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Total synthesis of steroidal derivatives : synthesis of hydrochrysene analogues and related compounds. By, Arnold William 1963

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TOTAL SYNTHESIS OF STEROIDAL DERIVATIVES« SYNTHESIS OF HYDROCHRYSENE ANALOGUES AND RELATED COMPOUNDS. by ARNOLD BY B.Sc, The University of Bri t i s h Columbia, I960 A THESIS SUBMITTED IN PARTIAL FULFILMENT OF THE REQUIREMENTS FOR THE DEGREE OF MASTER' OF SCIENCE in the Department of Chemistry We accept this thesis as conf orraing to the required standard THE UNIVERSITY OF BRITISH COLUMBIA Ap r i l , 1963 In presenting this thesis i n p a r t i a l fulfilment of the requirements for an advanced degree at the University of B r i t i s h Columbia, I agree that the Library sh a l l make i t freely available for reference and study, I further agree that per-mission for extensive copying of this thesis ,for scholarly purposes may be granted by the Head of my Department or by his representatives. It i s understood that copying, or publi-cation of this thesis for f i n a n c i a l gain shall not be allowed without my written permission. The University of B r i t i s h Columbia Vancouver 8, Canada. Department Date ABSTRACT A sequence leading to the total synthesis of cis-syn-cis-dodecahydrochrysene and cis-octahydrochrysene derivatives i s described. The synthesis employs the Robinson-Mannich base reaction and the Michael reaction to construct the tetracyclic skeleton. Condensation of 6-methoxy-2-tetralone with l-diethylamino-3-pentanone methiodide affords an isomeric mixture of t r i c y c l i c ketones. This mixture i s then condensed with methyl vinyl ketone to yield r6-dimethyl-6-.hydroxy-2,3-(21-methoxy-7',8'-dihydro-61,5'-naphtho)-A -bicyclo [3.3. I] nonene-9-one (IV). By appropriate modifications this compound can then be ut i l i z e d for the synthesis of a variety of hydrochrysene analogues. Oxidation of dodecahydrochrysenes with t-butyl chromate solution i s found to be dependent on the stereochemistry of the molecule. Whereas trans-anti-trans-2-methoxy-80 -acetoxy-lOa-me thyl-l|b, 5>,6,6a, 7,8,9,10,10a,10b,ll,12-dodecahydrochrysene (XVIII) gives the 12-keto derivative XIX, cis-syn-cis-2-methoxy-8»C -acetoxy-10a-methyl-b,b, 5,6,6a,7,8,9,10,10a,10b,U,12-dodecahydrochrysene (XVII) yields c i s -2-methoxy-8of -acetoxy-3>-keto-10a-methyl-f>,6,6a, 7,8,9,10,10a-octahydrochrysene (XXIY). In tike latter reaction, t-butyl chromate i s superior to chromium trioxide as an oxidizing agent.' Nuclear magnetic resonance spectra are found to be invaluable for the purpose of characterization of these rather complex molecules. ACKNOWLEDGEMENTS I wish to acknowledge with gratitude the guidance and encouragement given me throughout the course of these investigations by Dr. James P. Kutney. I would also l i k e to thank Dr.. Vfa. McCrae for his kind assistance at the beginning of my course of studies. Financial aid from the National Research Council of Canada, The National Cancer Institute of the National Institutes of Health, U. S. Public Health Service (grant No. CI-£037), and the Presidents Research Fund, University of Br i t i s h Columbia i s very gratefully acknowledged. Thanks are also due to Dr. D. McGreer for running some of the N. M. R. spectra and f o r discussions regarding these spectra. TABLE OF CONTENTS Page Introduction 1 Discussion 10 Conclusion .. 35 Experimental 36 Bibliography .. .. 65 Li s t of Figures I- Condensation of 2-methylcyclohexanone with the methyl iodide salt of l-diethylamino-3-butanone by Du Feu, McQuillin and Robinson k 2. Preparation of 2-keto-12-methyl- A ^^-dodecahydro-phenanthrene by Robinson and Weygand .. .. U 3. Preparation of l,7-diketo-2:,13-dimethylperhydrophenanthrene (I) by Cornforth and Robinson 5 i i . Wilds' procedure f o r introduction of rings A and B of steroidal compounds using the Robinson-Mannich base reaction 8 5>. Johnson's hydrochrysene approach to steroidal total synthesis 8 6. Robinson-Mannich base condensations and dehydration of ketol IV11 7. Ultraviolet spectra of the isomeric mixture of the t r i c y c l i c ketones and the pure isomers .. 12 8. N» m. r. spectrum of 1/5 ,6-dimethyl-6-hydroxy-2,3-(2;'-methoxy - 7 8 1 -dihydro-6 1,5 1 -naphtho)- A^-bicyclo (3»3«lD nonene-9 one (TV) 15 9. Ultraviolet spectrum of 2:-methoxy-8-keto-IOa-m3thyl-5,6,8,,9, 10,10a,Il,12-octahydrochrysene (v") 16 10.. N. m. r . spectrum of 2-methaxy-8-keto-10a-methyl-5,6,8,,9,10, 10a,ll,12-octahydrochrysene (V) 1? 11. Preparation of cis-syn-cis-dodecahydrochrysene derivatives 19 12. N. m. r . spectrum of the isomeric mixture of olefins, IX and X 21 13'.. U l t r a v i o l e t s p e c t r a o f s y n - c i s - l / t S , 6 - d m e t h y l - 6 - a c e t o x y - 2 , 3-(2:1 - m e t h o x y - ! ? ' 1 > 7 1 , 8 ' - t e t r a h y d r o - 6 1 , $ ' - n a p h t h o ) - b i c y c l o Q * 3 . l ] n o n a n e - 9 - o n e ( X I ) a n d l > 2 , 3 > l 4 - t e t r a h y d r o - 6 -m e t h o x y n a p h t h a l e n e ( X I a ) . . 23 lh> P r o p o s e d m e c h a n i s m o f o x i d a t i o n o f c i s - s y n - c i s - 2 - - m e t h o x y - 8 acetoxy-10a-niethyl-i|.b,5,6,6a,7,8,9,10,10a,10b,ll,12-d o d e c a h y d r o c h r y s e n e ( X V I I ) 28 15. P r e p a r a t i o n o f c i s - o c t a h y d r o c h r y s e n e d e r i v a t i v e s . . . . 30 INTRODUCTION Recently a considerable effort has been put forth to study the effect of substituents attached to the steroid skeleton on the biological properties of these compounds. Indeed dramatic effects have been obtained f o r substituents such as methyl, hydroxyl, and halogen, particularly fluorine, when these groups are situated at rather specific positions on the nucleus. Related to these studies, the removal of angular methyl groups, as i n 18-nor and 19-nor steroids, or of methylene groups from the ring skeleton to generate ring contracted steroidal nuclei has also been accompanied by important alterations i n the biological activity of these molecules (1,20. Very recently, interest has been aroused i n some research groups to prepare steroids with a nitrogen atom replacing a carbon atom i n the steroidal nucleus and to investigate the biological properties of such compounds (3,li-j5)» Most of the above researches have involved the use of the naturally occurring steroids as starting materials.. Although these are obviously the lo g i c a l choice i n most cases, they offered certain limitations i n synthesizing some of the steroidal derivatives which were of interest i n our studies of the relationship between structure and biological activity. For this reason, we initiated investigations directed toward the t o t a l synthesis of steroidal analogues, with particular emphasis on intermediates which would readily lend themselves to the introduction of substituents or alterations of the actual skeleton not conveniently possible from the natural steroids. More particularly, we are interested i n developing a total synthesis of compounds having the modified steroidal -2-skeleton, namely a C-nor-D-homo or B-nor-D-homo system. It should be noted that the C-nor-D-homo steroidal skeleton exists i n the ¥eratrum alkaloids of which jervine (i),, veratramine ( l l ) , and cevine (III) are cited as examples,, None of these alkaloids has been synthesized -3-as yet nor has the C-nor-D-horao steroidal skeleton been successfully put together. Of the various approaches which were available, the one u t i l i z i n g the Robinson-Mannich base reaction originally developed by Robinson and co-workers (6,7,8,,°) and so successfully applied i n the elegant researches of Johnson and co-workers (10) appeared most suitable. In a paper published i n 1937, Du Feu, McQuillin, and Robinson (6) found that the methiodide salt of l-diethylamino-3-butanone condensed with 2-methylcyclohexanone to give mainly 10-methyl- & "^^-2-decalone (Figure !.)• This reaction demonstrates that the i n i t i a l condensation of the two molecules takes place preferentially at the tertiary carbon atom oC to the carbonyl group and not at the secondary carbon oC to this group. In 191+1, Robinson and Weygand (7) condensed the same methiodide salt with l-methyl-2-decalone to give 2!-keto-12-metbyl-A •L^)-dodecahydrophenanthrene (Figure 2). They proved that the i n i t i a l condensation takes place at the tertiary carbon atom by dehydrogenating the above dodecahydrophenanthrene with selenium to phenanthrene and 2-hydroxyphenanthrene.. Cornforth and Robinson (9) prepared l,7-diketo-2,13-dimethylperhydrophenanthrene (Figure 3) which was identical to an authentic sample obtained from methyldiacetyldeoxy-cholate. The significance of this work is that the angular methyl group i n the condensation product of l-diethylamino-3-butanone methyliodide salt and 5-:methoxy-l-methyl-2-tetralone i s i n the /S -configuration. Wilds et a l (11) were the f i r s t to introduce the 0-19 angular methyl group by the Robinson-Mannich base reaction (Figure U)» Figure 1; Condensation of 2-methylcyclohexanone with the methyl-iodide salt of l-diethylamino-3-butanone by Du Feu, McQuillin and Robinson. Figure 2: Preparation of 2-keto-12-methyl- A ^ '-dodecadaydro-phenanthrene by Robinson and Weygand. R e v o l u t i o n as fcy-MCinc ' rS<(ec//i<ffc& (I) Figure 3' Preparation of l,7-diketo-2,13-dimethylperhydrophenanth^ (i) by Cornforth and Robinson. -6-It should be noted that Wilds assigned incorrect structures to some of his intermediates i n this paper. In 1956, Johnson (10) published his hydrochrysene approach to the total synthesis of steroids u t i l i z i n g the Wilds' procedure of condensation. Johnson's condensation sequence i s summarized i n Figure 5. This method of condensation gives a C-19 angular methyl group having the yfi -configuration. This was proven conclusively when Johnson, Bannister and Pappo (12) synthesized d l -epiandrosterone and showed that i t s infrared spectrum was identical to that of the naturally derived d-epi-androsterone. In a paper published i n I960, Johnson (13) describes i n de t a i l , evidence; for assigning the bridge structure to ketols I and II. -7 The conformational expressions for these ketols are represented i n I a and II a . In his earlier papers, Johnson (10) had indicated the structure of these ketols as shown by III and 17. However subsequent consideration of the nuclear magnetic resonance (NMR) spectra of these ketols showed that structures III and IV were incorrect. In particular, the presence of two signals at high f i e l d indicated the presence of two C-methyl groups. This evidence clearly excluded structures III and I? which should show only one C-methyl group absorption i n the NMR spectra. A good deal of chemical evidence was also presented to provide conclusive proof for structures I and II» With the structures of the ketols firmly established, i t follows that their f a c i l e conversion, i n the presence of sodium methoxide, to the unsaturated ketone X" must involve a reverse aldol reaction to i n i t i a l l y provide the intermediate diketone IX. -8-Figore ki Wilds' procedure f o r introduction of rings A and B of steroidal compounds using the Robinson-Mannich Base reaction. Figure 5>: Johnson's hydrochrysene approach to steroid total synthesis. - 9 -This ketone undergoes cyclization to give the originally postulated aldol structure III and/or IV which undergoes / S -elimination of water to the «C ,p -unsaturated ketone XT. Johnson has shown that the major ketol I a has an axial hydroxyl group at G-6 by reducing this ketol to a d i o l and treating t h i s d i o l with thionyl chloride, i n the presence of pyridine, to form a cy c l i c s u l f i t e ester. On the other hand, the d i o l of II a f a i l e d to give such a derivative. - 1 0 -DISCUSSION On the basis of previous results, we f e l t that the hydrochrysene approach would provide the most direct sequence to the steroidal derivatives which were of interest to us, and, therefore, we initia t e d our studies i n this direction. Condensation of 6 - m e t h o x y - 2 v t e t r a l o n e (I) with l-diethylamino - 3 -pentanone methiodide, i n the presence of sodium methoxide,, provided an isomeric mixture of the t r i c y c l i c ketones (II and III) (Figure 6 ) (LU). The arrangement of the double bond i n the t r i c y c l i c ketone permits i t s migration into conjugation with either the aromatic ring or with the carbonyl function ( 1 1 = ^ I I I ) . It was: not surprising, therefore, to find that our product was an o i l y mixture of both isomers. The ultraviolet spectrum of this mixture indicated a broad band i n the 2 5 0 - 2 6 0 m}x region, and the infrared spectrum indicated the presence of saturated and unsaturated carbonyl functions ( 5 * 8 6 and 6 . 0 5 / t ). Careful chromatography of this mixture, f i r s t on alumina and then on s i l i c a gel, allowed the separation into the two respective isomers, 1 1 ( ^  max 2 5 3 mM- > infrared 6 * 0 5 / * • ) and III ( A 2 7 5 m/< , infrared 5 » 3 5 y ^ t ) (Figure 7 ) « In general, this separation involved considerable losses, and for preparative purposes, i n the subsequent condensation, the isomeric mixture was employed. The common anion derived from either isomer II or III made i t unnecessary to isolate each isomer i n a pure state f o r the second Robinson-Mannich cyclization. Consequently, the t r i c y c l i c ketone mixture was treated with either 1-diethylamino-^-butanone methiodide - l i -belee Figure 6: Robinson-Mannich^eondensations and dehydration of ketol IV. -12--13-or methyl vinyl ketone, and the condensation was allowed to proceed, i n the presence of sodium methoxide, to yi e l d a tetracyclic product. In our hands, the use of methyl vinyl ketoneinstead of the Mannich base was more convenient a-ndiprovided better results and we have ut i l i z e d i t i n most of our condensations. It should be noted that a similar preference for the use of the parent ketone instead of the Mannich base methiodide i s indicated by Woodward and co-workers i n a related reaction (15>)» The nature of the tetracyclic product depended on the reaction conditions - the hydroxy ketone 17 was formed at lower temperatures, whereas the tetracyclic ketone V was the major product at refluxing methanol temperature. Since ketone V was readily obtained from the hydroxy ketone by treatment with base, and since the ketol IV allowed us to obtain some of the desired hydrochrysene derivatives,, we concentrated our efforts on developing optimum conditions for the sequence II, III ->- IV ->- 7. The nature of the ketol structure deserves some comment since at the outset the two formulations 17 and VI are possible depending on the manner of the f i n a l cyclization. The structure 17 was anticipated, since Johnson and co-workers (13) have recently published a detailed paper indicating that the correct structure f o r their ketols, obtained i n an analogous sequence, i s represented by a formulation of type 17 and not 71 as originally proposed. Indeed, our hydroxy ketonecould be readily assigned the bridge structure I? on the basis of the following evidence. The infrared spectrum of the substance indicated the presence of a saturated carbonyl chromophore (5»88/^ ) and a hydroxyl function, and the ultraviolet spectrum ( X max 27U m/* , A min 236 m/t ) was characteristic of a p-methoxystyrene chromophore. Subsequent comparison with the model compound, 3,U-dihydro-6-methoxynaphthalene (711)( A max. 269 M/U. , A min 237 m/* ), indicated that the ultraviolet spectra were v i r t u a l l y superimposable except for a slight s h i f t of the inaximum i n 17,, as expected for more substitution on the chromophore. This spectral data i s obviously consistent for both 17 or 71,, but when we turned to consider the n.m.r. data, we could exclude 71 very easily* The n. itu r . spectrum (Figure 8) run i n pyridine (16), showed two sharp signals at high applied magnetic f i e l d characteristic of proton resonance for methyl groups (9»38 f , -C-CKj and 9 - 2 2 . T , H0-6-CH^ ) - a situation clearly consistent with structure 17 but not 71* In addition, the characteristic signal for the methoxy group was present (see experimental portion). In the hope of providing hydrochrysene derivatives with a different stereochemistry from that of the derivatives obtainable from the ketol 17 we have subjected the ketol to a more drastic methoxide treatment and have obtained, in high y i e l d , the expected tetracyclic ketone 7* This material exhibited a strong carbonyl. absorption i n the infrared spectrum due to the conjugated chromophore i n ring A (6.01/A ) , and the ultraviolet spectrum of the material indicated two maxima (235 (broad) and 270 m/x )(Figure 9 ) . This substance has been independently -18-mentioned i n a recent communication by Nagata and co-workers (17) • The n. m. r . spectrum (Figure 10) had, among i t s important features, a single band at high f i e l d (8.52: f , -C-CH3) and a weak signal due to the olefinic proton (k+13'T )• Other n. m. r . signals appearing i n the spectrum are given i n the experimental portion. The mode of formation of V i s analogous to the one given by Johnson and his co-workers (13) and already discussed i n the introduction. Acetylation of IV with isopropenyl acetate provided a good yiel d of the expected acetate VIII (Figure 11). Apart from: the usual carbonyl absorption characteristic of the ketone and acetate functions (£,78, 5»85>>< ) i n the infrared spectrum, the n. m. r . spectrum of this substance, run i n pyridine, also indicated some interesting features. F i r s t l y , the presence of two high f i e l d signals (9Ji2:, 8*98 ~£ ) confirmed the presence of two methyl groups. In addition, i t i s to be noted that one of these signals i s shifted downfield upon acetylation. This is expected i n a structure such as IV. This evidence allows us to assign, with certainty, the highest-f i e l d signal to the angular methyl group. It i s well known (16) that pyridine exerts, a considerable solvent s h i f t i n the n. ra. r - spectrum and:linorder to see what effect i s noticed i n this series of compounds,; we also ran - the acetate VIII, under identical conditions,, with deuterochloroform as the solvent. In general, a l l the signals were shifted downfield with some signals being shifted much more than others. For example, the high-field signals now occurred at 8 .80 and 8.35> "C* In addition, the resolution i n pyridine was far superior to that i n deuterochloroform so that pyridine appears to be an excellent -19-Figure l i t Preparation of cis-syn-cis-dodecahydrocbrysene derivatives -20-solvent for compounds of this type. To obtain further proof of the bridge structure for the ketol, we heated the ketol i n a solution of pyridine and phosphorous .oxychloride and, after chromatography on Reichstein-treated F l o r i s i l , obtained a mixture of isomeric olefins (IX and X) (Figure 6). The ultraviolet spectrum on a purified sample ( A max 271+ m/x ,, A min 23S7 inM ) was identical to that of the ketol and no absorption due to a conjugated ketone was present* A l l the olefinic fractions from the chromatography showed a saturated carbonyl chromophore ($.Qk/{ ) i n their infrared spectra. A mixture of isomeric olefins was indicated by the gradually decreasing intensity of two peaks (6.12 and 11*11/* ) i n the infrared spectrum of the chromatography fractions as they were eluted off the column. It is well known that the 6.12yU. peak, which corresponds to the carbon-carbon double bond stretching frequency i s generally more intense for exocyclic carbon-carbon double bonds than for endocyclic olefinic linkages* The peak at 11.11/*/, which i s due to carbon-hydrogen out of plane bending, i s • characteristic for the terminal methylene group. Nuclear magnetic resonance spectra indicated that the early chromatography fractions contained about 65 percent of the endo olefin IX and 35 percent of the exo olefin X (Figure 12), while the later fractions contained approximately 85 percent IX: and 15 percent X* These results are based on the area of the endo vinyl hydrogen peak at 1+.70 t and the area of the exo vinyl hydrogen signal at 5*32 t . Two intense peaks at high f i e l d were also presentt a singlet at 8.85 tT corresponding to the angular methyl group and a quartet at 8*32 X. corresponding to the methyl group attached to the olefinic.c.arbon. The quartet had splittings (Of 1*5 to 1.8 cps. This data provided strong support for the ketol structure 17, These -22-results are consistent with those encountered by Johnson and co-workers i n a closely related series (13)«-It has been known for some time (13) that catalytic hydrogenation of the acetates of ketols of type IV effects: stereoselective reduction of the styrene double bond with the hydrogen being absorbed from the face of the molecule* A consideration of the conformational expression vTIIa 'for the keto-acetate VIII (Figure 11) reveals that ring A. prevents any absorption of hydrogen from the <»C side of the molecule. When this keto-acetate was catalytically reduced by the use of palladium hydroxide on strontium carbonate, a good yie l d of the reduction product XI was obtained. The ultraviolet spectrum of this substance ( 278 and 286 m/i ) (Figure 13) was vi r t u a l l y superimposable upon the spectrum of an authentic sample of l,,2,3,i+-tetrahydro-6-methoxynaphthalene (Xla), indicating that complete reduction had occurred. The infrared spectrum, with the typical saturated carbonyl chromophore and the acetate group (£.86, $J*>0/A.)t and the n. m. r . spectrum, with signals at high f i e l d (8.90 T, -C-CHoj 8 Ji7 X ,, -6-CHo), were entirely ^ OAc consistentwith the above formulation. When the above reduction product XI was refluxed i n benzene i n the presence of sodium methoxide, an excellent y i e l d of the expected tetracyclic ketone XII was obtained. -2JU-This substance now exhibited a conjugated carbonyl absorption i n the infrared spectrum (6»0U/t ) , and a new absorption also occurred at 2 3 3 m/< i n the ultraviolet spectrum apart from the usual aromatic absorption already mentioned i n XI. The nuclear magnetic resonance spectrum of this substance was completely different from that of the starting material, and, apart from a detailed description given i n the experimental portion, may be mentioned the presence of only one signal at high f i e l d (8*53-f , -C-CH3) and a weak signal i n the olefinic proton region (1+.16 t ). This data i s clearly i n support of structure XII. This interesting reaction may be rationalized as proceeding v i a a retro-aldolization followed by cyclization and dehydration as already described for an analogous compound i n the introduction. In order to provide further desirable derivatives i n this series, the unsaturated ketone XII was catalytically reduced by the use of palladium on charcoal containing ai trace of concentrated hydrobromic acid-reaction conditions known to provide ring A/B cis fusions i n compounds of this type (18)* The reduction product was; assigned the cis-syn-cis structure X I I l . The completeness of the reduction was indicated by the infrared spectrum of the product (5»86/< ) and i t s ultraviolet spectrum, which now showed a complete disappearance of the -conjugated carbonyl chromophore and a retention of the typical aromatic absorption. The ultraviolet spectrum was superimposable on that of the methoxy t e t r a l i n , Xla. The n. m. r» spectrum was also instructive, and indicated the absence of olefinic signals, and the presence of a sharp peak at 8.85 t , attributable to one -cV-CH-j, function. It i s interesting to note that i n XIII, where there are no ring olefinic bonds present -2$< to create a deshielding effect on the methyl signal, the peak now occurs at higher f i e l d and i n the region more normally attributable to methyl protons. The above saturated ketone XIII was reduced with lithium aluminum hydride i n a refluxing solution of ether, dioxane, and benzene to give the cis-syn-cis alcohol XIV. These reaction conditions are known to provide the equatorial (8«C ) hydroxyl group i n compounds of this type (19). This reaction sequence now provided the desired c i s -syn-cis hydrochrysene derivatives. It was then necessary to consider the synthesis of intermediates which allow entry into the preparation of compounds with an open ring C. With this i n mind, we decided to study the relative reactivities of positions Ub and 12 i n the cis-syn-cis series. It was already know from other work i n our laboratory that the introduction of substituents such as acetate or bromine at the desired C^ g, position could not be accomplished successfully (2.0). The predominant reaction which occurred under the attempted reactions was an aromatization of ring C. We concluded that this f a i l u r e may be due, at least i n part, to the activation of kb (see XIV i n Figure 11) by the para methoayl'-gsoup. Hence we chose to replace the methoxyl function by the less activating acetoxyl group. We therefore subjected the alcohol XIV to a demethylation procedure u t i l i z i n g methylmagnesium iodide at 175° (20, 21, 22, 230 • The product obtained, i n good yiel d , was the expected phenolic alcohol XV. The spectral data for this substance was i n complete agreement with the assigned structure. In particular, the ultraviolet spectrum, with i t s maximum absorption at 28l m/< i n neutral -26-solution, showed a bathochromic shift to 300 mju when taken i n alkaline solution. This s h i f t , which i s typical of phenolic substances of this type, was an excellent conformation for the success of t he demethy-lation procedure. The infrared spectrum also provided some information since two maxima (2.92/< , 3*l8>t ) were present indicating that two different types of hydroxyl groups existed i n this molecule. The n. m. r. spectrum of this compound, when taken i n pyridine, showed the complete absence of a methoxyl group and an intense singlet at 9.63 X due to the angular methyl group. Furthermore, the spectrum, when taken i n dimethyl sulfoxide, was particularly informative because two peaks, which were due to two hydroxyl functions, were present: 1*10 X , due to the phenolic hydrogen and 5*65 TT , due to the secondary alcoholic;proton* Acetylation of this phenolic alcohol with isopropenyl acetate provided the desired diacetate, XVI. We were unable to crystallize this compound even though i t was purified by chromatography* However, the infrared spectrum of this substance showed two carbonyl peaks at $.69 JU (Ar-0-C-CHo) and £.8l/< s (R^O-C'-CHj) i n accordance with the expected structure. At this point other work (20) i n our laboratory on the trans-anti-trans series indicated that even i f the methoxyl group had been replaced by an acetate function,, the undesirable aromatization reaction s t i l l persisted* It was. therefore decided to abandon any further work on this aspect of the problem. Our next consideration toward the introduction of a functional group at 0^2 (see XIV i n Figure 11) involved the preferential oxidation of this position by a st e r i c a l l y hindered oxidant such as t-butyl -27-chromate. This reagentwas proving successful i n the related trans-anti-trans series (20) and we decided to investigate i t s use i n our series. The saturated alcohol XIV was acetylated by means of isopropenyl acetate and the acetate XVII was oxidized with t-butyl chromate under identical conditions to those u t i l i z e d f o r the preparation of the trans-anti-trans-2-methoxy-12-keto compound, XIX (Figure 1U)» To our astonishment we obtained, i n about 19 percent yield after chromatography, the A/B cis-f>-keto compound, XXIV (Figure 11+) and not the expected cis-syn-cis-12-keto compound. An unambiguous synthesis of XXIV was accomplished i n some related studies to be discussed l a t e r . The formation of XXIV i s quite remarkable considering the f a c t that under identical conditions, the corresponding trans-anti-trans compound XVIII is converted to the expected ketonic substance XIX (Figure lU). It i s obvious that the reactivity of the tertiary carbon designated as kb i s considerably higher i n the cis-syn-cis series than i n the trans-anti-trans series. The reasons for this difference are not completely understood, although a study of molecular models of the two isomeric substances does reveal some information. It can be seen from models that carbon atom Ub i n the cis-syn-cis compound XVII i s more accessible to the approach of the oxidant, and i t seems reasonable to speculate that i t i s more easily oxidized. A mechanism for the formation of XXIV i s postulated (see Figure Hi), although i t must be emphasized that this i s merely speculation and we do not have any experimental evidence to support this mechanism. Figure l U : Proposed mechanism of oxidation of cis-syn-cis-2.-methoxy-8«£ -acetoxy-10a-methyl-Ub,5,6,6a,7,8,9,10,10a,10b,ll,12-dodecahydrochrysene (XVII) -29-It i s pertinent to point out that we chose t-butyl chromate as an oxidizing agent instead of the more conventional chromic acid, because the former appears more susceptible to steric considerations. It was found from other work i n the trans-anti-trans series (20), that undesirable side products presumably arising from preferential attack at the C^- tertiary carbon rather than the Gi2 secondary position, are greatly minimized by the use of t-butyl chromate. The ava i l a b i l i t y of the ketol IV allowed us to consider another attractive sequence which would provide entry into another novel skeleton - the B-nor-D-homo system. It was clear that the ketol should be capable of providing an intermediate i n which both rings C and D were aromatic and thereby allowing us to make modifications of ring B without any complication. Due to the bridged nature of the ketol structure, aromatization of ring B i s impossible without bond cleavage, and consequently^ one would expect that dehydrogenation of this system would provide a high y i e l d of the product possessing aromatic rings C and D. Indeed, when the acetate of this ketol 17 was dehydrogenated with 10$ palladium on carbon, i t gave, i n good yield,, the desired keto-acetate XXVI (Figure 15). The spectral data provided strong evidence for the success of the dehydrogenation. In particular, the ultraviolet spectrum was very informative here and showed the typical, complicated spectrum of naphthalenic chromophore ( X 231, 266, , 2 7 7 , 287, 3 0 7 , ca* 315 (shoulder), 321, 330 and 335.5 m x ) . Apart from the usual carbonyl absorption characteristic of the ketone and acetate functions i n the infrared spectrum (5»8U, 5»79/<- ), the nuclear magnetic resonance spectrum of this substance also indicated -30-i -31' some interesting features. For example, the C^-methyl peak now occurred at 8*i+7 V and the methoxyl absorption at 6*10 X represented a downfield s h i f t when compared to the corresponding signals i n the spectrum of the starting material. However, the signals for the methyl group at (8.32 X ) and for the acetate methyl.group (8.00 have not been affected to an appreciable extent. As expected,, the area of the aromatic region is now equivalent to five hydrogen atoms. During the reaction some acetic acid was devolved and hence some olefinic material was expected. This o l e f i n i c material was proven to be 1/3 ^6-dimethyl-2,3-(2 l-methoxy-6 , ,5 l-naphtho)-A 2' 6-bicyclo £3'3.l] -nonadiene-9-one (XXV) on the basis of the following evidence. The infrared spectrum of this olefin showed a ketonic function (5*8U/* ) and no absorption i n the region of 6 .0/^ due to carbon-carbon double bond stretching or at 11.2/x due to carbon-hydrogen out of plane bending frequencies. The ultraviolet spectrum gave a typical naphthalene absorption ( X max 23 L> 2 6 6 » 2 7 6 > 2 8 6 > 307, ca. 315 (shoulder), 320, 32-9, and 335 m>c ), and the n. m. r . spectrum was very instructive here. The significant signals which should be mentioned are a quartet having splittings of 1*7 to 1.8 cps. at 8.32 X- due to the C^-methyl function, and a weak broad absorption at 1+.75 T~ due to the endocyclic olefinic proton. It i s clear that the exocyclic olefin, which could have been formed from this reaction,would not exhibit any signal at high f i e l d for the C6-methyl group and would have an olefinic absorption around 5.2 t . -32-A refluxing solution of the keto-acetate XXVI, i n benzene-methanol, was treated with sodium methoxide and the expected tetra-c y c l i c , oC ,, p -unsaturated ketoneXXVII was obtained i n excellent y i e l d . The success of the reaction was indicated by the appearance of a conjugated ketonic absorption at 6 . 0 l ; / < - in the infrared spectrum, and also by the appearance of an additional chromophore ( \ 2 3 6 1 1 1 / f ) i n the ultraviolet spectrum. The n. m. r . spectrum of XXVII now showed only one methyl absorption at high f i e l d ( 8 . 3 7 X ), and a weak absorption at h»0hX due to the vinylic hydrogen. In order to provide further desirable derivatives i n this series, the unsaturated ketone XXVII was hydrogenated with 10$ palladium on carbon i n a benzene solution made slightly acidic with k$% hydrobromic acid. The reduction product XXVIII was assigned the cis configuration. The spectral properties were incomplete accord with this assignment. The conjugated carbonyl chromophore had disappeared from the ultraviolet and infrared spectra, and, i n the n. m. r . spectrum, the olefinic signals were also absent. The saturated ketone XXVIII was reduced to the alcohol XXIX with lithium aluminum hydride i n a refluxing solution of ether, dioxane and benzene5 and acetylated by the use of isopropenyl acetate to provide a crystalline acetate XXX. This sequence completed the f i r s t phase of the investigation, namely the construction of hydrochrysene derivatives possessing aromatic rings C; and D. It was now necessary to consider the introduction of a carbonyl function at the benzylic position (C^, see XXX) since this would allow -33-modification of ring B. For this purpose, three different reaction conditions for -this oxidation were investigated: 1) a refluxing solution of t-butyl chromate i n carbon tetrachloride and acetic anhydride, 2) a solution of chromium trioxide i n aqueous acetic acid at room temperature, and 3) a refluxing solution of t-butyl chromate i n carbon tetrachloride. The f i r s t set of conditions did not give the desired ketone, but instead some other material which was not investigated thoroughly. The second method, similar to that used by Barnes and Beachem ( 2 i j ) , gave about 12$ yield of desired ketone and about 12$ recovery of starting material, while the use of t-butyl chromate i n carbon tetrachloride proved most satisfactory- Under optimum conditions, the latte r oxidizing agent provided 30$ of the desired ketone XXIV" and allowed recovery of 19$ of starting material. The infrared spectrum of the desired ketone showed the presence of a conjugated ketone and an acetate group ( 6 . 0 3 , ..)t while the ultraviolet spectrum had maxima at 220, 2hl and 316 m /* . The n. m. r . spectrum showed some interesting changes from that of the starting material. For instance, the angular methyl signal:, was shifted down f i e l d to 8 . 6 3 , the C^-methylene was s p l i t into three doublets at 6 . 6 5 , 6.9U and 7»U0 "X. » and a considerable difference was noted i n the aromatic region. In particular, a doublet corresponding to one proton was found at 0.78 *£T , and i s suspected to be due to the Cj^-aromatic hydrogen atom.. It may be expected that this proton would be deshielded by the close proximity of the carbonyl group at C^. It i s pertinent to point out that although the substances described herein dif f e r from the ones previously prepared only i n the nature of -3U-. the aromatic nucleus, this difference represents an important modification f o r the synthesis of many steroidal substances:. The aromatic system i n the above compounds lends i t s e l f readily to numerous interesting variations not conveniently obtainable previously. Indeed, Nagata and co-workers (25) have very recently described the preparation of various C^g-substituted s teroids and related substances u t i l i z i n g such intermediates as V. -35-CONGLUSION These studies have provided the successful synthesis of c i s -syn-cis-dodecahydrochrysene and cis-octahydrochrysene derivatives. These compounds may prove to be excellent intermediates for the preparation of molecules having novel steroidal skeletons - the C-D-homo or the B-nor-D-homo system. Some of this work has been the subject of two recent publications (ll+>20). - 3 6 -EXPERIMENTAX A l l melting points were determined on a Fisher-Johns apparatus and are uncorrected. The ultraviolet spectra were recorded i n 3$% ethanol on a Cary 11 or 11+ recording spectrophotometer* Infrared spectra were recorded as potassium bromide pellets on a Perkin-Elmer model 21 spectrophotometer, except where otherwise stated. The n. m. r . spectra were taken at 60 megacycles on a Varian A60 instrument. In the condensation and cis-syn-cis-dodecahydrochrysene sequences tetramethyl silane (TMS) was the internal standard, and Jin the c i s -octahydrochrysene sequence TMS was the external standard (except where otherwise stated) set at 10.0 *t units. The positions of the signals are given in the Tiers t scale. In a l l cases, integration of areas under the signals was carried out, and the number of protons corresponding to each signal i s indicated i n parenthesis. Except where otherwise stated, deuterochloroform was used as the solvent. The analyses were performed by Dr. A. Bernhardt and his associates, Mulheim (Ruhr), Germany, and by Mrs. A. Aldridge, University of Br i t i s h Columbia* Reaction of 6-Methoxy-2-tetralone (I) with l-Diethylamino-3-pentanone  Methiodide We have performed numerous experiments in order to obtain optimum reaction conditions. We have found that maximum yields are only obtainable i f the reactions are conducted under absolutely anhydrous conditions and i n the complete absence of oxygen. The apparatus -37-described i n Org. Syntheses (26) was used throughout the entire condensation sequence. To a 250-ml 3-necked flask f i t t e d with a drying tube, a dropping funnel, and a source of dry nitrogen, l-diethylamino-3-pentanone (28.5 g.) dissolved i n dry benzene (83 ml.) was added. The solution was chilled (ice bath) and dry nitrogen was passed into the flask over a period of 20 minutes. With nitrogen s t i l l passing into the flask, methyl iodide (13*5 g») was added dropwise, over a period of 1 hour, to the s t i r r e d pentanone solution. The temperature of the reaction mixture was kept at 0° during the addition,, and after addition was complete, the reaction mixture was stirred at 0° for a further 3 hours, with a slow passage of nitrogen being maintained. In order to complete the reaction, the mixture was kept at 0° overnight and was then ready for use. This stock solution,, containing the gummy methiodide, could be used for several condensations. Just before use, dry methanol (30 ml.) was added to dissolve the methiodide and while s t i l l cold, aliquots of this solution were used in the various condensations. A 1-liter 3-necked flask was equipped with a pressure-equalized dropping funnel, a s t i r r e r , and a reflux condenser which was connected at the top through a 3-way stopcock to a vacuum source (water aspirator) and dry nitrogen (26). The system was evacuated, and with a rapid escaping stream of nitrogen passing through, the apparatus was flame dried. Anhydrous methanol (105 ml.) was put into the flask and sodium (k*h3 g») was added through an escaping stream of dry nitrogen. After the metal had dissolved, the methoxide solution was cooled to 0°, the system evacuated u n t i l the solvent began to b o i l , -38-then f i l l e d with dry nitrogen, and the procedure repeated once more. To this stirred, cold basic solution, a solution of 6-methoxy-2-tetralone (23.11 g.) i n dry benzene (51 •ml.) was added rapidly through the dropping funnel. The dropping funnel was then charged with an aliquot (0..73 parts of the above stock solution) of the cold Mannich base methiodide (in an escaping stream of nitrogen) and the methiodide was then added over a period of 1x0 minutes with sti r r i n g arid cooling to 0 ° . The reaction mixture gradually became green and s t i r r i n g was continued for 1.75 hours at 0° i n an atmosphere of nitrogen. Finally,, the mixture was refluxed for 1 hour, during which time the solution developed an orange color. After cooling to 0°, the reaction was treated with 2 N sulphuric acid (ll+7 ml.) and then diluted with water (90 ml.). The mixture was extracted with several portions of ether, the ethereal layer dried over anhydrous magnesium sulphate, and solvent evaporated i n vacuo to yi e l d a crude oi l y product. This o i l y product was partially d i s t i l l e d to yield a fraction (2.11+ g.) d i s t i l l i n g i n the range 100-119° at 0.1 mm. which proved to be unreacted tetralone. The residual o i l (28.1+2 g., 89.5$ yield) consisted almost entirely of the desired t r i c y c l i c ketone mixture, although the infrared spectrum of this material showed the presence of a hydroxy-containing material. Chromatography of this o i l on s i l i c a gel (330 g.) and elution with benzene yielded the desired product as an isomeric mixture: II, III (23.3 g*t $1% y i e l d ) . Finally, elution with ether removed the hydroxy-containing material, which was not further characterized. A small aliquot of the 23-3 g* fraction was d i s t i l l e d at 230-250° (bath temp.) at 0*15 mm. to yield an analytical sample of the t r i c y c l i c -39-ketone. The ultraviolet spectrum indicated A 225 (log 3«93)j 2$k roM (log e. U.06), >v ^ 235 m/<. (log €3-85); and the infrared spectrum (as film) showed 5.86 and 6.05• Found: C , 78.975 H, 7.50; 0, 13.65. Calc. for C l 6H l 8°2 : c> 79«31j H, 7.1*9; 0, 13.22..' In one experiment, a small portion ( l g.) of the t r i c y c l i c ketone mixture was chromatographed on deactivated alumina (grade I I - I I l ) . Elution with benzene and benzene-ether mixture yielded a poor recovery (600 mg.) of a yellow gum. This gum was then further rechromatographed on s i l i c a gel (6 g.). Elution with benzene-petroleum ether (1:1) yielded, i n the i n i t i a l fractions, a small amount of the isomer III, X max 2 7 ^ m ^ ( l o§ e 3.93), )\ min 2'U2 myu. (log €. 3.1+5)J infrared (as film) 5.85y". Found: C „ 79.10; H, 7.5U; 0, 13.31. Continued elution with the same solvent yielded a small amount of isomer II,.. X max 2^3; m^ (log €: 1+.10); infrared (as film) 6.-05^ ,. Found: C, 79.2k; H, 7+kl} 0, 13.12. Due to the poor recovery encountered in this experiment, this separation was abandoned. For the subsequent condensation with methyl vinyl ketone, the t r i c y c l i c ketone mixture, as obtained from the s i l i c a gel chromatography, was always d i s t i l l e d immediately before reaction so as to remove traces of water etc. Reaction of Tr i c y c l i c Ketone with Methyl Vinyl Ketone - Preparation of Ketol IV In numerous experiments attempted wherein we used 1-diethylamino-3-butanone methiodide or methyl vinyl ketone we found the latter reagent -Uo-to be much more convenient and better yields were realized. Consequently only the procedure with this reagent i s outlined here. A 250-ml 3-necked flask was f i t t e d with a s t i r r e r , a dropping funnel, etc., exactly as already indicated i n the f i r s t condensation above. After any moisture of oxygen was eliminated from the system as above, the flask was charged with a solution of the t r i c y c l i c ketone mixture (15*33 g») in anhydrous methanol (28 ml..) (in an escaping stream of nitrogen). The dropping funnel was now f i l l e d with a sodium methoxide solution (in an escaping stream of nitrogen) prepared from sodium metal (1.09 g.) i n dry methanol (28 ml.) and the entire system was evacuated u n t i l the solvent began to b o i l . Dry nitrogen was then admitted, the system evacuated, and the procedure repeated again. The sodium methoxide solution was now added rapidly to the stirred t r i c y c l i c ketone mixture, kept at 0 ° . To this reaction mixture, kept at 0 ° , a solution of dry methyl vinyl ketone (6.66 g., obtained from Matheson, Coleman and Be l l , dried over anhydrous potassium carbonate, and freshly d i s t i l l e d ) i n anhydrous methanol (20 ml.) was added dropwise over a period of 25 minutes, with a slow nitrogen stream beihg maintained. During the addition, the reaction mixture gradually attained a dark green color and after the addition was complete, the mixture was stirred f o r a further 2 hours at 0 ° . During this period a precipitate started to form. To complete the reaction, the ice bath was removed and the s t i r r i n g was continued for 18 hours at room temperature under a nitrogen atmosphere. The reaction mixture was cooled to 0° and glacial acetic acid (7 ml.) was added, ^he s o l i d product was f i l t e r e d off, washed with a small amount of ethyl ether, cold water, a small amount of ethanol, and then - l i l -dried. The yield of this white solid was 13.72 g. (69.5/0 and i t had a melting point of 200-206°. On one or two occasions, the melting started as low as 180°. A small portion of this product was recrystallized several times from methanol to yield the analytical sample, m.p. 216-218° (with some decomposition)* \ 27U m>< (log £ 1+.07), ,\ ^  236 m/i (log € 3.21+)5 infrared 5*88^ ; n. m. r . signals (pyridine)t 9*38 (angular methyl, area = 3 H), 9.22 (H0-C-CH3, area — 3 H), 6.92 (OCH^ ,, area -: 3 H), U-i+ij. (OH, area = 1 H), remaining signals i n region 7.0-9*0 (area •* 11 H) due to ring C^'s etc. The aromatic region i s masked by the solvent. Found: C, 76.765 H, 8.095 °» 1^.61; mol. wt. (Rast) 310. Calc* for C2oH2lt03: C, 76*895 H, 7-71+5 0, 15*365 mol. wt. 312. Synthesis of 2-Methoxy-8-keto-10a-methyl-5,6,8,9,10,10a,II,12-octahydrochrysene  (a) From the Ketol 17 Again the apparatus used was exactly the same as i n the previous condensations wherein anhydrous and oxygen-free conditions are maintained. Anhydrous methanol (280 ml.) was put into a 1 - l i t e r 3-necked flask which had been previously dried and evacuated to remove a i r . Sodium (2.07 g*) was then added gradually in small pieces, i n an escaping stream of nitrogen. The apparatus was evacuated u n t i l the solvent began to b o i l , dry nitrogen admitted, etc*, and to this methoxide solution, the dry ketol 17 (17.7 g.) was added. The mixture was refluxed for about li hours i n this inert atmosphere. The ketol, which -1+2-was not entirely soluble at the beginning, dissolved completely after about 2 hours and the solution attained a yellow coloration. The reaction mixture was cooled to 0°, glacial acetic acid (7 ml.) was added, and the resulting, pale yellow crystalline product was removed by f i l t r a t i o n . This solid was washed with a small amount of ether, water, a small volume of ethanol, and then dried to y i e l d crude tetracyclic ketone V (13-7 g«), m. p . ll4.0-lU2:.5°« The f i l t r a t e was diluted with water and the aqueous layer extracted with ether. The ethereal layer was washed with a saturated solution of sodium chloride and dried over anhydrous magnesium sulphate. Evaporation of the solvent yielded a residual gum which upon seeding provided an addition 2.3 g» (total 16 g.) of the desired product* Several recrystallizations of the product from dimethyl cellosolve provided analytically pure V, m. p. Ili2-ll*3°* X 235 (broad, log€ 1+.26), 270 ay* (log 6 1**2$); X jfljjj 2^ 2 m^c (log 6 1**17); infrared 6 . 0 1 / * ; n. m. r. signals: 8.52 (-C-CH3, area - 3 H ) , 6.19 (OCH3, area = 3 H ) , remaining signals in region 6.5-8.0 (area == 12 H), , 1*.13 (0=C-C^=cC « area = 1 H ) , multiplet centered at 3*09 (aromatic H , area » 3 H). Found: C, 81.30; H , 7.30; 0, 10.89; mol. wt. (Rast) 312. Calc. for C ^ H ^ O o , : C, 81.60; H , 7*53; 0, 10.87; mol. wt. 291*. This preparation of V was, i n our hands, superior to the one described i n part (b) and we have used i t i n most of our preparations. (b) Directly from T r i c y c l i c Ketone As before, the reaction was run under anhydrous conditions and i n an inert atmosphere* -U3-The methiodide of l-diethylamino-3-butanone was prepared crystalline i n the manner already described for the corresponding pentanone from l-diethylamino-3-butanone ( l . l l g.) and methyl iodide (1.2 g.). A solution of this methiodide (2.16 g..) i n anhydrous methanol (5 ml.) was added dropwise over a period of 1 hour to the ice-cold mixture of the t r i c y c l i c ketone (1.9 g.) i n dry benzene (30 ml*) and a dodium methoxide solution (from 0.278 g. sodium i n 10 ml. methanol). After the addition was complete, s t i r r i n g was continued for a further 30 minutes at 0°, and then the mixture was refluxed for iiO minutes. The reaction mixture was cooled, treated with 2 N sulphuric acid (15 ml.), and extracted with benzene. The benzene layer was washed with water and dried over anhydrous magnesium sulphate. The solvent was evaporated i n vacuo to yie l d a gummy product (2.5 g-)« This o i l could not be conveniently crystallized, so i t was then purified by chromatography on s i l i c a gel. Elution with benzene - petroleum ether (6:1+) yielded a small amount of semicrystalline gum (0.7 g.) which crystallized from; dimethyl cellosolve. Several more recrystallizations from this solvent yielded the desired product, V, m. p. ll+2-LU3°* This product was shown to be identical with the one obtained i n part (a). Acetylation of Ketol A mixture of the ketol 17 (5.25) , p-toluenesulphonic acid monohydrate (33*7 mg»), and isopropenyl acetate (27 ml.) was heated on a steattLbath for 5 hours. The solid which was present at the -uu-beginning of the reaction dissolved after about 1 hour. The reaction mixture was cooled to room temperature, 2 drops of pyridine were added, and the solvent was removed in a current of a i r . The residue was dissolved i n a small amount of hot 9S% ethyl alcohol, the solution was f i l t e r e d and then concentrated to a volume of 30 ml. Upon cooling of the solution, the f i r s t crop of crystals (1+.56 g.) separated and had a melting point of Hi.6-li+9°.. An additional 0.53 g. (total 5*09 g«, 85»l+$) was recovered as a second crop, m.p. 139-11+6°. Recrystallization of a small portion from aqueous ethanol provided a pure sample of the acetate VIII, m* p. 150-150.5°* \ 275 m/4 (log € 1+.16), X m i n 237 mM (log € 3-51+)5 iJifrared 5.78, $.Q$/4 j n. m. r. signals (pyridine): 9.1+2 (angular methyl, area = 3 H), •'/Ac 8.98 ( ,0-d-CH3, area = 3 H), 8*70 (—OAc, area = 3 H), 6.95 ( 0 C H 3 , area = J, H), remaining signals i n region 7*0-8*6 (area -: 11 H) due to ring CB^'s etc.3 n. m. r. signals: 8.80 (-C-CH^ , area 3 H), 8.35 (^-(f-CH^, area = 3 H), 8 . 0 2 (<AcO-, area - 3 H), 6.19 (OCHp area =• 3H), remaining signals i n region 6.5-8.0 (area = 11 H) due to ring CHg's etc., multiplet centered at 3.05 (aromatic H, area = 3H). Found: C, 74>06s H, 7.66; 0, 18.0l+* Calc. for G22E26°lx: c> 7l+.55j H, 7*395 0, 18.06. Dehydration of Ketol IV with Phosphorus Oxychloride To a solution of the ketol IV ( l g.) in pyridine (1+0 ml., dried over potassium hydroxide), freshly d i s t i l l e d phosphorous oxychloride (1.9 g«, 1*3 ml*) was added and the mixture immersed in an o i l bath. The temperature of the bath was slowly raised to 90° over a period of thirty minutes, and then maintained a V t h i s point for a further two - U 5 -and one half hours. At the end of the heating period the mixture had attained an orange-brown color. The reaction mixture was then cooled to 1 0 ° and treated with benzene. The benzene layer was separated, washed with cold 10$ hydrochloric acid, 10$ potassium hydroxide, and f i n a l l y twice with cold water. After drying the benzene extract over anhydrous magnesium sulfate, the solvent was removed to y i e l d a yellow crystalline solid, m. p.. <" l i j . 0 0 . This product was dissolved i n a mixture of benzene-petroleum ether (7 ml., 5*2) • then chromatographed on Reichstein-treated F l o r i s i l (35 g«) ( 2 7 ) . The desired olefins IX and X, (total 0 .60 g.) were eluted with l i k benzene-petroleum ether ( 3 0 - 8 0 ° ) . The i n i t i a l fractions represented a mixture of the olefinic isomers, but the later fractions were enriched with respect to endo isomer. In these latt e r fractions, the infrared spectra indicated a diminishing intensity of the 6 . 1 2M and 11.11 yU. peaks which are due mainly to the terminal carbon-carbon double bonds. One of the early fractions was recrystallized from ether-petroleum ether to give white crystals, m. p. l l r5- lU7»5° ' . N. m. r . signals: 8.85 (angular methyl, area = 3: H), 8.32 (=0=6-0113), 6.23 (CH3O-, area = 3 H), 5*32 (=0=01^, area = 0.65 H), i ; . 7 0 ( ^ = 0 ^ area » 0 . 6 H), multiplet centered at 3«10 (aromatic H, H area « 3 H). The second to last fraction was recrystallized to give crystals melting at 1 5 9 - 5 - 1 6 1 ° . N. m. r. signals (internal TMS): 8.85 (angular methyl, area = 3 H ) , quartet centered at 8.31 ( >=(} -CE,, splittings of 1.5 to 1.8 cps. ), U.66 ( > < . area — i H 0..85 H), 5 .28 ( )>CH2, area = 0 . 3 0 H). The last fraction from the chromatography melting at 1 U Q - 1 5 0 ° was used for an analytical sample. Infrared: $»o\^(non-conjugated ketone), 6 . 1 0 / t ( ^=G^ , very weak), -U6-11.22 (weak); ultraviolet:' A 271+ nt/C (log 6 1+.19), X m i n 237 m/t (log € 3.61). Found: C, 81.33} H, 7.U2; 0, 11.56. Calc* for C 2 0H2 2 0 2 : C, 81.60; H,. 7.53; 0, 11.87. Catalytic Hydrogenation of Unsaturated Tetracyclic Acetate A solution of the unsaturated acetate VIII (1+.56 g.) i n 9$% ethanol (170 ml., the alcohol was pretreated with Raney nickel) was hydrogenated over 30$ palladium hydroxide on strontium carbonate (lJ+7 g-) at hydrogen pressure of 1+0 l b . / i n . 2 and room temperature for 20 hours. The catalyst was removed by f i l t r a t i o n and the clear f i l t r a t e was concentrated to a small volume. The f i r s t crop (3«5 g«) of crystals which separated melted at 11+8-150°.. An additional 0.11+ g. (total, 3.61+ g.) was recovered from the mother liquors. A small portion was recrystallized twice from aqueous ethanol to yield the desired syn-cis product, XI, m. p. 152.5-153-5°• X 277 (log € I713JC 3.39), 286 (log £ 3-39), 226 m/4. (log e 3.96); X m i n 2l+8 (log fe 2.79), 283 m^ u (log € 3.20) v i r t u a l l y identical with the ultraviolet spectrum of XIA.which shows \ 278 (log 6 3*38), 287 (log Q 3.32), 223 myuc (log e 3.97); > 21+7 (log €. 2.58), 281+ m/< (log G 3.30). The infrared spectrum of XI shows bands at 5«80 and $.86/4 ; Ac, n. m. r. signals: 8.90 (Cj angular methyl, area = 3 H), 8.1+7 (O-C-CJhj, area = 3 H), 8.05 (AcO-), 6.21; (OCH3 area = 3 H), remaining signals i n region 6.6-8.2 (area = 16 H, including 3 H of acetate), multiplet centered at 3.08 (aromatic H, area = 3 H). Found: C, 7U.OO3 H, 7.86; 0, 17.87. Calc. for C 2 2H 2 80k: c> 7^.13j H> 7.92; 0, 17.96. -U7-Synthesis of syn-cis-2-Methoxy-8-keto-lOa-methyl-Ub.g,6,8,9,10,10a,  10b,11,12-decahydrochrysene (XII) The apparatus used i n this experiment was set up exactly as in the t r i c y c l i c ketone preparation in order to maintain anhydrous conditions and a nitrogen atomsphere at a l l times. Into the 25>0-ml 3-necked flask, which was flame-dried and evacuated as before, dry methanol (70 ml.) was added and then sodium (1*37 g.) was added gradually in small pieces. After the sodium had reacted, the methoxide solution was cooled and the entire apparatus evacuated un t i l the solvent began to b o i l j dry nitrogen was then admitted,, the system evacuated, and the entire process repeated several times. To the stirred methoxide solution, a solution of the acetate XI (3«5> g.) in dry benzene (20 ml.) was added through a dropping funnel under a flow of escaping nitrogen. After the addition was complete, the system was evacuated again, dry nitrogen admitted, etc* to ensure complete removal of exygen. The reaction mixture was then refluxed for 5 hours i n this inert atmosphere. At the end of the refluxing period the reaction was cooled in i i c e , g l a c i a l acetic acid (i; ml.) was added, and the mixture was swirled for several minutes. Some water and benzene were added to the reaction flask, the layers were then'separated, and the aqueous layer was extracted with ether. The combined organic solutions were washed with a saturated solution of sodium chloride and dried over anhydrous magnesium sulphate* Concentration of the solvent under reduced pressure provided a f i r s t crop (I.83 g.) of pale yellow needles, m. p. 155«5-158*5°* An additional 0.91 g. (total 2.7U g^9k%) was recovered from the mother liquors. Two recrystallizations -1+8-from ethanol provided an analytical sample of XII, m. p. 158-159°• X max 2 3 3 ( l 0 g € h' 2 3 )> 2 7 7 ( l 0 g € 3 * 3 5 ) * 2 8 7 m M ( l 0 g 3 , 2 9 ) i \ . 2 7 1 + (log € 3.32), 2 8 1 * myU (log e 3 - 2 % infrared 6.0l+/< j 1 H), multiplet centered at 3.12 (aromatic H , area = 3 H ) . Found: C, 80.68j H , 8.21; 0, 1 0 . 8 1 * • Calc- for ^ o ^ V °y 81.01+J H, 8 . I 6 5 0 , 1 0 . 8 0 . Synthesis of cis-syn-cis-2-Methoxy-8-keto-10a-methyl-l+b,5,6,6a,  7,8.9,10,10a,10b,11,12-dodecahydrochrysene (xill) A solution of the unsaturated tetracyclic ketone XII (2.6 g.) in a 1 * : 1 mixture of benzene - 95$ ethanol (82 ml., benzene was refluxed with sodium, then with Raney nickel, while the ethanol was refluxed with Raney nickel) was treated with 10$ palladium on carbon (0-33 g«) and 1 drop of 1*8$ hydrobromic acid. This mixture was hydrogenated at room temperature and atmospheric pressure for 5 hours, after which time 1 mole of hydrogen had been absorbed. The catalyst was removed by f i l t r a t i o n and the solvent removed i n vacuo, whereby a yellow gum was obtained. This gum was dissolved i n benzene (10 ml.) and chromatographed on deactivated alumina (2$ g«, approx. activity II-III)- Elution with benzene yielded 2.38 g. of a gum which crystallized nicely from a small volume of aqueous ethanol. Two further recrystallizations from the same solvent yielded pure XIII as plates, m. p. 7 6 . 5 - 7 7 . 5 ° . X M A X 2 8 7 (log e 3-15), 2 8 0 (log 6 3-16), 226 m/4 (log€ 3 .87)5 A min 2 8 1 * (log £• 3-15). 2 1 * 8 m/A. (log €• 2 . 1 1 + ) ; infrared , area 5 -86yH ; n. m. r . sx. ignals: 8.857j{-C-CH' [3, area «= 3 H), 6.2:8T(-OCH3, area -= -k9-3 H ) , remaining s i g n a l s i n r e g i o n 7.0-8.7 (area = 17 H ) , m u l t i p l e t centered a t 3'16 (aromatic H , a r e a = 3 H ) . Found: C, 80.60; H , 8.985 0, 10.1+9. C a l c - f o r C^R^^: C, ; 80.U95 H , 8.785 0, 10.73. Synthesis of cis-syn-cis-2-Methoxy-8 - h y d r oxy-lOa-methyl-1+b ,5,6,6a,  7,8,9,10,10a,10b,11,12-dodecahydrochrysene (XIV) The s a t u r a t e d ketone X I I I (1.1+3 g«) was d i s s o l v e d i n a mixture o f benzene (20 m l . ) and dioxane (1+9 m l . ) , and t o t h i s s o l u t i o n anhydrous e t h y l ether (98 m l , ) was added. A s o l u t i o n of l i t h i u m aluminum hydride (0.773 g .) i n anhydrous e t h y l ether (19»? m l . ) was added dropwise, over a 1$ minute p e r i o d , to the s t i r r e d r e f l u x i n g s o l u t i o n . A f t e r the a d d i t i o n was complete, t h e s o l u t i o n was r e f l u x e d f o r an a d d i t i o n a l hour a f t e r which time i t was cooled and t r e a t e d w i t h e t h y l acetate t o decompose the excess h y d r i d e . The r e a c t i o n mixture was made a c i d i c by the a d d i t i o n of a s o l u t i o n of concentrated s u l f u r i c a c i d (0.6 m l . ) i n water (7 m l . ) . F i n a l l y , the mixture was d i l u t e d w i t h water and the l a y e r was s e p a r a t e d . The aqueous l a y e r was e x t r a c t e d w i t h e t h e r , and the comined ether e x t r a c t was washed with a s a t u r a t e d s o l u t i o n of sodium b i c a r b o n a t e , then w i t h c o l d water, and f i n a l l y d r i e d over anhydrous magnesium s u l f a t e . Removal of the d r y i n g agent and evaporation of the s o l v e n t i n vacuo p r o v i d e d a s l i g h t l y yel low g:um.;(l.6 g . ) . I t was found t h a t p u r i f i c a t i o n c o u l d not be s u c c e s s f u l l y accomplished by r e c r y s t a l l i z a t i o n . F o r example, the f i r s t r e c r y s t a l l i z a t i o n from aqueous ethanol gave n e e d l e s , m. p . 70-88°. Therefore t h i s product was chromatographed on undeactivated alumina (1+0 g . ) . The substance i n i t i a l l y p l a c e d on the column i n - 5 0 -benzene (7ml.),was eluted with a 2:3 chloroform-benzene mixture to give the desired alcohol XIV (1.11 g.). After several recrystallizations from benzene-petroleum ether, colourless needles, m. p.., 121+-1250,.. were obtained. Infrared: 2.98/c (H0-); ultraviolet: X m 221 (log € 3.88), 2.79 (log € 3.31), and 287 m/t (log € 3.31)5 X m i n ( l 0S € 3.86), 21+6 (log e. 2.1+6),, and 285 xiyU (log 6 3»23')5• n. m. r. signals: 8.82 t (angular methyl, area = 3 H), signals i n region 6.7-8.7 V (area = 18 H ) ; , ca. 6.35 t (HO-i-H, area = 1 H), 6.17 T ( C H 3 O - , area = 3 H), multiplet centered at 3-03 ~C (aromatic H, area - 3 H). Found: C, 79*52; H,. 9-325 0, 11.1+5. Calc. for C 2 0 H2S 0 2J c> 19.9$; H, 9-395 0, 10.65. Synthesis of cis-syn-cis-2,8dC -Dihydroxy-10a-methyl-l+b,5,6,6a,7  8„9,10,10a,10b,11,12-dodecahydrochrysene (XV) The cis-syn-cis alcohol XIV (0.921+ g.), was added to an ethereal solution (5 ml.) of methylmagnesium iodide prepared i n the usual manner from magnesium turnings (0-261+ g.) and methyl iodide (0.68 ml..). This mixture was allowed to stand at room temperature for 1 hour, after which time the ether was removed by being warmed i n a stream of nitrogen and f i n a l l y i n vacuo. The residual solid reaction mixture was; plunged into a bath at 175° and kept at this temperature for 1 hour. An atmosphere of nitrogen was kept over the reaction mixture during this heating period. The mixture was then cooled to room temperature and water was added cautiously to decompose the excess Grignard reagent. The reaction mixture was then treated with ether and dilute sulphuric acid. The organic phase was separated and the aqueous phase was washed with several portions of ether. The combined b l -ether extract was dried over anhydrous magnesium sulphate and the solvent was removed to yield 700 mg. of a solid material. Recrystallizations of this material from acetone provided the pure phenolic alcohol, XV, m. p. 25U-255° (with some decomposition); infrared: 2.92/1 , 3 .18 / f ; ultraviolet: i n neutral solution, X max 217 (log € 3 « 9 l ) . 281 (log £ 3.36) and shoulder at 287 (log e 3 - 3 2 ) , \ m ± n 2kS m/c (log £ 2.11) j i n alkaline solution, \ 21$, 2li2 and 300 myOt, \ Tl)ijl 228 and 270 m^ ; n. m. r. signals: (pyridine), 9*63 "C (angular methyl, area = 3 H), no OCH^ absorption, 6.80 (H0-C-H, area K l H); (dimethyl sulfoxide), 1.10 X (phenolic H, area =; IH), 5«65 f (secondary alcoholic H, area = 1 H), multiplet centered at 3 * 3 9 f (aromatic H, area = 3 H). Found: C, 79.75; H, 9 .23; 0, 11*32. Calc. f o r G 19 H 26 0 2'- : c> 7 ? * 6 8 i H, 9.15; 0, 11.17. Synthesis of cis-syn-cis-2,8oC -Diacetoxy-10a-methyl-lib,5«.6,6a,7,8  9,10,10a,10b,11,12-dodecahydrochrysene (XVI) The phenolic alcohol, XV (0.579 g.), was treated with isopropenyl acetate (U»5 ml.) and p-toluenesulphonic acid monohydrate (30 mg.) and the whole mixture was heated on a steam bath f o r 15 minutes. The volume of the reaction mixture was slowly reduced to about one-half the original by a slow d i s t i l l a t i o n (about 15 minutes) and the remainder of the volatile materials was removed in vacuo. The residue was then treated with benzene and the benzene extract was washed successively with a saturated solution of sodium bicarbonate and water. The benzene extract was dried over anhydrous magnesium sulphate and the solvent was then removed to provide a yellow gum. This gum was taken up in a mixture of petroleum ether - benzene (9:1) and chromatographed on s i l i c a -52-gel (20 g.). Elution with benzene yielded the diacetate as a yellow glass. D i s t i l l a t i o n of this substance at a bath temperature of 190-200° at 0.01 mm. provided the pure diacetate, XVI, as a li g h t yellow solid glass (280 mg..)j infrared: $.69/A , 5«8l>* J ultraviolet: ^max 2 6 8 ^ 3.28) and 275 m/t (log €. 3-29); \ ^ 252 (log € 3«08)?and 272 m/t (log € 3»25), n. m. r. signals: 8.87 T (angular methyl, area = 3 H), 7.97 ~ t , 7*70 t (acetate methyl groups, area = 3 H each), 5«27t'(AcO-i-H, area = 1 H), multiplet centered at 2.95 X (aromatic H, area - 3 H). Found: C, 7U-83j H, 8.09j 0, 1.7.12. Calc. for C 2 3 H 3 0 0 ^ : C, 7U«56j H, 8 . l 6 j 0 , 17.28. Synthesis of cis-syn-cis-2-Methoxy-8<<r -ac^toxy-10a-methyl-ltb,5,6,6a,  7,8,9^10,10a,10b,11,12-dodecahydrochrysene (XVII) A solution of the saturated alcohol XIV (1.822 g.) i n isopropenyl acetate (21 ml.), and paratoluenesulfonic acid monohydrate (70 mg.) was refluxed for 5 hrs. The liqu i d was evaporated on a steam bath in vacuo and the residue was treated with ether and water. The layers were separated and the aqueous layer was extracted with ether. The combined ether extract was washed with a saturated solution of sodium bicarbonated until effervescence ceased and then washed twice with water. After drying over anhydrous magnesium sulfate, the solvent was removed to yield a crude gum (2.011 g.). One recrystallization from benzene-petroleum ether gave colorless plates (I.I4.OI4. g., m. p. 1 1 0 ° ) . Infrared: 5 . 8 l^t j ultraviolet: X 221 (log £ 3 .89) , 280 (log £ max 3 . 2 . 9 ) , and 287 m/^ilogG 3.29); \ ^ 216 (log Q 3 - 3 8 ) , 2 l £ (log £ -53-ca.. 0), and 285 VH/A, (log £ 3.22); n. m. r. signals (internal TMS): 8.90 X (angular methyl, area - 3 H), 8.00 X (AcO-, area = 3 H), remaining signals i n region 6.7-8.8 X (area = 17 H), 6.27 X ( C H 3 O - , area = 3 H), 5.22 X (AcO-^-H, area - 1 H), raultiplet centered at 3.O6T (aromatic H, area = 3H). Found: C, 77.22; H, 8.82; 0, LU.21. Calc. f o r C 2 2H 3 00 3: C, 77.15; H, 8.83; 0, U+.02. Oxidation of cis-syn-cis-2-methoxy-8^' -acetoxy-10a-methyl-l;a,5.6  6ai7,8.9.10.10a.l0bJ11.12-flodecahydrochrysene (XVII) A solution of t-butyl chromate i n carbon tetrachloride was prepared according to the procedure of Heusler and Wettstein (28) except the f i n a l solution was concentrated to 600 ml. instead of 1000 ml. Aliquots of this solution were then used for the various experiments. The acetateXVII (550 mg.) was dissolved i n dry carbon tetrachloride (17.5 ml.) and to this solution, acetic anhydride (8.7 ml.) and t -butyl chromate (17*5 ml., about 0.003 moles Cr0 3 per ml.) were added. The mixture was refluxed f o r three hours during which time a green precipitate gradually formed. The reaction mixture was cooled, and a solution of oxalic acid (5 g.) in water (35 ml.) was added. This mixture was stirred for two hours at room temperature. The resulting mixture was diluted with chloroform and water, and the layers were, separated. The aqueous layer was extracted twice with chloroform, and the combined reddish chloroform layer was washed twice with cold water and three times with a solution of sodium carbonate (10 g.) i n a saturated aqueous solution of sodium bicarbonate (100 ml.). The basic aqueous layer was extracted once with chloroform, and the chloroform -51+-was added to the main organic extract. The pink basic aqueous layer was acidified with concentrated sulfuric acid to yield a yellow solution. This color was extracted with chloroform and the chloroform extract was washed three times with cold water and dried over anhydrous magnesium sulfate. Evaporation of the solvent yielded a yellow, acidic gum (16 mg.). The chloroform extract containing the neutral material was washed several times with cold water and dried over anhydrous magnesium sulfate. Removal of the solvent provided the neutral product (0.578 g.). This neutral material was dissolved i n benzene (5 ml.) and then chromatographed on deactivated alumina (30 g., approximate activity I I - I I l ) . Elution with benzene gave an orange gum (75 mg.) which probably contained some starting material and some keto-acetate XXIV. Further elution with benzene gave more of the keto-acetate XXI? (0.108 g., 19$ y i e l d ) . The total amount of material eluted off the column was 0.37k g. One recrystallization of the keto-acetate from benzene-petroleum ether gave crystals (70 mg.), m. p. lU3-lUU.5°. A comparison of t h i s product with the compound prepared unambiguously via the octahydrochrysene series was carried out. -'There was no depression on mixed melting point and the infrared, ultraviolet and n. m. r . spectra were identical. Found: C, 75*06; H, 6.68. Calc. for C^H^O^: C, 7ix-975 H, 6.86. Synthesis of 1jB ,6-Dimethyl-6-acetoxy-2,3-(2'-methoxy-6',5l-naphtho)- A 2 - b i c y c l o f3.3.lJ nonene-9-one (XXVI) The unsaturated keto-acetate VIII (1.00 g.) was mixed and powdered with 10$ palladium on carbon (9.750 g.) i n a 250 ml. 3-necked flask The flask was heated for three minutes in a Wood's metal bath at 230-235° with nitrogen passing over the mixture,, Bubbling generally took place in the f i r s t two to two and a quarter minutes, and some acetic acid was evolved near the end of the heating period. The flask, while s t i l l maintained under a nitrogen atmosphere,was then allowed to cool to room temperature.. The residue was treated with hot benzene,, the catalyst f i l t e r e d off, and the solvent evaporated i n vacuo to yield 0 . 9 1 + grams of a product. This material was dissolved i n benzene (7 ml.) and chromatographed on deactivated alumina (60 g., approximate activity I l - I l t ) . Elution with 2:3 benzene-petroleum ether (30-80°) yielded the major by-product, lyfl . 6-dimethyl - 2 , 3 - ( 2 i m e t h o x y - 6 l , 5 ' -naphtho)-A 2» 6-bicyclo [ 3 . 3.I] -nonadiene-9-one (XXV ). Two recrystallizations of this material from benzene-petroleum ether gave an analytical sample of XXV as colourless plates, m. p. 1 8 1 . 5 - 1 8 2 . 0 ° . Infrared: 5 * 8 1 + /I (ketone), no absorption at about 6 .0/K or at 1 1 . 2 ^ ; ultraviolet: A ^ 231 (log € 1 * . 7 6 ) , 266 (log 6 3 . 7 7 ) , 276 (log & 3.16), 286 (log £ 3 . 5 7 ) , 307 (log £ 3 * 0 2 ) , broad shoulder at 315 (loge 3 . 0 6 ) , 320 (log e 3 . 7 2 ) , 329 (log <£- 3 . 1 6 ) , and 335 m^rf (log e 3 - 3 U ) ; \ min 261 (log €. 3 . 7 2 ) , 271 (log ^  3 - 7 1 ) , 28U.5 (log ^ 3 . 5 8 ) , 303 (log e 2 . 9 6 ) , 310 (log e 2 . 9 9 ) , 325 (log €: 3 . 1 2 ) , and 331 m/x. (log 3 « l 5)j n. m. r. signals: 8.U8"C (angular methyl, area • 3 H), quartet centered at 8.32 Z~ ( —6=0-0^, area = 3 H, splittings of 1.7 to 1.8 cps.), • 7.1*2 (Cg-CHg, area •= 2 H), multiplet centered at 6 .88 7J" (tertiary H, area = 1 H), multiplet centered at 6.37 X (benzylic H, area = 2 H), 6.12 T (CH .0-, area - 3 H), 1+.75 " f area = 5 H ) . Found: G , 8 2 . 0 1 * 3 H> 7-10. Calc. for C 2 Q H 2 O 0 2 : G> Q2ml5> H, 6.89. - 5 6 -Further elution with 3«2 benzene-petroleum ether gave the desired keto acetate XXVI (767 mg., 77$ y i e l d ) . Several recrystallizations from aqueous ethanol or benzene-petroleum ether gave colourless square plates, m. p. 1 8 5 . 5 - 1 8 6 . 0 ° . Infrared: 5«79>u (AcO-), 5.81+/4 (ketone); ultraviolet: \ ^  231 (log e 1+.75), 266 (log e 3 . 7 6 ) , 277 (log<£ 3.7l+),287 (log € 3 . 5 7 ) , 307 (log € 3 . 0 3 ) , broad shoulder at 315 (log 6 3.09), 321 (log€ 3 . 2 5 ) , 330 (log 3-18), and 335.5 m/t (log £ 3 . 3 6 ) ; ^ min 2 6 2 ( l o S e 3 * 7 2 ^ 2 7 2 ( l o g € 3-69), 303 (log € 21.97), 311 (log € 3 . 0 0 ) , 326 (log € 3 « U ) , and 331 m/< (log 6 3 « l 8 ) ; n. m. r. signals: 8.1+7 T - (angular methyl, area • 3 H), 8.32 X (GH3-6-OAC, area = 3 H), 8 .00 T (AcO-, area * 3 H), multiplet centered at 7.7J4.7T (tertiary H, area «= 1 H), multiplet centered at 6.50 t (benzylic H, area - ' 2 H), 6 . 10 T ( C H 3 O - , area - 3 H), multiplet centered at 2.1+6 "C (aromatic H, area = 5 H)., Found: G, 71+.89; H, 7.01+. Calc. for C22H2l+0^: C, 7U-98; H, 6.,86. Synthesis of 2-Methoxy-8-keto-lOa-methyl-5,6,8,9,10,lOa-hexahydrochrysene  (XXVII) The apparatus used i n this experiment was set up exactly as in the t r i c y c l i c ketone preparation i n order to maintain anhydrous conditions and a nitrogen atmosphere at a l l times. Into a 1 - l i t e r 3-necked flask, which was flame-dried and evacuated as before, dry methanol (318 ml.) was added, and then sodium (2*9k g.) was added gradually i n small pieces. After the sodium had reacted, the methoxide solution was cooled, and the entire apparatus evacuated u n t i l the solvent began to b o i l . Dry nitrogen was then admitted, the -57-system evacuated, and the entire process repeated several times. To the stirred methoxide solution, a solution of the acetate XXVI ( 7 * 1 8 8 g.) i n dry benzene (81 ml.) was added through a dropping funnel under a flow of escaping nitrogen. After the addition was complete, the system was evacuated, and dry nitrogen admitted to ensure complete removal of oxygen. The reaction mixture was then refluxed for five hours i n this inert atmosphere. At the end of the reflux period, the solution was cooled i n ice, g l a c i a l acetic acid (8.5 ml.) was added and the mixture was swirled for several minutes. Some water and benzene were added to the reaction flask, the layers were then separated, and the aqueous layer was extracted three times with benzene. The combined benzene extract was washed with a cold saturated solution of sodium chloride and dried over anhydrous magnesium sulfate. Evaporation of the solvent i n vacuo provided a yellow crystalline product (5.808 g.). Decoloration with Norit„, and three recrystallizations from benzene provided XXVII as pale green needles, m. p. 198-199°• Infrared: 6.0k/(. ; ultraviolet: >V max broad shoulder at 230 (log € U.83), 236 (log € 1+.86), broad shoulder at 262: (log C 3*9k), 2 7 1 + (log £ 3 . 8 1 + ) , broad shoulder at 28U ( l o g € 3.65), 306 (log € 3.05), broad shoulder at 3U+ (log € 3.12), 319 ( l o g € 3.28), 327 (log € 3.22:), and 333*5 m/t (log€: 3.38) j \ ^ 270 (log € 3 . 8 2 ) , 301 (log € 21.99), 308 (log € 3.03),, 32li (log 6 3.18), and 329 ryt (log e 3.20)- n. m. r . signals: 8 . 3 7 t (angular methyl, area «= 3 H), 6.10 T (CHjO-, area •= 3 H),. h»0k^C ( ~ § - C H = i , area = 1 H ) , , remaining signals in region 6.1 -8.3 t (area =•- 8 H ) , multiplet centered at 2.1+3 "C (aromatic H , area = -58-5H). Founds C, 82.1+5; H, 6.68; 0, 11.08. C a l c for ^cfctPl* C, 82.15; H, 6*89; 0, 10*95. Synthesis of cis-2:-Methoxy-8-keto-10a-methyl-5,6,6a,7„8,9.10,10a-octahydrochrysene (XXVIII) A solution of the oC , ^  -unsaturated ketone XXVII (1*390 g.) i n benzene (9k ml.) was treated with 10% palladium on carbon (0*338 g*) and 3 drops of 1+8$ hydrobromic acid.. This mixture was hydrogenated at room temperature and atmospheric pressure for 3"*"/2 hours:, after which time 1 mole of hydrogen had been absorbed. The catalyst was removed by f i l t r a t i o n and was washed with hot benzene. After evaporation of the solvent i n vacuo, a gum (1.1+97 g.) was obtained. This gum was dissolved in benzene (15 ml.) and chromatographed on deactivated alumina (80 g., approximate activity I I - I I l ) . Elution with 1:2: benzene-petroleum ether (30°-60°C) provided a fraction (1.1+05 g*) which crystallized from ethyl ether. Two further recrystallizations from benzene-petroleum ether yielded pure XXVIII, as colourless plates, m. p. 155.0-155.5°» Infrared: 5*87/-* : ultraviolet: J \ 229 max ( l o g € 1+.82), 255 (log€ 3 .69) , 266 (log € 3-76), 276 (log e 3-77), 286 (log C 3.5.9), 307 (log e 3.03), broad shoulder at 315 (log e. 3*11), 320 (log £ 3.28), 328 (log € 3.21), and 335 m/t (log ^ 3-38); X m ± n 259 (log € 3 .67), 271 (log G 3.71), 281+ (log €= 3 .59), 302 ( l o g € 2.9U), 309 (log <E 3 .01) , 325 (log e 3-17), and 331 m/t (log €. 3*2:0)j n* m. r* signals: 8.63 f (angular methyl, area = 3H), 6.15 t (CR^O-, area = 3 H), signals i n region 7*2-8*5 f (area = 9 H), t r i p l e t at 6*90 7_T (benzylic H, area = 2i H', splittings of 5 and 7 cps toward higher -59-f i e l d ) , multiplet centered at 2.56 T (aromatic H„ area = 5 H). Found: C, 81.60; H, 7.1+5; 0, 10.81;. Calc. for C2oH22°2 ! °> 8 l » 6 0 ; H, 7.53; 0, 10.87. Synthesis of cis-2-Methoxy-8£ -hydroxy-I0a-methyl-5.6,6a,7,8,9,  10,10a-octahydrochrysene (XXIX) This cis ketone XXVIII (3.750 g.) was dissolved i n 60 ml. of dry benzene and then put into the dropping funnel which already contained dry dioxane (100 ml.) and anhydrous ether (50 ml.). This solution was added dropwise, over a period of 12 minutes, to a stirred, refluxing solution of lithium aluminum hydride (2.11+ g.) i n a mixture of dry dioxane (3l+ ml.) and ether (150 ml.). The reaction mixture was refluxed f o r a further 65 minutes, and then cooled to 0°. The excess lithium aluminum hydride was destroyed by careful addition of water and the resulting mixture was acidified with concentrated sulfuric acid (7*2 ml.) diluted with water (81+ ml.). More water and benzene were then added and the layers were separated. The aqueous solution was extracted with benzene, the combined benzene extract was washed with cold water, and f i n a l l y dried over magnesium sulfate. Removal of the solvent yielded the crude product (3.737 g.). This material was purified by chromatography on deactivated alumina (260 g., approximate act i v i t y II-I1T). Elution with 1:1 benzene-petroleum ether (30-60°) provided a small amount of starting material and further elution with 3:2 chloroform-benzene yielded the desired alcohol XXIX. After two recrystallizations from benzene-petroleum ether, the pure product was obtained as..colorless needles, m. p. 150.0-150.5°C Infrared: 2.97(hydroxyl group); ultraviolet: \ m a x - 6 0 -228 (log € U.::82), 251w5 ( l o g € 3-67), 266 (log e 3-75), 276 (log € 3.76), 287 (log € 3 .60) , 307 (log e 3-08), broad shoulder at 31$ (log C 3 .15), 321 (log € 3.31), 329 (log e 3.2U), and 335-5 (log e 3 .U0); X m ± n 252 ( l o g C 3 .66) , 259 (log€- 3 .66), 271 (loge 3*70), 281* (log <= 3 .59), 302. (log ^  3 .01) , 310 (log - e 3.08),. 325 (log 3 .20) , and 331 \n yK. (log e 3«23); n.. m. r. signals: 8.83 X (angular methyl, area = 3 H), quartet centered at 6.98 f (benzylic H, area 5 2 H, splittings of 1*, 5, and 1* cps), 6.50 TT (HO-^-H, area =- 1 H), remaining signalsin region 6.8-9*3 T (area = 10 H), 6.17 tr (CH 3 0-, area = 3 H), multiplet centered at 2.58 X (aromatic H, area - 5 H>. Found: G , 80.82; H, 8.19; 0, I O . 6 3 . Calc. for CgQ^Og: C,, 8l.0l*; H , 8.16; 0, 10.80. Synthesis of cis-2-Methoxy-8 -acetoxy-10a-methyl-5,6,6a,7,8,9,,  10,10a-octahydrochrysene (XXX) The cis alcohol XXIX (L*.672 g.) was treated with p-toluene sulfonic acid monohydrate (156 mg.) and isopropenyl acetate (80 ml.), and the mixture was heated on a steam bath for four and one-half hours. The reaction mixture was cooled to room temperature and pyridine (10 drops) was added. After swirling the mixture, the solvent was evaporated on a steam bath i n vacuo. The residue was dissolved by adding benzene and water. The layers were separated, and the aqueous solution was extracted twice with benzene. The combined benzene extract was washed twice with cold water, and dried over anhydrous magnesium sulfate. Removal of the solvent on a steam bath i n vacuo gave the crude acetate (5«3l* g«). After four re.crystallizations -61-from benzene-petroleum ether, the pure acetate XXX (2.25 g.), m.p* 158-159°, was obtained. Infrared: 5.82/^ \ ultraviolet: A __ 228 {log 6 1+.82), 251+ ( l o g € 3*6U), 266 (log€ 3-73), 276 ( l o g € 3.75), 287 ( l o g 6 3*58), 308 (log € 3.06), broad shoulder at 315 ( l o g * 3.11), 321 (log e 3.29), 329 (log 6 3-22, and 335 m/x (log e 3*1+0); ^ r o i n 2 ^ 1 (log 6 3 . 6 3 0 , 259 (log € 3.63), 271 ( l o g fi 3.6.8), 281+ (log € 3.56), 302 (log € 2.92), 310 (log € 2.99), 325 ( l o g . € 3.18), and 331 m/U (log € 3«2l); n. m. r. signals: 8.78 T" (angular methyl, area - = 3 H), 8 . 1 3 f (AcO-, area = 3 H ) , 6 . 1 7 f " (CH3O-, area s 3 H), 5«21 "C (AcO-C-H, area = 1 H), remaining signals in region 7*2-9*1 f (area •» 9 H), quartet centered at 6 . 9 1 + f (benzylic H, area <= 2 H, splittingpof 5, 1+,,, and 1+ cps. toward higher f i e l d ) , multiplet centered at 2.55 7JT (aromatic H, area = 5 H). Found: C, 78.12j H, 7.6lj 0, H + . 1 + 0 . Calc. for Z^ztPy °> 78.07; H, 7.71*5 0,. 18.16. Synthesis of cis-2-Methoxy-8«C -acetoxy-5-keto-10a-methyl-5,6,6a,7,  8,9,10,IQa-octahydrochrysene (XXIV) (a) By Oxidation with t-Butyl Chromate The methoxy-acetate XXX: (250 mg., 0.00071+ moles) was dissolved i n dry carbon tetrachloride (9 ml., dried over anhydrous calcium chloride), and t-butyl chromate solution (3 ml., about 0.009 moles CrO^) (made by the procedure used i n the cis-syn-cis series) was added a l l at once. The mixture was refluxed with st i r r i n g for four and one half hours. After the mixture was cooled to 0°, a solution of oxalic acid dihydrate (0.9 g.) in water (10 ml.) was added. The reaction mixture was then s t i r r e d , with a l i t t l e cooling, f o r two hours. -62-Ghloroforra and water were added, and then the layers were separated. The aqueous solution was extracted several times with chloroform. The combined organic extract was washed several times with cold water and then with a 1:1 mixture of a saturated aqueous sodium bicarbonate and IN sodium carbonate solution. This carbonate solution was extracted once with chloroform, then acidified with concentrated sulfuric acid and the resulting aqueous acidic layer was extracted with chloroform to yi e l d an acidic fraction (6 mg.). The original organic layer and the f i r s t chloroform extraction of the carbonate solution were combined and washed with cold water u n t i l the washings were neutral to litmus. The organic layer was dried over anhydrous magnesium sulfate and, after removal of the solvent, provided a crude neutral product (186 mg..).. ^he material was purified by chromatography on s i l i c a gel (12 g.). Blution with 2':1 benzene-petroleum ether (30-60°) provided some starting material (1+8 mg.,, 19% recovery) ;and further elution with 3:1 benzene-petroleum ether yielded the desired ketone XXIV (81. mg.,,, 31$ y i e l d ) . After two recrystallizations from benzene-petroleum ether, ligh t yellow square plates, m. p. li+2.5-11+3.0°, were obtained* Infrared:: $.19/A. (acetate group), 6.03/K (conjugated ketone): ultraviolet: A max 22.0 (log € 1+.71), 21+7 (log € 1+.1+5), 316 (log € 3.87), and broad shoulder at 3*1+8 mJUL (log e 3«6l); }\ ^ 232 (log e 1+.28),, and 278 m/< (log £ 3.35); n. m. r . signals: 8.63 X (angular methyl, area = 3 H), 8.13 7j (AcO-, area = 3 H)",; remaining signals in region 7*1+5-9.0 X (area = 7 H ) , 7.1+0 X (a Cg-H, area = I H, doublet with s p l i t t i n g of 2 cps.), 6.65 X and 6.9h ~C (other C5 - H, total area = -63-1 H, doublets with s p l i t t i n g s of 6 and 5 cps., respectively), 6.12: T* (CEjO-, area = 3 H), $.20 T (AcO-C-H, area = 1 H),. multiplet centered at 2.-52 T (aromatic H, area = k H), O.78 77 (C^ - aromatic H, area = 1 H, doublet with s p l i t t i n g of 9 cps.)* Found: C,, 75*08j H, 6.935 0 , 18.09,. Calc. f o r Q22^Zk°ht C, 7U*97j H, 6.86* 0, 18.16. (b) By Oxidation with chromium t r i o x i d e The iTBthoxy-acetat XXX (0.500 g.) was dissolved in a mixture of g l a c i a l acetic a c i d (9*9 ml.) and water 0.1 ml.). A chromic acid solution (0.337 g. CrO^ i n O.63 ml. 80$ aqueous acetic acid) was added dropwise, over a period of 1*5 minutes, t o the mixture kept at room temperature.. The reaction mixture was s t i r r e d for a further t h i r t y - s i x hours at room temperature, the 95$ ethanol (15 ml.) was added to destroy the excess chromic acid.. Water and chloroform were then added and the layers separated. The aqueous solution was extracted several times with chloroform. The combined chloroform extract was washed twice with cold water, twice with saturated sodium bicarbonate o solution, and then four times with 1:1 saturated sodium bicarbonate -IN sodium carbonate solution. The a l k a l i n e aqueous extracts were combined and extracted twice with chloroform. These chloroform extracts were combined with the o r i g i n a l reddish-orange chloroform extract and washed twice with cold water, and f i n a l l y dried over anhydrous magnesium s u l f a t e . Removal of the solvent i n vacuo provided the crude neutral material (O.I46I g.). This material was dissolved i n 3:2: benzene-petroleum ether (30°-60°) (5 ml.) and chromatographed on s i l i c a gel (2:5 g.). Mution with benzene provided some st a r t i n g -6U-material {$9 mg., 12$ recovery), and further elution with the same eluant gave the desired ketone XXIV (6I4. mg.., 1 2 $ y i e l d ) . This ketone was identical to that obtained from the t-butyl chromate oxidation. -65-BIBLIOGRAPHY 1. C. Djerassi, L. Miramontes, G. Rosenkranz, and F. Sondheimer. J. Am,, Chem. Soc, 76, 1+092 (195U). D. A. McGinty and C. Djerassi.. Ann. N. I . Acad. Sci., J l , 500 (1958). V. A. D r i l l and B. Riegel. Recent Progr. i n Hormone Research, l U , 29, • (1958). 2. M. Rajic, T. Rull, and G. Ourisson. Bull . soc. chim. France, 1213 (1961). 3„ T. L. Jacobs and R. B. Brownfield. J. Am. Chem. Soc, 82:, 1+033 (i960). I*. Ch. R. Engel and S. Rakhit. Can. J. Shem., UO, 2153 (1962). 5. J. P. Kutney and R. A. Johnson. Chem. and Ind., 1713 (1961). J. P. Kutney, R. A. Johnson, and I. Vlattas. Can. J. Chem., U l , 613 (1963). J. P. Kutney, I. Vlattas, and G. V. Rao. Can. J. Chem., J x l , in press (1963). 6. E. C. Du Feu, F. J. McQuillin, and R. Robinson., J. Chem. Soc, 53 (19.37). 7. R. Robinson and F. Weygand. J. Chem. Soc, 386 (191+1). 8. J. G. Cook and R. Robinson. J. Chem. Soc, 391 (191+1). 9. J. W. Cornworth and R. Robinson. J.. Chem. Soc, 1855 (19^9)• 10. ¥. S. Johnson. J . Am. Chem. Soc, J_8, 6278 (1956) and subsequent papers. 11. A. L. Wilds, J. W. Ralls, W. C. Wildman, and K. S», McCaleb. J. Am. Chem. Soc, 72, 5791+ (1950). 12. W. S. Johnson, B. Bannister and R. Pappo. J. Am. Chem. Soc., 78, 6331 (1956). 13. W. S. Johnson, J. J. Korst, R. A. Clement, and J. Butta. J. Am. Chem. Soc, 82, 6li* (i960). l U . J. P. Kutney, Wm. McCrae,, and A. By. Can. J. Chem., UQ,\ 982 (1962). 15. R. B. Woodward, F. Sondheimer, D. Taub,, K. Heusler, and W. H, McLamore. J. Am. Chem. Soc, 7l+, 1+223 (1952). 16. G . Slomp and F. MacKellar. J. Am. Chem. Soc, 82, 999 (i960). 17. W. Nagata, T.. Terasawa, S. Hirai, and K. Takeda. Tetrahedron Letters, No._17_, 27 (I960). We found the ultraviolet data presented for <£ , /3 -unsaturated ketone V to be incorrect. We are very grateful to him for providing us with a comparison sample and thereby allowing us to establish, beyond doubt, that their material i s identical with ours. -66-18. ¥. S. Johnson, J. Ackerman, J* F. Eastman, and H. A. De Walt. J. Am. Chem. S o c , J_8 , 6302 (1956) . 19. W. S. Johnson, E. R. Rogier, J. Szmuszkovicz, H. I. Hadler, J. Ackerman, B. K. Bhattacharyya, B. M. Bloom, L. Stalmann,, R. A. Clement, B. Bannister, and H. Wynberg. J. Am. Chem. Soc, 78, 6289 (1956) . 2:0. J. P.. Kutney,. J. Winter, Wm. McCrae, and A. By. Can.. J. Chem., U , 1+70 ( 1963) . 2 1 . E. Sputh. Monatsh., 3 5 , 319 (191U). 2 2 . A. L. Wilds and W. B. McCormack. J . Am. Chem. Soc, 10, 1+127 (191+8). 23. W. S. Johnson, E. R. Rogier, and J . Ackerman. J. Am. Chem. Soc, 78,. 6322 (1956) . 2l+. R. A. Barnes and M., T. Beachem. J. Am. Chem. Soc, 77, 5388 (1955) . 2 5 . ¥. Nagata, T. Terasawa,; S. Hirai,, and K. Takeda. Tetrahedron, 13 , 295 (1961) . 2 6 . W. S. Johnson and W. P. Schneider.. Org. Syntheses, 3 0 , 18 (1950).. 27. A. Hunger and T. Reichstein.. Helv. Chim.. Acta,, 3 5 , 1+3U (1952) . 2 8 . K. Heusler and A. Wettstein. Helv. Chim. Acta, 35,, 281+ (1952:). 

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