Dynamic kinetic resolution in the hydrolysis of an a-bromo ester
Matthew M. Jones and Jonathan M. J. Williams*
Department of Chemistry, University of Bath, Claverton Down, Bath, UK BA2 7AY.
E-mail: j.m.j.williams@bath.ac.uk
Received (in Liverpool, UK) 15th September 1998, Accepted 6th October 1998
Bromide can be employed to racemise an a-bromo ester
more rapidly than the corresponding acid (carboxylate), and
this rate difference has been employed as the basis of a
dynamic kinetic resolution reaction.
process. We have not ruled out the possibility that racemisation
occurs by simple enolisation, but the racemisation of the ester is
not qualitatively dependent on pH (5–8)
The preferred sources of bromide were quaternary ammo-
nium bromides and quaternary phosphonium bromide. In
particular, the phosphonium salt produced by heating bromi-
Dynamic kinetic resolution strategies have been enjoying
1
increasing attention in the last few years. For an ideal dynamic
3
nated Wang resin with PPh in toluene for 10 h provided a
3
kinetic resolution, the two enantiomers of starting material must
react at very different rates. Furthermore, whilst the starting
material enantiomers must be in equilibrium, the product must
be essentially inert to racemisation. Recent work from this
group has described racemisation procedures which strongly
favour the starting material.2
particularly convenient bromide source. Simple salts such as
KBr were significantly less effective for the racemisation of
either ester or acid.
We chose to use an enzymatic procedure for the selective
hydrolysis of the bromo ester, which has some literature
4
precedent. Thus, ester 1 was hydrolysed by various enzymes in
Herein we report that the racemisation of the a-bromo ester
water, using a autotitrater to maintain a constant pH (7.0). A
representative selection of these enzymes in a simple kinetic
resolution reactions are shown in Scheme 2 and Table 2.
1
2
is significantly faster than for the corresponding a-bromo acid
under appropriate conditions. Thus, competition experiments
between enantiomerically enriched ester 1 and acid 2 show that
the ester racemises more quickly (Scheme 1 and Table 1).†
Br
Ph
CO2Me
Br
Br
(R)-1
Br
enzyme
Ph
Ph
CO2Me
Ph
Ph
CO Me
+
2
H2O (adjusted to pH 7)
M+ Br–
Ph
CO2Me
Br
(
R)-1
(±)-1
H2O (adjusted to pH 7)
1
Br
Br
Ph
CO H
2
(
S)-2
CO2H
S)-2
CO H
2
Scheme 2
(
(
±)-2
Scheme 1
Table 2 Kinetic resolution of ester 1a
Conversion Ee of 1
Ee of 2
(%)
Table 1 Racemisation of ester 1 and acid 2 with bromides
Enzyme
t/h
(%)
(%)
Ee of 1 (%) Ee of 2 (%)
CRLb
Altus 17
Altus 20d
18
2.5
144
42
47
32
69
81
51
74
80
65
c
Bromide
t/h
Initial Final Initial Final
KBr
18
18
4
18
6
38
80
80
80
55
43
28
77
0
4
5
34
35
64
33
38
34
35
35
31
36
58
a
Performed in H O.
b
Candida rugosa lipase.
c
CLEC-CRL - cross
2
CsBr
linked enzyme crystal (Candida rugosa lipase) CLEC-PCL - cross linked
enzyme crystal (Pseudomonas cepacia lipase). In this case the R enantiomer
of acid was formed preferentially.
d
Bu
4
Bu
4
NBra
PBr
C
16
H
33P+Ph
3
Br2
Wang polymer-CH
2
P+Ph
3
Br2
2
0.5 61
We favoured the commercially available cross-linked en-
a
Performed in H
2
O–MeOH (5:1).
5
zyme crystal, Altus 17 (Candida rugosa lipase, cross-linked),
which provided a fast reaction with reasonably good enantio-
selectivity in the resolution.
By combining the selective racemisation procedure with
simple kinetic resolution, we proceeded to investigate the
dynamic kinetic resolution reaction (Scheme 3 and Table 3).
Gratifyingly, the combination of the Wang phosphonium
We rationalise that the racemisation of the ester 2 occurs via
N
2 displacement by bromide (Fig. 1), which is enhanced by the
S
neighbouring carbonyl function (p* CNO). However, under the
reaction conditions, the carboxylic acid will be deprotonated,
N
and the carboxylate is less willing to assist the adjacent S 2
Br–
Br
Br–
O
O
H
OMe
O
H
_
Ph
CO Me
2
Ph
Ph
1
equiv. phosphonium bromide
enzyme
(
R)-1
Br
Br
Br
+
H2O (adjusted to pH 7)
Ph
CO2Me
Br
slow
1
fast
Ph
CO H
2
(
S)-2
Fig. 1 Preferential racemisation by SN2 bromide displacement of an a-
bromo ester.
Scheme 3
Chem. Commun., 1998, 2519–2520
2519