second ketone screened serves as the substrate for a classic
biocatalytic process (Zygosaccharomyces rouxi whole-cell
route, Zmijewski group at Lilly17) for the production of
Talampanel. Our screen identified two new DHs here,
CPADH and RS-1 ADH, each of which also gives the correct
antipode (S)-4, with high selectivity.
or 13. In this regard, the success we have had with KRED
132, in both cases, is quite notable. The ee’s are certainly
competitive with those seen using Itsuno-Corey oxazaboro-
lidine reduction (Senanayake)24 in the former case or Pd(II)-
sparteine-mediated oxidative kinetic resolution (Stoltz)25 in
the latter.
Ketones 5 and 7 are precursors to building blocks for the
promising chemotherapeutic candidate Dolastatin 10 and
Mitsubishi’s broad spectrum fungicide MA-20565, respec-
tively. In the former case, Genet has reported the use of
stoichiometric DIP-Cl (92% ee),18 whereas Masui employs
a diphenylprolinol-ligated borane reagent (92% ee).19 The
highly enantioselective reductions seen here (KREDs 108
and 132) open up alternative “green” processes. Similarly,
while both Ru(II)-diamine-20 and Rh-diamine-based21 asym-
metric hydrogenations of 7 have been reported, reductions
with CPADH, RS-1 ADH, and KRED 132, uncovered in
these studies, provide viable biocatalytic alternatives.
The final three entries (9, 11, 13) in Table 1 are precursors
to either (R)-Strattera or (R)-Fluoxetine. While there are
isolated reports of whole-cell procedures for the asymmetric
carbonyl reduction of 11, either with Saccharomyces22 or
Rhodotorula23 species, we find no previous literature de-
scriptions of asymmetric biocatalytic reductions of either 9
With a half-dozen promising new DH-based asymmetric
reductions in hand, we next set about to examine cofactor
regeneration. The most commonly used nicotinamide-
regenerating reagents, with favorable thermodynamics, are
collected in Figure 1 and compared with EtOH. Note that
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