Angewandte
Chemie
DOI: 10.1002/anie.200703296
Biocatalytic Deracemization
Deracemization of Secondary Alcohols through a Concurrent Tandem
Biocatalytic Oxidation and Reduction**
Constance V. Voss, Christian C. Gruber, and Wolfgang Kroutil*
The aim to obtain a highly valuable enantiomerically pure
product in 100% yield and with 100% ee from a cheap
racemic substrate in a one-pot process is currently a hot topic
in one-pot multiple catalysis.[1,2] In one-pot sequential catal-
ysis, the reaction conditions can be adjusted for each step;
however, concurrent catalysis is more demanding: The steps
must be balanced carefully to ensure that the catalytic
processes run at comparable rates and, probably most
importantly, that the different catalytic reactions do not
interfere with one another. Such processes in which multiple
catalysts operate concurrently circumvent the often time-
intensive and yield-reducing isolation and purification of
intermediates in multiple-step syntheses.
impractically long reaction times. Surprisingly, we observed
that the strains of interest showed a high oxidation activity;
thus, a significant amount of the ketone was detected along
with the alcohol. The best oxidizing strain was found in our
own culture collection: Both lyophilized and resting cells of
Alcaligenes faecalis DSM 13975 catalyzed the enantioselec-
tive oxidation of the R enantiomer of rac-2-octanol (rac-1a)
to yield optically pure (S)-2-octanol ((S)-1a; > 99% ee)
within 22 h at a substrate concentration of 60 mm. The
relative amount of the ketone formed was 29–41%; therefore,
the high ee value can not be attributed exclusively to a kinetic
resolution, in which case the ketone would need to be formed
in a relative amount of 50% for the alcohol to have an
ee value of 99%. We found subsequently in a separate
experiment that only negligible oxidation occurred when
oxygen was excluded and the reaction was carried out in an
argon atmosphere. On the other hand, when the reaction was
carried out in an oxygen-saturated environment at an oxygen
pressure of 2 bar, the reaction rate of the oxidation increased.
Therefore, we concluded that molecular oxygen, one of the
most environmentally benign oxidants, is required for this
oxidation.[10]
Such mild and selective oxidation methods are gaining
importance.[11] Oxidative enzymes (more precisely, amine
oxidases) are employed for the deracemization of chiral
amines, as optimized by Turner and co-workers,[12] who
coupled the enantioselective oxidation of chiral amines with
nonstereoselective reduction to give overall deracemization.
To date, no general comparable process has been reported for
the deracemization of secondary alcohols as a result of the
lack of an applicable sec-alcohol oxidase.[13,14] We envisaged
that we might couple our oxidation reaction with a highly
stereoselective enzymatic reduction step (Scheme 1), as
opposed to the nonstereospecific reduction described for
amines. We expected that the use of a stereoselective
reduction step would result in a more efficient process, as
For the deracemization[3] of racemic alcohols through a
chemical oxidation–reduction sequence, only sequential pro-
cesses with one[4] or two catalysts[5] have been reported
recently. In particular the combination of reaction sequences
that involve chemical oxidation and reduction steps with
tandem catalysis represents an almost impossible challenge
owing to the diverging reaction conditions required. In
contrast to the dynamic kinetic resolution[6] of secondary
alcohols through the racemization of the alcohol moiety
followed by enzymatic kinetic resolution, no general protocol
for the deracemization of alcohols through chemical oxida-
tion and simultaneous reduction of the corresponding ketone
has been reported. As oxidation and reduction processes
occur simultaneously in living cells, the application of
enzymes in concurrent oxidation–reduction sequences might
be feasible. Deracemization through the stereoinversion of
one alcohol enantiomer was observed in the presence of
fermenting or resting microorganisms;[7,8] however, the ap-
plication of this method was limited to specific substrates, and
only moderate substrate concentrations were possible.
In a first approach to the one-pot deracemization of
secondary alcohols, we tested the commercially available
microorganisms[9] for which deracemization through stereo-
inversion has been described, as well as the strains from our
own culture collection. The results confirmed the observa-
tions described previously, such as high substrate specificity,
the requirement for low substrate concentrations, and
[*] C. V. Voss, C. C. Gruber, Prof. Dr. W. Kroutil
Department of Chemistry, Organic and Bioorganic Chemistry
Karl-Franzens-Universität Graz
Heinrichstrasse 28, 8010 Graz (Austria)
Fax: (+43)316-380-9840
[**] This study was financed by the Austrian Science Fund (FWF Project
P18537-B03).
Supporting information for this article is available on the WWW
Scheme 1. Tandem biocatalysis for the deracemization of racemic
secondary alcohols through an oxidation–reduction sequence.
Angew. Chem. Int. Ed. 2008, 47, 741 –745
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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