Bull. SOC. Chim. Belg. vol. 99 / no 1 / 1990 0037-9646 I 9 0 / $ 2.00 + 0.00

Q 1990 Cornit6 van Beheer van het Bulletin V.Z.W.

THE UTILITY OF PODOCARPIC ACID IN THE SYNTHESIS OF NATURALLY OCCURRING TERPENES

Ajoy K. Banerjee*, Julio C. Acevedo and Nieves Canudas-Gonzalez Centro de Quimica, I.V.I.C., Apartado 21827, Caracas 1020-A, Venezuela

Received. 13/11/1989 -Accepted : 06/12/1989

INTRODUCTION

P o d o c a r p i c a c i d (1) i s n o t a t e r p e n e b u t i t s c h e m i s t r y r e s e m b l e s t h a t o f

r e s i n a c i d s w h i c h w e r e f i r s t i s o l a t e d f r o m P o d o c a r p u s i o n . ' E x a m i n a t i o n o f

c h e m i c a l l i t e r a t u r e revea ls t h a t p o d o c a r p i c a c i d (1) h a s been s e l e c t e d f o r t h e

s y n t h e s i s o f a number o f n a t u r a l l y t e r p e n o i d compounds . The i n f o r m a t i o n s o f

t h e s e s y n t h e t i c s t u d i e s w h i c h h a v e r e m a i n e d s c a t t e r e d i n t h e c h e m i c a l l i t e r a -

t u r e h a v e been b r o u g h t t o g e t h e r i n t h e f o r m o f a s h o r t r e v i e w a r t i c l e .

SYNTHESIS OF TERPENOID C O M P O U N D S

R o s e n o n o l a c t o n e

P o d o c a r p i c a c i d (1) was s e l e c t e d b y Mander ' a s m a t e r i a l f o r d e p a r t u r e i n d e -

v e l o p i n g an e f f i c i e n t s y n t h e s i s o f r o s e n o n o l a c t o n e (14) (Scheme I ) , whose

a l t e r n a t i v e s y n t h e s i s 3 f r o m i s o c u p r e s s i c a c i d has a l r e a d y b e e n r e p o r t e d . The

n o t e w o r t h y a s p e c t o f M a n d e r ' s s y n t h e s i s i s t h e c o n s t r u c t i o n o f t h e y - l a c t o n e

m o i e t y a n d t h e i n t r o d u c t i o n o f C - 2 0 m e t h y l b y o n e s p o t e x p e r i m e n t .

c a t i o n a n d m e t h y l a t i o n r e s p e c t i v e l y , o n r e d u c t i o n p r o d u c e d t h e a n i s o l e ( 3 )

t h a t was f u r t h e r s u b j e c t e d t o m e t a l a m m o n i a r e d u c t i o n a n d a c i d h y d r o l y s i s t o

o b t a i n t h e a , B - u n s a t u r a t e d k e t o n e ( 4 ) . Two s u c c e s s i v e o x i d a t i o n s o f k e t o n e ( 4 ) w i t h c h r o m i c a c i d r e a g e n t a f f o r d e d t h e a c i d ( 5 ) and e p o x i d a t i o n o f t h e k e t a l

d e r i v a t i v e ( 6 ) y i e l d e d t h e a - e p o x i d e ( 7 ) . On t r e a t m e n t w i t h 12 e q u i v a l e n t o f

b o r o n t r i f l u o r i d e e t h e r a t e i n p r e s e n c e o f n i t r o m e t h a n e , t h e e p o x i d e ( 7 ) u n d e r -

w e n t an i n t e r e s t i n g t r a n s f o r m a t i o n ( l a c t o n i z a t i o n + m e t h y l m i g r a t i o n ) t o

a f f o r d t h e l a c t o n e ( 8 ) , a l o n g w i t h o t h e r l a c t o n e s . The p o s s i b l e m e c h a n i s m f o r

t h e f o r m a t i o n o f l a c t o n e ( 8 ) i s d e p i c t e d i n Scheme I. The a m o u n t o f b o r o n t r i -

f l u o r i d e e t h e r a t e p l a y e d a n i m p o r t a n t r o l e i n t h e r e a r r a n g e m e n t o f e p o x i d e ( 7 ) t o l a c t o n e ( 8 ) . The u s e o f 2 m o l a r e q u i v a l e n t o f b o r o n t r i f l u o r i d e e t h e r a t e

d i d n o t p r o d u c e a n y l a c t o n e ( 8 ) , b u t o n l y a f f o r d e d t h e h y d r o x y l a c t o n e ( 9 ) i n

5 5 % y i e l d . An i n t e r e s t i n g r e a r r a n g e m e n t o f 8 a , 9 a - e p o x i d e o f p o d o c a r p i c a c i d

d e r i v a t i v e b y b o r o n t r i f l u o r i d e e t h e r a t e i n n i t r o m e t h a n e and b e n z e n e was o b -

s e r v e d b y Nakano .

The c a r b o m e t h o x y l a t i o n and m e t h y l a t i o n c o n v e r t e d t h e l a c t o n e ( 8 ) t o t h e

k e t o e s t e r (10) whose d i t h i o a c e t a l d e r i v a t i v e o n r e d u c t i v e d e s u l f u r i z a t i o n a n d h y d r o b o r a t i o n a f f o r d e d t h e t r i o l (11). T h i s t r i o l (11) o n o x i d a t i o n , f u r n i s h e d t h e k e t o a l d e h y d e ( 1 2 ) whose t r a n s f o r m a t i o n t o i s o r o s e n o n o l a c t o n e (13) was

a c h i e v e d o n t r e a t m e n t w i t h m e t h y l e n e t r i p h e n y l p h o s p h o r a n e . E q u i l i b r a t i o n o f

t h e i s o r o s e n o n o l a c t o n e (13) w i t h a c i d p r o d u c e d t h e d e s i r e d r o s a n e d i t e r p e n e

r o s e n o n o l a c t o n e ( 1 4 ) . I t i s w o r t h w h i l e t o m e n t i o n t h a t De G r a z i a and W h a l l e y a l s o a t t e m p t e d t o s y n t h e s i z e r o s e n o n o l a c t o n e (14) f r o m p o d o c a r p i c a c i d , and

0 - M e t h y l p o d o c a r p a t e ( 2 ) , p r e p a r e d f r o m p o d o c a r p i c a c i d (l), b y e s t e r i f i -

4

5

- 9 -

a l t h o u g h t h e p l a n was n o t r e d u c e d t o p r a c t i c e , s e v e r a l i m p o r t a n t s y n t h o n s w e r e

p r e p a r e d .

I I l R = O H , R = C O O H ( 2 ) R = O M e , R,: C O O M e (4) R Z C H 2 O H ( 3 ) R i O M 0 , R I : C H 2 0 H ( 5 1 R ; COOH w

HOOC Me H O O C M e

( 7 )

II 0

Me

(10)

R e a g e n t s : ( i) CH2N2, E t 2 0 ; (ii) Me2S04, NaOH;

Me

OH ( 1 1 ) R : CHzOH, RI =/ .- H , R 2 = 0 H

(12) R i C H O , R I ' R 2 = 0

( i i i ) LiAlH,, THF; ( i v ) L i , l i q NH3, t -BuOH, HC1-MeOH; ( i ) Cr03-H2S04; ( v i ) CrOj -HOAc; ( v i i )

(CH20H)2 , p-TsOH, C 6 H 6 ; ( v i i i ) MCPBA; ( i x ) BF3.Et20 , MeN02; ( x ) NaH, MeOC02Me; ( x i ) M e I ; ( x i i ) MeSH; ( x i i i ) R a - N i , w-2 ; ( X i V ) B Z H 6 ;

-10-

( x v ) C r 0 3

M o r i a n d M a t s u i ' u t

( x v i ) Ph3P=CH2; ( x v i i ) HC1, CC14.

Scheme I

T a x o d i o n e

l i z i n g p o d o c a r p i c a c i d a s s t a r t i n g m a t e r i a l d e v e l o p e d a n e x c e l l e n t s y n t h e s i s o f t a x o d i o n e ( 2 5 ) , a d i t e r p e n o i d q u i n o n e , t h a t h a s a t - t r a c t e d t h e a t t e n t i o n o f a number o f o r g a n i c c h e m i s t s 7 o w i n g t o i t s u n i q u e s t r u c t u r e a s a q u i n o n e m e t h i o d i d e a n d b e c a u s e o f i t s t u m o r i n h i b i t o r y a c t i v i - t y . 8 T h e s y n t h e s i s w h i c h i s o u t l i n e d i n Scheme I 1 i n v o l v e s t h r e e s t e p s : ( a ) f u n c t i o n a l i z a t i o n o f C - 4 c a r b o x y l g r o u p t o C-4 m e t h y l g r o u p , (b) i n t r o d u c t i o n o f C-11 h y d r o x y l and C-13 i s o p r o p y l g r o u p , a n d ( c ) c o n v e r s i o n o f t h e d i o l t o q u i n o n e .

The m e t h y l 0 - m e t h y l p o d o c a r p a t e ( 2 ) ( d e s c r i b e d i n Scheme I ) on a c e t y l a - t i o n y i e l d e d m e t h y l 0 - m e t h y l - 7 - a c e t y l p o d o c a r p a t e ( 1 5 ) a n d f o l l o w i n g G r i g n a r d r e a c t i o n , d e h y d r a t i o n a n d h y d r o g e n a t i o n r e s p e c t i v e l y , p r o d u c e d t h e i s o p r o p y l - p o d o c a r p a t e ( 1 6 ) . M e t a l h y d r i d e r e d u c t i o n , o x i d a t i o n and d e o x y g e n a t i o n s u b s e - q u e n t l y f u r n i s h e d a m i x t u r e o f f e r r u g i n o l m e t h y l e t h e r ( 1 7 ) a n d f e r r u g i n o l

( 1 8 ) . H e a t i n g t h e m i x t u r e w i t h a c i d a n d b e n z o y l a t i o n o f t h e r e s u l t i n g a l c o h o l g a v e t h e b e n z o a t e ( 1 9 ) and t r e a t m e n t w i t h b a s e and d i a z o t i z a t i o n f u r n i s h e d

a z o f e r r u g i n o l ( 2 0 ) . C o n v e r s i o n t o m e t h o x y f e r r u g i n o l m e t h y l e t h e r ( 2 1 ) was e f f e c t e d b y m e t h y l a t i o n , r e d u c t i o n and a c i d t r e a t m e n t , r e s p e c t i v e l y . A c e t o x y l - a t i o n o f ( 2 1 ) a n d h e a t i n g w i t h a c i d p r o v i d e d t h e o l e f i n ( 2 2 ) . The p y r o l y s i s o f t h e r e s u l t i n g e p o x i d e d e r i v e d f r o m ( 2 2 ) y i e l d e d 6 - k e t o m e t h o x y f e r r u g i n o l m e t h y l e t h e r ( 2 3 ) a n d d e m e t h y l a t i o n a f f o r d e d t h e d i o l ( 2 4 ) whose c o n v e r s i o n t o

t a x o d i o n e ( 2 5 ) was a c c o m p l i s h e d b y f u r t h e r o x i d a t i o n . R

OMe

Me M e

(22)

OMe

; \ H Me COOMe

Me Me

Me M e , .

Me Me

'201 R

MB M e ( 2 3 ) R:RI:OMe

( 24) R = R I G O H

yY Me Me (21)

- 11.

R e a g e n t s : ( i ) A c C l / P y ; ( i i ) MeMgC1; ( i i i ) MeCOOH; ( i v ) P t 0 2 / H 2 ; ( v ) ( v i ) Cr03-C6H5N; ( v i i ) NH2NH2, O E G , KOH; ( v i i i ) H B r - H I ; ( C 6 H 5 C O C l / p y r i d i n e ; ( x ) NaOMe, p-N02C6H4N2C1 ; ( x i ) Me2S04, Me2CO; ( x i i ) Na2S208; ( x i i i ) MeOH/H2S04; ( x i v ) Pb (OAc)4 ; ( x v i ) p y r o l y s i s ; ( x v i i ) B B r 3 , CH2C:2; ( x v i i i ) Ag20/CHC13.

Scheme I 1

M e t h y l V o u a c a p e n a t e

The u t i l i t y o f p o d o c a r p i c a c i d was a l s o e x p e r i m e n t e d b y S p e n c e r who s y n t h e - s i z e d ' (Scheme 1 1 1 ) m e t h y l v o u a c a p e n a t e ( 3 2 ) , a f u r a n o i d d i t e r p e n e , v i a t h e

enone ( 5 ) , p r e p a r e d f r o m a c i d (Scheme I ) . R e d u c t i o n a n d e s t e r i f i c a t i o n o f t h e enone ( 5 ) a f f o r d e d k e t o e s t e r ( 2 6 ) w h i c h was c o n v e r t e d t o t h e enone ( 2 7 ) b y b r o m i n a t i o n and d e h y d r o b r o m i n a t i o n . The c o n j u g a t e a d d i t i o n o f a m e t h y l g r o u p

t o t h e enone ( 2 7 ) y i e l d e d t w o m e t h y l a t e d k e t o e s t e r s ( 2 8 ) a n d ( 2 9 ) i n a r a t i o o f 5 5 : 4 5 as i n d i c a t e d b y n . m . r . s p e c t r o s c o p y . The k e t o e s t e r ( 2 8 ) o n f o r m y l a t i o n , a c e t y l a t i o n a n d m e t h a n o l y s i s r e s p e c t i v e l y was c o n v e r t e d t o compound ( 3 0 ) a n d f u r t h e r t r a n s f o r m a t i o n t o t h e f u r o i c e s t e r ( 3 1 ) was a c c o m p l i s h e d b y t r e a t i n g t h e

( 3 1 a l l

o f 111

f o r m e r w i t h e x c e s s e t h y l d i a z o a c e t a t e . The p a r t i a l a l k a l i n e h y d r o l y s i s o f o l l o w e d b y d e c a r b o x y l a t i o n y i e l d e d m e t h y l v o u a c a p e n a t e ( 3 2 ) whose o v e r

y i e l d f r o m p o d o c a r p i c a c i d was 1%. The m o s t i n t e r e s t i n g a s p e c t o f t h e p r e s e n t s y n t h e s i s i s t h e t r a n s f o r m a t

he compound ( 3 0 ) t o t h e f u r o i c e s t e r ( 3 1 ) w h i c h i s e x p l a i n e d " i n Scheme

The t r a n s f o r m a t i o n o f p o d o c a r p i c a c i d t o m e t h y l v o u a c a p e n a t e ( 3 2 ) was a l s o a c h i e v e d b y t h e I t a l i a n c h e m i s t s l e d b y G a r i b o l d i . l l (Scheme I V ) . T h e enone ( 2 7 ) ( d e s c r i b e d i n Scheme 1 1 1 ) a l s o p r e p a r e d b y B e l l a n d G r o v e s t o c k , was s e l e c t e d a s r e f e r e n c e m a t e r i a l . T r e a t m e n t o f t h e enone ( 2 7 ) b y l i t h i u m d i m e t h y l c u p r a t e y i e l d e d t h e e n o l a t e a n i o n ( 3 3 ) w h i c h was made t o r e a c t w i t h a l a r g e e x c e s s o f c h l o r o a c e t y l c h l o r i d e t o o b t a i n a m i x t u r e o f t w o 5 - f u r a n o n e s ( 3 4 ) ( 4 4 % ) and ( 3 5 ) ( 3 0 % ) , r e s p e c t i v e l y . R e d u c t i o n o f ( 3 4 ) a f f o r d e d t h e c r y s - t a l l i n e m e t h y l v o u a c a p e n a t e ( 3 2 ) i n 8 0 % . T h e r e i s no d o u b t t h a t t h e s y n t h e s i s o u t l i n e d i n Scheme I V p r e s e n t s a d v a n t a g e s i n b r e v i t y a n d y i e l d s i n c o m p a r i s o n

w i t h t h e one p r e v i o u s l y ' r e p o r t e d o n e s .

1 2

0

y3 Me COOMe

(26)

0 ,' H

Me COOMe

on

-12-

1

Me COOMe

R

M e 'cOOMe

(31) R = C O O E I

(32) R = H

R e a g e n t s : ( i ) L i / N H 3 ; ( i i ) CH2N2; ( i i i ) Er2/MeCOOH; ( i v ) DMF, CaC03; ( i v )

M e 2 C u L i ; ( v ) HCOOEt; ( v i ) A c 2 0 / P y r i d i n e ; ( v i i ) p-TsOH/MeOH; ( v i i i ) N2CHCOOEt, CuS04, C12CHCHC12; ( i x ) MeOH, NaOH; ( x ) c u , 215°C.

Scheme I 1 1

, . M e COOMe

(33) (35)

R e a g e n t s : ( i ) Me2CuL i ( 2 e q u i v ) ; ( i i ) ClCH2COCl; ( i i i ) 9-BEN i n THF.

Scheme I V

L a m b e r t a n i c A c i d

f o u n d p o d o c a r p i c a c i d a c o n v e n e n t s t a r t i n g m a t e r i a l f o r t h e s y n t h e s i s o f l a b d a n e d i t e r p e n e eg , l a m b e r t i a n i c a c i d ( 4 8 ) , a f u r a n o d i t e r p e n e . The s y n - t h e s i s o f t h e b i c y c l i c m o i e t y a l o n g w t h t h e s i d e c h a i n ( 1 1 + 1 6 ) o f l a m b e r t i a n

a c i d ( 4 8 ) was a c c o m p l i s h e d i n g e n o u s l y . (Scheme V ) . M e t h y l p o d o c a r p a t e ( 2 ) ( a l r e a d y d e s c r i b e d i n Scheme I ) o n o z o n o l y s i s a f -

f o r d e d h y d r o p e r o x i d e ( 3 6 ) w h i c h was c o n v e r t e d t o k e t o a c i d ( 3 7 ) o n h y d r o g e n a -

C

t i o n . E s t e r i f i c a t i o n o f k e t o a c i d ( 3 7 ) y i e l d e d k e t o e s t e r ( 3 8 ) a n d a R e f o r m a t s k y r e a c t i o n w i t h m e t h y l b r o m o a c e t a t e i n p r e s e n c e o f a 3 : l m i x t u r e o f b e n z e n e a n d

d i m e t h o x y e t h a n e p r o v i d e d t h e l a c t o n e - d i e s t e r ( 3 9 ) i n e x c e l l e n t y i e l d . The l a c t o n e - d i e s t e r ( 3 9 ) o n t r e a t m e n t w i t h m e t h a n o l i c s o d i u m h y d r o x i d e u n d e r w e n t r i n g c l e a v a g e t o a f f o r d t h e d i a c i d ( 4 0 ) w h i c h was c o n t a m i n a t e d w i t h a s m a l l amoun t o f u , B - u n s a t u r a t e d a c i d ( 4 1 ) . T h e r e a c t i o n m i x t u r e o n h y d r o l y s i s a n d e s t e r i f i c a t i o n f u r n i s h e d o l e f i n i c e s t e r ( 4 2 ) w h i c h was c o n v e r t e d t o t h e a l c o - h o l ( 4 3 ) a n d a l d e h y d e ( 4 4 ) b y m e t a l h y d r i d e r e d u c t i o n a n d o x i d a t i o n r e s p e c - t i v e l y e i t h e r w i t h C o l l i n s o r F e t i z o n ' s r e a g e n t . The c o n d e n s a t i o n o f t h e a l d e - h y d e ( 4 4 ) w i t h 3 - l i t h i o f u r a n p r o d u c e d a m i x t u r e o f a l c o h o l s ( 4 5 ) w h i c h o n

-13-

h y d r o l y s i s a f f o r d e d t h e a c i d s ( 4 6 ) and ( 4 7 ) . The m e t a l i n ammonia r e d u c t i o n o f

t h e mesy l d e r i v a t i v e o f e i t h e r ( 4 6 ) o r ( 4 7 ) l e d t o l a m b e r t i a n i c a c i d ( 4 8 ) , t h e m e t h y l e s t e r o f w h i c h was i d e n t i c a l t o t h e m e t h y l e s t e r d e r i v e d f r o m t h e n a t u - r a l m a t e r i a l .

t r o d u c t i o n o f e x o c y c l i c m e t h y l e n e a t C-8 v i a a R e f o r m a t s k y r e a c t i o n c a r r i e d o u t i n b e n z e n e - d i m e t h o x y e t h a n e as s o l v e n t t o a v o i d L e w i s a c i d - c a t a l y z e d r e a r - rangement , ( i i ) improvemen t i n t h e y i e l d o f o l e f i n i c e s t e r ( 4 2 ) compared w i t h l i t h i u m e t h o x y a c e t y l i d e r o u t e 1 4 , and ( i i i ) t h e d i f f i c u l t y i n t h e r e m o v a l o f 1 2 - h y d r o x y l g r o u p was overcome by r e d u c t i o n o f t h e 1 2 - m e s y l a t e w i t h l i t h i u m

and l i q u i d ammonia, t h e r e b y o b t a i n i n g a s a t i s f a c t o r y y i e l d o f l a m b e r t i a n i c a c i d ( 4 8 ) .

The i n t e r e s t i n g a s p e c t o f t h e above m e n t i o n e d s y n t h e s i s a r e ( i ) t h e i n -

(36)

Me / R

(43) R : C H 2 0 H

(44) R E CHO

M 0 Me /"OH

&pX), M: COOMe

R

Reagen ts : ( i ) 03, MeOH, MeCl; ( i i ) H 2 , Pd; ( i i i ) C H 2 N 2 ; ( i v ) BrCH2COOMe/Zn/ C H / D M E ; ( v ) NaOH-MeOH; ( v i ) q u i n o l i n e ; ( v i i ) L i A l H 4 / E t 2 0 ; ( v i i i ) C r03 , 2 C 6 H 5 N o r A g 2 C 0 3 / C e l i t e ; ( i x ) 3 - l i t h i o f u r a n / T H F ; ( x ) C 4 H g O K / DMSO; ( x i ) MsC1/Et3N; ( x i i ) L i l i q . N H 3 .

6 6

Scheme V

H i n o k i o n e M e t h y l E t h e r

The A u s t r a l i a n c h e m i s t s l e d by Cambie and F ~ l l e r t o n ' ~ showed t h e u t i l p o d o c a r p i c a c i d p u b l i s h i n g t h e f i r s t t o t a l s y n t h e s i s o f h i n o k i o n e ( 5 8

m e t h y l e t h e r ( 5 9 ) i n i t s o p t i c a l l y a c t i v e f o r m (Scheme V I ) H i n o k i o n e n a t u r a l l y o c c u r r i n g d i t e r p e n e , was i s o l a t e d f r o m s e v e r a l c o n i f e r spec

t y o f

581, a e s .

a s i t s

16,17

- 14-

The r e f e r e n c e m a t e r i a l o f t h e p r e s e n t w o r k i s t h e e s t e r ( 1 6 ) ( a l r e a d y d e -

s c r i b e d i n Scheme 111) w h i c h o n h y d r o l y s i s p r o d u c e d t h e a c i d ( 4 9 ) . O x i d a t i v e

d e c a r b o x y l a t i o n o f t h e a c i d g e n e r a t e d p r i n c i p a l l y a m i x t u r e o f t h r e e a l k e n e s , ( 5 0 ) ( 2 8 % ) , ( 5 1 ) ( 3 9 % ) , and ( 5 2 ) ( 3 3 % ) . E p o x i d a t i o n o f t h e m i x t u r e o f t h e a l k e n e s y i e l d e d t w o e p o x i d e s , ( 5 3 ) and (54), w h i l e t h e a l k e n e ( 5 1 ) was r e c o v - e r e d u n c h a n g e d . T h e r e d u c t i o n o f ( 5 4 ) y i e l d e d t h e a l c o h o l ( 5 5 ) t h a t was i s o m e r - i z e d t o t h e a - a l c o h o l (56), and o n o x i d a t i o n , ( 5 6 ) was c o n v e r t e d t o t h e a,B-

u n s a t u r a t e d k e t o n e ( 5 7 ) . R e d u c t i v e m e t h y l a t i o n o f t h e k e t o n e ( 5 7 ) a f f o r d e d a s i n g l e i s o m e r o f h i n o k i o n e m e t h y l e t h e r ( 5 9 ) whose a l t e r n a t i v e s y n t h e s i s i n r a c e m i c f o r m h a s been r e p o r t e d . 18

OMe ?Me

"2' L "1, H O O C Me (49)

M e 152)

I V ) >

I -0 M e , (53)

OMe I / M e

H 0,' *ffJi Me

(56)

R e a g e n t s : ( i ) C4HgOK/OMSO; (

( i v ) L i , E t2NH; ( v ( v i i ) L i , NH3, THF

O M e I / M e

M e

157)

Me Me

( 5 8 ) R = H ( 59)R = O M e

i ) Pb (OAc)4 /C6H6; ( i i i ) m o n o p e r p h t h a l i c a c i d ; N - l i t h i o e t h y l e n e d i a m i n e ; ( v i ) C r O g , H2S04;

M e I .

Scheme V I

C a l l i t r i s i c A c i d

A v e r y s h o r t s y n t h e s i s o f c a l l i s t r i c a c i d ( 6 3 ) (Scheme V I I ) f r o m p o d o c a r p i c a c i d was r e a l i z e d b y H u f f m a n . " I t s i s o l a t i o n f r o m n a t u r a l s o u r c e s a n d s y n t h e - s i s i n r a c e m i c f o r m h a s b e e n r e p o r t e d . " The e s t e r ( 1 6 ) ( a l r e a d y d e s c r i b e d i n Scheme 11) on d e m e t h y l a t i o n a f f o r d e d p h e n o l i c d e r i v a t i v e (60). A d d i t i o n o f 2 e q u i v a l e n t s o f phenyl-5-chlorotetrazole t o t h e a l k o x i d e o f ( 6 0 ) p r o d u c e d ( 6 1 ) ,

whose p r e p a r a t i o n c o u l d n o t b e r e a l i z e d b y a p u b l i s h e d m e t h o d . 2 0 The h y d r o - g e n o l y s i s o f ( 6 1 ) p r o d u c e d m e t h y l e s t e r ( 6 2 ) w h i c h o n h y d r o l y s i s was c o n v e r t e d t o c a l l i s t r i c a c i d ( 6 3 ) .

- 15-

(60) (61) (62)R' M e (63)R i H

R e a g e n t s : ( i ) B B r 3 ; ( i i ) NaH, O M F , 1-phenyl-5-chlorotetrazole; ( i i i ) 5% P d - c ; ( i v ) C 4 H g O K , DMSO.

Scheme V I I

N i m b i o l

P o d o c a r p i c a c i d has been f o u n d u s e f u l a s s t a r t i n g m a t e r i a l i n t h e s y n t h e s i s o f p h e n o l i c d i t e r p e n e n i m b i o l ( 7 2 1 , w h i c h was i s o l a t e d f r o m t h e t r u n k o f Melia a z a d i r a c h t a L i n n . ' l The t r a n s f o r m a t i o n o f p o d o c a r p i c t o n i m b i o l ( 7 2 ) was e f - f e c t d b y B i b l e z 2 (Scheme V I I I ) a n d W e n k e r t Z 3 (Scheme I X ) b y t w o r o u t e s . T h e d i f f e r e n t p r o c e d u r e s a d o p t e d f o r t h e t r a n s f o r m a t i o n o f C-4 c a r b o x y l g r o u p a n d i n t r o d u c t i o n o f m e t h y l g r o u p a t C-13 p o s i t i o n make t h e t w o p r o c e d u r e s q u i t e d i s t i n c t .

The p r o c e d u r e o f B i b l e (Scheme V I I I ) c o n s i s t s i n t h e o x i d a t i o n o f m e t h y l 0 - m e t h y l - 7 - a c e t y l p o d o c a r p a t e ( 1 5 ) ( a l r e a d y d e s c r i b e d i n Scheme 1 1 ) o n o x i d a - t i o n w i t h b r o m i n e i n a n a l k a l i n e med ium p r o d u c e d 7 - c a r b o x y p o d o c a r p a t e ( 6 4 ) .

R e d u c t i o n o f ( 6 4 ) p r o d u c e d t h e d i o l ( 6 5 ) and c o n v e r s i o n t o a l c o h o l ( 6 6 ) a n d ( 6 7 ) was a c c o m p l i s h e d b y h y d r o g e n o l y s i s a n d o x i d a t i o n , r e s p e c t i v e l y . R e d u c t i o n

o f t h e s e m i c a r b a z o n e ( 6 8 ) , y i e l d e d a m i x t u r e o f p r o d u c t s ( 6 9 ) a n d ( 7 0 ) . T h e c r u d e p r o d u c t was m e t h y l a t e d a n d o x i d i z e d t o o b t a i n n i m b i o l m e t h y l e t h e r ( 7 1 ) t h a t was d e m e t h y l a t e d t o f u r n i s h n i m b i o l ( 7 2 ) .

R e a g e n t s : i i ) Brp/NaOH; ( i i ) L i A 1 H 4 , THF; ( i i i ) Pd-C, H C l ; ( i v ) C r 0 3 . H2S04; ( v ) NH2CONHNH2.HC1, MeCOONa; ( v i ) N a , EtOH; ( v i i ) Me2S04/K2C03;

( v i i i ) C6H5N.HC1.

Scheme V I I I

16 -

W e n k e r t d e v e l o p e d a n a l t e r n a t i v e r o u t e f o r t h e s y n t h e s i s o f n i m b i o l ( 7 2 ) f r o m p o d o c a r p i c a c i d a s d e s c r i b e d i n Scheme I X . M e t h y l p o d o c a r p a t e ( 7 3 ) , p r e - p a r e d b y e s t e r i f i c a t i o n o f p o d o c a r p i c a c i d ( l ) , was s u b j e c t e d t o a M a n n i c h

r e a c t i o n t o o b t a i n t h e compound ( 7 4 ) . R e d u c t i o n o f t h e m e t h i o d i d e p r o d u c e d t h e a c i d ( 7 5 ) w h i c h on t r e a t m e n t w i t h a c e t i c a n h y d r i d e a n d t h i o n y l c h l o r i d e , f o l - l o w e d b y r e d u c t i o n , p r o d u c e d t h e a m i d e ( 7 6 ) a n d n i t r i l e ( 7 7 ) . The c o n v e r s i o n o f t h e a m i d e ( 7 6 ) t o t h e n i t r i l e ( 7 7 ) was a c c o m p l i s h e d b y t h i o n y l c h l o r i d e a n d b a s i c h y d r o l y s i s . The p o t a s s i u m s a l t o f t h e n i t r i l e ( 7 7 ) , o n t r e a t m e n t w i t h c h l o r o m e t h y l e t h e r , g a v e t h e d e r i v a t i v e ( 7 8 ) . M e t a l h y d r i d e r e d u c t i o n , W o l f f - K i s h n e r r e d u c t i o n and a c i d h y d r o l y s i s f u r n i s h e d d e s o x y n i m b i o l ( 7 9 ) a n d o n

a c e t y l a t i o n , o x i d a t i o n , a n d h y d r o l y s i s , c o n v e r t e d ( 7 9 ) t o n i m b i o l ( 7 2 ) .

OH OH OH

(fJ Me COOMe

(731

O C H 2 0 M e I

Me CN (78)

Me COOH 175)

(74)

OH

t i e M e (79)

Me

IIv)_

Me (76)R:CONH2

(77) R = C N

R e a g e n t s : ( i ) CH2N2; ( i i ) CH20, Me NH; ( i i i ) M e I , L i , l i q NH3; ( i v ) A c 2 0 ,

S O C l 2 , L i N H 2 / l i q NH3; ( v ) S 0 C l 2 , KOH, (CH20H) ; ( V i ) K , C4H90H, C1CH20Me; ( v i i ) L i A 1 H 4 , NH2NH2, (OHCH2CH2)20, H 2 S 0 4 ; ( v i i i ) MeCOONa, Ac20 ; ( i x ) Cr03, MeCOOH; ( x ) 2N KOH, C3H70H; ( x i ) P-TsOH, CgH5N;

( x i i ) L i A 1 H 4 , T H F .

Scheme I X

2 - D e s o x y s t e m o d i n o n e

P o d o c a r p i c a c i d h a s b e e n u t i l i z e d i n t h e s y n t h e s i s o f t e t r a c y c l i c d i t e r p e n e s

l i k e 2 - d e s o x y s t e m o d i n o n e ( 9 4 ) w h i c h was i s o l a t e d z 4 f r o m S t e m o d i a m a r i t i m a L . and whose s t r u c t u r e was d e t e r m i n e d b y s p e c t r a l means .25 I t s s t r u c t u r e was c o n -

f i r m e d b y c o r r e l a t i o n w i t h s t e m o d i n o n e ( 9 5 ) , a n o t h e r t e t r a c y c l i c d i t e r p e n e i s o l a t e d f r o m t h e same p l a n t , whose s t r u c t u r e was u n a m b i g u o u s l y d e t e r m i n e d b y s i n g l e X - r a y c r y s t a l l o g r a p h i c a n a l y s i s . 2 6 K e l l y has r e c e n t l y r e p o r t e d a n e l e - g a n t s y n t h e s i s z 4 o f ( + ) - 2 - d e s o x y s t e m o d i n o n e ( 9 4 ) f r o m p o d o c a r p i c a c i d . (Scheme X ) . The n o t e w o r t h y a s p e c t o f t h e p r e s e n t s y n t h e s i s i s t h e p h o t o a d d i t i o n o f a l l e n e t o t h e a , b - u n s a t u r a t e d k e t o n e a n d t h e r e a r r a n g e m e n t o f t h e r e s u l t i n g p r o d u c t t o o b t a i n 6 - h y d r o x y - b i c y c l o 12.2.2 o c t a n e - Z - o n e l s y s t e m .

The m e t a l h y d r i d e r e d u c t i o n o f t h e t o s y l d e r i v a t i v e o f p o d o c a r p a n o l ( 3 )

( d e s c r i b e d i n Scheme I ) y i e l d e d 0 - m e t h y l p o d o c a r p a n e ( 8 0 ) . S u b j e c t i o n o f ( 8 0 ) t o l i t h i u m i n ammonia r e d u c t i o n p r o d u c e d t h e a , b - u n s a t u r a t e d k e t o n e ( 8 1 ) . P h o t o a d d i t i o n o f a l l e n e t o t h e k e t o n e ( 8 1 ) p r o d u c e d t h e a d d u c t ( 8 2 ) w h i c h o n

- 17-

t r e a t m e n t w i t h d i m e t h y l c a r b o n a t e gave e s t e r ( 8 3 ) . The m e t h y l d e r i v a t i v e (84) was s a p o n i f i e d t o ( 8 5 ) and t h e k e t a l d e r i v a t i v e ( 8 6 ) was o x i d i z e d t o f u r n i s h t h e c y c l o b u t a n o l ( 8 8 ) and a c i d t r e a t m e n t y i e l d e d t h e k e t o a l c o h o l ( 9 0 ) . The c o n v e r s i o n o f t h e c y c l o b u t a n o l (88) t o k e t o a l c o h o l ( 9 0 ) i n v o l v e s d e k e t a l i z a - t i o n f o l l o w e d by r e t r o - a l d o l i z a t i o n t o g i v e t h e k e t o a l d e h y d e ( 8 9 ) w h i c h u n d e r - goes spon taneous a l d o l c o n d e n s a t i o n t o g i v e t h e k e t o a l c o h o l ( 9 0 ) . The t h i o - a c e t a l d e r i v a t i v e on d e s u l p h u r i z a t i o n f u r n i s h e d t h e a l c o h o l ( 9 1 ) whose t o s y l d e r i v a t i v e on h e a t i n g w i t h d i m e t h y l s u l f o x i d e i n t h e p r e s e n c e o f s u l f i n y l c a r - b a n i o n u n d e r w e n t r e a r r a n g e m e n t t o a f f o r d t h e o l e f i n ( 9 2 ) . The e p o x i d e ( 9 3 ) , o n r e d u c t i o n w i t h m e t a l h y d r i d e . y i e l d e d 2 - d e s o x y s t e m o d i n o n e ( 9 4 ) .

. . Me Me

(92)

Reagen ts : ( i ) T s C l / P y ; ( i i ) L iA1H4/THF; ( i i i ) L i /NH j / t -BuOH; ( i v ) H2C=C=CH2, hu; ( v ) (Me0)2C0, NaH; ( v i ) MeI , NaH; ( v i i ) K O H / E t O H ; ( v i i i ) ( C H 2 0 H ) 2 / p - T ~ O H ; ( i x ) Os04, N a I 0 4 ; ( x ) NaBH4/EtOH; ( x i ) HCl/THF; ( x i i ) (CH2SH)2, BF3* E t 2 0 ; ( x i i i ) Ra -N i , W-2; ( x i v ) DMSO, Me2S=CH2; ( x v ) M C P B A .

Scheme X

A p h i d i c o l - 1 5 - E n e

K e l l y and c o w o r k e r s 2 7 have a l s o d e m o n s t r a t e d a n o t h e r u t i l a c i d by d e v e l o p i n g an e f f i c i e n t s y n t h e s i s o f ( + ) - a p h i d i c o

t y o f p o d o c a r p i c -15 -ene ( l o o ) , wh c h

- 1 8 -

i s a d e r i v a t i v e o f t h e t e t r a c y c l i c d i t e r p e n e a p h i d i c o l i n ( 1 0 1 ) . 2 8 (Scheme XI).

t e r i a l f o r t h e p r e s e n t s y n t h e s i s . I n o r d e r t o r e a l i z e t h e t r a n s f o r m a t i o n o f

( 9 0 ) t o ( 9 9 1 , i t was n e c e s s a r y t o r e d u c e t h e s e c o n d a r y h y d r o x y g r o u p t o a m e t h y l e n e g r o u p and c o n v e r t t h e k e t o g r o u p t o an a p p r o p r i a t e l e a v i n g g r o u p .

T h i s was a c h i e v e d by p r e p a r i n g t h e S - m e t h y l d i t h i o c a r b o n a t e ( 9 6 ) , f o l l o w i n g t h e p r o c e d u r e o f B a r t o n , 2 9 w h i c h c o n s i s t e d i n h e a t i n g t h e a l c o h o l ( 9 0 ) w i t h sodium h y d r i d e , i m i d a z o l e , and c a r b o n d i s u l f i d e . The d i t h i o c a r b o n a t e ( 9 6 ) was

c o n v e r t e d i n t o a l c o h o l ( 9 7 ) by r e d u c t i o n . The b e n z o y l d e r i v a t i v e ( 9 8 ) , on h e a t i n g w i t h t r i - n - b u t y l t i n h y d r i d e i n t o l u e n e , f o l l o w e d by a l k a l i n e h y d r o l y - s i s , p r o d u c e d t h e a l c o h o l ( 9 9 ) . The t o s y l d e r i v a t i v e o f t h e a l c o h o l ( 9 9 ) , on

h e a t i n g w i t h d i m e t h y l s u l f o x i d e c o n t a i n i n g s u l f i n y l c a r b a n i o n , u n d e r w e n t r e a r - rangement f u r n i s h i n g t h e d e s i r e d ( + ) - a p h i d i c o l - 1 5 - e n e ( 1 0 0 ) . The s y n t h e t i c t e r p e n e e x h i b i t e d p h y s i c a l and s p e c t r o s c o p i c p r o p e r t i e s t h a t were i d e n t i c a l w i t h ( + ) - a p h i d i c o l - 1 5 - e n e ( 1 0 0 ) d e r i v e d f r o m a p h i d i c o l i n ( 1 0 1 ) . I t i s w o r t h - w h i l e t o m e n t i o n t h a t p o d o c a r p i c a c i d has a l s o been u t i l i z e d by I t a l i a n chem- i s t s l e d by B e t o l o 3 ' i n a s y n t h e s i s o f k e t o n e s ( 1 0 2 ) and ( 1 0 3 ) c h a r a c t e r i s t i c o f t h e C/O r i n g sys tems o f a p h i d i c o l i n ( 1 0 1 ) and s t e m o d i n o n e ( 9 5 ) .

K e t o a l c o h o l (90). ( d e s c r i b e d a l r e a d y i n Scheme X ) s e r v e d as s t a r t i n g ma-

Me M e

(102)

Reagen ts : ( i ) NaH, I m o d a z o l e , C S 2 ; ( i i ) NaBH4; ( i i i ) P h C O C l / P y r i d i n e ; ( i v ) B u 3 S n H / t o l u e n e , K O H / E t O H ; ( v ) T s C l / P y r i d i n e , OMSO, Me2C=CH2.

Scheme XI

T r a c h y l o b a n - 1 9 - O i c - A c i d

E n t - t r a c h y l o b a n - 1 9 - O i c a c i d ( 1 0 7 ) i s a p e n t a c y c l i c d i t e r p e n e o b t a i n e d i n a p p r e -

c i a b l e amounts f r o m t h e common s u n f l o w e r ( H e l i a n t h u s annus L . ) . 3 1 The r e c e n t f i n d i n g s 3 ' o f l a r v i c i d a l a c t i v i t y o f t h e a c i d ( 1 0 7 ) t o w a r d s s e v e r a l L e p i d o p - t e r a s p e c i e s , i n c l u d i n g t h e s u n f l o w e r mo th , has made i t a n a g r i c u l t u r a l i m p o r - t a n t m o l e c u l e . R e c e n t l y , t h e s y n t h e s i s o f t h e a c i d ( 1 0 7 ) f r o m p o d o c a r p i c a c i d was r e a l i z e d 3 3 b y t h e r o u t e i n Scheme X I I I .

The above m e n t i o n e d s y n t h e s i s was based o n t h e c o n c e p t o f b i c y c l o a n n u l a -

t i o n w h i c h c o n s i s t s on t h e r e a c t i o n o f v i n y l and i s o p r o p e n y l p h o s p h o n i u m b r o - m i d e w i t h a - e n o l a t e s f r o m a v a r i e t y o f a - c y c l o h e x e n o n e s t o y i e l d 13 .2 .1 .02 '71 o c t a n - 6 - o n e s w h i c h have p r o v e n t o be q u i t e v e r s a t i l e i n n a t u r a l p r o d u c t s y n -

- 19-

t h e s i s . 3 4 (Scheme XII).

p r o d u c e d a m i x t u r e o f a- and 8 - e p o x i d e s (104) t h a t w e r e s u b j e c t e d t o W h a r t o n r e a r r a n g e m e n t t o a f f o r d a m i x t u r e o f a l c o h o l s . O x i d a t i o n f u r n i s h e d t h e e n o n e e s t e r ( 1 0 5 ) w h i c h u n d e r w e n t b i c y c l o a n n u l a t i o n w i t h isopropenyltriphenilphos- p h o n i u m b r o m i d e t o a f f o r d t h e d e s i r e d p e n t a c y c l i c k e t o e s t e r (106). F u r t h e r W o l f f - K i s h n e r r e d u c t i o n p r o d u c e d t h e a c i d (107) t h a t was c o n v e r t e d i n t o t h e e s t e r ( 1 0 8 ) , i d e n t i c a l i n e v e r y r e s p e c t t o an a u t h e n t i c s a m p l e o f t h e e s t e r d e r i v e d f r o m ( 1 0 7 ) .

The enone e s t e r ( 2 7 ) ( a l r e a d y d e s c r i b e d i n Scheme IY), o n e p o x i d a t i o n ,

R e a g e n t s : ( i ) I s o p r o p e n y l p h o s p h o n i u m b r o m i d e .

Scheme X I 1

R e a g e n t s : ( i ) H202/NaOH; ( i i ) NH2NH2, MeCOOH; ( i i i ) PCC/CH2C12; ( i v ) H2C=

C(Me) P tPh3Br -2 ; ( v ) NH2NH2/ ( OHCH2CH2) 20/KOH; ( v i ) CH2N2.

Scheme X I 1 1

C o l e o n U

The C a n a d i a n c h e m i s t s l e d by B ~ r n e l l ~ ~ e x h i b i t e d t h e u t i l i t y o f p o d o c a r p i c a c i d b y d e v e l o p i n g s e v e r a l h i g h l y o x y g e n a t e d t r i c y c l i c d i t e r p e n e s l i k e C o l e o n U ( 1 1 7 ) as i t s t r i - 0 - m e t h y l e t h e r (118) and t e t r a - 0 - m e t h y l e t h e r (119) a s i s e x h i b i t e d i n Scheme X I V .

i n Scheme 11, g a v e on b e n z y l i c o x i d a t i o n s u g i o l m e t h y l e t h e r (109) t h a t was c o n v e r t e d b y o x i d a t i v e t r e a t m e n t i n t o t h e q u i n i c a c i d (110). B r o m i n a t i o n o f (110) p r o d u c e d t h e d i b r o m o d e r i v a t i v e (lll), a n d o n t r e a t m e n t w i t h b a s e , a f - f o r d e d t h e b r o m o q u i n o n e ( 1 1 2 ) . The h y d r o x y q u i n o n e (113), o b t a i n e d b y w a r m i n g t h e b r o m o q u i n o n e ( 1 1 2 ) w i t h b a s e , g a v e o n c a t a l y t i c h y d r o g e n a t i o n t h e a i r s e n -

s i t i v e h y d r o q u i n o n e t h a t was m e t h y l a t e d t o o b t a i n t h e e s t e r ( 1 1 4 ) . On a l k a l i n e k y d r o l y s i s , ( 1 1 4 ) a f f o r d e d t h e a c i d ( 1 1 5 ) whose t r a n s f o r m a t i o n i n t o t h e k e t o n e

F e r r u g i n o l m e t h y l e t h e r (17), p r e p a r e d f r o m p o d o c a r p i c a c i d , a s d e s c r i b e d

- 20 -

( 1 1 6 ) was e f f e c t e d b y t r e a t m e n t w i t h t r i f l u o r o a c e t i c a n h y d r i d e and b y m i l d a l -

k a l i n e h y d r o l y s i s . The k e t o n e ( 1 1 6 ) was t r e a t e d w i t h p o t a s s i u m t e r t - b u t o x i d e

a n d o x y g e n a c c o r d i n g t o t h e B a r t o n p r o c e d u r e t o o b t a i n c o l e o n U t r i - 0 - m e t h y l e t h e r ( 1 1 8 ) . F u r t h e r m e t h y l a t i o n l e d t o t h e f o r m a t i o n o f c o l e o n U t e t r a - 0 - m e t h y l e t h e r ( 1 1 9 ) .

o f c o l e o n C ( 1 2 0 ) a s i t s t r i - 0 - m e t h y l e t h e r ( 1 2 1 ) and t e t r a - 0 - m e t h y l e t h e r ( 1 ~ 1 , ~ ~ and c o l e o n B ( 1 2 3 ) a s i t s t e t r a - 0 - m e t h y l e t h e r ( 1 2 4 ) . 3 7

The a b o v e m e n t i o n e d c o n c e p t was a l s o e x t e n d e d b y B u r n e l l f o r t h e s y n t h e s i s

(I)_ g:: - ( 1 1 ) 8:: - (Ill) p:: (17)

**, ti '\, A . a ', A

Me Me Me Me COOH Me Me ''OH

(109) ( I 10) 1 1 1 1 )

( V I I I

R e a g e n t s :

(116)

Me Ma

Me

M e

0 # \ \

Me b R

( i ) Cr03 /AcOH; ( i i ) Ac20, H2S04, H202 ; ( i i i ) B r 2 , MeCOOH; ( i v ) E t3NH, E t 2 0 ; ( v ) NaOH, MeOH; ( v i ) H 2 , P t 0 2 , Me2S04, NaOH, MeOH, H20 ; ( v i i ) (CF3CO)20 ; ( v i i i ) 0 2 , C4H90K, t -BuOH; ( i x ) Me2S04, K2C03, Me2C0.

Scheme X I V

O e h y d r o c y c l o r o y l e a n o n e

D e h y d r o c y c l o r o y l e a n o n e ( 1 3 1 ) i s a d e g r a d a t i o n p r o d u c t a r i s i n g f r o m t h e h y d r o -

- 21 -

g e n o l y s i s o f l y c o x a n t h o l ( 1 3 2 1 , a d i t e r p e n o i d h y d r o q u i n o n e , i s o l a t e d f r o m L y c o p o d i ~ m . ~ ~ B u r n e l l d e y e l o p e d a s y n t h e s i s 3 ’ o f d e h y d r o c y c l o r o y l e a n o n e ( 1 3 1 ) f r o m p o d o c a r p i c a c i d (Scheme X V ) i n o r d e r t o c o r r o b o r a t e t h e p r o p o s e d s t r u c - t u r e . From t h e f o l l o w i n g d e s c r i p t i o n i t c a n be o b s e r v e d t h a t , o w i n g t o a s e l e c - t i o n o f p o d o c a r p i c a c i d a s r e f e r e n c e m a t e r i a l , t h e c o n s t r u c t i o n o f d i h y d r o f u - r a n m o i e t y i n d e h y d r o c y c l o r o y l e a n o n e ( 1 3 1 ) p r e s e n t e d no d i f f i c u l t y .

a l r e a d y d e s c r i b e d i n Scheme X . An a l t e r n a t i v e a p p r o a c h was a l s o d e v e l o p e d f o r t h e s y n t h e s i s o f ( 8 0 ) i n v o l v i n g t h e a c e t y l a t i o n o f p o d o c a r p a n o l ( 3 ) (Scheme I ) t o o b t a i n t h e a c e t a t e ( 1 2 5 ) a n d i r r i d a t i o n i n h e x a m e t h y l p h o s p h o r a m i d e t o a f - f o r d 0 - m e t h y l p o d o c a r p a n e ( 8 0 ) . F r i e d a l - c r a f t s a c e t y l a t i o n o f ( 8 0 ) a f f o r d e d a c e t y l d e r i v a t i v e ( 1 2 6 ) and d e m e t h y l a t i o n r e s u l t e d i n t h e f o r m a t i o n o f p h e n o l ( 1 2 7 ) . The i n t r o d u c t i o n o f t h e a c e t y l r e s i d u e t o t h e a c e t a t e ( 1 2 5 ) b y F r i e s r e a r r a n g e m e n t c o u l d n o t b e e f f e c t e d . The t r a n s f o r m a t i o n o f ( 1 2 7 ) i n t o a c i d ( 1 2 8 ) was r e a l i z e d b y a l k y l a t i o n a n d a l k a l i n e h y d r o l y s i s . The c y c l i z a t i o n o f t h e a c i d ( 1 2 8 ) t o f u r a n d e r i v a t i v e ( 1 2 9 ) was e f f e c t e d b y t r e a t m e n t w i t h a c e t i c a n h y d r i d e and a n h y d r o u s s o d i u m a c e t a t e , a n d h y d r o g e n a t i o n p r o d u c e d t h e d i h y - d r o f u r a n d e r i v a t i v e ( 1 3 0 ) . O x i d a t i o n y i e l d e d d e d e h y d r o c y c l o r o y l e a n o n e ( 1 3 1 ) , t h a t was i d e n t i c a l w i t h t h e d e h y d r o c y c l o r o y l e a n o n e o b t a i n e d f r o m l y c o x a n t h o l

The s t a r t i n g m a t e r i a l f o r t h e s y n t h e s i s was 0 - m e t h y l p o d o c a r p a n e ( 8 0 ) ,

( 1 3 2 ) . OM e

(3) $9 Me ‘\ C H 2 0 A c H

O M e

0 7

. . Ma Ma (130)

R e a g e n t s : ( i ) AcilO/Py; ( i i ) hu , H M P A ; ( i i i ) AcC1, C6H5N02; ( i v ) A 1 C l 3 , CH2C12; ( v ) K2C03, BrCH2COOEt; ( v i ) NaOH, MeOH, H20; ( v i i ) Ac20 , MeCOONa; ( v i i i ) P t 2 0 , MeCOOH; ( i x ) Ac20 , H2S04, H202 .

Scheme X V

M a y t e n o q u i n o n e

R e c e n t l y B u r n e l l and c o w o r k e r s 4 0 h a v e r e p o r t e d t h e s y n t h e s i s o f m a y t e n o q u i n o n e ( 1 4 3 ) , a d i t e r p e n o i d q u i n o n e , f r o m p o d o c a r p i c a c i d , a s shown i n Scheme X V I . The n o v e l t y o f t h e p r e s e n t s y n t h e s i s l i e s i n t h e i n t r o d u c t i o n o f C-13 h y d r o x y a n d C-14 i s o p r o p y l g r o u p s i n t h e a r o m a t i c p a r t o f p o d o c a r p i c a c i d b y a c o m b i - n a t i o n o f t h e D u f f r e a c t i o n and t h e C l a i s e n r e a r r a n g e m e n t .

a f f o r d t h e f o r m y l d e r i v a t i v e ( 1 3 3 ) t h a t was c o n v e r t e d b y o x i d a t i o n i n t o 0 - m e t h y l p o d o c a r p a n e ( 8 0 ) (Scheme X) was s u b j e c t e d t o D u f f r e a c t i o n t o

- 2 2 -

0 - f o r m y l d e r i v a t i v e (1341. The c a t e c h o l m o n o e t h e r (135), o b t a i n e d b y t h e a l k a -

l i n e h y d r o l y s i s o f ( 1 3 4 ) , o n a l k y l a t i o n w i t h c r o t y l b r o m i d e , a f f o r d e d t h e a l - l y l i c e t h e r ( 1 3 6 ) w h i c h u n d e r w e n t C l a i s e n r e a r r a n g e m e n t a f f o r d i n g t h e 1 4 - s u b - s t i t u t e d compound ( 1 3 7 ) . T h i s t h e n was c o n v e r t e d i n t o i t s m e t h y l d e t i v a t i v e

( 1 3 8 ) whose d o u b l e bond was c l e a v e d t o o b t a i n t h e a l d e h y d e ( 1 3 9 ) w h i c h u n d e r H u a n g - M i n l o n c o n d i t i o n y i e l d e d t h e 1 4 - i s o p r o p y l d e r i v a t i v e ( 1 4 0 ) . I t s d e m e t h - y l a t i o n y i e l d e d t h e c a t e c h o l d e r i v a t i v e ( 1 4 1 ) w h i c h o n o x i d a t i o n a f f o r d e d t h e m e t h y l e n e q u i n o n e ( 1 4 2 ) whose t r a n s f o r m a t i o n t o n a t u r a l m a y t e q u i n o n e ( 1 4 3 ) was e f f e c t e d b y s l o w c h r o m a t o g r a p h y o v e r s i l i c a g e l .

OMe I

R e a g e n r s :

The u i

( i ) H e x a m e t h y l l e n e t e t r a m i n e ; ( i i ) M C P B A / C H 2 C 1 2 ; ( i i i ) a q KOH; ( i v ) MeCH=CHCH2Br; ( v ) PhNMe2; ( v i ) Me2S04-NaOH; ( v i i ) N a I 0 4 , OS04; ( v i i i ) NH2NH2, DEG, KOH; ( i x ) B B r 3 , CH2C12; ( x ) Ag20 , CHC13; ( x i ) S i l i c a g e l .

Scheme X V I

D r i m e n i n , I s o d r i m e n i n , C o n f e r t i f o l i n a n d D r i m e n o l

y o f p o d o c a r p i c a c i d h a s n o t o n l y b e e n o b s e r v e d i n t h e s y n t h e s i s o f

d i t e r p e n e s b u t a l s o i n t h e s y n t h e s i s f o r d r i m e n i c s e s q u i t e r p e n e s , l i k e d r i m e n i n ( 1 5 5 1 , i s o d r i m e n i n ( 1 5 6 ) . c o n f e r t i f o l i n ( 1 5 8 ) , a n d d r i m e n o l ( 1 6 0 ) t h a t w e r e i s o l a t e d f r o m t h e b a r k o f D r i m y s w i n t e r i F o r ~ t . ~ ~ ’ ~ ~ W e n k e r t a n d c o w o r k e r s u t i l i z e d p o d o c a r p i c a c i d i n t h e s y n t h e s i s o f t h e a b o v e m e n t i o n e d s e s q u i t e r - p e n e s , a s d e p i c t e d i n Scheme X V I I .

0 - m e t h y l p o d o c a r p a n e ( 8 0 ) ( d e s c r i b e d i n Scheme X) o n o x i d a t i o n y i e l d e d t h e k e t o n e ( 1 4 4 ) w h i c h was s u b j e c t e d t o o x i d a t i o n , a l k a l i n e h y d r o l y s i s , o z o - n o l y s i s a n d c y c l i z a t i o n t o f u r n i s h t h e d r i m a n e a n h y d r i d e ( 1 4 5 ) . No i n t e r m e d i - a t e s w e r e c h a r a c t e r i z e d . T r e a t m e n t w i t h d i m e t h y l c a r d m i u m , f o l l o w e d b y m e t h y l -

43

- 23 -

a t i o n and c y c l i z a t i o n , y i e l d e d t h e 1 , 3 - d i o n e ( 1 4 6 ) . A c i d i c m e t h a n o l t r e a t m e n t

o f t h e d i o n e ( 1 4 6 ) p r o d u c e d t h e e n o l e t h e r s ( 1 4 7 ) a n d ( 1 4 8 ) i n 84% a n d 13%, r e s p e c t i v e l y , a n d r e d u c t i o n f o l l o w e d b y a c i d h y d r o l y s i s l e d t o t h e f o r m a t i o n o f t h e enones ( 1 4 9 ) a n d ( 1 5 0 ) . H y d r o c y a n a t i o n o f t h e m a j o r enone ( 1 5 0 ) y i e l d e d t h e a x i a l l y o r i e n t e d c y a n a t e d k e t o n e ( 1 5 1 ) w h i c h o n k e t a l i z a t i o n , a l k a l i n e h y d r o l y s i s a n d d e k e t a l i z a t i o n , f u r n i s h e d t h e k e t o a c i d ( 1 5 2 ) whose f o r m y l d e -

r i v a t i v e o n t r e a t m e n t w i t h s o d i u m a c e t a t e i n a c e t i c a n h y d r i d e , u n d e r w e n t l a c - t o n i z a t i o n t o y i e l d 7 - k e t o i s o d r i m e n i n ( 1 5 3 ) . H y d r o g e n a t i o n f o l l o w e d b y m e t a l h y d r i d e r e d u c t i o n p r o d u c e d t h e a l c o h o l ( 1 5 4 ) . H e a t i n g t h e p - t o l u e n e s u l f o n a t e d e r i v a t i v e o f t h e a l c o h o l ( 1 5 4 ) i n d i m e t h y l s u l f o x i d e p r o d u c e d t h e d r i m e n i n ( 1 5 5 ) and t h i s was c o n v e r t e d t o i s o d r i m e n i n ( 1 5 6 ) o n t r e a t m e n t w i t h 10% e t h a - n o l i c po t a s s i um h y d r o x i d e .

R e d u c t i o n o f i s o d r i m e n i n ( 1 5 6 ) p r o v i d e d t h e d i o l ( 1 5 7 ) and o x i d a t i o n c o n - v e r t e d ( 1 5 7 ) i n t o c o n f e r t i f o l i n ( 1 5 8 ) . S i m i l a r l y , t h e d i o l ( 1 5 9 ) , o b t a i n e d by

r e d u c t i o n o f d r i m e n i n ( 1 5 5 ) : was c o n v e r t e d t o d i a c e t a t e w h i c h o n m e t a l ammonia r e d u c t i o n , f o l l o w e d b y a l k a l i n e h y d r o l y s i s , a f f o r d e d d r i m e n o l ( 1 6 0 ) .

M e Me MI M e (1591

R e a g e n t s : ( i ) Cr04-HOAc; ( i i ) CF3COOH, NaOH-C3H70H, 03, Ac20 ; ( i i i ) Me2Cd; ( i v ) CH2N2; ( v ) t -BuOK; ( v i ) MeOH, HC1; ( v i i ) L i A 1 H 4 , H30; ( v i i i ) KCN, NH4Cl , DMF; ( i x ) (CH20H)2 , P t s ; ( x ) KOH, H30; ( x i ) HC02Et , t -BuOK; ( x i i ) (CH,CO),O, CH3COONa; ( x i i i ) H2, Pd-C; ( x i v ) NaBH4; ( X V ) p - T s C l / P y , D M S O ; ( x v i ) 10% KOH-EtOH; ( x v i i ) L i A 1 H 4 ; ( x v i i i )

- 24 -

Mn02; ( x i x

P e l l e i e r a n d Oh

MeCOONa/Ac20, L i / l i q N H 3 . NaOH.

Scheme X Y I I

W i n t e r i n

~ s k a ~ ~ h a v e a l s o shown t h e u t i l i t y o f p o d o c a r p i c a c i d i n r e l a t i o n w i t h t h e s y n t h e s i s o f w i n t e r i n ( 1 5 2 ) , a d r i m a n e s e s q u i t e r p e n e t h a t

was i s o l a t e d f r o m t h e s t e m b a r k o f & m y ' s W i ~ ~ t e r l . ~ ~ The r i n g c l o s u r e p r o c e s s b y " r o t a t i o n " o f t h e a r o m a t i c r i n g i s t h e m o s t i m p o r t a n t s t e p o f t h e p r e s e n t s y n t h e s i s a s h a s been d e p i c t e d i n Scheme X V I I I . I t i s w o r t h w h i l e t o m e n t i o n h e r e t h a t i n t h e a l r e a d y r e p o r t e d s y n t h e s i s o f c o l e o n C t r i - 0 - m e t h y l e t h e r

( 1 2 1 ) a n d c o l e o n B t e t r a - 0 - m e t h y l e t h e r ( 1 2 2 ) , t h e r i n g c l o s u r e p r o c e s s b y r o - t a t i o n o f t h e a r o m a t i c r i n g d e v e l o p e d b y P e l l e t i e r , 4 4 was a l s o u t i l i z e d .

0 - m e t h y l p o d o c a r p a t e ( 2 ) ( a l r e a d y d e s c r i b e d i n Scheme I ) on o x i d a t i o n

y i e l d e d 7-OX0 d e r i v a t i v e ( 1 6 1 ) w h i c h was c o n v e r t e d i n t o l a c t o n e ( 1 6 2 ) b y B a e y e r - V i l l i g e r o x i d a t i o n . M e t h a n o l y s i s o f t h e l a c t o n e ( 1 6 2 ) f o l l o w e d b y m e t h - y l a t i o n a n d p a r t i a l a l k a l i n e h y d r o l y s i s p r o d u c e d d i m e t h o x y m o n o e s t e r ( 1 6 3 ) w h i c h u n d e r w e n t c y c l i z a t i o n a f f o r d i n g t r i f l u o r o a c e t a t e ( 1 6 4 ) and t h i s y i e l d e d

t h e d i m e t h o x y o x o e s t e r ( 1 6 5 ) b y a l k a l i n e h y d r o l y s i s . The d i m e t h o x y e s t e r ( 1 6 6 )

o b t a i n e d b y h y d r o g e n a t i o n o f o x o e s t e r ( 1 6 5 1 , was r e d u c e d t o a l c o h o l ( 1 6 7 ) a n d

s u b j e c t e d t o t h r e e r e a c t i o n s : ( a ) o x i d a t i o n , ( b ) t h i o a c e t a l i z a t i o n , a n d ( c ) d e s u l f u r i z a t i o n , t o o b t a i n t h e d i m e t h o x y oxopodocarpa-8,11,13-triene ( 1 6 8 )

w h i c h u n d e r w e n t d e m e t h y l a t i o n a f f o r d i n g t h e h y d r o q u i n o n e ( 1 6 9 1 , and t h i s was

c o n v e r t e d t o w i n t e r i n ( 1 7 0 ) b y o z o n o l y s i s and o x i d a t i o n s u c c e s s i v e l y .

( 1 6 5 )

M e @ '., Me 6

M a R

(166) R Z C O O E t ( 1 6 7 ) R:CHzOH

(168) A - O M e (169 ) R:OH

( 1 7 0 )

R e a g e n t s : (i) Cr03-AcOH; ( i i ) MCPBA-CHC13; (iii) H2S04-MeOH; ( i v ) Me2S04,

K C O ; ( v ) 1 0 % KOH-MeOH; ( v i ) (CF3CO)20 ; ( v i i ) KOH-MeOH; ( v i i i ) H2, 10% Pd-c , AcOH-H2S04; ( i x ) L i A 1 H 4 - E t 2 0 ; ( x ) CrO3-C6H5N; ( X i ) (CH2SH)2 , BF3 E t 0 ; ( x i i ) Ra -N i ( W - 7 ) ; ( x i i i ) BBr3-CH2C12;

2 3

2

( x i v ) 03, CH2C12; ( x v ) C r 0 3 - H Z S 0 4

Scheme X V I I I

The a b o v e m e n t i o n e d d e s c r i p t i o n s show t h e u t i l i t y o f p o d o c a r p i c a c i d i n t h e s y n t h e s i s o f v a r i o u s n a t u r a l l y o c c u r r i n g t e r p e n e s . P o d o c a r p i c a c i d h a s a l s o been u t i l i z e d i n t h e s y n t h e s i s 4 6 o f b i o l o g i c a l l y a c t i v e n o r d i t e r p e n o i d l a c t o n e , N a g i l a c t o n e F . ( 1 7 1 ) . I n a d d i t i o n , t h e t r a n s f o r m a t i o n o f p o d o c a r p i c a c i d i n t o o d o r i f e r o u s h o m o l o g e s o f t h e c y c l i c e t h e r s Ambrox ( 1 7 2 ) a n d Iso- ambrox ( 1 7 3 ) h a s b e e n r e p o r t e d . 4 7 R e c e n t l y Cambie a n d c o w o r k e r s 4 8 h a v e a c h i e v e d

t h e s y n t h e s i s o f y - b i c y c l o h o m o f a r n e s a l s ( 1 7 4 ) f r o m p o d o c a r p i c a c i d . I t i s n o t e - w o r t h y t h a t p o d o c a r p i c a c i d has b e e n u t i l i z e d i n t h e s y n t h e s i s o f i n t e r m e d i a t e s w h i c h i n t h e n e a r f u t u r e may be u s e d f o r t h e t o t a l s y n t h e s i s o f t e r p e n o i d com- p o u n d s . D e t a i l e d d e s c r i p t i o n s a r e o m i t t e d f r o m t h i s r e v i e w , b u t a f e w e x a m p l e s a r e m e n t i o n e d b e l o w .

ApSimon a n d Edward4 ’ c o n v e r t e d p o d o c a r p i c a c i d i n t o N - a c e t y l p h e n o l ( 1 7 5 ) . T h i s m e t h o d o p e n s a new r o u t e t o t h e t o t a l s y n t h e s i s of d i t e r p e n o i d a l k a l o i d s a n d h a s been f o u n d u s e f u l i n t h e t o t a l s y n t h e s i s o f a t i s i n e b y M a ~ a m u n e . ~ ~ G i r o t r a and Z a l k o w 5 ’ i n a n a t t e m p t t o w a r d s t h e s y n t h e s i s o f a t i s i n e r e p o r t e d t h e t r a n s f o r m a t i o n o f p o d o c a r p i c a c i d i n t o t h e a l c o h o l ( 1 7 6 ) . P o d o c a r p i c a c i d h a s a l s o been u t i l i z e d b y Mander a n d c o w o r k e r s 5 2 i n t h e s y n t h e s i s o f l a c t a m

( 1 7 7 ) w h i c h was c o n s i d e r e d a s u i t a b l e m o d e l f o r t h e p r e l i m i n a r y s t u d y t o w a r d s t h e s y n t h e s i s o f C z 0 d i t e r p e n e a l k a l o i d s l i k e h e t i s i n e , k o b u s i n e , a n d p s e u d o -

k o b u s i n e . B u r n e l l a n d 0 u f 0 u r ~ ~ s y n t h e s i z e d t h e h e x a h y d r o p h e n a l e n e d e r i v a t i v e ( 1 7 8 ) w h i c h c o n s t i t u t e s t h e f u n d a m e n t a l s k e l e t o n o f e d u l o n e A , a d i t e r p e n e w i t h u n u s u a l s k e l e t o n .

n e a r f u t u r e p o d o c a r p i c a c i d w i l l be u t i l i z e d f o r t h e s y n t h e s i s o f m o r e c o m p l e x The above m e n t i o n e d d e s c r i p t i o n s l e a d one t o t h i n k t h a t p r o b a b l y i n t h e

n a t u r a l p r o d u c t s .

n

(171) (172)

O M 8

M*”- 8 A,, ( 1 7 7 )

A C O @ (178)

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