Page 474 - Cascade_Biocatalysis_Integrating_Stereoselective_and_Environmentally_Friendly_Reactions

450 19 Chemoenzymatic Multistep One-Pot Processes

lipase-catalyzed enantioselective acylation gave the desired O-acetyl (R)-β-hydroxy
ketone in 31% yield and with >99% ee [68]. In the presence of (R)-proline,
the remaining (S)-aldol adduct was isolated. Lipases are known as enzymes that
are highly suitable to operate in organic reaction media, and in this process
the lipase PS-C Amano I turned out to be compatible with the reaction mix-
ture of the initial proline-catalyzed aldol reaction. Evaporation of acetone before
the addition of vinyl acetate for the biotransformation step was found to be a
prerequisite to get sufficient conversion in the second biotransformation step
[68].
The combination of an enantioselective organocatalytic transformation with a
subsequent enzyme-catalyzed process running in aqueous medium offers the
advantage that one can make use of the full range of enzyme diversity for its
biotransformation since, naturally, enzymes operate in aqueous media. Such an
example of combining an asymmetric organocatalytic reaction and a subsequent
biotransformation in aqueous medium, exemplified for the combination of an
organocatalytic aldol reaction with diastereoselective biocatalytic reduction of the
aldol adduct, was reported by Gr¨ oger, Berkessel, and Hummel and coworkers
[69, 70]. This chemoenzymatic one-pot process led to the formation of 1,3-diols,
for example, 93, bearing two stereogenic centers. After demonstrating that by
such a modular approach conducted with the isolation of the aldol adduct all
four stereoisomers of the 1,3-diol with both high diastereo- and enantioselectivity
product were accessible efficiently by suitable combinations of organocatalyst
and enzyme [69], subsequent studies focused on the combination of these two
steps without the need for isolation of the aldol adduct as an intermediate.
When conducting the aldol reaction of aldehyde 89 in the presence of 5 mol%
of the Singh catalyst under neat conditions without any solvent, followed by a
enzymatic diastereoselective reduction of the in situ formed aldol adduct (R)-
92 in aqueous medium, a high conversion of 80% related to the formation of
the desired 1,3-diol (1R,3S)-93 accompanied by a high diastereomeric ratio of
dr(syn : anti) = 1 : 10 and an excellent enantioselectivity of >99% ee was obtained
(Scheme 19.28).
Furthermore, the Gr¨ oger, Berkessel, and Hummel groups [70] succeeded in
developing a one-pot process in which both steps could be conducted in aque-
ous medium, thus fulfilling also a prerequisite for a tandem process as a task
for the future. The organocatalytic reaction also proceeded very efficiently in the
aqueous medium even at a low catalyst loading of 0.5 mol% and turned out
to be highly compatible with the subsequent biotransformation. By means of
this chemoenzymatic one-pot two-step process in aqueous media, the desired
1,3-diols were obtained with high conversion of up to 89% (related to the for-
mation of the product) and excellent diastereoselectivity (with dr up to >25:1)
and enantioselectivity (up to 99% ee). Representative examples are shown in
Scheme 19.29.
The integration of a laccase-catalyzed biotransformation into a one-pot pro-
cess with an initial organocatalytic reaction was developed by Kudo et al. [71]
for the synthesis of oxy-functionalized indole and pyrrole derivatives. In detail,