Insect Pheromone Technology - American Chemical Society

2 Some Aspects of the Synthesis of Insect Sex Pheromones CLIVE A. HENRICK, ROBERT L. CARNEY, and RICHARD J. ANDERSON

Downloaded by PURDUE UNIV on August 28, 2014 | http://pubs.acs.org Publication Date: June 18, 1982 | doi: 10.1021/bk-1982-0190.ch002

Zoecon Corporation, Chemical Research Department, Palo Alto, C A 94304

Considerable progress has been made over the past decade in the a p p l i c a t i o n of i n s e c t sex pheromones to pest c o n t r o l programs. As the commercial appli cations of pheromones have expanded, the demand for l a r g e r q u a n t i t i e s of c e r t a i n of these compounds has i n c r e a s e d , but many of the p u b l i s h e d syntheses cannot readily be c a r r i e d out on a kilogram s c a l e . We have e x t e n s i v e l y i n v e s t i g a t e d a l t e r n a t i v e s y n t h e t i c methods f o r the p r e p a r a t i o n of pheromones in h i g h stereochemical p u r i t y . In t h i s paper we d i s c u s s some of the practical aspects of the l a r g e r s c a l e s y n t h e s i s (l00g to k i l o g r a m q u a n t i t i e s ) of i n s e c t sex pheromones w i t h emphasis on the types of compounds that are of p o t e n t i a l use in a g r i c u l t u r e . R e c e n t l y s e v e r a l e x c e l l e n t r e v i e w s have appeared w h i c h d e s c r i b e v a r i o u s a s p e c t s o f pheromone s y n t h e s i s ( 1 - 7 ) . A l t h o u g h many e l e g a n t s y n t h e s e s o f pheromones h a v e b e e n p u b l i s h e d , f e w of these r o u t e s a r e s u i t a b l e f o r p r o d u c i n g k i l o g r a m q u a n t i t i e s . E f f i c i e n t s y n t h e s i s o f t h e s e compounds depends o n d e v e l o p i n g u n c o m p l i c a t e d s y n t h e t i c r o u t e s and s i m p l e p u r i f i c a t i o n p r o c e d u r e s . Purification The c h e m i c a l a n d s t e r e o c h e m i c a l p u r i t i e s o f s y n t h e t i c pheromones a r e o f t e n o f c r i t i c a l i m p o r t a n c e f o r t h e i r u s e i n s u r v e y a n d m o n i t o r i n g t r a p s (_2,5). The p r o b l e m s a s s o c i a t e d w i t h i n h i b i t o r s r e q u i r e s , i n g e n e r a l , t h a t t h e s y n t h e t i c p r o d u c t s have high chemical p u r i t y . The f a c t t h a t a p r e c i s e m i x t u r e o f geometr i c a l isomers i s u s u a l l y e s s e n t i a l i f t h e s y n t h e t i c m a t e r i a l i s to be an e f f e c t i v e a t t r a c t a n t i n t h e f i e l d r e q u i r e s t h a t t h e s y n t h e t i c r o u t e g i v e a p r o d u c t o f r e p r o d u c i b l e and p r e d i c t a b l e stereochemical composition.

0097-6156/82/0190-0027$09.50/0 © 1982 American Chemical Society

In Insect Pheromone Technology: Chemistry and Applications; Leonhardt, B., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1982.


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INSECT P H E R O M O N E

TECHNOLOGY

One o f t h e s i m p l e s t methods o f p u r i f i c a t i o n i n v o l v e s c r y s t a l l i z a t i o n o f s y n t h e t i c i n t e r m e d i a t e s (and sometimes o f t h e pheromone i t s e l f ) a t l o w t e m p e r a t u r e . T h i s t e c h n i q u e has been e x t e n s i v e l y used i n the p u r i f i c a t i o n of f a t t y a c i d s ( 8 , 9 ) . L i k e u n s a t u r a t e d f a t t y a c i d s , many o f t h e r e l a t e d a l c o h o l s a r e v e r y i n s o l u b l e i n h y d r o c a r b o n s o l v e n t s a t low temperature. We r o u t i n e l y p u r i f y i n t e r m e d i a t e s and p r o d u c t s , when a p p l i c a b l e , by l o w t e m p e r a t u r e c r y s t a l l i z a t i o n f r o m p e n t a n e o r h e x a n e , u s i n g a v a c u u m - j a c k e t e d g l a s s f i l t e r s i m i l a r t o t h e one d e s c r i b e d by S c h l e n k ( 8 ) . Q u a n t i t i e s o f m a t e r i a l r a n g i n g f r o m one gram t o s e v e r a l h u n d r e d grams c a n be c o n v e n i e n t l y and e f f i c i e n t l y p u r i f i e d by t h i s method. A n o t h e r p o w e r f u l p u r i f i c a t i o n method, a p p l i c a b l e to l a r g e r s c a l e w o r k , i n v o l v e s t h e use o f u r e a i n c l u s i o n c o m p l e x e s . These c r y s t a l l i n e c l a t h r a t e s , i n which the "guest m o l e c u l e s a r e entrapped w i t h i n c a v i t i e s which appear i n the host h e l i c a l l a t t i c e , h a v e b e e n u s e d f o r many y e a r s i n t h e s e p a r a t i o n and p u r i f i c a t i o n o f f a t t y a c i d s ( 9 , 1 0 ) and more r e c e n t l y i n pheromone p u r i f i c a t i o n (11-14). We h a v e made e x t e n s i v e u s e o f u r e a c l a t h r a t i o n o v e r t h e p a s t t e n y e a r s and h a v e f o u n d t h e t e c h n i q u e t o be a v a l u a b l e aid i n p u r i f i c a t i o n . In general, for s t r a i g h t - c h a i n a l i p h a t i c compounds, t h e u r e a i n c l u s i o n c o m p l e x e s f o r m p r e f e r e n t i a l l y w i t h t h e s a t u r a t e d a n a l o g u e s , f o l l o w e d by t h e _E u n s a t u r a t e d a n a l o g u e s and t h e n by t h e c o r r e s p o n d i n g isomers. For example, a c o m m e r c i a l s a m p l e o f ( Z ) - 9 - t e t r a d e c e n - l - o l c o n t a i n i n g 3% t e t r a d e c a n o l and 7% ( _ E ) - 9 - t e t r a d e c e n - l - o l c a n be p u r i f i e d by s e l e c t i v e c l a t h r a t i o n o f b o t h t e t r a d e c a n o l and t h e ( _ E ) - o l e f i n . The i n c l u d e d m a t e r i a l s c a n be r e a d i l y r e c o v e r e d by t r e a t m e n t w i t h w a t e r . Complex f o r m a t i o n i s a l s o i n f l u e n c e d by t h e s k e l e t a l s t r u c t u r e and by t h e n a t u r e o f t h e t e r m i n a l f u n c t i o n a l g r o u p . D i f f e r e n t p o l a r t e r m i n a l groups can s u b s t a n t i a l l y a f f e c t the s e l e c t i v i t y of c l a t h r a t e formation (14). S e v e r a l c h e m i c a l p u r i f i c a t i o n t e c h n i q u e s c a n be u s e d t o separate and _E i s o m e r s . For example, attempted s e p a r a t i o n o f I and I I ( F i g u r e 1; components o f t h e s e x pheromone o f t h e r e d b o l l w o r m moth, D i p a r o p s i s c a s t a n e a ) by c h r o m a t o g r a p h y on s i l i c a g e l - A g N 0 ~ g i v e s o n l y p a r t i a l r e s o l u t i o n . However, t r e a t m e n t o f a m i x t u r e w i t h l i q u i d s u l f u r d i o x i d e a t -20° f o l l o w e d by c h r o m a t o g r a p h y on F l o r i s i l t o remove t h e u n r e a c t e d Z i s o m e r g i v e s the 1 , 4 - c y c l o - a d d i t i o n product I I I . Thermolysis of the s u l f o l e n e I I I o c c u r s s t e r e o s p e c i f i c a l l y (15) t o g i v e t h e _E d i e n e I i n h i g h y i e l d and 99+% p u r i t y ( 1 6 ) . The Z i s o m e r i s o b t a i n e d by t r e a t i n g a m i x t u r e w i t h e x c e s s t e t r a c y a n o e t h y l e n e i n t e t r a h y d r o f u r a n (THF) a t room t e m p e r a t u r e w h i c h s e l e c t i v e l y r e a c t s w i t h t h e 12 d i e n e . C h r o m a t o g r a p h y o f t h e p r o d u c t on F l o r i s i l enables the s e p a r a t i o n of the Z isomer I I from the D i e l s - A l d e r a d d u c t o f t h e E i s o m e r I ( 1 6 ) . We h a v e o f t e n u s e d t h i s l a t t e r technique. For example, treatment o f a m i x t u r e of E>E and _Z,_E c o n j u g a t e d d i e n e i s o m e r s w i t h t e t r a c y a n o e t h y l e n e s e l e c t i v e l y removes t h e E,_E i s o m e r as i t s D i e l s - A l d e r a d d u c t ( s e e 11


HENRICK E T A L .

Synthesis of Insect Sex

Pheromones


OAc

A=AVW°

A c

III Figure 1.

Separation of two components of the pheromone of the red bollworm moth.



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a l s o r e f s _17 and 1 8 ) . S e l e c t i v e u r e a c l a t h r a t i o n c a n a l s o be u s e d t o remove t h e E E i s o m e r f r o m a m i x t u r e o f c o n j u g a t e d d i e n e s o r t o remove t h e _E i s o m e r f r o m a m i x t u r e o f c o n j u g a t e d enynes ( e . g . 1 2 ) . y


Hydrogenation of Acetylenes One v e r y u s e f u l method o f o l e f i n s y n t h e s i s i n v o l v e s t h e i n t r o d u c t i o n o f a n a c e t y l e n e , d i y n e , o r enyne group i n t o a m o l e c u l e f o l l o w e d by semihydrogenation o r r e d u c t i o n o f t h e t r i p l e b o n d ( s ) . F o r t h e p r e p a r a t i o n o f a Z o l e f i n one o f t h e most c o n v e n i e n t methods i s t h e p a r t i a l s e l e c t i v e c a t a l y t i c hydrogenation o f an i s o l a t e d alkyne over L i n d l a r c a t a l y s t [Pd-CaCOg-PMOAc^] i n t h e presence o f s y n t h e t i c q u i n o l i n e ( 1 9 ) . S e m i h y d r o g e n a t i o n i s p o s s i b l e b e c a u s e t h e a c e t y l e n e group a d s o r b s very strongly to the catalyst surface. The o l e f i n p r o d u c t i s p r o t e c t e d f r o m s u b s e q u e n t r e a c t i o n by b e i n g r a p i d l y d i s p l a c e d f r o m t h e c a t a l y s t s u r f a c e by t h e a c e t y l e n e . When most o f t h e l a t t e r h a s b e e n consumed, f u r t h e r r e a c t i o n o f t h e o l e f i n i s possible. The s u p e r i o r i t y o f c o r r e c t l y p r e p a r e d L i n d l a r c a t a l y s t i s due t o i t s r e l a t i v e i n a c t i v i t y f o r e i t h e r h y d r o g e n a t i o n o r stereoisomerization of Z o l e f i n s . Non-polar s o l v e n t s such as pentane o r hexane a r e p r e f e r a b l e t o a l c o h o l s f o r t h e s e h y d r o g e n a t i o n s . When t h e r e a c t i o n i s c a r r i e d o u t a t room t e m p e r a t u r e , t h e p r o d u c t c o n t a i n s 1.5-4% o f t h e c o r r e s p o n d i n g _E i s o m e r . A t h i g h e r t e m p e r a t u r e s , e s p e c i a l l y i n a l c o h o l i c s o l v e n t s , t h e p e r c e n t a g e o f t h e E i s o m e r c a n be a s h i g h a s 5-10%. We f o u n d t h a t i f t h e h y d r o g e n a t i o n o f t h e a l k y n e o v e r L i n d l a r c a t a l y s t ( p o i s o n e d by s y n t h e t i c q u i n o l i n e ) i s c a r r i e d o u t a t l o w e r t e m p e r a t u r e s (-10 t o -30°) i n p e n t a n e , h e x a n e , o r hexane-THF, the r e s u l t i n g o l e f i n c o n t a i n s ^ 0 . 5 % o f t h e c o r r e s p o n d i n g _E isomer ( 2 ) . A s i m i l a r o b s e r v a t i o n has been r e c e n t l y r e p o r t e d by R o s s i a n d c o w o r k e r s (_3, 20) . We h a v e a l s o f o u n d w i t h L i n d l a r c a t a l y s t o r w i t h quinoline-poisoned palladium-on-barium s u l f a t e , t h a t t h e s m a l l amount o f _E i s o m e r t h a t i s p r o d u c e d , i s formed t h r o u g h o u t t h e r e a c t i o n ( 2 ) . The E:Z i s o m e r r a t i o i n t h e o l e f i n product i s nearly constant during the hydrogenation but the r a t i o d o e s i n c r e a s e a f t e r t h e a l k y n e i s consumed. I t h a s b e e n previously reported, with palladium catalysts i n general, that t h e f o r m a t i o n o f IS o l e f i n o c c u r s v i a r e - a d s o r p t i o n and i s o m e r i z a t i o n o f t h e Z o l e f i n and t h a t t h e s t e r e o m u t a t i o n o f t h e Z o l e f i n o c c u r s o n l y i n t h e presence o f hydrogen and i s n o t a major problem u n t i l most o f t h e a c e t y l e n e h a s b e e n consumed ( 1 9 c , 2 1 ) . Our o b s e r v a t i o n s s u g g e s t t h a t t h e E o l e f i n c a n a l s o be formed d u r i n g the h y d r o g e n a t i o n o f t h e a l k y n e by e i t h e r n o n - s t e r e o s p e c i f i c h y d r o g e n a t i o n or,more l i k e l y , b y i s o m e r i z a t i o n o f t h e newly-formed Z o l e f i n on t h e c a t a l y s t s u r f a c e b e f o r e t h e d e s o r p t i o n t a k e s p l a c e . I n o r d e r t o m i n i m i z e t h e i s o m e r i z a t i o n t o E o l e f i n and t h e over-reduction, i t i sa d v i s a b l e to use the s m a l l e s t p r a c t i c a l r a t i o of c a t a l y s t t o s u b s t r a t e . Even w i t h t h e L i n d l a r c a t a l y s t , a h i g h c a t a l y s t t o acetylene r a t i o can r e s u l t i n a r a p i d Z to E isomer-



2.

HENRICK E T A L .


Pheromones

31

i z a t i o n of the o l e f i n a f t e r the disappearance of the acetylene ( 2 2 a ) . The p r e s e n c e o f t h e s m a l l amount o f q u i n o l i n e a s a p o i s o n i s advantageous f o r s e l e c t i v i t y b u t t h e success o f t h e L i n d l a r c a t a l y s t i s e v e n more d e p e n d e n t on t h e p o i s o n i n g b y l e a d a c e t a t e . Use o f p a l l a d i u m - o n - c a l c i u m c a r b o n a t e , e v e n i n t h e p r e s e n c e o f s y n t h e t i c q u i n o l i n e , u s u a l l y g i v e s v e r y poor r e s u l t s (e.g. r e f 2 3 ) . R e p r o d u c i b i l i t y o f c a t a l y s t p r e p a r a t i o n c a n be a p r o b l e m . We h a v e found t h a t t h e a c t i v i t y and s t e r e o s e l e c t i v i t y o f t h e L i n d l a r c a t a l y s t c a n v a r y even among b a t c h e s p u r c h a s e d f r o m t h e same manufacturer. Thus, i t i s b e s t t o t e s t each b a t c h o f c a t a l y s t f o r b o t h a c t i v i t y and s e l e c t i v i t y p r i o r t o i t s use. * A l s o i t i s u s u a l l y necessary t o b e g i n w i t h pure alkyne t o prevent t o t a l poisoning of the catalyst. A l t e r n a t i v e c a t a l y s t s such as palladium-on-barium s u l f a t e ( p o i s o n e d b y s y n t h e t i c q u i n o l i n e ) (24) , "P-2" n i c k e l b o r i d e ( w i t h e t h y l e n e d i a m i n e ) ( 2 5 ) , and o t h e r n i c k e l c a t a l y s t s ( 1 9 c ) can be used i n p l a c e o f L i n d l a r c a t a l y s t . However, i n o u r hands s e l e c t i v e h y d r o g e n a t i o n o f t r i p l e bonds t o Z o l e f i n s p r o c e e d s with the greatest stereoselectivity with Lindlar catalyst. Palladium-on-barium s u l f a t e ( i n ethanol w i t h quinoline) can give c o n s i d e r a b l e o v e r - r e d u c t i o n and i s o m e r i z a t i o n t o t h e E i s o m e r ( 2 2 a ) . Use o f "P-2" n i c k e l b o r i d e a s t h e c a t a l y s t a t room t e m p e r a t u r e u s u a l l y g i v e s c a . 2% o f t h e E i s o m e r ( e . g . 2 3 ) . I n c o n t r a s t t o L i n d l a r c a t a l y s t we h a v e f o u n d t h a t t h e h y d r o g e n a t i o n o f a n a l k y n e o v e r e t h y l e n e d i a m i n e - p o i s o n e d "P-2" n i c k e l b o r i d e o r q u i n o l i n e - p o i s o n e d palladium-on-barium s u l f a t e always g i v e s a m i n o r amount o f t h e s a t u r a t e d h y d r o c a r b o n i n a d d i t i o n to t h e o l e f i n . The r a t i o o f s a t u r a t e d h y d r o c a r b o n t o o l e f i n ( a b o u t 0.01) a l s o i s n e a r l y c o n s t a n t t h r o u g h o u t t h e h y d r o g e n a t i o n u n t i l t h e a l k y n e i s consumed, and t h e n i t i n c r e a s e s . F u r t h e r r e a c t i o n o f t h e a l k e n e on t h e c a t a l y s t s u r f a c e b e f o r e d e s o r p t i o n would e x p l a i n these r e s u l t s . P a r t i a l h y d r o g e n a t i o n o f s k i p p e d 1 , 4 - d i y n e s o r 1,4-enynes over L i n d l a r c a t a l y s t proceeds s t e r e o s e l e c t i v e l y i n h i g h y i e l d ( e . g . 2 6 ) , b u t t h e p a r t i a l h y d r o g e n a t i o n o f t r i p l e bonds w h i c h a r e c o n j u g a t e d w i t h d o u b l e o r t r i p l e bonds p l a c e s h i g h demands on t h e c a t a l y s t . W i t h t h e s e compounds one does n o t , i n g e n e r a l , observe a prominent break i n t h e r a t e o f hydrogen uptake a t t h e completion o f semihydrogenation. Mixtures are usually obtained containing 40% o f t h e d e s i r e d conjugated d i e n e (2,27-29). An a l t e r n a t i v e method t o t h e s e l e c t i v e s e m i h y d r o g e n a t i o n of an i n t e r n a l alkyne i n v o l v e s hydroboration w i t h a s t e r i c a l l y h i n d e r e d r e a g e n t ( e . g . d i s i a m y l b o r a n e ) , and p r o t o n o l y s i s o f t h e vinylborane intermediate with a carboxylic acid to give the Z a l k e n e ( 3 0 ) . T h i s method u s u a l l y g i v e s good y i e l d s o f o l e f i n s (^98% Z i s o m e r ) a n d c a n e v e n b e a p p l i e d s u c c e s s f u l l y t o t h e r e d u c t i o n o f polymer-bound a l k y n e s t o polymer-bound Z a l k e n e s ( 3 1 ) . F o r n o n - c o n j u g a t e d a l k y n e s we p r e f e r t o u s e h y d r o g e n a t i o n over L i n d l a r c a t a l y s t a t l o w temperature because o f i t s g r e a t e r s t e r e o s e l e c t i v i t y and convenience b u t f o r c o n j u g a t e d d i y n e s and e n y n e s t h i s h y d r o b o r a t i o n - p r o t o n o l y s i s method i s v a s t l y s u p e r i o r .


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Reduction

TECHNOLOGY

of Acetylenes

The p r e p a r a t i o n o f p u r e i s o l a t e d E o l e f i n s i s r e a d i l y a c c o m p l i s h e d by t h e r e d u c t i o n o f an a l k y n e w i t h m e t a l l i c s o d i u m o r l i t h i u m i n l i q u i d ammonia ( 2 7 , 3 2 ) . This r e a c t i o n i s p r e f e r a b l y c a r r i e d o u t b y t h e a d d i t i o n o f t h e a l k y n e i n an e t h e r t o a m i x t u r e o f s o d i u m ( o r l i t h i u m ) i n l i q u i d ammonia a t -30°. The a l t e r n a t i v e r e v e r s e a d d i t i o n p r o c e d u r e c a n g i v e i n c o m p l e t e r e d u c t i o n o f t h e a l k y n e ( 3 3 ) . An i n c r e a s e i n t h e r a t i o o f l i q u i d ammonia t o a l k y n e ( 3 4 ) , t h e a d d i t i o n o f c o - s o l v e n t s ( 2 3 ) , the use o f l i t h i u m r a t h e r than sodium, o r t h e use o f a h i g h e r temperature i n an a u t o c l a v e a r e a d v i s a b l e f o r t h e r e d u c t i o n o f h i g h m o l e c u l a r w e i g h t a l k y n e s t o overcome s o l u b i l i t y p r o b l e m s which can a l s o r e s u l t i n incomplete r e d u c t i o n . The r e s u l t i n g o l e f i n i s u s u a l l y v e r y p u r e E i s o m e r c o n t a i n i n g no d e t e c t a b l e i s o m e r . Use o f an a l c o h o l a s a c o - s o l v e n t and p r o t o n donor c a n a c c e l e r a t e the r e d u c t i o n , but the r e s u l t i n g o l e f i n then contains a m i n o r amount o f t h e Z i s o m e r . P o l y m e r - b o u n d a l k y n e s c a n n o t be s u c c e s s f u l l y r e d u c e d w i t h s o d i u m i n l i q u i d ammonia ( 3 5 ) . C o n j u g a t e d 12,12 d i e n e s c a n n o t b e p r e p a r e d , i n g e n e r a l , b y the r e d u c t i o n o f conjugated d i y n e s w i t h sodium o r l i t h i u m i n l i q u i d ammonia ( 3 6 ) . A l s o t h e r e d u c t i o n o f 1 , 4 - d i y n e s ( i n t h e a b s e n c e o f added a l c o h o l ) i s o f t e n a c c o m p a n i e d b y , o r p r e c e d e d b y , b a s e - c a t a l y z e d i s o m e r i z a t i o n t o a compound w i t h c o n j u g a t e d u n s a t u r a t i o n , w h i c h i s t h e n r e d u c e d t o t h e monoene l e v e l ( 2 7 ) . However, one c a n s u c c e s s f u l l y r e d u c e a 1 , 4 - d i y n e o r a n ( E ) - l , 4 enyne i n good y i e l d t o t h e c o r r e s p o n d i n g ( E , E ) - l , 4 - d i e n e w i t h s o d i u m ( o r l i t h i u m ) i n l i q u i d ammonia-THF i n t h e p r e s e n c e o f t e r t b u t y l a l c o h o l (2,37). Reduction o f a 3 - a l k y n - l - o l such as IVa ( F i g u r e 2) w i t h s o d i u m i n l i q u i d ammonia-THF i s n o t c o m p l e t e l y s t e r e o s e l e c t i v e a n d t h e p r o d u c t i s r e p o r t e d t o c o n t a i n 2-4% o f t h e 3Z^ i s o m e r ( 2 3 ) . However, r e d u c t i o n o f t h e c o r r e s p o n d i n g t e t r a h y d r o p y r a n y l e t h e r IVb p r o c e e d s , i n o u r hands, w i t h h i g h s t e r e o s e l e c t i v i t y t o t h e 3E,13Z^ i s o m e r Vb. ( c f . r e f 2 3 ) . ( E ) - O l e f i n s c a n a l s o be prepared s t e r e o s e l e c t i v e l y i n h i g h y i e l d by t h e slow r e a c t i o n o f t h e c o r r e s p o n d i n g i s o l a t e d a l k y n e w i t h a l a r g e e x c e s s o f l i t h i u m a l u m i n u m h y d r i d e (LAH) i n d i g l y m e a t 140° ( 2 0 b , 3 8 ) . R e d u c t i o n o f a n a l k y n e w i t h MgH^-CuI o r MgHp-CuOtert-Bu i n THF a t -78° i s r e p o r t e d t o g i v e t h e ( Z ) - a l k e n e i n good y i e l d w i t h very high s t e r e o s e l e c t i v i t y (39). Reduction of the t r i p l e b o n d i n a c o n j u g a t e d enyne w i t h a l a r g e e x c e s s o f a c t i v a t e d powdered z i n c i n aqueous n - p r o p a n o l p r o c e e d s w i t h Z s t e r e o s e l e c t i v i t y (28,40). We h a v e f o u n d t h a t ( E ) - l l - t e t r a d e c e n - 9 - y n l - o l i s reduced under these c o n d i t i o n s t o ( 9 Z , l l E ) - 9 , l l - t e t r a d e c a d i e n - l - o l w i t h l e s s t h a n 0.1% c o n t a m i n a t i o n b y o t h e r i s o m e r s . However, t h i s method a p p e a r s s u i t e d o n l y t o s m a l l s c a l e w o r k because o f the l a r g e excess of z i n c r e q u i r e d .



2.

HENRICK E T A L .


33

Pheromones

OR

IVa,

R= H

IVb,

R= T H P

Li liq N H - T H F 3

/vwwww" «

3

Va, Figure 2.

R=

H

Vb, R= T H P Reduction of a 3-alkyn-l-ol and its THP ether.


34



(9Z,12E)-9,12-Tetradecadien-l-yl

Acetate

TECHNOLOGY

(XIV)

The compound XIV o c c u r s w i d e l y as a component o f l e p i d o p t e r o u s s e x pheromones, e s p e c i a l l y o f p e s t s o f s t o r e d g r a i n and d r i e d f r u i t (2_) . The s y n t h e s i s d i s c u s s e d b e l o w i s an example of the p r e p a r a t i o n of a "skipped" or "methylene-interrupted" 1 , 4 - d i e n e . I t i s i m p o r t a n t t o h a v e p u r e XIV f o r pheromone s t u d i e s s i n c e t h e o t h e r s t e r e o i s o m e r s c a n a c t as i n h i b i t o r s o f t h e b e h a v i o r a l r e s p o n s e i n some s p e c i e s . Most of the p u b l i s h e d s y n t h e s e s of XIV have been p r e v i o u s l y s u m m a r i z e d ( 2 ) . One o f t h e more p r a c t i c a l l a r g e - s c a l e s y n t h e s e s o f XIV i n h i g h p u r i t y i s t h e one o u t l i n e d i n F i g u r e s 3 and 4, w h i c h i s b a s e d on an e a r l i e r s y n t h e s i s by J a c o b s o n and c o - w o r k e r s ( 4 1 ; see a l s o 2 0 b ) . Thus t h e d i o l i s c o n v e r t e d t o t h e b r o m o h y d r i n V I b y r e a c t i o n w i t h aqueous HBr i n a t w o - p h a s e s y s t e m . The c r u d e p r o d u c t i s p u r i f i e d by c o n v e r s i o n o f t h e a l c o h o l g r o u p t o a n o n - v o l a t i l e b o r a t e e s t e r w i t h t r i e t h y l b o r a t e and r e m o v a l o f t h e 1 , 8 - d i b r o m o o c t a n e by d i s t i l l a t i o n . A f t e r h y d r o l y s i s of the b o r a t e any r e s i d u a l d i o l i s removed by e x t r a c t i o n w i t h w a t e r . The b r o m o h y d r i n i s t h e n q u a n t i t a t i v e l y c o n v e r t e d t o t h e THP e t h e r , w h i c h i s added t o L i C E C H - e t h y l e n e d i a m i n e c o m p l e x i n d i m e t h y l s u l f o x i d e to give VII i n very high y i e l d . No p u r i f i c a t i o n i s r e q u i r e d i n e i t h e r of these steps. A s h o r t e r s y n t h e s i s of 9 - d e c y n - l - o l ( I X ) was s u b s e q u e n t l y d e v e l o p e d . An a c e t y l e n e " z i p p e r " i s o m e r i z a t i o n (42) w i t h s o d i o - l , 3 - d i a m i n o p r o p a n e i s used to convert e i t h e r 3-decyn-l-ol ( V I I I ) or 2-decyn-l-ol i n t o the t e r m i n a l a l k y n o l IX. Both of these s t a r t i n g a l k y n o l s are c o m m e r c i a l l y a v a i l a b l e and t h e s a v i n g i n l a b o r i s a d v a n t a g e o u s f o r moderate s c a l e p r o d u c t i o n . One u s e f u l method f o r p r e p a r i n g ( E ) - 1 , 4 - e n y n e s i n v o l v e s the cuprous s a l t - c a t a l y z e d c o u p l i n g of 1-alkynylmagnesium h a l i d e s w i t h a l l y l i e h a l i d e s i n e t h e r o r THF ( 4 3 ) . We u t i l i z e d ( F i g u r e 4) the c o u p l i n g of l-chloro-2-butene i n THF i n t h e p r e s e n c e o f d i l i t h i u m t e t r a c h l o r o c u p r a t e , w i t h the Grignard reagent prepared from V I I ( w i t h EtMgCl), which g i v e s the (E)-l,4-enyne a l c o h o l X I I , mp. 19°, i n 65% y i e l d a f t e r h y d r o l y s i s o f t h e p r o t e c t i n g g r o u p and p u r i f i c a t i o n ( s e e b e l o w ) . The c r u d e p r o d u c t o f t h e c o u p l i n g r e a c t i o n c o n s i s t s o f a m i x t u r e o f t h e a l l y l i c i s o m e r s X, X I and X I I i n t h e r a t i o o f 7.5:7.5:85, r e s p e c t i v e l y , u n d e r t h e s e conditions. The i s o m e r i c c o m p o s i t i o n o f t h e p r o d u c t a p p e a r s t o be s i m i l a r i r r e s p e c t i v e of the i s o m e r i c c o m p o s i t i o n of the s t a r t i n g a l l y l i c c h l o r i d e ( c f . 44, 4 5 ) . Thus t e c h n i c a l c r o t y l c h l o r i d e f r o m A l d r i c h C h e m i c a l Company [ c o n t a i n i n g 59% ( E ) - l - c h l o r o - 2 b u t e n e , 11% o f t h e ( Z ) - i s o m e r and 30% o f 3 - c h l o r o - l - b u t e n e ] is used w i t h o u t p u r i f i c a t i o n . However, t h e r a t i o o f i s o m e r s i s i n f l u e n c e d somewhat by t h e r e a c t i o n c o n d i t i o n s . The s t r a i g h t c h a i n i s o m e r s a r e f a v o r e d o v e r X by a l o w e r r e a c t i o n t e m p e r a t u r e , t h e u s e o f c h l o r i d e r a t h e r t h a n b r o m i d e a s t h e c o u n t e r i o n , and d i l u t i o n o f t h e r e a c t i o n m i x t u r e w i t h THF. However, p r a c t i c a l s c a l e up c o n s i d e r a t i o n s r e q u i r e t h a t t h e r e a c t i o n be r u n a t h i g h e r c o n -


HENRICK E T A L .


Pheromones


2.


35


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INSECT

PHEROMONE

TECHNOLOGY

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HENRICK

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Pheromones

37

c e n t r a t i o n t h a n t h e optimum r e q u i r e d f o r r e g i o s e l e c t i v i t y . The c r u d e enyne X I I i s p u r i f i e d b y f i l t r a t i o n t h r o u g h a n e q u a l w e i g h t o f s i l i c a g e l i n e t h e r - h e x a n e ( t o remove c a t a l y s t p o i s o n s w h i c h i n t e r f e r e w i t h t h e h y d r o g e n a t i o n s t e p ) f o l l o w e d by r e p e a t e d c r y s t a l l i z a t i o n f r o m h e x a n e a t -30° t o remove t h e b r a n c h e d c h a i n i s o m e r X a n d m o s t o f t h e Z i s o m e r X I . The e n y n o l X I I i s t h e n s e m i h y d r o g e n a t e d o v e r L i n d l a r c a t a l y s t i n hexane-THF a t 0° i n t h e presence o f q u i n o l i n e . C r y s t a l l i z a t i o n o f t h e p r o d u c t from hexane a t -60° a n d e s t e r i f i c a t i o n g i v e X I V i n h i g h p u r i t y ( 9 8 . 4 % Z,E, 1.5% Z,Z, 0.1% E,E, a n d ,6R)-XV a n d ( 3 Z , 6 R ) - X V I ( F i g u r e 5 ) . F i e l d t e s t s h a v e a l s o shown t h a t t h e compounds XV a n d X V I a r e i n d e p e n d e n t l y a t t r a c t i v e t o m a l e s , a n d t h a t t h e r e i s no s y n e r g i s t i c e f f e c t when XV a n d XVI a r e combined. I n a d d i t i o n , t h e p r e s e n c e o f t h e i n a c t i v e s t e r e o i s o m e r s does n o t i n h i b i t t h e t r a p c a t c h o f m a l e s . Thus s y n t h e t i c compound f o r u s e i n m o n i t o r i n g t r a p s i n t h e f i e l d c a n b e e i t h e r XV o r X V I a n d need n o t be s t e r e o c h e m i c a l l y p u r e . Since i n i t i a l l y neither the stereochemistry of the t r i s u b s t i t u t e d d o u b l e bond n o r t h e a b s o l u t e c o n f i g u r a t i o n o f component XVI was known, we p r e p a r e d a l l f o u r o f t h e p o s s i b l e g e o m e t r i c and o p t i c a l i s o m e r s s t a r t i n g f r o m e i t h e r ( S ) - ( + ) - c a r v o n e ( F i g u r e 6) o r ( R ) - ( - ) - c a r v o n e , a n d o n l y t h e 3Z^6R i s o m e r was f o u n d t o b e a t t r a c t i v e t o t h e males ( 4 8 ) . T h i s i s n o t a p r a c t i c a l r o u t e t o X V I ; a s h o r t e r s y n t h e s i s o f r a c e m i c X V I was s u b s e q u e n t l y p u b l i s h e d by S t i l l and M i t r a ( 5 1 ) . F o r f i e l d a p p l i c a t i o n s , we n o r m a l l y u s e component XV a s a m i x t u r e w i t h i t s b i o l o g i c a l l y l e s s a c t i v e s t e r e o i s o m e r s . Our most p r a c t i c a l r o u t e ( F i g u r e 7) t o m a t e r i a l s u i t a b l e f o r c o m m e r c i a l u s e p r o d u c e s a m i x t u r e w h i c h i s o n l y p a r t i a l l y e n r i c h e d i n t h e S^ i s o m e r a t C-3 ( 5 2 ; s e e a l s o 5 3 ) . C o m m e r c i a l l y a v a i l a b l e ( S ) - ( - ) c i t r o n e l l o l o f moderate o p t i c a l p u r i t y ( c a . 75% e n a n t i o m e r i c e x c e s s ; 54) i s u s e d a s t h e s t a r t i n g m a t e r i a l . The c o p p e r ( I ) c a t a l y z e d a d d i t i o n o f 3 - b u t e n y l m a g n e s i u m c h l o r i d e t o 6,7-epoxy-



INSECT

XV Figure 5.

(3S,6R)

PHEROMONE

XVI

TECHNOLOGY

(3Z.6R)

Components of the pheromone of the California red scale.



2.

HENRiCK E T A L .

Synthesis of Insect Sex Pheromones

39

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Insect Pheromone Technology - American Chemical Society

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