Synthesis and Fungicidal Activity of Triazole Tertiary Alcohols - ACS

Chapter 27 Synthesis and Fungicidal Activity of Triazole Tertiary Alcohols Paul A. Worthington

Downloaded by MONASH UNIV on May 4, 2015 | http://pubs.acs.org Publication Date: November 3, 1987 | doi: 10.1021/bk-1987-0355.ch027

Department of Chemistry, Imperial Chemical Industries PLC, Plant Protection Division, Jealott's Hill Research Station, Bracknell, Berkshire, RG12 6EY, England Using a knowledge of the mode of action of the plant growth regulator paclobutrazol, it has been possible to design a series of 1,2,4 triazole containing tertiary alcohols which have high levels of plant fungicidal activity. From this group flutriafol and hexaconazole have been introduced into crop protection.

S i n c e t h e i r d i s c o v e r y i n t h e l a t e 1960s s e v e r a l compounds from t h e c h e m i c a l c l a s s o f 1 - s u b s t i t u t e d i m i d a z o l e s and 1 , 2 , 4 - t r i a z o l e s have been developed and s u c c e s s f u l l y used f o r t h e c o n t r o l o f p l a n t d i s e a s e s and f o r t h e t r e a t m e n t o f human f u n g a l i n f e c t i o n s . The f i r s t commercial t r i a z o l e compound was t r i a d i m e f o n (J_), i n t r o d u c e d by Bayer i n 1973 f o r t h e c o n t r o l o f powdery mildew, r u s t s , and seed-borne d i s e a s e s o f c e r e a l s . S i n c e t h a t time many o t h e r so c a l l e d " a z o l e - f u n g i c i d e s " have been i n t r o d u c e d i n t o c r o p p r o t e c t i o n (2^) and o t h e r s a r e s t i l l b e i n g d e v e l o p e d . These 1 , 2 , 4 - t r i a z o l e f u n g i c i d e s share a common mode o f a c t i o n by i n h i b i t i n g t h e C - 1 4 a - d e m e t h y l a t i o n s t e p i n e r g o s t e r o l b i o s y n t h e s i s ( F i g u r e 1) ( 3^ , between 24-methylenedihydrolanosterol and 4,4-dimethylergosta-8,14,24(28)-trienol. P a c l o b u t r a z o l was t h e f i r s t 1 , 2 , 4 - t r i a z o l e c o n t a i n i n g compound t o be i n t r o d u c e d i n a g r i c u l t u r e as a broad-spectrum p l a n t growth r e g u l a t o r (4). I n a d d i t i o n i t p o s s e s s e s good f u n g i c i d a l activity.

α

paclobutrazol

0097-6156/87/0355-0302$06.00/0 © 1987 American Chemical Society

In Synthesis and Chemistry of Agrochemicals; Baker, D., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1987.

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Mevalonate

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Triazole Tertiary Alcohols

Hydroxymethylglutaryl-CoA

Acetate

F i g u r e 1. I n h i b i t i o n o f 14a-demethylation i n e r g o s t e r o l biosynthesis



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SYNTHESIS AND CHEMISTRY OF AGROCHEMICALS

T h i s p l a n t growth r e g u l a t o r y a c t i v i t y i s due t o i n h i b i t i o n o f t h e b i o s y n t h e s i s o f g i b b e r e l l i n s (5), a t t h e t h r e e o x i d a t i o n s t e p s between ent-kaurene and e n t - k a u r e n o i c a c i d ( F i g u r e 2 ) . The s y n t h e s i s o f p a c l o b u t r a z o l s t a r t i n g from p i n a c o l o n e i s shown i n F i g u r e 3 and t h e f i n a l r e d u c t i o n s t e p w i t h sodium b o r o h y d r i d e i s h i g h l y s t e r e o s e l e c t i v e , g i v i n g o n l y t h e 2RS, 3RS d i a s t e r e o i s o m e r (6). R e d u c t i o n u s i n g n-butylmagnesium bromide g i v e s t h e o t h e r d i a s t e r e o i s o m e r , 2RS, 3SR, which has l e s s b i o l o g i c a l a c t i v i t y . This high s t e r e o s e l e c t i v i t y observed i n t h e sodium b o r o h y d r i d e r e d u c t i o n c a n be e x p l a i n e d by t h e d e l i v e r y o f h y d r i d e from t h e l e a s t h i n d e r e d d i r e c t i o n i n t h e uncomplexed (Cram) t r a n s i t i o n s t a t e ( F i g u r e 4 a ) . In contrast reduction using the G r i g n a r d r e a g e n t might be e x p e c t e d t o go t h r o u g h a s i x membered c h e l a t e d t r a n s i t i o n s t a t e , w i t h a t t a c k by t h e h y d r i d e s p e c i e s p r e f e r e n t i a l l y from one d i r e c t i o n ( F i g u r e 4 b ) . R e s o l u t i o n o f 2RS, 3RS p a c l o b u t r a z o l has shown t h a t t h e ( + ) 2R, 3R enantiomer p o s s e s s e s good f u n g i c i d a l a c t i v i t y and t h a t t h e p l a n t growth r e g u l a t o r y p r o p e r t i e s r e s i d e w i t h t h e (-) 2S3,3j3 enantiomer. The u s e f u l b i o l o g i c a l p r o p e r t i e s o f p a c l o b u t r a z o l have i n s p i r e d further chemical synthesis o f azole s t r u c t u r e s , culminating with the discovery of a series of t e r t i a r y alcohol compounds. The o r i g i n a l s y n t h e t i c s t r a t e g y was c o n c e i v e d as a d i s c o n n e c t i o n and r e c o n n e c t i o n a n a l y s i s from p a c l o b u t r a z o l ( F i g u r e 5 ) . These e a r l y compounds were good f u n g i c i d e s and f u r t h e r o p t i m i s a t i o n i n t h i s a r e a has l e d t o t h e commercial i n t r o d u c t i o n o f two p r o d u c t s f l u t r i a f o l and r e c e n t l y hexaconazole. Computer G r a p h i c S t u d i e s and C h e m i c a l

Synthesis

The 14a-demethylase enzyme i n v o l v e d i n s t e r o l b i o s y n t h e s i s has been shown t o be dependent on an i r o n h e m e - c o n t a i n i n g cytochrome P450 f o r t h e i n i t i a l o x i d a t i o n o f t h e -CH t o -CH 0H, which i s t h e r a t e d e t e r m i n i n g s t e p (7). U s i n g computer g r a p h i c s p r o c e d u r e s t h a t have been d e v e l o p e d (8) i t i s p o s s i b l e t o a l i g n RR p a c l o b u t r a z o l , a good i n h i b i t o r , w i t h 24-raethylene-24, 25d i h y d r o l a n o s t e r o l which i s t h e normal s t e r o l s u b s t r a t e f o r t h e 14a-demethylase enzyme. With RR p a c l o b u t r a z o l i n a computed minimum energy c o n f o r m a t i o n , t h e 4 - c h l o r o b e n z y l group i s o v e r t h e s t e r o l s i d e c h a i n a t t h e a c t i v e s i t e ( F i g u r e 6 ) . The N-4 o f t h e 1 , 2 , 4 - t r i a z o l e r i n g l i e s p e r p e n d i c u l a r l y above t h e heme, and t h e t e r t - b u t y l group f o l d s o v e r t h e A and Β r i n g s o f l a n o s t e r o l i n i t s extended form. From t h i s a n a l y s i s i t i s p o s s i b l e t o r e p r e s e n t t h e g e n e r a l s t r u c t u r a l r e q u i r e m e n t s f o r an i n h i b i t o r o f t h e 14a demethylase enzyme by F i g u r e 7. I n t h i s model t h e l i p o p h i l i c groups A,B,C and D may be any s u b s t i t u e n t s which on r o t a t i o n o f t h e c a r b o n c a r b o n bond w i l l a l l o w t h e gauche c o n f o r m a t i o n between t h e p o l a r f u n c t i o n and t h e t r i a z o l e . I n p a c l o b u t r a z o l A and D o f F i g u r e 7 a r e s u b s t i t u t e d , p r o d u c i n g a s t a b i l i s e d gauche c o n f o r m a t i o n . By s u b s t i t u t i n g a t A and B, b u t l e a v i n g C and D a s hydrogen i t i s p o s s i b l e t o g e n e r a t e t e r t i a r y a l c o h o l compounds w i t h a l l t h e c o r r e c t r e q u i r e m e n t s f o r 3

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Synthesis and Fungicidal Activity of Triazole Tertiary Alcohols - ACS

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