Bioregulators for Pest Control - American Chemical Society

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16 Proallatocidins FRANCISCO CAMPS

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Instituto Quimica Bio-Orgánica (C.S.I.C.), Jorge Girona Salgado, 18-26, 08034-Barcelona, Spain

The rationale for design of proallatocidins related to chromenic structure of precocenes is discussed. Stabi­ lization against environmental conditions and insect metabolic pathways, as well as modification of trans­ port properties, are some of the leads followed for the synthesis of more powerful insect growth regulators of this type. Some aspects of the chemistry of 3,4-epoxyprecocenes are also examined. P r e c o c e n e s I and I I a r e n a t u r a l p r o d u c t s w i t h a s i m p l e chromene s t r u c ­ t u r e (7-methoxy- and 6,7-dimethoxy-2,2-dimethylchromene) which were i s o l a t e d from p l a n t s o u r c e s and e x h i b i t e d p o w e r f u l a n t i j u v e n i l e h o r ­ mone a c t i v i t i e s i n s e v e r a l t y p e s o f i n s e c t s ( 1 ) .

CH3O. U

Precocene I

Precocene II

There i s now s t r o n g e v i d e n c e t h a t p r e c o c e n e s a c t a s p r o a l l a t o c i ­ d i n s , which a r e t r a n s f o r m e d by a l l a t a l mono-oxygenases i n t o a h i g h l y r e a c t i v e 3,4-epoxide. T h i s epoxide i s assumed t o be t h e t r u e c y t o x i c agent by s e l e c t i v e a l k y l a t i o n o f c e l l u l a r elements o f the i n s e c t c o r ­ pora a l l a t a glands (2). On the o t h e r hand, t h e r e c e n t d i s c o v e r y o f a n t i j u v e n i l e hormone a c t i v i t y i n s e v e r a l o - i s o p e n t e n y l p h e n o l s , compounds b i o g e n e t i c a l l y r e l a t e d t o chromenes, has l e d t o the p r o p o s a l o f a d i r e c t a l t e r n a t i v e a l k y l a t i o n pathway, v i a r e a r r a n g e m e n t o f p r e c o c e n e s t o quinone methides (3). F o r the above c h a r a c t e r i s t i c s , p r e c o c e n e s were c o n s i d e r e d a s p o t e n t i a l l e a d compounds f o r t h e development o f a new g e n e r a t i o n o f i n s e c t i c i d e s . A c c o r d i n g l y , i n the l a s t y e a r s , e x t e n s i v e r e s e a r c h has

0097-6156/85/0276-0237S06.00/0 © 1985 American Chemical Society

Hedin et al.; Bioregulators for Pest Control ACS Symposium Series; American Chemical Society: Washington, DC, 1985.

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been c a r r i e d o u t i n a v a r i e t y o f academic and i n d u s t r i a l l a b o r a t o r i e s f o r the d e s i g n o f more p o w e r f u l i n s e c t growth r e g u l a t o r s o f t h i s type, which s h o u l d s i m u l t a n e o u s l y combine, among o t h e r f e a t u r e s , g r e a t e r r e s i s t a n c e t o the p e r i p h e r a l d e t o x i f i c a t i o n i n the i n s e c t and minimal t o x i c i t y a g a i n s t n o n - t a r g e t organisms, p a r t i c u l a r l y v e r t e b r a t e s . In the p r e s e n t communication, we summarize some o f our e f f o r t s i n t h i s area. Chemical

S t a b i l i z a t i o n o f Precocene

Structures

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In view o f the r e p o r t e d l a b i l i t y o f the chromene s k e l e t o n under en­ v i r o n m e n t a l - l i k e c o n d i t i o n s , i . e . a c i d promotes d i m e r i z a t i o n and l i g h t causes rearrangement o f chromene t o quinone methide (4) one o f our f i r s t c o n c e r n s was t h e c h e m i c a l s t a b i l i z a t i o n o f the p r e c o c e n e structures for i t s potential application i n f i e l d t r i a l s .

Dimers

We a n t i c i p a t e d t h a t r e p l a c e m e n t o f one v i n y l hydrogen by f l u o r i n e i n the n a t u r a l compound would reduce the r e a c t i v i t y o f the chromene 3,4double bond w i t h o u t p r e v e n t i n g the above enzymatic e p o x i d a t i v e b i o a c t i v a t i o n o f t a k i n g p l a c e , due t o the s i m i l i t u d e o f atomic r a d i i o f f l u o r i n e and hydrogen. However, 3 - f l u o r o p r e c o c e n e a n a l o g I I I , p r e p a r e d by m o d i f i c a t i o n o f known p r o c e d u r e s f o r the s y n t h e s i s o f chromenes ( 5 ) was i n a c t i v e . L i k e w i s e , s u b s t i t u t i o n o f t r i f l u o r o m e t h y l group f o r one o f the two gem-dimethyl groups a t the C-2 s i t e ( 6 ) , t o s t r e n g h t e n the C-2 oxygen bond, p r e c l u d i n g the above rearrangement, r e s u l t e d i n a d e c r e a s e o f a c t i v i t y i n the c o r r e s p o n d i n g t r i f l u o r o m e t h y l a n a l o g IV.

Hedin et al.; Bioregulators for Pest Control ACS Symposium Series; American Chemical Society: Washington, DC, 1985.

16. CAMPS

239

Proallatocidins

S t a b i l i z a t i o n against

Insect Metabolic

Degradation

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One o f t h e c o n c l u s i o n s from AJH s t r u c t u r e a c t i v i t y s t u d i e s i s t h e im­ p o r t a n c e o f an u n s u b s t i t u t e d double bond and a C-7 a l k o x y s u b s t i t u e n t i n t h e chromene s t r u c t u r e t o e l i c i t AJH a c t i v i t y . However, r e s u l t s o f p r e c o c e n e metabolism i n d i f f e r e n t i n s e c t s p e c i e s r e v e a l e d t h a t c l e a ­ vage a t t h i s s u b s t i t u e n t i s one o f t h e main d e t o x i f i c a t i o n mechanisms o b s e r v e d . A c c o r d i n g l y , we e x p e c t e d t h a t an i n c r e a s e o f s t e r i c h i n ­ drance a t t h i s s i t e might p r e v e n t t h e o c c u r r e n c e o f such a c l e a v a g e and, i n t h i s way, enhance t h e AJH a c t i v i t y . T h i s r e q u i r e m e n t was f u l ­ f i l l e d by p r e p a r a t i o n o f d i h y d r o b e n z o d i p y r a n d e r i v a t i v e s V and VI, i n which a b u l k y p s e u d o t e r b u t o x y s u b s t i t u e n t i s p r e s e n t a t C-7 o f t h e chromene s t r u c t u r e , as p a r t o f a 2,2-dimethylchroman r i n g , l i n k i n g t h i s s i t e and C-6 o r C-8, r e s p e c t i v e l y i n l i n e a r i s o m e r s V o r a n g u l a r d e r i v a t i v e s VI ( 7 ) .

VI

V

P r e l i m i n a r y r e s u l t s o f a n t i j u v e n i l e hormone b i o a s s a y s f o r p r e c o ­ c i o u s metamorphosis i n immature s t a g e s o f O n c o p e l t u s f a s c i a t u s r e v e a l ­ ed t h a t some o f t h e n o n - l i n e a r d e r i v a t i v e s (VI) showed h i g h e r a c t i v i ­ t i e s and lower t o x i c i t i e s t h a t t h o s e e x h i b i t e d by n a t u r a l p r e c o c e n e s o r 7-ethoxy-6-methoxy-2,2-dimethylchromene, one o f t h e most a c t i v e s y n t h e t i c a n a l o g s known. I n a d d i t i o n , some o f t h e s e compounds were unexpectedly i n a c t i v e i n the s t e r i l i z a t i o n bioassay with adults o f the same s p e c i e s ( 8 ) . F u r t h e r i n v e s t i g a t i o n o f a n t i j u v e n i l e hormone a c t i v i t i e s o f s e l e c t e d compounds o f t h i s s e r i e s i n o t h e r i n s e c t s i s now i n p r o g r e s s . Modification o f transport

properties

A l t h o u g h t h e d i f f e r e n t i a l s e n s i t i v i t y o f hemi- and h o l o m e t a b o l o u s l a r v a e t o t h e p r e c o c e n e s remains u n e x p l a i n e d , i t has been shown t h a t the c o r p o r a a l l a t a o f h o l o m e t a b o l o u s s p e c i e s a r e s e n s i t i v e t o t h e p r e ­ cocenes i n v i t r o ( 9 ) . L i k e w i s e , i t has been demonstrated t h a t p r e c o c e ­ nes a r e r a p i d l y s e q u e s t e r e d by hemolymph p r o t e i n s i n s e v e r a l i n s e c t s p r e v e n t i n g an e f f e c t i v e amount o f the p r e c o c e n e s from ever r e a c h i n g the c o r p o r a a l l a t a ( 1 0 ) . C o n s e q u e n t l y , we a n t i c i p a t e d t h a t t o overcome t h e s e problems i t might be i m p o r t a n t t o i n c o r p o r a t e m o i e t i e s i n t h e p r e c o c e n e s t r u c t u r e t o a l t e r t h e t r a n s p o r t p r o p e r t i e s o f t h e n a t u r a l compounds. F o r t h i s aim, we s y n t h e s i z e d crown e t h e r p r e c o c e n e s V I I (11), i n which C-6 and C-7 o f t h e chromene s k e l e t o n were i n c o r p o r a t e d i n t o a 15-crown-5 o r 18-crown-6 e t h e r r i n g . We a l s o p r e p a r e d s e v e r a l chromene d e r i v a t i v e s VIII bearing polyoxyethylenated groups and s u g a r r e s i d u e s a t t h e C-8 p o s i t i o n (12).

Hedin et al.; Bioregulators for Pest Control ACS Symposium Series; American Chemical Society: Washington, DC, 1985.

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BIOREGULATORS F O RPEST C O N T R O L

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n= 3,4

CH

VIII

VII

So f a r a l l t h e s e compounds were i n a c t i v e i n t h e s t a n d a r d c o n t a c t t e s t b u t f u r t h e r i n v e s t i g a t i o n under i n v i t r o c o n d i t i o n s w i l l be c a r ­ r i e d o u t i n t h e near f u t u r e . Another s t r a t e g y used t o modify t h e t r a n s p o r t p r o p e r t i e s o f n a t ­ u r a l p r e c o c e n e s was t o p r e p a r e analogues i n which t h e double bond was masked i n such a way t h a t might be l i b e r a t e d under m i l d o x i d a t i v e c o n ­ d i t i o n s ( 1 3 ) . I t was thought t h a t by an a p p r o p r i a t e c h o i c e o f t h e s e p r o t e c t i v e groups, t h e AJH a c t i v i t y might be enhanced i f t h e p r o a l l a t o c i d i n s t r u c t u r e c o u l d be l i b e r a t e d c l o s e t o t h e c o r p o r a a l a t a . F o r t h i s aim we have p r e p a r e d i n o u r l a b o r a t o r y (14) p r e c o s y l t h i o p h e n y l e t h e r s IX, i n view o f t h e u s e f u l n e s s o f t h i s p r o t e c t i v e group i n o r ­ g a n i c s y n t h e s i s , a l l o w i n g t h e easy r e g e n e r a t i o n o f t h e double bond by o x i d a t i o n t o t h e c o r r e s p o n d i n g s u l f o x i d e s and s u l f o n e s f o l l o w e d by

IX e l i m i n a t i o n under v e r y m i l d c o n d i t i o n s ( 1 5 ) . B i o l o g i c a l s t u d i e s o f t h e s e compounds a r e under way w i t h d i f f e r e n t i n s e c t s . C h e m i c a l S t u d i e s o f 3,4-epoxyprecocenes I n v e s t i g a t i o n s o f t h e i n v i v o and i n v i t r o metabolism o f t h e p r e c o c e ­ nes d i s c l o s e d t h a t 3 , 4 - d i h y d r o x y p r e c o c e n e s were t h e most common me­ t a b o l i t e s . The abundance o f t h e s e d i o l s s u g g e s t e d t h a t p r e c o c e n e must have undergone e p o x i d a t i o n f o l l o w e d by h y d r a t i o n , l e a d i n g t o a c o n s ­ t a n t isomer r a t i o o f 70:30 t r a n s c i s i s o m e r s , (2,16). R e c e n t l y , i t was demonstrated by i n c u b a t i o n i n v i t r o w i t h L o c u s t a m i g r a t o r i a c o r ­ p o r a a l l a t a t h a t 4 - ^ H - p r e c o c e n e ~ was m e t a b o l i z e d s t e r e o s p e c i f i c a l l y t o (-)-trans-(3R,4S) and (+)-cis-(3R,4R) d i o l s ( 1 7 ) . To prove t h e above h y p o t h e s i s o f precocene mode o f a c t i o n , i t was r e q u i r e d t o s y n t h e s i z e t h e c o r r e s p o n d i n g 3,4-epoxyprecocenes and t o s t u d y i t s c h e m i c a l r e a c t i v i t y . When t h i s was a c c o m p l i s h e d i n two d i f f e r e n t l a b o r a t o r i e s (16,18) t h e l a b i l i t y o f t h e s e e p o x i d e s towards n u c l e o p h i l i c o r e l e c t r o p h i l i c a t t a c k was c o n f i r m e d . I n each case t h e c h e m i c a l h y d r o l y s i s o f t h e s e compounds gave t h e same isomer r a t i o o f d i o l s o b s e r v e d i n t h e enzymatic m e t a b o l i c p r o c e s s . We a n t i c i p a t e d t h a t s t a b i l i z a t i o n o f t h e s e type o f e p o x i d e s might be a c h i e v e d by r e p l a c e m e n t o f 7-alkoxy s u b s t i t u e n t by a f l u o r o a l k o x y group. I n f a c t , t h i s was t h e case and 7 - t r i f l u o r o e t h o x y - 3 , 4 -

Hedin et al.; Bioregulators for Pest Control ACS Symposium Series; American Chemical Society: Washington, DC, 1985.

16.

CAMPS

Proallatocidins

241

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epoxy precocene d e r i v a t i v e s X e x h i b i t e d h i g h e r s t a b i l i t i e s than t h e c o r r e s p o n d i n g n o n - f l u o r i n a t e d a n a l o g s ( 1 9 ) , w h i t h o u t l o s s o f AJH a c ­ t i v i t y i n the o l e f i n i c precursors.

In s e a r c h i n g f o r a r e l a t i o n s h i p between a n t i j u v e n i l e hormone a c ­ t i v i t i e s and epoxide c h e m i c a l r e a c t i v i t y , we attempted t o a p p l y as a c h e m i c a l probe t h e m - c h l o r o p e r o x y b e n z o i c - a l k a l i n e f l u o r i d e system, a reagent developed i n t h i s l a b o r a t o r y f o r p r e p a r a t i o n o f a c i d l a b i l e epoxides ( 2 0 ) . However, f o r m a t i o n o f h e m i e s t e r s o f 3,4-dihydroxy p r e ­ cocene , was t h e predominant r e a c t i o n i n t h e case o f a c t i v a t e d c h r o ­ mene s t r u c t u r e s . L i k e w i s e , as i t has been s t u d i e d i n t h e chromenes ( 2 1 ) , we exa­ mined t h e p o s s i b l e r e l a t i o n s h i p between p r e c o c e n e - l i k e a c t i v i t y and C c h e m i c a l s h i f t s o f C-3 and C-4 i n s e v e r a l 3,4-epoxides o f a c t i v e and i n a c t i v e chromenes. I n a l l c a s e s o b s e r v e d , t h e s e c h e m i c a l s h i f t s d i f f e r e d t o o s l i g h t l y , w i t h i n t h e range o f 0.5 ppm f o r C-3 and 0.7 ppm f o r C-4, t o be o f any d i a g n o s t i c v a l u e . R e c e n t l y , s e v e r a l n u c l e o p h i l i c r e a g e n t s have been used t o e s t a ­ b l i s h t h e mode o f a c t i o n o f t h e m e t a b o l i t e s o f p o l y c y c l i c a r o m a t i c hydrocarbons (PAH). Among them, s e v e r a l p h o s p h o d i e s t e r s have been examined t o c l a r i f y t h e p o s s i b i l i t y o f r e a c t i o n o f PAH e p o x i d e s w i t h the phosphate groups ( P - a l k y l a t i o n ) o f n u c l e i c a c i d s ( 2 2 ) . I n t h i s c o n t e x t we have s t u d i e d t h e r e a c t i o n o f 3,4-epoxyprecocene I I w i t h d i b e n z y l phosphate under a v a r i e t y o f c o n d i t i o n s . I n a l l c a s e s , i n s ­ t e a d o f t h e f o r m a t i o n o f phenol o r p h o s p h o t r i e s t e r s o b s e r v e d w i t h PAH e p o x i d e s , we o b t a i n e d p r e d o m i n a n t l y dimer X I . T h i s compound was a l s o t h e main component o f t h e m i x t u r e s o b t a i n e d by r e a c t i o n o f t h e above precocene epoxide w i t h o t h e r a c i d c a t a l y s t s , a l o n g w i t h dimers X I I and X I I . Dimer X I I was formed almost e x c l u s i v e l y by t h e r m a l t r e a t ­ ment. The s t r u c t u r e and c o n f i g u r a t i o n f o r compound X I I has been e s t a ­ b l i s h e d by s p e c t r a l and X-ray d i f f r a c t i o n a n a l y s e s ( 2 3 ) . 1 3

Hedin et al.; Bioregulators for Pest Control ACS Symposium Series; American Chemical Society: Washington, DC, 1985.

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R

R

R

R

XIII I t i s worth o f note t h a t t h e f o r m a t i o n o f a dimer, w i t h d i f f e r e n t dioxane s t r u c t u r e , i n t h e t r e a t m e n t o f 3,4-dihydroxyprecocene I with p - t o l u e n s u l f o n i c a c i d has been r e c e n t l y r e p o r t e d ( 1 3 ) . F u r t h e r work, t o s t u d y t h e r e a c t i v i t y o f precocene e p o x i d e s w i t h s e l e c t e d n u c l e o p h i l e s , which c a n shed l i g h t on t h e mode o f a c t i o n o f t h e s e compounds, i s i n progress. As a complement t o t h e s t u d y o f t h e c h e m i s t r y o f 3,4-epoxypreco­ cenes, we have a l s o p r e p a r e d t h e c o r r e s p o n d i n g 2 , 2 - d i m e t h y l - 3 - c h r o manones by p y r o l y s i s o f h e m i e s t e r s o f 3 , 4 - d i h y d r o x y p r e c o c e n e s . These chromanones might a f f o r d by e n o l i z a t i o n 3-hydroxyprecocenes, tautomers o f t h e 3,4-epoxyprecocenes, w i t h an enhanced r e a c t i v i t y towards n u c l e o p h i l e s a t C-4. However, p r e l i m i n a r y r e s u l t s o f a n t i j u v e n i l e

>H

hormone a c t i v i t y o f t h e s e chromanones were n e g a t i v e . In s h o r t , although precocenes are a very v a l u a b l e t o o l f o r c a r ­ r y i n g out chemical allatectomy i n i n s e c t physiology s t u d i e s , the f u t u r e a p p l i c a t i o n o f agents o f t h e p r e c o c e n e type i n i n s e c t c o n t r o l depends on overcoming two main problems o f t h e n a t u r a l p r e c o c e n e s , namely, i t s r e p o r t e d t o x i c i t y i n v e r t e b r a t e s (24,25) and i t s i n s e n s i t i v i t y t o holometabolous i n s e c t s . Acknowledgments F i n a n c i a l s u p p o r t from C o m i s i o n A s e s o r a de I n v e s t i g a c i o n C i e n t i f i c a y Técnica (Grant 1664-82) and J o i n t American-Spanish Committee f o r S c i e n t i f i c and T e c h n o l o g i c a l C o o p e r a t i o n (Grant 0394-11) i s g r a t e f u l ­ l y acknowledged.

Hedin et al.; Bioregulators for Pest Control ACS Symposium Series; American Chemical Society: Washington, DC, 1985.

16.

CAMPS

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Literature

Proallatocidins

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