Insecticidal Unsaturated Isobutylamides - American Chemical Society

Chapter 13

Insecticidal Unsaturated Isobutylamides From Natural Products to Agrochemical Leads 1

Downloaded by FUDAN UNIV on February 14, 2017 | http://pubs.acs.org Publication Date: February 23, 1989 | doi: 10.1021/bk-1989-0387.ch013

Masakazu Miyakado, Isamu Nakayama , and Nobuo Ohno Pesticides Research Laboratory, Takarazuka Research Center, Sumitomo Chemical Company, Ltd., 4-2-1, Takatsukasa, Takarazuka, Hyogo 665, Japan

For several years, our research group at Sumitomo has been conducting an extensive search for new biologically active natural products. In this chapter, a series of studies on unsaturated N-isobutylamide insecticides is described. An extract of black pepper (Piper nigrum) exhibited strong insecticidal activities against several insects. From the extract, an amide, N-isobutyl-11-(3,4-methylenedioxyphenyl)-(2E,4E,10E)2,4,10-undecatrienamide (pipercide) and two structurally related amides were isolated as insecticidal principles. In the course of synthetic modifications, N-isobutyl-12-(3-trifluoromethylphenoxy)-(2E,4E)-2,4dodecadienamide was found to have potent activity. This amide, as well as the amides from pepper plant, exhibited notable paralyzing effects and lethal activity against susceptible and pyrethroid-resistant insects. Electrophysiological studies using the central nerve cord of the American cockroach demonstrated that these amides are neurotoxic. Related synthetic studies of other groups are also described. From p l a n t s o f Compositae and Rutaceae, a number o f N - i s o b u t y l a m i d e s of u n s a t u r a t e d and C ^ - C ^ g a c i d s have been o b t a i n e d as i n s e c t i c i d a l substances. P e l l i t o r i n e and i t s analogues p r o v i d e t y p i c a l examples ( f o r d e t a i l s , see (JL) and ( 2) ). The o c c u r r e n c e o f p e l l i t o r i n e [I] was f i r s t d e s c r i b e d i n 1895 by Dunstan et_ a l . (_3) as pungent p r i n c i p l e i n the r o o t s o f the m e d i c i n a l p l a n t , A n a c y c l u s pyrethrum DC. ( C o m p o s i t a e ) . A f t e r a long and c o m p l i c a t e d study, the s t r u c t u r e o f p e l l i t o r i n e was deduced to possess a c o n j u g a t e d dienamide chromophore (-C=C-C=C-CONH-). I t was o n l y i n 1952 t h a t the c o r r e c t s t r u c t u r e was c o n f i r m e d by s y n t h e s i s to be N - i s o b u t y l - ( 2 E , 4 E ) - 2 , 4 - u n d e c a d i e n a m i d e ( 4 ) . J a c o b s o n r e p o r t e d Current address: Plant Protection Division—Domestic, Sumitomo Chemical Company, Ltd., Kitahama, Higashi-ku, Osaka 541, Japan 0097-6156/89/0387-0173$06.00/0 ° 1989 American Chemical Society

Arnason et al.; Insecticides of Plant Origin ACS Symposium Series; American Chemical Society: Washington, DC, 1989.


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INSECTICIDES OF PLANT ORIGIN

t h a t the a c t i v i t y o f p e l l i t o r i n e [ I ] on h o u s e f l i e s (Musca d o m e s t i c a ) was about o n e - h a l f t h a t o f the p y r e t h r i n s ) . F o l l o w i n g the s t r u c t r a l e l u c i d a t i o n o f p e l l i t o r i n e , a number o f N - i s o b u t y l a m i d e s o f u n s a t u r a t e d and a l i p h a t i c a c i d s were i s o l a t e d from many p l a n t s p e c i e s ( F i g u r e 1) (2). I n t e r e s t i n g l y , many o f these u n s a t u r a t e d amides o f p l a n t o r i g i n were r e p o r t e d to e x h i b i t v a r i o u s k i n d s o f b i o l o g i c a l a c t i v i t i e s such a s : i n s e c t i c i d a l (6ι), m o l l u s c i c i d a l (J), pungent (tongue-numbing) ( 8 ) , c o r o n a r y v a s o d i l a t i n g ( 9 ) , a n t i - o x i d a t i v e ( 1 0 ) , pyrethrum s y n e r g i s t i c ( 1 1 ) , i n t e r c e p t i v e ( p o s t c o i t a l a n t i f e r t i l i t y ) ( 1 2 ) , a n t i - t u b e r c u l a r a c t i v i t y ( 1 3 ) , and so on. Thus, p e l l i t o r i n e and i t s r e l a t e d amides c o u l d be looked upon as good s t r u c t u r a l leads f o r the development o f a new c l a s s o f i n s e c t i c i d e s or pharmaceuticals. S i n c e the s t r u c t u r a l e l u c i d a t i o n o f p e l l i t o r i n e , a number o f analogues were s y n t h e s i z e d to d e v e l o p more p o t e n t compounds ( 1 4 ) . Some o f the s y n t h e t i c amides were r e p o r t e d to e x h i b i t r a p i d p a r a l y z i n g a c t i o n (knockdown) and l e t h a l t o x i c i t y a g a i n s t h o u s e f l i e s , y e l l o w mealworms ( T e n e b r i o m o l i t o r ) and mustard b e e t l e s (Phaedon c o c h l e a r i a e ) ( F i g u r e 2) (2^). However, these s y n t h e t i c analogues had i r r i t a n t p r o p e r t i e s to human s k i n as w e l l as t o x i c i t y to mammals. In a d d i t i o n to these u n d e s i r a b l e s i d e - e f f e c t s , these u n s a t u r a t e d amides were q u i t e u n s t a b l e . Every a p p l i c a t i o n t r i a l o f p e l l i t o r i n e [ I ] and i t s s y n t h e t i c analogues as i n s e c t i c i d e s gave poor r e s u l t s because o f t h i s low s t a b i l i t y .

I s o l a t i o n and s t r u c t u r a l e l u c i d a t i o n o f i n s e c t i c i d a l from b l a c k pepper.

constituents

In a s e a r c h o f n a t u r a l s o u r c e s f o r new a g r o c h e m i c a l leads w i t h good e n v i r o n m e n t a l p r o p e r t i e s , we chose f o o d - s p i c e s as a p r o m i s i n g starting point. We expected t h a t s p i c e s would b r i n g l e a d s w i t h low mammalian t o x i c i t y . Among the 30 s p i c e s i n v e s t i g a t e d , o n l y b l a c k pepper e x t r a c t ( P i p e r nigrum) e x h i b i t e d h i g h i n s e c t i c i d a l a c t i v i t i e s a g a i n s t common mosquito l a r v a e (Culex p i p i e n s p a l l e n s ) and a d z u k i bean w e e v i l s ( C a l l o s o b r u c h u s c h i n e n s i s ) . The f r u i t s o f P i p e r a c e a e p l a n t s have been known t o c o n t a i n many p h y s i o l o g i c a l l y a c t i v e p r i n c i p l e s , and a number o f s t u d i e s on the c h e m i c a l c o n s t i t u e n t s o f the f r u i t s have been c o n d u c t e d . Among these components, u n s a t u r a t e d amides c o n s t i t u t e a major group o f secondary m e t a b o l i t e s . H e r v i l e_t a l . r e p o r t e d i n 1943 t h a t p i p e r i n e [ I I ] , a major h o t p r i n c i p l e o f b l a c k pepper, was more t o x i c than pyrethrum a g a i n s t h o u s e f l i e s (15). As d e s c r i b e d e a r i e r i n t h i s paper, Jacobson r e p o r t e d that p e l l i t o r i n e [ I ] , a p l a n t c o n s t i t u e n t o f Compositae, Rutaceae, and a l s o o b t a i n e d from P i p e r a c e a e , had a n o t a b l e knockdown e f f e c t on h o u s e f l i e s (5). L a t e r , Su (_16) and S c o t t e t a l . (17) r e p o r t e d t h a t crude and p u r i f i e d e x t r a c t s o f b l a c k pepper caused h i g h m o r t a l i t y a g a i n s t g r a i n p e s t s such as r i c e w e e v i l s ( S i t o p h i l u s o r y z a e ) and b o l l w e e v i l s (Anthonomus g r a n d i s ) on t o p i c a l application. In a d d i t i o n to t h i s , t h e r e a r e many s t u d i e s on the c h e m i c a l constituents of Piperaceae p l a n t s . Over f i f t y u n s a t u r a t e d amides have been i s o l a t e d from p l a n t s o u r c e s , so f a r ( 1 8 ) . However, most



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o f these amides were not s t u d i e d w i t h r e g a r d to i n s e c t i c i d a l a c t i v i t y , so the i n s e c t i c i d a l nature o f these amides from P i p e r a c e a e remained o b s c u r e . In 1979, Miyakado et^ al^. r e p o r t e d the i s o l a t i o n o f p i p e r c i d e [ I l i a ] (19), d i h y d r o p i p e r c i d e [ I l l b ] and g u i n e e n s i n e [ i l l c ] (20) as genuine i n s e c t i c i d a l p r i n c i p l e s from the f r u i t s o f b l a c k pepper ( F i g u r e 3 ) . A d z u k i bean w e e v i l s were used as t e s t i n s e c t s d u r i n g the i s o l a t i o n p r o c e s s . The s t r u c t u r e s o f p i p e r c i d e [ I l i a ] and i t s analogues [ I l l b ] and [ I l l c ] were c o n f i r m e d by s y n t h e s i s (20, 21). U n t i l the i s o l a t i o n o f [ i l i a ] , [ I l l b ] and [ i l l c ] , p i p e r i n e [ I I ] had been s a i d to be a major i n s e c t i c i d a l component o f b l a c k pepper ( 2 2 ) . In our o b s e r v a t i o n s , p i p e r i n e i t s e l f showed no l e t h a l a c t i v i t y a g a i n s t h o u s e f l i e s , a l t h o u g h i t e x h i b i t e d n o t a b l e synergisms w i t h p e l l i t o r i n e or p y r e t h r i n s ( 2 3 ) .

Insecticidal [Illc].

activity

of P i p e r a c e a e

amides

[Ilia],

[Illb]

and

The i n s e c t i c i d a l a c t i v i t y o f [ I l i a ] , [ I l l b ] and [ i l l c ] a g a i n s t a d z u k i bean w e e v i l s i s summarized i n T a b l e I . Among these amides, d i h y d r o p i p e r c i d e was most t o x i c ; g u i n e e n s i n e and p i p e r c i d e came next, r e s p e c t i v e l y . I n t e r e s t i n g l y , a m i x t u r e o f p i p e r c i d e and the two amides e x h i b i t e d n o t a b l e j o i n t a c t i o n . In p a r t i c u l a r , a m i x t u r e o f the amides [ i l i a ] , [ i l l b ] and [ i l l c ] i n 1 : 1 : 1 r a t i o demonstrated the h i g h e s t j o i n t a c t i o n (two to f i v e f o l d i n c r e a s e i n a c t i v i t y , which was comparable to t h a t o f p y r e t h r i n s ) . The knockdown times of the t h r e e amides a g a i n s t a d z u k i bean w e e v i l are a l s o g i v e n i n T a b l e I ( 2 4 ) . When p i p e r c i d e [ I l i a ] was a p p l i e d t o p i c a l l y , the knockdown a c t i v i t y (KT50) was observed at 11.8 min. However, d i h y d r o p i p e r c i d e and g u i n e e n s i n e e x h i b i t e d l o n g e r knockdown times than p i p e r c i d e . In t h i s case a l s o , the h i g h e s t knockdown a c t i v i t y was observed i n a m i x t u r e o f the amides [ I l i a ] , [ I l l b ] and [ I l l c ] at a r a t i o o f 1 : 1 : 1. As a r e f e r e n c e , the knockdown a c t i v i t y o f p y r e t h r i n s was examined. The KT50 o f p y r e t h r i n s was o n l y 1.0 min at the dosage o f 0.05 μg/insect. I t i s noteworthy t h a t the o r d e r o f knockdown a c t i v i t y i s the r e v e r s e o f the o r d e r o f l e t h a l t o x i c i t y f o r the t h r e e amides. In 1981, Su et a l .

T a b l e I . I n s e c t i c i d a l a c t i v i t y and knockdown time o f P i p e r a c e a e amides to a d u l t £ . c h i n e n s i s (male) on t o p i c a l a p p l i c a t i o n compds. pipercide [Ilia] dihydropipercide [Illb] guineensine [ I l l c ] [Ilia],[Illb],[Illc], 1:1:1

LD50 (μ%/insect!^ 0.56 " 0.23 0.36 0.11

6.46 p e l l i t o r i n e [I] piperine [II] >10.0 pyrethrins 0.10 a) M o r t a l i t i e s were e v a l u a t e d a f t e r 24 h r . applied, c) 0.05 /xg/insect was a p p l i e d .

KT50 ( m i n ) 11.8 30.0 20.5 6.0

>60.0 >60.0 . 1.0' 1.0 b) 0.1 μg/insect

b )

C


was

176


0

0

[ I ] peUitorine

affinin, spilanthol

W /

NH/

/W=WV Y

NAWVV Y


0

1.

anacyclin

ΛΛΛΤνΝΛΑγΝΗΎ

0

sanshool-I Figure

ο

0

sanshool-II

filfiline

Representative a l i p h a t i c of p l a n t o r i g i n .

0

unsaturated

0

(Tm)

ο

(Md.Tm)

(Pc)

0

0

(Md) F i g u r e 2.

isobutylamides

(Md) Synthetic a l i p h a t i c unsaturated insecticidal activity.

isobutylamides

ο

ο

[II] piperine

[ Ilia] pipercide

0

[inb]

0

dihydropipercide F i g u r e 3.

[Hie] guineensine

Piperaceae

amides.


with

13.

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177

a l s o s t u d i e d the c o n s t i t u e n t s of b l a c k pepper and r e p o r t e d the i s o l a t i o n of the f o l l o w i n g amides as i n s e c t i c i d a l i n g r a d i e n t s : p e l l i t o r i n e [ I ] , p i p e r c i d e [ I l i a ] and g u i n e e n s i n e [ I l l c ] ( 2 5 ) . The r e p o r t e d i n s e c t i c i d a l t o x i c i t i e s (LD50, 24 h r ) of [ I ] , [ I l i a ] and [ I l l c ] a g a i n s t cowpea w e e v i l ( C a l l o s o b r u c h u s m a c u l a t u s , male) were 2.18, 0.25 and 0.84 M g / i n s e c t , r e s p e c t i v e l y . These b i o l o g i c a l o b s e r v a t i o n s are concordant w i t h our d a t a i n T a b l e I .


Mode of a c t i o n of p i p e r c i d e

[Ilia].

As d e s c r i b e d above, p i p e r c i d e [ I l i a ] and i t s analogues [ I l l b ] and [ I l l c ] e x h i b i t e d n o t a b l e l e t h a l and knockdown a c t i v i t i e s a g a i n s t a d z u k i bean w e e v i l s . The t o x i c i t y o f these amides was almost comparable to t h a t o f the p y r e t h r i n s . S i n c e the d i s c o v e r y o f [ I l i a ] , [ i l l b ] and [ i l l c ] , s e v e r a l b i o l o g i c a l s t u d i e s have been conducted to examine i n s e c t i c i d a l c h a r a c t e r i s t i c s and mode o f action. Knockdown a c t i v i t y : F i r s t , the knockdown a c t i v i t y o f p i p e r c i d e [ i l i a ] a g a i n s t American c o c k r o a c h e s ( P e r i p l a n e t a americana) was i n v e s t i g a t e d ( 2 6 ) . The knockdown a c t i v i t y o f p i p e r c i d e , p y r e t h r i n I and DDT i s shown i n T a b l e I I . N e i t h e r p i p e r c i d e nor DDT showed knockdown a c t i v i t y w i t h i n 120 min when 10 μg o f these compounds were t o p i c a l l y a p p l i e d to the t h o r a x . On the c o n t r a r y , p y r e t h r i n I e x h i b i t e d a KT50 of 12.6 min (10 μg t r e a t m e n t ) . On the o t h e r hand, p i p e r c i d e showed a t y p i c a l knockdown e f f e c t by the i n j e c t i o n method. Burt and G o o d c h i l d have p o i n t e d out t h a t the e f f e c t s of p y r e t h r o i d s depend on the r a t e of t h e i r p e n e t r a t i o n and a r r i v a l at the s i t e o f a c t i o n (27). They a l s o mentioned t h a t p e n e t r a t i o n o f p y r e t h r o i d s a f f e c t e d knockdown a c t i v i t y but had no i n f l u e n c e on l e t h a l t o x i c i t y .

T a b l e I I . Knockdown a c t i v i t y a g a i n s t P. americana v i a abdominal i n j e c t i o n or t o p i c a l a p p l i c a t i o n to t h o r a x at 10 μg/male KT50 (mm) topical injection >120 10.0 pipercide [Ilia] 12.6 4.4 pyrethrin I >120 >120 DDT a) Only i n i t i a l KT50 times are g i v e n i n t h i s t a b l e . S e v e r a l r e c o v e r e d i n s e c t s were observed a f t e r i n i t i a l knockdown. compds.

As e x p e c t e d , p y r e t h r i n I e x h i b i t e d more r a p i d knockdown a c t i o n by the i n j e c t i o n method than by t o p i c a l a p p l i c a t i o n . S i m i l a r l y , p i p e r c i d e was more e f f e c t i v e when treatment was by the i n j e c t i o n method than by t o p i c a l a p p l i c a t i o n . T h e r e f o r e , i t c o u l d be assumed t h a t p i p e r c i d e had a slower p e n e t r a t i o n r a t e than t h a t o f pyrethrins. From these o b s e r v a t i o n s , i t was e s t i m a t e d t h a t p i p e r c i d e d i d not show knockdown a c t i v i t y owing to i t s slow



178


penetration. T h e r e f o r e , p i p e r c i d e e x h i b i t e d f a s t knockdown actionwhen a p r o p e r amount o f i t e x i s t e d i n the i n s e c t body. Synergism: Next, the e f f e c t of s y n e r g i s t s on p i p e r c i d e a c t i v i t y [ I l i a ] was studied. German c o c k r o a c h e s ( B l a t t e r a germanica, male) were used as t e s t organisms (Umeda, K.; Miyakado, M., Sumitomo Chem. Co. L t d . , unpublished data). PBO (100 M g / i n s e c t ) or NIA-16388 (28) (20 μg/insect) was a p p l i e d t o p i c a l l y 2 h r b e f o r e the i n j e c t i o n o f pipercide. The l e t h a l t o x i c i t y of p i p e r c i d e w i t h o u t s y n e r g i s t was 5.00 j u g / i n s e c t (LD50, 24 h r ) . However, the t o x i c i t y o f [ i l i a ] was s y n e r g i s t i c a l l y enhanced to 1.55 and 0.51 μg/insect, r e s p e c t i v e l y , when the i n s e c t s were p r e - t r e a t e d w i t h PBO or NIA-16388. This r e s u l t suggested that p i p e r c i d e had r e l a t i v e l y n o n r e s i s t a n t m o i e t i e s w i t h r e s p e c t to the a c t i o n o f o x i d a t i v e or h y d r o l y t i c enzymes. E f f e c t on nervous system: The e f f e c t o f p i p e r c i d e [ I l i a ] on the c e n t r a l nerve c o r d system (CNS) o f P. americana was i n v e s t i g a t e d ( 2 6 ) . P i p e r c i d e induced a s p i k e i n c r e a s e at 2.5 min and r e p e t i t i v e d i s c h a r g e at 2.5-3.0 min, w h i l e c o n d u c t i o n b l o c k a g e was not observed w i t h i n 30 min. On the o t h e r hand, p y r e t h r i n I caused a s p i k e i n c r e a s e at 0.3 min and r e p e t i t i v e d i s c h a r g e s at 0.3-1.0 min as a r a p i d r e s p o n s e . C o n d u c t i o n b l o c k a g e was a l s o observed on the CNS at 15 min. DDT e x h i b i t e d no e f f e c t on the CNS w i t h i n 30 min. Electrophysiological s t u d i e s showed t h a t p i p e r c i d e a c t e d on the CNS at 10 M: the same as p y r e t h r i n I but to a l e s s e r d e g r e e . E l e c t r o p h y s i o l o g i c a l studies using a pyrethroid-res i s t a n t American c o c k r o a c h CNS p r e p a r a t i o n r e v e a l e d the same response as t h a t o f s u s c e p t i b l e organisms. P i p e r c i d e e x h i b i t e d the same o r d e r o f t o x i c i t y when 5.0 μg/insect was i n j e c t e d to s u s c e p t i b l e or p y r e t h r o i d - r e s i s t a n t American c o c k r o a c h e s . A l t h o u g h the p o i s o n i n g symptoms o f p i p e r c i d e were q u i t e s i m i l a r to those o f the type I p y r e t h r o i d s , i t was e s t i m a t e d t h a t p i p e r c i d e might a c t at a d i f f e r e n t s i t e w i t h i n the nervous system.

Synthesis

of p i p e r c i d e

[Ilia].

The f i r s t s y n t h e s i s of p i p e r c i d e was r e p o r t e d by our group i n 1979 (21). The s y n t h e t i c scheme i s g i v e n i n F i g u r e 4. One o f the hydroxy groups of 1,6-hexanediol [ i V a ] was s e l e c t i v e l y p r o t e c t e d as a p y r a n y l e t h e r , then the o t h e r was o x i d i z e d w i t h p y r i d i n i u m c h l o r o c h r o m a t e to g i v e 6 - ( t e t r a h y d r o - 2 - p y r a n y l o x y ) - l - h e x a n a l [iVb], The aldehyde [IVb] was s u b j e c t e d to Wittig-Wadsworth-Emmons r e a c t i o n , u s i n g d i e t h y l 3-methoxycarbonyl-2-propenylphosphonate [ I V C ] i n the presence o f NaOMe, y i e l d i n g the ( 2 E , 4 E ) - c o n j u g a t e d diene e s t e r [IVd]. The u n s a t u r a t e d e s t e r [ i V d ] a f f o r d e d methyl 10-oxo-(2E,4E)-2,4-decadienoate [ i V e ] on s u c c e s s i v e treatment w i t h £-toluenesulfonic a c i d and subsequent o x i d a t i o n w i t h p y r i d i n i u m chlorochromate. The 10-oxo-ester a f f o r d e d the c o n d e n s a t i o n p r o d u c t ( ( E ) - r i c h ) [ i V f ] by W i t t i g r e a c t i o n o f 3,4-raethylenedioxyb e n z y l t r i p h e n y l p h o s p h o n i u m bromide i n benzene i n the presence of an e q u i m o l a r amount o f n - B u L i . T h i s c o n j u g a t e d e s t e r [ I V f ] gave the 1



13. MIYAKADOETAL.


179

c o r r e s p o n d i n g a c i d on h y d r o l y s i s w i t h KOH-MeOH. The a c i d was r e c r y s t a l l i z e d twice from benzene to g i v e pure l l - ( 3 , 4 methylenedioxyphenyl)-(2E,4E,10E)-2,4,10-undecatrienoic a c i d . The a c i d was c o n v e r t e d t o the c o r r e s p o n d i n g a c i d c h l o r i d e and f i n a l l y condensed w i t h i s o b u t y l a m i n e t o g i v e N - i s o b u t y l - l l - ( 3 , 4 methylenedioxyphenyl)-(2E,4E,10E)-2,4,10-undecatrienamide [ I l i a ] . The s y n t h e t i c m a t e r i a l was i d e n t i c a l i n a l l r e s p e c t s t o n a t u r a l pipercide. The s y n t h e s e s o f d i h y d r o p i p e r c i d e [ i l l b ] and g u i n e e n s i n e [ I l l c ] were a l s o completed a c c o r d i n g to almost same p r o c e d u r e as t h a t i n v o l v e d i n the p i p e r c i d e s y n t h e s i s (20). Okwute e_t al_. (29) and V i g e_t a l . (30) have a c h i e v e d s y n t h e s i s o f g u i n e e n s i n e i n d e p e n d e n t l y and almost a t the same t i m e . S i n c e the f i r s t t o t a l s y n t h e s i s o f p i p e r c i d e , s e v e r a l f a c i l e and c o n v e n i e n t s y n t h e t i c r o u t e s t o p i p e r c i d e have been r e p o r t e d by s e v e r a l groups. Crombie

pipercid~was ^VW/vO-THP > ^0Λ

II

Λ

/

~ ^W^ >CNH Y V

S

/

Λ

_

>

Ο

+

[ΠΙθ]

dienoates. They -SO2 applied a cheletropic r e a c t i o n w i t h t h e r m a l S 0 e x t r u s i o n from c i s - 2 , 5 - d i a l k y l - 2 , 5 - d i h y d r o t h i o f e n e - 1 , 1 - d i o x i d e s g e n e r a t e d by a r e t r o D i e l s - A l d e r reaction. The ( E , E ) - d i e n o a t e thus o b t a i n e d has been r e p o r t e d to be o f 95% s t e r e o i s o m e r i c p u r i t y . In a d d i t i o n t o those s y n t h e s e s d e s c r i b e d above, t h e r e are many r e p o r t s on p e l l i t o r i n e analogue ((2E,4E)-2,4-dienamide) s y n t h e s i s . As an example, Mandai e t a l . r e p o r t e d ( 2 E , 4 E ) - c o n j u g a t e d d i e n o a t e s y n t h e s i s from a l k y l - S C ^ P h v i a a double e l i m i n a t i o n r e a c t i o n o f /?-acetoxy s u l f o n e w i t h good s e l e c t i v i t y (_33). T h i s might be a g e n e r a l l y a p p l i c a b l e s y n t h e t i c method f o r ( E , E ) - c o n j u g a t e d dienamides. 2

Structural

modifications.

As d e s c r i b e d , t h r e e P i p e r a c e a e amides [ I l i a ] , [ I l l b ] and [ I l l c ] showed d i s t i n c t i n s e c t i c i d a l and p h y s i o l o g i c a l c h a r a c t e r i s t i c s as summarized h e r e a f t e r ( 3 4 ) : (a) r a p i d knockdown a c t i o n (b) h i g h t o x i c i t y a g a i n s t p y r e t h r o i d r e s i s t a n t p e s t s ( c ) enhanced t o x i c i t y by m i x i n g [ I l i a ] , [ I l l b ] and [ I l l c ] ( j o i n t action)


180



(d) i n c r e a s e d m o l e c u l a r pellitorine

stability

i n comparison to t h a t o f

The c h e m i c a l s t r u c t u r e s o f these amides [ I l i a ] , [ I l l b ] and [ I l l c ] p r o v i d e v a l u a b l e i n f o r m a t i o n i n d e s i g n i n g more a c t i v e s y n t h e t i c analogues. Among these amides, d i h y d r o p i p e r c i d e [ i l l b ] was most t o x i c to a d z u k i bean w e e v i l s , so [ I l l b ] was chosen as the key s t r u c t u r a l l e a d f o r s y n t h e t i c m o d i f i c a t i o n s . The s t r u c t u r a l s i m i l a r i t i e s and d i f f e r e n c e s between p e l l i t o r i n e [ I ] and d i h y d r o p i p e r c i d e [ I l l b ] were q u i t e s u g g e s t i v e . A l t h o u g h both m o l e c u l e s have a common s t r u c t u r a l u n i t ( P a r t A and P a r t B: the N-isobutyl-(2E,4E)-2,4-dienamide m o i e t y , see F i g u r e 5 ) , the i n s e c t i c i d a l a c t i v i t y o f the former was f a r i n f e r i o r to t h a t o f the l a t t e r (Table I ) . As d e s c r i b e d i n the p r e v i o u s a r t i c l e ( 2 4 ) , p e l l i t o r i n e [ i ] i s q u i t e u n s t a b l e compound. However, w i t h the i n t r o d u c t i o n o f a p h e n y l r i n g i n the m o l e c u l e , [ I l l b ] , as w e l l as [ I l i a ] and [ I l l c ] , e x h i b i t e d improved s t a b i l i t y . These o b s e r v a t i o n s encouraged us t o s u s p e c t t h a t by changing the s t r u c t u r e , one might be a b l e to improve the i n s e c t i c i d a l a c t i v i t y o f t h i s c l a s s o f compounds. I n the c o r r e s p o n d i n g s t r u c t u r a l m o d i f i c a t i o n s t u d i e s , a d z u k i bean w e e v i l s ( a d u l t , male) were used as t e s t i n s e c t s . As shown i n F i g u r e 5, the key m o l e c u l e [ I l l b ] was d i v i d e d i n t o t h r e e p a r t s . D e t a i l s o f these syntheses were g i v e n i n our p r e v i o u s r e p o r t (350 and ( 3 6 ) . P a r t A: Our f i r s t study was conducted on the amine m o i e t y . The r e s u l t s are summarized i n T a b l e I I I . Among them, the n a t u r a l amide [ I l l b ] was most t o x i c (0.23 / i g / i n s e c t ) . By changing the amide m o i e t y from i s o b u t y l a m i n e to o t h e r branched o r c y c l i c a l i p h a t i c amines [ V b , c , d ] , t h e i r t o x i c i t i e s d e c r e a s e d by o n e - t h i r d o r o n e - f o u r t h compared with that o f [ I l l b ] , Only 1,2-dimethylpropylamide [Va] e x h i b i t e d the same o r d e r o f a c t i v i t y as t h a t o f [ I l l b ] . I n v e s t i g a t i o n of other amines, such as a n i l i n e o r benzylamine [Vf,g] o r the oxygen c o n t a i n i n g amine [Ve] , gave o n l y poor r e s u l t s . These r e s u l t s were i n good agreement w i t h our p r e v i o u s study i n which i n s e c t i c i d a l t o x i c i t i e s o f p e l l i t o r i n e [ I ] and i t s amine analogues were i n v e s t i g a t e d . I n t h a t communication, we r e p o r t e d t h a t p e l l i t o r i n e ( N - i s o b u t y l a m i d e ) was the most t o x i c amide and N - c y c l o h e x y l a m i d e was n e x t . Recently, E l l i o t t et a l . also i n v e s t i g a t e d the a d a p t a b i l i t y o f v a r i o u s amines f o r d i f f e r e n t types of u n s a t u r a t e d a c i d s i n c o n n e c t i o n w i t h i n s e c t i c i d a l a c t i v i t i e s (37). They s e l e c t e d s e v e r a l branched a l i p h a t i c amines, w i t h f o u r t o s i x carbon atoms, as the a p p r o p r i a t e components. These r e s u l t s a r e comparable w i t h our p r e v i o u s o b s e r v a t i o n s . In s h o r t , i t was c o n c l u d e d t h a t t h e r e i s a s t e r i c l i m i t a t i o n on the s i z e o f the amine i n r e l a t i o n t o the c o r r e s p o n d i n g i n s e c t i c i d a l a c t i v i t y . P a r t B: As a next s t e p , our study was f o c u s s e d on p a r t B; i . e . , w h i l e the N - i s o b u t y l a m i d e and 3,4-methylenedioxyphenyl m o i e t i e s were kept


13.

181


MIYAKADOETAL.

(IVd 9Λ^/0ΜΘ-

(EtO) P' 2

ô

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^

[IVb] T H P

.

0

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C H 0

T H p

. /VVWV°Me 0

_

d.e (—OHCww^OMe

[M] a, DHRH* g, OH

b, PCC

c, NaOMe

h, (COCD2

d, H® e, PCC

f, n-BuLi

i, i-BuN^

F i g u r e 4.

Synthesis

of p i p e r c i d e

ΝΗ

III

NH^

[Illb]

\ΑΜ^ Ύ

[Ilia].

d /O-

\oparte Figure

5.

part Β

part A

S t r u c t u r e o f p e l l i t o r i n e [ I ] and dihydropipercide [ I l l b ] .


[IVe]


182

Table I I I . I n s e c t i c i d a l a c t i v i t i e s o f l l - ( 3 , 4 - m e t h y l e n e d i o x y phenyl)-(2E,4E)-2,4-undecadienamides w i t h v a r i o u s amine m o i e t i e s to a d u l t C. c h i n e n s i s (male)

R (amine)

0.23

[Illb]


LD50 ( M g / i n s e c t )

[Va]

-NH^V

0.32

[Vb]

-NH-C

1.05

[Vc]

- N H O T

0.81

[Vd]

-NH-O

1.00 >10

[Ve] [Vf]

-NH-O

>10 >10

[Vg]

a) t o p i c a l a p p l i c a t i o n ( m o r t a l i t i e s were e v a l u a t e d a f t e r 24 h r ) . (Reproduced w i t h p e r m i s s i o n from Ref. 35. C o p y r i g h t 1985, P e s t i c i d e S c i e n c e S o c i e t y o f Japan.) unchanged, the s u i t a b i l i t y o f c o n j u g a t e d o l e f i n s , c h a i n l e n g t h and the i n t r o d u c t i o n o f an e t h e r group i n a s t r a i g h t c h a i n were examined ( T a b l e I V ) . The s a t u r a t e d or monoene amide [VIa,b] e x h i b i t e d no toxicity. By i n t r o d u c i n g a 3,4-methylenedioxyphenoxy group [VId] i n t o the m o l e c u l e , i n s t e a d o f the c o r r e s p o n d i n g b e n z y l group [ V i c ] , almost no change i n t h e i r a c t i v i t y was o b s e r v e d . However the phenoxy analogues were s u p e r i o r to the b e n z y l analogues i n view o f the s i m p l i c i t y o f t h e i r s y n t h e s i s . I n t r o d u c t i o n o f a methyl group at C-3 i n the (2E,4E)-dienamide moiety [ V i e ] showed marked enhancement o f a c t i v i t y . In c o n t r a s t , compound [ V l f ] , w i t h a (2Z,4E)-dienamide, e x h i b i t e d n e g l i g i b l e t o x i c i t y . P a r t C: The e f f e c t of the a r o m a t i c r i n g s u b s t i t u e n t s on i n s e c t i c i d a l a c t i v i t y was s t u d i e d w i t h the phenoxy analogues ( T a b l e V ) . I t t u r n e d out t h a t the 3,4-methylenedioxyphenyl group, a common s u b s t i t u e n t o f P i p e r a c e a e amides, was not e s s e n t i a l f o r t o x i c i t y . 4 - H a l o g e n - s u b s t i t u t e d analogues [VIId,e] e x h i b i t e d t e n times the t o x i c i t y o f the c o r r e s p o n d i n g m e t h y l e n e d i o x y analogue [ V I d ] . 3- H a l o g e n - s u b s t i t u t e d a n a l o g u e s , e s p e c i a l l y , 3-Br [ V l l h ] , as w e l l as the 3-C1 [ V l l g ] and 3-CF [ V l l i ] analogues, e x h i b i t e d the h i g h e s t toxicity. These amides were f i f t y to e i g h t y times more t o x i c than the n a t u r a l p r o d u c t , d i h y d r o p i p e r c i d e [ i l l c ] . The 4-CH-, 4-N0 and 4- OCH d e r i v a t i v e s ( [ V i l a ] , [ V l l b ] and [ V I I c ] , r e s p e c t i v e l y ) r e v e a l e d almost no t o x i c i t y . I t i s noteworthy t h a t the amides 3

2

3



13. MIYAKADO ET AL.

183

T a b l e TV. I n s e c t i c i d a l a c t i v i t i e s o f N - i s o b u t y l - ( 3 , 4 - m e t h y l e n e dioxyphenylaraides w i t h v a r i o u s carbon c h a i n l e n g t h to a d u l t £ · c h i n e n s i s (male) compds .

[nib]

Μ Ο Ρ ν ν ν ν ν Λ /

Ν

Η

'

ι

Β

υ

[VIa]

M D P w V W > H i a

[ V I b ]

M D P v w w Y N H i B u

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LD50

[via] [

V

I

E

[ V I f ]

H

i

o.23

B

u

MDP\ AAAAA^NHBu 0

M D P N

]

N

M D P w v W v Y

(Mg/insect)

0

A ^ A A A ^

0

N H B U

M D P y v w v y / ^ B u

>

1

0

MDP : 3,4-methylenedioxyphenyl, iBu : isobutyl. (Reproduced w i t h p e r m i s s i o n from R e f . 35. C o p y r i g h t 1985, P e s t i c i d e S c i e n c e S o c i e t y o f Japan.) [ V I I h , i ] showed the same o r d e r o f a c t i v i t y as t h a t o f f e n i t r o t h i o n , one o f the w e l l known organo phosphorous i n s e c t i c i d e s . T a b l e V. I n s e c t i c i d a l a c t i v i t i e s of N-isobutyl-12-(substituted phenoxy)-(2E,4E)-2,4-dodecadienamides to a d u l t C. c h i n e n s i s (male)

*

^ \ / w v w y

n

h

/

Y

compds . LD50 (/xg/insect) [VId] X = 3,4-methylenedioxy 2.00 [Vila] 4-CH. >10 [Vllb] 4-N0^ 8.00 [VIIc] 4-0CH >10 [Vlld] 4-C1 0.15 [Vile] 4-Br 0.25 [Vllf] 3,4-diCl 0.070 [Vllg] 3-C1 0.068 [Vllh] 3-Br 0.038 [Viii] 3-CF 0.043 pyrethrins 0.10 fenitrothion 0.045 (Reproduced w i t h p e r m i s s i o n from R e f . 36. C o p y r i g h t 1985, P e s t i c i d e S c i e n c e S o c i e t y o f Japan.) J

3

A c c o r d i n g to these s t r u c t u r a l m o d i f i c a t i o n s , N - i s o b u t y l - 1 2 - ( 3 trifluoromethylphenoxy)-(2E,4E)-2,4-dodecadienamide [ V i i i ] was s e l e c t e d as the eminent s t r u c t u r e .

Compound

[Viii]



184


e x h i b i t e d s t r o n g l e t h a l a c t i v i t y a g a i n s t a d z u k i bean w e e v i l l s as w e l l as r i c e stem b o r e r s ( C h i l o s u p p r e s s a l i s ) and h o u s e f l i e s . However, t h i s amide d i d not show any t o x i c i t y a g a i n s t tobacco cutworms (Spodoptera l i t u r a ) . F u r t h e r i n v e s t i g a t i o n s must be performed on the r e l a t i o n s h i p s between s t r u c t u r e and insect-spectrum o f t h i s amide s e r i e s . R e c e n t l y , s e v e r a l groups have r e p o r t e d s t r u c t u r a l m o d i f i c a t i o n research. B l a c k e_t a l . s e l e c t e d N - i s o b u t y l - 9 (3-trifluoromethylbenzyloxy)-(2E,4E)Γ 1 Q NH^Y 2,4-nonadienamide as one o f the most CF^^^V I p o t e n t amides a g a i n s t h o u s e f l i e s (37^). Q The s t r u c t u r e o f t h i s amide was c l o s e to our amide [ V l l i ] and the r e p o r t e d i n s e c t i c i d a l a c t i v i t y of t h i s amide was a l s o s i m i l a r to [ V l l i ] . E l l i o t t and h i s group conducted t h e i r work on d i f f e r e n t types of u n s a t u r a t e d amides (38.). They s e l e c t e d two amides: N-(2,2-dimethylpropyl)-6-(3,5-difluoroΡ p h e n y l )-(2E,4E)-2,4-hexadienamide ^ \ η a g a i n s t h o u s e f l i e s and N - i s o b u t y l - 6 Γ 1 U ( 3,4-dibromophenyl )-(2E,4E)-2,4-hexaΓ ^^VW\fyJ|-|A/ dienamide a g a i n s t mustard b e e t l e s , as I" p o t e n t amides, r e s p e c t i v e l y . They a l s o Q s t u d i e d the i n s e c t i c i d a l a c t i o n o f p h e n y l L H 0 hexadienamides on a p y r e t h r o i d - r e s i s t a n t B^'^ V\\^KIUA/ (super-kdr) s t r a i n of h o u s e f l i e s (39). NH Y As e x p e c t e d , these amides e x h i b i t e d l e t h a l and knockdown a c t i v i t i e s a g a i n s t the R - s t r a i n s as w e l l as the S-strains. S y n e r g i s t s were a l s o e f f e c t i v e i n i n c r e a s i n g the i n s e c t i c i d a l a c t i v i t i e s of these phenylhexadienamides ( 3 9 ) . X

Much p r o g r e s s have been a c h i e v e d s i n c e the 1979 d i s c o v e r y o f p i p e r c i d e [ I l i a ] as a new l e a d f o r i n s e c t i c i d a l amides. However, f u r t h e r i n v e s t i g a t i o n must be conducted f o r p r a c t i c a l development o f t h i s c l a s s of compounds as new i n s e c t i c i d e s . To s t a t e these g o a l s c l e a r l y , ( i ) More l i p o p h i l i c i t y must be g i v e n to the m o l e c u l e to i n c r e a s e the p e n e t r a t i o n r a t e through the insect c u t i c l e . ( i i ) I n s e c t i c i d a l potency must be improved as much as p o s s i b l e . ( i i i ) Mode of a c t i o n must be understood ( e s p e c i a l l y , against p y r e t h r o i d - r e s i s t a n t s t r a i n s ) . ( i v ) The c o n f o r m a t i o n s o f u n s a t u r a t e d amides ( i n s o l u t i o n ) must be c l a r i f i e d . C o n t i n u e d s y n t h e t i c work i s c u r r e n t l y i n p r o g r e s s and w i l l be r e p o r t e d i n due c o u r s e .

C o n c l u d i n g Remarks. In t h i s c h a p t e r , we

described

the p r o g r e s s of s e a r c h

on


the

13. MIYAKADO ET AL.


185


insecticidal unsaturated N-isobutylamides from the natural pellitorine era to Piperaceae amides including isolation, structure elucidation, mode of action, synthesis and structural modifications. Most of the potent insecticides are modeled on natural products. They include esfenvalerate, based on the pyrethrins of chrysanthemum flowers, and caltap, modeled on a marine worm toxin, nereistoxin. This research on insecticidal unsaturated amides is s t i l l in progress, and future discoveries will certainly bring this type of amide to market. We believe that the present research offers an innovative example of how natural product chemistry can provide new leads for tomorrow's agrochemicals. To this end, the present chapter should be read in conjunction with references (1) and (2). Acknowledgment. We wish to thank to Dr. H. Yoshioka of the Institute of Physical and Chemical Research, Japan and Prof. N. Nakatani of the Faculty of Science of Living, Osaka City University, Japan for their valuable advice. We are indebted to Dr. David P. Richardson of the Department of Chemistry, Williams College, MA, USA for his critical reading of the manuscript. Finally, the authors wish to thank to Dr. Y. Nishizawa of the Sumitomo Chemical Co. Ltd., for encouragement. Literature Cited. 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11.

Jacobson, M. In Naturally Occurring Insecticides; Jacobson, Μ., Crosby, D. G., Ed.; Marcel Dekker: New York, 1971; p 137. Su, H. C. F. In Comprehensive Insect Physiology Biochemistry and Pharmacology; Kerkut, G. A., Gilbert, L. I., Ed.; Pergamon Press: Oxford, 1985; Vol. 12, p 603. Dunstan, W. R.; Garnett, H. J. Chem. Soc. 1895, 67, 94. Crombie, L. Chem. Ind. (London) 1952, 2997. Jacobson, M. J. Amer. Chem. Soc. 1953, 75, 2584. Jacobson, M. J. Amer. Chem. Soc. 1949, 71, 366. LaLonde, R. T.; Wong, C. F.; Hofstead, S. J.; Morris, C. D.; Gardner, L. C. J. Chem. Ecol. 1980, 6, 35. Jondiko, I. J. O. Phytochem. 1986, 25, 2289. Kubo, I.; Klocke, J. Α.; Matsumoto, T.; Kamikawa, T. In Pestic. Synth. Ration. Approaches; ACS Symposium Series No. 255; American Chemical Society: Washington, DC, 1984; p 163. Yasuda, I.; Takeya, K.; Itokawa, H. Chem. Pharm. Bull. 1981, 29, 1791. Greger, H.; Hofer, O. Phytochem. 1984, 23, 1173. Shoji, N.; Umeyama, Α.; Saito, N.; Takemoto, T.; Kajiwara, Α., Ohizumi, Y. J. Pharm. Sci. 1986,75,1188. Nakatani, N.; Inatani, R.; Ohta, H.; Nishioka, A. Environ. Health Perspect. 1986, 67, 135. Atal, C. K.; Dhar, K. L.; Gupta, O. P.; Gupta, S.C.;Saxena, B. P.; Koul, O. Indian J. Exp. Biol. 1977, 15, 1230.


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Insecticidal Unsaturated Isobutylamides - American Chemical Society

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