mixture H 46a « 46b A mixture of o l e f i n i c compounds (46 a,b) was isolat e d and p a r t i a l l y characterized. Again the u l t r a v i o l e t spectrum was t y p i c a l of t h i s series ( X m a x 278, 286 my) and was superimposable on an authentic spectrum of trans-anti-trans alcohol (42a). This result indicated the presence of an unconjugated anisole system, proving that i n this molecule, as well as i n the other by-products studied, the double bond i n C-ring had been reduced. Great d i f f i c u l t y was encountered i n c r y s t a l l i z i n g t h i s substance. An nmr spectrum of the s o l i d showed the following resonances; a single methyl group at T8.84, a methoxyl singlet at T6.15, o l e f i n i c multiplets gornered at T4.5 and T4.0 which integrated for two protons and the normal aromatic multiplet centred at T3.15. From the above data the following conclusions were made: f i r s t , that the substance was a mixture; secondly, that the backbone of t h i s mixture of compounds was most l i k e l y trans-anti-trans; f i n a l l y , that the mixture resulted from the elimination of a hydroxyl group i n the A ring. However, no further characterization of t h i s compound was made at th i s time. 33 B. THE t-BUTYL CHROMATE REACTION In order to obtain access to the C-nor-D-homo steroid skeleton, the trans-anti-trans acetate (42b).must be converted to a seco or ring-opened compound (47). For this reason, activation at the C - l l or C-12 47 0 48 carbon was essential. After a survey of the available methods, i t was 84 decided that the C-12 carbon was most susceptible. Wlntersteiner had prepared 6-ketoestradiol diacetate (48) by direct oxidation of the benzylic position. Two related factors complicated the s i t u a t i o n . F i r s t , i n the hydrochrysene molecule (42b) there are two benzylic carbons. Second, the methoxyl group of the anisole system exists meta to the required C-12 s i t e of activation but para-relative to the nonrequired 83 benzylic carbon, C-4b. It was shown that attack of various reagents occurred p r e f e r e n t i a l l y at the C-4b carbon, even though i t was t e r t i a r y rather than at the secondary and less hindered benzylic carbon. .This 71 was another deviation from the findings of Johnson and his collaborators i n t h e i r studies of the hydrochrysene homologues. In order to overcome aromatization of the C-ring by attack at the t e r t i a r y C-4b p o s i t i on, consideration of s t e r i c a l l y hindered o x i d i z i n g 85 agents was undertaken. t-Butyl chromate was found to give a substantial improvement i n the y i e l d of 12-keto-acetate (49) over the chromium t r i o x i d e 84 method of Wintersteiner . The infrared spectrum of the desired hydrochrysene 34 analogue showed bands at 1730 cm * and 1670 cm The u l t r a v i o l e t spectrum had the following maxima: 222, 254, and 322 my. The effect of the C-12 ketone (48) on the nmr spectrum of the aromatic protons as compared to that of the parent compound was to deshield the C-l proton so that the doublet now appeared at lowest f i e l d . This was characteristic of a l l C-12 keto compounds. On the average, this compound was obtained i n yields of 15% with a 40% recovery of s t a r t i n g material. In the large number of cases this reaction was repeated, the y i e l d of this 12-keto-acetate (49) varied from 12% to 18% while the recovery of sta r t i n g material varied inversely from 50% to 32%. Separation of the desired material from the by-products of the oxidation reaction proved d i f f i c u l t . Careful column chromatography, combined with cross c r y s t a l l i z a t i o n , proved to be successful i n separating the desired 12-keto-acetate (49) from the mixture of products. These by-products (37, 38, and 39, figure 10), were previously isolated 81 and characterized by T. Inaba i n this laboratory. Dr. W.A.F. Gladstone 86 of t h i s laboratory prepared and characterized the following derivatives of these compounds (5 1, E 2, 53 ). O 35 Gladstone also isolated a small amount of a novel peroxide (54 J from t h i s reaction mixture. This compound proved to be surprisingly stable. The peroxide i l l u s t r a t e s a possible mechanism for aromatization of the C-ring during the oxidation reaction. When the t-Butyl chromate oxidation reaction was carried out on impure trans-anti-trans acetate, i n several cases, an additional compound, mp 162-165°C, was isolated. This compound had been previously characterized and was shown to be an isomer of the 12-keto-acetate ( 4 9 ) . C. SODIUM BOROHYDRIDE REDUCTION 1. Normal Reduction The trans-anti-trans keto acetate ( 4 9 ) was reduced with sodium boro-hydride to give a colourless o i l i n very high y i e l d (5s). Infrared spectroscopy showed, as expected, a strong hydroxyl absorption (3503 cm *) and no carbonyl band. This finding was confirmed by u l t r a v i o l e t spectro-scopy. In the l a t t e r case the anisole spectrum was obtained, indicating that the previously conjugated carbonyl function had been reduced. The major product of t h i s reaction was c r y s t a l l i z e d to give a pure sample, mp 147.5-149°C. The u l t r a v i o l e t spectrum had maxima at 226, 281, and 288 my and minima at 247 and 286 mp. The nmr spectrum showed i n addition 36 to the methyl group at x9.15, and an acetoxy group at x8.03 (each integ-ra t i n g for 3 protons), a multiplet centred at x5.3 which integrated for 2 protons. This absorption was due vo the proton geminal to the C-12 hydroxyl superimposed upon that of the C-8 acetoxy geminal proton. The diacetate (56), mp. 175°C, was readily prepared and as expected, i t s RX=R=H 57 u l t r a v i o l e t spectrum was v i t u a l l y superimposable with that of the st a r t i n g material. The infrared showed evidence for two acetoxy groups (1730, 1720 cm *) and no hydroxyl absorption was observed. The nmr spectrum, i n addition to the usual singlet absorptions of methyl acetate and methoxyl protons, indicated two separate one-proton multiplets at x4.09 and x5.35. Since both of the multiplets were broad, the geminal protons were assigned a x i a l configurations. Hence, both hydroxyl groups of the major product of the sodium borohydride reaction are equatorial. The considerations which were used to draw t h i s conclusion were discussed extensively i n the assignments of configuration to the products of the Birch reduction reaction. 2. Sodium Borohydride Reduction with Hydrolysis I f the sodium borohydride reaction mixture i s refluxed, not only i s the 12-ketone reduced, but the borohydride i s s u f f i c i e n t l y basic to hydrolyze the C-8-acetoxy group to give a d i o l (57) with the cha r a c t e r i s t i c anisole u l t r a v i o l e t spectrum. The major product, mp. 190°C, was sparingly soluble i n a l l solvents except pyridine. The nmr spectrum indicated the 37 the me'hyl absorption at x9.22 and the methoxyl absorption at T6.38 both integrating for the usual three protons. In addition, a broad septet was observed at T6.24, and a broad quartet at x5.00 both integrating for one proton. The former was assigned the C-8S configuration and the l a t t e r the C-12B configuration for reasons discussed above. 3. Lead Tetra-acetate Oxidation of the Diol When the d i o l (57) was subjected to lead tetraacetate oxidation i n dry pyridine overnight at room temperature the major product was the 83-hydroxy-12-ketone (50), mp 177°C. The u l t r a v i o l e t spectrum was super-imposable with that of the 8B-acetoxy-12-ketone (49) (X 222, 253, 322, 238, 279 my). The infrared spectrum of this compound showed a hydroxyl absorption as well as a carbonyl absorption. The minor product of t h i s reaction was the diketone (58), mp 170-172°C. The u l t r a v i o l e t spectrum (X 224, 253, 320, X . 233, 279 my) was v i r t u a l l y super-r max mm ^ r imposable with that of the monoketo compound. The infrared spectrum indicated two keto groups (1708, 1672 cm * ) . The nmr spectrum indicated the usual singlets for C-methyl and methoxyl groups (x8.90 and x6.24) while a quartet due to the C - l l hydrogen was observed at x7.21, while that of the C - l l hydrogen was p a r t i a l l y obscured by other resonances. The coupling constant between the C - l l geminal hydrogens was found to be 16 cps. 38 D. PHOSPHORUS PENTOXIDE DEHYDRATION REACTION . The action of phosphorus pentoxide i n refluxing benzene on the o i l produced by sodium borohydride reduction at room temperature gave the desired styrene compound (59). The expected product had an u l t r a v i o l e t spectrum which was ch a r a c t e r i s t i c of the m-methoxystyrene chromophore (A 221, 262.5, 270, 302, 312; A . 247, 284 my). The infrared v max ' nun ' spectrum showed only one saturated carbonyl attributed to the acetoxy group (1720 cm * ) , while the C - l l , C-12 double bond absorbed at 1625 cm The nmr spectrum i n addition to the usual C-methyl, acetate, and methoxyl singlets showed a multiplet at x8.15 which was assigned to the C-lOb hydrogen atom. The usual broad septet for the C-8 hydrogen absorption was present at x5.33.. In addition to the usual aromatic absorptions, two downfield one-proton quartets had appeared at x4.11 and x3.67. These l a t t e r signals were assigned to the C-12 and C - l l protons respectively. E. OSMIUM TETROXIDE HYDROXYLATION 1. Oxidation To pursue the o r i g i n a l intention of entry into the C-nor-D-homo series, i t was f i r s t necessary to find an e f f i c i e n t sequence to the "key" 39 compound (60) i n th i s conversion. To synthesize the essential "C-seco" or ring-opened compound, ozonization was abandoned i n favour of the much higher y i e l d i n g combination of osmium tetroxide hydroxylation followed 89 90 by periodate cleavage ' . These reactions allow the interconversion of the olef i n i c . compound to the desired seco dialdehyde (60) . The hydroxylation reaction was carried out i n ether solution at room 89 temperature whereupon a mixture of diols was obtained i n good y i e l d . The best yields of d i o l were obtained when a minimum amount of ether and a minimum amount of time for work-up was employed. The d i o l eliminated e a s i l y i n presence of moisture, giving a pa i r of red spots on TLC i n the same r a t i o as the d i o l isomers. Although there are two isomers of the d i o l (61), one i s predominant. This l a t t e r compound was isolated and c r y s t a l l i z e d , mp 225-226°C. The features of i t s infrared spectrum included a broad absorption of the hydroxyl groups (3950 cm ^) as well as the strong acetyl absorption i n the carbonyl region (1704 cm The u l t r a v i o l e t absorption was t y p i c a l l y that of an anisole chromophore (X 276, 282 my; X . 244.5, 280 my). r max min ' J The nmr spectrum, i n addition to the usual singlets at r9.05, T8.02, and x6.24 due to C-methyl, acetyl and methoxyl protons respectively, showed a pai r of doublets at x8.24 and x7.22 which disappeared on addition of D_0. 40 On this basis these l a t t e r signals were assigned to the hydroxylic protons. A multiplet, integrating for one proton, appeared at x5.94 while a quartet at x5.60 was also evident. Both of these absorptions s i m p l i f i e d upon addition of D^ O, the former collapsing to a t r i p l e t while the l a t t e r was now seen as a doublet. From deshielding considerations as well as a comparison of the degree of s p l i t t i n g i t was decided unequivocally that the absorption at T5.60 was due to the C-12 proton which was geminal to the hydroxyl while the multiplet at higher f i e l d was due to the analogous C - l l proton. The multiplet for the proton geminal to the acetate group was observed at x5.3. The coupling constant J ^ Q 6 n w a s e c l u a l t 0 ^ j i 12' both being 4.5 cps. Assuming that the C-lOb proton i s a x i a l , this a x i a l -equatorial interaction requires the C - l l proton to be a, hence a 3-configuration for the C - l l hydroxyl. Since an attack by osmium tetroxide on a double bond i s known to produce a cis v i c i n a l d i o l , the C-12 hydroxyl must also be 3 oriented. This i s confirmed from the result that the coupling constant ^ l s 4.5 cps. The best data for the stereo-chemistry of the d i o l was obtained from the d i o l i t s e l f . In an analogous hydrochrysene series, Johnson demonstrated that the compound (63, figure 5) gave the d i o l acetate (64, figure 5). The chemical proof of B-cis stereo-chemistry of the hydroxyl groups was established by f i r s t producing the 36, 116-diol (65, figure 5). This compound was converted to 33,113-dihydroxy-androstane-17-one (66, figure 5), a known natural product and th i s evidence provided unequivocal proof for i t s structure and configura-7 2 t i o n 41 2. Acetylation The above compound v/as acetylated to give a very stable t r i a c e t a t e (62) mp 19'1--195.5°C. The u l t r a v i o l e t spectrum was s i m i l a r to that of the anisole series described above. The nmr spectrum indicated that the usual singlets of th^ ,- C-methyl, C-8 acetoxyl and methoxyl protons with respect t o the trans-anti-trans acetate (42b) were shift e d s l i g h t l y downfield and resonated at T8.95, T8.00, and T6.22 respectively. Two new acetoxyl methyl resonances appeared, one at T8.11, the other at T7.87. By studying the deshielding effects deduced from the s t r u c t u r a l model, i t was a simple matter to assign these signals to the C - l l and C-12 positions respectively. The proton geminal to the C-8 acetate group was shi f t e d s l i g h t l y u p f i e l d t o T5.33 i n t h i s compound while a multiplet at T4.33 which integrated for two protons could be assigned to the protons geminal to the C - l l and C-12 acetate groups. ! I t was toped that this compound would provide a further opportunity to study the stereochemistry of the oxygen functions but due to the overlap of protons, t h i s hope was not realized. F. CLEAVAGE OF THE DIOL The d i o l mixture obtained above was reacted with periodic acid i n 90 methanol to y i e l d a single product, mp 135-137°C which on the basis of the following data was shown to be the desired dialdehyde acetate (60). The u l t r a v i o l e t spectrum with maxima at 225, 255.5 and 321 my, and minima at 242.5 and 281 my supported the presence of the aromatic aldehyde. The infrared spectrum, besides in d i c a t i n g the saturated carbonyl of the C-8 acetate (1713 cm showed two new carbonyl absorptions due to the 42 _ i presence of the aldehyde groups (1633 cm " ) . The nmr spectrum indicated the usual si n g l e t s due to C-lOa methyl, C-8 acetate and C-2 methoxyl protons at T8.87, T8.01, and x6.23 respectively. The C-lOb proton showed up as a quartet at T7.63, while the benzylic C-4b proton multiplet appeared at T5.5. The C-8 proton geminal to the acetate appeared as the usual multiplet at x5.3 while the aromatic protons absorbed i n t h e i r normal region. Most importantly two aldehydic protons which appeared as a doublet at x0.50 and a singlet at x-0.27 could be assigned to the a l i p h a t i c and aromatic aldehyde functions. Irradiation of the xO.50 region caused the collapse of the signal at x7.63 to a doublet with 92 J"lOb = 12 cps, thereby confirming the previous assignment . Irradia-t i o n of the x5.5 region collapsed the signal at x7.63 to a doublet ( J = 4.5 cps). The nmr spectrum confirms the trans stereochemistry of the C-lOb and C-4b positions since the coupling constant, J^Q^ ^ = 12 cps, i s only consistent with d i a x i a l coupling. G. ALDOL CONDENSATION Entry into the C-nor-D-homo steroid series was f i n a l l y achieved by inter n a l aldol condensation of the above ring-opened dialdehyde (60). This conversion was accomplished by reaction of the dialdehyde with sodium hydroxide i n refluxing methanol solution. The re s u l t i n g aldol product (67), mp 192°C, had the ch a r a c t e r i s t i c anisole u l t r a v i o l e t spectrum (X 284 and 289 mp; X . 257 my) while the infrared spectrum showed max min *J r absorptions due to hydroxyl (3380 cm *") and saturated aldehyde carbonyl absorptions (1713, 1698 cm * ) . 43 R = R = H 67 R = R = Ac 68 The nmr spectrum showed the usual singlets at T8.91 and x6.27 attributed to the C-lOa methyl and methoxyl protons. The former signal was displaced downfield while the l a t t e r was unaffected. The C-4b proton resonance appeared at T6.6 as a well resolved quartet. Evidence for ring closure was available from the nmr spectrum of the compound. F i r s t of a l l the occurrence of a closely spaced doublet at low f i e l d ( ^4.6 J = 1.5 cps) could be attributed to the C - l l proton. The same coupling occurs i n the single aldehydic proton absorbing at T0.30. I t i s to be noted that t h i s proton i s on a benzylic carbon atom, to which i s attached a hydroxyl function and furthermore, the aldehydic function on the adjacent carbon i s i n close proximity to i t . It i s therefore not surprising that i t occurs at low f i e l d . On the other hand, i t should normally appear as a singlet and therefore some coupling, probably with the aldehydic proton i s occurring (J .. .., =1.5 cps). The appearance of th i s C - l l proton and the absence of the benzylic proton i s ample evidence for ri n g closure. For some reason the C-8 proton appears u p f i e l d and i s p a r t i a l l y obscured by the methoxyl s i n g l e t . The aromatic protons occurred i n the t y p i c a l array, the only deviation being the superposition of the C-l doublet spike onto the C-4 doublet spike. 44 H. ACfTYLATION OF THE DIOL ALDEHYDE The diacetate (68) of the above C-nor-D-homo compound (67) was c r y s t a l l i n e mp 158.5-159.5°C. Its molecular formula, C24H^O^, was established by mass spectrometry (found: C, 69.81; H, 7.40; 0, 22.11, calculated: C, 69.54; H, 7.30; 0, 23.16). Again the t y p i c a l anisole u l t r a v i o l e t spectrum was evident (X 222, 286, and 291 my; X . 252 my) r -max ' min J while the infrared spectrum indicated the disappearance of the hydroxyl absorption and the appearance of two new carbonyl absorptions (1720, 1703 cm . The nmr spectrum of t h i s diacetate aldehyde showed singlets at: x9.02 (C-lOa methyl); T8.02 (C-8 acetate); 7.84 ( C - l l acetate), and 6.35 (OCH^) . A quartet, which was assigned to the single C-4b benzylic proton appeared at x6.58. A x i a l - a x i a l as well as axial-equatorial \ couplings of 12 cps and 7 cps respectively, are observed between t h i s • proton and the pair of C-5 protons, giving r i s e to the above mentioned quartet. This confirms that the C-4b proton i s 3 oriented and thereby a x i a l . The C-8 proton geminal to the acetate showed the usual multiplet at x5.30 while the C - l l proton geminal to the acetate group due to i t s deshielding by the aromatic ri n g appears as. a singlet amongst the aromatic protons at x2.26. The aromatic protons appear at lower f i e l d than usual. A quartet registers at x2.32, and a p a i r of doublets at x2.51 and x2.00. This i s due to deshielding by the C - l l acetate carbonyl. The resonance of the aldehyde proton i s seen as a singlet at xO.10. I. DEFORMYLATION The desired C-nor-D-homo steroid series do not possess a C-lOb aldehyde group. For this reason, e f f o r t s were made to deformylate the 45 C-nor-D-homo aldol product (67) synthesized i n the above reaction. As mentioned i n the beginning of the discussion, i t was essential to develop a sequence i n which i t would be possible to reta i n the carbonyl i n ring C of the C-nor-D-homo skeleton. This l a t t e r series would permit subsequent removal of thi„ function leads to the veratramine series i n which t h i s function i s lacking. Keeping t h i s consideration i n mind, several possible approaches were studied, two of which were developed. 92 One method developed i n these laboratories u t i l i z e d an oxidation of the C - l l hydroxyl (CrO^ i n acetone, Jones reagent) to a diketo aldehyde 9 3 52 (69) and subsequent deformylation ' of the l a t t e r with 10% KOH solution i n dioxane and water. The resultant product (70) was obtained i n low y i e l d , 9 4 hence an elimination reaction involving loss of both the C-lOb aldehyde and C - l l acetate to give the o l e f i n (71) was considered. I 46 Upon heating the C-nor-D-homo diacetate aldehyde (68) for eight days i n a sodium acetate-acetic acid solution, an 80% y i e l d of the o l e f i n (71), mp 140-141°C, was obtained. The u l t r a v i o l e t spectrum (A 227, 239, 263, •-'in 3.x 293, and 305 my; A m i n 248, 289, and 301 my)- was s i m i l a r though not i d e n t i c a l to the D-homo styrene compound (58) obtained e a r l i e r i n the sequence. The infrared spectrum indicated the disappearance of one acetate and the aldehyde carbonyl leaving only the C-9 acetate carbonyl absorption (1731 cm * ) . The nmr spectrum showed a C-methyl singlet displaced downfield when compared with the spectrum of the trans-anti-trans acetate (42b) due to deshielding by the newly introduced double bond. Further evidence for the presence of a double bond was the presence of a very narrow singlet at x3.80. The methoxyl singlet was only s l i g h t l y displaced downfield from x6.35 i n the st a r t i n g material to x6.27 while the signal for the remaining acetate function at C-8 was unaffected ( x8.02). The C-4b hydrogen appeared at x6.71 as a quartet. The C-5 a and 3 hydrogens were evident at x9.1 and x7.61 respectively, as multiplets. A possible explanation for the deshielding of the C-58 methylenic hydrogen was 88 95 95 provided i n two separate studies ' . Nagata , studying the model t r i -c y c l i c hydrophenanthrenes, observed a strong deshielding of the C-4 aromatic protons which varied d i r e c t l y with the amount of s t e r i c compression. I f the compression of the C-4 proton electron cloud by that of the C-5 proton has a deshielding e f f e c t , then the C-5 proton i n question should s i m i l a r l y 88 95 be deshielded. In a l l the previously studied compounds ' , no C-5 proton resonance had been observed. In the C-nor-D-homo o l e f i n case (71), the compressing C-5 proton i s observed at T7.61 free of the methylenic envelope. It was proposed that the downfield s h i f t was due only to the presence of an 88 extended ring current. Studies by A. By of the D-homo-11,12-olefin (59) indicated that electronic contributions of the conjugated double bond were o C>J 3.39 c_ c_ — OJ OJ > II II ro oo ro x3 o •o in coP CTl | 5.32 T CO — 6.26 H O c_ c_ c_ c_ Ol Ol Ol Ol o "CO O tb O) CT) 4^  Ol « "Co O" Q 11 H li ll OJ OJ GL OJ ro c_ c_ c_ c_ 9l ' cn cn oi oi a a p Q oi cn *4> "In o to cr to " II _ » ^- r\5 w oi •8.00 •8.88 48 not s i g n i f i c a n t , hence any displacements of the C-4 proton would be due to a charge i n van der Waals compression. To dare the established range for A l p h a s been 0.39-0.61, with the value of A T , . = 0.39 for the case when no interaction i s present. 1 y 4 From figure 15„. the Ax1 a for the C-nor-D-homo-olefin (71) was found to be A T . - 0.38 confirming that van der Waals compression was not responsible for the deshielding. The shielding of the C-5 proton must be due to i t s position i n the extended aromatic f i e l d . The fact that i t i s the C-5 proton that occurs at T9.1 was confirmed i n the decoupling studies performed to establish the stereochemistry of the C-4b proton (figure 16). Irr a d i a t i o n at T6.71 caused a collapse of the nine l i n e multiplet at T7.61 to a pai r of t r i p l e t s (J,. = 13 cps, ^ = ^ =3 cps). I r r a d i a t i o n at T7.61 caused a collapse of the quartet at T6.71 to a doublet (J = 12 cps). In each of the above experiments changes were observed at T9>1> thus establishing conclusively the i d e n t i t y of the proton resonating at T9.1. A S for the stereochemistry at C-4b the second experiment shows that a trans-trans coupling e x i s t s . This could only be possible i f the C-4b proton was g oriented. This o l e f i n would then be subjected to c a t a l y t i c hydrogenation or some other reduction method, to y i e l d the desired trans-anti-trans 94 dihydro compound. In Johnson's series the wrong isomer was obtained when these reactions v/ere performed. This result was r a t i o n l i z e d by concluding that t h i s was due to the s t e r i c hindrance C-7 and C-9 a x i a l protons i n ring A since the reactions performed by Johnson's collaborators were on the A / B c i s compound. DECOUPLING at 6.71 DECOUPLING at 7.61 • • • • . i * i i i i i 7 FIG. 16 r 50 J . CATALYTIC HYDROGENATION Waen c a t a l y t i c hydrogenation was performed on the o l e f i n under study, i v . gave i n good y i e l d , a single sharp melting substance (mp 98.5-100°C) whose data allowed the assignment of structure (72a). The u l t r a v i o l e t spectrum once again assumed the cha r a c t e r i s t i c anisole type absorption (X 207, 219, 282, and 288 my; X . 214, 245, and 286 mu). r max min The nmr spectrum recorded the usual singlets for the C-methyl and methoxyl protons. A quintet which appeared at x7.00 was attributed to the C-4b axi a l proton s p l i t into a t r i p l e t (J = 6.5 cps) and then into a doublet (J = 12.5 cps). The models of the compounds show that the conformation of the o l e f i n i s not greatly changed by removal of the double bond. It may be concluded that the coupling constant between C-4b and C-10b protons i s 6.5 cps, hence the C-lOb proton must be B . The coupling cons-tant between trans-diaxial protons i s normally between 8 to 14 cps. Si m i l a r l y , an ABX system was observed for the C-lOb, C - l l a and 6 protons OCH2 R=H 72a R=OH 72b i n which the resonance for C-lOb proton also appeared as a quintet. One li n e of t h i s quintet was obscured by the C-8-acetate resonance. Nonethe-less, this quintet i s consistent with J,„, =12.5 cps, J,„. •,,„ = n 10b,11a r 10b, 113 6.5 cps, complementing the above conclusion about the C-lOb stereochemistry. 51 - K. BIRCH REDUCTION -Birch reduction of the o l e f i n was undertaken, since this reaction tends to produce i n most cases the thermodynamically most stable isomer. On carrying out this reaction on t h i s compound, a substance i d e n t i c a l with the product of c a t a l y t i c hydrogenation (72) was obtained. None of the other isomer was detectable. • L. HYDROBORATION Another alternative appraoch to the desired compound u t i l i z e d the 96 hydroboration of the o l e f i n followed by a reductive or oxidative work-up. Hydroboration of the o l e f i n i n diglyme, followed by addition of propionic acid under r e f l u x , gave a complex mixture. This mixture was s i m p l i f i e d somewhat by hydrolysis of the acetate"" i n aqueous methanol potassium carbonate followed by reacetyla'tion. Column chromatography followed by preparative T.L.C. gave a 14% y i e l d of two acetates with an R,- i d e n t i c a l to that of the product of the preceding two reactions. The presence of these two compounds was also noted i n the nmr spectrum where two signals for the methoxyl and C-lOa angular methyl groups were noted. These signals were" in" the r a t i o 5:1 in d i c a t i n g a predominance .of one isomer (72a). M. BIRCH REDUCTION AND ISOMERIZATION The previous discussion has considered the synthesis of C-nor-D-homo compound i n which ri n g D i s aromatic. I t was,now:necessary to convert t h i s r i n g system into one i n i t i a l l y possessing a conjugated carbonyl function (73) as shown on page 52 and subsequently to introduce a methyl group into the a-position of the carbonyl system as required .52 i n (74). In a separate investigation by J. Cable ' of our laboratory, the l a t t e r substance (73) could be prepared from hecogenin (75) by the procedure of J o h n s ^ ' ^ and used for the t o t a l synthesis of verarine (76). This compound (74), possessed the required trans-anti-trans "backbone" as well as a methyl group i n the a position of the a-8 unsaturated ketone. The most recent compound (73) synthesized i n our sequence lacked the methyl substituent. In order to show that the stereochemistry of the above degradation product was indeed i d e n t i c a l with that of the synthetic material, an a-methylation of the synthetic material was necessary. To conserve the small amounts of C-nor-D-homo compound (67) available, the conditions of the Birch reduction and 53 methylation were developed on model D-homo-a,8-unsaturated ketones (77,78) These l a t t e r substances were preared from trans-anti-trans and trans-a n t i - c i s alcohols (42a, 44) respectively, produced from the t e t r a c y c l i c ketone (36) , by Birch reduction (Section "A"). 1. Birch Reduction of the Anisole Ring (a) The trans-anti-trans compound The trans-anti-trans alcohol (42a) i n tetrahydrofuran was subjected to reduction using lithium metal in dry ammonia for 13 minutes. After destroying the excess lithium with ethanol the reaction mixture was worked up and r e c r y s t a l l i z e d to give a product (79) melting at 124.5-127°C OCH: 7 9 The compound, as expected, was transparent i n the u l t r a v i o l e t region above 210 my. • The nmr spectrum indicated that the methoxyl proton singlet was s h i f t e d u p f i e l d to x6.5. The aromatic complex had disappeared in favour of an unresolved multiplet at T5.40 which was attributed to 54 the single o l e f i n i c hydrogen at C-3. The v i n y l i c hydrogen were not disce.rnable. (b) The trans-anti-cis compound The trans-anti-cis compound (43a) was subjected to s i m i l a r reaction conditions to give a good y i e l d of the analogous reaction product (80) HO OCH: H 80 97 mp 129-130°C. Nagata quotes a melting point of 133-135°C for t h i s compound. Some of the spectral characteristics (UV and nmr) of this compound were almost i d e n t i c a l with those for the trans-anti-trans product while the infrared spectrum diff e r e d only i n the fingerprint region. 2. Enol Ether Hydrolysis and Isomerization (a) The trans-anti-trans compound The enol ether (79) was dissolved i n an aqueous methanolic s u l f u r i c acid solution and was refluxed for one hour. Upon workup and column chromatography a good y i e l d of an a, 3 unsaturated ketone (77) mp 182-55 185.5°C, was obtained. The u l t r a v i o l e t spectrum showed maxima at 239.5 my and 308 my with a minimum at 284.5 my. The infrared spectrum indicated the cha r a c t e r i s t i c "enone" absorption (1650 and 1670 cm *) as well as the hydroxyl absorption (3415 cm * ) . The nmr spectrum showed a broad singlet at x4.22 due to the C-1 o l e f i n i c proton, as well as the usual resonances mentioned previously for the angular methyl protons, etc. (b) The trans-anti-cis methyl ether .cleavage and isomerization Under the same hydrolytic conditions the trans-anti-cis compound yielded the compound (78), mp 199-202°C. The u l t r a v i o l e t spectrum was 78 superimposable with that of the previous isomer. The infrared spectrum showed minor variations i n the f i g e r p r i n t region. The broad o l e f i n i c singlet i n the nmr spectrum was displaced s l i g h t l y downfield to x4.16. The C-lOa methyl resonance showed a s i g n i f i c a n t downfield s h i f t to x8.97 as compared with x9.23 for the preceding isomer. The C-8 proton geminal to the hydroxyl function was shift e d u p f i e l d to x6.42 as 88 compared with x5.33 f o r the other isomers 3. Birch Reduction, Hydrolysis and Isomerization of the C-nor-D- homo Trans-Acetate (72) When th i s compound was subjected to the above.described reactions, 56 a pioduct (73) mp 178-180°C, was i s o l a t e d i n good y i e l d . The u l t r a -v i o l e t spectrum showed a maximum at 242 mu completely c o n s i s t e n t w i t h the c a l c u l a t e d value of 244 my (Woodward's r u l e s ) f o r the a n t i c i p a t e d chromophore. The i n f r a r e d spectrum showed the c h a r a c t e r i s t i c absorptions f o r the hydroxyl (3475 cm *) as w e l l as conjugated carbonyl f u n c t i o n a l groups (1645, 1605 cm . The broad s i n g l e t due to the o l e f i n i c proton appeared downfield at x4.07. S i m i l a r l y the C-lOa methyl s i n g l e t was s h i f t e d downfield to x8.99 while the C-8 proton septet was s h i f t e d up-f i e l d i n a manner c h a r a c t e r i s t i c o f a bent molecule. This compound w i l l be used as a more r e a l i s t i c model f o r the methylation r e a c t i o n . N . METHYLATION The model compounds preapred i n s e c t i o n "M", 1-3, were now used t o optimize the methylation procedure. 1. Studies on D-homo Compounds 98 (a) Stork had shown that a methyl group could be introduced i n t o simple cyclohexanones by the r e a c t i o n of a magnesium bromide s a l t o f a S c h i f f ' s base with methyl i o d i d e . For the simple system the y i e l d i n t h i s r e a c t i o n exceeded that produced by the enamine a l k y l a t i o n . When t h i s r e a c t i o n was attempted on the t r a n s - a n t i - t r a n s enone(77) no c r y s t a l l i n e compounds were i s o l a t e d . :o 73 57 (b) The enamine a l k y l a t i c n The pyrrolidine enamine of the trans-anti-trans enone was synthe-sized i n good y i e l d and i t s formation quickly established by u l t r a -v i o l e t spectroscopy (^ m a x 276 my). Complete formation of this deriva-t i v e was evident from the l a t t e r spectrum which never showed any evidence of the s t a r t i n g material (X 239 my). On working up the reaction 6 max mixture (after 48 hours of reflux) only low yields of methylated material were obtained with recovery of 35-60% of the s t a r t i n g material (77). The alkylated enone acetate (81), p u r i f i e d by preparative T.L.C., was i d e n t i f i e d by a disappearance of the o l e f i n i c proton singlet and appearance of a new singlet at x8.24 integrating for three protons and attributed to the o l e f i n i c methyl group. O 81 The u l t r a v i o l e t spectrum complemented this result by providing a maximum at 250 my, i n excellent agreement with the calculated value ^max ' Mass spectrometry of the p u r i f i e d material gave a peak at m/e 344 as required by the monomethy1ated products, (c) Enolate trapping and methylation (A) The trans-anti-cis isomer Due to repeated low yields i n the enamine reaction, an alternative procedure was developed. Since the trans-anti-trans isomer was i n 58 low supply i t was decided to use the above mentioned trans-anti-cis isomer (78) as a substitute model for the reaction. On reacting this compound with l i t h i u m i n ammonia under scrupulously dry conditions, then replacing the ammonia with tetrahydrofuran and/or methyl iodide under r e f l u x , 25% of a dihydro methylatea compound (82) was isolated. 82 83 This compound, upon bromination and dehydrobromination yielded a compound (83) with the correct molecular weight c f 344 as established by mass spectrometry. Unfortunately t h i s compound exhibited a maximum at 240 my i n ,the u l t r a v i o l e t spectrum rather than 250 my as mentioned above. Hence t h i s compound, must be the result of enolate migration p r i o r to methylation and the resultant attack of methyl iodide on the other side of the carbonyl group. (B) The trans-anti-trans isomer With the above evidence i n hand, we turned to an investigation of the above reaction i n the less readily available trans-anti-trans series. When the reaction was repeated on th i s isomer, a dihydro compound (84) was isolat e d at 40% y i e l d . This compound had a very weak maximum at 2§6 my i n the u l t r a v i o l e t spectrum. The mass spectrum showed a parent peak of 304 i n accordance with the required structure. The only revealin absorbance i n the nmr spectrum was the presence of a doublet at x9.02. 59 84 85 From the spectral evidence thus far i t was impossible to determine whether the methylation had taken place .in the correct d i r e c t i o n . To determine the position of methylation the above product was brominated, then dehydrobromiated. The compound (85) re s u l t i n g from this treatment showed (maxima) at 250 and 309 my with the minimum at 287 my i n the u l t r a v i o l e t region. The parent peak i n the mass spectrum was decreased by two units to 302. This new data established unequivocally that the methylation proceded i n the proper position. 60 CONCLUSION The enolate trapping-methylation sequence cleared the way for methylation of the trans-anti-trans-C-ncr-D-homo compound (86) necessary for comparison with the relay substance (72) derived from hecogenin (73). This route w i l l be possible after oxidation of the hydroboration product (87) to the C - l l ketone (88a) and epimerization of the C-lOb position to produce the required stereochemistry (88b). The compound (90) required for methylation w i l l be prepared by reduction of the C - l l ketone (88b) to the alcohol (89) under non-epimerizable conditions, and reducing the anisole r i n g using the conditions worked out above. Since John Cable of these laboratories has already synthesized verarine, a naturally occurr-ing Veratrum a l k a l o i d , using the above relay substance, the completion of the sequence described i n this thesis would f i l l the la s t gap i n the t o t a l synthesis of th i s Veratrum a l k a l o i d . 74 90 89 0 . EXPERIMENTAL The melting points were determined on the Kofler block unless otherwise stated and are uncorrected. The u l t r a v i o l e t spectra were recorded i n methanol on a Cary 11 recording spectrophotometer and the infrared spectra were taken on a Perkin-Elmer Model 21 spectrophotometer as potassium bromide p e l l e t s unless otherwise stated. The nmr spectra were measured at 100 Mc/s on a Varian HA100 instrument using deutereo-chloroform as solvent unless otherwise .stated. The centres of gravity of the multiplets were recorded using the Tiers x scale with tetramethyl-silane as the int e r n a l standard. The proton types, m u l t i p l i c i t y , h a l f -height width (W n~) and the coupling constants, J i n cycles per i/£ x,y second (cps) are indicated i n parentheses. The microanalyses were performed by Mr. P. Borda, Microanalytical Laboratory, University of B r i t i s h Columbia. Every molecular weight quoted was determined mass spectrometrically on an AEI MS9 or the Atlas CH-4 mass spectrometer. Birch Reduction of 2-methoxy-8-keto-10a-methyl 5,6,8,9,10,10a,11,12,  octahydrochrysene (36) Sodium metal (3.5 g) was added slowly to a mixture of anhydrous Analine (35 ml) and anhydrous ammonia (210 ml) contained i n a flame dried apparatus. The former l i q u i d was freshly d i s t i l l e d from sodium hydroxide p e l l e t s while the l a t t e r was d i s t i l l e d through a drying tube containing sodium hydroxide p e l l e t s . A solution of t e t r a c y c l i c ketone (•36 ) ,3.5 g)C74,75,76) anhydrous tetrahydrofuran (70 ml) was added to the blue-bronze solvent mixture over a period of 7 minutes. Dry nitrogen was passed through the apparatus during the addition. The 62 mixture was s t i r r e d for a further 14 minutes. Ammonium chloride (8.5 g) was added i n small portions to destroy the excess sodium. The ammonia was allowed to evaporate and the resulting residue was treated with water and extracted with ethyl ether. The organic phase was washed with d i l u t e hydrochloric acid u n t i l the aqueous phase was no longer coloured. The organic phase was then washed with sodium bicarbonate, and f i n a l l y with water u n t i l neutral. After drying over anhydrous magnesium sulphate, the solvent was removed and a yellow s o l i d (3.24 g) was obtained. This s o l i d was p u r i f i e d by chromotography on alumina (175 g - Grade I I I ) . Elution with benzene-ethyl ether (2:1) provided trans-anti-trans-2-methoxy-8-keto-10a-methyl-4b,5,6,6a,7,8,9,10,10a,10b,ll,12-dodecahydro-chrysene (41, 773 mg). Several r e c r y s t a l l i z a t i o n s from ethanol provided a pure product (600 mg), mp 143-145.5°C, u l t r a v i o l e t : X (log e), 277 (3.20), 286 (3.17) mp, infrared: 1710, 1620, 1575, 1500 cm"1, nmr: 8.97 (C-lOa-angular methyl, 3H, s i n g l e t ) , 7.21 (C-12, C-12, 2H, quartet), 6,27 (CH30-, 3H, s i n g l e t ) , 3.43 (C-1, IH, doublet 3 = 2 1/2 cps), 3.33 (C-3, IH, quartet j " 3 4 = 8 1/2 cps), 2.82 (C-4, IH, doublet 4 = 0 cps), found C, 80.77; H, 8.56; 0, 10.93,calculated for c 2 o H26°2' G ' 80.49; H, 8.78; 0, 10.72, NW 298.4; empirical formula, C^H^Gy Further elution with benzene-ethyl ether (1:2) provided trans-anti-trans-2-methoxyl-8e-hydroxy-10a-methyl-4b-5,6,6a,7,8,9,10,10a,10b,ll,12-dodeca-hydrochrysene (42a, 2.193 g) . This s o l i d on r e c r y s t a l l i z a t i o n from ethyl ether or a mixture of benzene and petroleum ether (65-110°C) provided a pure sample of the alcohol (1.9 g) mp 156-158°C, u l t r a v i o l e t : X 277 ( loge 3.20) 286 (3.17) my, infrared: 3405, 1615, 1575, 1500 63 cm , nmr: 9.18 (C-lOa angular methyl, 3H, s i n g l e t ) , 8.22 (C-8 hydroxyl proton removed by ^O, IH, s i n g l e t ) , 7.25 (C-12aH , C-12gK , 2H, doublet), 6.42 (C-8 H , IH, m u l t i p l e t ) , 6.29 (methoxyl, 3H, sing.'et), 3.45 ( C - l , IH, s i n g l e t , ^ 4 = 0 cps), 3.35 (C-3, IH, quartet, 3 = 3 cps), 2.84 (C-4, IH, doublet, J 3 4 = 8 cps), found: C, 80.32; H, 9.55; 0, 10.60, calculated for ^2§2 : C' 7 9 - 9 5 ' H> 9- 3 9i °> 10.65, MW 300.42 empirical formula C20H28°2' M S ( a t l a s ) parent peak 300, prominent peaks 147, 159, 160, 161, 173, 174, 187, 200, 213, 214. The r e l a t i v e quantities of lactone and alcohol were found to vary unreproducibly especially i f excesses of sodium were used. In general longer reaction times (greater than 30 minutes) gave r i s e to almost pure alcohol. This i r r e p r o d u c i b i l i t y was due to traces of H^ O from incomplete drying of the ammonia. Fractional c r y s t a l l i z a t i o n of the o i l y , mother liquors (35 g) gave r i s e to small amounts of other stereoisomers. A trans-anti-cis-2-methoxy-86-hydroxy-10a-methyl-4b,5,6,6a,7,8,9,10,10a,10b,ll,12-dode-cahydrochrysene (44a, 17g) . This compound was i d e n t i c a l with that 96 ' characterized by Nagata . Sodium Borohydride Reduction of trans-anti-trans-2-methoxy-8-keto- 10a-methyl-4b,5,6,6a,7,8,9,10,10a,10b,ll,12-dodecahydrochrysene (41) A solution of saturated ketone (2.66 g) i n methanol (105 ml) was heated with a solution of sodium borohydride (1.37 g) i n methanol and water (26 ml). The mixture was refluxed for 3 hours. The mixture was treated with concentrated hydrochloric acid (26 ml) and refluxed for 64 a further hour. The solution was concentrated i n vacuo, water and ethyl ether were added and the ether layer was separated. The organic layer w.is washed with water and dried over anhydrous magnesium sulphate. On concentration a c r y s t a l l i n e product was obtained, trans-anti-trans-2-methoxy-8 -hydroxy-10a-methyl-4b,5,6,6a,7,8,9,10,10a,10b,ll,12-dodecahydrochrysene (44a, 2.5g) mp 154-156°C, u l t r a v i o l e t : 278 (3 .22) , 286 (3.17) mu, infrared: 3480, 3420, 1245 cm"1,nmr: 9.19 (C-lOa angular methyl, 3H, s i n g l e t ) , 6.28 (C-2 methoxyl, 3H, s i n g l e t ) , 5.98 (C-86, IH, multiplet-narrow), 3.1 (aromatic protons, 5H, m u l t i p l e t ) , found: C, 80.08; H, 8.99; 0, 10.97, calculated for C H 0 : C, 79.94; 20 28 2 H, 9.41; 0, 1065, MW (MS-9) 300.209 empirical formula C o„H„ o0 o. Another compound presented i n the discussion remains uncharacterized, mp 135-138°C. This substance was shown by nmr to be a mixture of two isomers. The C-7 and C-8 o l e f i n mixture :was not characterized since the two compounds were also inseparable. This compound was i d e n t i c a l with (42a), obtained i n the Birch reduction. Acetylation of trans-anti-trans-2-methoxy-86-hydroxy-lOa-methyl-4b,5,  6,6a,7,8,9,10,10a,10b,ll,12-dodecahydrochrysene (42a) The crude alcohol (95 g) was dissolved i n a 1:1 mixture of pyridine (120 ml) and acetic anhydride (120 ml). This mixture stood overnight at room temperature. After 22 hours the acetic anhydride was d i s t i l l e d o f f and the residue was treated with ice water. The mixture was then allowed to stand for 30 minutes after which time i t was extracted with benzene. The organic phase was extracted with d i l u t e hydrochloric acid, sodium bicarbonate and water. After drying the benzene over anhydrous 65 sodium sulphate, the solvent was removed to y i e l d the crude acetate (100 g) (42b).. This product was chromatographed on alumina (500 g - Grade I I - I I I ) . Elution with petroleum ether (65-110tC) -benzene 2:1 provided a semi-pure acetate (42b) (91 g) while elution with chloroform-methanol - 1:1 provided a polar material (8 g). Rechromatography of semi-pure (42b) and r e c r y s t a l l i z a t i o n of the early fractions from petroleum ether (65-110°C) and ethyl ether yielded trans-anti-cis acetate (44b) (2.0 g) as needles mp 142-142.5°C, infrared: 1732, 1250 cm u l t r a v i o l e t : X r ' max 280 (3.27), 286 (3.24) my, 247 (2.26), 284.5 (3.21 my, nmr: 9.75 (C-lOa angular methyl, 3H, s i n g l e t ) , 8.07 (C-86 acetate methyl, 3H, s i n g l e t ) , 6.31 (methoxyl, 3H, s i n g l e t ) , 5.35 (C-86, IH, multiplet-wide), 3.41 (C-1, IH, doublet, 4 = 0), 3.36 (C-3, IH, quartet, 1 - 3 cps), 2.96 (C-4, IH, doublet, J"3 4 = 8 cps), found: C, 77.06; H, 8.55; 0, 14.15, calculated for C H 0 : C, 77.15; H, 8.83; 0, 14.15, MW 342.46 empirical 22 3 0 3 formula C22H30°3' M S C A T L A S) parent peak 342, prominent peaks 147, 159, 160, 173, 174, 187, 200, 203, 225, 283. Later fractions 84 g were r e c r y s t a l l i z e d from ethanol or methyl cyclohexane to provide pure trans-anti-trans-2-methoxy-8B-acetoxy-10a-methyl-4b,5,6,6a,7,8,9,10,10a,10b,11,12-dodecahydrochrysene (42b) mp 101°C, infrared: 1728, 1603, 1575, 1497, 1246 cm"1, u l t r a v i o l e t : X ' ' max 278 (3.18), 287 (3.14) my, nmr: 9.15 (C-lOa angular methyl, 3H, s i n g l e t ) , 8.01 (C-86 acetate, 3H, s i n g l e t ) , 7.25 (C-12a,-C-12B, 2H, quartet, J1 = 3 3/4, J 2 = 8 1/4 cps), 6.31 (methoxyl, 3H, s i n g l e t ) , 5.32 (C-8a, IH, multiplet-broad), 5.47 (C-1, IH, doublet, J 4 : 0 cps), 3.36 (C-3, IH, quartet, 3 = 3 cps), 2.87 (C-4, IH, doublet, J 3 4 = 8 cps), found: 66 C, 77.06; H, 8.55; 0, 14.15, calculated for C 22 H30°3 : C, 77.15; H, 8.83; 0, 14.02, MW = 3.42.46; empirical formula, ^ ^ o ^ ' M S ( a t i a s) parent peak 342, prominent peaks 147, 159, 160,.173, 174, 187, 199, 200, 213, 225, 239, 267, 282. The acetate of trans-anti-trans-2-methoxy-"8a-hydroxy-10a-methyl-4b,5,6,6a,7,8,9,10,10a,10b,ll,12-dodecahydrochrysene (45a) was prepared i n the same manner mp 138-139.5°C, infrared: 1725, 1602, 1574, 1497, 1245 cm"1, u l t r a v i o l e t : A 223 max (3.83), 279 (3.26), 287 (3124), A m i n 247 (2.10), 285 (3.19) my, nmr: 9.18 (C-lOa angular methyl, 3H, s i n g l e t ) , 8.00 (C-8a acetoxy methyl, 3H, s i n g l e t ) , 7.24 (C-12a, C-128, 2H, quartet), 6.29 (methoxyl, 3H, s i n g l e t ) , 4.98 (C-86, IH, narrow m u l t i p l e t ) , 3.46 (C-1, IH, doublet, J = 0 cps), 3.36 (C-3, IH, quartet, 3 = 2.5 cps), 2.86 (C-4, IH, doublet, J3 4 = 8 cps), found: C, 77.42; H, 9.01; 0, 13.57, calculated for C^H^G^: C, 77.15; H, 8,83; 0, 14.02, MW 342.46, empirical formula, C^H^Cy MS (atlas) parent peak 342, prominent peaks 147; 159, 160, 173, 174, 187, 200, 213, 225, 267, 282. A mixture of two isomers was isolat e d mp 134.5-136°C, u l t r a v i o l e t : A 225 (3.76), 278 (3.34), 286 (3.31) my, A . 246 (2.35), 284 (3.27) max - , , v J nun . J my. The elemental analysis was i n good agreement with the empirical formula C 2 2H 3 0C> 3, nmr: 9.02 (C-lOa angular methyl, 3H, s i n g l e t ) , 8.86 (C-lOa angular methyl, 3H, s i n g l e t ) , 8.01 (C-88 acetate methyl, 3H, s i n g l e t ) , 7.25 (C-12a, C-128, 2H, m u l t i p l e t ) , 6.31 (methoxyl, 3H, singlet) 5.30, 5.08 (C-8a, IH, overlappying septets), 3.3-3.5 (C-1, C-3; 2H, m u l t i p l e t ) , 2.8-3.0 (C-4, IH, doublets); the doubling i n the . 6 7 above spectrum conclusively proves the existance of at least twc compounds. A s i m i l a r s i t u a t i o n occured i n the o l e f i n i c mixture. A T.L.C. study showed that the C-8 a x i a l alcohol was e a s i l y eliminated. Charac-t e r i z a t i o n of these mixtures was not pursued. Oxidation of trans-anti-trans-2-metHoxy-8 -acetoxy-10a-methyl-4b,5,  6,6a,7,8,9,10,10a,10b,ll,12-dodecahydrochrysene (42b) A solution of t-butyl chromate was prepared by the addition of chromium tr i o x i d e to t-butyl alcohol i n the manner of Heusler and-Wettstein 1^ except the f i n a l solution was concentrated to 600 ml rather than 100 ml as suggested. Aliquots were used for. the various experiments. The acetate (42b) (6.70 g) was dissolved i n carbon tetrachloride (180 ml) and the t-butyl chromate solution (90 ml) was mixed with acetic anhydride (15 ml) before adding. The mixture was s t i r r e d under reflux for 4 hours and the excess oxident was destroyed by s t i r r i n g with a solution of ox a l i c acid (75 g i n 100 ml water) for 2 hours. Frothing was controlled by emersion i n ice water when necessary. The reaction mixture was partitioned between water and chloroform. The aqueous layer was extracted with chloroform. Incomplete decomposition of the oxidant was heralded by a yellow coloration of the chloroform extracts. I t was found emulsions could be minimized by t h i s type of a workup. The pooled organic phase was washed with water to remove inorganic s a l t s , with sodium bicarbonate to remove residual acetic acid and f i n a l l y with a 1:1 solution of saturated sodium bicarbonate and sodium carbonate, 68 to remove a c i d i c reaction products. The f a i n t l y pink basic Washings were extracted once with chloroform. The combined organic solutions were dried over anhydrous magnesium sulphate. After removal of the drying agent and evaporation of the solvent a crude neutral product (6.25 g) was obtained. The weight of acidic by products was ne g l i g i b l e . The neutral material was chromatographed on Grade III alumina (300 g). Elution with benzene-petroleum ether (7:3) provided 56% recovery of s t a r t i n g material (42b, 3.74 g) and further elution with benzene-ethyl 77 ether (1:1) yielded the desired crude keto acetate (4g) i n 16% y i e l d (1.16 g). After a more careful chromatography and r e c r y s t a l l i z a -t i o n of the middle fractions from benzene-petroleum ether (65-110°C) colourless needles of the desired trans-anti-trans-2-methoxy-88-acetoxy-12-keto-10a,methyl-4b,5,6,6a,7,8,9,10,10a,10b,ll,12-dodecahydrochrysene (48) (0.73 g) was isolated with mp 145.5-147°C, infrared: 1803, 1672, 1600, 1565, 1491 cm"1, u l t r a v i o l e t : X 222 (4.08), 254 (3.68), 322 max (3.14 my, nmr: 9.05 (C-lOa angular methyl, 3H, s i n g l e t ) , 7.99 (C-8 acetoxy methyl, 3H, s i n g l e t ) , 7.70 (C-l 18, IH, quartet, ug = 14 cps), 7.24 ( C - l l a , IH, quartet, J 1 Q b n a = 3.5 cps), 6.22 (methoxyl, 3H, s i n g l e t ) , 5.32 (C-8a, IH, septet, J g 7g = J 8 gg = 5 CPS)> 2 - 9 7 (C - 3 , IH, quartet, 3 = 3 cps), 2.72 (C-4,1H, doublet, J 3 4 = 8.5 cps), 2.53 ( C - l , IH, doublet, J j 4 = 0 cps), found: C, 74.10; H, 7.76; 0, 18.14, calculated for C o oH_ o0. : C, 74.13; H, 7.92; 0, 17.96, MW 356.44, empirical ZZ Zo 4 formula ^22^28^4' ^ (atlas) parent peak 356; prominent peaks 135, 161, 174, 175, 187, 188, 200,. 201, 213, 214, 239, 242, 281, 296, 314, 341. I f a crude sample of trans-anti-trans acetate (42b) was oxidized an 69 isomer of the 12-ketoacetate (49) was isolated i n very small quantity. U l t r a v i o l e t absorption was almost i d e n t i c a l with that of the trans-anti-trans isomer. The infrared d i f f e r e d sMghtly i n fingerprint region, nmr: 8.88 (C-lOa angular methyl, 3H, singlet) the other resonsjices were t y p i c a l of th i s class of compound. This displacement of the C-lOa methyl has become in d i c a t i v e of the trans-anti-cis isomer. The by products of t h i s oxidation reaction were isolated and various modifica-tions of functional groups were i n i t i a t e d to study the stereochemistry and r e a c t i v i t y of said molecules. The trans-anti-trans-12-keto acetate (49) was deacetylated to give trans-anti-trans-2-methoxy-8g-hydroxy-10a-methyl-12-keto-4b,5,6,6a,7,8,9,10,10a,10b-dodecahydrochrysene (50) mp 177°C, infrared: 3460, 1665, 1600, 1490 cm"1 u l t r a v i o l e t :A 222 (4.39), 253 » » > • » m a x (3.99), 322 (3.54) my, 238 (3.76), 279 (2.71) my, nmr: 9.09 (C-lOa angular methyl, 3H, s i n g l e t ) , 8.03 (C-8-OH, IH, singlet removed by D 20), 7.71 ( C - l l g , IH, quartet, J 1 Q b n g - 3.5 cps), 7.26 ( C - l l a , IH, quartet, J 1 0 b , l l a = 1 4 d p S ' J l l a , H 6 = 1 6 C P S ) ' 6- 4° ( C " 8 a ' 1 H ' S G p t e t ' J8,9a" J 7 a 8 " 5 c p S ' J 8 93 = J8 76 = 1 0 c P s ) > 6 - 2 3 (methoxyl, 3H, s i n g l e t ) , 2.99 (C-3, IH, quartet J x 3 = 3 cps), 2.73 (C-4, IH, doublet, J j 4 = 0 cps), 2.55 (C-1, IH, doublet, J = 8 cps), found: C, 76.54; H, 8.55; 0, 14.91, calculated for C^H^O^ C, 76.40; H, 8.34; 0, 15.27, MW 314.41, empirical formula c2oH2'6°3' ^  f a t l a s ^ P a r e n t P e a k 314, prominent peaks 135, 161, 174, 187, 188, 189, 201, 213, 257, 310. Under the conditions of deacetylation, ie 12-keto-acetate (1.4 g) i n methanol (40 ml) and r e f l u x with 10 ml 1.5 N ^ CO^ for 2 hours some cleavage of the methoxyl group occured. Reacetylation i n the usual manner gave a 70 diacetate (56, 10 g) mp 240-243°C; infrared, 1762, 1724, 1672, 1603, 1492 cm"1, u l t r a v i o l e t : A 214 (4.37), 247 (4.02), 300 (3.41), X . ' max v min 233 (3.86), 274 (3.16) my, nmr: 9.07 (C-lOa angular methyl, 3H, s i n g l e t ) , 8.03 (C-88acetoxy, 3H, s i n g l e t ) , 7.77 (aromatic acetate, 3H, s i n g l e t ) , 7.71 (C-116, IH, quartet, J i r i 1 1 Q = 14 cps), 7.25 ( C - l l a , IH, quartet, iua,lip J „ 1 1 n = 16 cps, J • =3.5 cps), 5.35 (C-8a, IH, m u l t i p l e t ) , 2.84 11a,llg r 10a,11a r v f •> > (C-3, IH, quartet, J =2 1/2 cps), 2.62 (C-4, IH, doublet, J_ = 8 1/2 cps), 2.35 (C-1, IH, doublet, J . = 0 cps), found: C, 72.00; 1,4 H, 7.40, 0, 20.60, calculated for Co_H.o0_: C, 71.85; H, 7.34; 0, 20.81, MW 384.45, empirical formula C__H 0 , MS (atlas) parent peak 384, " Zj Ao b prominent peaks 140, 147, 173, 174, 199, 228, 267, 282, 342. This data i s consistent with the structure trans-anti-trans-2-acetoxy-8B-12 diacetoxy-10a-methyl-4b,5,6,6a,7,8,9,10,10a,10b,ll, dodecahydrochrysene (56). One of the novel compounds (2.2 g) (54) isolated from the mother" liquors (23 g) proved to be remarkably stable. The data below i s consistent with the following compound, trans-anti-trans-2-methoxy-86 acetoxy-4b-t-butyl peroxy-lOa, methy!04b,5,6,6a,7,8,9,10,10a,10b,11,12 dodecahydrochrysene (5 4) mp 140°C, infrared: 1715, 16667, 1592, 1495 cm"1, u l t r a v i o l e t : X 206 (4.19), 224 (4.04), 273 (4.17), 285 (4.08), in 3.x 298 (3.94), 216 (3.95), 241 (3.23)my,nmr: 8.74 (C-lOa angular methyl, 3H, s i n g l e t ) , 8.54 (C-4b t - b u t y l , 9H, s i n g l e t ) , 8.02 (C-8 acetoxy, 3H, s i n g l e t ) , 7.10 (C-12 , C-14 , 2H, quartet), 6.21 (methoxyl, 3H, s i n g l e t ) , 5.40 (C-8d, IH, septet), 3.41 (C-1, IH, doublet), 3.29 (C-3, IH, quartet), 2.15 (C-4, IH, doublet) normal couplings value were observed. The mother liquors of the t-butyl oxidation were treated with Girard's "T" reagent, a compound which s p e c i f i c a l l y derivatizes ketones 71 and makes them soluble in water. It was found that the 12-keto-acetate was f i v e times more reactive than the corresponding naphthalenic-5-keto acetate (37). Girard's "T" reagent (60 g) was added to mother liquors (30 g) i n methanol (750 ml) and a mixture of g l a c i a l acetic acid (75 ml) and acetic anhydride (2 ml) reflux was continued for 35 minutes a f t e r which the reaction mixture was extracted with water and ether. The aqueous phase was refluxed for one hour with concentrated sulphuric acid (10 ml) and re-extracted with ether. After drying the ether layer over anhydrous magnesium sulphate and the solvent an o i l (8 g) was obtained enriched as described above i n the two ketones. The process was repeated several times and after each rep e t i t i o n not more than 5% of the o r i g i n a l weight remained unaccounted for. Fractional c r y s t a l l i z a t i o n i n the usual manner yielded two compounds. F i r s t , the compound of in t e r e s t , 12-keto-acetate (49) (13 g) and second, the impurity trans-2-methoxy-5-keto-8g-acetoxy-10a methy1-5,6,6a,7,8,9,10, lOa-octahydrochrysene (37) (4.5 g) mp 156-157.5°C, infrared: 1718, 1662, 1619, 1591 cm"1, u l t r a v i o l e t ; X 219.5 (4.66), 248 (4.43), 315 (3.79), ' max . 348 (3.48), 233 (4.23, 278 (3.02) mu, nmr: 8.81 (C-lOa angular methyl, 3H, s i n g l e t ) , 7.99 (C-86-acetoxy, 3H s i n g l e t ) , 7.44 (C-6a, C-6g, 2H, doublet, J 5 6 = 9 cps), 6.18 (methoxyl, 3H, s i n g l e t ) , 5.30 (C-8a, IH, septet, J y g = J g 9 = 11 cps.; J ? g = J g Q = 5 1/2 cps (equatorial-equatorial)), 2.99 ( C - l , IH, doublet, ^  3 = 2 1/2 cps), 2.82 (C-3, IH, quartet, J 3 4 =9 1/2 cps), 2.62 ( C - l l , IH, doublet, J n u = 8.5 cps), 2.22 (C-12, IH, doublet), 0.96 (C-4, IH, doublet, ^  4 = 0 cps), found: C, 75.10; H, 7.25; 0, 17.82, calculated for C 22 H24°4 : C' 7 4 9 7 > H ' 6' 8 6> 0, 18.16, MW 352.41, empirical formula C 7 ?H .0 MS (atlas) parent peak 352, 72 prominent peaks 152, 153, 165, 171, 211, 249, 277, 292. From the remaining underivatizable material f r a c t i o n a l c r y s t a l l i z a -t i o n yielded two compounds. The f i r s t : trans-2-methoxy-8g-acetoxy-10a-methyl-5,6,6a,7,8,9,10,10a-octahydrochrysene (39, figure 10) mp 169-172.5°C, infrared: 1718, 1626, 1604, 1578 cm"1, u l t r a v i o l e t : A m a x 227 (4.74), 256 (3.55), 266 (3.64), 276 (3.66), 287 (3.44), 307 (2.97), 314 (3.04), 319 (3.18), 328 (3.10), 334 (3.27), 2 5 4 ' ( 3 . 5 2 ) , 259 (3.54) , 271 (3.60), 284 (3.47), 302 (2.91), 309 (2.97), 324 (3.06), 331 (2.10) my, found: C, 77.89, H, 7.69; 0, 14.76, calculated for CoH^O • C, 78.07; H, 7.74; 0, 14.18, MW' 338.43, empirical formula l l lb 3 C22 H26°3 5 ^ ( a t l a s ) P arent peak 338, prominent peaks 149, 165, 171, 178, 179, 185, 197, 207, 221, 263, 278, 323. The second compound obtained from f r a c t i o n a l c r y s t a l l i z a t i o n was trans-2-methoxy-86-acetoxy-10a-methyl-6a,7,8,9,10,10a hexahydrochrysene (38, figure 10) (2.2 g) mp 158.5-160.5°C, u l t r a v i o l e t : A 244 (4.59), 276 (3.58), 288 (3.65), 301 (3.82), 314 (3.90), X^ , 273 (3.56), 281 (3.55) , 293 (3.64), 307 (3.73), 327 (3.38), 342 (3.41)my, found: C, 78.55; H, 7.67; 0, 13.64, calculated for C^H^Cy C, 78.54; H, 7.19; 0, 14.27, MW 336.41 empirical formula C22H24°3' M S ( a t l a s ) P a r e n t peak 336, prominent peaks 115, 128, 158, 159, 165, 171, 172, 173, 178, 179, 221, 235, 246, 261, 276. In order to study lead tetraacetate i n pyridine as a selective oxidizing agent for bifunctional secondary alcohol, one of which i s benzylic, the 5 keto acetate (37 ) was dissolved i n methanol and refluxed with a 1.5 N aqueous solution of potassium carbonate in the usual manner to give trans-2-methoxy-5-keto-83-hydroxy-10a-methyl-6,6a,7,8,9,10,10a-73 heptahydrochrysene ('52 ) (75% y i e l d ) , mp 135.5-137°C, infrared: 3395, 1664, 1649, 1620, 1594, 1505 cm"1, u l t r a v i o l e t : X 221 (4.70), max 248 (4.46), 315 (3.87), 355 (3.60), \^ 233 (4.27, 278 (3.40)mu, nmr: 8.81 (C-lOa angular methyl, 3H, s i n g l e t ) , 7.81 (C-88hydroxyl, IH, s i n g l e t , removed with DO), 7.41 (C-6a, D-68, 2H, doublet, J = J c = 9 cps), 6.35 (C-8a, IH, m u l t i p l e t ) , 6.18 (methoxyl, 3H, s i n g l e t ) , bot,Dp 2.99 ( C - l , IH, doublet), 2.81 (C-3, IH, quartet, J = 2 1/2 cps), 2.61 ( C - l l , IH, doublet, J n u = 8.5 cps), 2.21 (C-12, IH, doublet, 0.96 (C-4, IH, doublet), found: C, 77.17; H, 7.32; 0, 15.31, calculated for C 2 QH 2 20 3: C, 77.39; H, 7.14; 0, 15.47, MW, 310.38 empirical formula ^20^22^3* ^ (atlas) parent peak 310, prominent peaks 140, 152, 165, 211, 225, 235, 249, 251, 277, 290, 308. The above compound (1.4 g) was reduced i n methanol (140 ml) with sodium borohydride (4 g) i n water (15 ml) by refluxing for four hours. The mixture was poured into water and f i l t e r e d r e c r y s t a l l i z a t i o n from ethyl acetate gave an a n a l y t i c a l sample of trans-2-methoxy-5a,88-dihydroxy-10a-methyl-5,6,6a,7,8,9,10,10a-octahydrochrysene (53) mp 207.5-208.5°C, infrared: 3300, 1623, 1600, 1506, 860, 836, 785 cm"1, u l t r a -v i o l e t : X 333.5 (3.36), 327 (3.23), 319 (3.27), 306 (3.01), 285 (3.57), 275 (3.73), 265 (3.70), 255 (3.60), 232 (4.95), X^ 324 (3.20), 299 (2.90), 282 (3.56), 269 (3.66), 258 (3.59), 252 (3.58)mu, nmr: (in Pyridine - D 20), 8.80 (C-10a methyl, 3H, singlet),6.24 (methoxyl, 3H, s i n g l e t ) , 6.2 (C-8a, IH, multiplet) (other resonances obscured by solvent) 4.39 (C-58 , IH, t r i p l e t , J , . = J = 8 cps), found: C, 76.66; 68,78 6a,76 H, 7.86; 0, 15.39, calculated for C^H^O^ C, 76.89; H, 7.74; 0, 15.37, MW 312.39, empirical formula ^20^24^3' ^ (atlas) parent peak 312, 74 prominent peaks 139, 165, 167, 200, 221, 235, 246, 261, 279, 294. The above d i o l (53, 930 mg) was reacted with lead tetra-acetate (1.18 g) i n anhydrous pyridine (15 ml) at room temperature overnight. The mixture was poured into d i l u t e hydrochloric acid and extracted with ethyl ether. After drying and evaporating the ethyl ether the gum (304 mg) was chromotographed on Grade III alumina (30 g). In addition to recovered s t a r t i n g material and a mixture of keto l s , major product was found to be trans-2-methoxy-5,8-diketo-6,6a,7,9,10,10a-hexahydrochrysene (52) mp 193°C, infrared: 1700, 1670, 1620, 1590, 1502 cm"1, u l t r a v i o l e t : X 221 (4.70), 249 (4.46), 316 (3.88), 356 ID3.X (3.60), X m i n 233 (4.27), 279 (3.41)mu, nmr: 8.63 (C-lOa methyl, 3H, s i n g l e t ) , 6.18 (methoxyl, 3H, s i n g l e t ) , 2.99 ( C - l , IH, doublet, J = 2 1/2 cps), 2.82 (C-3, IH, quartet,, J = 9 1/2 cps), 2.62 ( C - l l , 0 , 4 IH, doublet, J n 1 2 = 8 1/2 cps), 2.19 (C-12, IH, doublet), 0.94 (C-4, IH, doublet, J = 0 cps), found: C, 78.17; H, 6.68; 0, 15.50, calculated for C^U^Oy C, 77.90; H, 6.54; 0, 15.57, MW 308.36, empirical formula C2oH20°3' M S ( a t l a s ) parent peak ,308, prominent peaks 175, 209, 211, 223, 225, 237, 239, 251, 265, 293. Further study of the oxidation products of this d i o l (53) was abandoned. Synthesis of trans-anti-trans-2-methoxy-8B-acetoxy-10a-methyl-12- 1 hydroxy-4b,5,6,6a,7,8,9,10,10a,10b,ll,12-dodecahydrochrysene (55 ) The 12 keto acetate (49) (3.2 g) was dissolved i n methanol (400 ml) and a solution of sodium borohydride (1.0 g) i n methanol (400 ml) and •water (20 ml) was added. The mixture was s t i r r e d at room temperature 75 fo r 3.5 hours. Acetic acid (15 ml) was added and the solution was s t i r r e d for a further 1/2 hour. The reaction mixture was partitioned between water and ethyl ether then washed with sodium bicarbonate solution and water. After drying the organic layer over magnesium sulphate (anhydrous) and removal of the l i q u i d , a gum (3.2 g) was iso l a t e d . On T.L.C., two spots of r a t i o 2:iwere observed. The slower major product was c r y s t a l l i z e d from ethanol or benzene - high b o i l i n g petroeum ether gave an an a l y t i c a l sample of trans-anti-trans-20methoxy-83-acetoxy-10a-methyl-128-hydroxy-4b,5,6,6a,7,8,9,10,10a,10b, 11,12-dodecahydrochrysene (55) mp 147.5-149°C, infrared: 3503, 1708, 1609, 1504 cm"1, u l t r a v i o l e t : X 226 (3.86), 281 (3.33), 288 (3.31), - > max v • Xmin 2 4 7 ( 2- 7 7)> 2 8 6 (3.27)my, nmr: 9.15 (C-lOa methyl, 3H,. singlet) ,. 8.03 (C-86acetoxyl, 3H, s i n g l e t ) , 7.93 (C-123 hydroxyl, 3H, singlet removed by D^O exchange), 6.29 (C-2 methoxyl, 3K, s i n g l e t ) , 5.3 (C-8a, C-12d-2H, m u l t i p l e t ) , 3.30 (C-3, IH, quartet, ^  3 = 3 cps), 2.96 (C - l , IH, doublet, J = 0 cps), 2.90 (C-4, IH, doublet, J = 9 cps), 1 , 4 , 0 4 found: C, 73.91; H, 8.31; 0, 17.70, calculated for C^H^O^: C, 73.71; H, 8.44; 0, 17.85, MIV 358.46, empirical formula C22 H30 O4' M S ( a t l a s ) parent peak 358, prominent peaks 158, 159, 171, 172, 173, 174, 185, 265, 280, 296, 298, 316, 340, 342, 356. I f the above sodium borohydride reaction mixture was refluxed for as l i t t l e as one hour the major product i s a mixture of C-12 epimeric d i o l s (57) trans-anti-trans-2-methoxy-88,12g-dihydroxy-lOa-methy1-4b,  5,6,6a,7,8,9,10,10a,10b,11,12-dodecahydrochrysene (57) mp 190°C, infrared 5370, 3310,- 1615, 1572, 1495, 887 cm"1, u l t r a v i o l e t : X 224 (3.81), > > . > > > max v 280 (3.24), 288 (3.21), A . 247 (2.05), 286 (3.18>p, nmr: (in Pyridine) 76 9.22 .(C-10a methyl,3H, s i n g l e t ) , 6.38 (C-2 methoxyl, 3H, s i n g l e t ) , 6.24 (C-8a, IH, septet, J = J Q - 5 1/2 cps - axia l : e q u a t o r i a l , Ji o = Q = 1 1 C P S " a x i a l ; a x i a l ) , 5.00 (C12a, IH, quartet, J , , Q , - = / , o o , y l i p , i z i 10 cps, J. =5 cps). The other resonance were obscured by the JL J.0t y 1 Z £1 solvent, found: C, 76.02; H, 8.97; 0, 15.16, calculated for C_.H_.0_: C, 75.91; H, 8.92; 0, 15.17, MW 316.42, empirical formula C^H^O-, MS (atlas) parent peak 316, prominent peaks 298, 185, 175, 174, 173, 159, 158, 150, 149. The diacetate (56) of the above compound was synthesized i n the usual manner, trans-anti-trans-2-methoxy-8B,126-diacetoxy-lOa-methyl, 4b,5,6,6a,7,8,9,10,10a,10b,11,12-dodecahydrochrysene (56) mp 175°C, infrared: 1730, 1720, 1608, 1506, 1378 cm"1, u l t r a v i o l e t : X 226 5 max (3.84), 281 (3.33), 288 (3.30), X^ 246 (2.18), 286 (3.28) m y; nmr: 9.16 (C-10a methyl, 3H, s i n g l e t ) , 8.03 (C-86 acetoxyl, 3H, s i n g l e t ) , 7.92 (C-126 acetoxyl, 3H, s i n g l e t ) , 6.30 (C-2 methoxyl, 3H, s i n g l e t ) , 5.35 (C-8a, IH, septet, = = 5 cps, = J ^ a = 10 cps), 4.09 (C-12a, IH, quartet, J n 1 2 a = 6 C p S ' J l l a , 1 2 a = 9 c p s ) ' 3 , 3 5 ( C " 1 , IH, doublet, 4 = 0 cps), 3.28 (C-3,1H, quartet, J J _ = 3 cps), 2.86 (C-4, IH, doublet, J = 8 1/2 cps), found: C, 71.72; H, 7.91; 0, 3 , 4 20.20, calculated for C^H^O.: C, 71.91; H,.8.05; 0, 19.98, MW 400.50, empirical formula ^ ^ I ' P s ' ^ (atlas) parent peak 400, prominent peaks 158, 159, 171, 172, 173, 174, 184, 185, 265, 280, 325, 340, 358. Selective oxidation of the epimeric d i o l (54 ) The d i o l (3.7 g) was oxidized with lead tetra-acetate (5.5 g-1.0 mole) i n anhydrous p u r i f i e d pyridine (70 ml). After several minutes the solution • . 77 became warm. This solution was worked up after 12 hours and chromato-graphed on Grade III alumina (150 g). Elution with benzene gave trans-anti-tran/;-2-methoxy-8,12-diketo 10a-methyl-4b ,5,6,6a,7,8,9,10,10a, 10b , 11,12-dodecahydrochrysene (58) (0.34 g- 9.3%) mp 170-172°C, infrared: 1706, 1672, 1605, 1497 cm"1, u l t r a v i o l e t : A 224 (4.23), 253 (3.92), IUclX 320 (3.49) my, * m i n 233 (3.71), 2.79 (2.69) my, nmr: 8.90 (C-lOa methyl, 3H, s i n g l e t ) , 7.21 ( C - l l a , IH, quartet, J 1 Q b u = 3 1/2 cps, J - . 1 1 D = 16 cps), 6.24 (methoxyl, 3H, s i n g l e t ) , 2.98 (C-3, IH quartet, 1la,1lp J x _ = 3 cps), 2.72 (C-4, IH, doublet, J _ 4 = 8 cps), 2.55 (C-1, IH, doublet), found: C, 76.67; H, 7.91; 0, 15.51, calculated for C ^ H ^ C y C, 76.89; H, 7.74; 0, 15.37, MW 312,39, empirical formula C20H24°3' MS (atlas) parent peak 312, prominent peaks 149, 161, 174, 187, 255, 270, 297. . . . Elution with benzene-ethyl acetate (9:1) gave 74.3% of the product as a mixture of ketols r e c r y s t a l l i z a t i o n of these fractions from ethanol gave a compound i d e n t i c a l with the above characterized ketol (50) (2.39 g '- 65%) obtained by deacetylation of 13 keto acetate (49). Further elution with ethyl acetate.•methanol (1:1) gave unchanged d i o l (0.47 g - 12.7%). Dehydration of the crude alcohol (54) The crude alcohol (3.2 g) was dissolved i n anhydrous benzene (150 ml) and phosphorus pentoxide (3.2 g) was added. After 2 hours of reflux the reaction mixture was cooled i n ice water then decanted into another flask. A small amount of ice was added, and the yellow-green fluorescent solution was swirled occassionally while most of the residue 78 i n th.? reaction flask was dissolved i n ice water. To the suspension in the reaction flask ethyl ether and saturated sodium chloride s o l u t i o n , were added. Sodium bicarbonate was added in small portions u n t i l the solution became basic. At th i s point i t was as d i f f i c u l t to destroy the tmulsions formed as i t was to completely dissolve the residue. The aqueous layer was extracted several times with ether and pooled with the decanted solution. The pooled organic phase was washed with sodium bicarbonate, water, and dried over magnesium sulphate. On removal of solvent the crude material (2.7 g) was isol a t e d . P u r i f i c a -t i o n by column chromatography on alumina (Grade I I I , 100 g) gave the desired o l e f i n (59) (2.2 g) with benzene-petroleum ether (1:1). R e c r y s t a l l i z a t i o n from ethanol gave pure trans'-anti-trans-2-methoxy-8g-acetoxy-10a-methyl-4b,5,6,'6a,7,8,9,10,10a,10b-decahydrochrysene (59) -mp 105-106.5°C, infrared: 1725, 1628, 1600, 1565, 1485 cm"1, u l t r a v i o l e t : A 221 (4.44), 262.5 (3.84), 270 (3.88), 302 (3.51), 312 (3.40) my, fficiX Xmin 2 4 7 ( 3 ' 8 3 ) > 2 8 4 C 3 - 4 8 ) mV, n m r : 9 - n (c-10a methyl, 3H, s i n g l e t ) , 8.15 (C-lOaa, IH, m u l t i p l e t ) , 8.04 (C-8 acetoxyl, 3H, s i n g l e t ) , 6.32 (C02 methoxyl, 3H, s i n g l e t ) , 5.33 (C-8a, IH, septet, J_ . = J _ _ = 5 1/2 cps, J 7 a > 8 a = J 8 a j 9 a = 11 cps), 4.11 (C-12, IH, quartet, J 1 0 a a > 1 2 = 2 cps), 3.67 ( C - l l , IH, quartet, 1 2 = 10 cps, J 1 0 b a n = 3 CP S) > 3.49 (C-1, IH, doublet, J 1 4 = 0 cps), 3.39 (C-3, IH, quartet, _ -2 1/2 cps, J = 8 cps), 2.98 (C-4, IH, doublet), found: C, 77.48; o, 4 H, 8.23; 0, 14.44, calculated for C^H^O.: C, 77.61; H, 8.29; 0, 14.10, MW 340.44, empirical formula C^H-gO,, MS (atlas) parent peak 340, prominent peaks 158, 159, 160, 161, 171, 172, 173, 184, 185, 197, 263, .265, 280, 325, -338. 79 Synthesis of the d i o l (6l) by osmj.c acid oxidation The o l e f i n (59) characterized above (600 mg), was dissolved i n dry ethyl ether (10 ml) . Osmium tetioxide (500 mg, 12% excess.) was dissolved i n dry ethyl ether (10 ml) and l a t t e r and former solutions were rapidly mixed. The osmium tetroxidt container was rinsed with more ether (10 ml) and added. The solution was allowed to stand at room temperature i n the dark for 57 hours. The dark precipitate which separated was treated with methanol (6 ml) and water (1 ml). Hydrogen sulphide gas was passed into the solution for 5 minutes, the solution was s t i r r e d for a further 5 minutes and the precipitate f i l t e r e d i n a sintered glass funnel. The precipitate was washed with methanol then removed and subjected to the hydrogen sulphide treatment twice more to insure decomposition of the osmate ester. When for some unknown reason the osmium sulphide did not aggragate s u f f i c i e n t l y and was passed through the sintered glass funnel i t was found that only c e n t r i -fugation was able to remove this impurity. When the solvent was removed from the f i l t r a t e solution a crude s o l i d product (0.688 g) was obtained. This substance was refrigerated u n t i l p u r i f i e d by chromatography. Elution of the trans-anti-trans-2-methoxy-8g acet'oxy-11,12-dihydroxy- 10a-methyl-4b,5,6,6a,7,8,9,10,10a,10b,11,12-dodecahydrochrysene (61 ,  590 mg), from Woelm s i l i c a gel was accomplished with 5% methanol i n chloroform. T.L.C. showed two isomers with values 0.17 and 0.13 the l a t t e r being the major constituent. Recrystallization of the polar fractions from chloroform and petroleum ether (65-110°C) produced an an a l y t i c a l sample mp 225-226°C, infrared: " 3450, 1705, 1610, 1585, 1500 cm , u l t r a v i o l e t : X 276 (3.21), 282 (3.19) my, X . 244.5 80 (2.13), 280 (3.16) mp, nmr: 9.05 (C-lOa methyl, 3H, s i n g l e t ) , S.48 ( C - l l or 12 hydroxyl, IH, doublet - removed by D_0 exchange), 8.02 (C-83 acetoxyl, 3H, s i n g l e t ) , 7.22 ( C - l l or 12 hydroxyl, IH, doublet-removed by D_0 exchange), 6.24 (C-2 methoxyl, 3H, s i n g l e t ) , 5.94 ( C - l l , IH, multiplet, to t r i p l e t on D_0 addition), 5.60 (C-12, IH, quartet, to doublet on D_0 addition), 5.3 (C-8, IH, m u l t i p l e t ) , 3.25 (C-3, IH, quartet, J =2 1/2 cps), 2.94 (C-4, IH, doublet, J = C , 1 J , 4 8 1/2 cps), 250 (C-1, IH, doublet), found: C, 70.18; H, 7.99; 0, 21.83, calculated for C^H^O.: C, 70.56; H, 8.08; 0, 21.36, MW 374.46, empirical formula ^22^30^5' ^  (atlas) parent peak 374. Acetylation of the d i o l The above d i o l acetate (61) was acetylated i n the usual manner to give the triacetate trans-anti-trans-2-methoxy-83,11,12-triacetoxy-10a-methyl-4b,5,6,6a,7,8,9,10,10a,10b,11,12-dodecahydrochrysene (62) mp 194-195.5, infrared: 1732, 1612, 1497 cm"1, u l t r a v i o l e t : X 283 max (3.32), 277 (3.33), 225 (3.88), A M I N 280 (3.30), 243 (2.48) ..mu, nmr: 8.95 (C-lOa methyl, 3H, s i n g l e t ) , 8.11 ( C - l l acetoxyl, 3H, s i n g l e t ) , 8.00 (C-86 acetoxyl, 3H, s i n g l e t ) , 7.87 (C-12 acetoxyl, 3H, s i n g l e t ) , 6.22 (C-2 methoxyl, 3H, s i n g l e t ) , 5.33 (C8a, IH, septet), 4.33 ( C - l l , C-12, 2H, m u l t i p l e t ) , 3.19 (C-3, IH, quartet), 3.13 (C-1, IH, doublet), 2.87 (C-4, IH, doublet), found: C, 68.89; H, 7.24; 0, 23.87, calculated for C^H,„0 • C, 68.10; H, 7.47; 0, 24.43, MW 438.53, empirical formula lb 34 7 C26 H34°7' M S (atlas) parent peak 458, prominent peaks 149, 159, 161, 171, 174, 175, 176, 187, 188, 230, 263, 279, 296, 313, 338, 356, 372, 383, 398, 416, 443. 81 Peiodate cleavage of the d i o l (61) The above d i o l mixture (166.7 i.ig) was dissolved i n methanol (77.5 ml) and a solution of periodic iAcid i n water (24 ml, 0.0219 M i n acid) was added to the reaction mixture. A 10% increase of tempera-ture was noted. The reaction^which was followed by u l t r a v i o l e t spectroscopy proceeded rapidly. After two hours i n the dark at room temperature ethylene glycol (0.39 ml) was added and mixed. On stand-ing for one hour the reaction mixture was partitioned between aqueous sodium bicarbonate and benzene washed with water and dried over anhydrous sodium sulphate. After removing the solvent the expected acetoxy dialdehyde (60) 173.4 mg) was obtained. T.L.C. showed one spot. R e c r y s t a l l i z a t i o n from benzene-petroleum ether (65-110°C) produced an a n a l y t i c a l sample bf trans-anti-trans-11,12-seco-2-methoxy-8B- acetoxy-10a-methyl-ll,12-diformyl-4b,5,6,6a,7,8,9,10,10a,10b,11,12- dodecahydrochrysene (60) mp 135-137°C, infrared: 2750, 1730, 1715, 1678, 1602, 1501 cm - 1, u l t r a v i o l e t : X 225 (4.33), 255.5.(3.86), 321 max . (3.50) my, 242.5 (3.75), 281 (2.70) my, nmr: 8.87 (C-lOa methyl, 3H, s i n g l e t ) , 8.01 (C-8 acetoxyl, 3H, s i n g l e t ) , 7.63 (C-lOb, IH, quartet, J^Ob 11 = ^ CPS> ^10b 4b = ^ CP S) * 6>23 (C-2 methoxyl, 3H, s i n g l e t ) , 5.5 (C-4b, IH, m u l t i p l e t ) , 5.3' (C-8 , IH, m u l t i p l e t ) , 2.98 (C-3, IH, quartet, J = 2 1/2 cps), 2.74 ( C - l , IH, doublet), 2.74 (C-4, IH, doublet, J 3 4 = 9 cps), 0.50 ( C - l l , IH, doublet, J 1 Q b n = 6 1/2 cps), -0.27 (C-12, IH, s i n g l e t ) , found: C, 70.96; H, 7.46; 0, 21.84, calculated for C 22 H28°5 : C, 70.94; H, 7.58; 0, 21.44, MIV 327.44, empirical formula '-'22^ 28^ 5" Since chromatography of t h i s compound gave a very poor recovery i t 82 was used d i r e c t l y for the next reaction, both these reactions being carried out on the same day. Aldol condensation of the dialdehyde (60) A solution of crude dialdehyde (60) (480 mg) i n methanol (110 ml) was added to a solution of sodium hydroxide (100 mg i n 1.4 ml water). Reflux was continued for three hours, after which time the reaction mixture was partitioned between chloroform and water several times. After drying over sodium sulphate and removing the solvent, a crude orange reaction product (67) 397 mg), T.L.C. showed an intense orange fluorescent spot when sprayed with antimony t r i c h l o r i d e - a c e t i c acid (1:1) and heated i n the oven. R e c r y s t a l l i z a t i o n from benzene-petroleum ether (65-J10°C) gave an an a l y t i c a l sample of C-nor-2-methoxy-88,11-dihydroxy-10a-methyl-10b-formyl-4b,5,6,6a,7,8,9,10,10a,10b,ll-undecahydrochrysene (67) mp 192°C, infrared: 3380, 2740, 1713, 1697, 1616, 1588, 1482 cm"1, u l t r a v i o l e t : X 284 (3.36), 2.89 (3.32) my, max Xmin 2 5 7 ( 2- 7 4) m ' n m r : 8 , 9 1 (C-10a methyl, 3H, s i n g l e t ) , 6.6 (C-4b, IH, quartet), 6.35 (C-8a, IH, multiplet - obscured), 6.27 (C-2 methoxyl, 3H, s i n g l e t ) , 4.6 ( C - l l , IH, doublet), 3.32 (C-3, IH, quartet), 3.08 (C-4, IH, doublet - overlaps with C - l ) , 3.02 ( C - l , IH, doublet), 0.30 (C-lOb formyl, IH, doublet), found: C, 72.66; H, 7.85; 0, 19.49, calculated for C,rtH0,0.: C, 72.70; H, 7.93; 0, 19.37, MIV 330.41, ZU Zo 4 empirical formula ^20H26^4' ^ (atlas) parent peak 330, prominent peaks 158, 171, 172, 173, 174, 175, 186, 204, 213, 225, 235, 251, 269, 279, 284, 297, 312, 328. 83 Acetylation of the dihydroxy aldehyde (6 7) Upon acetylating the an a l y t i c a l sample of the above C-nor-dihydroxy aldehyde under the usual conditions a 85% y i e l d of C-nor-2-methoxy-8S,ll-diacetoxy-10a-methyl-10b formyl-4b,5,6,6a,7,8,9,10, 10a,10b,11-undecahydrochrysene (68) was obtained, mp 158.5-159.5°C, u l t r a v i o l e t : A 222 (3.91), 286 (3.50), 291 (3.44) my, A . 252 max v v mm (2.57) my, nmf: 9.02 (C-lOa methyl, 3H, s i n g l e t ) , 8.02 (C-86 acetoxyl, 3H, s i n g l e t ) , 7/84 ( C - l l acetoxyl, 3H, s i n g l e t ) , 6.58 (C-4b, IH, quartet, j " 4 b a 5 a = 7 cps, J 4 b c ( ) 5 g = 12 cps), 6.35 (C-2 methoxyl, 3H, s i n g l e t ) , 5 .3o'(C-8a, IH, m u l t i p l e t ) , 2.51 (C-1, IH, doublet), 2.32 (C-3, IH, quartet), 2.26 ( C - l l , IH, s i n g l e t ) , 2.00 (C-4, IH, doublet), 0.10 (C-lOb formyl, IH, s i n g l e t ) , Found: C, 69.81; H, 7.40; 0, 22.79, calculated for C..H_„0,: C, 69.54; H, 7.30; 0, 23.16, MW 414.48 <i4 3 U o i empirical formula ^24^30^6' M S ( a t l a s ) P a r e n t peak - not v i s i b l e , prominent peaks 158, 172, 251, 266, 211, 324, 326, 356. Deacetyl-deformylation of the diacetate aldehyde (68) The diacetate (68) was dissolved i n g l a c i a l acetic acid (15.0 ml) containing sodium acetate (50 g - 4 molar) and acetic anhydride (3 ml) and refluxed for 20 hours. The reaction mixture was poured into water, partitioned between aqueous sodium bicarbonate-benzene, washed with water and dried over sodium sulphate. After removal of the solvent the crude product was chromatographed on 50 g of alumina. Elution with benzene-hexane (1:9) gave the o l e f i n (7 1) (621 mg, 57.6% y i e l d ) . Elution with chloroform gave a polar material (521 mg) which was reacted once more and worked up i n the above manner to give more 84 o l e f i n (71) (293 mg). The overall y i e l d was 84.8%. C r y s t a l l i z a t i o n of this compound from hexane-benzene gave an ana l y t i c a l sample of large plates which was trans-C-nor-2 methoxy-83-acetoxy-10a methyl-4b,5,6, 6a,7,8,9,10,10a-monahydrochrysene (71), mp 140-141°C, infrared: 1731, 1609, 1573, 1480, 1470, 1447 cm"1, u l t r a v i o l e t : X 227 (4/41), ' ' ' max . 239 (4.21), 263 (3.88), 293 (3.54), 305 (3.51) mp, A 248 (3.75), 289 (3.47), 301 (3.42) mp, nmr: 9.11 (C-5a, IH, multiplet - by spin decoupling), 8.89 (C-10a methyl, 3H, s i n g l e t ) , 8.02 (C-86 acetoxyl, 3H, s i n g l e t ) , 7.61 (C-56, IH, multiplet, J c c o = 13 cps, J , _D = 6 1/2 cp DO. , J R 4D , D p J56,6B = J56,6a = 3 c p s ) ' 6 " 7 2 ( C " 4 b ' 1 H ' ^ a r t e t > J 4b,56 = 6 1 / 2 C p S ' J4b 5a = 1 2 c p s ^ ' 6 - 2 7 ( C - 2 methoxyl, 3H, s i n g l e t ) , 3.80 ( C - l l , IH, s i n g l e t ) , 3.40 (C-3, IH, quartet), 3.19 (C-1, IH, doublet), 2.86 (C-4, IH, doublet), found: C, 77.55; H, 7.97; 0, 14.48, calculated for C 2 1H 2 60_: C, 77.27; H, 8.03; 0, 14.71, MW 326.42, empirical formul C21H26°3' M S ( a t l a s ) P a r e n t P e a k 3 2 6> prominent peaks 158, 172, 249, 251, 311, 324. Cata l y t i c hydrogenation of the o l e f i n (71) The o l e f i n (71) (47 mg) was dissolved i n ethanol (10 ml) was hydrogenated over palladium on charcoal (100 mg) at s l i g h t l y over one atmosphere for 24 hours. The reaction mixture was dilute d with ethanol (40 ml) and f i l t e r e d . The f i l t r a t e was evaporated and the residue dissolved i n chloroform and f i l t e r e d again to leave a clear gum. The nmr spectrum showed that no o l e f i n i c proton was present. On c r y s t a l l i z a t i o n from methanol an analytic sample of trans-syn-cis-C-nor-2-methoxy-8B-acetoxy-10a-methyl-4b,5,6,6a,7,8,9,10,10a,10b,11-85 undecahydrochrysene (72a), mp 98.5-100°C, infrared: 1727, 1620, 1586, 1490, 1475 cm"1, u l t r a v i o l e t : A 207 (3.97), 219 (3.88), 282 (3.45), 288 (3.41) mp, A ^ 214 (3.86), 245 (2.11), 286 (3.38) my, nmr: 8.99 (C-10a methyl, 3H, s i n g l e t ) , 8.03 (C-88 acetoxyl, 3H, s i n g l e t ) , 7.89 (C-lObB, IH, quintet, J ^ ^ g = 7 1/2 cyS . J 1 0 b B t l l o - 12 cps), 7.43 (C-116, IH, quartet, J J l a n _ = 15 cps), 7.26 ( C - l l a , IH, quartet), 7.00 (C-4ba, IH, quintet, J 4 b g ; 1 0 b B = J m ^ = 6 cps, = 12 cps), 6.31 (C-2 methoxyl, 3H, s i n g l e t ) , 5.33 (C-8a, IH, multi-p l e t ) , 3.43 (C-3, IH, quartet), 3.29 (C-4, IH, doublet), 3.05 (C-1, IH, doublet), found: C, 76.52; H, 8.81; 0, 14.67, calculated for C21 H28°3 : C' 7 6 ' 7 9 ; H> 8- 5 9> °» 1 4- 61» MW 328.44, empirical formula C21H28°3' ^ C a t l a s ) parent peak 328, prominent peaks 146, 158, 159, 160,;173, 186, 197, 214, 225, 227, 253, 268. Birch reduction of the o l e f i n (71) The o l e f i n (71) (272 mg) was dissolved.in t-butanol (20 ml) and tetrahydrofuran (25 ml) i n a three necked flask. Ammonia (190 ml) was condensed i n and lithium (2 g) was added. After s t i r r i n g under re f l u x for 40 minutes the blue colour disappeared. The ammonia was evaporated i n a stream of nitrogen. The residue was partitioned between benzene-ethyl ether and water. The benzene layer was washed w i t h water and dried over sodium sulphate. On removal of the solvent a p a r t l y c r y s t a l l i n e material (317 mg) was obtained. Chromatography on alumina (35 g, Grade III) after a one and one-half hour re f l u x in methanol (50 ml) and 12 N hydrochloric acid (2.5 ml). Elution with benz ene-ethyl acetate (9:1) gave four fractions (183 mg). The f i r s t 86 (29 .ug) fraction showed two s i m i l a r coloured spots on antimony t r i c h l o r i d e - a c e t i c acid (1:1) sprayed s i l i c a T.LC. plate. The remaining three f i a c t i o n s (154 mg - 66%) appeared to consist of only one of these substances. The f i r s t f r a c tion (29 mg) was not further investigated. Reductive hydroboration of the o l e f i n (71) Diborane generated by the slow addition of sodium boro-hydride (0.6 g) i n diglyme (30 ml) to boron t r i f l u o r i d e etherate (5 ml) i n diglyme (20 ml) was passed i n a stream of nitrogen into a solution of the o l e f i n (71) (225 mg) i n diglyme (30 ml). Generation of the diborane took two hours and the solution of o l e f i n was allowed to stand overnight i n contact with the gas. One drop of water was added followed by propionic acid (7 ml) and the mixture was heated under r e f l u x for f i v e hours, poured into water and extracted with ethyl ether. The ether extract was washed with d i l u t e aqueous a l k a l i c sodium chloride solution and dried over magnesium sulphate. The solvent was removed to give a brown gum (290 mg). This material showed several blue spots on TLC when sprayed with antimony t r i c h l o r i d e . This material (290 mg) was dissolved i n a mixture of methanol (35 ml) water (15 ml) and potassium carbonate (1 g). Reflux was maintained for two hours. The product was partitioned between chloroform and water and dried over sodium sulphate. The residue was reacetylated i n the usual manner. The usual workup gave an o i l (236 mg) which was chromatographed on alumina (50 g, Grade I I I ) . Elution with hexane-benzene (17:3) 87 gave (69 mg) a material with comparable to that of the two birch reduction products of the reaction immediately above. Further elution with herane-benzene (3:1) gave a complex mixture (121 mg) not further investigated. The major product (32 mg, 14%) after two preparative T.LC.*s of the f i r s t fractions was submitted to nmr. The product appeared to consist of two isomers i n a r a t i o of 5:1 i n favour of what appears to be the trans-syn-cis-C-nor-2-methoxy-8B-acetoxy-10a-methyl-4b,5,6,6a,7,8,9,10,10a,10b,ll-undecahydrochrysene (72a) • The r a t i o was estimated from the doubling of the methoxyl acetoxyl and methyl peaks, the C-ring protons appeared to be i d e n t i c a l . Oxidative hydroboration of the o l e f i n (7l) The o l e f i n (130 mg) and the ethyl ether adduct of boron t r i f l u o r i d e (0.5 ml) were dissolved in ethyl ether (10 ml) and s t i r r e d under nitrogen at 0°C. Lithium aluminum hydride (130 mg) in ether (15 ml) was added gradually over f o r t y - f i v e minutes. S t i r r i n g was continued for two hours during which time the temperature was allowed to r i s e to 20°C. The solution was worked up i n the usual manner and 70% ethanol (10 ml) containing sodium hydroxide (0.25 g) was added to the residue. Hydrogen peroxide solution ( 3 ml, 20%) was added dropwise. When effervescence subsided the solution was heated to 70°C. Further effervescence was observed for ten minutes. The solution was cooled, d i l u t e d , and neutralized with acid. This solution was partitioned between water and chloroform. The product (125 mg) was p u r i f i e d by preparative TLC on s i l i c a gel "GF", 0.5 mm thick, developed with ethyl acetate:petroleum ether (2:1). Bands 88 were located by water spray. The main band was removed and extracted to give a 52% y i e l d (68 mg) of trans-anti-trans-C-nor-2-methoxy-83-dihydroxy-10a-methyl-4b,5,6,6a,7,8,<> ,10,10a,10b,ll-undecahydrochrysene (72b) mp 180-181°C, nmr: 8.97 (C-lOa-methyl, 3H, s i n g l e t ) , 8.39 (C-8,11 hydroxyls, 2H, singlets - removed by D20 exchange), 6.86 (C-4b, IH, quintet, = 12 1/2 cps, = J ^ ^ = 6 1/4 cps), 6.3 (C-8a, IH, m u l t i p l e t ) , 6.24 (C-2 methoxyl, 3H, s i n g l e t ) , 4.91 ( C - l l , IH, doublet, J = 10 cps), 3.27 (C-3, IH, quartet, J = ±\J Si y X ± • X y O 2 1/2 cps), 3.07 ( C - l , IH, doublet, J 3 4 = 8 cps), 2.98 (C-4, IH, doublet). Birch Reduction of Anisole Compounds Reduction and hydrolysis of the trans-anti-cis acetate (44b) The' trans-anti-cis acetate (9.4 g) was dissolved i n t -butanol (120 ml) and tetrahydrofuran (150 ml) in a three necked flask which had been flame dried and f i t t e d with a dry ice condenser. Dry ammonia (400 ml) was condensed into the flask. Lithium (6 g) was added and the mixture s t i r r e d for s i x hours. Addition of ethanol destroyed the excess lithium. After removal of the ammonia i n a stream of nitrogen the residue was poured into water and the butanol and tetrahydrofuran were d i s t i l l e d . The mixture was cooled to room temperature and f i l t e r e d . The white s o l i d (8.7 g) was c r y s t a l l i z e d from hexane to give an ana l y t i c a l sample of trans-anti-cis-2-methoxy  8B-hydroxy- 10a-methyl-l,4,4b,5,6,6a,7,8,9,10,10a,10b,ll,12-tetra- decahydrochrysene (80) mp 129-130°C, nmr: 9.14 (C-lOa methyl, 3H, s i n g l e t ) , 8.23 (C-8 hydroxyl, IH, singlet - removed with DO), 6.50 89 (C-2 methoxyl, 3H, s i n g l e t ) , 6.40 ( C - 8 c t , IH, unresolved m u l t i p l e t ) , found: C, 80.21; H, 10.21; 0, 9.53, calculated for c 2 0 H 3 0 O 2 : C' 7 9 A 2 > H, 10.00; 0, 10.58, MW 302.44, empirical formula C20H30°2' MS (atlas) parent peak 302, prominent peaks 140, 147, 159. 160, 161, 173, 175, 176,.177, 187, 213, 215, 283, 298, 300. The crude e n o l (80) (8.7 g) from the preceding reaction was dissolved i n methanol (500 ml) and 6-N hydrochloric acid (50 ml) followed by r e f l u x for twelve hours. After p a r t i t i o n i n g between chloroform-water, drying over sodium sulphate, and evaporating the solvent gave the crude product (8.1 g). Chromatography on alumina (400 g, Grade III) gave a complex mixture (1.4 g) i n the f i r s t fractions were the eluent was benzene-chloroform (9:1). The l a t t e r fractions with the same eluent consisted of a white s o l i d (0.79 g) which on c r y s t a l l i z a t i o n from hexane-acetone gave an a n l y t i c a l sample of trans-anti-cis-2-keto-8 hydroxy-10a-methyl-l,3,4,4b,5,6,6a,7,8,9,10,10a,10b,ll,12-hydrochrysene, mp decomposed >140°C, u l t r a v i o l e t : A m a x 2 0 8 (3.38), 286 (1.59) my, Xmin 2 7 4 (1-56) my, nmr: 9.15 (C-lOa methyl, 3H, s i n g l e t ) , 8.36 (C-86, l.H, singlet - removed by D-0), 7.28 (C-1, 2H, broad s i n g l e t ) , 6.43 (C-8, IH, septet), found: C, 79.38; H, 9.88; 0, 11.86, calculated for C 1 9H 2 g0 2: C, 79.12; H, 9.79; 0, 11.10, MW 288.41, empirical formula C19 H28^2' M S ( a t l a s ) parent peak 288, prominent peaks 145, 146, 147, 158, 159, 160, 161, 162, 172, 173, 179, 186, 1 9 9 , 249, 251, 268, 270, 286. The desired material (4.6 g) was eluted with benzene-chloroform (4:1). R e c r y s t a l l i z a t i o n from hexane-acetone gave an analyti c a l sample of trans-anti-cis-2-keto-8-hydroxy-10a-methyl-3,4,4a,4b,5,6,6a,7,8,9, 10,10a,10b,ll,12-pentadecahydrochrysene (78). This compound was 90 characterized by Nagata , mp 199-202°C, nmr: 8.97 (C-lOa methyl, 3H, singlet), 8.04 (C-8 hydroxyl, IH, singlet, removed with D20) , 6.42 (C-8ct, IH, septet), 4.16 (C-l, IH, singlet), found: C, 78.91; H, 9.52; 0, 11.57, calculated for C^H^Cy C, 79.12; H, 9.79; 0, 11.10, MW 283.41, empirical formula CigH28°2* Reduction and hydrolysis of the trans-anti-trans alcohol (42a) A solution of trans-anti-trans alcohol (1.63 g) in dry t-butanol (25 ml) and dry tetrahydrofuran (30 ml) was added to dry ammonia (80 ml). Lithium (1.1 g) was added and the mixture stirred under reflux for six hours. Addition of ethanol destroyed the excess lithium and the ammonia was evaporated under a stream of nitrogen. The residue was partitioned between benzene and water. Removal of the solvent after drying left a white solid (1.67 g). Crystallization from benzene-hexane provided an analytical sample of trans-anti-trans-2-methoxy-8B-hydroxy-10a-methyl-l,4,4b,5,6,6a,7,8,9,10,10a,10b,ll,12-tetradecahydrochiysene (77) mp 124.5-127°C, infrared: 3238, 1696, 1668, 1228 cm"1, nmr: 9.24 (C-lOa methyl, 3H, singlet), 8.02 (C-8 hydroxyl, IH, removed with D20), 6.54 (C-2 methoxyl, 3H, singlet), 5.44 (C-3, IH, multiplet), found: C, 79.54; H, 9.80; 0, 10.66, calculated for C20 H30°2 : C' 7 9 ' 4 2 ' H> 1 0-°°; °> 10-58, MW 302.44, empirical formula C 2 0H 3 00 2, MS (atlas) parent peak 302, prominent peaks 140, 147, 161, 173, 174, 175, 176, 186, 188, 213, 215, 285, 287, 300. The methyl enol (77) (4.4 g) was dissolved in methanol (100 ml) and 12-N-hydrochloric acid (10 ml). Reflux was continued for three hours after which the reaction mixture was partitioned between 91 ethyl ether and water. Upon removal of solvent, to give a white s o l i d (3.7 g). Several c r y s t a l l i z a t i o n s from hexane-benzene gave an an a l y t i c a l sample of trans-anti-trt.ns-2-keto-83-hydroxyl-10a-methyl-::,3,4,4a,4b,5,6,6a,7,8,9,10,10a, 10b, 11,12-pentadecahydrochrysene (7 75 > mp 182-183°C, infrared: (nujol) 3425, 3350, 1671, 1652, 1623, 1617 cm"1, u l t r a v i o l e t : A 239.5 (4.23), 308 (1.91) my, nmr: 9.24 ' max ^ • 1 K J (C-lOa methyl, 3H, s i n g l e t ) , 7.86 (C-8 hydroxyl, IH, singlet removed by D.O), 6.41 (C-8a, IH, septet), 4.22 (C-1, IH, s i n g l e t ) , found: C, 79.21; H, 10.01; 0, 10.78; calculated for C^H-gCy C, 79.12; H, 9.79; 0, 11.10, MW 288.41, empirical formula Cj-H^O-, MS (atlas) parent peak 288, prominent peaks 110,, 134, 147, 160, 165, 179, 228, 246, 260, 270. Birch reduction of the C-nor-D-homo o l e f i n (71) The o l e f i n (350 mg) was dissolved i n t-butanol (15 ml) and tetrahydrofuran (20 ml). Dry ammonia was condensed into the three-necked flask and lithium (1 g) was added. After refluxing for f i v e hours the blue colour disappeared. The ammonia was evaporated in a stream of nitrogen. The residue was partitioned between benzene and water. The dry solvent was evaporated to give a c r y s t a l l i n e product. The product was dissolved i n methanol (100 ml) and 12-N-hydrochloric acid (5 ml). The mixture was refluxed for three hours before the usual simple workup. Chromatography on alumina (30 g, Grade III) gave a mixture (2.48 mg) when the eluent was benzene-ethyl acetate (9:1). Several c r y s t a l l i z a t i o n s gave an ana l y t i c a l simple of trans-2-keto-83-hydroxy-10a-methyl-3,4,4a,4b,5,6,6a,7,8,9,10,10a, 92 10Li,il-tetradecahydrochrysene (73), mp 178-180°C, infrared: 1727, 1620, 1586.. 1490, 1475 cm"1, u l t r a v i o l e t : X 242 (4.19) mu, nmr: 8.99 . max J (C-lOa methyl, 3H, s i n g l e t ) , 7.78 (C-8 hydroxyl, IH, singlet - removed by D 20), 6.45 (C-8a, IH, septet), 4.07 (C-1, IH, broad s i n g l e t ) , found: C, 78.51; H, 9.58; 0, 11.91, calculated for "cioH_,0_: C, 78.79; H, 9.55; 0, 11.66, MW 214.39, empirical formula C 1 8 H 2 6 ° 2 -Enamine Alky l a t i o n of trans-anti-trans - c t , B-unsaturated ketone (77) The conjugated ketone (260 mg) was dissolved i n a mixture of benzene (11 ml) and pyraolidine (0.5 ml) before refluxing for three hours during which time water was removed by azeotropic d i s t i l l a t i o n . The u l t r a v i o l e t of the residue spectrum showed a strong peak at 276 my and no s i g n i f i c a n t absorption at 239 my. This indicated that the y i e l d of dienamine was quantitative. Dry methanol (6 ml) and dry methyl iodide (1 ml) where added.to the residue and the solution was refluxed for 56 hours. The solvent was removed and replaced with methanol (4 ml), water (1 ml), acetic acid (0.4 ml) and sodium acetate (0.5 g anhydrous). This solution was refluxed for 250 minutes. The reaction mixture was partitioned between water and chloroform. The organic layer was dried over sodium sulphate. The removal of the dry solvent after f i l t r a t i o n l e f t an o i l y residue (350 mg). Column chromatography on alumina (20 g, Grade I I - I I I ) gave fiv e f r a c t i o n s , the f i r s t containing the methylated material. Preparative XIX. gave a semi c r y s t a l l i n e o i l (18 mg) which c r y s t a l l i z e d to give a compound melting over a seven degree range. The u l t r a v i o l e t spectrum had the following absorbances: X 250, 309 my; X . 287 my, MS (atlas) 5 max mm ' ^ 9 3 parent peak 302, prominent peaks 99, 123, 124, 136, 147, 149, 161, 175, 176, 177, 260, 284, MW 302.44, empirical formula C20H30°2' The acetate of this compound was prepared but so f a r ha.^  not been c r y s t a l l i z e d . The u l t r a v i o l e t of this compound as expected i s superimpossable with that of the alcohol, MIV 344.48, MS (atlas) parent peak 344, prominent peaks, 145, 147, 149, 161, 171, 177, 183, 218, 257, 269, 272, 284, 302. 50% of the crude s t a r t i n g material (130 mg) was recovered i n the remaining four fractions. Enolate Trapping and methylation birch reduction of the trans-anti- cis-q,8-unsaturated ketone (78) A solution of the ketone (1.44 g) in.dry tetrahydrofuran (80 ml) was added dropwise to a scrupulously dry ammonia solution (150 ml) of lit h i u m (160 mg). The solution was s t i r r e d for twenty minutes after which time the dry ice condenser was replaced by a dry water condenser. The ammonia was removed i n a stream of dry nitrogen while more tetrahydrofuran (120 ml) was added. The solution was refluxed for twelve minutes to remove the last traces of ammonia. Methyl iodide (20 ml) was added and the solution was refluxed for three hours. The mixture was poured into water and extracted with benzene. The benzene extract was washed with water dried and evapora-ted to y i e l d an o i l (1.63 g). This o i l , when chromatographed on alumina (200 g, Grade I I I ) . The eluent was benzene with increasing amounts of chloroform. The volumes of each f r a c t i o n collected was 200 ml. The f i r s t two fractions (98mg,208ngrespectively) were a complex mixture and were not further investigated. The t h i r d f r action 94 (700 mg) contained one major component. This fraction was subjected to 0.19 M bromine (10 ml) after being dissolved i n acetic acid (5 ml). This mixture was refluxed for one hour with magnesium oxide (3 g) i n dimethyl formamide (30 ml). The crude product was chromatographed on alumina (35 g, Grade I I I ) . Eluting with l i g h t petroleum ether-benzene (4:1), the f i r s t s i x fractions were a complex mixture while the next seven contained 281 mg of a pure compound. Sublimation of t h i s material gave an a n a l y t i c a l sample of trans-anti-cis-2-keto-3- methyl-8g acetoxyl-lOa-methyl-4,4a,4b,5,6,6a,7,8,9,10,10a,10b,11,  12,13-heptadecahydrochrysene (S3), mp 188-189°C, infrared: 1731, 1670, 1482, 1457 cm"1, u l t r a v i o l e t : X 240 (3.98) mp, nmr: 8.77 • ' max (C-lOa methyl, 3H, s i n g l e t ) , 8.23 (C-3 methyl, 3H, quartet, J3 4 = 1.4 cps, 3 = 2.2 cps), 7.89 (C-16, IH, quartet, J = 16 cps, 0 ^ 4 3 . . J. Ct ^ J. p J, . = 315 cps, J 1 Q = 12 cps), 7.56 (C-la, IH, quartet), 5.33 lot ^ 1 o I p , 1 J (C-8, IH, septet), 3.19 (C-4, 1H, broad s i n g l e t ) , found: C, 76.90; H , 9.42; 0, 13.68, calculated for C ^ H ^ C y C, 76.70; H, 9.36; 0, 13.93, MW 344.48, empirical formula C22H32°3' ^ ( a t l a s ) parent peak 344, prominent peaks 145, 147, 149, 159, 161, 174, 185, 200, 214, 260, 269, 274, 284, 316, 342. Enolate synthesis and methylation of the trans-anti-trans - c t , 6 - unsaturated ketone (77) The tetrahydropyran of the ketone was prepared by dissolving the ketone (624 mg) i n freshly d i s t i l l e d tetrahydropyran (10 ml) along with several milligrams of toluene-p-sulfonic acid. After sixteen hours powdered potassium carbonate was added. S t i r r i n g was continued 95 for s i x hours. The mixture was diluted with ether f i l t e r e d and the f i l t r a t e evaporated to leave a gum (1040 mg) [some loss at t h i s p o i n t ] . A solution containing most of the tetrahydropyranyl ether ketone i n dry tetrahydrofuran (25 ml) was added to scrupulously dry solution of ammonia (50 ml) containing lithium (49 mg) a further amount of lithium (20 mg) was added to maintain the blue colour. The solution was allowed to evaporate slowly while more tetrahydrofuran (50 ml) was added. When the ammonia was.completely removed methyl iodide (20 ml), which, had been freshly d i s t i l l e d was added and the solution refluxed for three hours. Most of the solvent was d i s t i l l e d o f f and the rest partitioned between benzene and water. The dried benzene layer was evaporated and replaced with 3% aqueous oxa l i c acid (20 ml) i n ethanol (25 ml). After the usual workup the residue (890 mg) was chromatographed on alumina (85 g, Grade I I I ) . Benzene-chloroform (4:1) gave a ketone fr a c t i o n (393 mg). This fraction was rechromato-graphed on alumina (60 g, Grade I I I ) . The center fractions (278 mg) were c r y s t a l l i n e . R e c r y s t a l l i z a t i o n from acetone-hexane gave an a n a l y t i c a l sample (65 mg) of trans-anti-trans-l-methyl-2-keto-8- hydroxy-lOa-methyl-1,3,4,4a,4b,5,6,6a,7,8,9,10,10a,10b,11,12,13- heptadecahydrochrysene (84) mp 182-183°C, u l t r a v i o l e t : * m a x 280 my (very weak), nmr: 9.26 (C-lOa methyl, 3H, s i n g l e t ) , 9.02 (C-l methyl, 3H, doublet), 8.24 (C-8 hydroxyl, IH, singlet removed by D 20), 6.43 (C-8ct, IH, septet), MS (atlas) parent peak 304, prominent peaks 149, 232, 247,. 271, 272, 286, 290. This crude ketone (213 mg) was acetylated i n the usual manner. The acetate was treated with 0.19 M bromine in a c i d i c acid (4.4 ml) 96 a f t e r the acetate was dissolved i n acetic acid (7 ml). The product was refluxed with magnesium oxide (2 g) i n dimethyl formamide (25 ml) for one hour. The product, which was a complex mixture, was chioma-tographed on alumina (35 g, Grade I I I ) . 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