The Chemistry of Allelopathy - American Chemical Society


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Strigol Syntheses and Related Structure-Bioactivity Studies SIDNEY L. VAIL, OLIVER D. DAILEY, JR., W.J.CONNICK, JR., and A. B. PEPPERMAN, JR. Southern Regional Research Center, Agricultural Research Service, U.S. Department of Agriculture, New Orleans, LA 70179

The a b i l i t y of some chemicals to stimulate seed germination is well known. The synthesis of s t r i g o l , its precursors, and analogs has attracted considerable attention because of the very high a c t i v i t y of strigol as a germination stimulant f o r seeds of some parasitic weeds. Strigol has been isolated only from the root exudate of a nonhost plant (cotton) and does not occur commonly i n nature. Therefore, there is no known natural source at a useful level f o r i s o l a t i o n and p u r i f i c a t i o n of the compound. Considerable effort has been expended on alternate synthetic routes and improvements in the methods of preparation of amounts needed f o r field and laboratory research. Compounds other than strigol from host plants produce allelopathic effects that stimulate p a r a s i t i c seed germination and ultimately result i n extensive crop damage from the parasitic weeds. None of these other naturally occurring a l l e l o p a t h i c compounds have been isolated and i d e n t i f i e d . However, some correlations between chemical structure and biological a c t i v i t y can be made on the basis of prior work. Strigol is a very useful compound for basic research on seed germination and plant growth, but there are many more promising options f o r solution of practical problems related to the induced germination of dormant seeds of parasitic weeds.

There a r e numerous examples o f a l l e l o p a t h y i n v o l v i n g seed o f p a r a s i t i c weeds t h a t r e q u i r e a chemical s i g n a l f o r g e r m i n a t i o n . A l l e l o p a t h i c c h e m i c a l s a r e g e n e r a l l y r e l e a s e d by t h e h o s t p l a n t at times f a v o r a b l e f o r the 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 the parasite. S i n c e p a r a s i t i c weeds can s i g n i f i c a n t l y reduce crop y i e l d s , a number o f a g r i c u l t u r a l p r a c t i c e s have been d e v i s e d t o reduce t h i s l o s s . Some o f t h e more e f f e c t i v e methods t o e r a d i c a t e o r reduce the e f f e c t s o f these p a r a s i t e s a r e t o p l a n t nonhost crops which s t i m u l a t e s u i c i d a l g e r m i n a t i o n o r t o a p p l y s y n t h e t i c 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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THE CHEMISTRY OF ALLELOPATHY

germination stimulants to the f i e l d growth o f the p a r a s i t e s U - 3 ) . Isolation,

Identification,

a t an i n a p p r o p r i a t e time f o r t h e

and E a r l y S y n t h e t i c

Schemes f o r

Strigol

( + ) - S t r i g o l is a n a t u r a l p r o d u c t w i t h u n u s u a l l y s t r o n g p r o p e r t i e s a g e r m i n a t i o n s t i m u l a n t f o r p a r a s i t i c weeds of t h e genera S t r i g a (witchweed) and Orobanche (broomrape).

as

The s t r u c t u r e o f s t r i g o l is shown above w i t h the r i n g s i d e n t i f i e d as A, B, C, and D f o r f u r t h e r r e f e r e n c e . Because t h e t o t a l s y n t h e s i s of the compound f o r the p r o d u c t i o n o f even small amounts has proven t o be e x c e e d i n g l y d i f f i c u l t , i t is e s t i m a t e d t h a t o n l y about f i v e grams o f pure m a t e r i a l had been i s o l a t e d p r i o r t o 1984. The s y n t h e s e s o f s t r i g o l , i t s p r e c u r s o r s , and a n a l o g s have thus a t t r a c t e d c o n s i d e r a b l e a t t e n t i o n , and s e v e r a l papers p r e s e n t e d i n t h i s symposium d i s c u s s v a r i o u s f a c e t s o f the p r o b l e m . The compound, o r i g i n a l l y i s o l a t e d from the root exudate o f c o t t o n (a nonhost p l a n t ) ( £ ) , has not been found t o o c c u r commonly i n n a t u r e . A total s y n t h e s i s appears t o be n e c e s s a r y to o b t a i n u s e f u l amounts. The known (.5,6.) s y n t h e t i c paths a r e not c o m p l e t e l y s a t i s f a c t o r y f o r p r o d u c t i o n o f the r e q u i r e d amounts f o r f i e l d t e s t i n g as a g e r m i n a t i o n s t i m u l a n t or f o r o t h e r u s e s . C o n s i d e r a b l e e f f o r t has been expended on a l t e r n a t e s y n t h e t i c r o u t e s , improvements i n the o r i g i n a l s y n t h e t i c scheme, and i n t h e s y n t h e s i s o f a n a l o g s . Many o f t h e s e a n a l o g s , t h e i r p r e c u r s o r s , as w e l l as o t h e r o r g a n i c compounds a r e a l s o e f f e c t i v e g e r m i n a t i o n s t i m u l a n t s and have been s t u d i e d i n both t h e f i e l d and i n the l a b o r a t o r y . Such s t u d i e s w i t h s t r i g o l and r e l a t e d compounds f o r a l l e l o p a t h i c p r o p e r t i e s have been l i m i t e d p r i m a r i l y to t h e i r e f f e c t s upon s e l e c t e d p a r a s i t i c weed seeds ( 2 i 10). The comments i n t h i s paper c o n c e r n i n g b i o a c t i v i t y o f t h e compounds are s i m i l a r l y l i m i t e d , but assays o f t h e i r e f f e c t s upon o t h e r c r o p and weed seeds w i t h v a r y i n g g e r m i n a t i o n r e q u i r e m e n t s a r e i n progress.

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

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V A I L ET A L .

Effects

Strigol: Syntheses and Structure-Bioactivity Relationship

of Various

Chemicals on G e r m i n a t i o n o f S e l e c t e d

447

Seed

S t r i g a a s i a t i c a , one o f many s p e c i e s o f S t r i g a found commonly i n t h e E a s t e r n Hemisphere, was a l s o d i s c o v e r e d i n North and South C a r o l i n a i n 1956. The seed may remain dormant i n t h e ground f o r many y e a r s u n t i l s t i m u l a t e d by a chemical or c h e m i c a l s r e l e a s e d by c e r t a i n plants. The germinated seed r a p i d l y d e v e l o p s a r a d i c l e , r e c e i v e s a second chemical s i g n a l from the h o s t , and i n a r e l a t i v e l y s h o r t p e r i o d o f time p a r a s i t i z e s t h e host p l a n t . The h o s t , e . g . c o r n , s o r ghum, s u g a r c a n e , r i c e or numerous f o r a g e crops and weeds b e l o n g i n g t o t h e g r a s s f a m i l y , g e n e r a l l y appears d r o u g h t - s t r i c k e n and o f t e n d i e s i f the p a r a s i t i c p l a n t is not removed. Crop l o s s e s o f t e n have approached 100% i n h e a v i l y i n f e s t e d f i e l d s ( 1 - 3 ) . The g e r m i n a t i o n s t i m u l a n t o r s t i m u l a n t s from host p l a n t s have not y e t been i d e n t i f i e d , but r e s e a r c h on i s o l a t i o n and i d e n t i f i c a t i o n o f t h e s e a l l e l o p a t h i c compounds c o n t i n u e s . Other nonhost p l a n t s , such as c o t t o n , a l s o r e l e a s e c h e m i c a l s which s t i m u l a t e t h e g e r m i n a t i o n o f witchweed seed and t h e s e c r o p s can r e p l a c e t h e c e r e a l crops i n w i t c h w e e d - i n f e c t e d f i e l d s . I f no a c c e p t a b l e host is p r e s e n t , t h e witchweed p l a n t is unable t o mature and produce s e e d . The importance o f c e r e a l crops as a s t a p l e food i n underdeveloped count r i e s makes growth o f nonhost c r o p s o n l y p a r t i a l l y a c c e p t a b l e , and t h e r e are numerous w i l d hosts t h a t a l l o w t h e witchweed t o g e r m i n a t e , mature, and produce more seed ( s e v e r a l thousand seeds can be produced by a s i n g l e p l a n t ) . N e v e r t h e l e s s , a p p l i c a t i o n o f e i t h e r n a t u r a l or s y n t h e t i c s t i m u l a n t s i n t h e absence o f a host p l a n t is an e f f e c t i v e way o f r e d u c i n g and e v e n t u a l l y e l i m i n a t i n g the witchweed p r o b l e m . In a r e v i e w , Morel a n d , e t al_. ( 1 1 ) r e p o r t e d t h a t t h i o u r e a , a l l y l t h i o u r e a , D - x y l u l o s e , sodium d i e t h y l d i t h i o c a r b a m a t e , L - m e t h i o n i n e , n - p r o p y l - d i - n - p r o p y l t h i o l c a r b a m a t e , twelve 6 - ( s u b s t i t u t e d ) p u r i n e s , and two coumarin d e r i v a t i v e s s t i m u l a t e d S t r i g a seed g e r m i n a t i o n . None o f these compounds has been r e p o r t e d i n n a t u r a l s t i m u l a n t p r e parations. S i m i l a r l y , R i o p e l ( 2 J i n a more r e c e n t review noted t h a t many compounds promote or i n h i b i t seed g e r m i n a t i o n . E t h y l e n e is an e f f e c t i v e g e r m i n a t o r , but i t s use i n under developed c o u n t r i e s is minimal. Many a u t h o r s note t h a t t e s t c o n d i t i o n s have a s t r o n g i n f l u e n c e on r e s u l t s , and a c t i v i t y v a r i e s w i d e l y w i t h a v a r i a t i o n i n c o n c e n t r a t i o n of the germination stimulant. A r e l a t i v e l y high c o n c e n t r a t i o n of a s t i m u l a n t o f t e n causes i n h i b i t i o n o f g e r m i n a t i o n . Preconditioni n g t h e seed i n t h e presence o f a g e r m i n a t i o n s t i m u l a n t can a l s o cause i n h i b i t i o n o f g e r m i n a t i o n . The apparent n e c e s s i t y o f a second s i g n a l f o r h a u s t o r i a l i n i t i a t i o n p r o v i d e s another p o s s i b i l i t y f o r chemical c o n t r o l . R i o p e l and coworkers ( 2 , 1 2 - 1 4 ) observed a few y e a r s ago t h a t gum t r a g a c a n t h , a f o l i a r e x t r a c t , was a very potent h a u s t o r i a l i n i t i a t o r . Two a c t i v e compounds were i s o l a t e d (Xenognosin A shown below, and a f l a v o n o i d with s i m i l a r s t r u c t u r e ) . The s t r u c t u r a l f e a t u r e s r e q u i r e d f o r h a u s t o r i a l f o r m a t i o n i n c l u d e a meta r e l a t i o n s h i p o f hydroxyl and methoxyl groups and an a l k y l b r a n c h i n g o r t h o t o the methoxy substituent.

American Chemical Society Library 1155 16th St., H.W. Thompson; The Chemistry Allelopathy Washington, O.C.of20036

ACS Symposium Series; American Chemical Society: Washington, DC, 1985.

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A number o f a n a l o g s were prepared t o a r r i v e at t h e above relationship. However, the i d e n t i t y o f the c h e m i c a l s needed f o r h a u s t o r i a l i n i t i a t i o n and produced by any c e r e a l crop remains unknown. The p o s s i b i l i t y o f u s i n g a chemical t o suppress or c o n f u s e h a u s t o r i a l f o r m a t i o n has been r e c o g n i z e d , but o n l y a l i t t l e work has been done on t h i s a s p e c t o f c o n t r o l . The germinated seed w i l l d i e i n a s h o r t time i f h a u s t o r i a l i n i t i a t i o n and attachment a r e not realized. S t u d i e s t o c o r r e l a t e m o l e c u l a r s t r u c t u r e o f t h e compound w i t h b i o a c t i v i t y i n seed g e r m i n a t i o n i n the soil are d i f f i c u l t . I t is u n c e r t a i n whether t h e a c t i v i t y is e l i c i t e d from compounds i n an exudate o f t h e p l a n t or m e t a b o l i t e s o f compounds i n the e x u d a t e . In g e n e r a l , i t is assumed t h a t t h e u n a l t e r e d exudate c o n t a i n s t h e a c t i v e compound. The s i t u a t i o n is f u r t h e r c o m p l i c a t e d by the p r e s e n c e of numerous compounds i n t h e exudate t h a t may p l a y o n l y a secondary r o l e (but a n e c e s s a r y o n e ) , y e t possess no a c t i v i t y when s e p a r a t e d from the e x u d a t e . S t u d i e s have c o n f i r m e d t h a t some compounds a c t i v e i n the l a b o r a t o r y do not possess the i n d i c a t e d a c t i v i t y i n the f i e l d . R e s u l t s from f i e l d s t u d i e s a r e d i f f i c u l t t o a s s e s s because t h e s t a t e of the seed i n the soil v a r i e s and g e r m i n a t i o n is l e s s l i k e l y t o o c c u r i f seed a r e not p r o p e r l y c o n d i t i o n e d . G e r m i n a t i o n is i n h i b i t e d by m a t e r i a l s o r c o n d i t i o n s t h a t are d i f f i c u l t o r i m p o s s i b l e t o c o n t r o l i n f i e l d s t u d i e s a n d , as noted p r e v i o u s l y , h i g h c o n c e n t r a t i o n s of germination stimulants often r e s u l t in i n h i b i t i o n of germination. F u r t h e r , seed counts i n soil a r e very d i f f i c u l t , e s p e c i a l l y because o f t h e small s i z e of S t r i g a s e e d . Thus, some t h e o r e t i c a l q u e s t i o n s i n v o l v i n g g e r m i n a t i o n i n the soil may never be answered s a t i s f a c t o r i l y even though s o l u t i o n s t o the p r a c t i c a l problems o f c o n t r o l have or w i l l be a c h i e v e d . R e s i s t a n t V a r i e t i e s o f Cereal Crops. S e v e r a l v a r i e t i e s of c e r e a l crops possess r e s i s t a n c e t o some s p e c i e s o f witchweed which is a t t r i b u t e d t o t h e absence o f an e f f e c t i v e chemical s t i m u l a n t i n t h e r o o t exudate o f t h e crop p l a n t . W i l l i a m s (15) compared t h e e f f e c t s of r o o t exudate from a r e s i s t a n t and a s u s c e p t i b l e v a r i e t y o f sorghum (grown i n sand) on g e r m i n a t i o n o f S t r i g a a s i a t i c a seed ( d e s i g n a t e d S t r i g a l u t e a by W i l l i a m s ) . The aqueous e l u e n t s were compared at f u l l s t r e n g t h and at d i l u t e d s t r e n g t h s . The f u l l s t r e n g t h e l u e n t from t h e r e s i s t a n t v a r i e t y produced o n l y a low l e v e l of g e r m i n a t i o n and d i l u t i o n reduced g e r m i n a t i o n l e v e l s almost t o zero. S i m i l a r s t u d i e s w i t h e l u e n t from t h e s u s c e p t i b l e v a r i e t y produced a h i g h l e v e l o f g e r m i n a t i o n at f u l l s t r e n g t h and a f t e r dilution. These s t u d i e s have been extended by P a r k e r , et al_. ( 1 6 ) , and r o o t exudates o f 24 sorghum v a r i e t i e s were s c r e e n e d f o r a c t i v i t y i n g e r m i n a t i o n o f S. a s i a t i c a s e e d . In a d d i t i o n , r o o t exudates o f 15

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

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Strigol: Syntheses and Structure- Bioactivity Relationship

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sorghum v a r i e t i e s were t e s t e d w i t h S. h e r m o n t h i c a , S . a s i a t i c a , and S. d e n s i f l o r a s e e d . There appeared t o be a good c o r r e l a t i o n between t h e g e r m i n a t i o n responses o f S. hermonthica and S . a s i a t i c a , but g e r m i n a t i o n responses o f S. d e n s i f l o r a e x h i b i t e d l i t t l e o r no c o r r e l a t i o n with the other s p e c i e s . Some s u c c e s s e s have been a c h i e v e d i n b r e e d i n g c e r e a l c r o p s t h a t possess r e s i s t a n c e t o witchweed and a r e s u i t a b l e f o r commercial use (1_); however, i n d u c e d g e r m i n a t i o n o f witchweed seed u s i n g s y n t h e t i c c h e m i c a l s f o r c o n t r o l or e r a d i c a t i o n c o n t i n u e s as the more p r o m i s i n g approach t o t h e u l t i m a t e s o l u t i o n o f t h e p r o b l e m . However, as noted i n t h e above d i s c u s s i o n s , t h e chemical s t r u c t u r e s o f t h e n a t u r a l p r o ­ d u c t s from host p l a n t s r e s p o n s i b l e f o r g e r m i n a t i o n i n n a t u r e remain unknown. The root exudates o f host p l a n t s c o n t a i n many compounds t h a t may a c t s i n g l y o r i n c o m b i n a t i o n w i t h o t h e r m a t e r i a l s p r e s e n t to produce g e r m i n a t i o n . The problem is f u r t h e r c o m p l i c a t e d by t h e f a c t t h a t t h e a c t u a l s t i m u l a n t may be t h e product o f a chemical o r b i o l o g i c a l m o d i f i c a t i o n o f a component o r components o f t h e r o o t exudate i n t h e soil. Improvements i n t h e S y n t h e s i s o f S t r i g o l

and I t s Analogs

In the t o t a l s y n t h e s i s o f s t r i g o l , t h e f i r s t s e r i e s o f s t e p s i n v o l v i n g t h e Α - r i n g a r e o f primary importance i n t h e p r e p a r a t i o n o f l a r g e q u a n t i t i e s o f t h e compound. C l e a r l y , large quantities of t h e s e s t a r t i n g m a t e r i a l s a r e needed t o compensate f o r t h e l o s s e s i n y i e l d s in the l a t e r steps. Several separate i n v e s t i g a t i o n s ( 1 7 - 2 1 ) , not i n c l u d i n g t h o s e i n t h i s symposium, have been concerned p r i m a r i l y w i t h improvements i n t h i s phase o f t h e s y n t h e s i s . The procedures d e s c r i b e d i n t h i s symposium by Brooks and by Dai l e y r e p r e s e n t new s y n t h e t i c paths with s e v e r a l advantages f o r s c a l e d - u p s y n t h e s i s . The p r o c e d u r e s d e s c r i b e d by Pepperman o u t l i n e improvements o r m o d i f i c a t i o n s i n a path suggested by Si h (J5). S t r i g o l s y n t h e s i s has been completed by both Brooks and Pepperman u s i n g t h e new o r improved p r o c e d u r e s . Review o f C o u p l i n g R e a c t i o n s f o r C- and D - R i n g s . The c o u p l i n g o f the two l a c t o n e r i n g s is a s i m i l a r step i n the s y n t h e s i s o f s t r i g o l and s t r i g o l a n a l o g s . Y i e l d s and isomer d i s t r i b u t i o n a r e t h e primary considerations. The c o n f i g u r a t i o n about t h e double bond c o n n e c t i n g t h e C- and D - r i n g s of n a t u r a l l y - o c c u r r i n g s t r i g o l is E. ( 4 J ; t h e r e f o r e , i t is e s s e n t i a l t h a t r e a c t i o n schemes chosen t o form t h e enol e t h e r bond i n s y n t h e t i c a l l y - p r e p a r e d s t r i g o l , i t s i s o m e r s , and i t s analogs preserve t h e Ε s t e r e o c h e m i s t r y . The c o n f i g u r a t i o n can be e a s i l y determined by Ή NMR where the alkoxymethylene v i n y l p r o ­ t o n o f t h e 1 isomer o f many o f t h e s e compounds absorbs a t 6 7 . 3 - 7 . 6 , whereas t h e more h i g h l y s h i e l d e d 1 isomer p r o t o n absorbs a t 6 6 . 6 - 6 . 9 (5,6,22,23).

R e s e a r c h e r s i n t h i s f i e l d have u s u a l l y begun r i n g c o u p l i n g w i t h the p r e p a r a t i o n o f t h e sodium s a l t o f t h e hydroxymethylene (sodium e n o l a t e ) d e r i v a t i v e o f t h e l a c t o n e c o r r e s p o n d i n g o r analogous t o t h e fused r i n g p o r t i o n of the s t r i g o l molecule. T h i s d e r i v a t i v e has been p r e p a r e d u s i n g sodium h y d r i d e and methyl formate i n e t h e r a t room temperature under anhydrous c o n d i t i o n s . An a l t e r n a t i v e method i n v o l v e s t h e r e a c t i o n i n e t h e r o f m e t a l l i c sodium, m e t h a n o l , e t h y l f o r m a t e , and t h e l a c t o n e (S 9). In many c a s e s , t h e crude sodium 9

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THE CHEMISTRY OF ALLELOPATHY

e n o l a t e can be used i n f u r t h e r r e a c t i o n s w i t h o u t i s o l a t i o n , but a c i d i f i c a t i o n o f t e n g i v e s the hydroxymethylene l a c t o n e t h a t can be p u r i f i e d by r e c r y s t a l l i z a t i o n . The f i n a l r i n g c o u p l i n g r e a c t i o n is u s u a l l y an O - a l k y l a t i o n o f the sodium e n o l a t e w i t h a methyl s u l f o n a t e - , bromo-, o r c h l o r o b u t e n o l i d e i n a c e t o n i t r i l e o r an e t h e r s o l v e n t ( 8 , 2 2 - 2 4 ) . Use o f the methyl s u l f o n a t e d e r i v a t i v e is l e a s t p r e f e r r e d because o f i t s poor s t a b i l i t y ( 9 , 2 4 ) . The i s o l a t e d hydroxymethylene l a c t o n e can be a l l o w e d t o r e a c t w i t h the bromobutenolide u s i n g p o t a s s i u m c a r b o n a t e i n hexamethylphosphoric t r i a m i d e ( c a u t i o n : a potential carcinogen). These r e a c t i o n s a r e h i g h l y s e l e c t i v e f o r t h e d e s i r e d JE isomer o f s t r i g o l , i t s i s o m e r s , and a n a l o g s . I t has been p o s t u l a t e d {§) t h a t t h e JE isomer o f t h e hydroxymethylene l a c t o n e is t h e r m o d y n a m i c a l l y f a v o r e d because i t has t h e maximum s e p a r a t i o n o f t h e n e g a t i v e oxygen c e n t e r s . Correlations Germination

of Molecular Structure with B i o a c t i v i t y

i n Seed

E a r l i e r i n t h i s paper s t u d i e s were r e p o r t e d t h a t i n d i c a t e d c o r r e l a ­ t i o n o f the m o l e c u l a r s t r u c t u r e o f the compound w i t h b i o a c t i v i t y i n seed g e r m i n a t i o n i n l a b o r a t o r y t e s t s , as compared t o t e s t s performed i n the f i e l d , o f f e r d i s t i n c t advantages. Most o f what we know on t h i s s u b j e c t was o b t a i n e d from l a b o r a t o r y t e s t p r o c e d u r e s . Results from f i e l d t e s t s are a l s o dependent upon the s t a b i l i t y o f the com­ pound and p h y s i c a l f a c t o r s such as s o l u b i l i t y and a d s o r p t i o n i n t h e soil. Most o f t h e work on c o r r e l a t i o n o f m o l e c u l a r s t r u c t u r e w i t h b i o a c t i v i t y i n witchweed seed g e r m i n a t i o n has been produced by two groups ( 7 - 1 0 ) . J o h n s o n , e t a]_. ( 7 - 9 ) p r e p a r e d and e v a l u a t e d a l a r g e number o f s t r i g o l analogs and many approached the a c t i v i t y o f strigol. In many s t u d i e s by o t h e r s , t h e r e s u l t s o f t h e b i o a s s a y s are p r e s e n t e d , but the compounds from Johnson are d e s c r i b e d only by GR-number. GR-7 and - 2 4 , p r o b a b l y t h e more p r o m i s i n g o f t h e s e compounds, have been used i n e x t e n s i v e f i e l d s t u d i e s , and t h e i r s t r u c t u r e s a r e known. The work o f Pepperman and coworkers (10) is t a k e n as t h e b a s i s f o r t h i s s t r u c t u r e - a c t i v i t y d i s c u s s i o n because about t h i r t y com­ pounds were t e s t e d f o r t h e i r a c t i v i t y i n a b i o a s s a y t h a t i n v o l v e d o n l y one t y p e o f seed - S . a s i a t i c a . These compounds have been d i v i d e d i n t o groups a c c o r d i n g t o low, moderate, and h i g h a c t i v i t y i n the bioassay (Table I ) . C o n s i d e r a b l e a c t i v i t y is noted i n t h e twoand t h r e e - r i n g analogs o f s t r i g o l and i n the p r e c u r s o r s t h a t a r e s i m i l a r t o t h e A- and D - r i n g s i n t h e s t r i g o l . 3-Hydroxy-2,6,6t r i m e t h y l c y c l o h e x - l - e n e - l - c a r b o x a l d e h y d e (AB-4) has an a c t i v i t y e s s e n t i a l l y equal t o t h a t o f s t r i g o l . U n f o r t u n a t e l y , t h i s hydroxyaldehyde is u n s t a b l e and is r e a d i l y o x i d i z e d t o the l e s s a c t i v e a c i d (10). GR-24 has t h e h i g h e s t a c t i v i t y o f a l l o f J o h n s o n ' s compounds (9). I t is e s s e n t i a l l y s t r u c t u r a l l y i d e n t i c a l t o s t r i g o l except t h a t t h e Α - r i n g has been r e p l a c e d w i t h a phenyl i n the same p o s i ­ tion. The isomer o f GR-24 w i t h a phenyl r i n g a t t a c h e d t o t h e o t h e r nonbridgehead atoms o f t h e B - r i n g was found t o be l e s s a c t i v e . Cook et al_. (22) p r e p a r e d an a n a l o g o f GR-24 wherein one h y d r o x y l and one methyl group were on the a r o m a t i c r i n g and i n p o s i t i o n s i d e n t i c a l t o

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31.

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Bioactivity

Strigol: Syntheses and Structure-Bioactivity Relationship

451

Table I o f S t r i g o l , S t r i g o l A n a l o g s , . t h e i r P r e c u r s o r s , and R e l a t e d Compounds-

Number o r D e s i g n a t i o n ^

Activity-/

Structure

Low A c t i v i t y : 55% a t 10-4

AB-5

CH3CH3 COOH CH

A

SA-4

48% a t 10-5

SA-3

55% a t Ι Ο "

D-7

60% a t Ι Ο "

Moderate

5

Activity: 83% a t Ι Ο "

Epi-strigol AB-1

5

CH

3

CH

3

55% a t Ι Ο "

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

6

7

452

THE CHEMISTRY OF ALLELOPATHY

Table

I

(continued)

α

2-RAS

SA-2

XH, 61% a t 10-7

CI

<

62% a t 1 0 "

7

CI

3-RAS

(High

Melting)

66% a t 10-7

CH,

High

Activity:

3-RAS

(Low m e l t i n g )

60% a t 10-3

3-RAS

(Isomer

68% a t 10-8

Mixture)

D-l

"CH

40% a t 10-9 3

COOH AB-3

CHO CH

3

CH

D-2

60% a t 10-9

3

72% a t 10-10

CH CH 0"^ Ο 3

2

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

31.

VAIL ET AL.

Table

I

Strigol: Syntheses and Structure-Bioactivity Relationship

453

(continued)

Strigol

50% a t H T

AB-4

60% a t 1 0 "

1 1

— S . a s i a t i c a seed were c o n d i t i o n e d p r i o r t o t h e b i o a s s a y . Details on t h e b i o a s s a y and r e s u l t s o f a d d i t i o n a l b i o a s s a y s on these and o t h e r compounds were p u b l i s h e d ( 1 0 ) . —^See R é f . _10. AB r e f e r s t o p r e c u r s o r s o f t h e A-B r i n g s o f s t r i g o l . SA r e f e r s t o p r e c u r s o r s ( o r s i m i l a r compounds) o f s t r i g o l a n a l o g s . D r e f e r s t o precursors of the D-ring of s t r i g o l . 2-RAS is a two r i n g a n a l o g o f s t r i g o l and 3-RAS is a t h r e e r i n g a n a l o g . A mixt u r e o f isomers o f 3-RAS is a l s o known as GR-7. c/ — Numbers r e p o r t e d a r e a p e r c e n t g e r m i n a t i o n a t t h e shown c o n c e n t r a t i o n (1 χ 10M t o the exponent shown). Many o t h e r v a l u e s a r e shown i n t h e r e f e r e n c e d a r t i c l e ( 1 0 ) , but t h e v a l u e s r e c o r d e d i n t h i s paper r e p r e s e n t t h e h i g h e s t a c t i v i t y at t h e lowest c o n c e n t r a t i o n . There is a g r e a t deal o f v a r i a b i l i t y i n t h e r e s u l t s o f g e r m i n a t i o n t e s t s as noted by many r e f e r e n c e s i n t h i s t e x t . See a l s o r e f . 25 and 2 6 .

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454

THE CHEMISTRY OF ALLELOPATHY

those i n the Α - r i n g of s t r i g o l . The ^ - i s o m e r was s a i d t o have o n l y 2% o f the b i o l o g i c a l a c t i v i t y o f n a t u r a l s t r i g o l . Johnson and coworkers a l s o prepared s e v e r a l t w o - r i n g a n a l o g s and more t h r e e - r i n g a n a l o g s , but t h e s e compounds, e x c e p t f o r GR-7 ( 3 - R A S ) , have r e c e i v e d l i t t l e or no a t t e n t i o n . Many o f t h e t h r e e r i n g analogs had a c t i v i t i e s s i m i l a r t o GR-7 but reduced s t a b i l i t y and more d i f f i c u l t s y n t h e s e s o f t h e compounds appear t o be t h e major reasons f o r t h e i r l i m i t e d u s e . F o r example, the isomer o f G R - 7 , wherein t h e double bond is moved t o t h e o t h e r nonbridgehead atoms o f the B - r i n g , was found t o be s u s c e p t i b l e (as is GR-7) t o d e g r a d a t i o n by l i g h t and a l k a l i n e c o n d i t i o n s . There is no r e p o r t e d s e p a r a t i o n by Johnson and coworkers o f geo­ m e t r i c o r o p t i c a l isomers from t h e i r r e a c t i o n m i x t u r e s . Connick, Pepperman, and coworkers (10,24) and Cook e t a K (22) s e p a r a t e d g e o m e t r i c isomers i n t o t h e i r two d i a s t e r e o m e r i c racemates and noted d i f f e r e n c e s i n a c t i v i t y f o r the geometric isomers. Many o f t h e r e p o r t e d a c t i v i t i e s o f s t r i g o l - r e l a t e d compounds have been o b t a i n e d with mixtures of isomers. Both a p p l i e d and b a s i c a s p e c t s o f the use of c h e m i c a l s t o s t i m u ­ l a t e g e r m i n a t i o n o f seed c o n t i n u e . S t r i g o l is p r i m a r i l y o f b a s i c i n t e r e s t because i t is so a c t i v e i n t h e g e r m i n a t i o n o f some p a r a s i t i c plant seeds. Because o f q u a r a n t i n e s on the seed and r e s t r i c t i o n o f much o f t h e r e s e a r c h t o a f f e c t e d a r e a s , p r o g r e s s i n b a s i c s t u d i e s has been l i m i t e d . E f f o r t s a r e underway t o f i n d b i o a s s a y s o t h e r than s i m p l e witchweed g e r m i n a t i o n (27) so t h a t t h e complete b i o l o g i c a l and chemical s i g n i f i c a n c e o f s t r i g o l and i t s r e l a t e d compounds can be e v a l u a t e d . C o n t r o l o f witchweed and o t h e r p a r a s i t i c p l a n t s w i l l l i k e l y i n v o l v e an i n t e g r a t e d program o f b r e e d i n g r e s i s t a n t host c r o p s , s e l e c t e d a g r i c u l t u r a l p r a c t i c e s , and e f f e c t i v e use of chemicals. Much remains t o be a c c o m p l i s h e d i n t h e s e p a r a t i o n , i s o l a t i o n , and i d e n t i f i c a t i o n o f both n a t u r a l l y o c c u r r i n g and s y n t h e t i c b i o a c t i v e m a t e r i a l s e f f e c t i v e i n t h e g e r m i n a t i o n o f p a r a s i t i c weed s e e d s . S t r u c t u r e - a c t i v i t y s t u d i e s s u f f e r from the l a c k o f s e p a r a t i o n o f isomers i n most s y n t h e t i c samples. S t r i g o l is an i m p o r t a n t t o o l i n b a s i c s t u d i e s on the e f f e c t o f c h e m i c a l s on seed g e r m i n a t i o n , but i t is h i g h l y u n l i k e l y t h a t t h e compound w i l l meet p r a c t i c a l f i e l d

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Relationship

455

r e q u i r e m e n t s even i f t h e Α - r i n g s y n t h e s i s o p t i o n s , d i s c u s s e d above, are o p t i m i z e d and t o t a l l y s u i t a b l e f o r l a r g e s c a l e s y n t h e s i s . More l i k e l y , s m a l l e r , a c t i v e m o l e c u l e s and/or s t r i g o l a n a l o g s w i l l be used i n f i e l d p r o c e d u r e s f o r e r a d i c a t i o n o f p l a n t p a r a s i t e s .

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5. 6. 7. 8. 9.

10. 11.

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13. 14. 15. 16.

17. 18. 19. 20. 21. 22.

Ramaiah, K. W.; Parker, C.; Vasudera Rao, M. J.; Musselman, L. J. 1983. "Striga Identification and Control Handbook", Information B u l l e t i n No. 15, Patancheru, A. P., India: International Crops Research Institute for the Semi-Arid Tropics. Riopel, J. L. In "Vegetative Compatibility Responses i n Plants"; Moore, R. Ed.; Academic Press, New York, 1983, p. 13. Shaw, W. C.; Shepard, D. R.; Robinson, E. L.; Sand, P. F. Weeds, 1962, 10, 182. Cook, C. E.; Whichard, L. P.; Wall, M. E.; Egley, G. H.; Coggon, P.; Luhan, P. Α.; McPhail, A. T. J. Am. Chem. Soc. 1972, 94, 6198. Heather, J. B.; M i t t a l , R. S. D.; Sih, C. J. J. Am. Chem. Soc. 1976, 98, 3661. MacAlpine, G. Α.; Raphael, R. Α.; Shaw, Α.; Taylor, A. W.; Wild, H. J. J. Chem. Soc., Perkin Trans. 1, 1976, 410. Johnson, A. W.; Rosebery, G.; Parker, C. Weed Res., 1976, 16, 223. Johnson, A. W.; Rosebery, G. U. S. Patent 4 002 457, 1977. Johnson, A. W.; Gowda, G.; Hassanali, Α.; Knox, J.; Monaco, S.; Razavi, Z.; Rosebery, G. J. Chem. Soc., Perkin Trans. 1, 1981, 1734. Pepperman, A. B.; Connick, W. J.; V a i l , S. L.; Worsham, A. D.; P a v l i s t a , A. D.; Moreland, D. E. Weed S c i . , 1982, 30, 561. Moreland, D. E.; Egley, G. H.; Worsham, A. D.; Monaco, T. J. In "Natural Pest Control Agents"; ADVANCES IN CHEMISTRY SERIES No. 53, American Chemical Society: Washington, D.C., 1966, p. 112. Lynn, D. G.; Steffens, J. C.; Kamat, V. S.; Graden, D. W.; Shabanowitz, J.; Riopel, J. L. J. Am. Chem. Soc. 1981, 103, 1868. Kamat, V. S.; Graden, D. W.; Lynn, D. G.; Steffens; J. C.; Riopel, J. L. Tetrahedron Lett., 1982, 23, 1541. Steffens, J. C.; Lynn, D. G.; Kamat, V. S.; Riopel, J. L. Ann. Bot. (London), 1982, 50, 1. Williams, C. N. Nature, 1959, 184, 1511. Parker, C.; Hitchcock, A. M.; Ramaiah, Κ. V. Proceedings of the Sixth Asian-Pacific Weed Society Conference, Jakarta, Indonesia, 1977, p. 57. Dolby, L. J.; Hanson, G. J. Org. Chem., 1976, 41, 563. Cooper, G. K.; Dolby, L. J. J. Org. Chem., 1979, 44, 3414. Pepperman, A. B. J. Org. Chem., 1981, 46, 5039. Brooks, D. W.; Kennedy, E. J. Org. Chem., 1983, 48, 277. S i e r r a , M. G.; Spanevello, R. Α.; Ruveda, E. A. J. Org. Chem., 1983, 48, 5111. Kendall, P. M.; Johnson, J. V.; Cook, C. E. J. Org. Chem., 1979, 44, 1421.

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23.

Cassady, J. M.; Howie, G. A. J. Chem.Soc.,Chem. Commun., 1974, 512. 24. Connick, W. J.; Pepperman, A. B. J. Food Agric. Chem., 1981, 29, 984. 25. Hsiao, A. I.; Worsham, A. D.; Moreland, D. E. Weed Sci., 1981, 29, 98. 26. Musselman, L.J.;Worsham, A. D.; Eplee, R. E., Eds. Proceedings of the Second Symposium on Parasitic Weeds. North Carolina State University, Raleigh, N. C., 1979. 27. Bradow, J. M.; Fites, R. C.; Menetrez, Μ., Personal Communication. RECEIVED July 24, 1984

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