DMSO-triggered enhancement of enantioselectivity in Novozyme[435]-catalyzed transesterification of chiral 1-phenylethanols

Article abstract of DOI:10.1016/j.tetlet.2005.03.147

Dimethyl sulfoxide as cosolvent enhances the enantioselectivity of resolved products up to 100% in the Novozyme[435]-catalyzed transesterification of chiral 1-phenylethanols but not 1-phenyl-2-haloethanols in THF. The reaction does not proceed in lipophilic and water-miscible polar solvents.

Full text of DOI:10.1016/j.tetlet.2005.03.147

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 4411–4413
DMSO-triggered enhancement of enantioselectivity in
Novozyme[435]-catalyzed transesterification of chiral
1-phenylethanols
Amrit Goswami* and Jonali Goswami
Regional Research Laboratory, Jorhat 785006, Assam, India
Received 20 December 2004; revised 16 March 2005; accepted 21 March 2005
Available online 10 May2005
Abstract—Dimethyl sulfoxide as cosolvent enhances the enantioselectivity of resolved products up to 100% in the Novozyme[435]-
catalyzed transesterification of chiral 1-phenylethanols but not 1-phenyl-2-haloethanols in THF. The reaction does not proceed in
lipophilic and water-miscible polar solvents.
ꢀ 2005 Elsevier Ltd. All rights reserved.
Enantiomericallypure secondaryalcohols are important
synthetic intermediates and are also useful chiral auxili-
aries for both synthetic and analytical applications.1
However, some of the reported methods for preparing
such compounds in pure form have limited practical
applicabilitydue to drawbacks including tedious work-
up, expensive chiral auxiliaries, large reaction volumes,
etc. Studies2 on enzymatic reactions in low polarity or-
ganic solvents have widened their use in the resolution3
of racemic mixtures for the preparation of enantiomeri-
callypure secondaryalcohols. This in turn helps to over-
come some of the practical problems such as hydrolysis
in water, recovery of the enzyme for recycling, pH
adjustment during the reaction process, etc. Lipases
have been established as valuable catalysts for such
purposes.
tile acyl donor such as ethyl octanoate, the enantioselec-
tivitywas raised to 93–97% with enantiomeric ratios ( E)
of more than 100. The limitation of the reaction is that it
strictlyrequires a non-volatile acyl donor to afford a vol-
atile leaving group. It is known5,6 that the enzyme Can-
dida antarctica lipase-B (CAL-B) shows extremophile
7
properties, but onlya few ssytematic investigations
have been undertaken on the influence of additives on
such lipase-catalyzed reactions. Accordingly we have
studied the resolution of some secondaryalcohols with
CAL-B lipase under immobilized conditions (Novo-
zyme[435]) in the presence of an additive.
A series of racemic alcohols (2a–g) prepared bysodium
borohydride reduction of prochiral carbonyl com-
pounds (1a–g) were subjected to Novozyme[435] using
vinyl acetate as the acetylating agent and acetonitrile
as solvent, however, in this solvent CAL-B was washed
awayfrom its support. When carried out in dryTHF,
the enantioselectivityof the products ( 3a–e) and (4a–e)
was found to be moderate, low in the case of (3f) and
(4f) and almost nil in the case of (3g) and (4g) (Table
1, data in parentheses). The rigid conformation8,9 of
CAL-B in an organic solvent mayprevent its active site
from accepting a non-natural substrate with a structure
significantlydifferent from that of the natural one.
Although addition of a trace amount of water to enzy-
matic reactions in organic solvents has a lubricating ef-
fect with a consequent rise in conformational flexibility,
the onset of hydrolytic pathways competing with the
derived process10 is a major drawback. It has been
reported11 that addition of a trace amount of a mild
Even though lipases have found various uses, their full
potential has far from fullybeen explored. Sometimes
a suitable lipase in a suitable medium does not exhibit
satisfactoryresults, and onlyon fine tuning of the reac-
tion conditions, can a shift of the thermodynamic equi-
librium in favor of the forward direction be achieved.
Application of reduced pressure plays a positive role
in the equilibrium conversion in lipase catalyzed reac-
tions. In the resolution4 of racemic 2-octanol and several
other secondaryalcohols in the presence of a non-vola-
Keywords: Dimethyl sulfoxide; Transesterification; Lipase; Novozyme.
*
Corresponding author. Tel.: +91 376 2370117; fax: +91 376
2370011; e-mail: goswam@rediffmail.com
0040-4039/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.03.147

4412
A. Goswami, J. Goswami / Tetrahedron Letters 46 (2005) 4411–4413
Table 1. Novozyme[435] mediated resolution of secondary alcohols in the presence and absence (parentheses) of DMSO
Substrates 2
Time (h)
7
Temp (ꢁC)
Yield (%)a,b
Conf.c
Eed
Yield (%)a,b
Conf.c
Eed
Ee
OH
25
3a
51 (40)
S
100 (41)
4a
55 (42)
R
100 (43)
>200 (3.7)
a
OH
HO
7
30
3b
29 (21)
17 (8)
S
S
S
51 (40)
73 (39)
99 (42)
4b
27 (19)
13 (8)
R
R
R
100 (39)
99 (60)
98 (45)
>200 (3.3)
>200 (5.9)
>200 (3.9)
b
3b1
3c
4b1
4c
OH
8
28 (25)
45 (35)
49 (38)
MeO
c
OH
7
7
25
25
3d
3e
50 (39)
S
S
>99 (39)
4d
4e
47 (40)
R
R
>99 (42)
>200 (3.5)
>200 (2.6)
O2N
d
OH
57 (44)
100 (21)
54 (24)
100 (37)
O
Ph
e
OH
Cl
7
30 (25)
3f
28 (25)
R
R
90 (19)
4f
29 (20)
S
S
91 (18)
65 (1.7)
f
OH
Br
75 (24)
70
3g
3 (Nil)
4 (Nil)
4g
3 (Nil)
4 (Nil)
1.1 (Nil)
g
14–18
a Characterized from their corresponding IR, NMR, LC–MS, and HPTLC data and bycomparison with reported values.
b Isolated yields after column chromatography.
c The absolute configuration was assigned bythe sign of rotation and comparison with the literature values.
d Determined bychiral HPLC.
e Determined as reported.19
base enhances the enantioselectivityin Pseudomonus
lipase catalyzed resolution of racemic 2-aryloxy propio-
nate. Considering the above points we carried out the
transesterification reactions of (2a–g) in the presence
of a catalytic amount of the denaturing organic cosol-
vent DMSO (Scheme 1).
tivityof ( 3a–f) and (4a–f) (Table 1). However, in the case
of (3g) and (4g) the enantioselectivitywas enhanced only
verypoorly(4–60%) ( Table 1). Increasing the amount of
DMSO had a detrimental effect. The observed increase
of the enantioselectivitymaythus be attributed to
DMSO-induced flexibilityof the restricted conforma-
tion of the lipase. On the other hand, the poor selectivity
in resolving (3g) and (4g) conforms to KazlauskasÕ13
rule. In the transesterification reaction of 1-(3-hydroxy-
phenyl ethanol (2b), four acetylated products viz (3b),
(3b1), (4b), and (4b1) were produced due to the addi-
tional presence of a phenolic hydroxyl group. The ratio
In the course of our study12 it was indeed observed that
although enzymes are denatured in solvents such as
DMSO, addition of a catalytic amount (about 5% of
the reaction volume) in the transesterification reaction
strikinglyenhanced the chemical yield and enantioselec-

A. Goswami, J. Goswami / Tetrahedron Letters 46 (2005) 4411–4413
OH
R4
4413
O
R4
R3
R2
R3
R2
R1
R2
R2
R3
R3
i.
ii
+
R1
R1
R1
1a-g
2a-g
3a-g, b1
4a-g, b1
Scheme 1. Reagents and conditions: R1 = H, OMe, NO2, OCH2Ph; R2 = H, OH, OAc (for 3b1 and 4b1); R3 = H, Cl, Br; R4 = OH, OAc; i = NaBH4/
MeOH/0–5 ꢁC; ii = Novozyme[435]/THF/25–70 ꢁC.
9. Ueji, S.-I.; Nishimura, M.; Kudo, R.; Matsumi, R.;
Watanabe, K.; Ebara, Y. Chem. Lett. 2001, 912–913.
10. Almarsson, O.; Klibanov, A. M. Biotechnol. Bioeng. 1998,
49, 87–92.
of (3b) to (4b) was 1.07:1 and that of (3b1) to (4b1) was
1.3:1.
From the foregoing studies we conclude that veryhigh
enantioselectivityin transesterification reactions of sec-
ondaryalcohols with CAL-B (Novozyme[435]) in the
presence of 5% DMSO byvolume can be achieved when
the sizes of the substituents at the chiral center are sig-
nificantlydifferent.
11. Theil, F. Tetrahedron 2000, 56, 2905–2919.
12. General procedure: To a solution of the racemic alcohol
(1.86 mmol) in dryTHF (5 mL) were added Novo-
zyme[435] (0.318 g), vinyl acetate (32 mmol), and DMSO
(5% of the total reaction volume). The mixture was stirred
for about 7–75 h at 25–70 ꢁC depending upon the
substrate. After completion (TLC), the reaction mixture
was filtered, the solvent evaporated under reduced
pressure, and the residue quenched with water (20 mL).
The products were extracted with ethyl acetate, the
extract was dried and the solvent was distilled under
reduced pressure. The two products formed were sepa-
rated bysilica gel column chromatographyeluting with
pet.ether–ethyl acetate mixture and were identified from
their spectroscopic data which matched with the
reported14–18 values. The enantiomeric excesses of the
products were determined byHPLC analysis in a Chiral-
cel OD column (250 · 46 mm i.d.), particle size 10 lm
using 15% isopropanol in hexane as the mobile phase,
flow rate 1 mL/min.
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