@prefix vivo: . @prefix edm: . @prefix ns0: . @prefix dcterms: . @prefix skos: . vivo:departmentOrSchool "Science, Faculty of"@en, "Chemistry, Department of"@en ; edm:dataProvider "DSpace"@en ; ns0:degreeCampus "UBCV"@en ; dcterms:creator "Roller, Peter Paul"@en ; dcterms:issued "2011-09-15T20:33:37Z"@en, "1965"@en ; vivo:relatedDegree "Master of Science - MSc"@en ; ns0:degreeGrantor "University of British Columbia"@en ; dcterms:description """Two sequences leading to the total synthesis of several octahydrochrysene derivatives are described; in particular, the synthesis of B-nor-cis-2-methoxy-8α-acetoxy-5-keto-10a-methyl-5,6,7,8,9,10,10a-octahydrochrysene (XL) is achieved. In one sequence an olefinic bond at the 5,6 position of ring B (XXXII) was introduced by reduction of cis-2-methoxy-8α-acetoxy-5-keto-10a-methyl-5,6,6a, 7,8,9,10,lOa-octahydrochrysene (XIV) with sodium borohydride, followed by dehydration with phosphorus pentoxide.Subsequent reaction at the olefinic linkage by osmium tetroxide provided the α-diol (XXX), which upon treatment with periodic acid yielded a hemiacetal (XXXIV). Cyclization on alumina then provided the B-nor internal aldol condensation product (XXXIX). The latter readily underwent / oxidation with Jones' reagent to result in the B-nor-5-keto acetate (XL). In an alternate sequence the cis-2-methoxy-8α-acetoxy-5-keto-5,6,6a,7,8, 9,10, 10a-octahydrochrysene (XIV) is oximinated at the 6-position with isoamyl nitrite and the oxime is converted by acid hydrolysis to a 5,6-diketo-8-hydroxy compound (XLII). An attempt was made to accomplish a benzilic acid rearrangement on the α-diketo compound and the resulting product (XLVII) was subjected to lead tetra-acetate oxidation in the hope that the B-nor-5-keto system (XLVIII) could be obtained. The structures from the last two reactions were only tentatively established. A critical discussion of the n.m.r. data is reserved to a separate section of the thesis. Tentative assignments of all the aromatic protons were made. Of special note is the chemical shift dependence of the proton at C₄ on the substitution at C₅. Configurational and conformational assignments of the ring A/B system were made on the basis of angular methyl and 8β-proton frequencies."""@en ; edm:aggregatedCHO "https://circle.library.ubc.ca/rest/handle/2429/37396?expand=metadata"@en ; skos:note "TOTAL SYNTHESIS OF CERTAIN HYDROCHRYSENE ANALOGUES by PETER PAUL ROLLER B . S c , U n i v e r s i t y o f B r i t i s h C o l u m b i a , 1963 A THESIS SUBMITTED IN PARTIAL FULFILMENT OF THE REQUIREMENTS FOR THE DEGREE OF MASTER OF SCIENCE i n t h e Department o f C h e m i s t r y We a c c e p t t h i s t h e s i s as c o n f o r m i n g t o t h e r e q u i r e d s t a n d a r d THE UNIVERSITY OF BRITISH COLUMBIA J u l y , 1965 In presenting th i s thes i s in p a r t i a l f u l f i lmen t of the requirements for an advanced degree at the Un ivers i ty of B r i t i s h Columbia, I agree that the L ibrary sha l l make i t f r ee l y ava i l ab l e fo r reference and study. I fur ther agree that per-mission for extensive copying of t h i s thes i s for scho la r l y purposes may be granted by the Head of my Department or by h i s representat ives . It is understood that copying or p u b l i -cat ion of th i s thes i s for f i n a n c i a l gain sha l l not be allowed without my wr i t ten permiss ion. Department of wWf< The Un ivers i ty of B r i t i s h Columbia Vancouver 8, Canada Date ( i i ) ABSTRACT Two sequences l e a d i n g t o the t o t a l s y n t h e s i s o f s e v e r a l 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 a r e d e s c r i b e d ; i n p a r t i c u l a r , t h e s y n t h e s i s o f B - n o r - c i s - 2 - m e t h o x y -8 a - a c e t o x y - 5 - k e t o - 1 0 a - m e t h y l - 5 , 6 , 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 (XL) i s a c h i e v e d . I n one sequence an o l e f i n i c bond a t t h e 5,6 p o s i t i o n o f r i n g B (XXXII) was i n t r o d u c e d by r e d u c t i o n o f c i s - 2 - m e t h o x y - 8 a - 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 , l O a - o c t a h y d r o c h r y s e n e (XIV) w i t h sodium b o r o h y d r i d e , f o l l o w e d by de-h y d r a t i o n w i t h phosphorus p e n t o x i d e . S u b s e q u e n t r e a c t i o n a t t h e o l e f i n i c l i n k a g e by osmium t e t r o x i d e p r o v i d e d t h e c t - d i o l (XXX), 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 a h e m i a c e t a l (XXXIV). C y c l i z a t i o n on a l u m i n a t h e n p r o v i d e d t h e B-nor 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 p r o d u c t (XXXIX). The l a t t e r r e a d i l y underwent / o x i d a t i o n w i t h J o n e s ' r e a g e n t t o r e s u l t i n t h e B- n o r - 5 - k e t o a c e t a t e ( X L ) . I n an a l t e r n a t e sequence t h e c i s - 2 - m e t h o x y - 8 a - a c e t o x y - 5 - k e t o - 5 , 6 , 6 a , 7 , 8 , 9,10, 1 0 a - o c t a h y d r o c h r y s e n e (XIV) i s o x i m i n a t e d a t t h e 6 - p o s i t i o n w i t h i s o a m y l n i t r i t e and t h e oxime i s c o n v e r t e d by a c i d h y d r o l y s i s t o a 5 , 6 - d i k e t o - 8 - h y d r o x y compound ( X L I I ) . An at t e m p t was made t o a c c o m p l i s h a b e n z i l i c a c i d rearrangement on t h e c t - d i k e t o compound and t h e r e s u l t i n g p r o d u c t ( X L V I I ) was s u b j e c t e d t o l e a d t e t r a - a c e t a t e o x i d a t i o n i n t h e hope t h a t t h e B - n o r - 5 - k e t o s y s t e m ( X L V I I I ) c o u l d be o b t a i n e d . The s t r u c t u r e s f r o m t h e l a s t two r e a c t i o n s were o n l y t e n t a t i v e l y e s t a b l i s h e d . A c r i t i c a l d i s c u s s i o n o f t h e n.m.r. d a t a i s r e s e r v e d t o a s e p a r a t e s e c t i o n o f t h e t h e s i s . T e n t a t i v e a s s i g n m e n t s o f a l l t h e a r o m a t i c p r o t o n s were made. Of s p e c i a l n o t e i s t h e c h e m i c a l s h i f t dependence o f t h e p r o t o n a t on t h e s u b s t i t u t i o n a t C 5 . C o n f i g u r a t i o n a l and c o n f o r m a t i o n a l a s s i g n m e n t s o f t h e r i n g A/B s y s t e m were made on t h e b a s i s o f a n g u l a r m e t h y l and 8 B - p r o t o n f r e q u e n c i e s . ( i i i ) TABLE OF CONTENTS Page T i t l e Page ( i ) Abs t r a c t .. . ( i i ) Table of Contents . .. ( i i i ) L i s t o f Tables ( i v ) L i s t o f Figures ( i v ) Acknowledgements (v) I n t r o d u c t i o n . . . 1 Di s c u s s i o n 9 I n t e r p r e t a t i o n of N.M.R. Spectra 32 Experimental 47 Bi b l i o g r a p h y , 59 (iv) LIST OF TABLES Page Table I. Aromatic proton resonances of the octahydrochrysene analogues .......... 33 Table I I . N.M.R. data on 8g, lOa-methyl and the 8cx-acetoxy methyl protons of the hydrochrysene analogues .... 43 LIST OF FIGURES Page Figure 1 2 Figure 2 2 Figure 3 4 Figure 4 6 Figure 5 ' , . . . 8 Figure 6 8 Figure 1 ..... . . . . 10 Figure 8 13 Figure 9 . . 15 Figure 10 17 Figure 11 .... 18 Figure 12 23 Figure 13 ... 24 Figure 14 26 Figure 15 28 Figure 16 29 Figure 17 .. 34 Figure 18 . . 35 Figure 19 . 37 Figure 20 39 Figure 21 42 Figure 22 44 (v) ACKNOWLEDGEMENTS My g r a t e f u l t h a n k s a r e due t o Dr. J . P. Kutney f o r g i v i n g me t h e o p p o r t u n i t y t o work under h i s e x p e r t g u i d a n c e and f o r h i s encouragement and i n s p i r i n g s u p e r v i s i o n d u r i n g t h e c o u r s e o f t h i s p r o j e c t . F i n a n c i a l a i d from t h e P r e s i d e n t ' s Fund., t h e U n i v e r s i t y o f B r i t i s h C o l u m b i a , S m i t h , M i l l e r and P a t c h , New B r u n s w i c k , New J e r s e y and t h e N a t i o n a l R e s e a r c h C o u n c i l o f Canada i s v e r y g r a t e f u l l y acknowledged. - 1 -INTRODUCTION The work p r e s e n t e d h e r e e v o l v e d i n c o n n e c t i o n w i t h a program d i r e c t e d t o w a r d t h e t o t a l s y n t h e s i s o f c e r t a i n V e r a t r u m a l k a l o i d s . H y d r o c h r y s e n e i n t e r m e d i a t e s o b t a i n e d e a r l i e r i n t h i s p r o j e c t e d s y n t h e s i s have p r o v i d e d an o b v i o u s a c c e s s t o 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 p o s s e s s i n g a r o m a t i c C,D r i n g s and t h e p r e s e n t work d e s c r i b e s t h e s y n t h e s i s o f t h e new B-nor-D-homo s t e r o i d a l s k e l e t o n . The s y n t h e t i c i n t e r m e d i a t e s o f f e r many i n t e r e s t i n g s t r u c t u r a l f e a t u r e s , i n v i t e s t e r e o c h e m i c a l p r o b l e m s , and may p o s s e s s n o v e l b i o l o g i c a l a c t i v i t y . B i o l o g i c a l s t u d i e s on m o d i f i e d s t e r o d i a l s t r u c t u r e s have r e c e n t l y been o f v e r y c o n s i d e r a b l e i n t e r e s t . F o r example, 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 and 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 can r e t a r d growth o f tumor c e l l s ( 1 ) . The B-nor analogues o f c e r t a i n s t e r o i d s a r e f o u n d t o be a n t i a n d r o g e n i c , and such an agent would be t h e r a p e u t i c a l l y u s e f u l i n p o s t - p u b e r t a l and i d i o p a t h e t i c h i r s u t i s m i n women, th e S t e i n - L e v e n t h a i syndrome, androgen dependent p r o s t a t i c tumors and a d o l e s c e n t and p r e m e n s t r u a l ' acne. ( 2 , 3 ) . E q u i l e n i n w i t h r i n g C open ( I ) has h a l f t h e a n d r o g e n i c a c t i v i t y o f e q u i l e n i n ( 4 ) . I t has been s u g g e s t e d , t h a t t h e D-homo s t e r o i d ( I I ) may have m y o t r o p i c and a n d r o g e n i c a c t i v i t y ( 5 ) . J e r v i n e ( I I I ) , a n a t u r a l l y o c c u r r i n g a l k a l o i d w i t h a C-nor D-homo s t e r o i d a l s k e l e t o n , was o b s e r v e d to, 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 (6).. U r a n e d i o l , (IV) an example o f a n a t u r a l l y o c c u r r i n g D-homo s t e r o i d , was i s o l a t e d from mare's pregna n c y u r i n e . ( 7 ) . -2-Figure 2. -3-A r o r a a t i c systems i n g e n e r a l o c c u r i n n a t u r a l l y o c c u r r i n g e s t r o g e n i c hormones ( 8 ) . E s t r o n e c o n t a i n s r i n g A a r o m a t i c and e q u i l e n i n c o n t a i n s b o t h r i n g s A and B a r o m a t i c . S y n t h e t i c approaches t o v a r i o u s a r o m a t i c s t e r o i d a l s t r u c t u r e s a r e o f g r e a t d i v e r s i t y . Recent p u b l i c a t i o n s by t h e M a n c h e s t e r group (9) d i s c l o s e d t h e p r e p a r a t i o n o f f i v e o f t h e 7 s t e r e o i s o m e r s o f e s t r o n e m e t h y l e t h e r , D - h o m o - e s t r a d i o l , D - h o m o - e q u i l e n i n , e q u i l e n i n m e t h y l e t h e r and i s o e q u i l e n i n . The s y n t h e t i c method a p p l i e d i n b u i l d i n g up t h e b a s i c s t e r o d i a l s k e l e t o n i s e x e m p l i f i e d on F i g u r e 2. Anachenko and Torgov r e p o r t e d t h e s y n t h e s i s o f r e l a t e d e s t r a p o l y e n e s from s i m i l a r open C r i n g k e t o n i c i n t e r m e d i a t e s (-10, 1 1 ) . S t r u c t u r e s where a h e t e r o atom i s c o n t a i n e d i n t h e methoxynaphthalene s y s t e m o f t h e s t e r o i d (V) have r e c e n t l y been s y n t h e s i z e d ( 1 2 ) . The sequence o f r e a c t i o n s w h i c h was s e l e c t e d by Kutney and c o - w o r k e r s (13 , 14) u t i l i z e d t h e R o b inson-Mannich base r e a c t i o n o r i g i n a l l y d e v e l o p e d by R o b i n s o n and c o - w o r k e r s (15, 16, 17, 18) and so s u c c e s s f u l l y a p p l i e d i n t h e e l e g a n t r e s e a r c h e s o f J o h n s o n and co-workers (19, 2 0 ) . W h i l e Johnson's sequence e l a b o r a t e d t o w a r d t h e 1-methoxy h y d r o c h r y s e n e s y s t e m and T a y l o r (21) s y n t h e s i z e d some o f t h e 3-methoxy and nor-methoxy h y d r o -c h r y s e n e s t r u c t u r e s , t h e sequence d e v e l o p e d i n o u r l a b o r a t o r y p r o d u c e d t h e 2-methoxy h y d r o c h r y s e n e a n a l o g u e s as o u t l i n e d i n F i g u r e 3. The c o n d e n s a t i o n sequence has been d e s c r i b e d e a r l i e r ( 1 3 , 14) and t h e e x c e l l e n t c h e m i s t r y i n v o l v e d w i l l be d i s p e n s e d w i t h h e r e , however, t h e immediate pathway l e a d i n g t o t h e key i n t e r m e d i a t e , 5-keto a c e t a t e (XIV) i s d e s c r i b e d ( 2 2 ) ; F i g u r e 4. A f t e r c a t a l y t i c r e d u c t i o n o f t h e b r i d g e d a c e t a t e (VII) by t h e use o f p a l l a d i u m h y d r o x i d e on s t r o n t i u m c a r b o n a t e , r e t r o a l d o l r e a r r a n g e m e n t i n base g i v e s t h e u n s a t u r a t e d k e t o n e (X), w h i c h on c a t a l y t i c r e d u c t i o n i n p r e s e n c e Figure 3. -5-of palladium on charcoal and a t r a c e of concentrated hydrobromic a c i d y i e l d s the c i s - s y n - c i s s t r u c t u r e ( X I ) . The carbonyl group can be reduced to the e q u a t o r i a l a l c o h o l (XII) w i t h l i t h i u m aluminium h y d r i d e , which i n t u r n i s a c e t y l a t e d to ( X I I I ) . The o x i d a t i o n of t h i s acetate w i t h t e r t i a r y b u t y l chromate y i e l d s not the 12-keto compound but the octahydrochrysene 5-keto acetate (XIV). P o s s i b l e explanation f o r a r o m a t i z a t i o n l i e s i n the s t r u c t u r a l arrangement of ( X I I I ) : the 4b p o s i t i o n i s h i g h l y r e a c t i v e by v i r t u e of i t s para p o s i t i o n to the methoxyl group; i n a d d i t i o n , the conformation of the r i n g system i s such, that attack at the 4b p o s i t i o n i s unhindered as compared to an analogous t r a n s - a n t i - t r a n s compound, where the 12-keto acetate was obtained on o x i d a t i o n under s i m i l a r c o n d i t i o n s . According to the suggested mechanism, the i n i t i a l step i n o x i d a t i o n i n v o l v e s formation of the t e r t i a r y 4 b - a l c o h o l , followed by immediate dehydration. This l a t t e r intermediate possessing an a l l y l i c carbon (Cyi) and a b e n z y l i c carbon-(C12) could be o x i d i z e d at e i t h e r one of these p o s i t i o n s to provide a secondary a l c o h o l , which would immediately aromatize to a C aromatic system. Subsequent o x i d a t i o n then y i e l d s the keto acetate (XIV). This m a t e r i a l was synthesized by another route a l s o . The bridged keto acetate (VII) provided an obvious access to the octahydrochrysene d e r i v a t i v e s , s i n c e a r o m a t i z a t i o n at t h i s stage i s reserved t o r i n g C only. Further a r o m a t i z a t i o n would be hindered, because of the bridge nature of r i n g s A and B. Aromatization thus was achieved r e a d i l y when the keto-acetate (VII) was t r e a t e d w i t h 10% palladium on carbon. This intermediate was'then subjected to a r e t r o - a l d o l rearrangement and the r e s u l t i n g unsaturated ketone (XVII) hydrogenated i n presence of 10% p a l l a d i u m on carbon i n benzene s o l u t i o n c o n t a i n i n g a t r a c e of hydrobromic -6-AcO* (XIV) t-BuCrO 30H ( X I I ) R = H ( X I I I ) R = Ac L i A l H i , Pd/C (XIX) R (XX) R H Ac ( X V I I I ) (XI) ( X V I I ) e OCH. C H 3 0/b (vii) (xv) CH3 6Ac (xvi) F i g u r e 4. P r e p a r a t i o n o f c i s - 2 - M e t h o x y - 8 a - 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 , l O a - o c t a h y d r o c h r y s e n e (XIV) by Kutney and By ( 2 2 ) . -7-a c i d . The s a t u r a t e d ketone (XVIII) was then reduced with l i t h i u m aluminum hydride to the satura t e d a l c o h o l (XIX) and t h i s l a t t e r substance a c e t y l a t e d to provide the acetate (XX). T e r t i a r y b u t y l chromate o x i d a t i o n produced the keto acetate (XIV). The cis-2-Methoxy-8a-acetoxy-5-keto-10a-methyl-5,6,6a,7,8,9,10,10a-octahydrochrysene (XIV) thus obtained was chosen t o be the s t a r t i n g m a t e r i a l f o r the work presented i n t h i s t h e s i s . An e a r l i e r d i s s e r t a t i o n (23d) from our l a b o r a t o r y had presented unpublished work, c a r r i e d out c o n c u r r e n t l y w i t h some of the work presented here, and d e a l t w i t h the conversion of trans-2-Methoxy-83-acetoxy-5-keto-10a-methyl-5,6,6a,7,8,9, 10, lOa-octahydrochrysene to B r i n g modified analogues. I t i s to be noted that the keto acetate i n t h a t case contains an A/B-trans r i n g j uncture and the. 8-acetoxy e s t e r i s 3 o r i e n t e d . Figure 5 demonstrates the sequence of r e a c t i o n s . The f i n a l compound (XXIX) however, has not been obtained i n a pure s t a t e . -8-(XXVII) ( X X V I I I ) (XXIX) F i g u r e 5. I t may be p e r t i n e n t t o m e n t i o n h e r e a communication by J o h n s o n e t a l (24) w h e r e i n a n o v e l r i n g c o n t r a c t i o n method l e a d i n g t o C-nor h y d r o c h r y s e n e d e r i v a t i v e s i s d e s c r i b e d . [ F i g . 6 ] . Even though t h e r e a c t i o n s a p p l i e d a r e d i f f e r e n t , t h e s i m i l a r i t y i n s t r u c t u r a l f e a t u r e s l e n d s i n t e r e s t t o t h e s p e c t r a l p r o p e r t i e s o f t h e s e compounds. S t u d i e s i n o u r l a b o r a t o r y have a l s o been c o n d u c t e d t o o b t a i n C-nor h y d r o c h r y s e n e d e r i v a t i v e s . F i g u r e 6. -9-DISCUSSION With an o b j e c t i v e i n mind to prepare B-nor s t e r o i d a l analogues a s u i t a b l e intermediate was chosen to be cis-2-Methoxy-8a-acetoxy-5-keto-10a-methyl-5,6,6a,7,8,9,10,lOa-octahydrochrysene (XIV). The u t i l i z a t i o n of t h i s compound was prompted because of i t s s e v e r a l advantageous f e a t u r e s : i ) i t was r e a d i l y a v a i l a b l e i n our l a b o r a t o r y ; i t s synthesis evolved i n connection w i t h the p r o j e c t of the hydrochrysene approach to the t o t a l s y n t h e s i s of modified s t e r o i d a l analogues, i i ) the r i g i d aromatic C and D r i n g s i m p l i f i e s stereochemical problems; i i i ) the aromatic system has an a c t i v a t i n g e f f e c t on the neighboring r i n g B, and i v ) the carbonyl group at p o s i t i o n 5 i s already a s u i t a b l e f u n c t i o n a l group f o r the proper intermediate necessary f o r s k e l e t a l rearrangement. Of the s e v e r a l a t t r a c t i v e p r e p a r a t i v e pathways p o s s i b l e toward the s y n t h e s i s of the B-nor s k e l e t o n , two were given c o n s i d e r a t i o n i n the l a b o r a t o r y . One of these i n v o l v e d a r i n g B a-keto-oxime int e r m e d i a t e , that could be hydrolysed to an a-diketo compound, which would undergo a b e n z i l i c a c i d rearrangement t o achieve the rearranged new s k e l e t a l system. The other sequence i n v o l v e d an a - d i o l (XXX) which when cleaved w i t h p e r i o d i c a c i d would give a dialdehyde (XXXI). The B-nor system could be obtained therefrom by an i n t e r n a l a l d o l condensation. The s u b s t i t u t e n t s could then be modified by s u i t a b l e o x i d a t i o n . Since the l a t t e r sequence was a l s o being c a r r i e d out c o n c u r r e n t l y on an isomeric compound (XXI) (23d), thereby a l l o w i n g f o r meaning-f u l comparison of s t r u c t u r a l p r o p e r t i e s of intermediates, t h i s approach was i n v e s t i g a t e d i n more d e t a i l . -10-Figure 7. -11-Th e o c t a h y d r o c h r y s e n e k e t o a c e t a t e (XIV) had been c h a r a c t e r i z e d e a r l i e r ( 22, 2 3 a ) . The f i r s t c o n s i d e r a t i o n was t o c o n v e r t t h i s compound t o t h e hexa-h y d r o c h r y s e n e analogue c o n t a i n i n g an o l e f i n i c bond i n r i n g B ( X X X I I ) . Re-d u c t i o n o f t h e k e t o a c e t a t e (XIV) w i t h sodium b o r o h y d r i d e i n wet methanol gave a crude p r o d u c t , w h i c h was an a p p r o x i m a t e l y e q u a l m i x t u r e o f t h e two i s o m e r i c a l c o h o l s ( X X X I I I ) w i t h a g r e e a b l e s p e c t r a l p r o p e r t i e s . 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 phosphorus p e n t o x i d e i n d r y benzene t o p r o v i d e t h e d e h y d r a t i o n p r o d u c t XXXII i n 85% y i e l d . The u l t r a -v i o l e t s p e c t r u m i n d i c a t e d a t y p i c a l n a p h t h a l e n i c chromophore (^ m a x 243, 277, 289, 301, 314, 335, 345 and 351 my), b u t t h e e n t i r e a b s o r p t i o n p a t t e r n had undergone a b a t h o c h r o m i c s h i f t i n a c c o r d w i t h t h e e x t e n d e d c o n j u g a t i o n b e i n g a f f e c t e d as compared t o t h e o c t a h y d r o c h r y s e n e s y s t e m (XX) (228, 254, 266, 276, 287, 308, 315s, 321, 329 and 335 my) ( 2 2 ) . The i n f r a r e d s p e c t r u m showed no h y d r o x y l o r 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 b u t o n l y t h e u s u a l a c e t a t e c a r b o n y l _ l a t 1722 cm . I n good agreement w i t h t h e s t r u c t u r e X X X I I , t h e o l e f i n i c h ydrogen on Cg was found t o be a q u a r t e t c e n t e r e d a t 3.92x i n t h e n.m.r. s p e c t r u m . The o t h e r o l e f i n i c h y d r o g e n (G5) was d e s h i e l d e d s u f f i c i e n t l y t o be l o c a t e d i n t h e a r o m a t i c r e g i o n s o , t h a t t h e l a t t e r now i n t e g r a t e d f o r 6 p r o t o n s . The r e l a t i v e l y h i g h c h e m i c a l s h i f t ( 8 . 9 0 T ) f o r t h e a n g u l a r m e t h y l group d e s e r v e s m e n t i o n . I t appears a t 0.12 ppm t o h i g h e r f i e l d t h a n i t does f o r t h e o c t a h y d r o c h r y s e n e a c e t a t e (XX) s u g g e s t i n g t h a t t h e 5, 6 d o u b l e bond has an o v e r - a l l s h i e l d i n g e f f e c t on t h e a n g u l a r m e t h y l group. Long range s h i e l d i n g e f f e c t s due t o e t h y l e n i c double bonds have been r e p o r t e d i n t h e l i t e r a t u r e ( 2 5 ) . T h i s s h i e l d i n g e f f e c t c o u l d be b r o u g h t about a l s o by a change i n t h e s p a t i a l o r i e n t a t i o n o f t h e a n g u l a r m e t h y l group w i t h r e s p e c t t o t h e a r o m a t i c system. E x a m i n a t i o n o f t h e m o l e c u l a r models i n d i c a t e s no such change however. -12-I t was now n e c e s s a r y t o e f f e c t t h e c l e a v a g e o f t h e 5, 6 d o u b l e bond i n X X X I I . I t i s w e l l known t h a t osmium t e t r o x i d e i s c a p a b l e o f h y d r o x y l a t i n g o l e f i n i c l i n k a g e s (26) and i t seemed t h e r e a g e n t o f c h o i c e . T h i s c o n v e r s i o n was i n d e e d a c h i e v e d by r e a c t i n g t h e o l e f i n i c compound (XXXII) w i t h osmium t e t r o x i d e a t room t e m p e r a t u r e f o r f o u r days and t h e osmate e s t e r t h u s formed was decomposed by means o f hydrogen s u l p h i d e . The p u r i f i e d p r o d u c t showed one s p o t on a t h i n l a y e r chromatography p l a t e , one a n g u l a r m e t h y l group s i g n a l (8.52x) and no o l e f i n i c a b s o r p t i o n i n t h e n.m.r. s p e c t r u m , t h u s i t was t h e r e f o r e a p p a r e n t , t h a t t h e h y d r o x y l a t i o n had p r o c e e d e d i n t h e e x p e c t e d manner. The u l t r a v i o l e t s p e c t r u m i n d i c a t e d a t y p i c a l n a p h t h a l e n i c chromophore (A 234, 254, 263, 273, 283, 305, 313, 318, 327 and 333 my) and i n t h i s c o n n e c t i o n t h e u l t r a v i o l e t s p e c t r u m compared w e l l w i t h t h e o t h e r analogous s t r u c t u r e s p o s s e s s i n g a h y d r o x y l group on carbon-5 ( F i g u r e 8 ) . Two s t r o n g .1 bands a t 3470 and 3390 cm , c h a r a c t e r i s t i c o f hydrogen bonded h y d r o x y l groups were e v i d e n t i n t h e i n f r a r e d s p e c t r u m o f t h i s r e a c t i o n p r o d u c t . Thus t h e s p e c t r a l d a t a and t h e e x c e l l e n t e l e m e n t a l a n a l y s i s were i n complete agreement w i t h t h e 5 , 6 - d i h y d r o x y o c t a h y d r o c h r y s e n e s t r u c t u r e (XXX). I t was now e s s e n t i a l t o c l e a v e t h i s v i c i n a l d i o l (XXX) w i t h p e r i o d i c a c i d i n t h e hope o f o b t a i n i n g t h e c o r r e s p o n d i n g d i a l d e h y d e ( F i g u r e 7 ) . T h i s r e a c t i o n was s e t up i n d i o x a n e and i t was f e l t t h a t t h e e x t e n t o f t h e con-v e r s i o n c o u l d be f o l l o w e d by w i t h d r a w i n g a l i q u o t s o f t h e r e a c t i o n m i x t u r e and m e a s u r i n g t h e u l t r a v i o l e t s p e c t r u m . Dioxane was used as a s o l v e n t i n t h e r e a c t i o n , b e c a u s e a t t h i s t i m e i n v e s t i g a t i o n s i n our l a b o r a t o r y on t h e i s o m e r i c compound (XXIV) i n d i c a t e d p e r p l e x i n g r e s u l t s i n a m e t h a n o l i c medium. The u l t r a v i o l e t s p e c t r u m d i d n o t show any s i g n i f i c a n t change d u r i n g t h e r e a c t i o n and a f t e r 16 hours t h e p r o d u c t was i s o l a t e d . On t h e b a s i s o f t h i n l a y e r chromatography, however, i t was i m m e d i a t e l y o b v i o u s , t h a t some r e a c t i o n Figure 8 -14-had t a k e n p l a c e , s i n c e t h e p r o d u c t appeared as a s t r e a k e d band w i t h an a p p r o x i m a t e R f v a l u e o f 0.24-0.56 as compared t o 0.10 f o r t h e s t a r t i n g diol... ( S i l i c a G e l G , 6 : l , c h l o r o f o r m : e t h y l a c e t a t e ) . S i n c e t h e u l t r a v i o l e t s p e c t r u m ( F i g u r e 8C) showed no c o n j u g a t e d n a p h t h a l e n i c chromophore, t h e i n f r a r e d s p e c t -rum i n d i c a t e d 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 and t h e i n f r a r e d s p e c t r u m ( i n c h l o r o f o r m ) r e v e a l e d t h e . p r e s e n c e o f h y d r o x y l a b s o r p t i o n i n t h e r e g i o n _ l 3200-3500 cm , t h e assignment o f a d i a l d e h y d e s t r u c t u r e w o u l d have been i l l o -g i c a l . The u l t r a v i o l e t s p e c t r u m f o r t h e d i a l d e h y d e . w o u l d have been e x p e c t e d t o have no f i n e s t r u c t u r e and t o be somewhat s i m i l a r t o chromophores as shown i n F i g u r e 9, i n s t e a d , i t r e s e m b l e d more t h e 5-hydroxy n a p h t h a l e n i c chromophores shown i n F i g u r e 8. The i n f r a r e d s p e c t r u m w o u l d have been e x p e c t e d t o have s t r o n g a b s o r p t i o n i n t h e c a r b o n y l r e g i o n f o r t h e c o n j u g a t e d and s a t u -r a t e d a l d e h y d i c groups i n t h e d i a l d e h y d e s t r u c t u r e . A l t h o u g h t h i s l a t t e r s t r u c -t u r e was i n c o n s i s t e n t w i t h t h e above s p e c t r a l d a t a , t h e n.m.r. s p e c t r u m p r o v i d e d some e v i d e n c e w h i c h c o u l d be a t t r i b u t e d t o s u c h a f o r m u l a t i o n . S i g n i f i c a n t l y , one s h a r p s i n g l e t ' (-1.12T ) and a n a rrow d o u b l e t ( 0 . 4 2 x ) appeared a t u n u s u a l l y low f i e l d , each c o r r e s p o n d i n g t o one p r o t o n . A l d e h y d i c p r o t o n s a p p e a r - i n - t h i s r e g i o n g e n e r a l l y and on b a s i s o f t h e n.m.r. s p e c t r u m t h e d i a l d e h y d e s t r u c t u r e * c o u l d n o t be e x c l u d e d , s i n c e t h e two s i g n a l s c o u l d be. a s s i g n e d c o n v e n i e n t l y t o t h e c o n j u g a t e d and t h e n o n - c o n j u g a t e d a l d e h y d i c p r o t o n s r e s p e c t i v e l y . In. a d d i t i o n t h e r e were at l e a s t two a n g u l a r m e t h y l s i g n a l s i n t e g r a t i n g f o r t h r e e p r o t o n s i n a l l and t h e r e b y i n d i c a t i n g t h e p r e s e n c e o f i s o m e r s . F u r t h e r i n v e s t i g a t i o n s were n e c e s s a r y and now t h e p e r i o d i c a c i d . c l e a v a g e r e a c t i o n was r e p e a t e d i n methanol s o l v e n t . The p r o d u c t was l e s s p o l a r and more s t a b l e on t h i n l a y e r chromatography p l a t e s t h a n t h e one p r e -p a r e d above i n d i o x a n e . The u l t r a v i o l e t s p e c t r u m d i d n o t change s i g n i f i c a n t l y d u r i n g t h e r e a c t i o n and t h e i n f r a r e d s p e c t r u m showed n e i t h e r c o n j u g a t e d F i g u r e 9 -16-c a r b o n y l a b s o r p t i o n n o r h y d r o x y l bands. F i n a l l y , t h e n.m.r. s p e c t r u m . p r o v i d e d t h e answer t o t h e s t r u c t u r e o f t h i s m a t e r i a l . I n p a r t i c u l a r , t h e r e g i o n n o r m a l l y c h a r a c t e r i s t i c o f m e t h o x y l m e t h y l groups i n o u r s e r i e s showed t h r e e s i n g l e t s o f a p p r o x i m a t e l y e q u a l i n t e n s i t y at 6.10, 6.25 and 6.38 T ' . ' , T h i s i n d i c a t e d t h e p r e s e n c e o f t h r e e m e t h o x y l groups i n t h e p r o d u c t and s i n c e o n l y one -0CH 3 i s p r e s e n t i n t h e s t a r t i n g d i o l (XXX), two new -0CH 3 groups appear d u r i n g t h e p e r i o d i c a c i d c l e a v a g e . C o u p l e d w i t h t h e i n f r a r e d d a t a , t h e above e v i d e n c e s u g g e s t e d i m m e d i a t e l y , t h a t t h e p e r i o d i c a c i d r e a c t i o n p r o d u c t i n methanol c o u l d be a s s i g n e d s t r u c t u r e (XXXV). I n o t h e r words, c l e a v a g e o f t h e d i o l had i n d e e d o c c u r r e d b u t t h e i n t e r m e d i a t e d i a l d e h y d e (XXXI) c y c l i z e d t o a h e m i a c e t a l s t r u c t u r e ( X X X I V ) , . w h i c h r e a c t e d w i t h methanol under t h e a c i d i c c o n d i t i o n s t o form t h e c y c l i c a c e t a l t y p e p r o d u c t (XXXV). There i s ample p r e c e d e n t f o r t h e s e r e a c t i o n s i n c a r b o h y d r a t e c h e m i s t r y . I t can be argued t h a t t h e f o r m a t i o n o f a c e t a l (XXXV) was p r e v e n t e d by t h e use o f a s o l v e n t o t h e r t h a n m e t h y l a l c o h o l and t h e r e a c t i o n p r o d u c t i s o -l a t e d i n d i o x a n e was t h e h e m i a c e t a l (XXXIV). The i n f r a r e d , u l t r a v i o l e t and n.m.r. s p e c t r a m e n t i o n e d e a r l i e r a r e i n p e r f e c t agreement w i t h t h i s c o n c l u s i o n i f t h e low f i e l d n.m.r. s i g n a l s (0.42 and -1,12 x ) a r e t e n t a t i v e l y a s s i g n e d t o t h e Ce and C5 p r o t o n s r e s p e c t i v e l y . I f t h e s t r u c t u r e .{XXXV) was c o r r e c t , i t s h o u l d r e g e n e r a t e t h e h e m i a c e t a l (XXXIV) on\" t r e a t m e n t w i t h g l a c i a l a c e t i c a c i d ( 2 7 ) . Indeed, when t h e a c e t a l (XXXV) was warmed w i t h t h i s a c i d on a steam b a t h t h e p r o d u c t i s o l a t e d was f o u n d t o be i d e n t i c a l t o t h e h e m i a c e t a l , XXXIV, o b t a i n e d e a r l i e r by p e r i o d a t e c l e a v a g e o f t h e d i o l i n d i o x a n e as s o l v e n t . F o r c o m p a r i s o n i t may be r e l e v a n t t o n o t e , t h a t t h e i s o m e r i c h e m i a c e t a l (XXVI) was a l s o i s o l a t e d i n o u r l a b o r a t o r y , w h i l e t h e open C - r i n g a n a l o g u e , d i a l d e h y d e (XXXVI) d i d n o t form a h e m i a c e t a l ( 2 3 d ) . T a h a r a (28) r e c e n t l y -17-(XXXVI) r e p o r t e d t h e p e r i o d i c a c i d c l e a v a g e o f an a - d i o l (XXXVII) and i t s f u r t h e r c o n v e r s i o n t o a l a c t o n e - h e m i a c e t a l t y p e compound ( X X X V I I I ) . COOCjf 0 H (xxxvii) 3 HlOt MeOH 1) d i l NaOH 2) cone HCl 0 HO \\ AOCHj >--0 d i l H2S04 (X X X V I I I ) F i g u r e 10. A l t h o u g h t h e 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 t h e hemi-a c e t a l and t h e a c e t a l s t r u c t u r e s (XXXIV and XXXV), i t was n o t p o s s i b l e t o pro-v i d e any a n a l y t i c a l d a t a f o r t h e s e compounds. I n each i n s t a n c e t h e r e a c t i o n p r o d u c t s were h a r d gums and a p a r t from t h e f a c t , t h a t o n l y v e r y l i m i t e d amounts were a v a i l a b l e t o u s , t h e y were a l s o n o t 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 . Our u n s u c c e s s f u l a t t e m p t s t o p u r i f y t h e above m a t e r i a l s by p r e p a r a t i v e t h i n l a y e r chromatography r e v e a l e d n o t o n l y t h e i r i n s t a b i l i t y , b u t a l s o -18-suggested a procedure f o r the next step i n the s y n t h e t i c sequence. When the hemiacetal (XXXIV) was developed on a Woelm alumina p l a t e , the major d i f f u s e band e x t r a c t e d and i t s u l t r a v i o l e t spectrum recorded (Figure 8 cl), the general shape of the curve was found to be s i m i l a r to the spectrum of the hemiacetal, but now there was bathochromic s h i f t of the absorption maxima by about 4 mu. Furthermore, one sharp s i n g l e t appeared i n the n.m.r. spectrum at -0.09T while the other two low f i e l d s i g n a l s due to the hemiacetal had disappeared. This type of spectrum would be expected f o r the c y c l i c s t r u c t u r e (XXXIX), and i t (XXXIV) Ac£T AI2O3 (XXXIX) Jones' Ox'n (XL) Figure 11. was s e r i o u s l y considered as a d i s t i n c t p o s s i b i l i t y . I t s formation i s e a s i l y r a t i o n a l i z e d i f one co n s i d e r s , that the hemiacetal opens to the dialdehyde, which immediately undergoes an i n t e r n a l a l d o l condensation to provide XXXIX. There i s precedent i n the l i t e r a t u r e f o r the alumina-catalyzed i n t e r n a l a l d o l r e a c t i o n . For example, Tanabe (29) reported t h i s type o f c y c l i z a t i o n i n the -19-t e r p e n e s e r i e s . The c y c l i z a t i o n p r o c e d u r e was improved upon by s h a k i n g t h e h e m i a c e t a l s o l u t i o n w i t h a l u m i n a f o r s e v e r a l h o u r s , t h e r e b y a l l o w i n g c y c l i z a t i o n t o o c c u r b e f o r e t h e p u r i f i c a t i o n s t e p on p r e p a r a t i v e t h i n l a y e r chromatography p l a t e s . T h i s m o d i f i c a t i o n had t h u s t h e e f f e c t o f n a r r o w i n g t h e b a n d - w i d t h o f t h e d e s i r a b l e m a t e r i a l from t h e r e a c t i o n m i x t u r e . The s p e c t r a l p r o p e r t i e s o f t h e 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 c y c l i z e d s t r u c t u r e ( X XXIX). A p a r t from t h e u l t r a -v i o l e t d a t a m e n t i o n e d above, t h e i n f r a r e d s p e c t r u m i n d i c a t e d an a l d e h y d e _1 _1 C - H s t r e t c h i n g band (2690 cm ) , a h y d r o x y l band (3450 cm ) , a c e t a t e and _ l _ l a l d e h y d e c a r b o n y l a b s o r p t i o n s a t 1715 cm ( s h o u l d e r a t 1730 cm ) , and no con-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. s p e c t r u m was p a r t i c u l a r l y h e l p f u l . Above a l l , t h e low f i e l d s i g n a l a t -0.09 T, i n d i c a t i v e o f one a l d e h y d i c p r o t o n showed, t h a t o n l y one a l d e h y d e f u n c t i o n c o u l d be p r e s e n t . The m e t h y l r e g i o n i n d i c a t e d t h e p r e s e n c e o f s e v e r a l i s o m e r s . 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 t h e 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 XXXIX. A l t h o u g h t h e p r o d u c t was o b t a i n e d i n s o l i d f orm (m.p. 70-79°C), a t t e m p t e d p u r i f i c a t i o n by r e c r y s t a l l i z a t i o n s e t c . was n o t s u c c e s s f u l and a s a t i s f a c t o r y e l e m e n t a l a n a l y s i s c o u l d n o t be o b t a i n e d . I n t h i s c o n n e c t i o n i t was o b s e r v e d , t h a t on s t a n d i n g • t h i s m a t e r i a l was t r a n s f o r m e d , perhaps by a i r o x i d a t i o n , t o a p r o d u c t i n d i c a t i n g a c o n j u g a t e d c a r b o n y l i n t h e i n f r a r e d s p e c t r u m and a l s o a c o n j u g a t e d n a p h t h a l e n e chromophore ( o f a t y p e i d e n t i c a l t o F i g u r e 9t>) i n t h e u l t r a v i o l e t s p e c t r u m . I t was l a t e r shown t o have t h e same t . l . c . p r o p e r t i e s as the f i n a l keto. a c e t a t e (XL) . P a r t i a l o x i d a t i o n t h u s c o u l d have e f f e c t e d t h e r e s u l t s o f e l e m e n t a l a n a l y s i s and 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 t h e above assignment f o r 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 was c o r r e c t . I t must be emphasized h e r e t h a t t h e o r i e n t a t i o n o f the; a l d e h y d e and t h e h y d r o x y l group a r e not p r e s e n t l y known. -20-Our next c o n s i d e r a t i o n was to o x i d i z e the hydroxyl group on C5 i n XXXIX. The Jones' reagent (30) i s w e l l known as a m i l d oxidant, and i t was s e l e c t e d f o r t h i s purpose. No d i f f i c u l t i e s were a n t i c i p a t e d , f o r i t appeared that the secondary a l c o h o l was s u s c e p t i b l e even t o a i r o x i d a t i o n as noted above. When the a l d o l product (XXXIX) was t r e a t e d with Jones' reagent we observed not only the conversion of the secondary hydroxyl group to a ketone, but a complete loss o f the aldehyde f u n c t i o n . The n.m.r. spectrum of the crude product i n d i -cated no aldehyde s i g n a l s at low f i e l d . This i s s i g n i f i c a n t , because from other work i n our lab o r a t o r y (23d) i t was found, that when the 8-acetoxy group i s 3-oriented i n the s t a r t i n g m a t e r i a l (XXVII) only p a r t i a l deformylation took place under i d e n t i c a l c o n d i t i o n s . Further i n v e s t i g a t i o n by t h i n l a y e r chromatography of the crude r e a c t i o n product i n d i c a t e d immediately that r e a c t i o n had taken p l a c e . A new blue f l u o r e -scent spot appeared with an Rf value (0.33) twice as large as that of the s t a r t i n g m a t e r i a l , XXXIX . In a d d i t i o n a minor spot was als o evident on the p l a t e (Rf: 0.28) and i t appeared with a greenish-blue fluorescence. These two ma t e r i a l s were s u c c e s s f u l l y separated by p r e p a r a t i v e t h i n l a y e r chromatography (Woelm S i l i c a G e l , 6:1 benzene-ethylacetate). The n.m.r. spectrum o f the major product i n d i c a t e d two angular methyl groups (8.50 and.8.74x, the former more intense) i n t e g r a t i n g f o r three protons i n a l l . T h i s observation suggested the presence o f an isomeric mixture even though t h i n l a y e r chromatography i n d i c a t e d only one spot (Rf.: 0.33). Con-sequently the mixture was subjected 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 . A f t e r s e v e r a l r e c r y s t a l l i z a t i o n s from benzene-petroleum ether a c o l o u r l e s s c r y s t a l l i n e m a t e r i a l was obtained. The u l t r a v i o l e t spectrum o f t h i s m a t e r i a l i n d i c a t e d a t y p i c a l conjugated chromophore, s i m i l a r i n p a t t e r n to the spectrum of the o r i g i n a l octahydrochrysene 5-keto-acetate (XIV) (Figure 9(443.3cps) (XXXII) 2.02x (479.4cps)(458.1cps)(444.7cps) J 10.3cps 1.79T (493 cps) J 9.1cps 2.37T J 8.8cps 2.23T (465.9cps)(446.9cps) J=9.2 cps 2.59T J 8.7cps 2.56T J 8.2cps:: J=8.8cps 2.94T (424 cps) 2.85T (429cps) J 3 > l t= :9cps J3^a ^.gcps. • 2.7T (435cps) J3 , t s 9 c P s J 3 , l= ? not well resolved 1.53x (508 cps) .98T (541 cps) J 8.6cps not well resolved 2.07x J 8.5cps 2.52T (476 cps)(448.5cps) J 8.3cps .12 1 2.09T (592.7cps)(474.7cps) J 9.1cps J 9.0cps 2.38x (456.9cps) J 9.0cps 2.73x (436cps) r 3 > 4 - 9 cps J3>l~2.5cps 2.65x (441cps) J 3 i+~9cps J 3 ) 1~2.8cps 2.93T (424.5cps) 2.82T (431 cps) 2.90T (425.5cps) 2.77T (433 cps 2.81T (432 cps) 2.90x (425.6cps) Table J. Aromatic proton resonances of the octahydrochrysene analogues. -34-i n p a r t i c u l a r , t h e p o l y s u b s t i t u t e d 2-Methoxy n a p h t h a l e n i c s y s t e m s . To i l l u s t r a t e t h e g e n e r a l s p l i t t i n g p a t t e r n , t h e a r o m a t i c r e g i o n o f t h e 5-keto a c e t a t e , ;(XL), „ , i s r e p r o d u c e d i n F i g u r e 17. 12 1 1 1 1 1 1 1 I i i i i I i , i , _ _ 1 ' ' L i 1 1 1 L—i 1 1—_J i L I I i i_ 1.0 2.0 3.0 T F i g u r e 17. N.M.R. s p e c t r u m o f t h e a r o m a t i c r e g i o n o f - 5 - k e t o a c e t a t e , XL, a t 60 Mc/s i n CDC1 3 s o l u t i o n . Some r a t i o n a l i z a t i o n s - p r e s e n t e d i n ' t h e f o l l o w i n g p a r a g r a p h s l e n d meaning t o t h e a s s i g n m e n t s made on T a b l e * 1° The i n t e n s e b r o a d s i g n a l a p p e a r i n g i n t h e r e g i o n 2.75-2.93x (435-425 cps) was a s s i g n e d t o t h e C - l p r o t o n s and t h e p a r t i a l l y h i d d e n q u a r t e t ( J l j 3 ~ 2 „ 5 cps) J 3 h ~ 8.5-9.5 cps) f o r t h e C-3 p r o t o n appears a t about 0.1 p.p.m, lo w e r f i e l d . -35-Figure 18 -36-Also, tiic C-l proton appears at a chemical s h i f t 0.4-0.6 ppm lower f o r C,D-aromatic compounds (those i n Tabic I ] than for compounds with the aromatic system i n r i n g D only (see XLIX f o r example, (23a)). This s h i f t i s due to the a d d i t i o n a l paramagnetic e f f e c t of an e x t r a fused r i n g i n the aromatic system. 1 (XLIX) (L) Fur t h e r , for u n s u b s t i t u t e d naphthalenes,(L), the 6-proton s i g n a l s are u s u a l l y 0.34 ppm. to higher f i e l d than the a-proton s i g n a l , because the a-protons are more proximate to the center of the e x t r a aromatic r i n g . However, s u b s t i t u -t i o n of a methoxyl group at Cz a l t e r s the resonance frequencies f o r the 1,3-protons. Although the e l e c t r o n donating methoxyl group has an o v e r a l l s h i e l d i n g e f f e c t on a l l r i n g protons, the r e s u l t i n g r e l a t i v e e f f e c t was found to be one i n which the a-proton s i g n a l (H-l) appears about 0.1 ppm h i g h e r , than the 6-proton ( f o r example H-l and H-3 i n Figure 17). This can be r a t i o n a l i z e d i n the f o l l o w i n g way: any i n d u c t i v e e f f e c t o f a 2-methoxy s u b s t i t u e n t can appear at the 1 - p o s i t i o n , using valence bond s t r u c t u r e s with the second r i n g f u l l y aromatic (see p ) . For the i n d u c t i v e e f f e c t to be t r a n s m i t t e d to the 3 - p o s i t i o n the second r i n g must be quinonoid (see q ) . These observations are i n good agreement with r e s u l t s expressed by Dudek (39) on methoxy s u b s t i t u t e d naphtha-lenes . -37-1 The C-11 and C-12 protons appear as a regular p a i r of doublets ( J i i } i 2 ~ 8 - 8 cps), with the B-type C-11 hydrogen thought te be at the higher f i e l d . The difference i n chemical s h i f t between the two doublets was found to be 0.16 ppm. ^ T n - T = I 2 , 6 6 \" 2 - 5 0 = ° - 1 6 PP m I 2.61 - 2.16 = 0.45 ppm. Figure 19. The deshielding of the aromatic proton on C 1 2 situated para to a carbonyl group. fo r the p a r t i c u l a r acetate, XX. Introduction of a carbonyl function into r i n g B has a deshielding e f f e c t on both protons, but a greater e f f e c t on the para C-12 proton. As a r e s u l t , a wider separation of doublets occurs. (Figure 19). Such deshielding of an aromatic proton situated para to a -38-c a r b o n y l group has been r e p o r t e d i n t h e l i t e r a t u r e ( 4 0 ) . The C-4 p r o t o n was found t o be t h e most d e s h i e l d e d one i n t h e s t r u c t u r e s examined. I t appears as a r e g u l a r d o u b l e t due t o t h e s p l i t t i n g by: t h e o r t h o . s i t u a t e d C-3 p r o t o n w i t h t h e e x p e c t e d (38) c o u p l i n g c o n s t a n t o f 8.6-9.8 cps.. . I t s c h e m i c a l s h i f t was found t o be g r e a t l y dependent on s u b s t i t u t i o n i n r i n g B. E a r l i e r R e i d (41) had r e l a t e d t h e d e s h i e l d i n g o b s e r v e d f o r p r o t o n s 4. and 5 o f phen a n t h r e n e ( L I ) and i t s 1 , 2 - d i h y d r o d e r i v a t i v e s t o t h e change i n e l e c t r o n d i s t r i b u t i o n i n t h e C-H bond, w h i c h must o c c u r when r e p u l s i v e f o r c e s come i n t o ( L I ) ( L I I ) p l a y between s t e r i c a l l y c l o s e h y d r o g e n s . A l s o t h e r e e n t r a n t p o s i t i o n o f hydrogens-4 and 5 b r i n g s t h e s e p r o t o n s c l o s e t o a r o m a t i c r i n g s o t h e r t h a n t h o s e t o wh i c h . . t h e y a r e a t t a c h e d . T o r i and N a g a t a (42) a s c r i b e d t h e r e m a r k a b l e d e s h i e l d i n g o f C-4 p r o t o n s i n systems o f t y p e L I I , t o t h e van d e r Waal c o n t a c t between p r o t o n s a t C-4 and C-5. They a l s o c o n c l u d e d , t h a t t h e degree o f d e s h i e l d i n g i s c l o s e l y r e l a t e d t o t h e d i s t a n c e between t h e C-4 p r o t o n and t h e e q u a t o r i a l p r o t o n on c a r b o n - 5 . A s e r i e s o f a r t i c l e s by M a r t i n e t a l (40) d e a l s w i t h t h e n.m.r. s p e c t r a o f numerous f u s e d a r o m a t i c h y d r o c a r b o n s y s t e m s . Of s i g n i f i c a n c e a r e compounds o f t y p e L I I I and LIV w i t h c h e m i c a l s h i f t s f o r t h e p e r i hydrogens ( c i r c l e d ) a t -39-0.58T (565 cps) and 0.85T (549 cps) r e s p e c t i v e l y . I t i s i m m e d i a t e l y o b v i o u s f r o m t h e d a t a i n T a b l e I , t h a t t h e c h e m i c a l s h i f t o f the C-4 p r o t o n i s v e r y much dependent on s u b s t i t u t i o n a t ca r b o n - 5 . P a r t i c u l a r l y , t h e i n t r o d u c t i o n o f a c a r b o n y l group a t p o s i t i o n 5 causes an u n u s u a l p a r a m a g n e t i c s h i f t o f t h e C-4 p r o t o n . T h i s c o u l d be due t o t h e d i a -magnetic a n i s o t r o p y o f t h e c a r b o n y l group ( F i g u r e 20) where p r o t o n s so p o s i t i o n e d as t o be i n s i d e t h e cone w i l l be s h i e l d e d and t h o s e c l o s e t o 0 t h e p l a n e o f t h e ^ C - ^ s y s t e m w i l l be d e s h i e l d e d ( 3 8 i i ) . I n o u r case t h e c a r b o n y l group c o n j u g a t e d w i t h t h e a r o m a t i c s y s t e m i s e x p e c t e d t o be i n a p p r o x i m a t e l y t h e same plane.. S e c o n d l y , t h e d i s t a n c e between t h e oxygen and t h e C-4 p r o t o n i s c e r -t a i n l y l e s s t h a n t h e normal h y d r o g e n 0 bond d i s t a n c e i n many s t r o n g hydrogen bonds ( u s u a l l y about 2.7 A ) . I f t h i s F i g u r e 20. The d i a m a g n e t i c a n i s o t r o p y o f c a r b o n y l group. -40-arrangement can be c o n s i d e r e d a t y p e o f hydrogen bond, t h e n t h e c o n t r i b u t i o n w ould be a hydrogen bond p a r a m a g n e t i c d i s p l a c e m e n t . 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 on c o n t r a c t i o n o f r i n g B from a 6 t o a 5-membered 5-keto s y s t e m , t h e c a r b o n y l bond i s i n e f f e c t b e n t away i n p l a n e from t h e C-4 h y d r o g e n and t h u s a l l o w s f o r somewhat l e s s d e s h i e l d i n g f o t h e C-4 p r o t o n . The most d e s h i e l d e d C-4 p r o t o n (x 0.12) was o b s e r v e d f o r t h e d i k e t o compound X L I I l . I n t h e s y n t h e t i c sequence, d e s c r i b e d i n t h e \" D i s c u s s i o n \" s e c t i o n , s k e l e t a l changes have been a f f e c t e d on t h e s t a r t i n g m a t e r i a l , 5-keto a c e t a t e ( X I V ) , t h e s t r u c t u r e o f which, i s c h a r a c t e r i z e d by a c i s - A / B r i n g arrangement and an a c e t a t e group a t t h e 8a p o s i t i o n . I f b o t h r i n g s A and B e x i s t i n t h e n o r m a l l y more s t a b l e c h a i r c o n f o r m a t i o n s , t h e 8-proton on carbon-8 w i l l be i n an a x i a l o r i e n t a t i o n . The c h e m i c a l l i t e r a t u r e o f f e r s ample p r e c e d e n t on t h e c h e m i c a l s h i f t and s p i n c o u p l i n g b e h a v i o r o f p r o t o n s g e m i n a l t o a h y d r o x y l f u n c t i o n o r i t s a c e t y l a t e d a n a l o g u e i n s t e r o i d a l o r c y c l i c systems i n g e n e r a l ( 3 8 i i i , 43, 44, 4 5 ) . An a x i a l p r o t o n g e n e r a l l y o c c u r s about 20-45 cps t o h i g h e r f i e l d t h a n an e q u a t o r i a l p r o t o n , due t o t h e l o n g range s h i e l d i n g e f f e c t s a s s o c i a t e d w i t h t h e d i a m a g n e t i c a n i s o t r o p y o f t h e c a r b o n - c a r b o n s i n g l e bond ( 3 8 i i i ) . More s i g n i f i c a n t l y , and a x i a l p r o t o n o f t y p e , LV, i s s u b j e c t e d t o two l a r g e d i a x i a l ORc (XIV) - 4 1 -Thus, t h e c o n b i n a t i o n o f s p l i t t i n g r e s u l t s i n a v e r y b r o a d s i g n a l f o r an a x i a l h y drogen ( h a l f - b a n d widths 15-20 c p s ) . On t h e o t h e r hand, an e q u a t o r i a l h y d r o -gen i n a c y c l i c s y s t e m o f t y p e , L V I , i s s u b j e c t e d t o two e q u a t o r i a l - e q u a t o r i a l and two a x i a l - e q u a t o r i a l v i c i n a l c o u p l i n g s ( J ~ J ~ 2 . 5 - 5 c p s ) . The com-, 9- j © © > © b i n a t i o n o f s p l i t t i n g s i n . t h i s c a s e r e s u l t s i n a r e l a t i v e l y narrow m u l t i p l e t ( h a l f - b a n d widths 6-9 c p s ) . These f i n d i n g s a r e o f fundamental r e l e v a n c e t o the c o n f o r m a t i o n a l a n a l y s i s o f r i g i d systems ( 4 4 ) . The n.m.r. s p e c t r u m o f t h e above mentioned s t a r t i n g m a t e r i a l (XIV) a c c o r d i n g l y shows a v e r y b r o a d s i g n a l ( h a l f band w i d t h = 18 cps) a t 5 . 2 0 T ( 2 8 3 cps) c o r r e s p o n d i n g t o an a x i a l p r o t o n at C - 8 . The v a r i o u s C -8 p r o t o n f r e q u e n c i e s and t h e h a l f - b a n d w i d t h s a r e l i s t e d i n T a b l e I I f o r t h e s i g n i f i c a n t 8 o t-acetates p r e p a r e d . I t i s o f i n t e r e s t a t t h i s p o i n t t o d i s c u s s t h e n.m.r s p e c t r u m o f t h e r e a c t i o n m x i t u r e o b t a i n e d from t h e Jones o x i d a t i o n o f compound XXXIX. The n.m.r. s p e c t r u m o f t h i s p r o d u c t ( L V I I ) , w h i l e i n d i c a t i n g two a n g u l a r m e t h y l g r o u p s , one a t 8 . 5 0 T (90 cps) and t h e o t h e r a t a c h e m i c a l s h i f t o f 8 . 7 4 T (76 c p s ) , -42-i i i i - i ' J 1 1 1 1 1 1 U _ _ ' ' I I I I • • I I • < 5.Or 5.0? S.sr F i g u r e 21. Comparison o f t h e r e s o n a n c e f r e q u e n c y and t h e s p l i t t i n g ' p a t t e r n o f an e q u a t o r i a l l y and o f an a x i a l l y o r i e n t e d p r o t o n . Spectrum r u n i n CDCI3 a t 60 Mc/s a t a p p r o x i m a t e l y same i n t e n s i t i e s . showed o n l y one peak f o r t h e C-8 hydrogen a t a c h e m i c a l s h i f t o f 4.97T (302 cps) w i t h a h a l f - b a n d w i d t h o f 9 cps and i n t e g r a t i n g f o r one p r o t o n . (LVII) -43-F o r m u l a 8B-H h a l f - b a n d w i d t h 8R-H a n g u l a r methyl-H's 8 a - a c e t o x y methyl-H's 5.21T (287 cps) 19 cps 8.78T (73 cps) 8.13T (112 cps) (xiv) 5.20T (286 cps) 18 cps 8.63T (82 cps) 8.90T (66 cps) 8.52T (89 cps) 8.13T (112 cps) (XXXII) 5.29x (283 cps) 19 cps 8.14T (112 cps) 7.98x (122 cps) y_0 (xxxiv) 4.97T (302 cps) 9 cps (?) major: 8.70T(78 cps) min o r : 8.45x(93 cps) 8.10x (114 cps) * ^OH (XXXIX) 4.98x (302 cps) 19 cps (?) maj o r : 8.54T(87 cps) min o r : 8.71T(78 cps) 8.10x (114 cps) r 5 i n CDC13 5.00x (302 cps) 9 cps 8.50T (90 cps) 8.17x (110 cps) i n ienzene 5.04T 298 (cps) 9 cps 8.87T (68 cps) 8.32x (101 cps) (XLIII) o .... _ . 4.71T (318 cps) 8 cps 8.50x (90 cps) 8.08x (115 cps) T a b l e I I . N.M.R. d a t a on 88, 10a m e t h y l and 8 a - a c e t o x y m e t h y l p r o t o n s o f the h y d r o c h r y s e n e a n a l o g u e s . Act)'* (XXXII) Solvent: CDC1 3 (3-H.5-H) area=5H (12-H)! (11-H) A (4-H) A . N\\ 3.92(6-H) A 6.14 (-OCHj) 5.23(8-H) 8.14 (-Ok) 8 3 0 (CH5 4 t C 1 0 a) TMS inb 10T Figure 22. The N.M.R. spectrum o f cis-2-Methoxy-8a-acetoxy-10a-methyl-6a,7,8,9,10,10a-hexahydrochrysene (XXXII). -45-On i n s p e c t i n g t h e m o l e c u l a r models t h r e e c o n f o r m a t i o n a l s t r u c t u r e s l e n d t h e m s e l v e s t o c o n s i d e r a t i o n , i f i t i s assumed, t h a t t h e r e was no e p i m e r i z a t i o n a t p o s i t i o n - 8 d u r i n g t h e c o u r s e o f t h e t r a n s f o r m a t i o n s i n v o l v e d . Thus t h e ( L V I I a ) ( L V I I b ) ( L V I I c ) Otic 86-hydrogen i s e q u a t o r i a l i n t h e t r a n s A/B compound (F o r m u l a L V I I . a ) , and a l s o i n t h e c i s A/B compound w i t h r i n g A i n t h e n o n s t e r o i d a l c o n f o r m a t i o n ( f o r m u l a L V I I . b ) . Oh t h e o t h e r hand, t h e 8B-hydrogen i s a x i a l l y o r i e n t e d when the compound w i t h A/B c i s c o n f i g u r a t i o n has a s t e r o i d a l c o n f o r m a t i o n i n r i n g A ( f o r m u l a . L V I I . c . ) On b a s i s o f t h i s e v i d e n c e i t i s t e n t a t i v e l y p r o p o s e d t h a t -46-the i s o m e r i c m i x t u r e o f k e t o a c e t a t e s ( L V I I ) c o n s i s t s o f compounds L V I I a and L V I I b , a l t h o u g h f u r t h e r work w i l l be n e c e s s a r y s i n c e o n l y one o f t h e two components i n t h e m i x t u r e was s u c c e s s f u l l y i s o l a t e d i n p u r e form. T h i s low m e l t i n g compound i n d i c a t e d o n l y one a n g u l a r m e t h y l s i g n a l a t 8.50T and as e x p e c t e d a m u l t i p l e t a t 5.00T(300 cps) w i t h a h a l f - b a n d w i d t h o f 9 cps c o r r e s p o n d i n g t o an e q u a t o r i a l 83-hydrogen. On comparing t h e m o l e c u l a r models, o f L V I I a and L V I I b , i t becomes a p p a r e n t , t h a t i n case o f t h e L V I I b c o n f o r m a t i o n t h e a n g u l a r m e t h y l group i s b e n t c o n s i d e r a b l y t o w a r d t h e p l a n e o f t h e a r o m a t i c s y s t e m and a l s o t o w a r d t h a t o f t h e C-5 c a r b o n y l group. T h i s s p a t i a l o r i e n t a t i o n a l l o w s f o r more e f f i c i e n t d e s h i e l d i n g o f t h e a n g u l a r m e t h y l group by a l o n g range e f f e c t r e s u l t i n g f r o m t h e d i a m a g n e t i c a n i s o t r o p y o f t h e a r o m a t i c s y s t e m and t h e 0 5 c a r b o n y l group ( 3 8 i ) . C o n s e q u e n t l y t h e p u r e i s o m e r i s o l a t e d , p o s s e s s i n g t h e a n g u l a r m e t h y l group w i t h t h e l o w e r c h e m i c a l s h i f t ( 8 . 5 0 T ( 9 0 c p s ) ) was a s s i g n e d t h e c o n f o r m a t i o n a l s t r u c t u r e L V I I b (=XL). I t w o u l d be i n t e r e s t i n g t o s u b m i t t h i s p u r e i s o m e r t o base t r e a t m e n t and t o change t h e bond h y b r i d i z a t i o n on c a r b o n s 5 and 8 i n an e f f o r t t o i n -v e s t i g a t e t h e s t a b i l i t y r e l a t i o n s h i p s o f d i f f e r e n t c o n f o r m a t i o n s and t h e e f f e c t o f changes i n bond s t r a i n o f t h e m o l e c u l e . Such i n v e s t i g a t i o n s have been c a r r i e d out on B-nor s t e r o i d s by Dauben e t a l ( 4 6 ) . -47-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 block and are uncorrected. The u l t r a v i o l e t s p e c t r a were recorded i n 95% ethanol on Cary r e c o r d i n g spectro-photometers (Models C-14 or C - l l ) . Except where otherwise s t a t e d , the i n f r a r e d s p e c t r a were recorded as potassium bromide p e l l e t s on a Perkin-Elmer Model 21 spectrophotometer. The n u c l e a r magnetic resonance (n.m.r.) s p e c t r a were taken on a V a r i a n A60.high r e s o l u t i o n spectrometer i n deuteriochlproform with t e t r a -m e t h ylsilane as i n t e r n a l reference. 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 T s c a l e . The analyses were performed by Dr. A. Bernhardt and a s s o c i a t e s , Mulheim (Ruhr) Germany. Synthesis of cis-2-Methoxy-8a-acetoxy-10a methyl-6a,7,8,9,10,10a-hexahydro-chrysene (XXXII). A s o l u t i o n o f the ketone (XIV) (100 mg) i n methanol (50 ml.) was t r e a t e d with a s o l u t i o n of sodium borohydride (100 mg.) i n wet methanol (50 ml) and the mixture was s t i r r e d at room temperature f o r two hours. The mixture was then heated w i t h 10% a c e t i c a c i d (5ml.). The s o l u t i o n was concentrated i n vacuo to a volume of 10 ml., water and ether were added, and the ether l a y e r was separated. The ether l a y e r was washed with water, aqueous sodium bicarbonate, and water, and then d r i e d over anhydrous magnesium s u l f a t e . Removal of the solvent provided a c o l o r l e s s o i l y product (XXXIII) (105 mg.). I n f r a r e d _ l _ l ( I n f r a c o r d , chloroform):3555 and 3430 cm (-0H), 1722 cm ; u l t r a v i o l e t ; X ; 230, 255, 265, 275, 284, 306(sh), 313(shi) , 319, 327(sh) and 334 my; X . max J > ^ •> M I N 252/258, 269, 282, 300 and 323 my; t h i n l a y e r chromatography on S i l i c a Gel G r e s o l v e d the o i l i n t o 2 d i s t i n c t spots (Rf.: 0.20 and 0.30, eluent: 10:1 benzene-ethyl a c e t a t e ) . -48-Th i s crude o i l (XXXIII) was d i s s o l v e d i n dry benzene (50 ml, d r i e d over sodium) and phosphorus pentoxide (100 mg.) was added. A f t e r r e f l u x i n g f o r two hours, the mixture was poured onto crushed i c e . E t h y l ether was added and the ether l a y e r was separated. The ether l a y e r was washed with water, with aqueous sodium bicarbonate and f i n a l l y with water. A f t e r d r y i n g over anhydrous magnesium s u l f a t e , the s o l v e n t was removed to y i e l d a c o l o r l e s s i n t r a c t a b l e gum (105 mg.) The m a t e r i a l was p u r i f i e d by chromatography on alumina (8 g., WOELM, a c t i v i t y : grade 1 ) . E l u t i o n with petroleum ether-benzene y i e l d e d the d e s i r e d o l e f i n (XXXII) (85 mg.) which melted at 136-139° a f t e r r e c r y s t a l l i z a t i o n from c y c l o -1 hexane. I n f r a r e d : 1722 cm ; u l t r a v i o l e t : X 243fe 46,800)-, 2 7 7 ( ^ 3,050), max 289 (e 3,870), 301 (e 6,000), 314 (e 7230), 335 (e 2,850), 345 (e 2,540) and 351 my (e 3,260) ;..X m i n.281'(e 3,050), 307 (e 4,880), 326 (e 2,140) and 341 my (e 2,340); n.m.r. s i g n a l s : 8.90 (angular methyl, area = 3H), 8.14 (CH 3 C 0 0 - , area = 3H), 6.i4 (CH3O-, area = 3H), broad s i g n a l centered at 5.29x (H-C-OAc, area = IH, h a l f width = 19 c p s ) , quartet centered at 3.92 (Cg o l e f i n i c H, area = IH, J s , 6 = 9.9 cps, J6}6 = 6-.1 c p s ) , m u l t i p l e t i n region 1.9 - 2.9T (aromatic H's + C 5 H , area = 6H) ... Found G, 78.40; H, 7.32; 0 , 14.13. Ca l c . f o r C22H24O3: C, 78.54; 7.19; 0 , 14.27. Synthesis of cis-2-Methoxy^5,6-dihydroxy-8a-acetoxy-lOa-methy1-5,6,6a,7,8,9 , 10, lOa-octahydrochrysene (XXX). The naphthalene o l e f i n (XXXII) (81 mg.,0.24 m i l l i m o l e ) was d i s s o l v e d i n anhydrous ether (5 ml.). A s o l u t i o n of osmium t e t r o x i d e (70 mg., 0.27 m i l l i -mole, 12% excess) i n anhydrous ether (10 ml.) was added and the mixture was allowed to stand f o r 4 days. Methanol (10 ml.) was then added and hydrogen s u l f i d e gas was bubbled through the s o l u t i o n f o r 15 minutes. The black pre--49-c i p i t a t e was f i l t e r e d o f f , and t h e s o l v e n t was e v a p o r a t e d i n vacuo t o y i e l d a c o l o r l e s s h a r d gum (80 mg.)- T h i s m a t e r i a l was chromatographed on s i l i c a g e l (10 g., WOELM, n e u t r a l ) . E l u t i o n w i t h c h l o r o f o r m y i e l d e d w h i t e c r y s t a l s (55 mg.), w h i c h on r e c r y s t a l l i z a t i o n from c h l o r o f o r m - b e n z e n e gave an a n a l y t i c a l sample o f t h e d i o l (XXX), m.p. 198-202°C. T h i s m a t e r i a l i s d i s t i n c t l y one s p o t on t h i n l a y e r chromatography ( S i l i c a G e l G, e l u e n t : 1:1 c h l o r o f o r m - e t h y l 1 a c e t a t e , Rf. 0.34). I n f r a r e d : 3470 (-0H), 3390 (-0H), 1711 cm (-OAc); u l t r a -v i o l e t : X . 2 3 0 ( s h ) ( e 66,800), 234(e 77600), 254(e 4,540), 263(e 5,730), 273 ( £ 5,970), 283(e 3,820), 3 0 5 ( s h ) ( e 9 5 5 ) , 3 1 3 ( s h ) ( e 1,310), 318 ( e l , 9 7 0 ) , 327(sh) ( e l , 7 9 0 ) and 333 my(e 2,510); X A 250(E 4,180), 257(e 4,420), 268(e 5,010), 280(e 3,820), 297(e 720) and 323 mu(e 1,550); n.m.r. s i g n a l s : 8.52 ( a n g u l a r m e t h y l , a r e a = 3H), 7.98 (CH 3C00-, a r e a = 3H), 6.08 ( C H 3 O - , a r e a = 3H), wide m u l t i p l e t i n r e g i o n 5.6 ( a r e a ~ IH) narrow m u l t i p l e t a t 4.62 ( a r e a = IH) and a t 4.87 ( a r e a = IH) m u l t i p l e t i n r e g i o n 1.7 - 2,9 ( a r o m a t i c H's, a r e a = 5 H ) • Found: C, 71.09; H, 7.61; 0, 21.30. C a l c . f o r C22H26O5: C, 71.33; H, 7.08; 0, 21.60. P e r i o d a t e c l e a v a g e o f t h e d i o l (XXX) i n d i o x a n e s o l u t i o n . The d i o l (XXX) (50 mg.) was d i s s o l v e d i n d i o x a n e (30 m l . ) , and 0.0219M s o l u t i o n o f p e r i o d i c a c i d (7.2 m l , 5% e x c e s s ) i n w a t e r was added. The m i x t u r e was a l l o w e d t o s t a n d o v e r n i g h t , and t h e n e t h y l e n e g l y c o l (0.1 ml) was added. A f t e r one h o u r t h e s o l v e n t was c o n c e n t r a t e d i n vacuo t o a volume o f 5 ml and t h e m i x t u r e was d i s t r i b u t e d between c h l o r o f o r m and w a t e r . The o r g a n i c 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 w a t e r , and d r i e d o v e r anhydrous magnesium s u l f a t e . Removal o f t h e s o l v e n t y i e l d e d a h a r d y e l l o w gum (49 mg) ( XXXIV). T h i n l a y e r chromatography on S i l i c a G e l G: l o n g s t r e a k e d band; Rf. : 0.24-0.56 ( e l u e n t : 6:1 c h l o r o f o r m - e t h y l a c e t a t e ) ; t h e c o l o u r o f t . l . c band a f t e r s p r a y i n g w i t h 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 h e a t i n g : -50-_ 1 grey-brown. I n f r a r e d ( I n f r a c o r d , chloroform): 3200-3500 (-0H), 1724 cm (-OAc); u l t r a v i o l e t : A m a x 234(e 48, 500), 319(e 2,420) 333 my(e 2,580); A m i n 302 (e 2,020), 328 my(e 2,280); n.m.r. s i g n a l s : 8.49 and 8.74 (two s i n g l e t s , angular methyl, area = ~ 3H), 8.10 (CH 3C00-), 7.14 (6a-C-H(?), area = IH), 6.12 (CH3O-, area = 3H), 4.97 (H-C-OAc, area = IH, h a l f width = 10 c p s ) , m u l t i p l e t i n region 2.1 -2.9 (aromatic H's, area = 5H), narrow doublet at 0.42 (C 6H, J = 2 c.p.s., area = ~ 1 H ) , s i n g l e t at -1.12T ( C 5 H , area = IH) . Periodate cleavage of the d i o l (XXX) i n methanol s o l u t i o n . The d i o l (XXX) (31 mg.) was d i s s o l v e d i n methanol (18 ml.), and 0.0219M s o l u t i o n of p e r i o d i c a c i d (5.5 ml, 40% excess) i n water was added. The mixture was allowed t o stand f o r 24 hours, and was worked up i n the same way as i n the previous cleavage i n dioxane. The product obtained was c o l o r l e s s hard gum (32 mg.) (XXXV). Thin l a y e r chromatography on S i l i c a Gel G i n d i c a t e d the main component as a f a i r l y w e l l defined band, Rf: 0.74- 0.84, (eluent: 6:1 chloroform-ethyl acetate) the colour of t . l . c . band a f t e r s praying with 1:1 antimony t r i c h l o r i d e -acetate a c i d and heating : grey-brown. I n f r a r e d ( I n f r a c o r d , chloroform): no _ l hydroxyl and no conjugated carbonyl band, 1724 cm (-OAc); u l t r a v i o l e t : A 233(e 50,100) , 267(E 4,180), 278(e 3,940), 288(e 2,960), 307(e 1,160), 320(e 1,700) 334 mu(e 1,970); X : 263(E 4,020), 273(e 3,690), 286(e 2,940), 303(e 1,150) and 325 my(e 1,530); n.m.r. s i g n a l s : 8.60 and 8.72 (two s i n g l e t s , a n g u l a r methyl), 8.12 (CH3COO), 638 (CH3O at C 6 ) , 6.25 (CH 30 at C 5 ) , 6.10 (CH 30 at C 2 ) , m u l t i p l e t at 2.0 - 3.0T (aromatic H's). C y c l i z a t i o n of the hemiacetal (XXXIV) on alumina. The hemiacetal (XXXIV) (95 mg.) was d i s s o l v e d i n chloroform (9 ml.) Alumina ( t . l . c . grade, n e u t r a l W0ELM, 7.5 gm.) was added, and the mixture was -51-s w i r l e d to obta i n an even suspension and then allowed t o stand at room tem-perature f o r 6 hours. The alumina was e x t r a c t e d with chloroform (200 ml.), followed by f u r t h e r washing with 1:1 chloroform: methanol mixture ( 50 ml.). On removal of the solvent a pale yellow i n t r a c t a b l e gum (92 mg.) was obtained. This m a t e r i a l was chromatographed on s i l i c a gel (7 g., WOELM, n e u t r a l ) . E l u t i o n with chloroform-benzene (1:12) y i e l d e d a pale yellow p a r t i a l l y c r y s t a l -l i n e a l d o l condensation product (60 mg.) (XXXIX). M.p.: 70-79°C; i n f r a r e d : _1 3450 (broad) (-0H), 1715 and 1730 cm (shoulder) (OAc and -CHO); i n f r a r e d _ l ( I n f r a c o r d , chloroform): sharp spike at 2690 cm (CH of aldehyde); u l t r a v i o l e t : 234 (e 57, 200), 255(sh)(e 4, 180), 265(e 4,650),275(e 4,730), 285(e 3,090), nicix 310(sh)(e 1,150), 323 (e 1,840), 332(sh)(e 1,800) and 338 my(e 2,170); X m i n 259 (e 3,940), 270 (e 4,100), 283(e 3,050), 300(e 920) and 328 my(e 1,640); n.m.r. s i g n a l s : 8.89 (minor), 8.74 (major) and 8.55x (angular methyl, isomers), 8.10 (CH3COO-, area = 3H), broad peak at 4.98 . (H-C-OAc, area = IH, h a l f width = 19 cps), small s i g n a l s at 3.78 ( h a l f width 4 cps) and 4.48x ( h a l f width 2cps) isomeric hydrogens on C5, t o t a l area - >-j 0.84), m u l t i p l e t i n region 1.45 - 2.9 (aromatic H's), s i n g l e t at -0.09x (CH0-, area =~0.84; t . l . c . on S i l i c a Gel G: Rf.: 0.26 (eluent: 6:1 chloroform-ethyl a c e t a t e ) ; the c o l o r o f band a f t e r s p raying 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 and heating: grey-brown. Conversion of the a c e t a l (XXXV) to the,hemiacetal (XXXIV) i n a c e t i c a c i d . The a c e t a l (XXXV) (30 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 a c i d (5 ml.), and the mixture was the put on a stream bath f o r one hour. A f t e r c o o l i n g to room temperature 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 aqueous sodium bicarbonate and water. A f t e r d r y i n g over; anhydrous magnesium s u l f a t e , the solvent was evaporated o f f i n vacuo t o y i e l d 31 mg. of a r e a c t i o n product. This product was found t o be a 5:3 mixture o f the hemiacetal (XXXIV) and the a l d o l condensation porduct (XXXIX) ( u l t r a v i o l e t and nuc l e a r magnetic resonance s p e c t r a ) . O x idation o f the a l d o l condensation product (XXXIX). the c y c l i z e d m a t e r i a l (XXXIX) (30 mg., 0.091 m i l l i m o l e ) was d i s s o l v e d i n acetone ( 6 ml.)) a s o l u t i o n of 1.6N Jones' reagent (2 ml.) (38) was added and then the mixture was s t i r r e d at room temperature f o r 30 minutes. A small amount o f methyl a l c o h o l was then added to destroy the orange c o l o r and the mixture was poured onto d i s t i l l e d water (70.ml). Chloroform was added to the mixture and the chloroform l a y e r was separated from the aqueous l a y e r . The chloroform l a y e r was washed with water, aqueous sodium bicarbonate and water and d r i e d over anhydrous magnesium s u l f a t e . The solvent was evaporated i n vacuo to y i e l d a gum. (25 mg.). Pr e p a r a t i v e t h i n l a y e r chromatography on t h i s m a t e r i a l (WOELM S i l i c a G e l , Thickness: 0.4 mm, Eluent: 6:1-benzene-ethyl acetate) r e s u l t e d i n success-f u l i s o l a t i o n of the most s i g n i f i c a n t band. The major product (XL) (15 mg.) shows a blue f l u o r e s c e n t spot i n the u l t r a v i o l e t (WOELM S i l i c a l G e l , Rf.: 0.33, Eluent as above). Repeated r e c r y -s t a l l i z a t i o n from benzene-petroleum ether r e s u l t e d i n c o l o r l e s s c r y s t a l s ; _ l . m.p.: 95 - 100°C; i n f r a r e d : 1722 (OAc) and 1700 cm (conjugated c a r b o n y l ) ; u l t r a v i o l e t : X 219(e 36,400), 245(E 33,400), 297(sh ) (e 5,240), 306 IT13.X (e 6,250) and 350 mu(e 2,960); A m i n 229 (e 16,500), 273 (e 1,860) and 327 my ( E 1,980); n.m.r. s i g n a l s (CDC1 3): 8.50 (angular methyl, area = 3H), 8.17 (CH3COO-, area 3H), 6.11 (CH3O-, area = 3H), m u l t i p l e t at 5.00 IH-C-OAc, area = IH, h a l f width = 9 cps ) , m u l t i p l e t i n region 2.0 - 2.9 (aromatic hydrogens, area - 4H), doublet centred at 0.98x (C^H, J 3 j t + = 8.6 cps; n.m.r. s i g n a l s (Benzene): 8.87 (angular methyl), 8.32 (CH3COO-), 6.57 (CH3O-) and -53-5.04x (H-C-OAc, h a l f width = 9 cps); Found: C, 74,93; H, 6.81; 0, 18.35. Calc. f o r C21H22C-1+; C, 74.53; H, 6.55; 0, 18.91. The mother l i q u o r from c r y s t a l l i z a t i o n of XL was evaporated down and the r e s u l t i n g gummy m a t e r i a l (6 mg.) showed one spot on t . l . c (Rf. 0.33, eluent as above). I n f r a r e d ( i n f r a c o r d , chloroform): 1730 and 17 cm ; n.m.r. s i g n a l s : 8.50 and 8.74 (-jC-CH3 i s o m e r i c , area ~ 3H), 6.10 (-0CH3, area - 3H),4.97 (H-C-OAc, area - IH, half-band width = 9 c p s ) , 8.17 (CH 3C00-, area ~ 3H), m u l t i p l e t i n region 1.9 - 2.9 (aromatic H's, area = 4H) and 0.92x (C^H, J 3 ) i + = 8.6 cps, area = IH). A minor gummy component (XLl) (3 mg.) was als o i s o l a t e d from .the p r e p a r a t i v e t . l . c . s e p a r a t i o n s . Rf.: 0.28 (eluent as above) b l u i s h - g r e e n f l u o r e -scence,U.V. l i g h t ) . Subsequent attempts at c r y s t a l l i z a t i o n were un s u c c e s s f u l . U l t r a v i o l e t : X 222, 245, 299(sh) 309 and 347 mu; X . 230, 277 and 332 mu; max mm _ 1 i n f r a r e d ( I n f r a c o r d , chloroform): 1730 and 1700 cm ; n.m.r. s i g n a l s : 7.82 (-C-CH3) , 6.06 (-0CH3) , 0.86 (CLJH, doublet, J 3 } h 9 c p s ) , s i g n a l s at 9.08, 8.22, 8.14, 6.35 and ^ 4 . 8 x . P r e p a r a t i o n of the ketoxime (XLIV) from cis-2-methoxy-8a-acetoxy-5-keto-10a- methyl-5,6,6a,7,8,9,10,lOa-octahydrochrysene (XIV). Potassium (1.10 g.) was d i s s o l v e d i n anhydrous t - b u t y l a l c o h o l (75 ml.) already contained i n a flame-dried two-neck f l a s k and kept under a dry n i t r o g e n atmosphere. The keto acetate (XIV) (725 mk.) was added, and the mixture s t i r r e d i n i t i a l l y at room temperature f o r 5 hours. F r e s h l y d r i e d and d i s t i l l e d (b.p. 95 - 96°C) isoamyl n i t r i t e (10 ml) was then introduced, and the s t i r r i n g continued f o r 4 hours, then at 50° f o r 2 hours, and f i n a l l y at room temperature f o r 15 hours. The whole operation was conducted under a dry n i t r o g e n atmosphere. A f t e r the a d d i t i o n of ice-water (100 ml.), the s o l u t i o n was ex t r a c t e d with e t h y l ether. The aqueous l a y e r was separated , a c i d i f i e d w i t h g l a c i a l a c e t i c -54-a c i d and t h e p r o d u c t e x t r a c t e d w i t h e t h y l e t h e r . A f t e r d r y i n g t h i s e t h e r l a y e r w i t h anhydrous magnesium s u l f a t e , e v a p o r a t i o n o f t h e s o l v e n t l e f t a deep y e l l o w s o l i d (600 mg., 86% y i e l d ) . T h i s m a t e r i a l was p u r i f i e d by t h i n l a y e r chromatography on S i l i c a G e l G ( e l u e n t : 15:1 b e n z e n e - e t h y l a l c o h o l ) . Two s i g n i f i c a n t components were i s o l a t e d . The m a j o r p r o d u c t (XLIVa) (360 mg.), e x h i b i t i n g an o c r e y e l l o w band on the t . l . c . p l a t e ( u l t r a v i o l e t lamp, e l u e n t as above, Rf.: 0.30), was p u r i f i e d a g a i n w i t h t h e t . l . c . method and f i n a l l y c r y s t a l l i z e d from e t h a n o l - w a t e r t o y i e l d a b r i g h t y e l l o w amorphous m a t e r i a l (115 mg.); m.p. 151.5 - 153°C; i n f r a r e d ( i n b o t h KBr p e l l e t (P.E. 21) and c h l o r o f o r m ( I n f r a c o r d ) ) : 3 2 4 0 - 3420 ( b r o a d , l -OH), 1672 ( c o n j . C = 0 ) , 1622 and 1597 cm ( a r o m a t i c ) ; u l t r a v i o l e t : X 225(e 48,600), 264(e 15,300), 334(e 7,580) and 368(sh) mu(e 5,060); X m i n 243 (e 9.030) and 297 mu(e 3,030); on a d d i t i o n o f base the s h o u l d e r a t 368mu was i n t e n s i f i e d t o a d i s t i n c t peak; n.m.r. s p e c t r u m was b a d l y r e s o l v e d : 8.86 (-C-CH 3), 8.75 ( s m a l l s i n g l e t ) , 6.14 (CH3O-), m u l t i p l e t i n r e g i o n 2.0 - 3.0 ( a r o m a t i c H ' s ) , 0.98x (C^- H, d o u b l e t J3 ^ 8.1 c p s ) . T h i s compound was v e r y d i f f i c u l t t o a n a l y s e and t h e b e s t a n a l y s i s a l t h o u g h : s t i l l u n s a t i s f a c t o r y i s g i v e n ; Found: C, 65.40; H, 6.49; 0, 19.17; N, 5.17. C a l c . f o r CaoHziO^N: C, 70-78; H, 6.24; 0, 18.86; N, 4.13.. The m i n o r p r o d u c t (XLIVb) (90 mg.), a b l a c k band (under u l t r a v i o l e t lamp, R f . : 0.40 e l u e n t as above) on t h e t h i n l a y e r chromatography p l a t e , was o b t a i n e d as a y e l l o w i n t r a c t a b l e gum. F u r t h e r t . l . c . i n v e s t i g a t i o n i n d i c a t e d t h a t t h i s p r o d u c t c o n t a i n e d some o f t h e o c r e y e l l o w (XLIVa) component as an i m p u r i t y . I n f r a r e d ( I n f r a c o r d , c h l o r o f o r m ) : 3520 - 3200 (-0H), 1672 (weak _ l c o n j u g a t e d C = 0 ) , 1622 (C = 0 + a r o m a t i c ) , and 1597 cm ( a r o m a t i c ) . The r e m a i n d e r o f t h e s p e c t r u m was v e r y s i m i l a r t o t h a t o f t h e o c r e y e l l o w p r o d u c t ; u l t r a v i o l e t : X 226, 259 and 338 my; X . 247 and 300 my; on r ' max mm a d d i t i o n o f base a d i s t i n c t maximum appears a t 368 my. -55-Preparation of 2-Methoxy-5,6-diketo-8a-hydroxy-10a-methyl-5,6,6a,7,8,9,10, 10a-octahydrochrysene (XLII) from ketoxime (XLIV). The aximino compound (XLIV) (117 mg,) was r e f l u x e d with a c e t i c a c i d (0.7 ml,) f o r 18 hours, The s o l u t i o n was poured i n t o water, and the product e x t r a c t e d with e t h y l ether, and washed with water, 5% potassium carbonate s o l u t i o n , and wi t h . water again. A f t e r d r y i n g the ether e x t r a c t over anhydrous magnesium s u l f a t e the solvent was removed to y i e l d a brown gummy prqduct (103 mg.) This m a t e r i a l . Was p u r i f i e d by s i l i c a gel chromatography. E l u t i o n with benzene gave the diketo. acetate (XLIII) (26 mg.) and f u r t h e r e l u t i o n w i t h chloroform: benzene (1:3) y i e l d e d the di k e t o a l c o h o l (XLII) (42 mg.). The d i k e t o acetate f r a c t i o n was c r y s t a l l i z e d from benzene to y i e l d an a n a l y t i c a l sample, m.p. 219 -221°C (block preheated to 210°), Thin l a y e r chromatography o f t h i s compound on S i l i c a Gel G (Rf.: 0,56, eluent: e l t h y l acetate-benzene (1:5)) i n d i c a t e d a brown spot under the u l t r a v i o l e t lamp, which turned to b r i g h t blue on f u r t h e r standing. I n f r a r e d : 3360 (-OH, sharp), 1725 (OAc) 1680, 1620 - 1615. and 1598 cm\"' (C = 0 of a-diketone and aromatic C = C) ; u l t r a v i o l e t : A 222 (e 18,500), 258 (e 13,500),. 334'(e 8,970) and 365 my (weak TH3.X shoulder, e 3,520); A . 245 (e 11,100) and 282 my (e 3,330); base added: A ' ' -\" mm ' J ' max 220, 247, 311, 347 and 390 my; A i n 234, 298 and 373 my; n.m.r. s i g n a l s : 8.50 (angular methyl, area = 3H), 8,08 (CH 3C00-, area = 3H), 6.08 (CH3O-, area = 3H) , 4.71 (H-C-OAc, area = IH, h a l f width = 8 c . p . s . j , m u l t i p l e t i n region 1,90 - 200 (aromatic H's, area = 4H) , doublet at 0,12r ( C 4 H , area = IH, J 3 4 = 9.1 cp s ) ; Found: C, 71.57 (72.60); H, 5.97 (5.66); 0, 22.44 (21„74). Calc. f o r C 2 2 H 2 2 0 5 : C, 72,11; H, 6.05; 0, 21.83. The d i k e t o a l c o h o l (XLII) was c r y s t a l l i z e d from chloroform-petroleum ether to y i e l d pale yellow m o n o c l i n i c c r y s t a l s ; m.p, 207 - 209° (melts f i r s t at 200 -202°, s o l i d i f i e s again at 202 - 203°). Thin l a y e r chromatography on S i l i c a Gel G (Rf.: 0.20, eluent: e t h y l acetate-benzene (1:5) provided an ocre brown spot -56-under the ultraviolet lamp. Infrared: 3450 and 3350 cm - 1 (-0H), 1675, 1620 - 1615 _1 and 1600 cm (C = 0 of a-diketone and aromatic C = C ; ultraviolet: A 222 max (e 21,600), 258 (e 13,600), 334 (e 8,700) and 365 my (weak shoulder, e 3,240); \\nin 2 4 5 ^ e 1 0 , 9 0 0 ^ a n d 2 8 2 m ^ (e 2,510); n.m.r. signals: 8.51 (angular methyl, area = 3H), 6.08 (CH30-, 3H), multiplet at 5.70 (H -C - O H , area = IH), multiplet in region 2.0 - 3.0 (aromatic H's, area = 4H) doublet centered at 0.17T (CL+H, area = IH, J 3 4 = 9 cps); Found: C , 73.89; H, 6.14; 0, 19.78. Calc. for C20H20O1+: C, 74.05; H, 6.22; 0, 19.73. Ozonolysis of benzylidene derivative ( X L V ) . Determination of ozone concentration in saturated glacial acetic acid was carried out as follows: Galcial acetic acid (20 ml.) was first saturated with ozone at room temperature for 45 minutes. After addition of excess potassium iodide (2 gm.) to several 20 ml. portions, the liberated iodine was titrated with aqueous sodium thiosulphate (0.01M) (22 ml. (average)). On this basis the ozone concentration was found to be 0.11 millimoles/20 ml. glacial acetic acid. A glacial acetic.acid solution (60 ml.) of the benzilidene derivative (65 mg., 0.16 m.moles, dry) was added to a glacial acetic acid solution of ozone(43 ml., containing 0.24 m.moles ozone, 50% excess). The mixture was stirred at room temperature for 4.5 hours. Then a Small amount of active zinc was added and the stirring continued overnight. After fi ltration, the solvent was taken off to yield a light brown gum. Thin layer chromatography (Silical Gel G) indicated at least twelve distinct spots and very l i t t l e starting material. Elution with '••on:•:enc-ch 1 orof o rm (3:1, on Sil ica Gel G column) yielded a gummy material (about 7 mg.) whose t . l . c . and infrared and ultraviolte spectra agreed with the diketo alcohol (XLII) characterized earlier. The remaining components were not isolated since i t was apparent that this was an undesirable reaction. -57-B e n z i l i c a c i d rearrangement of 2-Methoxy-5,6-diketo-8a-acetoxy-10a-methyl- 5,6,6a,7,8,9,10,10a-octahydrochrysene..,, (XLIf) . A s o l u t i o n of the d i k e t o a l c o h o l (XLl1) (30 mg.) i n &thyl a l c o h o l (10 ml.) was r e f l u x e d : w i t h aqueous potassium hydroxide s o l u t i o n (25%, 2.5 ml.) f o r 18 hours. The e t h y l a l c o h o l was, evaporated i n vacuo, water (20 ml -) was added and. the mixture e x t r a c t e d with chloroform. The aqueous b a s i c s o l u t i o n was a c i d i f i e d with concentrated h y d r o c h l o r i c a c i d and the r e s u l t a n t lemon yellow t u r b i d s o l u -t i o n was e x t r a c t e d with e t h y l ether. The ether e x t r a c t was d r i e d over anhydrous magnesium sulphate, the s o l v e n t removed to y i e l d the crude a c i d i c m a t e r i a l (20 mg.). This m a t e r i a l was p u r i f i e d on a s i l i c a gel chromatographic column. E l u t i o n w i t h benzene-ethyl a l c o h o l (15:1) y i e l d e d the b e n z i l i c a c i d rearrange-ment product (XLVII) (10 mg.). Attempts at c r y s t a l l i z a t i o n of t h i s m a t e r i a l were not s u c c e s s f u l . This m a t e r i a l showed one spot on a t . l . c . p l a t e ( S i l i c a Gel G, Rf.: very c l o s e t o the b a s e - l i n e , eluent: 9:1 benzene-ethanol, blue fluorescence under U.V. l i g h t . I n f r a r e d ( I n f r a c o r d , chloroform): 3300 - 3500 _1 (weak), 1720 and a shoulder at 1690 cm (COOH); u l t r a v i o l e t (approximate) ^ m a x 219 (e 15,500) 233 ( e 13,300), 245(sh) (e 8,600), 275(sh) (e 2,600),285 (e 2,500), 308 (e 2,400), 337 (e 1,420), and 350 my, (sh) ( e 1,220); A m i n 226 (e 12,900), 282 ( e 2,450), 293 ( e 2,160), and 33 my ( e 1,400). , Lead t e t r a - a c e t a t e o x i d a t i o n of b e n z i l i c a c i d rearrangement product (XLVII). A g l a c i a l a c e t i c a c i d s o l u t i o n (5 ml.) of the b e n z i l i c a c i d (XLVII) (38 mg.) and l e a d t e t r a - a c e t a t e ( 70 mg.) was kept at 60 - 70° f o r 1 hour and allowed t o stand at room temperature f o r a f u r t h e r 2 hours. The s o l u t i o n was then d i l u t e d w i t h water and e x t r a c t e d w i t h chloroform. A f t e r washing the chloroform e x t r a c t w i t h sodium bicarbonate s o l u t i o n and water, i t was d r i e d -58-over anhydrous magnesium sulfate.. Evaporation of the solvent y i e l d e d a dark s o l i d gum (30 mg,). Thin l a y e r chromatography o f t h i s crude m a t e r i a l (Woelm S i l i c a G e l , 6:1 benzene-ethyl acetate) i n d i c a t e d a number of components Rf.: 0.45, 0.17, 0.09, 0.04., 0.00 and 0.28 (major s p o t ) ) . N.M.R. spectrum on crude m a t e r i a l : 8.71 (-C-CH3), 6.04 (-OCH3), d i f f u s e doublet at 0,92 (C 3- H), m u l t i p l e t i n region 2.0 - 3.0 (aromatic H's), small, r e s o l v e d s i g n a l s at' 8.49, 8.37, and 7.87x. The major component (Rf.: 0.28) (XLVIII) was i s o l a t e d by p r e p a r a t i v e t h i n l a y e r chromatography (Woelm S i l i c a G e l , eluent: benzene-ethyl acetate (6:1)) i n a poor y i e l d ( 4 mg.) as a hard i n t r a c t a b l e gum. 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Additional conditions apply, see Terms of Use https://open.library.ubc.ca/terms_of_use."@en ; ns0:scholarLevel "Graduate"@en ; dcterms:title "Total synthesis of certain hydrochrysene analogues"@en ; dcterms:type "Text"@en ; ns0:identifierURI "http://hdl.handle.net/2429/37396"@en .