Synthesis of (1R,cis,αS)-cypermethrine via lipase catalyzed kinetic resolution of racemic m-phenoxybenzaldehyde cyanohydrin acetate

Article abstract of DOI:10.1016/S0957-4166(98)00047-0

A technical scale preparation of optically active (1R,cis, αS)- cypermethrine 4 from racemic m-phenoxybenzaldehyde cyanohydrin acetate (RS)- 1 and (1R,cis)-3-(2,2-dichlorovinyl)-2,2-dimethylcyclopropane-carboxylic acid chloride (1R,cis)-3 is described. Key steps of the new procedure are a lipase catalyzed enantioselective transesterification of (RS)-1 with n-butanol and direct acylation of the mixture of (R)-1 and (S)-cyanohydrin (S)-2 with (1R,cis)-3 to give enantiomerically pure (1R,cis,αS)-4. The unchanged (R)-1 is removed from (1R,cis,αS)-4 by distillation, and is racemized with triethylamine to give (RS)-1 which is returned to the process. The total yield of (1R,cis,αS)-4 referred to (RS)-1 is 80%.

Full text of DOI:10.1016/S0957-4166(98)00047-0

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 9 (1998) 1043–1049
Synthesis of (1R,cis,αS)-cypermethrine via lipase catalyzed
kinetic resolution of racemic m-phenoxybenzaldehyde
1
cyanohydrin acetate
†
∗
Jürgen Roos, Uwe Stelzer and Franz Effenberger
Institut für Organische Chemie der Universität Stuttgart, Pfaffenwaldring 55, D-70569 Stuttgart, Germany
Received 27 January 1998; accepted 2 February 1998
Abstract
A technical scale preparation of optically active (1R,cis,αS)-cypermethrine 4 from racemic m-
phenoxybenzaldehyde cyanohydrin acetate (RS)-1 and (1R,cis)-3-(2,2-dichlorovinyl)-2,2-dimethylcyclopropane-
carboxylic acid chloride (1R,cis)-3 is described. Key steps of the new procedure are a lipase catalyzed
enantioselective transesterification of (RS)-1 with n-butanol and direct acylation of the mixture of (R)-1 and
(
S)-cyanohydrin (S)-2 with (1R,cis)-3 to give enantiomerically pure (1R,cis,αS)-4. The unchanged (R)-1 is
removed from (1R,cis,αS)-4 by distillation, and is racemized with triethylamine to give (RS)-1 which is returned
to the process. The total yield of (1R,cis,αS)-4 referred to (RS)-1 is 80%. © 1998 Elsevier Science Ltd. All rights
reserved.
1. Introduction
2
Plant extracts of Chrysanthemum cinerariefolium are known to have strong insecticidal activities. For
2
b
a long time it has been known that pyrethrine I is the most active compound in these plant extracts.
A disadvantage of pyrethrine I for practical applications as an insecticide is its relatively low stability.3a
Specific variations of both the alcohol and the acid component gave photostable and highly efficient
derivatives. Previous investigations showed strongly increased stability in the presence of cyano
3
b
substituents in the α-position of the alcohols. Cypermethrine is one of the most important insecticides of
2
this type.
∗
†
Corresponding author. E-mail: franz.effenberger@po.uni-stuttgart.de
Part of dissertation, Universität Stuttgart, 1998.
0957-4166/98/$19.00 © 1998 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(98)00047-0

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J. Roos et al. / Tetrahedron: Asymmetry 9 (1998) 1043–1049
From the eight possible stereoisomers, cypermethrine which has the (1R,cis,αS)-configuration, has by
2
a,b,4
far the highest biological activity.
have therefore been made.
Many efforts for the stereoselective syntheses of cypermethrine
For the stereoselective preparation of (S)-m-phenoxybenzaldehyde cyanohydrin, the alcohol compo-
nent of cypermethrine, many procedures have been developed. m-Phenoxybenzaldehyde cyanohydrin
is accessible, for example, by enantioselective addition of HCN to m-phenoxybenzaldehyde catalyzed
5
by cyclic dipeptides. Further methods are the (S)-oxynitrilase catalyzed addition of HCN to the
6
aldehyde and the enantioselective cleavage of racemic m-phenoxybenzaldehyde cyanohydrin with (R)-
7
oxynitrilase, respectively. Lipase catalyzed preparations applied are the enantioselective transesterifi-
8
8a,9
cation of racemic cyanohydrin esters and the esterification of racemic cyanohydrins
as well as the
enantioselective transesterification of racemic cyanohydrin esters using primary alcohols.8
a,10
Kinetic
resolutions of racemates for technical applications require in any case racemization of the undesired
stereoisomer. This could be realized by enantioselective acetylation of racemic cyanohydrins with iso-
propenyl acetate in an organic solvent and in the presence of a basic ion exchange resin that is sufficiently
basic to cause racemization of the cyanohydrin enantiomers but not the optically active cyanohydrin
9
a
acetate formed. Unfortunately, this procedure cannot be applied to the preparation of enantiomerically
pure cyanohydrins.
In the present publication we report on the preparation of (1R,cis,αS)-cypermethrine 4 for technical
scale application involving a lipase catalyzed transesterification of the racemic acetate with high boiling
alcohols as the key reaction.
2. Enantioselective transesterification of acetylated (RS)-m-phenoxybenzaldehyde cyanohydrin
(RS)-1
Former investigations of lipase catalyzed transesterification of racemic cyanohydrin esters have
demonstrated that lipase P from Amano gave the best results using acetylated aromatic cyanohydrins.8
a
The reactions were carried out with the primary alcohols n-butanol or n-octanol in n-hexane and
dichloromethane, respectively, as solvents. We have now optimized the parameters for the lipase cat-
alyzed transesterification of (RS)-1 to give (S)-m-phenoxybenzaldehyde cyanohydrin 2 as outlined in
Scheme 1.
Preliminary investigations of the application of lipase P have shown that the reaction times could be
11
significantly shortened by enzyme immobilization on Celite. Furthermore, the phosphate buffer (0.05
11
M, pH 7) used for the treatment of Celite was replaced by sodium acetate buffer (0.01 M, pH 4.5)
resulting in enhanced enantiomeric excesses. Finally, the amount of the primary alcohol has been found
to influence both reaction time and ee values. While a molar ratio of alcohol: (RS)-1=1:1 resulted in short
reaction times and high ee values, a molar ratio of alcohol: (RS)-1=0.5:1 decelerated drastically the lipase
catalyzed transesterification, and lower enantiomeric excesses were obtained (Table 1).

J. Roos et al. / Tetrahedron: Asymmetry 9 (1998) 1043–1049
1045
Scheme 1.
Table 1
Lipase P catalyzed transesterification of (RS)-1 (0.50 mmol) with n-octanol in n-hexane at 30°C
Table 2
Application of different primary alcohols and solvents, respectively, in the lipase catalyzed transester-
ification of (RS)-1 (7.5 mmol) to (S)-m-phenoxybenzaldehyde cyanohydrin (S)-2 at 30°C
Considering these results with respect to a technical application, we have increased the batch size of
(RS)-1 from 0.5 mmol (Table 1) to 7.5 mmol and have varied the organic solvent and the primary alcohol
as listed in Table 2.
As can be seen from Table 2, (S)-m-phenoxybenzaldehyde cyanohydrin (S)-2 was obtained in all
cases with high enantiomeric excess. With respect to reaction times, butanol is more advantageous than
octanol, and moreover, the excess of butanol and butyl acetate can easily be removed in vacuo. Since
(S)-2 subsequently should be acylated directly from the reaction mixture without further purification, it
is important to remove the unreacted alcohol before acylation. The transesterification proceeded faster in
n-hexane than in dichloromethane resulting in 49% conversion in 6 hours reaction time compared with
only 30% in dichloromethane (Table 2).
The lipase can be applied for several reaction cycles. Thereby the enzymatic activity of the lipase
decreases continuously with the number of cycles. The enantiomeric excess of (S)-2, however, is not
influenced by reduced activity as shown in Table 3, summarizing the results of four reaction cycles.
The disadvantage of kinetic resolutions of racemates generally is a maximum yield of the desired

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J. Roos et al. / Tetrahedron: Asymmetry 9 (1998) 1043–1049
Table 3
Multiple application of lipase P in the transesterification of (RS)-1 with butanol in n-hexane at 30°C
product of only 50%. For technical applications it is therefore necessary to racemize the undesired
enantiomer (R)-1 and to return the resulting racemic (RS)-1 to the process.
3
. Acylation of (S)-2 with the cyclopropanecarboxylic acid derivative (1R,cis)-3 to (1R,cis,αS)-
cypermethrine 4 and racemization of (R)-1
(
R)-Cyanohydrin acetate (R)-1 could be separated from (S)-2 only by a time-consuming
8
b
chromatography. In order to avoid this difficult separation, we have directly acylated the mixture
of (S)-2/(R)-1 with (1R,cis)-3-(2,2-dichlorovinyl)-2,2-dimethylcyclopropanecarboxylic acid chloride
13
(
1R,cis)-3 to give a mixture of (1R,cis,αS)-4 and (R)-1 as outlined in Scheme 2.
Scheme 2.
The salts formed during the reaction were filtered off. Unchanged (R)-1 could now be separated by
bulb-to-bulb distillation. The residue consists of crude (1R,cis,αS)-cypermethrine 4. After recrystalliza-
tion from petroleum ether, pure (1R,cis,αS)-4 (99% de) was obtained in 82% yield based on (S)-2.
8
b
The distilled (R)-1 was racemized based on a literature-known procedure. In contrast to the described
8
b
method, equimolar amounts of triethylamine were used, and the reaction mixture was heated in toluene
until completion of the reaction. Based on the reaction sequence outlined in Schemes 1 and 2, (RS)-1
could be reisolated in 91% yield and returned to the process.
4. Summary
The reactions described allow a continuous process for the preparation of (1R,cis,αS)-cypermethrine
from racemic (RS)-1, involving four reaction steps as illustrated in Scheme 3.
4
The lipase P catalyzed transesterification of racemic m-phenoxybenzaldehyde cyanohydrin acetate
(
(
RS)-1 with butanol in n-hexane gave enantiomerically pure (S)-m-phenoxybenzaldehyde cyanohydrin
S)-2 in a maximum yield of nearly 50% and >99% ee (step 1). After removal of the excess of butanol and

J. Roos et al. / Tetrahedron: Asymmetry 9 (1998) 1043–1049
1047
Scheme 3.
butyl acetate, the mixture of (S)-2 and (R)-1 was acylated directly with (1R,cis)-3 to give cypermethrine
1R,cis,αS)-4 and unchanged (R)-1 (step 2). Compound (R)-1 was separated from (1R,cis,αS)-4 by
(
distillation (step 3) and racemized with triethylamine to (RS)-1 (step 4). By this procedure (1R,cis,αS)-4
could be obtained in high optical yield (99% de) and a total chemical yield of 80% referred to (RS)-1.
5. Experimental
5.1. Materials and methods
Lipase P (30 units/mg) was purchased from Amano, Celite 503 from Roth and (1R,cis)-3 from
FMC Corp. Racemic m-phenoxybenzaldehyde cyanohydrin acetate (RS)-1 was prepared according to
13
1
a literature method. Melting points were determined on a Büchi SMP-20 and are uncorrected. H
NMR spectra were recorded on a Bruker AC 250 F (250 MHz) and ARX 500 (500 MHz) with TMS as
an internal standard. Optical rotations were determined in a Perkin–Elmer polarimeter 241 LC. GC for
determination of enantiomeric and diastereomeric excess: (a) Hewlett–Packard 5890 Series II with FID,
0
.45 bar hydrogen, column 30 m×0.32 mm, phase OV 1701; (b) Hewlett–Packard 6890 Series with FID,
0.9 bar hydrogen, column 30 m×0.32 mm, phase Chiraldex B-TA (ITC). GC–MS was performed on a

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J. Roos et al. / Tetrahedron: Asymmetry 9 (1998) 1043–1049
Varian Star 3400 CX (carrier gas helium) and Varian Saturn 4 D GC/MS/MS, column 30 m×0.25 mm,
phase DB-5MS.
5.2. Enantioselective transesterification of (RS)-1; general procedure
Immobilized lipase P [2 g Celite was washed with 0.01 M sodium acetate buffer (pH 4.5) and added
to 0.5 g lipase in 10 ml 0.01 M sodium acetate buffer (pH 4.5). This mixture was dried at room
11
temperature ] was added to a solution of (RS)-1 (2.0 g, 7.48 mmol) in 25 ml of organic solvent and
the respective alcohol (7.45 mmol). The reaction mixture was stirred at 30°C for the times given in
Tables 1 and 2. Then the lipase was filtered off, and the filtrate was concentrated in vacuo to remove the
solvent, alcohol and acetylated alcohol. The residue was used for the determination of ee values.
5.3. Determination of enantiomeric excesses
Pyridine (10 µl) in 0.5 ml dichloromethane and chloroacetic anhydride (65 mg) were added to 10 mg
of the crude mixture (S)-2/(R)-1. After heating to 60°C for 4 h, the reaction mixture was filtered through
a silica gel column (3×0.5 cm) with ca 3 ml dichloromethane. The enantiomeric excess of (R)-1 and
chloroacetylated (S)-2 was determined by GC directly from the filtrate. The enantiomers were assigned
0
1
by coinjection of the racemate. [2-Chloroacetyloxy-2-(3 -phenoxy)phenylacetonitrile: H NMR (CDCl )
3
δ 4.14 and 4.15 (2s, 2H, CH Cl), 6.41 (s, 1H, CH), 7.02–7.41 (m, 9H, Ph); GC–MS: m/z (%): 301 (52)
2
+
[
M ], 225 (100), 206 (9), 197 (36), 181 (32), 169 (10), 152 (14), 141 (11)].
5.4. Acylation of (S)-2 using (1R,cis)-3
To a solution of the mixture (S)-2/(R)-1 in 25 ml of dichloromethane (1R,cis)-313 (86% ee, 0.92 g,
.04 mmol) was added followed by pyridine (0.33 ml, 4.1 mmol) under ice cooling. After stirring for
h at room temperature, the reaction mixture was filtered through a silica gel column (4×5 cm) with
4
6
dichloromethane. The filtrate was concentrated and distilled bulb-to-bulb (130°C/0.001 torr) to give 0.95
g (93%) (R)-1. The residue was recrystallized from petroleum ether yielding 1.25 g (82%) (1R,cis,αS)-4,
2
0
1
mp 53–55°C; 99% de, [α]D = +29.7 (c 1.0, CHCl ); H NMR (CDCl ) δ 1.19 (s, 3H, CH ), 1.25 (s,
3
3
3
3
H, CH ), 1.90 (d, J=8.5 Hz, 1H, CHCO), 2.15 (dd, 1H, CHCH_), 6.18 (d, J=8.8 Hz, 1H, CH_), 6.39
3
(
1
s, 1H, CHCN), 7.02–7.42 (m, 9H, Ph). Anal. calcd for C H Cl NO : C, 63.47; H, 4.60; N, 3.36; Cl,
7.03. Found: C, 63.45; H, 4.60; N, 3.31; Cl, 16.75. The data correspond with those in the literature.
22 19 2 3
13
5
.5. Racemization of (R)-1 according to Mitsuda et al.8b
A solution of (R)-1 (0.95 g, 3.54 mmol) and triethylamine (0.5 ml, 3.6 mmol) in 10 ml toluene was
heated to 80°C for 3 h (control by optical rotation). Then the reaction mixture was concentrated and
distilled in vacuo to give 0.93 g (98%) (RS)-1, bp 150°C/0.005 torr.
References
1
2
. Enzyme-catalyzed Reactions, Part 34. Part 33: Effenberger, F.; Syed, J. Tetrahedron: Asymmetry 1998, 9, 817–825.
. (a) Naumann, K. Chemistry of Plant Protection, Synthetic Pyrethroid Insecticides, Vol 5. Springer: Berlin, 1990. (b) Tombo,
G. M. R.; Belluš, D. Angew. Chem. 1991, 103, 1219–1241; Angew. Chem. Int. Ed. Engl. 1991, 30, 1193–1215. (c) Krief, A.
Pestic. Sci. 1994, 41, 237–257.

J. Roos et al. / Tetrahedron: Asymmetry 9 (1998) 1043–1049
1049
3. (a) Elliott, M.; Farnham, A. W.; Janes, N. F.; Needham, P. H.; Pulman, D. A.; Stevenson, J. H. Nature 1973, 246, 169–170.
(
b) Elliott, M. Pestic. Sci. 1989, 27, 337–351.
4. Ackermann, P.; Bourgeois, F.; Drabek, J. Pestic. Sci. 1980, 11, 169–179.
5
. (a) Danda, H.; Nishikawa, H.; Otaka, K. J. Org. Chem. 1991, 56, 6740–6741. (b) Danda, H. Synlett 1991, 263–264. (c)
Mori, A.; Ikeda, Y.; Kinoshita, K.; Inoue, S. Chem. Lett. 1989, 2119–2122. (d) Jackson, W. R.; Jayatilake, G. S.; Matthews,
B. R.; Wilshire, C. Aust. J. Chem. 1988, 41, 203–213.
6
. (a) Effenberger, F.; Hörsch, B.; Förster, S.; Ziegler, T. Tetrahedron Lett. 1990, 31, 1249–1252. (b) Schmidt, M.; Hervé, S.;
Klempier, N.; Griengl, H. Tetrahedron 1996, 52, 7833–7840. (c) Effenberger, F.; Roos, J.; Bühler, H., unpublished results.
. Effenberger, F.; Schwämmle, A. Biocatalysis Biotransformation 1997, 14, 167–179.
7
8
. (a) Effenberger, F.; Gutterer, B.; Ziegler, T.; Eckhardt, E.; Aichholz, R. Liebigs Ann. Chem. 1991, 47–54. (b) Mitsuda, S.;
Yamamoto, H.; Umemura, T.; Hirohara, H.; Nabeshima, S. Agric. Biol. Chem. 1990, 54, 2907–2912.
. (a) Inagaki, M.; Hiratake, J.; Nishioka, T.; Oda, J. J. Org. Chem. 1992, 57, 5643–5649. (b) Hsu, S.-H.; Wu, S.-S.; Wang,
Y.-F.; Wong, C.-H. Tetrahedron Lett. 1990, 31, 6403–6406.
9
10. Bevinakatti, H. S.; Banerji, A. A.; Newadkar, R. V. J. Org. Chem. 1989, 54, 2453–2455.
11. Bianchi, D.; Cesti, P.; Battistel, E. J. Org. Chem. 1988, 53, 5531–5534.
12. Ziegler, T.; Hörsch, B.; Effenberger, F. Synthesis 1990, 575–578.
13. Hatch, C. E.; Baum, J. S. J. Org. Chem. 1980, 45, 3281–3285.