The high level of technology available for the biocatalytic reduction of carbonyl
compounds has allowed its implementation for the industrial-scale production of
chiral building blocks containing sec-alcohol moieties. The system applied – either
whole microbial (wild-type) cells, a designer bug containing a dehydrogenase plus
cofactor-recycling enzyme, or the use of isolated enzymes – depends on the case
and is mainly dependent on the economic and the patent situation. Representative
examples are depicted in Scheme 2.126 [1019–1025].
Deracemization via Biocatalytic Stereoinversion Racemic secondary alcohols
may be converted into a single enantiomer via stereoinversion which proceeds
through a two-step redox sequence (Scheme 2.127) [37, 1031, 1032]: In a first
step, one enantiomer from the racemic mixture is selectively oxidized to the
corresponding ketone while the other enantiomer remains unaffected. Then, the
ketone is reduced in a second subsequent step by another redox-enzyme displaying
Cl
OH
CO 2 Et
Cl
O
CO 2 Et
OH
CO 2 Et
O
CO 2 Et
OH
O
O
O
O
O
glucose / NADP
+
biphasic medium
Bacillus megaterium GDH
Candida magnoliae ADH
pharmaceuticals
(Atorvastatin)
e.e. 99.5%
E. coli containing
benzodiazepine
35 t / a
kg-scale
fragrances
agrochemicals
pharmaceuticals
e.e. 99.8%
acetone (stripping)
2-propanol
(crude enzyme solution)
Lactobacillus brevis ADH
(whole cells)
Zygosaccharomyces rouxii
e.e. 99.9%
in-situ product removal
N
Cl
O
CO 2 Me
233 kg
ADH (mutant)
CDX-026
NADPH-recycling
OH
yield 97%, e.e. 99.9%
Montelukast
(anti-astmathic)
O
O
CO 2 Et
BnO
OH OH
CO 2 Et
BnO
O
CO 2 H
OH
CO 2 H
O
O
R
R
OH
OH
R
R
Acinetobacter calcoaceticus
(cell extract)
Glucose dehydrogenase
e.e. / d.e. 99%
anti-cholesterol drugs
glucose / NAD +
d.e. 99%, e.e. >99%
Lactobacillus kefir
250 kg / a
(whole cells)
glucose
R = Me; n = 1, 2, 3
R = Et, i-Pr; n = 2
chiral lligands
e.e. 99.9%
D-Lactate dehydrogenase
(solubilised enzyme)
formate dehydrogenase
NH 4
+ HCO 2
- / NAD +
ACE inhibitors
( ) n
( ) n
Scheme 2.126 Industrial-scale bioreduction of carbonyl compounds
154
2 Biocatalytic Applications
compounds has allowed its implementation for the industrial-scale production of
chiral building blocks containing sec-alcohol moieties. The system applied – either
whole microbial (wild-type) cells, a designer bug containing a dehydrogenase plus
cofactor-recycling enzyme, or the use of isolated enzymes – depends on the case
and is mainly dependent on the economic and the patent situation. Representative
examples are depicted in Scheme 2.126 [1019–1025].
Deracemization via Biocatalytic Stereoinversion Racemic secondary alcohols
may be converted into a single enantiomer via stereoinversion which proceeds
through a two-step redox sequence (Scheme 2.127) [37, 1031, 1032]: In a first
step, one enantiomer from the racemic mixture is selectively oxidized to the
corresponding ketone while the other enantiomer remains unaffected. Then, the
ketone is reduced in a second subsequent step by another redox-enzyme displaying
Cl
OH
CO 2 Et
Cl
O
CO 2 Et
OH
CO 2 Et
O
CO 2 Et
OH
O
O
O
O
O
glucose / NADP
+
biphasic medium
Bacillus megaterium GDH
Candida magnoliae ADH
pharmaceuticals
(Atorvastatin)
e.e. 99.5%
E. coli containing
benzodiazepine
35 t / a
kg-scale
fragrances
agrochemicals
pharmaceuticals
e.e. 99.8%
acetone (stripping)
2-propanol
(crude enzyme solution)
Lactobacillus brevis ADH
(whole cells)
Zygosaccharomyces rouxii
e.e. 99.9%
in-situ product removal
N
Cl
O
CO 2 Me
233 kg
ADH (mutant)
CDX-026
NADPH-recycling
OH
yield 97%, e.e. 99.9%
Montelukast
(anti-astmathic)
O
O
CO 2 Et
BnO
OH OH
CO 2 Et
BnO
O
CO 2 H
OH
CO 2 H
O
O
R
R
OH
OH
R
R
Acinetobacter calcoaceticus
(cell extract)
Glucose dehydrogenase
e.e. / d.e. 99%
anti-cholesterol drugs
glucose / NAD +
d.e. 99%, e.e. >99%
Lactobacillus kefir
250 kg / a
(whole cells)
glucose
R = Me; n = 1, 2, 3
R = Et, i-Pr; n = 2
chiral lligands
e.e. 99.9%
D-Lactate dehydrogenase
(solubilised enzyme)
formate dehydrogenase
NH 4
+ HCO 2
- / NAD +
ACE inhibitors
( ) n
( ) n
Scheme 2.126 Industrial-scale bioreduction of carbonyl compounds
154
2 Biocatalytic Applications