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Chapter 13 Conformational Analysis of Fenvalerate and an Ether-Type Pyrethroid

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Yasuyuki Kurita, Kazunori Tsushima, and Chiyozo Takayama Pesticides Research Laboratory, Takarazuka Research Center, Sumitomo Chemical Company, Ltd., 4-2-1 Takatsukasa, Takarazuka, Hyogo 665, Japan A candidate for the active conformer of esfenvalerate (the most insecticidally active stereo isomer of fenvalerate) has been presented based on conformational analyses using the AMI molecular orbital method and shape comparisons with low activity pyrethroids. Esfenvalerate and a new type pyrethroid, 3-phenoxybenzyl (R)-2-(4-ethoxyphenyl)-3,3,3-trifluoropropyl ether, which has a configuration opposite to that of esfenvalerate, were reasonably superimposed. Design of highly bioactive drugs should be assisted with the knowledge of their active conformers. If conformation of a drug can be fixed in its active form by ring closure or other methods without losing factors needed for its activity, the drug becomes more active. However, it is very difficult to know the active conformers of flexible molecules such as pyrethroids. Pyrethroids are insecticides having high activity against various insects and low toxicity to mammalia. Hopfinger et al. investigated the conformational energy maps of some ester type pyrethroids with their activities and proposed the active conformers (1). Tosi and his coworkers (2,3) presented the candidates for active conformers of chrysanthemic acid (lR-trans) and the acid component of esfenvalerate (the most insecticidally active stereo isomer of fenvalerate) with the FMFIT (Flexible Molecular Fit) method and conformational energy calculations. According to their assumption, which was originally proposed by Ohno et al. (4), the configurations at the carbon atom a to the carboxyl group are superimposable in the two molecules and the 4- and 3-positions of the phenyl ring of esfenvalerate acid correspond to the terminal part of the side chain of chrysanthemic acid. They also assumed that the dimethyl moieties at the carbon atom 0 to the carboxyl group are superimposable. Heritage (5) used the Venn diagram to search for the active conformers of permethrin etc. As to biphenyl pyrethroids, Plummer and his coworkers (6) got experimentally or calculated dihedral angles in the biphenyl moieties substituted or ring-closed at the ortho position(s) and correlated them with their activities. They speculated that the dihedral angle 0097-6156/89W13-0183mOO$ © 1989 American Chemical Society

Magee et al.; Probing Bioactive Mechanisms ACS Symposium Series; American Chemical Society: Washington, DC, 1989.

184

PROBING BIOACTIVE MECHANISMS

a r o u n d t h e two b e n z e n e r i n g s i s a b o u t 50 d e g r e e s i n t h e a c t i v e f o r m , B y b e r g et^ a l . (7_) o f f e r e d t h e a c t i v e c o n f o r m e r s o f b o t h a c i d a n d a l c o h o l c o m p o n e n t s o f e s t e r t y p e p y r e t h r o i d s by u s i n g t h e method s i m i l a r to that of T o s i et a l . R e c e n t l y , T s u s h i m a e_t a l . s y n t h e s i z e d a new s y n t h e t i c p y r e t h r o i d , 3-phenoxybenzyl 2-(4-ethoxyphenyl)-3,3,3-trifluorop r o p y l e t h e r , w i t h o u t a g e m i n a l d i m e t h y l g r o u p and f o u n d t h e f a c t t h a t the t r i f l u o r o m e t h y l g r o u p i n the more a c t i v e o p t i c a l i s o m e r o f the m o l e c u l e i s o r i e n t e d i n the o p p o s i t e d i r e c t i o n to t h a t of the i s o p r o p y l group i n e s f e n v a l e r a t e ( 8 ) . T h e r e f o r e , we t h o u g h t it n e c e s s a r y t o r e c o n s i d e r t h e a s s u m p t i o n a d o p t e d b y T o s i e_t a l . a n d B y b e r g e_t a l . I n t h i s a r t i c l e , we r e p o r t t h e r e s u l t s o f c o n f o r m a t i o n a l analyses of e s f e n v a l e r a t e , 3-phenoxybenzyl (R)-2-(4-ethoxyphenyl)3 , 3 , 3 - t r i f l u o r o p r o p y l e t h e r , t h e o t h e r two p y r e t h r o i d s , and t h e i r stereo isomers. We c o m p a r e them o n t h e a s s u m p t i o n t h a t t h e p o s i t i o n o f benzene r i n g s i n the 3 - d i m e n s i o n a l space i s d e t e r m i n a n t i n t h e i r insecticidal activities. I n o t h e r w o r d s , we a s s u m e t h a t t h e o v e r a l l shape o f p y r e t h r o i d s i s t h e most i m p o r t a n t f a c t o r f o r h i g h a c t i v i t y and t h a t t h e b o n d s a n d s u b s t i t u e n t s b e t w e e n b e n z e n e r i n g s a r e n e c e s s a r y to f i x the benzene r i n g s at the p o s i t i o n a p p r o p r i a t e f o r r e c o g n i t i o n by the r e c e p t o r . T h i s a s s u m p t i o n seems t o be r e a s o n a b l e c o n s i d e r i n g n o t o n l y t h e f a c t f o u n d b y T s u s h i m a et_ a l . b u t a l s o t h e e x i s t a n c e o f h i g h l y a c t i v e n o n - e s t e r type p y r e t h r o i d s such as e t h o f e n p r o x , M T I - 8 0 0 (9), o x i m e e t h e r t y p e s (10), and a l k e n e t y p e s (11). We p r o p o s e c a n d i d a t e s f o r t h e a c t i v e c o n f o r m e r s o f t h e p y r e t h r o i d s s u c h as e s f e n v a l e r a t e and i n t e r p r e t t h e f a c t f o u n d by T s u s h i m a et_ a l . Methods C o n f o r r a a t i o n a l a n a l y s e s were c a r r i e d out f o r the s u b s t r u c t u r e s o f f e n v a l e r a t e ( I ; S £ ( e s f e n v a l e r a t e ) and SR i s o m e r s ) , 3 - p h e n o x y b e n z y l 2-(4-ethoxyphenyl)-3,3,3-trifluoropropyl ether (II; R isomer), a cyano-3-phenoxybenzyl 2-(4-chlorophenyl)-2-methylpropionate (III; £ i s o m e r ) , and d e l t a m e t h r i n ( I V ) shown i n F i g u r e 1. In these p y r e t h r o i d s , compounds I ( S J S ) , I I ( R ) , and IV a r e h i g h l y a c t i v e and compounds I ( S R ) , I ( R S ) , I ( R R ) , I I ( S ) , I I I ( S ) , and I I I ( R ) have low a c t i v i t y (8, 12-14). Conformers of the o p t i c a l isomer of each s u b s t r u c t u r e were o b t a i n e d s i m u l t a n e o u s l y w i t h o u t f u r t h e r c a l c u l a t i o n s b e c a u s e t h e S c h r o d i n g e r e q u a t i o n y i e l d s t h e same energies for both o p t i c a l isomers. For c o n f o r m a t i o n a l energy c a l c u l a t i o n s and o p t i m i z a t i o n s o f m o l e c u l a r s t r u c t u r e , t h e AMI m o l e c u l a r o r b i t a l method ( 1 5 ) and B r o y d e n - F l e t c h e r - G o l d f a r b - S h a n n o o p t i m i z a t i o n m e t h o d ( 1 6 ) i n t e g r a t e d i n t o MOPAC ( 1 7 ) w e r e u s e d . These methods a r e the most r e l i a b l e ones a p p l i c a b l e to the a n a l y s e s . A l t h o u g h ab i n i t i o m o l e c u l a r o r b i t a l m e t h o d s a r e more r e l i a b l e w h e n a p p r o p r i a t e b a s i s s e t s a r e u s e d , t h e y r e q u i r e much more c o m p u t a t i o n t i m e and m e m o r i e s f o r i n t e g r a l s . M o l e c u l a r m e c h a n i c s (MM) m e t h o d s r e q u i r e l e s s computat i o n t i m e . H o w e v e r , g e n e r a l l y , MM m e t h o d s a r e l e s s r e l i a b l e when some h e t e r o a t o m s a r e c o n t a i n e d i n t h e m o l e c u l e . F i r s t , g e o m e t r y o f e a c h s u b s t r u c t u r e was f u l l y o p t i m i z e d e x c e p t some i n t e r n a l c o o r d i n a t e s d e s c r i b e d b e l o w . The b o n d l e n g t h s i n b e n z e n e r i n g s w e r e f i x e d t o 1.399 a n d 1 . 1 0 1 A f o r C - C a n d C - H b o n d s , respectively. A l l t h e b o n d a n g l e s i n b e n z e n e r i n g s w e r e f i x e d t o 120


KURITA ET A L .

Analysis of Fenvalerate and an Ether-Type Pyrethroid

F i g u r e 1. S t r u c t u r e s o f compounds I, I I , I I I , and IV. C o n f o r m a t i o n a l a n a l y s e s were c a r r i e d out f o r the s u b s t r u c t u r e s e n c l o s e d w i t h dashed l i n e s .


186


degrees. Benzene r i n g s , c a r b o n y l g r o u p s , and 2 , 2 - d i b r o m o e t h e n y l group were assumed to be f l a t , and the cyano groups were assumed t o be l i n e a r . E s t e r m o i e t i e s were s e t to t r a n s - c o p l a n a r i n s t a r t i n g geometries. The e x t r a c t i o n o f the s u b s t r u c t u r e s and such f i x a t i o n o f g e o m e t r i e s were c a r r i e d out i n o r d e r to s h o r t e n the computation t i m e . Such a treatment i s r e a s o n a b l e s i n c e benzene r i n g s , c a r b o n y l groups, 2 , 2 - d i b r o m o e t h e n y l group and cyano groups are r e l a t i v e l y r i g i d , and e s t e r m o i e t i e s a r e not c i s i n low energy c o n f o r m e r s . As the s u b s t i t u e n t s o m i t t e d i n the c a l c u l a t i o n s are not at the o r t h o p o s i t i o n , they do not have a l a r g e e f f e c t on c o n f o r m a t i o n o f the substructures. F u r t h e r m o r e , the s u b s t i t u e n t s o m i t t e d i n compounds I and I I I to s e a r c h f o r the a c t i v e conformers are i d e n t i c a l . Second, the s u b s t r u c t u r e s thus o p t i m i z e d were f u r t h e r d i v i d e d i n t o the segments d e p i c t e d i n F i g u r e 2. S t a r t i n g g e o m e t r i e s were produced f o r these segments by adding 0, 120, and -120 degrees to each d i h e d r a l a n g l e shown w i t h arrows i n F i g u r e 2. Twenty seven (=3X3X3) s t a r t i n g g e o m e t r i e s were produced f o r segments A and B, and n i n e (=3X3) f o r segments C, D, E, and F. These d i h e d r a l a n g l e s were o p t i m i z e d to get s t a b l e c o n f o r m e r s . As t h e r e was no g u a r a n t e e t h a t a l l low-energy minima had been found ( 1 8 ) , the r o t a t i o n a l energy diagrams f o r each d i h e d r a l a n g l e o f the conformers were drawn t o o b t a i n conformers m i s s e d i n the above a n a l y s e s . These s t a b l e c o n f o r m e r s were combined to r e c o n s t r u c t s u b s t r u c t u r e s I(SS and SR i s o m e r s ) , I I ( R ) , I I I ( S 0 , and IV, and d i h e d r a l a n g l e s shown w i t h arrows i n F i g u r e 1 were o p t i m i z e d . T h i r d , comparisons o f the shape were c a r r i e d out among the s u b s t r u c t u r e s w i t h a l e a s t square f i t t i n g method ( 1 9 ) . A l l the a n a l y s e s d e s c r i b e d above were done by u s i n g the ACACS (Advanced Computer A i d e d C h e m i s t r y System), which has been d e v e l o p e d through the j o i n t c o o p e r a t i o n o f t h i s company, Sumitomo P h a r m a c e u t i c a l s , and NEC ( 2 0 ) . Hydrophobic l o g P v a l u e s o f compounds I I and I I I were c a l c u l a t e d w i t h the CLOGP program ( 2 1 ) . Those o f compounds I and IV were o b t a i n e d from the l i t e r a t u r e ( 2 2 ) . Results

and

Discussion

The d i h e d r a l a n g l e s and c o n f o r m a t i o n a l e n e r g i e s are l i s t e d i n T a b l e s I-V f o r the conformers o f the s u b s t r u c t u r e s . The s i g n o f d i h e d r a l a n g l e s are r e v e r s e d f o r o p t i c a l isomers o f the s u b s t r u c t u r e s . For the s u b s t r u c t u r e I I , a l l the conformers (15 c o n f o r m e r s ) have c o n f o r m a t i o n a l e n e r g i e s w i t h i n 6 k c a l / m o l e o f the most s t a b l e conformer, whereas t h e r e are 11, 11, 4, and 5 conformers i n the same energy range f o r the s u b s t r u c t u r e s I(SS and RR i s o m e r s ) , I(SR and RS i s o m e r s ) , I I I , and IV, r e s p e c t i v e l y . In o t h e r words, compound I I i s more f l e x i b l e than compounds I, I I I , and IV. T h i s may be one r e a s o n why the d i f f e r e n c e i n a c t i v i t y between o p t i c a l isomers o f compound I I i s s m a l l e r than t h a t between j>S and RS isomers of compound I ( 8 , 1 2 ) . When comparisons a r e c a r r i e d out among h i g h l y a c t i v e compounds, i t g e n e r a l l y i s a problem whether the r e c e p t o r s i t e s f o r them are same or n o t . But t h i s problem does not tend to appear when a h i g h l y a c t i v e compound i s compared w i t h a v e r y low a c t i v e one. The low a c t i v i t y s h o u l d be a t t r i b u t e d to e i t h e r the low a f f i n i t y f o r the r e c e p t o r ( e . g . the low s t e r i c c o m p l e m e n t a r i t y to the r e c e p t o r ) or the low c o n c e n t r a t i o n around the r e c e p t o r . T h e r e f o r e , f i r s t , the


13.

KURITA E T A L .

Analysis of Fenvalerate and an Ether-Type Pyrethroid


187

188


Table

conformer 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31

I.

91 -52 -43 -60 -40 11 -34 -45 -75 5 25 -52 -51 -43 -42 -62 -66 -40 -40 -66 10 -33 13 -75 -45 -34 -76 4 12 27 -65 -65

Conformers

02 -110 -113 77 -112 -119 87 76 40 71 58 -110 -110 -114 -113 77 34 -113 -113 70 -118 88 -118 43 77 89 44 72 65 57 40 39

o f the s u b s t r u c t u r e

03 179 179 180 179 -180 178 179 180 178 179 173 179 174 179 175 -180 175 179 -175 173 171 180 -174 176 177 -165 175 -175 180 -174 -166

04 136 137 140 137 137 135 134 129 140 137 -68 -69 -68 -69 -68 124 -69 -69 -72 -69 -67 -69 -75 -69 -68 -76 -68 -72 -71 -75 -76

05 41 42 37 41 41 43 42 29 37 39 -83 -37 -82 -37 -82 32 -82 -37 -43 -83 -83 -37 -84 -82 -40 -43 -81 -45 -82 -84 -43

I(SS)

06 72 -179 69 -46 113 -28 -163 137 -165 102 72 72 -180 -179 70 -91 -46 -46 64 113 -29 112 139 -163 -29 141 -165 -169 101 -90 -89

E 0.0 0.5 0.9 1.3 3.5 3.5 3.7 3.7 4.3 5.2 5.8 6.1 6.3 6.5 6.9 6.9 7.1 7.3 7.5 9.5 9.6 9.7 9.8 9.9 9.9 10.3 10.3 10.6 11.2 13.0 13.4

T o r t i o n a l a n g l e 8 i i n degrees i s d e f i n e d as f o l l o w s : 91, 2-3-4-•5; 02, 3--4-5-6; 03, 4- 5-6-7; 04 5--6-7-8; 05, 6-7-8-' 06, 12-11-4-5. The numbering o f atoms i s shown i n F i g u r e 1. E i s the d i f f e r e n c e i n heat o f f o r m a t i o n from t h a t o f the most s t a b l e conformer ( k c a l / m o l e ) .


K U i U T A ET AL.

Analysis of Fenvalerate and an Ether- Type Pyrethroid 189

Table

conformer 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 0i

91 -52 -43 -63 -40 11 -75 -33 -45 7 21 -51 -51 -42 -42 -66 -64 -39 -65 -40 -75 7 -32 5 -74 -29 -43 -31 -51 22 32 -66 -65

I I . Conformers o f the s u b s t r u c t u r e I ( S R )

02 -110 -113 74 -113 -118 45 89 76 68 59 -106 -112 -110 -ill 39 75 -110 72 -112 44 -116 89 -115 44 82 78 108 69 58 60 39 41

and E a r e d e f i n e d

03 179 179 -179 -180 -179 -177 -180 -179 -180 179 -179 178 -178 179 -176 -176 -175 179 -179 -171 -179 -177 180 -177 -177 -178 175 174 -178 174 -171 -176

94 -137 -137 -139 -138 -135 -135 -134 -137 -142 -133 71 70 71 70 -139 70 69 69 69 67 71 70 70 68 70 71 73 70 70 72 67 67

05 -40 -40 -37 -40 -39 -35 -32 -52 -45 -33 83 35 83 37 -44 83 83 34 37 83 82 82 38 36 83 83 45 35 83 41 83 36

06 72 -179 68 -46 113 137 -29 -163 -166 105 71 69 -179 -180 -91 68 -46 69 -46 138 114 -29 116 139 -172 -164 -34 -164 104 97 -91 -90

E 0.0 0.4 1.1 1.3 3.6 3.6 3.6 4.1 4.4 5.2 6.0 6.2 6.4 6.5 6.9 7.1 7.1 7.2 7.5 9.4 9.6 9.6 9.7 9.8 10.1 10.1 10.4 10.6 11.3 11.9 12.6 12.9

i n Table I.



Table

former 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15

I I I , Conformers o f the s u b s t r u c t u r e

81 61 61 56 54 58 63 60 57 62 60 62 59 54 -23 -22

8 i and E a r e d e f i n e d

Table

conformer 1 2 3 4 5 6 7 8 9 10 11 8i

82 112 113 140 145 -77 167 167 143 99 115 104 -73 149 83 81

84 70 74 70 70 70 81 81 -65 -67 177 161 -65 -66 69 -64

83 91 95 172 173 177 -106 -105 179 -89 93 -82 179 -94 160 177

i n Table

85 71 39 30 30 26 40 40 -31 -32 -5 10 -31 -35 41 -37

and E a r e d e f i n e d

82 87 -86 91 -91 86 -87 86 -92 90 90 -92

83 -180 178 180 179 173 176 176 -179 175 178 178

i n Table

E 0.0 0.1 0.2 0.5 1.0 1.2 1.6 2.0 2.6 3.2 3.3 3.3 3.3 3.4 5.5

I.

IV. Conformers o f the s u b s t r u c t u r e

81 -54 -47 -145 -152 -55 -48 -55 -49 -146 -146 -156

II(R)

84 136 138 136 137 -68 -69 -68 -70 -69 -69 -70

85 33 38 35 36 -83 -82 -36 -38 -83 -36 -83

III(S)

0.0 0.3 1.1 1.9 6.1 6.2 6.4 6.5 6.9 7.1 7.8

I.


13.

KUWTAETAL.

Table

conformer 1 2 3 4 5 6 7 8 9 10 11 12 13 14

Analysis of Fenvalerate and an Etlier-Type Pyrethroid V. Conformers of the

61 175 180 120 173 173 172 116 •170 •168 -33 -33 -33 -33 -33

02 153 45 15 153 •151 -68 8 42 40 133 -51 131 131 -48

93 180 178 174 174 179 178 178 171 175 160 162 140 143 144

substructure

04 137 139 143 -68 -68 -70 -70 -67 -71 142 105 -58 -59 -91

05 41 55 85 82 37 81 82 81 49 39 48 90 •40 89

IV

E 0.0 4.0 4.8 5.7 6.0 7.8 9.5 9.9 10.5 84.4 85.2 90.4 91.5 92.1

T o r t i o n a l angle 0 i i n degrees i s d e f i n e d as f o l l o w s : 01, 1-2-3-4; 02, 3-4-5-6; 03, 4-5-6-7; 04, 5-6-7-8; 05, 6-7-8-9. The numbering o f atoms i s shown i n F i g u r e E i s d e f i n e d i n T a b l e I.

1.

c o n f o r m e r s o f the s u b s t r u c t u r e I ( S S ) were compared w i t h those o f the s u b s t r u c t u r e I I I ( | 0 i n o r d e r to s e a r c h f o r the a c t i v e conformer o f the p y r e t h r o i d . Compound I i s a h i g h l y a c t i v e p y r e t h r o i d and the most a c t i v e isomer o f i t has £ c o n f i g u r a t i o n s at b o t h a c i d and a l c o h o l moieties (12). The i n s e c t i c i d a l a c t i v i t y o f compound I I I i s much lower than t h a t of compound I (_13). On the o t h e r hand, l o g P v a l u e s o f compounds I, I I , I I I , and IV are 6.2, 5.8, 6.2, and 6.2, respectively. D i f f e r e n c e s i n the v a l u e s are not l a r g e . Hence, i t was assumed t h a t the low a c t i v i t y o f compound I I I s h o u l d be a t t r i b u t e d to the 3 - d i m e n s i o n a l s t r u c t u r e and not to the t r a n s p o r t p r o c e s s from the s k i n o f i n s e c t s to the r e c e p t o r s i t e . As we assumed t h a t the o v e r a l l shape i s important f o r the i n s e c t i c i d a l a c t i v i t y o f p y r e t h r o i d s , we made i t a c r i t e r i o n f o r the resemblance o f shape t h a t the r o o t mean square v a l u e (RMS) o f d i s t a n c e s between atoms used to f i t the s u b s t r u c t u r e s and the angle between benzene r i n g s b shown i n F i g u r e 1 (

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