Enzymatic resolution of racemic lactones

Tetrahedron Letters,Vol.29,Nd.l6,pp Printed in Great Britain

ENZYMATIC

RESOLUTION

L. Blanco, Laboratoire

: PPL, HLE or PLE’ enzymatic

lactones

(ee

to methods

various

bifonctionnal

lactones

synthons

Recently

giving are

in organic

it has been

thought

direct

enzymatic

letter

we describe

In this

by different

(“crude”

horse

enzymes

allows

main

features

LACTONES

and G. Rousseau

of racemic

and

to isolate of our

Y,6

Moleculaire

and E -1actones

gives optically

active

is stimulated

by the

our findings

catalyze

of these

racemates

concerning

HLE and

outlined

(I), pheromones

intramolecular

(4). Since racemic

: pig pancreatic

esterase,

purity

and’ wines

(2) or useful

(3). lipases

resolution

are

with high enantiomeric of fruits

lactones

R and S lactones

method

n = 5,6,7

that

active

hydrolases

pig liver

lactones

components

chemistry

claimed

and led to optically

that

chiral

flavor

hydroxyesters

catalyzed

resolution

+ .OO

: 60 to 90%).

The search that

‘OF RACEMIC

E. Guibe-Jampel

0040-4039/88 $3.00 Pergamon Press plc

des Carbocycles, Associe au C.N.R.S, Institut de Chimie BSt. 420, Universite de Paris-Sud, 91405 ORSAY (France)

Abstract

fact

1915-1918,1988

PLE) : the

3 2 from racemic in Scheme

R (or

e-chiral

and pig liver

use of these onesIwith

obtained

S) 2

commercial

and

are

S (or

reported

RI 2

(n=5

J S (or R) i 1915

or

6)

1

powder,

inexpensive

in the

H30+

Scheme I

lactones

acetone

a good enantioselectivity.

I and our results

we

way.

of y, 6 and

(PPL.), horse

of some

can be easily

was a promising

the hydrolysis

lipase

transesterification

lactones

The table.

1916

For

‘)‘-butyrolactones by PPL.

catalyzed

isolated &

with an enantiomeric

hydrolysis

was conducted

7.2). For the fact

the

the

reaction

albumin

remaining

presence

conversion

after

good

of lactone

(entries

resolutions.

As for

enzymes.

some

If. when

treatment.

6-9) were

Interestingly,

-4c) by relactonization. With

hydrolysis

a better

made

observed

absolute

using

The absolute

by addition

of lactones

a,

give the

Corey’s

those

of the

the

3 : ee )

15%

deduced

Experimental

part

or OJM Ya2HP04 After

: Lactones

addition

remaining by ether

products

were

for the

chloride.

three

resolution

At the

opposite

chloride.

were

opposite.

by acidic

satisfactory

The

treatment,

resolutions

hydroxyacids

however

the

their

optical

&

and

cyclisation

were --2a-2f - 4&J The configurations 2

was transformed

(6), bromine their

reduction

optical

deduced

from

of lactones to (-)-lactone

E

via its

(7) and hydrogenation.

rotations

and comparison

5

C5Rll

NEt3

0

rotations

2h, 4h were

found

by

silylketene

The configurations with

those

of 2h, 4h.

0

U -2h

aqueous

(12-24 hours).

only

of these

(8).

litterature.

from

; however

enzymes

substrates

was observed

-2e

The

serum

were catalyzed

(entry

(HLE and PLE) gave

lactones

3) HPO(OEt)2, 4) H2, Pd/C

of the

bovine

at

lactones -4a-4f (ee N 40-50%) by acidic 4a-4f could be improved (for example 93% -stopped at 40% conversion followed by a

lactones

1) LDA/ClSiMes 2) HCB rS/KOtBu

followed

allows

solution

gave back the

remaining

of lactones

of dibromocarbene

checked better

of calcium

of calcium

E -caprolactones

method

three were

presence

hydrolysis

: (-)-S- 6 -decalactone

ftg were

of the

10-13) two enzymes

of the back

configurations

with

correlation

solution.

lactone

salts

similarly

(5). When the hydrolyses

enantioselectivity

absence

--3a-3f of these

(entries

configurations

and comparison

conversion

are

at pH = 7.2. In

in Na2HP04

that

were

latter

0.1 M, pH =

calcium

a low enantioselectivity

in the

enzyme-catalyzed

e -caprolactones

be made

acetal

solution

of their

were

R-enantiomers

was made

excesses

a second

>/ 50%) did not

chemical

(Na2HP04,

in 10% CaC12

We have

with

solution

precipitation

hydrolysis

substrates the

Y-butyrolactones

the

The enantiomeric

for

could

the

isolated

-le was best resolved in the After separation, the hydroxyacids

the

conducted

and a partial

and the

For the more hydrophilic

in a buffer

conversion).

lactone

but

were

when the hydrolyses

R-enantiomers

55% conversion.

up to 50% conversion

were

obtained

their

&).

HLE gave

J~J (ee

were

than

of hexane

(when

30-40%

S lactones

&Valerolactones

ee

of 60-769/o after

lactones --lb-Id hydrolyses acids 3 inhibit the reaction stopped

resolutions

substrates

excess

(BSA) allows to drive the reaction

lactone

best

better

in the

to go to 55-60%

by HLE the

the

I-5) the are

other

hydroxy

pH = 7.2, reactions

for

(entries

The S-lactones

_! (10s2 mole) solution.

(9) were

of 1 g of the

crude

enzyme

Then the reactions

were

2. Acidification

of the

lactones extraction purified

gave

stirred

The pH was maintained

the

by liquid

lactones

to 7.2 using

(13) the

stopped

hydrolyses

by filtration

Celite

cake

2 (entries

chromatography

with 20 ml of 10% CaC12 (-2 were

on Celite

and the

1-9) or the

on silicagel

a pH stat

and

carried phase

hydroacids

a 2M NaOH out

and ether

aqueous their

equivalents)

with

55%

(HCI, pH = 2)

2 (entries

optical

to

extraction

rotations

10-13). were

1917

Table

Lactones Entrie

Lactones

Reaction

1.

PPL,

1

c2H5 -Q 6’

conditionsa)

H20

buffer

al-, (Ref.1 +47.4 (101

7.2

2

Corl,(b

ee (96) ’

Configurations

+42.8

75 (90)

+38.0

72 (67)

R

(15)

S

R

R

hexane

-la

2 3

PPL,

0

C3H7--Q

H20,

+56.2

10% CaC12

(101

-56.2

-7.0

10% CaC12

+48.6 (10)

+33,0

60 (68)

10% CaC12

+42.2 (II)

+321)

76 (76)

-60.2

HLE, H20

buffer

PPL,

H20,

PPL,

H20,

7.2

-lb

4

5 C7Hl5

0

O/-O

-Id

n

o-c

C5HU

HLE, H20

buffer

7.2

-48.0

78 (80)

PPL,

H20

buffer

7.2

-27.0

(45)

PLE, H20

buffer

7.2

-10.8

(18)

-47.5

92 (97)

S

(IO)

-le 9 C7H15

CL *

-48.8

(12)

HLE, H20,

10% CaCI;

HLE, H20,

10% CaCl2

-15.0

35

6)

10% CaC12

+26.7

62

(RI

HLE, H20,

10% CaCl2

-29.3

72

S

PLE, H20,

10% CaCl,

+29.3

72

R

(

-If

10 11

n n

PLE, H20

00

C3H7

ls

12 13

-C

C5Rll

*

-lh

a) The hydrolyses diol

in presence

were

stopped

of f+)thfc-Eu.

after

55% conversion

In brackets

are

; b) in THF (c=2.0) ; c) from NMR spectra

reported

the

ee calculated

from

the

measured

of the [a 1.

1918

determined lactones

in THF (c=2.0). 2 were about

presence

The overall

35-40%).

of (+)-thfc-(Eu),

recoveries

The enantiomeric

of the dials

of these excesses

prepared

reactions

were

by addition

were

determined

about

80-90%

(Yields

of

by NMR (250 MHz), in the

of methyllithium

(14) to the lactones

g-b

4a-f and to the methyl hydroxyesters resulting from the reaction of CH2N2 with the hydroxyacids 29 -and -3h. Working with chiral lactones substituted at different positions, we are now investigating the scope of this new method

of resolution.

moment

the

to isolate

The

progress

For example

(+)-IS-6R

of our results

in the case

lactone

6 with

will

be published

of the bicyclic

60% enantiomeric

in due

Iactone

2 we are able

at the

excess.

course.

References U. Ravid, R.M. Silverstein, C. Bayonove, J. Sci. Food

2)

J.M. Brand,

3)

See for example 1981, Vol. 4.

4)

A. Makit, Boltansky,

5)

Addition of BSA in the PLE-catalyzed hydrolysis of meso-dimethyl tetrahydrophtalate has been W.K. Brtimmer, H.J. Gais, p. 347 in “Enzymes as also reported to favor the reaction : B.F. Riefling, NATO ASI Series, Vol. I78 (1986). Catalysts in Organic Synthesis”.

J.C.

Young,

L.R. Smith, Tetrahedron, Agric., 3, 497 (1983).

R.M. Silverstein,

K. Mori in “Total

2,

I449 (1978) ; P. Etievant,

1)

Fortschr.

Synthesis

Chem.

of Natural

T. Nihira, Y. Yamada, Tetrahedron Lett., Tetrahedron Lett., 28, 3861 (1987).

P. Amice,

L. Blanco,

T. Hirao,

Y. Fujihara,

E.J. Corey,

K.C.

J.M. Conia,

Synthesis,

K. Kurokawa,

Lactones la-If are commercially -7 an overall yield of 40-50%.

Y. Ohshiro, Sot.,

available.

Naturst.,

7 (1979).

Wiley-Interscience

Products”.

Publication

805 (1987) ; A.L. Gutman,

T. Agawa, 96,

K. Zuobi,

A.

Lactones

J. Org.

Chem.,

2,

2830

(1986).

5614 (1974). k-h

were prepared

following

the scheme

with

0

0 COOEt

COOEt

R

RBr , EtONa/EtOH H. Watabu,

mCPBA , CH2C12

10)

M. Utaka,

11)

L. Thijs, P.P. Waanders, (1986).

12)

G. Tuynenburg

13)

The enzymes

14)

I.J. Jakovac, J.B. Jones, J. Org. Chem., 4& 2165 (1979). We found Iactones (20”~) to an etheral solution of methyllithium followed solution gave a more selective reaction. (Received

7,

196 (1976).

J. Am. Chem.

Nicolaou,

g,

Org.

S. Issanchov,

Muys, were

in

A. Takeda,

E.H.M. Stkkingreef, B. Van der

purchased

France

J. Org.

from

Chem.,

2,

Sigma

15 December

4363 (1987).

B. Zwanenburg,

Ven, A.P. de Jonge,

&-I&

Appl.

Rec.

Trav. Chim.

Microbial.,

fi,

Pays-Bas,

5,

332

389 (1963).

: PPL (L 3126) ; “HLE” (L 9627) ; “PLE” (L 8251).

1987)

that addition in 1 hour of the by a work-up using a NH4CI