[870]. Attempted reduction of the corresponding N-heterocyclic ketones led to
deactivation of the enzyme via complexation of the essential Zn
2+ ion in the active
site [881].
Every kinetic resolution of bi- and polycyclic ketones suffers from one particular
drawback because the bridgehead carbon atoms make it impossible to recycle the
undesired ‘wrong’ enantiomer via racemization. Hence the desymmetrization of
prochiral diketones, making use of the enantioface- or enantiotopos-specificity of
HLADH, is of advantage. For instance, both the cis- and trans-forms of the
decalinediones shown in Scheme 2.114 were reduced to give (S)-alcohols with
excellent optical purity. Similar results were obtained with unsaturated derivatives
[828, 882].
The wide substrate tolerance of HLADH encompassing nonnatural compounds
is demonstrated by the resolution of organometallic derivatives possessing
axial chirality [883]. For instance, the racemic tricarbonyl cyclopentadienyl
manganese aldehyde shown in Scheme 2.115 was enantioselectively reduced
to give the (R)-alcohol and the residual (S)-aldehyde with excellent optical
purities [884].
In order to predict the stereochemical outcome of HLADH-catalyzed reductions,
a number of models have been developed, each of which having its own merits. The
most useful substrate model based on a flattened cyclohexanone ring is shown in
Fig. 2.16 [885]. It shows the Zn
2+ in the catalytic site which coordinates to the
carbonyl oxygen atom and the nucleophilic attack of the hydride occurring from the
bottom face. The preferred orientation of the substrate relative to the hydride
delivered from NADH can be estimated by placing the substituents into the
‘allowed’ and ‘forbidden’ zones.
H
H
OH
X
H
H
O
X
OH
O
O
H
H
O
X
E = 39
+
1R,3S,6R
1S,6S
rac
NADH-recycling
HLADH
e.e. 90%
e.e. 68%
rac-twistanone
+
HLADH
NADH-recycling
1
6
8
3
X
Selectivity (E)
e.e. Ketone [%]
e.e. Alcohol [%]
O
> 1 2 0
6 0
> 9 7
S
> 1 1 0
5 3
> 9 7
Scheme 2.113 Kinetic resolution of bi- and polycyclic ketones using horse liver alcohol dehydrogenase (HLADH)
142
2 Biocatalytic Applications
deactivation of the enzyme via complexation of the essential Zn
2+ ion in the active
site [881].
Every kinetic resolution of bi- and polycyclic ketones suffers from one particular
drawback because the bridgehead carbon atoms make it impossible to recycle the
undesired ‘wrong’ enantiomer via racemization. Hence the desymmetrization of
prochiral diketones, making use of the enantioface- or enantiotopos-specificity of
HLADH, is of advantage. For instance, both the cis- and trans-forms of the
decalinediones shown in Scheme 2.114 were reduced to give (S)-alcohols with
excellent optical purity. Similar results were obtained with unsaturated derivatives
[828, 882].
The wide substrate tolerance of HLADH encompassing nonnatural compounds
is demonstrated by the resolution of organometallic derivatives possessing
axial chirality [883]. For instance, the racemic tricarbonyl cyclopentadienyl
manganese aldehyde shown in Scheme 2.115 was enantioselectively reduced
to give the (R)-alcohol and the residual (S)-aldehyde with excellent optical
purities [884].
In order to predict the stereochemical outcome of HLADH-catalyzed reductions,
a number of models have been developed, each of which having its own merits. The
most useful substrate model based on a flattened cyclohexanone ring is shown in
Fig. 2.16 [885]. It shows the Zn
2+ in the catalytic site which coordinates to the
carbonyl oxygen atom and the nucleophilic attack of the hydride occurring from the
bottom face. The preferred orientation of the substrate relative to the hydride
delivered from NADH can be estimated by placing the substituents into the
‘allowed’ and ‘forbidden’ zones.
H
H
OH
X
H
H
O
X
OH
O
O
H
H
O
X
E = 39
+
1R,3S,6R
1S,6S
rac
NADH-recycling
HLADH
e.e. 90%
e.e. 68%
rac-twistanone
+
HLADH
NADH-recycling
1
6
8
3
X
Selectivity (E)
e.e. Ketone [%]
e.e. Alcohol [%]
O
> 1 2 0
6 0
> 9 7
S
> 1 1 0
5 3
> 9 7
Scheme 2.113 Kinetic resolution of bi- and polycyclic ketones using horse liver alcohol dehydrogenase (HLADH)
142
2 Biocatalytic Applications