Chemistry Reference
In-Depth Information
reaction type, one can obtain access to, for example, chiral ketones, aldehydes, carboxyl-
ates and derivatives thereof, and nitroalkanes. However, in contrast to reduction of C= O
double bonds of ketones and keto esters (see Section 6.5.2) with ADHs, the fi eld of
biocatalytic C=C reduction is still rarely explored. This is, in part, due to the limited
number of readily available and suffi ciently stable recombinant enoate reductases. The
“ workhorses ” in this fi eld are enoate reductases from lower fungi and bacteria, belonging
to the family of so-called old yellow enzymes. These enzymes show a broad substrate
range, and many of them are available in recombinant form.
In the fi eld of chiral ketone synthesis, an impressive contribution has been reported
by Shimizu et al. in the asymmetric reduction of the C=C double bond in ketoisopho-
rone (
152
) [262,263]. In the presence of a recombinant whole-cell catalyst overexpressing
an enoate reductase from
Candida macedoniensis
and a GDH, the desired reduction of
the C=C double bond proceeds under the formation of (
R
) - levodione ((
R
) -
153
) with
both excellent conversion and enantioselectivity. Furthermore, the process runs at a high
substrate concentration leading to (
R
)-levodione with 96.9% conversion at a substrate
input of 98.2 g/L (Scheme 6.66). Thus, this process also fulfi ls the criteria for a technically
feasible process and can be regarded as one of the major pioneering works in the fi eld
of asymmetric enzymatic C= C bond reduction.
E. coli-
whole-cell catalyst
containing
ennoate reductase from
Candida macedoniensis
,
glucose dehydrogenase,
NADP
+
O
O
M
Me
NADP
+
,
D-glucose,
buffer, pH 7.4, 28 °C
M
Me
Me
Me
O
O
(
R
)-
153
96.9% conversion
>99% ee
152
(98.2 g/L
substrate input)
Scheme 6.66.
Other cyclic α , β-unsaturated enones serve as substrates as well, and reduction of
these types of substrates can be carried out in a highly enantioselective manner as has
been demonstrated by the Stewart group using recombinant old yellow enzymes [264].
Notably, also α , β-unsaturated carboxylic acids and their esters with very different
substitution pattern can be used as substrates. For example, the C=C double bond in
α - chloroacrylic acid (
154
) has been reduced in the presence of an enoate reductase from
Burkholderia
sp., leading to the desired α - chloropropionate (
S
) -
155
, which is an impor-
tant pharmaceutical building block, in high enantioselectivity (Scheme 6.67) [265].
Enoate reductases were also applied successfully in asymmetric synthesis of γ - lactones,
which were obtained in high enantiomeric excess [266]. In addition, enzymatic reduction
of 2 - decen - 5 - olide for the synthesis of δ-decalactone has found commercial interest due
to its use as a constituent of natural fl avorings [267] .
