Biocatalytic preparation of (R)-(−)-1,1,1-trichloro-2-hydroxy-4-methyl-3-pentene, a synthon for potent agricultural pyrethroids

Tetrahedron:&mm&y Printed in Great Britain

Vol. 2 No. 4, pp. 239242.1991

@x74166/91 $3.00+.00 Pqymon Press plc

Biocatalytic Preparation hydroxy-4-methyl-3=pentene, Agricultural

of

(R)-(-)-l,l,l-trichloro-2a Synthon for Potent Pyrethroidsl

Zainab Muljiani,* Smita R. &ire. Shrikrishna Modak, Nuzhat Pathan and RB. Mitra NationalChemical Laboratory, Pune 411008,

India.

(Received 14 February 1991)

Abstract: Asymmetric hydrolysis of acetate (It)-2 mediated by B.subrilis provided a very simple and cheap method for obtaining alcohol (R)-(-)-la in high chemical yield and optical purity (ee r 98%).

In the context of our program2 on synthetic pyrethroidss, we required optically active (R)-(-)-l,l,ltrichloro-2-hydroxy-4-methyl-3-pentene

la4, the starting material for the syntheses

of NRDC

optically active form of commercial cypennethrin (B), both potent agricultural pyrethroids.

182 (A) and the

While the race&

alcohol 1 is readily available by a modification of the reported pmcedure4, its chemical resolution is particularly difficult, due to the low reactivity of the alcohol functionality.

-v o”voyJ

w-1, R = H o-2, R = CDCH~

(R)-(-)-la. R = H (R)-(+)-2a, R = COCH3

Cl

Cl

A

239

(S)-(+)-lb, R = H (S)-(-)-Zb, R = COCH3

240

Z. MULJIANI et

We therefore resorted to a biocatalytics

chemical

hydrolysis

yield (402,

(k)-27 to furnish

of acetate

theoretical

50%) and optical

although at reduced rates, with a marked preference was hydrolysed hydrolysed

very rapidly,

however,

at all. The experiments

culture broth of Bmbtilis

For a preparative described

the desired

purity (ee L 98%). for the R isomer.

the nitrobenzoate

method

the acetate

As may be expected,

(rt)-2 was hydrolysed

time 24 hr).

After extraction

directly (petroleum ether) avoiding chromatography, d,e).

Chromatography

the formate ester 8

in the series, was not

in 3 batches

separated

Acetate 2b soobtained

of 1.5 ml each under the

with ether, the material

was combined

and

to yield la (1.7 g, 38%), with ee 2 98% (Table

of the residue gave the unhydrolysed

The optical purity of this material

used for the studies described

acetate

was enhanced

(S)-(-)-2b

by resubjecting

in good chemical it to the action of

[CZ]D23 -0.82 (c 7.5, CHC13), ee 2 98% (by nmr, Table I, footnote d,e) was

below.

Chemical

hydrolysis

(KOH, EtOH, 90%) provided

the antipodal alcohol

[a]D25 +12.0 (c 2, CHC13), mp 109OC.

The high degree of enantiospecificity enantiomers hydrolysis

3-6 were also hydrolysed,

ester.

I, footnote

(S)-(+)-lb

Esters

the

(mp 109oC)g in high

7, the only solid compound

crystallised

Bmbtilis.

(R)-(-)-la

were carried out by incubating the substrate (0.5% v/v) in 100 ml of a 24 hr

(incubation

yield (2.18 g, 40%).

alcohol

on a shaker at 30’ for 48 hr. Ether extraction followed by chromatography

the alcohol la and unhydrolysed

conditions

On subjecting racemic esters 2-86

resolution procedure.

we found (Table 1) that the organism Bacillus subtilis 2010 from NCIM, effected

to whole cell biocatalysis enantiospecific

al,

(R)-(+)-2a

and (S)-(-)-2b

(Table II). After 2 hr the R-isomer

negligible conversion

observed

in the above work was confirmed

to the action of B.subtilis

separately

was almost completely

hydrolysed,

by subjecting

and monitoring

the

the rates of

while the S-isomer

showed

even with extended reaction times.

With a facile method in hand for preparing the desired la,we sought to improve the overall efficiency the process.

It was observed

that good hydrolytic

up to 1% acetate concentration successfully

tried to overcome

improvement

are recorded

concentration), use of increased

satisfactory biomass,

can be used to advantage reaction time.

conversions

beyond which the conversions this limitation.

Some

in Table III. Working results were real&d increased

decreased

drastically.

of the promising

with a substrate

results,

concentration

by the incorporation

(cell : substrate ratio l:l), allowing

(-38%) could be obtained

concentration

with

Several strategies

were

with scope

for further

of 2% (4 times the original

of surfactant TX-100 (entry 1) and by the

(entry 2). With optimisation,

substrate

of

in experiments

the formate ester (entry 3)

along with considerable

reduction

in

241

Potent agricultural pyrethroids

2-8 Table I : Asymmetric hydrolysis of racemates 2-8 to produce la Substrate, R

[a]D25 b,c

Conversiona.% GC

2

PcH3‘

42

-12.0

98dP

3

nQH5-

40

-12.0

98f

4

nC4Hg-

30

-11.6

96.6f

5 6

nC7Ht5CgH5-

12 15

I 8

PNO~-Cd-k H-

-11.5 -11.9 ___ ___

95.8f 99f ___

0 100

___

a Isolated yields are of the same order. h (c 2, CHQ3), c Lit.4 [U]D 12.1 ( c 1, CHC13). d Determined 300 MHZ lH nmr of the acetate using Eu(tfc)3 e The value indicates that no trace of the other enantiomer was detected by nnq an artificially prepared mixture of R and S enantiomers (95:5) under the conditions shows well separated peaks with a clear base line for the methyl ester group of the two enantiomers. f Determined by by

COrIqXWkOn

With

[a]~

12.@;g

Incubation

tim

x

hs.

Table II : Hydrolysisa Tii (Inw

of (R)-(+)&a

and (S)-(-)-2b

Conversion 5% (R)-(+)A

(S)-(-)-2b

40

13.3

0

40

25.2

0

80 120

38 97

0 0.2

240

100

0.6

a Experimental conditions : 0.1 ml of substrate was added to cells from a 50 ml culture broth of B.subtiiis, suspendedin tris-HCl buffer (50 ml, H 8.0) and incubated at 300. Plasks were removed at intervals

and the ether extract monitored by GC. b [a]~ % Mt.93 (c. 7.5, CHClg), ee 2 98% (Table I, foomote d,c)

242

Z. Mf3iA4.M et al.

Table III : Asymmetric Substrate

Time hr.

1

(*j-2

48

2

W-2

3

W-8

Entry

Hydrolysis at 2% substrate

Reaction conditions

c~~ntration

Conversion%

[a]D 25d

ee,%e

a

45

-11.8

97.5

48

b

40

-11.2

92.5

6

c

33

-11.0

90.0

a Substrate dispersed in 10 ml buffer (Tris HCI. pH 8.0) along with 0.1 ml Triton X-100 added to the reaction medium. b Cells harvested from one culture flask were resuspended in another culture broth to obtain medium with increased biomass. CNormal d (c 2, CHCl3) e Calculated by comparisou with [a]~= -12.0. In conclusion,

the biocatalytic method described here is distinctly superior to the reported chemical

resolution, in terms of cost, experimental ease and consequently for scale-up work. Acknowledgement :

We are indebted to Drs. P.R. Rajmohau for NMR spectra. B.V. Bapat for extensive

GC analyses aud R.V. Gadre for ~~iol~c~

experiments in the latter part of the work.

References and notes: 1.a) Presented in part at the 17th IUPAC International

Symposium on Chemistry of Natural Products, New

Delhi, India, Feb 4-9, 1990. b) 2.

Z. Muljiaui, S.R. Gadre. S. Modak and R.B. Mitra, Indian Patent Appi. No. 65l/DE5&7. Z. Muljiani, A.R.A.S. Deshmukb, S.R. Gadre and V.S. Joshi, Synth. Common. 1987, 17, 25 and

references therein. M. Elliot, Synthetic Pyrethroids, ACS Symposium Series 42, ACS, Washington, IX. 1977. 3. C.E. Hatch III, J.S. Baum, T. Takashima and K. Kondo. J. Org. Ckm., 1980,45,3281. 4. 5.

For reviews on biocatalysis in organic synthesis see a) J.B. Jones, Tetrahedron, 1986,42, 3351. b) S. Butt and S.M. Roberts, Natural Product Reports, 1986,489.

Prepared from 1: 2, acetic anhydride pyridine, 92%; 3-7, corresponding acid chloride, triethyamine in 6. CH2C12; 8, acetic formic auhydride. Preliminary experiments with PPL (Sigma) were not encouraging. Whole cell hydroIysis with 7. ~se~~~

aeruginosa and P. iemmeri gave 25-30% conversion. The repuned mp 79-8 l°C is incorrect. We found alcohol (i-)-l exists as a conglomerate,

8. compound exhibiting minimum melting point 79-80°C.

the racemic