Science, Faculty of
Chemistry, Department of
DSpace
UBCV
Inaba, Tadanobu
Master of Science - MSc
University of British Columbia
A sequence leading to the total synthesis of certain derivatives in the 11, 12-seco (see XXIV) and 5, 6-seco hydro-chrysene (see XXXI) series is described. The synthesis employs in its initial stages the Robinson-Mannich base reaction and the Michael condensation reaction to construct the parent tetracyclic skeleton. Condensation of 6-methoxy-2-tetralone with 1-diethylamino-3-pentanone methiodide produced an isomeric mixture of tricyclic ketones. This mixture was then condensed with methyl vinyl ketone to yield a tetracyclic ketol (XII) which in turn was converted to the tetracyclic ketone (XIII) by reaction with sodium methoxide. By appropriate modifications, this latter substance may then be utilized for the synthesis of a variety of hydrochrysene analogues. Oxidation of trans-anti-trans-2-methoxy-8β-acetoxy-10a -methyl-4b, 5, 6, 6a, 7, 8, 9, 10, 10a, 10b, 11, 12-dodecahydrochrysene (XVI) with t-butyl chromate solution gave not only the 12-keto derivative (XIX), but the 5-keto octahydrochrysene analogue (XX) as well as small amounts of the octahydrochrysene (XVII) and the hexahydrochrysene analogue (XVIII). The olefinic bond at the 11, 12 position of ring C (XXII) was introduced by reduction of the 12-keto derivative (XIX) with sodium borohydride, followed by dehydration with phosphorus pentoxide. Subsequent ozonization of XXII yielded the dialde-hyde (XXIV). The olefinic bond at the 5, 6 position of ring B (XVIII) was introduced by the same procedure as in the ring C series. This hexahydrochrysene analogue (XVIII) was reacted with osmium tetroxide to provide the diol (XXVI), which upon treatment with periodic acid yielded the aldol condensation product directly without isolation of the dialdehyde. Nuclear magnetic resonance (n. m. r.) spectroscopy was found to be a powerful tool for the purpose of the characterization of these rather complex molecules.
TOTAL SYNTHESIS OF CERTAIN HYDROCHRYSENE ANALOGUES by TADANOBU INABA B.Eng., U n i v e r s i t y of Osaka Pref., 1962 A THESIS SUBMITTED IN PARTIAL FULFILMENT OF THE REQUIREMENTS FOR THE DEGREE OF MASTER OF SCIENCE i n the Department of Chemistry We accept t h i s t h e s i s as conforming to the requ i r e d standard THE UNIVERSITY OF BRITISH COLUMBIA August, 1964 In p r e s e n t i n g t h i s t h e s i s i n p a r t i a l f u l f i l m e n t of the requirements f o r an advanced degree at the U n i v e r s i t y of • B r i t i s h Columbia, I agree that the L i b r a r y s h a l l make i t f r e e l y a v a i l a b l e f o r r e f e r e n c e and study* I f u r t h e r agree that per-m i s s i o n f o r extensive copying of t h i s t h e s i s f o r s c h o l a r l y • purposes may be granted by.the Head of my Department or by h i s r e p r e s e n t a t i v e s . .It i s understood t h a t ; c o p y i n g or p u b l i -c a t i o n of t h i s t h e s i s f o r f i n a n c i a l gain s h a l l not be allowed without my w r i t t e n permission* Department 1 of CHEMISTRY The U n i v e r s i t y . o f B r i t i s h Columbia, Vancouver 8. Canada Date >t=^T . J©. l i l t ( i i i ) ABSTRACT A sequence leading to the t o t a l synthesis of c e r t a i n derivatives i n the 11, 12-seco (see XXIV) and 5, 6-seco hydro-chrysene (see XXXl) series i s described. The synthesis.employs i n i t s i n i t i a l stages the Robinson-Mannich base reaction and the Michael condensation reaction to construct the parent t e t r a c y c l i c skeleton. Condensation of 6-methoxy-2-tetralone with l-diethylamino -3-pentanone methiodide produced an isomeric mixture of t r i c y c l i c ketones. This mixture was then condensed with methyl v i n y l ketone to y i e l d a t e t r a c y c l i c k e t o l (XII) which i n turn was converted to the t e t r a c y c l i c ketone (XIIl) by reaction with sodium methoxide. By appropriate modifications, th i s l a t t e r substance may then be u t i l i z e d for the synthesis of a variety of hydrochrysene analogues. i Oxidation of trans-anti-trans-2-methoxy-8(3-acetoxy-10a -methyl -4b, 5, 6, 6a, 7, 8, 9, 10, 10a, 10b, 11, 12-dodecahydro-chrysene (XVI) with t-butyl chromate solution gave not only the 12-keto derivative (XIX), but the 5-keto octahydrochrysene analogue (XX) as well as small amounts of the octahydrochrysene (XVII) and the hexahydrochrysene analogue (XVIII). The o l e f i n i c bond at the 11, 12 p o s i t i o n of ri n g C (XXII) was introduced by reduction of the 12-keto derivative (XIX) with sodium borohydride, followed by dehydration with phosphorus pentoxide. Subsequent ozonization of XXII yielded the dialde-hyde (XXIV). The o l e f i n i c bond at the 5, 6 position of ri n g B (XVIII) was introduced by the same procedure as i n the r i n g C s e r i e s . ( i v ) T h i s h e x a h y d r o c h r y s e n e a n a l o g u e ( X V I I I ) was r e a c t e d w i t h osmium t e t r o x i d e t o p r o v i d e t h e d i o l ( X X V T ) , w h i c h upon t r e a t m e n t w i t h p e r i o d i c a c i d y i e l d e d t h e a l d o l c o n d e n s a t i o n p r o d u c t d i r e c t l y w i t h o u t i s o l a t i o n o f t h e d i a l d e h y d e . N u c l e a r m a g n e t i c r e s o n a n c e ( n . m. r . ) s p e c t r o s c o p y was f o u n d t o be a p o w e r f u l t o o l f o r t h e p u r p o s e o f t h e c h a r a c t e r i z a -t i o n o f t h e s e r a t h e r complex m o l e c u l e s . ACKNOWLEDGEMENTS I wish to express my very sincere thank and a p p r e c i a t i o n to Dr. James P. Kutney f o r h i s help and encouragement throughout the. course of the research and the pr e p a r a t i o n of t h i s t h e s i s , and to Mr. Arnold W. By f o r h i s i n v a l u a b l e i n s t r u c t i o n s and patience i n the experimental aspects. ( v ) TABLE OF CONTENTS Page I n t r o d u c t i o n 1 D i s c u s s i o n 10 Experimental 46 B i b l i o g r a p h y • gj_ L i s t of Figures Pa ge Figure I 3 Figure 2 • • • 4 Figure 3 • 5 Figure 4 • • • 6 Figure 5 7 Figure 6 7 Figure 7 9 Figure 8 • 11 Figure 9 12 Figure 10 15 Figure 11 15 Figure 12 • 17 Figure 13 17 Figure 14 18 Figure 15 • * • ' 18 Figure 16 19 Figure 17 21 Figure 18 21 Figure 19 23 Figure 20 23 Figure 21 • • 24 Figure 22 24 Figure 23 25 Figure 24 • 27 Figure 25 27 Figure 26 29 Figure 27 28 Figure 28 •• • • 29 Figure 29 30 Figure 30 33 Figure 31 • 3 3 Figure 32 35 Figure 33 ' 3 6 Figure 34 36 Figure 35 38 ( v i ) Figure 36 * • v . ^ ^ * ^ * ^ ^ ' * 38 Figure 37 " 42 Figure 38 42 Figure 39 .*. 43 F i g u r e 40 I^ v^ -^ v:.-;.^ ;. . . . ;•. . , n 4 ^ . Figure 4 l 44 •• Figure' 42 c ; • • ';•:>•• •(• >;vr>> 44 - 1 -INTRODUCTION Recently a considerable e f f o r t has been put forward to study the effects of substituents attached to steroid skeleton on the b i o l o g i c a l properties of these compounds. Indeed dra-matic effects have been obtained with substituents such as methyl, hydroxyl, and halogen, p a r t i c u l a r l y f l u o r i n e , when these groups are situated at s p e c i f i c positions on the nucleus. Related to these studies, the removal of an angular methyl group, as i n 1 8 - n o r and 1 9 - n o r steroids, or of methylene groups from the r i n g skeleton to generate ri n g contracted s t e r o i d a l n u c l e i , has also been accompanied by important al t e r a t i o n s i n the b i o l o g i c a l a c t i v i t y of these molecules ( l , 2 ) . 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 s t e r o i d a l nucleus and to investigate the b i o l o g i c a l properties of such compounds ( 3 7 4 , 5 ) . Most of the above researches have involved the use of the nat u r a l l y occurring steroids as s t a r t i n g materials. Although these are obviously the l o g i c a l choice i n most cases, they offered c e r t a i n l i m i t a t i o n s i n synthesizing some of the s t e r o i d a l derivatives which were of interest i n our studies concerned with the relationships between 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 directed toward the t o t a l synthesis of s t e r o i d a l analogues, with p a r t i c u l a r emphasis on i n t e r --2-m e d i a t e s w h i c h w o u l d r e a d i l y l e n d t h e m s e l v e s t o t h e i n t r o d u c t i o n o f s u b s t i t u e n t s o r a l t e r a t i o n s o f t h e a c t u a l s k e l e t o n n o t c o n -v e n i e n t l y p o s s i b l e f r o m t h e n a t u r a l s t e r o i d s . More p a r t i c u l a r l y , we were i n t e r e s t e d i n d e v e l o p i n g a t o t a l s y n t h e s i s o f compounds h a v i n g t h e m o d i f i e d s t e r o i d a l s k e l e t o n , namely a C - n o r - D - h o m o o r B - n o r - D - h o m o s y s t e m . I t s h o u l d be n o t e d t h a t t h e C - n o r - D - h o m o s k e l e t o n e x i s t s i n t h e V e r a t r u m a l k a l o i d s o f w h i c h j e r v i n e ( I ) and v e r a t r a m i n e ( I I ) a r e c i t e d as e x a m p l e s . To t h e p r e s e n t t h e s e a l k a l o i d s have n o t b e e n p r e p a r e d s y n t h e t i c a l l y , b u t r e -c e n t l y t h e C - n o r - D - h o m o n u c l e u s has b e e n s u c c e s s f u l l y a s s e m b l e d b y J o h n s o n a n d h i s c o - w o r k e r s ( 6 ) . I : H I t I s i n t e r e s t i n g t o n o t e t h a t t h e V e r a t r u m a l k a l o i d s were o b s e r v e d t o be i n s t r u m e n t a l i n r e d u c i n g e l e v a t e d b l o o d p r e s s u r e o f p a t i e n t s w i t h e s s e n t i a l h y p e r t e n s i o n (7). F u r t h e r m o r e some D-homo s t e r o i d s e x h i b i t h i g h m y o t r o p i c a c t i v i t y a n d may p r o v e t o be u s e f u l as a n a b o l i c a g e n t s whereas c e r t a i n a r o m a t i c s t e -r o i d a l a n a l o g u e s c a n r e t a r d t h e g r o w t h o f tumor c e l l s (8). - 3 -Several 19-nor s t e r o i d a l hormones are more b i o l o g i c a l l y active than the normal steroids themselves. ( 9 ) . Furthermore, the f u l l y aromatic D-homo analogue, chrysene i t s e l f , has some a b i l i t y to induce enzyme and protein synthesis. ( 1 0 ) . The B-nor analogues of cert a i n steroids are found to be antiandrogenic, and such an agent would be therapeutically use-f u l i n post-puberal and idlopathetic hirsutism i n women, the Stein-Leventhal syndrome, androgen dependent prostatic tumors and adolescent and premenstrual acne. (.11, 1 2 ) . Of the various synthetic approaches which were av a i l a b l e , the one u t i l i z i n g the Robinson-Mannich base reaction o r i g i n a l l y developed by Robinson and co-workers ( 1 3 , 14, 1 5 , 16) and so successfully applied i n the elegant researches of Johnson and co-workers (17) appeared most suitable. In a paper published i n 1 9 3 7 , BuFeu, McQulllin, and Robin-son (13) found that the methiodide s a l t of l-diethylamino - 3 -butanone (DABM) condensed with 2-methylcyclohexanone to give 1 ( 9 ) mainly 10-methyl- _ v -2-decalone. Figure 1 -4 -This r e a c t i o n demonstrated that the i n i t i a l condensation of the two molecules took place p r e f e r e n t i a l l y at the t e r t i a r y c a r -bon atom ok to the carbonyl group and not at the secondary carbon d to t h i s group. In 1941, Robinson and Weygand ( l4) condensed the same meth-io d i d e s a l t (DABM) with 1-methyl -2-decalone to give 2-keto -12 -methyl-/^'1'''' ^-dodecahydrophenanthrene. Figure 2 They proved that the i n i t i a l condensation took place at the t e r t i a r y carbon atom by dehydrogenating the above dodecahydro-phenanthrene with selenium to phenanthrene and 2-hydroxyphen-anthrene. Cornfort.h and Robinson ( l6 ) prepared 1, 7~diketo - 2 , 13-dimetbylperhydrophenanthrene (Figure 3) which was i d e n t i c a l with an authentic sample obtained from methyldiacetyldeoxycho-l a t e . The s i g n i f i c a n c e of t h i s work was that the angular methyl group i n the condensation product of l-diethylamino - 3-butanone methiodide and 5 -i Tiethoxy-l-methyl - 2-tetralone i s i n the (3 -con-f i g u r a t i o n . -5-F i g u r e 3 - 6 -W i l d s e t a l (19) were the f i r s t t o i n t r o d u c e the a n g u l a r m e t h y l group by the Robinson-Mannich base r e a c t i o n . F i g u r e 4 I t s h o u l d be noted t h a t W i l d s a s s i g n e d i n c o r r e c t s t r u c t u r e s t o some of h i s i n t e r m e d i a t e s i n t h i s p a p e r . I n 1956, Johnson (17) p u b l i s h e d h i s "hydrochrysene appro-ach" t o the t o t a l s y n t h e s i s of s t e r o i d s u t i l i z i n g the W i l d s p r o c e d u r e of c o n d e n s a t i o n . Johnson's c o n d e n s a t i o n sequence i s summarized i n F i g u r e 5« T h i s method of c o n d e n s a t i o n gave a G-19 a n g u l a r m e t h y l group h a v i n g the (B>-conf i g u r a t i o n . T h i s was pro v e n c o n c l u s i v e l y when Johnson, B a n n i s t e r and Pappo (21) s y -n t h e s i z e d d l - e p i a n d r o s t e r o n e and showed t h a t i t s i n f r a r e d spectrum was i d e n t i c a l t o t h a t of ttie n a t u r a l l y d e r i v e d d - e p i -a n d r o s t e r o n e . -7-Figure 5. In a paper published i n I 9 6 0 , Johnson ( 2 2 ) described i n d e t a i l , evidence f o r a s s i g n i n g the bridged s t r u c t u r e to k e t o l s ( i l l ) and (IV) obtained as i n d i c a t e d i n Figure 5« -8-The conformational expressions f o r these k e t o l s are represented i n ( I l i a ) and ( i V a ) . In h i s e a r l i e r papers, Johnson (17) had i n d i c a t e d the s t r u c t u r e of these k e t o l s as shown by (V) and ( V I ) . However subsequent c o n s i d e r a t i o n of the nuclear magnetic resonance (n. m. r.) spectra of these k e t o l s showed that the s t r u c t u r e s (V) and (VI) were i n c o r r e c t . I n p a r t i c u l a r , the presence of two s i g n a l s at high f i e l d i n d i c a t e d the presence of two C— methyl groups. This evidence c l e a r l y excluded s t r u c t u r e s (V) and (VI) which should show only one C-methyl s i g n a l i n the n. m. r . s p e c t r a . A considerable amount of chemical evidence was a l s o presented to provide conclusive proof f o r s t r u c t u r e s ( I I I ) and ( I V ) . With the s t r u c t u r e s of the k e t o l s f i r m l y e s t -a b l i s h e d , i t f o l l o w s that t h e i r f a c i l e conversion, i n the pre-sence of sodium methoxide, to the unsaturated ketone ( V I I I ) had to i n v o l v e a reverse a l d o l r e a c t i o n to i n i t i a l l y provide the intermediate diketone ( V I I ) . -9-OCH, OH ( V , V l ) ( V I I I ) Figure 7 This ketone undergoes c y c l i z a t i o n to give the o r i g i n a l l y post-ulated a l d o l s t r u c t u r e (V) and / or (VI) which undergoes ^ - e l i -m ination of water to the o(,^-unsaturated ketone ( V I I I ) . John-son has shown that the major k e t o l ( I l i a ) has an a x i a l hydroxy group at C-6 by reducing t h i s k e t o l to a d i o l and t r e a t i n g t h i s d i o l with t h i o n y l c h l o r i d e , i n the presence of p y r i d i n e , to form a c y c l i c s u l f i t e e s t e r . On the other hand, the d i o l from (IV a) f a i l e d to. give such a d e r i v a t i v e . -10-DISCUSSION The s u c c e s s of the "hydrochrysene approach" to our problem has been d e s c r i b e d i n r e c e n t p u b l i c a t i o n s from our l a b o r a t o r i e s ( 2 3 , 24, 2 5 ) and the p r e s e n t d i s c u s s i o n d e a l s o n l y w i t h the a s p e c t s r e l e v e n t t o t h i s t h e s i s . F i g u r e s 8 and 9 i n d i c a t e the s y n t h e t i c sequence l e a d i n g to the t r a n s - a n t i - t r a n s s e r i e s of h y d r o c h r y s e n e a n a l o g u e s . Now t h a t the t r a n s - a n t i - t r a n s s e r i e s c o u l d be o b t a i n e d i n h i g h y i e l d we c o n s i d e r e d the i n t r o d u c t i o n of a f u n c t i o n a l group i n t o r i n g C of the hydrochrysene s k e l e t o n (see XVI) i n o r d e r t o p r o v i d e an e n t r y i n t o s y n t h e t i c i n t e r m e d i a t e s where r i n g C has been opened. A p o s s i b l e approach t o t h i s problem was a v a i l a b l e from the work of Johnson and c o l l a b o r a t o r s (20) w h e r e i n an a c e -t a t e f u n c t i o n was i n t r o d u c e d i n r i n g C ( C 1 2 ) °f t h e i r h y d r o -chrysene analogue by means of l e a d t e t r a a c e t a t e . I n i t i a l c o n s i d e r a t i o n was g i v e n t o t h i s r e a c t i o n a l t h o u g h i t was r e -c o g n i z e d a t the o u t s e t t h a t the m e t h o x y l f u n c t i o n i n ( X V I ) , by v i r t u e o f i t s para r e l a t i o n s h i p t o the carbon atom d e s i g n a t e d as 4b, c o u l d s e r i o u s l y a f f e c t the s u c c e s s of t h i s a p p r o a c h . I t was f e l t , however, t h a t the a c t i v a t i o n by t h i s m e t h o x y l f u n c t i o n which c o u l d f a v o r the i n t r o d u c t i o n of s u b s t i t u e n t s a t 4b i n s t e a d of the d e s i r e d p o s i t i o n C 1 2 may be overcome by the ease of r e a c t i o n a t the secondary c a r b o n C-^ r e l a t i v e t o the t e r t i a r y c e n t e r ( 4 b ) . I t s u b s e q u e n t l y became known from o t h e r work i n our l a b o r a t o r y (24) t h a t the i n t r o d u c t i o n of s u b s t i t u e n t s -11-C H 3 ] ? ; EtoN^-CHo-CHo-C-Et (IX) Synthesis of T e t r a c y c l i c Ketone X I I I Figure 8 - 1 2 -X I I I Synthesis of Trans-Anti-Trans Hydrochrysene Analogues Figure 9 -13-such as a c e t a t e or bromine a t the d e s i r e d p o s i t i o n c o u l d not be a c c o m p l i s h e d s u c c e s s f u l l y s i n c e the predominant r e a c t i o n which always o c c u r r e d under the attempted c o n d i t i o n s was an a r o m a t i z a t i o n of r i n g C. I t was t h e n f e l t t h a t a d i r e c t o x i d a -t i o n of t h i s b e n z y l i c p o s i t i o n (C-^) may prove f e a s i b l e , and t h e r e f o r e the o x i d a t i o n of (XVI) w i t h chromium t r i o x i d e i n ace- : t i c a n h y d r i d e a t 0° was a t t e m p t e d . The y i e l d of the d e s i r e d 12-k e t o p r o d u c t was v e r y low s i n c e as i n the above i n s t a n c e s , p r o -d u c t s r e s u l t i n g from i n i t i a l o x i d a t i o n a t were always a com-p l i c a t i n g f a c t o r . I t was c o n s i d e r e d t h a t any o x i d a t i o n a t the t e r t i a r y c arbon 4b c o u l d presumably be e l i m i n a t e d i f a s t e r i c -a l l y l a r g e o x i d a n t was used. For t h i s r e a s o n , the methoxy a c e -t a t e (XVI) was o x i d i z e d w i t h t - b u t y l chromate and indeed a sub-s t a n t i a l improvement was r e a l i z e d — o n e of the r e a c t i o n p r o d u c t s b e i n g the d e s i r e d dodecahydrochrysene analogue (XIX) ( 2 4 ) . A l t h o u g h the s y n t h e t i c i n t e r m e d i a t e f o r f u r t h e r s t u d y at r i n g C was now a v a i l a b l e i t was c l e a r t h a t the r e a c t i o n p r o v i d e d a m i x t u r e of s e v e r a l p r o d u c t s . I n o r d e r t o u nderstand more f u l l y the n a t u r e of t h i s r e a c t i o n i t became, n e c e s s a r y t o i s o l a t e and c h a r a c t e r i z e some of the minor components. The f i r s t p a r t of t h i s t h e s i s i s concerned w i t h t h i s a s p e c t . Our i n i t i a l o x i d a t i o n e x p e r i m e n t s were c a r r i e d out on l a r -ger amounts of m a t e r i a l t h a n had been p r e v i o u s l y done (24) i n o r d e r ' t o o b t a i n s u f f i c i e n t amounts of the minor components f o r complete c h a r a c t e r i z a t i o n . Some s t a r t i n g m a t e r i a l was a l s o r e c o -v e r e d from the o x i d a t i o n r e a c t i o n and was e a s i l y s e p a r a t e d from -14-the d e s i r e d 12-keto compound (XIX) (Figure 10, 11, 12) by a l u -mina chromatography. Since XIX had been w e l l c h a r a c t e r i z e d i n previous work i n t h i s l a b o r a t o r y (24) no f u r t h e r d i s c u s s i o n r e -garding i t s s t r u c t u r e i s necessary here. Further i n v e s t i g a t i o n s were c a r r i e d out on the minor compo-nents present i n the mother l i q u o r s from r e c r y s t a l l i z a t i o n of the 12-keto compound (XIX). Another alumina chromatography was a t -tempted whereupon e l u t i o n with 15:1 benzene:chloroform y i e l d e d a very small amount of a c r y s t a l l i n e f r a c t i o n . The i n f r a r e d spec-trum of t h i s f r a c t i o n indicated, that a conjugated carbonyl chro-mophore could not be present. The u l t r a v i o l e t spectrum was q u i t e complex and immediately suggested a s u b s t i t u t e d naphthalene chromophore. I n v e s t i g a t i o n on t h i n - l a y e r chromatoplates i n d i c a t -ed only one spot however a nuclear magnetic resonance (n. m. r.) spectrum showed two sets of methyl, a c e t y l and methoxyl peaks. I t was t h e r e f o r e c l e a r that the above f r a c t i o n contained two com-ponents which possessed very S i m i l a r R f values on t h i n - l a y e r chromatography (TLC). From other work i n our l a b o r a t o r y (25) I t was apparent that the components of the mixture were probably the octahydrochrysene analogue (XVII) and the hexahydrochrysene ana-logue ( X V I I I ) . The evidence to confirm these s t r u c t u r e s i s given i n the f o l l o w i n g d i s c u s s i o n . The s e p a r a t i o n of the two components of the mixture was best accomplished by 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 since f o r t u n a t e l y one of these was l e s s s o l u b l e i n e t h y l a l c o h o l . A f t e r two r e c r y s t a l -l i z a t i o n s s u f f i c i e n t amounts of the pure compounds could be ob-- 1 5 -Pigure 1:1 U.V. spectrum of XIX -16-t a i n e d f o r c h a r a c t e r i z a t i o n . The u l t r a v i o l e t spectrum ( F i g u r e 13) of the more s o l u b l e co-mponent was v e r y i n f o r m a t i v e here and showed the t y p i c a l c o m p l i -c a t e d spectrum of a n a p h t h a l e n i c chromophore (2v 227* 256, max. 266, 276, 287, 307, 314, 319, 328 and 334 mu). A p a r t from the u s u a l c a r b o n y l a b s o r p t i o n c h a r a c t e r i s t i c of the a c e t a t e f u n c t i o n i n the i n f r a r e d spectrum (1718 cm 1 ) ( F i g u r e 1 4 ) , the n. m. r . spectrum ( F i g u r e 15) of t h i s s ubstance a l s o i n d i c a t e d some i n t e -r e s t i n g f e a t u r e s . For example, the a n g u l a r m e t h y l and the meth-o x y l s i g n a l s (8 .8 l-and 6 . l i t ) were down f i e l d when compared to the c o r r e s p o n d i n g s i g n a l s i n the spectrum of the dodecahydro-chrysene analogue ( X V I ) . However the s i g n a l f o r the a c e t a t e m e t h y l group (7.95^) had not been e f f e c t e d t o an a p p r e c i a b l e e x t e n t . F u rthermore the area under the a r o m a t i c s i g n a l s i n d i -c a t e d f i v e a r o m a t i c p r o t o n s and c o n f i r m e d the u l t r a v i o l e t e v i -dence which had suggested a naphthalene chromophore. I n o r d e r t o e s t a b l i s h the s t r u c t u r e o f t h i s compound as i n d i c a t e d i n X V I I , t h i s l a t t e r s u b s t a n c e was s y n t h e s i z e d by an unbiguous r o u t e and i t s s y n t h e s i s i s p r e s e n t e d below. I t was c l e a r t h a t d e h y d r o g e n a t i o n s t u d i e s on the compound ( X X I I ) may p r o v i d e b e 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 p o s s e s s i n g an a r o m a t i c r i n g C. S i n c e X X I I can be s y n t h e s i z e d from the 12-keto dodecahydrochrysene analogue (XIX) by r e d u c t i o n , f o l l o w e d by de-h y d r a t i o n , t h i s sequence was s e r i o u s l y c o n s i d e r e d ( F i g u r e 16). F u r t h e r m o r e , the i n t r o d u c t i o n of an o l e f i n i c bond a t the 11,12 p o s i t i o n ( X X I I ) would a l l o w e n t r y i n t o the p r e p a r a t i o n of - 1 7 -Pigure 13 U.V. specrum of XVII / V T H S F i g u r e 1 5 n.m.r. spectrum-ov XVII (CDC.1-,) -19-compounds w i t h an open r i n g C arid t h i s p r o v i d e d f u r t h e r encourage-F i g u r e 16 With t h i s i n mind, the 12-keto compound (XIX) was reduced w i t h sodium b o r o h y d r i d e t o p r o v i d e a c o l o r l e s s o i l . S i n c e t h i s o i l c o u l d be a m i x t u r e of 12d- and 12(^-hydroxy compounds and s i n c e the subsequent d e h y d r a t i o n of both o f these would g i v e the same f i n a l p r o d u c t , the i s o l a t i o n of each a l c o h o l was not a t t e m p t e d . As e x p e c t e d , t h i s o i l had a s t r o n g h y d r o x y l a b s o r p t i o n and no c o n j u g a t e d c a r b o n y l band i n the i n f r a r e d spectrum. The u l t r a -v i o l e t spectrum a l s o i n d i c a t e d the absence of a c o n j u g a t e d chromophore, and now was a l m o s t i d e n t i c a l w i t h the spectrum of the methoxy a c e t a t e ( X V I ) . I t was now o b v i o u s t h a t the r e d u c t i o n had proceeded i n a v e r y h i g h y i e l d . The f o l l o w i n g d e h y d r a t i o n -20-{ o f the a l c o h o l (XXI) w i t h phosphorus p e n t o x i d e was c a r r i e d out a t the temperature of r e f l u x i n g benzene. The p r o d u c t o b t a i n e d was the e x p e c t e d methoxy a c e t a t e ( X X I I ) . The i n f r a r e d spectrum ( F i g -ure 17) of t h i s l a t t e r m a t e r i a l showed the d i s a p p e a r a n c e of the hydroxy group and the u l t r a v i o l e t spectrum ( F i g u r e 18) i n d i c a t e d a t y p i c a l m-methoxy s t y r e n e chromophore (^X m Q V 221,262,270,302 md x . and 313 mu). I n p a r t i c u l a r , the n.m.r. spectrum ( F i g u r e 19) i n d i c a t e d a c o n s i d e r a b l e d i f f e r e n c e i n the low f i e l d r e g i o n . An o l e f i n i c p r o t o n on C-^ now appeared as a d o u b l e t c e n t e r e d a t 4.11T and the o t h e r o l e f i n i c p r o t o n on C o c c u r r e d as a q u a r t e t c e n t e r e d a t 3.63T. However the a n g u l a r m e t h y l (9.14T), the a c e t a t e (8.02T) and the methoxyl (6.29T) peaks were not s h i f t e d t o an a p p r e c i a b l e e x t e n t . I t was t h e r e f o r e c l e a r from a l l of the above e v i d e n c e t h a t the s t r u c t u r e of the d e h y d r a t i o n p r o d u c t was the decahydro-chrysene analogue as d e p i c t e d i n ( X X I I ) . When t h i s l a t t e r com-pound was t r e a t e d w i t h 10$ p a l l a d i u m on c h a r c o a l a t 240 - 2 4 5 ° , i t gave a new c r y s t a l l i n e compound. The s p e c t r a l data p r o v i d e d s t r o n g e v i d e n c e f o r the su c c e s s of the d e h y d r o g e n a t i o n and was i n complete agreement w i t h the exp e c t e d s t r u c t u r e ' ( X V I I ) . T h i s sequence now a l l o w e d us t o e s t a b l i s h the s t r u c t u r e of one of the minor components from the t - b u t y l chromate o x i d a t i o n of the methoxy a c e t a t e ( X V I ) . I t was shown that the more a l c o h o l - s o l u b l e component mentioned above was i d e n t i c a l i n e v e r y r e s p e c t w i t h the oc t a h y d r o c h r y s e n e analogue ( X V I I ) from the above s y n t h e s i s . The o t h e r minor component from the t - b u t y l chromate o x i d a t i o n - 2 1 -F i g u r e 1.8 U.V. spectrum of XXII - 2 2 -of compound (XVI) was thought to be the hexahydrochrysene analogue ( X V I I I ) . The i n f r a r e d spectrum i n d i c a t e d the usual carbonyl ab-s o r p t i o n c h a r a c t e r i s t i c of the a c e t y l f u n c t i o n (Figure 2 0 ) , and the u l t r a v i o l e t spectrum (Figure 2 1 ) showed some i n t e r e s t i n g f e a t u r e s . The naphthalenic chromophore was suggested by the complex spectrum (7^. 2 4 4 , 2 7 6 , 2 8 8 , 3 0 1 , 3 1 4 , 3 3 5 and 351 mu) and ma x • j the bathochromic s h i f t of the absorption bands f u r t h e r suggested that t h i s compound had an extra double bond conjugated with the aromatic system. The n.m.r. spectrum (Figure 2 2 ) showed the angu-l a r methyl at 8 . 9 3 T , the acetate at 7>9^% a ^ d the methoxyl peak at 6 . 1 0 1 — a l l of these being c h a r a c t e r i s t i c of a naphthalenic compound. At lower f i e l d s i g n a l s i n the o l e f i n i c r egion (lH) and i n the aromatic r e g i o n (6H) were observed, and s t r o n g l y suggested the s t r u c t u r e ( X V I I I ) f o r t h i s component. Apart from the f i v e aromatic protons, one would expect that the o l e f i n i c proton at C^ (see X V I I I ) should be i n the aromatic r e g i o n , because of i t s p r o x i m i t y to the aromatic system. In order to e s t a b l i s h the s t r u c t u r e of t h i s hexahydrochrysene analogue ( X V I I I ) , t h i s compound was hydrogenated with 10$ palladium on charcoal (Figure 2 3 ) . The compound was shown to absorb one mole of hydrogen and a new c r y s t a l l i n e product was i s o l a t e d . This hydrogenation product turned out to be i d e n t i c a l i n every respect with the octahydrochrysene analogue ( X V I I ) . I t was now e s t a b l i s h e d that the other component separated by 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 from the t - b u t y l chromate o x i d a t i o n mixture was the hexahydro-chrysene analogue ( X V I I I ) . -23-J 1 • ! . 1 1 ! L. 3 V 5 6 7 % t\ F i g u r e 19 n.m.r. spectrum of X X I I (CDC1,) WRV6 L E N & T U C M i C R O M S " i F i g u r e 20 I.R. spectrum of X V I I I (CHC1-J - 2 4 -Pigure 22 n.m.r. spectrum of XVIII - 2 5 -F i g u r e 23 A f t e r d e s c r i b i n g the above two minor components from the o x i -dation-, one more compound which was i s o l a t e d from the mother l i q -uor from c r y s t a l l i z a t i o n of the 1 2-keto compound (XIX) w i l l be p r e s e n t e d h e r e . As b e f o r e , an i n i t i a l s e p a r a t i o n was made by column chromatography. E l u t i o n w i t h 15 :1 benzene : c h l o r o f o r m gave the above compounds ( X V I I ) and ( X V I I I ) , but f u r t h e r e l u t i o n w i t h 8 : 2 benzene : c h l o r o f o r m p r o v i d e d another f r a c t i o n which Showed two s p o t s on t h i n l a y e r chromatography (TLC). One of those c o r r e s p o n d e d to the known 1 2-keto dodecahydrochrysene ( X I X ) . S i n c e the o t h e r compound was l e s s s o l u b l e than XIX, i t was p u r i -f i e d by 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 from e t h e r . T h i s c r y s t a l l i n e compound showed two c a r b o n y l bands i n the i n f r a r e d spectrum ( F i g -ure 24) (1718 and 1662 c m - 1 ) which suggested t h a t an a c e t y l and a c o n j u g a t e d c a r b o n y l group was p r e s e n t . The p o s i t i o n of t h i s l a t t e r band was i d e n t i c a l w i t h t h a t observed i n the spectrum of a 5-keto o c t a h y d r o c h r y s e n e w i t h a r i n g A/B c i s f u s i o n which had been p r e v i o u s l y p r e p a r e d i n our l a b o r a t o r y ( 2 5 ) . The u l t r a v i o l e t spectrum ( F i g u r e 2 5 ) was a l s o v i r t u a l l y s u p e r i m p o s i b l e w i t h t h a t of t h i s s ubstance ( c i s - 2 - m e t h o x y - 8 c ( a c e t o x y - 5 - k e t o - 1 0 a - m e t h y l --26-Pigure 25 U.V. spectrum of XX - 2 7 -5 , 6 , 6 a , 7 , 8 , 9 i l O , 1 0 a - o c t a h y d r o c h r y s e n e ) . T h i s s p e c t r o s c o p i c d a t a s u g g e s t e d t h a t the new compound was t h e 5 - k e t o o c t a h y d r o c h r y s e n e a n a l o g u e (XX) w h i c h has the r i n g A / B t r a n s j u n c t i o n . The n . m . r . s p e c t r u m ( F i g u r e 26) a l s o showed some i n t e r e s t i n g f e a t u r e s . F o r i n s t a n c e , the a n g u l a r m e t h y l peak was s h i f t e d d o w n f i e l d t o 8 . 7 6 T and a c o n d i d e r a b l e d i f f e r e n c e was n o t e d i n the a r o m a t i c r e g i o n when compared t o t h a t o f the s t a r t i n g m a t e r i a l ( X V I ) . More s i g -n i f i c a n t l y , a low f i e l d d o u b l e t c o r r e s p o n d i n g t o one p r o t o n ,. • was ;found( a t O . 9 3 T j ; , tfnom i p r e v i o u s i . i w o r k . i n o u r ; l a b o r a t o r y (25); it-,was a p p a r e n t t h a t ' t h i s ; d o u b l e t was. due to the C4 a r o m a t i c h y d r o -gen atom .(see X X ) . I t may be e x p e c t e d t h a t t h i s p r o t o n w o u l d be d e s h i e l d e d by v i r t u e o f i t s c l o s e p r o x i m i t y t}-.o t h e c a r b o n y l o x y -gen a t Cpj. . I n o r d e r t o e s t a b l i s h t h e s t r u c t u r e ' o f t h i s m i n o r component as the t r a n s 5 - k e t o compound ( X X ) , a n a t t e m p t was made t o c o n v e r t t h i s compound t o the h e x a h y d r o c h r y s e n e a n a l o g u e ( X V I I I ) ( F i g u r e 2 7 ) . R e d u c t i o n o f t h e above w i t h s o d i u m b o r o h y d r i d e p r o v i d e d a c r u d e p r o d u c t w h i c h e x h i b i t e d the u s u a l s p e c t r a l p r o p e r t i e s f o r t h e e x p e c t e d a l c o h o l ( X X I I I ) . W i t h o u t f u r t h e r p u r i f i c a t i o n , t h i s p r o d u c t was r e f l u x e d w i t h p h o s p h o r u s p e n t o x i d e i n d r y benzene t o p r o v i d e a c r y s t a l l i n e compound w h i c h was f o u n d t o be i d e n t i c a l i n e v e r y r e s p e c t w i t h t h e h e x a h y d r o c h r y s e n e a n a l o g u e ( X V I I I ) . T h i s I n t e r c o n v e r s i o n e s t a b l i s h e d the s t r u c t u r e o f the t h i r d m i n o r component f r o m t h e o x i d a t i o n as t r a n s - 2 - m e t h o x y - 8 ( i - a c e t o x y - 5 - k e t o -1 0 a - m e t h y l - 5 ,6,6 a , 7 , 8 , 9 , 1 0 , 1 0 a - o c t a h y d r o c h r y s e n e ( X X ) . I t c o u l d be c o n c l u d e d t h a t t h e t - b u t y l chromate o x i d a t i o n o f the methoxy a c e t a t e ( X V I ) gave a p a r t f r o m some r e c o v e r e d -28-OCH, (XX) ( X X I I I ) (XVIII) Figure 27 s t a r t i n g m a t e r i a l , four products. The major compound was the d e s i r e d 12-keto d e r i v a t i v e (XIX) and three minor components— the octahydrochrysene analogue ( X V I I ) , the hexahydrochrysene ana-logue (XVIII) and f i n a l l y the 5-keto octahydrochrysene analogue (XX). Now that the synthesis of the 12-keto intermediate had been completed i t was then necessary to consider the synthesis of r i n g C modified s t e r o i d a l analogues. The i n t r o d u c t i o n of an o l e f i n i c . bond at the £±±,±2 p o s i t i o n (XXII) was c a r r i e d out by r e d u c t i o n of the 12-keto dodecahydrochrysene analogue (XIX), followed by dehy-d r a t i o n as already mentioned above (Figure 16) f o r the synthesis o f . the octahydrochrysene analogue ( X V I I ) . The o l e f i n i c linkage now o f f e r e d a convenient "handle" to inte-rmediates i n which r i n g G ihad been opened. One of the obvious methods involved o z o n o l y s i s of the double bond (see X X I I ) . Consequently the o l e f i n (XXII) was t r e a t e d . w i t h ozone at - 7 8 ° and the ozonide was cleaved r e d u c t i v e l y (Hg,Pd/C) to pr o v i d e , i n very low y i e l d , the d e s i r e d dialdehyde (XXIV). The s p e c t r a l p r o p e r t i e s of t h i s substance were i n complete agreement with the assigned s t r u c t u r e . For example the u l t r a v i o --29-Figure 28 U.V. spectrum of XXIV - 3 0 -l e t spectrum ( F i g u r e 2 8 ) i n d i c a t e d t h a t the chromophore ( . X max. 2 1 1 , 2 5 3 , and 320 mu) p r e s e n t was q u i t e s i m i l a r t o t h a t o f the 1 2 -k e t o dodecahydrochrysene analogue ( X I X ) . F u r t h e r m o r e , there.was an aldehyde C-H s t r e t c h i n g a b s o r p t i o n (2735 cm" 1) and a c o n j u g a t e d c a r b o n y l band a t 1683 cm" 1 i n the i n f r a r e d spectrum. I n a d d i t i o n the s a t u r a t e d c a r b o n y l a b s o r p t i o n band was broad and more i n t e n s e t h a n the c o n j u g a t e d c a r b o n y l a b s o r p t i o n which i n d i c a t e d t h a t the s a t u r a t e d aldehyde and a c e t a t e c a r b o n y l groups were a b s o r b i n g i n the same r e g i o n . A l l the s p e c t r a l data agreed w i t h the s t r u c t u r e (XXIV) which was s u b s e q u e n t l y e s t a b l i s h e d i n a n o t h e r s e r i e s of i n v e s t i g a t i o n as d e s c r i b e d below ( F i g u r e 2 9 ) . , F i g u r e 29 D u r i n g the course of our s t u d i e s on the o z o n i z a t i o n r e a c t i o n i t was o b v i o u s t h a t the y i e l d of the d e s i r e d d i a l d e h y d e was v e r y poor and an o t h e r pathway f o r s y n t h e s i z i n g t h i s d i a l d e h y d e (XXIV) was s i m u l t a n e o u s l y a t t e m p t e d by Mr. A r n o l d By i n our l a b o r a t o r y . - 3 1 -I t Is w e l l known that osmium t e t r o x i d e i s capable of hydroxyla t i n g o l e f i n i c l i n k a g e s ( 2 9 ) and i t seemed the reagent of choice f o r t h i s purpose. The expected d i o l could be cleaved by means of p e r i o d i c a c i d to the dialdehyde ( 3 0 ) . A c t u a l l y i t turned out that these r e a c t i o n s proceeded w e l l and an o v e r - a l l y i e l d of 54$ of the dialdehyde was r e a l i z e d . This l a t t e r compound was found to be i d e n t i c a l i n every respect (TLC, UV) with the product syn-t h e s i z e d by the o z o n i z a t i o n technique. Further c h a r a c t e r i z a t i o n by Mr. By e s t a b l i s h e d the dialdehyde s t r u c t u r e . I t was t h e r e f o r e decided to abandon any f u r t h e r work on the o z o n i z a t i o n r e a c t i o n since undesirable complications arose by t h i s procedure. Our next c o n s i d e r a t i o n turned to the synthesis of r i n g B modified s t e r o i d a l analogues, since the necessary hexahydrochryse-ne (XV I I I ) and octahydrochrysene (XVII) analogues were a v a i l a b l e £from the t - b u t y l chromate o x i d a t i o n . I t was reasonable to con- , jsider the o x i d a t i o n of the Ccj-Cg double bond i n XVIII since a s i m i l a r s e r i e s of r e a c t i o n s were already s u c c e s s f u l i n the r i n g C s e r i e s . Reaction of osmium t e t r o x i d e on XVIII (four days at room temperature with 3 0 $ excess osmium t e t r o x i d e ) followed by decomposition of the osmate este r by means of hydrogen s u l f i d e provided a c r y s t a l l i n e product. The u l t r a v i o l e t spectrum of t h i s compound immediately i n d i c a t e d a naphthalenic chromophore ( A a x < 234, 2 5 4 , 264, 274, 284, 3 0 6 , 3 1 8 , 327 and 333. mu) and the i n f r a r e d spectrum (Figure 3 0 ) i n d i c a t e d very intense hydro-x y l absorption (3420 cm 1 ) . I t was therefore q u i t e obvious that the r e a c t i o n gave the d e s i r e d d i o l (XXVI). F u r t h e r , the n. m. r . spectrum i n d i c a t e d some i n t e r e s t i n g f e a t u r e s . Although t h i s - 3 2 -d i o l (XXVI) d i d not d i s s o l v e i n deuteriochloroform or d e u t e r i o -acetone, i t was s o l u b l e i n p y r i d i n e . I t i s w e l l known that p y r i -dine g e n e r a l l y causes an u p f i e l d s h i f t of the various s i g n a l s ( 2 8 ) and t h i s was observed i n t h i s instance as w e l l . The n. m. r . spectrum of the d i o l (Figure 3 1 ) showed the angular methyl peak at 9 . 2 7 T , the acetate peak at 8.457T and the methoxyl s i g n a l a t 6 . 6 7 T — a l l r e p r e s e n t i n g an u p - f i e l d s h i f t when compared to the corresponding s i g n a l s i n the spectrum of the s t a r t i n g m a t e r i a l i n deuteriochlorofornt. A quartet centered at 6 . 3 7 T and corresponding to one proton could be assigned to the proton at Cg, whereas a doublet centered at 4.92Tand corresponding to one proton was a t t r i b u t e d to the proton on C^. This s p e c t r a l data was i n comp-l e t e agreement with the s t r u c t u r e of a 5 , 6-dihydroxy octahydro-chrysene analogue (XXVI). I t was now e s s e n t i a l to cleave t h i s v i c i n a l d i o l (XXVI) with p e r i o d i c a c i d i n the hope of o b t a i n i n g the corresponding d i a l d e -hyde (Figure 3 2 ) . This r e a c t i o n was set up i n methanol s o l u t i o n and i t was f e l t that the extent of the conversion could be f o l -lowed by withdrawing a l i q u o t s of the r e a c t i o n mixture and measu-r i n g the u l t r a v i o l e t spectrum. However the spectrum d i d not seem to change at a l l d u r i n g the course of the r e a c t i o n . A f t e r a l l o w -i n g to stand f o r 16 hours, the r e a c t i o n product was i s o l a t e d and compared with the s t a r t i n g m a t e r i a l (XXVI) on t h i n l a y e r chroma-tography. I t was immediately obvious that some r e a c t i o n had taken place since the product was completely d i f f e r e n t from the s t a r t i n g m a t e r i a l and showed a R f value of 0 . 8 as compared to 0 . 3 f o r the s t a r t i n g d i o l ( s i l i c a g e l G, 1:1 CHCl^:Et0Ac). Since the u l t r a -- 3 3 -F i g u r e 31 n . m . r . spectrum o f X X V I ( p y r i d i n e ) - 3 4 -v i o l e t spectrum showed no conjugated naphthalenic chromophore and a l s o the i n f r a r e d spectrum i n d i c a t e d no conjugated carbonyl ab-s o r p t i o n , t h i s product could not be the dialdehyde. The n. m. r . spectrum (Figure 3 3 ) provided the answer as to the s t r u c t u r e of t h i s m a t e r i a l . In p a r t i c u l a r the re g i o n normally c h a r a c t e r i s t i c of methoxyl methyl groups i n our s e r i e s showed three s i n g l e t s of equal i n t e n s i t y at 6 . 1 2 , 6 . 2 2 and 6 . 4 5 ^ . This i n d i c a t e d the pre-sence of three methoxyl groups i n the product and since only one OCH^ i s present i n the s t a r t i n g d i o l (XXVI), two new OCH^ groups appear dur i n g the p e r i o d i c a c i d cleavage. Coupled with the i n f r a red and u l t r a v i o l e t data the above evidence suggested immediately that the p e r i o d i c a c i d r e a c t i o n product could be assigned s t r u c -ture (XXVII). -35-XXIX (XXX) (XXXII) Figure 32 In other words, cleavage had indeed occurred but the intermediate dialdehyde c y e l i z e d to a hemiacetal-structure (XXVIII) which r e -acted with the methanol under the a c i d i c c o n d i t i o n s to form the c y c l i c a c e t a l - t y p e s t r u c t u r e (XXVII). There i s ample precedent f o r these r e a c t i o n s i n carbohydrate chemistry. I f the s t r u c t u r e XXVII was c o r r e c t i t should regenerate the hemiacetal XXVIII on treatment with g l a c i a l a c e t i c a c i d (31). Indeed when the above substance was warmed with t h i s a c i d on a steam bath f o r 40 minutes, a new product was obtained which had l o s t two OCH^ groups as i n d i c a t e d i n the n. m. r . spectrum ( F i g -ure 34) on t h i s product. Apart from the lone methoxyl s i g n a l (6.12T) a considerable d i f f e r e n c e was a l s o noted on the low f i e l d r e g i o n of the n. m. r . spectrum. This r e g i o n i n d i c a t e d two s i g -n a l s (0 .62 and -1.15) each corresponding to one proton which must be a t t r i b u t e d to the two protons of the hemiacetal system present i n XXVIII. I t could a l s o be argued that the formation of the c y c l i c a c e t a l (XXVII) d u r i n g the p e r i o d i c a c i d cleavage could be pre-vented by the use of a solvent other than methyl a l c o h o l . Con-sequently the d i o l (XXVI) was reacted with p e r i o d i c a c i d i n d i o x a -ne s o l u t i o n and, as expected, the r e a c t i o n product was indeed the -37-h e m i a c e t a l ( X X V I I I ) . I t was i d e n t i c a l i n e v e r y r e s p e c t w i t h the p r o d u c t o b t a i n e d from the a c e t i c a c i d h y d r o l y s i s of the a c e t a 1 X X V I I . A l t h o u g h the ' s p e c t r a l e v i d e n c e was i n complete agreement w i t h the h e m i a c e t a l and'aceta1 s t r u c t u r e s (XXVII and X X V I I I ) i t was not p o s s i b l e t o p r o v i d e any a n a l y t i c a l data f o r t h e s e com-pounds. I n each i n s t a n c e the r e a c t i o n p r o d u c t s were v i s c o u s o i l s and a p a r t from the f a c t t h a t o n l y minute amounts were a v a i l -a b l e t o us, t h e y were a l s o not s u f f i c i e n t l y s t a b l e f o r f u r t h e r p u r i f i c a t i o n as mentioned below. D u r i n g the course of our i n v e s t i g a t i o n which always i n v o l v e d r e a c t i o n s of v e r y s m a l l amounts we had d e v e l o p e d t h i n - l a y e r c h r o -matography t e c h n i q u e s f o r the s e p a r a t i o n and p u r i f i c a t i o n of p r o -d u c t s i n amounts as low as s e v e r a l m i l l i g r a m s . A p p l i c a t i o n of _ t h i s method t o the above compounds r e v e a l e d not o n l y t h e i r i n s t -a b i l i t y but a l s o suggested a p r o c e d u r e f o r the next s t e p i n the s y n t h e t i c sequence. When the h e m i a c e t a l X X V I I I was p l a c e d on an alumina t h i n - l a y e r c h r o m a t o p l a t e a gray spot (R^ 0.7) was shown a f t e r s p r a y i n g w i t h antimony t r i c h l o r i d e - a c e t i c a c i d s o l u t i o n . On the o t h e r hand, when the h e m i a c e t a l was p l a c e d on a s i l i c a g e l p l a t e , a brownish y e l l o w s p o t . (R^ 0.8) was o b s e r v e d . These r e -s u l t s s uggested t h a t a r e a c t i o n may be o c c u r r i n g d u r i n g the a t -tempted p u r i f i c a t i o n and i d e n t i f i c a t i o n . T h i s s u g g e s t i o n was c o n f i r m e d when the compound was e x t r a c t e d from t h e alumina p l a t e and i t s u l t r a v i o l e t spectrum ( F i g u r e 36) was r e c o r d e d . The ge-n e r a l shape of the curve was the same as o r i g i n a l l y o bserved i n the spectrum o f the h e m i a c e t a l but now t h e r e was a bathoehromic Figure 36 U.V. spectrum of XXIX -39-s h i f t of the a b s o r p t i o n maxima by about 4 mu. T h i s type of s p e c t -rum would be e x p e c t e d f o r the c y c l i c s t r u c t u r e XXIX and i t was s e r i o u s l y c o n s i d e r e d as a d i s t i n c t p o s s i b i l i t y . I t s f o r m a t i o n i s e a s i l y r a t i o n a l i z e d i f one c o n s i d e r s t h a t the h e m i a c e t a l opens t o the d i a l d e h y d e which i m m e d i a t e l y undergoes an i n t e r n a l a l d o l c o n d e n s a t i o n t o p r o v i d e XXIX. There i s p r e c e d e n t i n the l i t e r -a t u r e f o r an a l u m i n a - c a t a l y z e d i n t e r n a l a l d o l r e a c t i o n . For ex-ample, Takeda r e p o r t e d t h i s type of c y c l i z a t i o n i n the t e r p e n e s e r i e s (32). The s p e c t r a l p r o p e r t i e s o f the above compound i n q u e s t i o n p r o v i d e d s t r o n g s u p p o r t f o r the s t r u c t u r e XXIX. A p a r t from the u l t r a v i o l e t data mentioned above, the i n f r a r e d spectrum ( F i g u r e 35) i n d i c a t e d an a l d e h y d e C-H s t r e t c h i n g band and no c o n j u g a t e d . c a r b o n y l a b s o r p t i o n . The n. m. r . spectrum ( F i g u r e 37) was p a r t -i c u l a r l y h e l p f u l . Above a l l , a low f i e l d s i g n a l a t 0.41T i n d i c a -t i v e o f one aldehyde p r o t o n showed t h a t o n l y one aldehyde f u n c -t i o n c o u l d be p r e s e n t . The o t h e r s i g n a l s were a l s o i n e x c e l l e n t agreement w i t h the s t r u c t u r a l f e a t u r e s e x p r e s s e d i n XXIX. A l -though the o i l y n a t u r e of the p r o d u c t and the s m a l l q u a n t i t i e s a v a i l a b l e p r e v e n t e d f u r t h e r c h a r a c t e r i z a t i o n a t t h i s t i m e , we f e l t r e a s o n a b l y c e r t a i n t h a t the above assignment was c o r r e c t . As i t t u r n e d o u t , a n o t h e r i n v e s t i g a t i o n on r i n g C analogues was b e i n g conducted and analogous s t r u c t u r e t o the above was o b t a i n -ed and c o m p l e t e l y e s t a b l i s h e d . The p e r t i n e n t f e a t u r e s o f the n. m. r . spectrum of t h i s l a t t e r m a t e r i a l a r e v e r y s i m i l a r t o the above mentioned data f o r XXIX. T h i s p r o v i d e d s t r o n g s u p p o r t f o r -40-the r a t i o n a l i z a t i o n s mentioned above. I t must be emphasized t h a t the o r i e n t a t i o n of the aldehyde and the h y d r o x y l groups a r e not p r e s e n t l y known and f u r t h e r i n v e s t i g a t i o n s are n e c e s s a r y t o c o m p l e t e l y e s t a b l i s h t h i s c y c l i c s t r u c t u r e . Our next c o n s i d e r a t i o n was t o o x i d i z e the hydroxy group on C_ i n XXIX. The Jone's r e a g e n t (33) i s w e l l known as a m i l d • 5 o x i d a n t , and i t was s e l e c t e d f o r t h i s p u r p o s e . When the above substance was t r e a t e d w i t h t h i s r e a g e n t , we observed not o n l y the c o n v e r s i o n o f the h y d r o x y l group t o a ketone but a l s o the p a r t i a l l o s s of the aldehyde f u n c t i o n . The i n f r a r e d spectrum of the crude o x i d a t i o n p r o d u c t i n d i c a t e d the complete d i s s a p p e a r a n c e of the h y d r o x y l group and a weak aldehyde C-H s t r e t c h i n g a b s o r p t i o n , (2755 c m - 1 ) . T h i s data suggested t h a t the o x i d a t i o n r e a c t i o n y i e l d e d a m i x t u r e of the ketone w i t h the aldehyde group s t i l l i n t a c t (XXX) and the p r o d u c t i n which the aldehyde group was l o s t ( X X X I I ) . From o t h e r work i n our l a b o r a t o r y , i t was o b v i o u s t h a t the d e f o r -m y l a t i o n r e a c t i o n can occur d u r i n g the course o f Jone's o x i d a t i o n . I n s p i t e of t h i s s p e c t r a l data which suggested a m i x t u r e of com-po n e n t s , t h i n l a y e r chromatography ( a l u m i n a , CHCl^) i n d i c a t e d o n l y one s p o t . T h e r e f o r e i t appeared t h a t the components of the m i x t u r e must have v e r y s i m i l a r R f v a l u e s under the above TLC c o n d i t i o n s . C o n s e q u e n t l y the m i x t u r e was s u b j e c t e d to p u r i f i c a -t i o n by 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 . The compound t e n t a t i v e l y a s s i g n e d s t r u c t u r e XXX c r y s t a l l i z e d from e t h e r q u i t e e a s i l y . The o t h e r ketone ( X X X I I ) remained i n the mother l i q u o r and c o u l d t h r e -f o r e be s e p a r a t e d . U n f o r t u n a t e l y t h i s l a . t t e r substance was a gum and r e s i s t e d a l l a t t e m p t s a t c r y s t a l l i z a t i o n . -41-The u l t r a v i o l e t spectrum (Figure 3 8 ) of the c r y s t a l l i n e ketone (XXX) showed a t y p i c a l conjugated chromophore, and the i n f r a r e d spectrum (Figure 3 9 ) i n d i c a t e d the conjugated carbonyl band (1686 cm"1) and an a-ldehyde C-H s t r e t c h i n g a b sorption (2755 cm - 1) i n good accordance with the s t r u c t u r e depicted i n (XXX). Furthermore, the n.m.r. spectrum (Figure 40) showed some i n t e r e s t -i n g f e a t u r e s i n the lower f i e l d r e g i o n . A doublet centered at ; 1 .25T i n d i c a t e d an aromatic proton on C^, as observed i n the 5~ keto octahydrochrysene analogue (XX), and a sharp s i n g l e t at 0 .87T corresponding to one proton confirmed the presence of one aldehydic proton at p o s i t i o n C^ a. These spectroscopic data were i n complete agreement with the s t r u c t u r e (XXX). The mother l i q u o r from the c r y s t a l l i z a t i o n of the ketone (XXX) was evaporated down to y i e l d a gum. Thin l a y e r chromato-graphy (alumina jCHCl^) i n d i c a t e d only one spot, but as already mentioned above t h i s component had the same R^ , value as the c r y s -t a l l i n e ketone (XXX). The i n f r a r e d spectrum i n d i c a t e d a conjuga-ted carbonyl a b s o r p t i o n , but d i d not show any aldehyde C-H s t r e t -ching band. The u l t r a v i o l e t spectrum (Figure 4 l ) a l s o i n d i c a t e d a conjugated chromophore ( A 2 1 9 , 245 and 308 mu, broad shoul-ma x. j der at 345 mji) s i m i l a r to that of the 5-keto octahydrochrysene analogue (XX). I n p a r t i c u l a r , the n.m.r. spectrum (Figure 42) looked q u i t e s i m i l a r to that of the ketone (XXX) except f o r the complete absence of the aldehydic proton s i g n a l . A doublet cen-tered at 1.14T showed that the ketone group was present at C ' 5 ' and i t s close p r o x i m i t y to the aromatic proton at caused t h i s downfield s h i f t . Since t h i s ketone could not be c r y s t a l l i z --42-Pigure 38 U.V. spectrum of XXX - 4 3 -I L JL J _ (• "I Z °l VVPrVE LEN6-TH ( MlCRoMS ") to ' i F igu re 39 I . R . spectrum of XXX CHO OCH3 (XXX) 2.00 <=pvr o~ sft set F i g u r e - 4 0 n .m. r . spectrum of XXX - 4 4 -- 4 5 -ed, : • t h i s s t r u c t u r a l assignment (XXXII ) r e s t s s o l e l y on spec t roscop i c ev idence . I t must be emphasized tha t i t w i l l be \ necessary to c h a r a c t e r i z e t h i s compound f u r t h e r when l a r g e r amounts are a v a i l a b l e f o r f u r t h e r work. In c o n c l u s i o n , the above i n v e s t i g a t i o n has p rov ided an ent ry i n t o the r i n g B-nor s t e r o i d a l d e r i v a t i v e s but f u r t h e r work w i l l be necessary to complete t h i s aspect of the prob lem. -46-EXPERIMENTAL A l l m e l t i n g p o i n t s were determined on a K o f l e r - b l o c k appara -tus and are u n c o r r e c t e d . The u l t r a v i o l e t spect ra were recorded i n 95$ e thano l on Cary r e c o r d i n g spectrophotometers (Model C-l4 or C - l l ) . Except where otherwise s t a t e d , the i n f r a r e d spect ra were recorded as potass ium bromide p e l l e t s on a Pe rk in -E lmer Model 21 spect rophotometer . The nuclear. ' magnetic resonance (n.m. r . ) spec t ra were taken on a V a r i a n A - 6 0 h igh r e s o l u t i o n s p e c t r o -meter i n deu te r i och lo ro fo rm or p y r i d i n e wi th te t ramethy l s i l a n e as i n t e r n a l r e f e r e n c e . The p o s i t i o n s of the s i g n a l s were recorded i n the T i e r s % s c a l e . The ana lyses were performed by D r . A . Bernhardt and a s s o c i a t e s , Mulheim (Ruhr) Germany, and by M iss C . J e n k i n s , U n i v e r s i t y of B r i t i s h Co lumbia . Reduc t ion of 2 - M e t h o x y - 8 - k e t o - 1 0 a - m e t h y l - 5 . 6 , 8 . 9 . 1 0 , 1 0 a , 1 1 , 1 2 - octahydrochrysene ( X I I I ) To a s t i r r e d mix ture of anhydrous l i q u i d ammonia (210 m l , d r i e d by p a s s i n g through sodium hydrox ide p e l l e t s ) and a n i l i n e (35 m l , f r e s h l y d i s t i l l e d and d r i e d over sodium hydroxide p e l l e t s ) , sodium (3-5 g) was added i n sma l l p i e c e s . A s o l u t i o n of the t e t r a -c y c l i c k e t o n e , X I I I , ( 3 . 5 g ) ( 2 3 ) i n anhydrous t e t r ahyd ro fu ran (70 ml) was added to the b lue ammonia s o l u t i o n over a pe r i od of 7 m i -nutes w i th n i t r o g e n p a s s i n g through the appa ra tus . The mix ture was s t i r r e d f o r a f u r t h e r 14 minu tes , a f t e r which time ammonium c h l o r i d e ( 8 . 4 g) was added i n p o r t i o n s . The ammonia was a l lowed - 4 7 -to evaporate and the r e s u l t i n g res idue was t rea ted wi th water and then ex t rac ted w i th e t h e r . The ether l a y e r was washed w i th d i l u t e h y d r o c h l o r i c a c i d , aqueous sodium carbonate , and f i n a l l y w i th wa te r . A f t e r the s o l u t i o n was d r i e d over anhydrous magnesium s u l -pha te , the so l ven t was removed to y i e l d ye l l ow s o l i d (3 .24 g . ) . Th i s s o l i d was p u r i f i e d by chromatography on alumina (175 &•> grade I I I ) . E l u t i o n w i th 2 : 1 benzene : e ther p rov ided t r a n s - a n t i -t rans - 2 - m e t h o x y - 8 - k e t o - 1 0 a - m e t h y l - 4 b , 5 , 6 , 6 a , 7 , 8 , 9 , 1 0 , 1 0 a , 1 0 b , 1 1 , 12 -dodecahydrochrysene (XIV) (773 m g . ) . ( 2 ^ ) Fu r the r e l u t i o n wi th 1:2 benzene : e ther p rov ided t r a n s - a n t i -t r a n s - 2 - m e t h o x y - 8 ^ - h y d r o x y - l O a - m e t h y l - 4 b , 5 , 6 , 6 a , 7 , 8 , 9 , 1 0 , 1 0 a , 1 0 b , 11 ,12 -dodecahydrochrysene (XV ) ( 2 . 1 9 3 g . ) . ( 2 4 ) Syn thes i s of t r a n s - a n t i - t r a n s - 2 - M e t h o x y - 8 ^ - h y d r o x y - 1 0 a - m e t h y l - 4 b , 5 , 6 , 6 a , 7 , 8 , 9 , 1 0 , 1 0 a , 1 0 b , 1 1 . 1 2 - d o d e c a h y d r o c h r y s e n e (XV) A s o l u t i o n of the sa tu ra ted ke tone ,X IV , ( 2 . 6 6 g . ) i n methanol (105 m l . ) was t r ea ted w i th a s o l u t i o n of sodium borohydr ide ( 1 . 3 7 g . ) i n methanol (105 m l . ) and water (26 m l . ) , and the mix ture was r e f l u x e d f o r 3 hou rs . The mix ture was then t rea ted wi th concen-t r a t e d h y d r o c h l o r i c a c i d (26 m l . ) and r e f l u x e d f o r a f u r t h e r hour. The s o l u t i o n was concent ra ted i n vacuo to a volume of 30 m l . , water and e ther were added, and the ether l a y e r was sepa ra ted . The e ther l a y e r was washed wi th water and then d r i e d over anhy-drous magnesium s u l p h a t e . Removal of the so l ven t p rov ided a c r y s -t a l l i n e product ( 2 . 5 7 g . ) ' Th i s compound was i d e n t i c a l w i th that obta ined from the B i r c h r e d u c t i o n . -48-Syn thes i s of t rans -an t i - t rans -2 -Me thoxy -8 f t -ace toxy -10a -methy l -4b , 5 , 6 ,6a ,7 .8 .9 ,10 ,10a ,10b ,11 ,12-dodecahydrochrysene (XVI) The a l c o h o l , X V , ( 3 . 7 6 g . ) was d i s s o l v e d i n an excess of a c e t i c anhydr ide (70 m l . ) c o n t a i n i n g s e v e r a l drops of p y r i d i n e . A f t e r r e f l u x i n g ove rn i gh t , the mix ture was coo led down to room tempera-t u r e , then poured onto cracked i c e and a l lowed to stand f o r 30 m i -nu tes . The r e s u l t i n g o i l was ex t r ac ted w i th e ther and the e ther e x t r a c t was washed w i th aqueous sodium b icarbonate and wa te r . A f t e r the s o l u t i o n was d r i e d over anhydrous magnesium s u l p h a t e , the so l ven t was removed and the remain ing product was taken up i n benzene - petro leum ether and chromatographed on alumina (200 g . , a c t i v i t y grade I I I ) . E l u t i o n wi th 3:2 benzene : petro leum ether p rov ided the major f r a c t i o n (3*70 g . ) , which was the d e s i r e d t r a n s -ant i - t r a n s -2 -methoxy -8^ -ace toxy-10a - m e t h y l - 4 b , 5 . 6 , 6 a , 7 . 8 , 9 , 1 0 , 1 0 a , 10b,. 11,12-dodecahydrochrysene ( X V l ) / 2 m ? p . 101-102°; n .m. r . s i g n a l s (CDC1 3 ) : 9.18 (angular me thy l , area=3H), .8.02 (CH^COO-, area=3H), 6.28 ( C H 3 O - , area=3H),broad s i g n a l centered a t 5.28 (H-C-OAc, a rea= lH) , m u l t i p l e t centered a t 2.85 (aromat ic H, area=3H). O x i d a t i o n of the Methoxy ace ta te (XVI) A s o l u t i o n of t - b u t y l chromate i n carbon t e t r a c h l o r i d e was prepared acco rd ing to the procedure of Heus le r and W e t t s t e i n (34) except the f i n a l s o l u t i o n was concent ra ted to 600 m l . i n s t ead of 1000 m l . . A l i q u o t s of t h i s s o l u t i o n were then used fo r the v a r i -ous exper iments . - 4 9 -The methoxy a c e t a t e , XV I , (6.70 g . ) was d i s s o l v e d i n carbon t e t r a c h l o r i d e ( l80 m l . ) , and the t - b u t y l chromate s o l u t i o n (90 m l . ) , which was mixed wi th a c e t i c anhydr ide (15 m l . ) , was added. The mix ture was s t i r r e d under r e f l u x f o r 4 hours and the excess ox idant was then dest royed by s t i r r i n g wi th a s o l u t i o n of o x a l i c a c i d (75 g . ) i n water (500 m l . ) f o r 2 hours . The carbon t e t r a -c h l o r i d e l a y e r was separated and the so lven t was removed i n vacuo. The res idue was taken up i n e t h e r . The ether s o l u t i o n was washed wi th aqueous sodium b icarbonate to remove any r e s i d -ua l a c e t i c a c i d , and then washed wi th a 1:1 mixture of a s a t u r -a ted aqueous sodium b icarbonate and a IN potass ium carbonate s o l u t i o n . The organ ic l aye r was d r i e d over anhydrous magnesium su lphate and, a f t e r removal of the s o l v e n t , p rov ided 6.25 g . of a crude n e u t r a l p roduc t . The m a t e r i a l was p u r i f i e d by chromato-graphy on alumina (300 g . , grade I I I ) . E l u t i o n wi th 7:3 benzene: pet ro leum ether p rov ided s t a r t i n g m a t e r i a l (3.74 g . , 56$) and f u r t h e r e l u t i o n w i th 9:1 benzene:ether y i e l d e d the d e s i r e d ketone (XIX)(24) (1 .16 g . , 16%), m. p. 145.5 -147°. n . m. r . s i g n a l s : (CDCI3) 9.0.6 (angular me thy l , area--3H), 7.98 (CH^COO-, area - -3H) , 6.I7 (CH^O-, a r e a :3H), 5-20 (b road, H-C-OAc, a rea= lH) , m u l t i p l e t centered a t 2.66 (aromat ic H, area~3H). The mother l i q u o r from the r e c r y s t a l l i z a t i o n of the 12-keto compound XIX was i n v e s t i -gated i n more d e t a i l . A f t e r evapora t i ng o f f the so lven t the gum-my product was p u r i f i e d by another alumina chromatography (WOELM, GRADE I ) . E l u t i o n wi th 15:1 benzene:ch loro form y i e l d e d a very sma l l amount of. c r y s t a l l i n e f r a c t i o n . F r a c t i o n a l c r y s t a l l i z a t i o n from 95$ e thano l gave two compounds: F i r s t , l e s s so l ub le compo--49-The methoxy a c e t a t e , XV I , ( 6 . 7 0 g . ) was d i s s o l v e d i n carbon t e t r a c h l o r i d e ( l 8 0 m l . ) , and the t - b u t y l chromate s o l u t i o n (90 m l . ) , which was mixed wi th a c e t i c anhydr ide (15 m l . ) , was added. The mix ture was s t i r r e d under r e f l u x f o r 4 hours and the excess ox idant was then dest royed by s t i r r i n g wi th a s o l u t i o n of o x a l i c a c i d (75 g . ) i n water (500 m l . ) f o r 2 hours . The carbon t e t r a -c h l o r i d e l a y e r was separated and the so l ven t was removed i n vacuo. The res idue was taken up i n e t h e r . The ether s o l u t i o n was washed w i th aqueous sodium b icarbonate to remove any r e s i d -ua l a c e t i c a c i d , and then washed wi th a 1:1 mixture of a s a t u r -a ted aqueous sodium b icarbonate and a IN potass ium carbonate s o l u t i o n . The organ ic l aye r was d r i e d over anhydrous magnesium su lphate and, a f t e r removal of the s o l v e n t , p rov ided 6 . 2 5 g . of a crude n e u t r a l p roduc t . The m a t e r i a l was p u r i f i e d by chromato-graphy on alumina (300 g . , grade I I I ) . E l u t i o n w i th 7 : 3 benzene: pet ro leum ether p rov ided s t a r t i n g m a t e r i a l (3*74 g . , 5 6 $ ) and f u r t h e r e l u t i o n w i th .9:1 benzene te ther . .y ie lded the d e s i r e d ketone (X IX ) (24 ) ( 1 . 1 6 g . , 1 6 $ ) , m. p. 1 4 5 . 5 - 1 4 7 ° . n . m. r . s i g n a l s : ( C D C I 3 ) 9 . 0 . 6 (angular me thy l , area--3H), 7 - 9 8 (CH^COO-, area--3H), 6.I7 (CH^O-, area,3H), 5 . 2 0 (b road, H-C-OAc, a rea- - lH) , m u l t i p l e t centered a t 2 . 6 6 (aromat ic H, a reax3H) . The mother l i q u o r from the r e c r y s t a l l i z a t i o n of the 12 -keto compound XIX was i n v e s t i -gated i n more d e t a i l . A f t e r evapora t i ng o f f the so lven t the. gum-my product was p u r i f i e d . b y another alumina chromatography (WOELM, GRADE I ) . E l u t i o n wi th 15 :1 benzene:ch loro form y i e l d e d a very sma l l amount o f c r y s t a l l i n e f r a c t i o n . 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 from 95$ e thano l gave two compounds: F i r s t , l e s s so l ub le compo-- 5 0 -nent , t rans-2-methoxy-8f> - ace toxy - lOa -methyl-5,6,6a , 7 , 8 , 9 , 1 0 , 1 0 a -octahydrochrysene (65 mg.) ( X V I I ) , m. p . 1 6 9 - I 7 2 . 5 0 . I n f r a r e d : 1718 c m " 1 ; u l t r a v i o l e t : X q v 227 (t 5 5 , 0 0 0 ) , 256 (6 3 , 5 1 0 ) , ma x . ; 266 ((: 4 , 3 6 0 ) , 276 4 , 5 7 0 ) , 287 it 2 , 8 8 0 ) , 307 (* 9 2 5 ) , 314 (£ 1 , 0 9 0 ) , 319 ( * 1 , 5 1 0 ) , 328 1 , 2 6 0 ) and 334 mu (e 1 , 8 7 0 ) ; A ^ l n > 254 3 , 4 0 0 ) , 259 ( £ 3 , 4 6 0 ) , 271 U 4 , 0 0 0 ) , 284 (£ 2 , 9 6 0 ) , 302 8 0 5 ) , 309 (e 9 2 5 ) , 324 (e 1 , 1 5 0 ) and 331 mji ( € 1 ,250) ; n . -m. r . s i g n a l s : 8 . 8 l (angular me thy l , a rea -3H), 7-95 (CH 3 C00- , area = 3H), 6 .11 ( C H 3 0 - , area--3H), broad s i g -n a l centered a t 5 . 2 (H-C-OAc, a rea= lH) , m u l t i p l e t centered a t 2 . 5 (aromat ic H. a r e a - 5 H ) . Found: C , 7 7 . 8 9 ; H, 8 . 0 2 ; 0 , 1 4 . 7 6 . C a l c . f o r C 2 2 H 2 6 0 3 : C , 7 8 . 0 1 ; H, 7 .69.: 0 , 14 .20 . Second, more s o l u b l e component, t rans-2-methoxy-8(^ - ace toxy -10a-methyl-6a , 7 , 8 , 9 , 10 ,10a-hexahydroch rysene (40mg) (XVT I I ) . m. p. 1 5 8 . 5 - 1 6 0 . 5 ° . I n f r a r e d : 1 7 l 8 c m ' 1 ; u l t r a v i o l e t : X 2 4 4 (* - • - max. 3 8 , 9 0 0 ) . . 276 3 , 7 6 0 ) , 288 ( £ 4 , 5 1 0 ) , 301 U 6 , 6 0 0 ) , 314 (e 7 , 9 1 0 ) , 335 U 3 , 3 6 0 ) and 351 mu (e 3 , 4 7 0 ) ; > f n i n > 273 U 3 , 6 4 0 ) , 281 (i 3 , 5 8 0 ) , 293 (6 ^ 3 5 0 ) , 307 U 5 , 3 9 0 ) , 327 ( e 2 ,410) and 342 mu ( £ 2 , 5 8 0 ) ; n . m. r . s i g n a l s : 8 . 9 3 (angular me thy l , area;3H), 7 . 9 4 ( C H ^ O O - , area = 3H), 6 . 1 0 ( C H 3 O - , area--3H), broad s i g n a l centered a t 5 .2 (H-C-OAc, a rea- - lH) , qua r te t centered a t 4 .2 (Cg o l e f i n i c H, a rea= lH) , m u l t i p l e t centered a t 2 . 4 (aromat ic H, C 5 o l e f i n i c H, area--6H). Found: C , 7 8 . 5 5 ; H, 7 . 6 7 ; 0 , 13-64. C a l c . f o r C o o H o ) 1 0 o : C , 7 8 . 5 4 ; H, 7 . 1 9 ; 0, 14 .27 . - 5 1 -Fur ther e l u t i o n w i th 8 : 2 benzene:ch loro form prov ided a m ix -ture of two compounds, one of which was found to be 12 -ke to com-pound ( X I X ) . S ince the other compound was l e s s so lub le than the 12 -ke to compound ( X I X ) , the former was p u r i f i e d by 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 from ether to g ive an a n a l y t i c a l sample of t r a n s -2 - m e t h o x y - 8 ( 3 - a c e t o x y - 5 - k e t o - 1 0 a - m e t h y l - 5 , 6 , 6 a , 7 , 8 , 9 , 1 0 , 10a -oc tahydrochrysene (XX) , m. p. 1 5 6 - 1 5 7 . 5 ° . I n f r a r e d : 1718 and 1662 c m " 1 ; u l t r a v i o l e t : A 2 1 9 . 5 U 4 6 , 0 0 0 ) , 2 4 8 ( £ • - max. 2 6 , 7 0 0 ) and 315 tnu ( £ 6 , 2 1 0 ) , broad shoulder a t 3 4 8 mu ( £ 3 , 0 0 0 ) ; A . 233 ($ 1 6 , 9 0 0 ) and 278 mu ( e 1 . 0 5 0 ) ; r u m . r . s i g n a l s : 8 . 7 6 (angular me thy l , area--3H), 7-94 (CH^COO-, area--3H), 6 . 1 0 ( C H 3 O - , area = 3H), broad s i g n a l centered at , 5 . 3 (H-Q-OAc, a r e a - l H ) , m u l t i p l e t centered a t 2 . 5 (aromat ic H, a r e a - 4 H ) , doublet centered a t 0 . 9 3 ( H - G ^ - , aromat ic H, a r e a : l H ) . Found: G, 7 5 . 1 0 ; H, 7 . 2 5 ; 0 , 1 7 . 8 2 . C a l c f o r C g ^ ^ O ^ : ° ' 7 4 * 9 7 ; H ' 6 * 8 6 ; °> 1 8 • 1 6 . Syn thes i s of t r a n s - a n t i - t r a n s - 2 - M e t h o x y - 8 f t -ace toxy - lOa-methy1 -4b," 5 , 6 , 6 a 7 , 8 , 9 •' 1 0 , 10a lOb-deca hydrochrysene (XXI I ) The ketone (XIX) ( 3 . 2 g . ) was d i s s o l v e d i n t o methanol (400 m l . ) and a s o l u t i o n of sodium borohydr ide (1 .0 g . ) i n methanol (200 m l . ) and water (20 m l . ) was added. The mixture was s t i r r e d f o r 3 . 5 hou rs . A f t e r the r e a c t i o n was over , a c e t i c a c i d (15 m l . ) was added and l e t stand f o r 30 m inu tes . A f t e r evapora t ing -the methanol o f f i n vacuo to a volume of 35 m l . , water and ether were added. The organ ic l aye r was separated and washed wi th wa te r , - 5 2 -aqueous sodium b icarbonate and wa te r . The e t h e r e a l s o l u t i o n was d r i e d over magnesium sulphate and evaporated o f f i_n vacuo to y i e l d a. gum ( X X I . ) ( 3 . 2 g . ) (,.The, u l t r a v i o l e t and i n f r a -red spect ra showed no conjugated ca rbony l ). Th is a l c o h o l (XXI) ( 3 . 2 g . ) was used f o r the next dehydra t ion r e a c t i o n w i t h -out p u r i f i c a t i o n . The a l c o h o l was d i s s o l v e d i n benzene (15© m l . , d r i e d over sodium) and phosphorous pentox ide ( 3 - 2 g . ) was added. A f t e r r e -f l u x i n g f o r 1 hour , the r e a c t i o n mix ture was poured onto cracked i c e . E ther was added to the mix ture and separated a f t e r the e x -t r a c t i o n . The ether l a y e r was washed wi th water , aqueous sodium b icarbonate and f i n a l l y wate r , and d r i e d over anhydrous magnesium s u l p h a t e . Evapo ra t i ng o f f the. so l ven t y i e l d e d a crude m a t e r i a l ( 2 . 7 g . ) . Th is m a t e r i a l was p u r i f i e d by alumina chromatography (100 g . , a c t i v i t y grade I I I ) . E l u t i o n wi th 1:1 petro leum ether (30-60° ) :benzene gave the d e s i r e d o l e f i n i c product ( 2 . 2 g . ) , t r a n s -a n t i - t r a n s - 2 - m e t h o x y - 8 ^ - a c e t o x y - l O a - m e t h y l - 4 b , 5 , 6 , 6 a , 7 , 8 , 9 , 10 , 1 0 a , lOb-decahydrochrysene ( X X I I ) , m. p. I O 5 - I O 6 . 5 0 . I n f r a -r e d : 1720 and 1599 c m " 1 ; u l t r a v i o l e t : A 221 ( e 2 9 , 6 0 0 ) . 262 - • • • max. ( f 7 , 6 5 0 ) , shoulder a t 270 mu ( (: 5 , 8 3 0 ) , 302 ray ( f 2 , 9 1 5 ) and 313 mu (* 2 , 6 7 0 ) ; A . 257 (£ 7 , 1 6 0 ) , 284 (£ 1 , 4 6 0 ) and 308 J rain. my ( f 1 , 6 9 0 ) ; n . m. r . s i g n a l s : (CDCl^) 9.14 (angular me thy l , area--3H), 8 . 0 2 (CJL^COO-, area-l3H), 6 . 2 9 (CH^O-, area.-3H), broad s i g n a l s centered a t 5«3 (H-C-OAc, area=LH), double t centered a t 4 . 1 1 ( H - C 1 2 , o l e f i n i c H, a r e a - L H ) , qua r te t centered at 3 . 6 3 (H-C l l ' o l e f i n i c H J a r e a - l H ) , m u l t i p l e t centered a t 3 . 1 5 (aromat ic H, area--3H). Pound: C , 77.48; H, 8 . 2 3 ; 0 , 1 4 . 4 4 . C a l c . f o r C 0 0 H o 0 : C , 7 7 - 6 l ; H, 8 . 2 9 ; 0 , 14 . 1 0 . -53-' S y n t h e s i s of t r a n s - 2 - M e t h o x y - 8 f t - a e e t o x y - l O a - m e t h y l - 5 . 6 , 6 a , 7, 8", '9, 10", JOa - o c t a h y d r o c h r y s e n e ' (XVI I ) The o l e f i n i c methoxy a c e t a t e , X X I I , (286 mg.) was mixed and powdered w i t h 10$ p a l l a d i u m on c h a r c o a l (215 mg.) i n a 50 m l . Erlenmeyer f l a s k : . The f l a s k was then heated f o r 3 minutes a t 240-245° w i t h n i t r o g e n p a s s i n g over the m i x t u r e . Some a c e t i c a c i d was e v o l v e d near the end of the h e a t i n g p e r i o d . A f t e r the f l a s k had c o o l e d t o room t e m p e r a t u r e , the r e s i d u e was t r e a t e d w i t h c h l o r o f o r m , the c a t a l y s t was f i l t e r e d , and the s o l v e n t was removed In vacuo t o y i e l d 232 mg. of a p r o d u c t . T h i s m a t e r i a l was d i s -s o l v e d i n benzene and chromatographed on alumina (14 g. WOELM, a c t i v i t y grade I ) . E l u t i o n w i t h 1 0 : 1 b e n z e n e - c h l o r o f o r m y i e l d e d f i r s t a s o l i d m a t e r i a l (140 mg.) wh i c h , a f t e r t h r e e r e e r y s t a l l i -z a t i o n s from 95$ e t h a n o l , gave an a n a l y t i c a l sample of t r a n s - 2 -m e t h o x y - 8 ^ - a c e t o x y - l O a - m e t h y l - 5 , 6 , 6 a , 7, 8 , 9 , 1 0 , l O a - o c t a -h y d rochrysene ( X V I I). m. p. 1 6 9 - 1 7 2 . 5 0 . T h i s compound was c o m p l e t e l y i d e n t i c a l w i t h one of the t - b u t y l chromate o x i d a t i o n p r o d u c t s . ( mixed m e l t i n g p o i n t , u l t r a v i o l e t and i n f r a r e d s p e c t r a ) C a t a l y t i c h y d r o g e n a t i o n of hexahydrochrysene analogue (XVI I I ) The naphthalene o l e f i n (XVI I I ) (10 mg. or 2 9 . 7 M mole) was d i s s o l v e d i n c h l o r o f o r m ( 3 m l . ) . 10% p a l l a d i u m on c h a r c o a l (3 mg.) was put i n t o the m i c r o - h y d r o g e n a t i o n a p p a r a t u s . A f t e r the a b s o r p t i o n of an e q u i m o l a r amount of hydrogen, the c a t a l y s t was - 5 4 -f i l t e r e d o f f . Evapo ra t i ng o f f the so lven t i n vacuo y i e l d e d 10 mg. of o i l y product ( X V I I ) . When petro leum ether was poured i n to the o i l , i t s o l i d i f i e d and gave a m. p. 169-172 . Mixed m e l t i n g po in t w i th the dehydrogena t i o n product of the s tyrene comjjfwind. (XXI I ) gave no d e p r e s s i o n . U l t r a v i o l e t and i n f r a r e d spec t ra were a l s o i d e n t i c a l . Syn thes i s of t r a n s - 2 - M e t h o x y - 8 ^ - a c e t o x y - l O a - m e t h y l - 6 a , 7 , 8 , 9 , 1 0 , 10a -hexahydrochrysene (XVI I I ) A s o l u t i o n of the ketone (XX) (100 mg.) i n methanol (50 m l . ) was t rea ted w i th a s o l u t i o n of sodium borohydr ide (100 mg.) i n QOfo methanol-20$water (50 m l . ) and the mix ture was s t i r r e d a t room temperature f o r two hours . The mix ture was then t rea ted w i th 10$ a c e t i c a c i d (5 m l . ) . The s o l u t i o n was concent ra ted i n vacuo to a volume of 10 m l . , water and e ther were added, and the e ther l aye r was separated. . The e ther l aye r was washed wi th water , aqueous sodium b i c a r b o n a t e , and water , and then d r i e d over anhy-drous magnesium s u l f a t e . Removal of the so lven t p rov ided an o i l y product ( XX I I I ) (101 mg.)> The i n f r a r e d spectrum showed no conjugated carbony l band, but bad an i n tense hyd roxy l absorption'•'•(•• 3600 cm' " 1 ) . The u l t r a v i o l e t 'spectrum showed t y p i c a l complex 1 pea k's for ' the sa tufa ted naphtha -lehe chromophore ' ( - X ' ^ : 227, 2 5 6 , 2 6 6 , '276, 287, 3 0 7 , 314, 3 1 9 , H i d A • 328 and 334 mu ). . . . . . . '•-••:L'; rJ--r^ Th i s o i l (XX I I I ) was d i s s o l v e d i n dry benzene (50 m l . , d r i e d over sodium) and phosphorous pentox ide (100 mg.) - 5 5 -was added. A f t e r r e f l u x i n g f o r two hours , the mix ture was poured onto crushed i c e . E t h y l e ther was added and the ether l aye r was sepa ra ted . The e ther l a y e r was washed wi th water , w i th aqueous sodium b icarbonate and f i n a l l y wi th water . A f t e r d r y i n g over a n -hydrous magnesium s u l f a t e , the so lven t was removed to y i e l d an o i l y m a t e r i a l (94 mg . ) . The m a t e r i a l was p u r i f i e d by chromato-graphy on alumina (10 g . , WOELM a c t i v i t y grade l ) . E l u t i o n wi th pet ro leum ether-benzene y i e l d e d the d e s i r e d o l e f i n (XVI I I ) ( 6 l mg.) which melted a t 1 5 8 . 5 - 1 6 0 . 5 0 a f t e r r e c r y s t a l l i z a t i o n from cyc lohexane . Th is compound was i d e n t i c a l w i th o n e : o f the ml nor i ic omp one nt so of the t - b u t y l bhrOmate : o x i d a t i d n r e a c t l d n ( XV1I-I-) Cmixed^meltingKpdlntv i^R^uyvy) J -Syn thes is of A / B t rans - 1 1 , 1 2 - seco - 2 -me thoxy - 8 - a c e t o x y - l O a - me thy l - 1 1 , 1 2 -d ioxo -4b , 5 , 6 , 6 a , 7 , 8 , 9 . 1 0 . 1 0 a , 1 0 b , 1 1 , 1 2 - dodeca - hydrochrysene (XXIV) The o l e f i n i c compound,XXII, (485 mg.) was d i s s o l v e d i n dry e t h y l ace ta te (40 m l . ) and ozon ized oxygen was passed through the s o l u t i o n at - 7 8 ° over a pe r i od of 20 m inu tes . When the r e a c t i o n was over , the s o l u t i o n was pa le b lue i n c o l o r . The ozonide was c a t a l y t i c a l l y c leaved by shak ing w i th hydrogen and 10$ p a l l a d i u m on cha rcoa l under a p ressure of about 3 atm. (Parr mach ine) . A f t e r shak ing f o r 20 hours , the c a t a l y s t was f i l t e r e d o f f . The so lven t was evaporated o f f i n vacuo to y i e l d a crude product (609 mg . ) . Th is m a t e r i a l was p u r i f i e d by chroma-tography (30 g . s i l i c a g e l , B. D. H . ) . E l u t i o n wi th ch lo ro form -56-y i e l d e d the d e s i r e d d ia ldehyde (243 mg. ), A / B t r a n s - 1 1 , 1 2 - s e c o -2-methoxy-8 (i - a c e t o x y - l O a - m e t h y l - 1 1 , 1 2 - d i o x o - 4 b , 5 ,6 ,6a ,7,8,9, 1 0 , 1 0 a , 1 0 b , 11 ,12 -dodecahydrochrysene (XXIV) . A f t e r r e c r y s t a l -l i z a t i o n from 95$ e thano l i t gave an a n a l y t i c a l sample, m.p. r 148-150° ( C 2 2 H 2 g 0 5 - C 2 H 5 0 H ) . I n f r a r e d : 2 7 3 5 , 1713 and 1683 cm" U l t r a v i o l e t : A m a x 211 U 9 2 , 0 0 0 ) , 253 (fe 6 , 0 3 0 ) and 320 mu ($ 2 , 5 9 0 ) ; \ ± n 241 (e 4 , 7 3 0 ) and 282 mu. (* 5 4 7 ) . Pound: C, 6 9 . 1 0 ; H, 7 . 76 ; 0 , 2 3 . 2 2 . C a l c . f o r C 2 2 H 2 8 0 5 CgHgOH: C, 6 8 . 8 7 ; H, 8 . 19; 0 , 2 2 . 9 4 . Syn thes is ' of t rans -2 -Methoxy -5 , 6 -d ihydroxy -8 ' f t - a o e t o x y - l O a - methyl-5".6.6a . 7 , 8 , 9 , 1 0 , 1 0 a - o c t a h y d r o c h r y s e n e (XXVI) The naphthalene o l e f i n (XVI I I ) (170 mg. , 0 . 5 m i l l i - m o l e ) was d i s s o l v e d i n anhydrous ether (25 m l . ) . A s o l u t i o n of osmium t e t a r o x i d e (166 mg. , O .65 m i l l i - m o l e , 30$ excess ) i n anhydrous ether (10 m l . ) was added and the mix ture was a l lowed to stand f o r 4 days . Then methanol (35 m l . ) was added to the mixture and hydrogen s u l f i d e was bubbled through the s o l u t i o n f o r 5 m inu tes . The b lack p r e c i p i t a t e was f i l t e r e d o f f , and then so l ven t was evaporated i n vacuo to y i e l d gum (213 mg . ) . Th i s m a t e r i a l was d i s s o l v e d i n benzene and chromatographed on s i l i c a ge l (20 g . , WOELM, n e u t r a l ) . E l u t i o n wi th ch lo ro fo rm y i e l d e d whi te c r y s t a l s wh ich , on r e c r y s t a l l i z a t i o n from e t h e r , gave an a n a l y t i c a l sample of t r a n s - 2 - m e t h o x y - 5 , 6 - d i h y d r o x y - 8 - a c e t - * o x y - 1 0 a - m e t h y l - 5 , 6 , 6 a , 7 , 8 , 1 0 , 1 0 a - o c t a h y d r o c h r y s e n e (XXVI ) , m.p. 1 9 9 - 2 0 9 0 1 . - 5 7 -I n f r a r e d : 3420 and 1698 cm" ; u l t r a v i o l e t : X 234 ( 9 6 , 0 0 0 ) , ' max. 254 (€ 3 , 8 0 0 ) , 264 (€ 5 , 4 7 0 ) , 274 U 5 , 7 0 0 ) , 284 ( 4 3 , 5 6 0 ) , 306 (e 8 5 0 ) , 318 ( t 1 , 7 7 0 ) , 327 ( 6 1 , 6 5 0 ) and 333 mu ( t 2 , 3 8 0 ) ; Xm i n . 251 ( c- 3 , 5 6 0 ) , 257 (* 3 , 8 0 0 ) , 269 (C- 4 , 4 7 0 ) , 282 ( £ 3 , 4 5 0 ) , 303 ( 4 7 0 ) . 323 ( 1- 1,420) and 329 mu ( I 1 , 6 5 0 ) ; n.m.r. s i g n a l s : ( p y r i d i n e ) 9*27 (angular methyl, area^3ffi)', 8 . 4 5 CR^COO-, areai3H), 6 . 6 7 (CH^O-, area-.3H), quartet centered at 6 . 3 7 (H-Cg, area.-LH), m u l t i p l e t centered at 5 . 5 7 (H-C3, a r e a . l H ) , doublet centered at 4 . 9 2 (H-C^, area--lH), broad peak centered at 4 . 7 4 (H0-G 3 6 , area.2H). Found: C, 7 1 . 2 9 ; H, 7 - 0 0 ; 0 , 2 2 . 0 1 . C a l c . f o r ^22\eQ5' °' 7 1 " 3 3 ; E' 7 ' ° 8 ' ° ' 2 1 . 6 0 . Periodate cleavage of the d i o l (XXVI) i n methanol s o l u t i o n The d i o l (XXVI) (37 mg.) was d i s s o l v e d i n methanol (20 ml.), and 5 . 9 ml. of a 0 . 0 2 1 9 M s o l u t i o n of pa r a p e r i o d i c a c i d (30$ exc-ess) i n water was added. The mixture was allowed to stand f o r 16 hours, and then the solvent was evaporated o f f in. vacuo to a volume of 6 ml. The mixture was d i s t r i b u t e d between chloroform and water. The organic l a y e r was washed with water, aqueous sodium bicarbonate and water, and d r i e d over anhydrous magnesium sulphate. Evaporating o f f the solvent y i e l d e d 35 mg. of an o i l y product (XXVII). This m a t e r i a l had a l a r g e r R f. value ( 0 . 8 ) than that of s t a r t i n g value (R f. 0 . 3 ) on s i l i c a g e l G t h i n l a y e r p l a t e with e l u t i o n of 4 : 1 choloform:ethyl a c e t a t e . A f t e r spraying with 1:1 antimony t r i c h l o r i d e : a c e t i c a c i d s o l u t i o n , t h i s m a t e r i a l showed up a spot w i t h a f a i n t p u r p l e c o l o r center and d u l l blue - 5 8 -f r i n g e compared to tha t of s t a r t i n g m a t e r i a l (XXVI) which was green ish brown. I n f r a r e d : 1715/ 1620 and 1600 c m " 1 ( C H C ^ ) ; u l t r a v i o l e t : ~\ 2 2 7 , 2 5 6 , 2 6 6 , 2 7 6 , 2 8 7 , 3 0 7 , 3 1 4 , 3 1 9 , 328 max. • ;y . . . . and 334 mu; A . 2 5 4 , 259 2 7 1 , 2 8 4 , 3 0 2 , 3 0 9 , 324 and 331 mu; J m.in. •> n . m. r . s i g n a l s : (CDC1 ) 8 . 7 3 (angular m e t h y l ) , 8 . 0 0 (CR^COO-), 6 . 4 5 (CHgO-Cg-).. 6 . 2 2 (CH 3 0-C 6 . 12 ( C H ^ - C ^ ) , m u l t i p l e t a t 2 . 2 ~ 3-1 (aromat ic H ) . Pe r i oda te c leavage of the d i o l (XXVI) i n dloxane The d i o l (XXVI) (47 mg.) was d i s s o l v e d i n d ioxan (12 m l . ) , and 7 . 7 m l . of a 0 . 0 2 1 9 M s o l u t i o n of pa rape r i od ie a c i d (30$ excess ) i n water was added. The mix ture was a l lowed to stand ove r -. n i g h t , and was^worked up i n the same way as i n the p rev ious c l e a -vage i n methano l . The y i e l d of the product (XXVI I I ) was 40 mg. : Th in l a y e r chromatography showed a d i f f e r e n t spot ( R f . 0 . 8 ) from the s t a r t i n g m a t e r i a l (R . 0 . 3 ) , and the c o l o r of the product a f t e r ' sp ray ing -1 : 1 antimony t r i c h l o r i d e : a c e t i c a c i d and. hea t i ng was dark g rey . I n f r a r e d : 2 6 9 0 , 1720, 1620 and 1595 cm ( C H C I 3 ) ; u l t r a v i o l e t : A 320.and 333 mu, shoulder a t 287 mu; X ' max. / > m in . 303 and 3 2 8 mu ( E t 2 0 ) ; n .m.r . s i g n a l s (CDC l^ ) : 8 . 7 1 (angular m e t h y l ) , 7-94 (CH^COO-), 6 . 0 8 (CH" 3 0-) , m u l t i p l e t a t 2 . 0 - 3 - 0 (aromat ic H ) , 0 . 6 2 (H-Cg) , - 1 . 1 5 (H -C ' 5 ) . Convers ion of the a c e t a l (XXVII ) to the hemiaceta l (XXVI I I ) w i th a c e t i c a c i d ' The a c e t a l (XXVII ) (35 mg.) was d i s s o l v e d i n g l a c i a l a c e t i c - 5 9 -a c i d (5 m l . ) , and the mix ture was then put on a steam bath f o r 40 minu tes . C o o l i n g to room temperature, the mixture was d i s t r i -buted between ether and water . The ether l aye r was washed w i th aqueous sodium b icarbonate and water . A f t e r d r y i n g over anhydro-us magnesium s u l p h a t e , t h e . s o l v e n t was evaporated o f f i n vacuo to y i e l d 31 mg. Th i s product was i d e n t i c a l w i th the hemiace ta l (XXVI I I ) produced from the d i o l i n d ioxan ( U l t r a v i o l e t , i n f r a r e d and nuc lear magnetic resonance s p e c t r a ) . C y c l i z a t i b n " o f the hemiace ta l ( (XXVI I I ) on alumina The hemiaceta l (XXVI I I ) (71 mg.) was put on alumina column (WOELM, n e u t r a l , a c t i v i t y grade I ) . E l u t i o n w i th 3:7 b e n z e n e : c h l -oroform y i e l d e d the d e s i r e d c y c l i z e d m a t e r i a l (39 mg.) (XXIX) . T .L.C. showed one spot ( R f . 0 .8) on alumina (WOELM, n e u t r a l ) ; I n f r a r e d : 3220, 2680, 1710, 1625 and 1595 c m " 1 (gum); u l t r a v i o l e t : X 233, 264, 275, 285, 323,and 337 mu, broad shoulder a t 255. m a x . J 310 and 332 mu; > m i n > 259, 270, 283: 301 and 328 mu; n.m.r. s i g n a l s (CDC1 3 ) : 8.74 (angular m e t h y l ) , 7-94 (CH~ 3C00-), 6.0& (CH^O-) , broad peak a t 5.00 (H-C -OAc ) , m u l t i p l e t centered a t 4.20 (H-C^-OH ) , m u l t i p l e t centered at 2.35 (aromat ic H ) , doub le t centered a t 0 . l 8 (CH0- ) . Ox ida t i on of the a l d o l condensat ion product (XXIX) The c y c l i z e d ^ m a t e r i a l (XXIX) (20 mg.,^0.O6l m i l l i m o l e ) was d i s s o l v e d i n 3 m l . of ace tone . 0 .6 m l . of a I.'6 N J o n e ' s reagent (33) was added, and then the mixture was s t i r r e d f o r 40 'm inu tes . -6o-A f t e r the r e a c t i o n was o v e r , the m i x t u r e was poured onto 70 m l . of d i s t i l l e d w a t e r . E t h e r was added ...to the m i x t u r e and then the e t h e r l a y e r was s e p e r a t e d . The etH;er<eal l a y e r was washed w i t h w a t e r , aqueous sodium b i c a r b o n a t e and water and d r i e d over a n-hydrous magnesium s u l p h a t e . The s o l v e n t was e v a p o r a t e d o f f i n vacuo to y i e l d a gum. T h i s gum was c r y s t a l l i z e d from e t h e r t o y i e l d compound (XX-X I I ) , m.p, 149-156°. I n f r a r e d : 2755 cm" 1 (weak ) , 1726 and l 6 8 l cm" 1: u l t r a v i o l e t : >- 2 l 8 .( ( 32 , 8 0 0 ) , 246 (£' 22,400), 308 max. ( t 4,700) and 353 y U 2,340); X m i n 231 ( £ 13,500), 275 («• 1,100) and 333 t n p . U 1,92-0); n.m.r. s i g n a l s ( C D C l g ) : 8.52 ( a n g u l a r m e t h y l , a r e a , 3 H ) , 8.05 (CH^COO-, area-3H), 6.21 (CH3O-, ar e a - 3 H ) , broad m u l t i p l e t c e n t e r e d a t 5-4 (H-C-OAc, a r e a - l H ) , m u l t i p l e t c e n t e r e d a t 2 .55 ( a r o m a t i c H, area;5H), d o u b l e t c e n t -e r e d a t 1.25 (H-C4, a r e a ^ l H ) , O.87 (CH0-, area--lH). Found: C,72.32 : H. 6 . 2 1 : 0, 21.60. C a l c . f o r C 0 0 H 0 : C, 72.1.1): H, d d 22 5 6.05; 0, 21.83. The mother l i q u o r ' : : f f r b m ^ p r y s t a l l i z a t i o n of compound (XXX) was ev a p o r a t e d down and y i e l d e d a gummy p r o d u c t 'w'|iiclK.;showed one s p o t on T'.L.C . T h i s gummy m a t e r i a l was compound ( X X X I I ) . I n f r a r e d : 1720 and 1590 c m - 1 , s h o u l d e r a t 1695 cm" 1 ( C H C l ^ ) ; u l t r a v i o l e t : X 219, 245 and 308 mu, broad s h o u l d e r a t 345 mu: X 231 max. . J 1 mm. and 275 mu; n.m.r. s i g n a l s ( C D C l ^ ) : 8.75 ( a n g u l a r m e t h y l ) , 8.02 (CH 3C00-), 6.17 (CH^O-), broad s i g n a l c e n t e r e d a t 5.4 (H-C-OAc), m u l t i p l e t c e n t e r e d a t 2 .6 ( a r o m a t i c H ) , d o u b l e t c e n t e r e d a t 1.4 (H-C,). - 6 1 -BIBLIOGRAPHY ( 1 ) C . D j e r a s s i , L. Miramontes, G. Rosenkranz and P . Sondhe i -mer, J . Am. Chem, S o c , J_6, 4092 (1954) V. A . D r i l l and B. R i e g e l , Recent P r o g r . i n Hormone R e -s e a r c h , 14, 29 ( 1 9 5 8 ) ( 2 ) M. R a j e c , T . R u l l , and 0 . O u r i s s o n , B u l l . Soc . Chem., P rance , 1 2 1 3 . ( 1 9 6 1 ) ( 3 ) T . L . Jacobs and R. B. B r o w n f i e l d . J . Am. Chem. S o c , 82_, •. 4033 ( I 9 6 0 ) ( 4 ) C . R. Enge l and S . R a b b i t , Can. J . Chem., 4p_, 2153 ( 1 9 6 2 ) ( 5 ) J... P- Kutney and R. A . Johnson, Chem. and I n d . , 1713 (1961) J . ' P . Kutney, R. A . Johnson, and I. V l a t t a s , Can. J . Chem., 4 r , 613 ( 1 9 6 3 ) J . P . Kutney, I. V l a t t a s , and G. V . Rao, Can. J . Chem., 4 1 , 958 ( 1 9 6 3 ) ( 6 ) P. W.' S c h i e s s , D. M. B a i l e y and W. S . Johnson, Tet rahedron L e t t e r s , No. 9., 549 ( 1 9 6 3 ) ( 7 ) J . P r i e d , H. L. Wh i te , and 0 . W i n t e r s t e i n e r , J . Am. Chem. S o c , 22, 4621 ( 1 9 5 0 ) ( 8 ) A . Haddow, Natu re , 136, 868 (1935) ( 9 ) A . J . B i r c h and H. Smi th , J . Chem. S o c , 4909 ( 1 9 5 6 ) ( 1 0 ) H. He rbs t , N. J . Harper , E . S c h l i t t e r , ' J . Druey, A . Marxer , and H. G r a s s h o f f , " Drug Resea rch . Vol.4•.'•''•-3irk-ha.-user-'-Vi-..-, B a s e l . ( 1 9 6 2 ) (11 ) H. L. Saunders, K. Holden and J . F . Ke rw in , S t e r o i d 3_, 675 ( 1 9 6 4 ) - 6 2 -R. I . Dorfman, J . F a j o k o s and J . Jo s k a , S t e r o i d 3_, 675 ( 1 9 6 4 ) E. C. DuFeu, F. J . M c Q , u i l l i n and R. R o b i n s o n , J . Chem. S o c , 53 ( 1 9 3 7 ) R. R o b i n s o n and F. Weygand, J . Chem. Soc., 3§6 (19^1) J . C. Cook and R. R o b i n s o n , J . Chem. S o c , 391 (19^1) J . W. Cornworth and R. R o b i n s o n , J . Chem. Soc., 1855 ( 1 9 4 9 ) V/. S. Johnson, J . Am. Chem. S o c , J_8., 6278 ( 1 9 5 6 ) W. S. Johnson, E. R. R o g i e r , , J . S z m u s z k o v i c z , H. I . H a d l e r , J . Ackerman, B. K. B h a t t a c h a r y y a , B. M. Bloom, L. Stalmann, R. A. Clement, B. B a n n i s t e r and H. Wynberg, ' J . Am. Chem. S o c , J_8, 6289 ( 1 9 5 6 ) A. L. W i l d s , J . W. R a l l s , W. C. Wildman and K. E. McCaleb, J . Am. Chem. S o c , J2_, 5794 ( 1 9 5 2 ) W. S. Johnson, A. D. Kemp, R Pappo, J . Ackerman and W. F. John s , J . Am. Chem. S o c , J_8, 6312 ( 1 9 5 6 ) W. S. Johnson, B. B a n n i s t e r , R. Pappo and J . E. P i k e , J . Am. Chem. S o c , j8_, 6354 ( 1 9 5 6 ) V/. S. Johnson, J . J . K o r s t , R. A. Clement and J . D u t t a , J . Am. Chem. S o c , 8 2 , 6 l 4 ( i 9 6 0 ) J . P. Kutney, Wm. McCrae and A. By, Can. J . Chem., 40, 982 ( 1 9 6 2 ) J . P. Kutney, J . W i n t e r , Wm. McCrae and A. By, Can. J . Chem.., 4l_, 470 .(1963) J . P. Kutney and .A. By, Can. J Chem., 4_2_,.591 ( 1 9 6 4 ) - 6 3 -( 2 6 ) W. I\Ta• ,a ..a , T. Terasawa, S. H i r a i .and K. Takeda, T e t r a h e -dron L e t t e r s , ] j \ 27 ( i 9 6 0 ) ( 2 7 ) W. Nagata e t a l . , Chem. and Pharm. B u l l . (Japan) 9_, 770 (1961) (28) . S. M. Kupchan, W. S. Johnson and S. R a j a g o p a l a n , T e t r a -hedron J_, 47 ( 1959) ( 2 9 ) P. D. Gunstone, Advances i n Org. Chem., Methods and Re-s u l t s . V o l . 1, • I n t e r s c i e n c e P u b l i s h e r s , N.Y. p.103-143, <V;W ( i 9 6 0 ) ( 3 0) S. J A j A n g y a l and R. J . Young, J . Am. Chem. Soc., 8l_, 5251 ( 3 1 ) S. B e r a s t e i n , M. H e l l e r , F . J . McEvoy and .S. M. S t o l a r , J . Org. Chem., 2 6 , 505 (1961) ( 3 2 ) K. Takeda, Chem.. and Pharm. B u l l . ( Japan) £, 1 ( 1961) (33) C. D j e r a s s i e t a l . , J.- Org. Chem., 2 1 , 1547 ( 1 9 5 6 ) ' ( 3 4 ) K. H e u s l e r and A. W e t t s t e i n , H e l v . Chim. A c t a . , 3JL-284 ( 1 9 5 2 )
Thesis/Dissertation
eng
Chemistry
Vancouver : University of British Columbia Library
For non-commercial purposes only, such as research, private study and education. Additional conditions apply, see Terms of Use https://open.library.ubc.ca/terms_of_use.
Graduate
Total synthesis of certain hydrochrysene analogues
Text