The Chemistry of Allelopathy - American Chemical Society

28 Improvements in the Synthesis of Strigol and Its Analogs

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A. B. PEPPERMAN, JR., and E. J. BLANCHARD Southern Regional Research Center, Agricultural Research Service, U.S. Department of Agriculture, New Orleans, LA 70179

Conditions have been found for improving the yield of products from some of the steps in the synthesis of strigol reported by Sih. For several of the other steps, such as closure of the B-ring and C-ring, efforts to improve the yield were unsuccessful and some consistently gave lower yields than reported. Several of the simplest analogs of strigol, alkoxybutenolides containing only the D-ring, were prepared by etherification of a hydroxybutenolide with an alcohol. Conditions and limitations of the reaction were determined. Preparation of two-ring strigol analogs have been carried out by a modification of the literature procedure.

Witchweed C S t r i g a a s i a t i c a ( L . ) K u n t z e ] is an e c o n o m i c a l l y i m p o r t a n t r o o t p a r a s i t e a f f e c t i n g many warm season g r a s s e s , i n c l u d i n g such i m p o r t a n t crop members o f t h e Gramineae f a m i l y as c o r n , g r a i n sorghum, and sugar cane (1_). The p a r a s i t e has l o n g been a problem i n South A f r i c a ( 2 ) and is now widespread throughout t h e E a s t e r n Hemisphere. S i n c e i t s d i s c o v e r y i n t h e Western Hemisphere i n North and South C a r o l i n a i n t h e 1 9 5 0 s , i t has been t h e o b j e c t o f q u a r a n t i n e , c o n t r o l , and e r a d i c a t i o n programs by t h e U n i t e d S t a t e s Department o f A g r i c u l t u r e ( 3 ) . A l t h o u g h t h e q u a r a n t i n e program has been e f f e c t i v e , and t h e c o n t r o l program has p e r m i t t e d s i g n i f i c a n t a c r e a g e t o be removed from q u a r a n t i n e , t h e problem s t i l l e x i s t s and f u r t h e r r e s e a r c h is needed. The a b i l i t y o f v i a b l e witchweed seed t o remain dormant i n t h e soil f o r many y e a r s , o n l y t o germinate when f a v o r a b l e c o n d i t i o n s p r e v a i l , makes e r a d i c a t i o n d i f f i c u l t ( 2 J . U s u a l l y , seed w i l l not germinate u n l e s s p r e t r e a t e d i n a warm, m o i s t environment f o r s e v e r a l days b e f o r e exposure t o a chemical exuded from t h e r o o t s o f a host p l a n t o r some non-host p l a n t s ( 4 ) . An a c t i v e chemical i n t h e r o o t

This chapter not subject to U.S. copyright. Published 1985, American Chemical Society

Thompson; The Chemistry of Allelopathy ACS Symposium Series; American Chemical Society: Washington, DC, 1985.

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d a t e s of c o t t o n was i s o l a t e d i n 1966 (j>) and i d e n t i f i e d i n 1972 (6) by Cook and co-workers as compound I . The compound (I) was g i v e n t h e t r i v i a l name s t r i g o l and i t has been shown t o be a very potent witchweed seed g e r m i n a t i o n s t i m u l a n t .

T o t a l s y n t h e s i s of ( + ) - s t r i g o l was r e p o r t e d i n 1974 by S i h and c o - w o r k e r s (7) and t h e d e t a i l s o f t h e i r scheme and r e s o l u t i o n o f ( ± ) - s t r i g o l was r e p o r t e d i n 1976 ( 8 ) . Raphael and co-workers r e p o r t e d t h e s y n t h e s i s of s t r i g o l by a d i f f e r e n t method a l s o i n 1974 (9) and 1976 ( 1 0 ) . Cook and co-workers suggested t h a t s t r i g o l may be r e p r e s e n t a t i v e of a new c l a s s o f p l a n t hormones and t h a t o t h e r b i o l o g i c a l e f f e c t s s h o u l d be examined (6). In 1976 Johnson and co-workers (11) r e p o r t e d t h e s y n t h e s i s and t e s t i n g of s e v e r a l s t r i g o l a n a l o g s , some o f which were e x c e l l e n t seed g e r m i n a t i o n s t i m u l a n t s f o r both S t r i g a and Orobanche s p e c i e s . In 1982, Pepperman and c o - w o r k e r s t e s t e d a number of p r e c u r s o r s and a n a l o g s o f s t r i g o l and showed t h a t s e v e r a l compounds which c o n t a i n e d o n l y p a r t o f t h e s t r i g o l m o l e c u l e were a c t i v e as witchweed seed g e r m i n a t i o n s t i m u l a n t s ( 1 2 ) . A p r o j e c t has been undertaken a t t h e Southern R e g i o n a l Research C e n t e r which has as i t s goal t h e p r e p a r a t i o n o f s u f f i c i e n t q u a n t i t i e s o f s t r i g o l and i t s analogs t o permit t h e broad spectrum o f t e s t s n e c e s s a r y t o u n d e r s t a n d t h e r o l e o f t h e s e compounds i n t h e g e r m i n a t i o n , growth, and r e p r o d u c t i o n o f witchweed, and t o determine t h e i r p o t e n t i a l as c o n t r o l agents f o r witchweed when a p p l i e d t o i n f e s t e d fields. For a s c a l e - u p of the s y n t h e s i s of s t r i g o l , the f i r s t approach was t o modify one o f t h e e x i s t i n g s y n t h e t i c sequences t o give overall better y i e l d s . S i h and co-workers {8} d e s c r i b e d two r o u t e s t o s t r i g o l , one s t a r t i n g with α - c y c l o c i t r a l (2,6,6-trimethylc y c l o h e x - 2 - e n e - l - c a r b o x a l d e h y d e ) and t h e o t h e r w i t h 3 - c y c l o c i t r a l (2,6,6-trimethylcyclohex-l-ene-l-carboxaldehyde). The two r o u t e s converged a f t e r s e v e r a l s t e p s and t h e remainder of t h e s y n t h e s i s was identical. The α - c y c l o c i t r a l scheme appeared t o us t o p r e s e n t fewer e x p e r i m e n t a l problems t h a n t h e 3 - c y c l o c i t r a l scheme and was s e l e c t e d f o r further study. R e s u l t s and D i s c u s s i o n T h e r e a r e 11 s t e p s i n t h e b u i l d - u p o f t h e A-B-C r i n g p o r t i o n o f s t r i g o l a c c o r d i n g t o S i h ' s s y n t h e t i c scheme. These a r e shown i n F i g u r e 1. By r e p e a t i n g t h e s e s t e p s i n our l a b o r a t o r y both on a small s c a l e and on t h e same s c a l e used by S i h , we found t h a t we c o u l d not


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d u p l i c a t e some o f t h e y i e l d s r e p o r t e d . A material balance f o r a l a r g e s c a l e s y n t h e s i s o f s t r i g o l u s i n g t h e s e s t e p s and t h e y i e l d s r e p o r t e d by S i h showed t h a t s t a r t i n g w i t h 8 . 3 kg o f c i t r a l , which is about t h e upper l i m i t f o r o u r p i l o t p l a n t equipment s i n c e such a l a r g e excess o f H 2 S O 4 is r e q u i r e d , one would o b t a i n o n l y 417 g o f XIII with t h e p r o p e r c o n f i g u r a t i o n t o produce s t r i g o l . However, t h e c o u p l i n g s t e p a l s o produces 4 ' - e p i s t r i g o l and t h e t o t a l y i e l d o f s t r i g o l would o n l y be 156 g . Examination of the f i r s t step of the s y n t h e s i s , r i n g c l o s u r e o f c i t r a l ( I I ) t o a mixture of c y c l o c i t r a l s , i n d i c a t e d that temperature c o n t r o l and molar r a t i o o f r e a c t a n t s were o f c r i t i c a l importance t o o b t a i n maximum y i e l d . Gedye and co-workers (13) r e p o r t e d a y i e l d o f 57% o f c y c l o c i t r a l s u s i n g a 10 t o 1 molar r a t i o o f H 2 S O 4 t o c i t r a l a n i l and a t e m p e r a t u r e o f - 2 0 ° . In o u r work, we found t h a t t h e use o f a 10 t o 1 m o l a r r a t i o o f H 2 S O 4 t o c i t r a l a n i l gave y i e l d s o f o n l y about 34% o f c y c l o c i t r a l s . A 1 4 . 5 molar excess o f a c i d upped t h e y i e l d t o 54%. Maximum y i e l d o f 66% was o b t a i n e d with an 18.7 molar excess of H 2 S O 4 . T h i s i n c r e a s e o f 9% o v e r t h e l i t e r a t u r e y i e l d g i v e s us 16% more α - c y c l o c i t r a l t o go i n t o t h e next s t e p o r 750 g a t pilot-plant scale. Temperature c o n t r o l a t - 1 5 ° t o -25°C was a l s o r e q u i r e d f o r maximum y i e l d . The best r e s u l t s were o b t a i n e d by m a i n t a i n i n g a t e m p e r a t u r e o f - 2 0 t o -25°C d u r i n g t h e a d d i t i o n o f c i t r a l a n i l t o t h e a c i d and a t -15°C f o r t h e d u r a t i o n o f t h e r e a c t i o n . At t h i s t e m p e r a t u r e r a n g e , t h e f o r m a t i o n o f α - c y c l o c i t r a l ( I I I ) is f a v o r e d . H i g h e r t e m p e r a t u r e s caused e x c e s s i v e polymer f o r m a t i o n and f a v o r e d f o r m a t i o n o f β - c y c l o c i t r a l whereas lower temperatures caused a reduction i n the y i e l d of the c i t r a l mixture. At l e a s t p a r t o f t h e problem with t h e lower t e m p e r a t u r e r e a c t i o n was t h e f a c t t h a t t h e s u l f u r i c a c i d tended t o f r e e z e around t h e i n s i d e o f t h e r e a c t i o n v e s s e l c a u s i n g t h e e f f e c t i v e molar r a t i o o f a c i d t o a n i l t o be reduced. These lower t e m p e r a t u r e r e a c t i o n m i x t u r e s were a l s o l i g h t e r i n c o l o r which i n d i c a t e d l e s s polymer f o r m a t i o n but t h i s was accompanied by a lower y i e l d o f c y c l o c i t r a l s . The next s t e p o f t h e s y n t h e s i s , t h e e p o x i d a t i o n o f α - c y c l o c i t r a l ( I I I ) t o 2 , 3 - e p o x y - 2 , 6 , 6 - t r i m e t h y l c y c l o h e x a n e - l - c a r b o x aldehyde (IV) proceeded smoothly and i n e x c e l l e n t y i e l d (96%) as r e p o r t e d by S i h (8). I s o m e r i z a t i o n o f t h e e p o x i d e ( I V ) w i t h p y r r o l i d i n e was c a r r i e d out as d e s c r i b e d by S i h (8) and c o n s i s t e n t l y gave y i e l d s o f 35-60% r a t h e r than t h e 73% r e p o r t e d . Changes i n e x p e r i m e n t a l c o n d i t i o n s i n c l u d i n g l o n g e r r e a c t i o n t i m e s a t lower t e m p e r a t u r e s , use o f f r e s h l y d i s t i l l e d p y r r o l i d i n e , use o f NaOH d r i e d p y r r o l i d i n e , and use o f d i s t i l l e d epoxide (IV) had l i t t l e e f f e c t on t h e y i e l d . The o n l y v a r i a t i o n t h a t improved t h e y i e l d was t o a l l o w t h e r e a c t i o n t o p r o c e e d a t ambient t e m p e r a t u r e f o r a l o n g e r p e r i o d o f time t h a n t h e recommended 3 h o u r s . A l l o w i n g t h e r e a c t i o n t o proceed f o r 40 hours p r o v i d e d a maximum 67.5% y i e l d . O t h e r bases such as sodium c a r b o n a t e , t r i e t h y l ami ne, d i e t h y l a m i d e l , 5 - d i a z a b i c y c l o [ 4 . 3 . 0 ] n o n 5-ene(DBN), and sodium methoxide a l l gave lower y i e l d s o f d i s t i l l e d product than p y r r o l i d i n e . I t is important t o use t h e hydroxyaldehyde (V) as soon as p o s s i b l e s i n c e i t is a very u n s t a b l e m a t e r i a l . The next s t e p i n t h e S i h sequence i n v o l v e d o x i d a t i o n o f t h e a l l y l i c a l c o h o l and t h e a , e - u n s a t u r a t e d a l d e h y d e t o t h e k e t o a c i d V I I , which was a c c o m p l i s h e d by s i m u l t a n e o u s o x i d a t i o n with t h e Jones


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reagent ( 1 4 ) . While a d m i t t i n g t h a t t h e r e were problems with t h i s r e a c t i o n , S i h e t a l . r e p o r t e d y i e l d s o f 45-55% o f c r u d e p r o d u c t . Our r e s u l t s were not as good, with y i e l d s o n l y i n t h e range o f 10-30%. The 30% y i e l d s were o b t a i n e d o n l y when a double ( o r t r i p l e ) d i s t i l l a t i o n o f crude V was c a r r i e d out t o g i v e hydroxy aldehyde o f 95% o r g r e a t e r p u r i t y f o r use i n t h e o x i d a t i o n s t e p . The a c i d ( V I I ) formed i n t h e Jones o x i d a t i o n is r e a d i l y s e p a r a t e d from t h e n o n a c i d i c o r g a n i c m a t e r i a l by e x t r a c t i o n o f t h e e t h e r l a y e r with NaHC03 s o l u t i o n . The m a t e r i a l not e x t r a c t e d by NaHC03 ( n e u t r a l o r g a n i c s ) was shown by NMR s p e c t r o s c o p y t o c o n s i s t o f p r i m a r i l y t h e keto a l d e h y d e V I . In our e x p e r i e n c e , t h e s t e r i c a l l y h i n d e r e d a l d e h y d e group was l a r g e l y untouched by t h e Jones r e a g e n t . The l o n g r e a c t i o n time (10 h) used by S i h e t a l . was r e q u i r e d t o cause o x i d a t i o n o f t h e a l d e h y d e group s i n c e o x i d a t i o n o f t h e a l c o h o l proceeds r e a d i l y and rapidly. However, t h i s l o n g exposure t o t h e J o n e s reagent caused byproduct f o r m a t i o n as was r e a d i l y a p p a r e n t from t h e NMR spectrum o f t h e crude a c i d i c p r o d u c t s , s i n c e s e v e r a l d i f f e r e n t methyl groups were e v i d e n t which were not a t t r i b u t a b l e t o V I I . Based on t h e s e r e s u l t s , a t w o - s t e p p r o c e d u r e f o r t h e o x i d a t i o n t o V I I , gave a s u b s t a n t i a l improvement o f y i e l d . In work r e p o r t e d p r e v i o u s l y ( 1 5 ) , a l k a l i n e s i l v e r ( I ) o x i d e gave t h e c r u d e a c i d i n 72% y i e l d . The r e a c t i o n was exothermic and r a p i d and t h e crude p r o d u c t had o n l y a small p e r c e n t a g e o f b y p r o d u c t s as shown by NMR. The f a c i l i t y o f o x i d a t i o n o f VI by Ag?0 was unexpected s i n c e e a r l i e r workers (16) had o b t a i n e d low y i e l d s (30-40%) i n o x i d a t i o n s o f a , 3 - u n s a t u r a t e d a l d e h y d e s , and we had observed y i e l d s o f about 20% i n t h e room t e m p e r a t u r e o x i d a t i o n s o f e - c y c l o c i t r a l and V w i t h Ag2Û. The extended c o n j u g a t i o n p r o v i d e d by t h e k e t o group appears t o be t h e a c t i v a t i n g i n f l u e n c e f o r t h e f a c i l e o x i d a t i o n o f VI by Ag20. The r e l a t i v e p u r i t y o f t h e product was a n t i c i p a t e d s i n c e i t is known t h a t Ag2Û does not a t t a c k c a r b o n - c a r b o n double bonds. Using the t w o - s t e p p r o c e d u r e and combining t h e a c i d produced i n t h e Jones o x i d a t i o n s t e p w i t h t h a t produced by Ag2Û o x i d a t i o n , t o t a l y i e l d s o f 70-85% o f a c i d VII were o b t a i n e d . E s t e r i f i c a t i o n o f t h e a c i d ( V I I ) t o produce V I I I proceeded smoothly as d e s c r i b e d by S i h (8) and no attempt was made t o modify t h i s s a t i s f a c t o r y procedure. B r o m i n a t i o n o f V I I I t o produce IX was q u a n t i t a t i v e as d e s c r i b e d by S i h and no f u r t h e r m o d i f i c a t i o n was necessary. C l o s u r e o f t h e B - r i n g i n s t r i g o l i n v o l v e s t h e use o f d i m e t h y l malonate t o g i v e t h e k e t o - e n o l m i x t u r e X which we o b t a i n e d i n o n l y 30-55% y i e l d s r a t h e r t h a n t h e 86% r e p o r t e d by S i h ( 8 ) . Changes i n e x p e r i m e n t a l c o n d i t i o n s i n v o l v i n g t i m e and t e m p e r a t u r e d i d not improve t h e y i e l d p a s t 55%. P r e p a r a t i o n o f XI t y p i c a l l y produced 50-60% y i e l d s r a t h e r than t h e 72% r e p o r t e d by S i h ( 8 ) . C l o s u r e o f t h e C - r i n g and concomitant r e d u c t i o n o f t h e Α - r i n g k e t o group is a c o m p l i c a t e d r e a c t i o n , g i v i n g a m i x t u r e which r e q u i r e s chromatography t o s e p a r a t e t h e isomers from t h e b y p r o d u c t s . For preparation of X I I , we have not y e t r e a l i z e d t h e y i e l d s r e p o r t e d by S i h . P r e p a r a t i o n o f X I I I proceeded as d e s c r i b e d by S i h (8) and y i e l d s o f about 85% ( r e p o r t e d 93%) were o b t a i n e d . The c o u p l i n g s t e p o f X I I I w i t h t h e bromobutenolide (XIV) (see F i g u r e 2) proceeded t o form a m i x t u r e o f s t r i g o l and e p i s t r i g o l i n a p p r o x i m a t e l y t h e y i e l d s r e p o r t e d by S i h ( 8 ) . An attempt t o use t h e sodium e n o l a t e w i t h t h e


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b r o m o b u t e n o l i d e i n t h e manner o f Cassady and Howie ( 1 7 ) , r e s u l t e d i n a very low y i e l d o f t h e s t r i g o l i s o m e r s , d e s p i t e t h e T a c t t h a t t h i s method is more e f f e c t i v e f o r f o r m a t i o n o f t h e a n a l o g s . The D - r i n g o f s t r i g o l is p r e p a r e d i n a s i x s t e p sequence. The f i r s t t h r e e s t e p s a r e O r g a n i c S y n t h e s i s p r e p a r a t i o n s (18) and i n v o l v e ; (1) c o n v e r s i o n o f 4 , 4 - d i m e t h o x y - 2 - b u t a n o n e t o m e t h y l - 5 , 5 d i m e t h o x y - 3 - m e t h y l - 2 , 3 - e p o x y p e n t a n o a t e by t h e a c t i o n o f methyl c h l o r o a c e t a t e and sodium e t h o x i d e ; (2) c o n v e r s i o n o f t h e e p o x i d e t o m e t h y l - 3 - m e t h y l - 2 - f u r o a t e by p r o l o n g e d h e a t i n g a t 160° w i t h d i s t i l l a t i o n o f r e l e a s e d m e t h a n o l ; and (3) h y d r o l y s i s o f t h e e s t e r t o 3 - m e t h y l - 2 - f u r o i c a c i d (XV) by t h e a c t i o n o f sodium h y d r o x i d e f o l l o w e d by a c i d i f i c a t i o n . The next t h r e e s t e p s i n v o l v e ; (4) p h o t o o x y g e n a t i o n (19) o f XV i n e t h a n o l ( o r methanol) t o g i v e t h e a l k o x y b u t e n o l i d e ( X V I ) ; (5) h y d r o l y s i s by c o n c e n t r a t e d HC1 t o t h e h y d r o x y b u t e n o l i d e ( X V I I ) ; and (6) b r o m i n a t i o n o f XVII by t h e use o f c a r b o n t e t r a b r o m i d e i n t h e p r e s e n c e o f t r i p h e n y l p h o s p h i n e (8) t o form t h e bromobutenolide ( X I V ) .

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3

XIV

In our l a b o r a t o r y , we found t h a t r e a c t i o n o f XV w i t h o t h e r a l c o h o l s such as m e t h a n o l , p r o p a n o l , i s o - p r o p a n o l , and butanol gave y i e l d s o f 60-80% o f XVI which were comparable t o e t h a n o l and r e q u i r e d about t h e same r e a c t i o n time o f 35-45 h o u r s . For p r e p a r a t i o n o f X V I , none o f t h e s e a l c o h o l s o f f e r e d any p a r t i c u l a r advantage over e t h a n o l , but t h e h y d r o l y s i s ( i n d i l u t e HC1) o f t h e m e t h o x y b u t e n o l i d e (XVIb) proceeded more r a p i d l y ( 4 - 8 h r s . ) t h a n t h a t o f t h e e t h o x y b u t e n o l i d e (XVIa) which can r e q u i r e up t o 24 h r s f o r complete h y d r o l y s i s . A l s o i n t h e h y d r o l y s i s o f XVIb t h e p r o d u c t was c l e a n e r thus g i v i n g a b e t t e r y i e l d o f X V I I . In e a r l i e r work ( 1 2 ) , i t was shown t h a t a c t i v i t y as a witchweed seed g e r m i n a t i o n s t i m u l a n t o c c u r r e d with j u s t t h e D - r i n g o f s t r i g o l , i n p a r t i c u l a r f o r X V I a . I t was o f i n t e r e s t then t o p r e p a r e s e v e r a l a l k o x y b u t e n o l i d e s (XVI) for testing. Some can be p r e p a r e d by p h o t o - o x y g e n a t i o n as s t a t e d


422


above. Some t h a t c o u l d n o t , such as t h e b e n z y l , a l l y l , and l a u r y l d e r a t i v e s , were p r e p a r e d from t h e h y d r o x y b u t e n o l i d e (XVII) by r e a c t i o n with t h e a p p r o p r i a t e a l c o h o l i n benzene i n t h e presence o f c a t a l y t i c amounts o f p - t o l u e n e s u l f o n i c a c i d . The e t h e r i f i c a t i o n r e a c t i o n ( o r p s e u d o e s t e r i f i c a t i o n r e a c t i o n ) proceeds w i t h t h e s p l i t t i n g out o f water which a z e o t r o p e s with t h e benzene and is

XVII

XVI

c o l l e c t e d i n a Dean-Stark t r a p . The f o l l o w i n g a l c o h o l s were s u c c e s s f u l l y employed i n t h i s r e a c t i o n : η - p r o p y l , i s o - p r o p y l , c y c l o h e x y l , l a u r y l , a l l y l , and b e n z y l . P h e n o l , t r i phenyl c a r b i n o l , and t - b u t y l a l c o h o l d i d not g i v e t h e d e s i r e d a l k o x y b u t e n o l i d e s . Triphenyl c a r b i n o l and t - b u t y l a l c o h o l a r e e v i d e n t l y t o o b u l k y s t e r i c a l l y and w i l l not f o r m X V I . The t - b u t y l d e r i v a t i v e can be formed by t h e photooxygenation r e a c t i o n . The use o f t r i f l u o r o a c e t i c a n h y d r i d e as a s p e c i f i c c a t a l y s t f o r e s t e r i f i c a t i o n w i t h phenols (20) was attempted but was u n s u c c e s s f u l . In some o f the e t h e r i f i c a t i o n r e a c t i o n s , t h e b u t e n o l i d e dimer XVIII was observed as a byproduct i n y i e l d s up t o 40%. The dimer

was a l s o observed i n t h e h y d r o l y s i s o f XVIb when t h e volume o f HC1 became t o o low and t h e m i x t u r e o v e r h e a t e d . The dimer was f i r s t o b s e r v e d i n our e f f o r t s t o m e s y l a t e X V I I , but o n l y one isomer was isolated. In both t h e h y d r o l y s i s experiment and t h e e t h e r i f i c a t i o n reactions, a m i x t u r e o f two isomers o f XVIII r e s u l t e d which were s e p a r a b l e by s i l i c a gel column chromatography. The lower m e l t i n g isomer (LMI) had a mp of 141-142° whereas t h e p r e v i o u s l y i s o l a t e d h i g h e r m e l t i n g isomer (HMI) had a mp o f 180-182°. Elemental a n a l y s e s were s a t i s f a c t o r y f o r both i s o m e r s . When t h e NMR s p e c t r a o f t h e isomers were taken i n C D C I 3 , c l e a r d i f f e r e n c e s were o b s e r v a b l e s i n c e t h e H p r o t o n appeared a t 66.97 f o r LMI and at 66.87 f o r HMI w h i l e t h e H p r o t o n s d i f f e r e d by O.18 ppm (66.02 f o r LMI v s . 66.20 f o r HMI). When t h e NMR s p e c t r a o f t h e two isomers were t a k e n i n c^-acetone no d i f f e r e n c e s i n chemical s h i f t o f t h e s e p r o t o n s were o b s e r v e d . In an e f f o r t t o form t h e dimer as t h e major p r o d u c t and t o determine what e f f e c t t h e t e m p e r a t u r e o f r e a c t i o n had on t h e r a t i o o f HMI t o L M I , t h e h y d r o x y b u t e n o l i d e XVII was heated t o r e f l u x i n benzene (bp = 8 0 . 1 ° C ) , t o l u e n e (bp = 1 1 0 . 6 ° C ) , and x y l e n e ( m i x t u r e bp = 137-144°C) i n t h e p r e s e n c e o f c a t a l y t i c p - t o l u e n e s u l f o n i c a c i d 2

1


28.


423


w h i l e m o n i t o r i n g water e v o l u t i o n w i t h a Dean-Stark t r a p . The y i e l d o f dimer XVIII was 50% i n benzene, 98% i n t o l u e n e , and 99% i n x y l e n e . The p e r c e n t a g e s o f t h e HMI and LMI i n t h e r e a c t i o n m i x t u r e were d e t e r m i n e d by NMR s p e c t r o s c o p y i n C D C I 3 and found t o be r e l a t i v e l y c o n s t a n t a t 55-60% HMI and 40-45% LMI f o r a l l t h r e e s o l v e n t s . The h i g h e r temperatures d i d cause more complete r e a c t i o n but had l i t t l e e f f e c t on t h e r a t i o o f d i m e r s . The l i t e r a t u r e p r e p a r a t i o n (11) o f t h e t w o - r i n g a n a l o g o f s t r i g o l (2-RAS) i n v o l v e d r e a c t i n g t h e sodium e n o l a t e (XIX) w i t h t h e m e s y l a t e (XX) t o form 2-RAS ( X X I ) . In our work we found i t very d i f f i c u l t t o p r e p a r e and p u r i f y t h e m e s y l a t e . Low y i e l d s o f 2-RAS c o n t a m i n a t e d with XVIII r e s u l t e d .

S>^0 XIX

XX

XXI

In our e x p e r i e n c e , b e t t e r r e s u l t s were o b t a i n e d u s i n g t h e method o f Cassady and Howie (17) t h a n by t h e m e s y l a t e r o u t e . Thus t h e sodium e n o l a t e (XIX) is r e a c t e d w i t h t h e bromobutenolide (XIV) i n a c e t o n i t r i l e t o form t h e 2-RAS (XXI) i n 50-60% c r u d e y i e l d s which a f t e r column chromatography p r o v i d e d 20-30% o f X X I . S i m i l a r y i e l d s were o b t a i n e d when t e t r a h y d r o f u r a n (THF) was used as t h e s o l v e n t ,

.CH

3

ONa*

XXI XIX

XIV

but improved y i e l d s and c l e a n e r p r o d u c t s r e s u l t e d when t h e r e a c t i o n was conducted i n hexamethyl p h o s p h o r i c t r i ami de (HPT) o r o t h e r p o l a r a p r o t i c s o l v e n t s such as d i m e t h y l s u l f o x i d e (DMSO) o r d i m e t h y l formamide (DMF). Crude y i e l d s c o u l d not be determined s i n c e i t is very d i f f i c u l t t o remove t h e l a s t t r a c e s o f t h e s e h i g h b o i l i n g s o l v e n t s , but column chromatography o f t h e o i l y r e s i d u e s p r o v i d e d 30-40% o f r e l a t i v e l y pure 2-RAS which was t h e n amenable t o r e c r y s t a l lization. The p o l a r a p r o t i c s o l v e n t s o f f e r e d t h e advantages o f a c l e a n e r product which r e q u i r e d l e s s chromatography and t h e r e s u l t i n g h i g h e r y i e l d s o f 2-RAS. A n o t h e r two r i n g a n a l o g o f s t r i g o l was p r e p a r e d i n a s i m i l a r manner from t h e sodium e n o l a t e o f α - v a l e r o l a c t o n e (XXII) and X I V . T h e r e is a methyl group a t t h e 5 - p o s i t i o n o f t h e r i n g which would c o r r e s p o n d t o t h e C - r i n g o f s t r i g o l , so t h e s h o r t h a n d f o r t h i s compound is Me-2-RAS ( X X I I I ) . Johnson and co-workers (21) had


424


XXIII r e p o r t e d t h i s compound as an o i l . We were a b l e t o i s o l a t e i t as a s o l i d w i t h a wide mp range which gave a good elemental a n a l y s i s , which is i n d i c a t i v e o f a m i x t u r e o f d i s a s t e o m e r s . E f f o r t s t o reduce t h e mp range have t h u s f a r been u n s u c c e s s f u l . Polar aprotic s o l v e n t s d i d not help i n i n c r e a s i n g y i e l d o r p r o v i d i n g a c l e a n e r product. Attempts t o p r e p a r e s e v e r a l o t h e r 2-RAS d e r i v a t i v e s have t h u s f a r been u n s u c c e s s f u l . Summary In p r e p a r a t i o n f o r s c a l e - u p o f t h e s t r i g o l s y n t h e s i s d e s c r i b e d by S i h ( 8 ) , e f f o r t s were made t o improve t h e y i e l d o f some o f t h e seven s t e p s i n v o l v e d i n t h e scheme. Of t h e s e s t e p s , n i n e a r e s a t i s f a c t o r y from t h e s t a n d p o i n t o f y i e l d and e x p e r i m e n t a l c o n d i t i o n s . For three o f t h e s t e p s , we have improved t h e y i e l d and/or e x p e r i m e n t a l c o n d i t i o n s such t h a t t h e y i e l d o f ( + J - s t r i g o l would be r a i s e d t o 2.85% o v e r a l l from c i t r a l r a t h e r t h a n 1.53% based on S i h ' s p r o c e d u r e and reported y i e l d s . Improvements were d e v e l o p e d p r e p a r a t i o n o f a - c y c l o c i t r a l ( I I I ) , t h e o x i d a t i o n o f t h e hydroxyaldehyde (V) t o t h e k e t o a c i d ( V I I ) , and f o r t h e p r e p a r a t i o n o f t h e h y d r o x y b u t e n o l i d e (XVII). F o r t h e r e m a i n i n g f i v e s t e p s , o u r attempts t o change e x p e r i mental c o n d i t i o n s have f a i l e d t o improve, and i n most cases t o even o b t a i n , t h e y i e l d s r e p o r t e d i n t h e l i t e r a t u r e ( 8 ) . We have c o n s i d e r e d t h e p r e p a r a t i o n o f s t r i g o l a n a l o g s and determined t h e c o n d i t i o n s and l i m i t a t i o n s f o r t h e p r e p a r a t i o n o f a s e r i e s o f a l k o x y b u t e n o l i d e s (XVI) and a b u t e n o l i d e dimer ( X V I I I ) . Modificat i o n o f t h e l i t e r a t u r e p r o c e d u r e (11) t o e l i m i n a t e t h e use o f t h e m e s y l a t e (XX) and t h e use o f p o l a r a p r o t i c s o l v e n t s gave b e t t e r y i e l d s o f t h e 2-RAS ( X X I ) . Acknowledgments The a u t h o r s wish t o acknowledge t h e a b l e t e c h n i c a l Lynda H. W a r t e l l e .

assistance

of

Literature Cited 1. 2.

Shaw, W. C.; Shepard, D. R.; Robinson, E. L. and Sand, P. F. Weeds, 1962, 10, 182. Saunders, A. R. Union of South Africa Dep. Agric. Sci. Bull. No. 128, 56 pp.


28.



425

3. Pavlista, A. D. Weeds Today, 1980, 11(2), 19. 4. Brown, R. Encycl. Plant Physio., 1965, 15, 925. 5. Cook, C. E.; Whichard, L. P.; Turner, B.; Wall, M. E. and Egley, G. H. Science, 1966, 154, 1189. 6. Cook, C. E.; Whichard, L. P.; Wall, M. E.; Egley, G. H.; Coggan, P.; Luban, P. A. and McPhail, A. T. J. Am. Chem. Soc., 1972, 94, 6198. 7. Heather, J. B.; Mittal, R. S. D.; and Sih, C. J. J. Am. Chem. Soc., 1974, 96, 1976. 8. Heather, J. B.; Mittal, R. S. D.; and Sih, C. J. J. Am. Chem. Soc., 1976, 98, 3661. 9. MacAlpine, G. Α.; Raphael, R. Α.; Shaw, Α.; Taylor, A. W. and Wild, H. J. J. Chem.Soc.,Chem. Commun., 1974, 1834. 10. MacAlpine, G. Α.; Raphael, R. Α.; Shaw, Α.; Taylor, A. W. and Wild, H. J. J. Chem.Soc.,Perkin T. I, 1976, 410. 11. Johnson, A. W.; Rosebery, G. and Parker, C. Weed Res., 1976, 16, 223. 12. Pepperman, A. B; Connick, W. J. Jr.; Vail, S. L.; Worsham, A. D.; Pavlista, A. D., and Moreland, D. E. Weed Sci., 1982, 30, 561. 13. Gedye, R. N.; Arora, P. C. and Deck, K. Can. J. Chem., 1971, 49, 1764. 14. Bowden, K.; Heilbron, I. M.; Jones, E. R. H. and Weedon, B. C. L. J. Chem.Soc.,1946, 39. 15. Pepperman, A. B. J. Org. Chem., 1981, 46, 5039. 16. Thomason, S. C. and Kubler, D. G. J. Chem. Educ., 1968, 45, 546. 17. Cassady, J. M. and Howie, G. A. J. Chem.Soc.,Chem. Commun., 1974, 512. 18. Burness, D. M. Org. Syn., Coll. Vol. IV, N. Rabjohn, Ed. John Wiley and Sons, Inc., New York, 1963, 628, 649. 19. Farina, F. and Martin, M. V. An. Quim., 1971, 67, 315. 20. Bourne, E.J.,Stacey, M., Tatlow, J. C. and Tedder, J. M. J. Chem.Soc.,1949, 2976. 21. Johnson, A. W.; Gowda, G.; Hassanali, Α.; Knox, J.; Monaco, S.; Razave, Z. and Rosebery, G. J. Chem.Soc.,Perkin I, 1981, 1734. RECEIVED August 6, 1984


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