Racemic 2,3-dihydroxy carboxylates, protected as their respective acetonides,
were resolved by CRL [440] by using their lipophilic n-butyl esters (Scheme 2.55).
It is particularly noteworthy that the bulky α-methyl derivatives could also
be transformed, although compounds of this type are usually not accepted by
hydrolases.
A number of cyclohexane 1,2,3-triols were obtained in optically active form
via resolution of their esters using CRL as shown in Scheme 2.55 [441]. To
prevent acyl migration which would lead to racemization of the product, two
of the hydroxyl groups in the substrate molecule were protected as the
corresponding acetal. In this case, a variation of the acyl chain from acetate to
butanoate increased the reaction rate, but had no significant effect on the selectivity
of the enzyme.
The ideal substrates for CRL are esters of cyclic sec-alcohols, which usually
give excellent enantioselectivities [425, 442–445]. In contrast, straight-chain substrates are only well resolved when sterically demanding substituents are
present (Scheme 2.56) [446]. Esters of prim-alcohols usually yield modest
stereoselectivities.
In order to provide a general tool which allows to predict the stereochemical
outcome of CRL-catalyzed reactions, a substrate model for bicyclic sec-alcohols
[52, 369, 447, 448] and an active site model [449] have been developed.
The fact that crude Candida rugosa lipase occasionally exhibits a moderate
selectivity particularly on α-substituted carboxylic esters could be attributed to the
presence of two isomeric forms of the enzyme present in the crude preparation
[450, 451]. Both forms—denoted as A and B—could be chromatographically
separated and were shown to possess identical enantiopreference, but different
enantioselectivity (Scheme 2.57). Thus, racemic α-phenyl propionate was resolved
with low selectivity (E ¼ 10) using crude CRL, whereas isoenzyme A was highly
selective (E > 100). The isomeric lipase B showed almost the same moderate
selectivity as the crude enzyme.
R
CO 2 -n-Bu
O
O
R
CO 2 H
O
O
R
CO 2 -n-Bu
O
O
O-CO-n-Pr
O
O
OH
O
O
O-CO-n-Pr
O
O
rac
+
CRL
buffer
E
8
91
E >150
rac
+
CRL
buffer
R
H
CH 3
Scheme 2.55 Enzymatic resolution of cyclic esters by Candida rugosa lipase
2.1 Hydrolytic Reactions
93
were resolved by CRL [440] by using their lipophilic n-butyl esters (Scheme 2.55).
It is particularly noteworthy that the bulky α-methyl derivatives could also
be transformed, although compounds of this type are usually not accepted by
hydrolases.
A number of cyclohexane 1,2,3-triols were obtained in optically active form
via resolution of their esters using CRL as shown in Scheme 2.55 [441]. To
prevent acyl migration which would lead to racemization of the product, two
of the hydroxyl groups in the substrate molecule were protected as the
corresponding acetal. In this case, a variation of the acyl chain from acetate to
butanoate increased the reaction rate, but had no significant effect on the selectivity
of the enzyme.
The ideal substrates for CRL are esters of cyclic sec-alcohols, which usually
give excellent enantioselectivities [425, 442–445]. In contrast, straight-chain substrates are only well resolved when sterically demanding substituents are
present (Scheme 2.56) [446]. Esters of prim-alcohols usually yield modest
stereoselectivities.
In order to provide a general tool which allows to predict the stereochemical
outcome of CRL-catalyzed reactions, a substrate model for bicyclic sec-alcohols
[52, 369, 447, 448] and an active site model [449] have been developed.
The fact that crude Candida rugosa lipase occasionally exhibits a moderate
selectivity particularly on α-substituted carboxylic esters could be attributed to the
presence of two isomeric forms of the enzyme present in the crude preparation
[450, 451]. Both forms—denoted as A and B—could be chromatographically
separated and were shown to possess identical enantiopreference, but different
enantioselectivity (Scheme 2.57). Thus, racemic α-phenyl propionate was resolved
with low selectivity (E ¼ 10) using crude CRL, whereas isoenzyme A was highly
selective (E > 100). The isomeric lipase B showed almost the same moderate
selectivity as the crude enzyme.
R
CO 2 -n-Bu
O
O
R
CO 2 H
O
O
R
CO 2 -n-Bu
O
O
O-CO-n-Pr
O
O
OH
O
O
O-CO-n-Pr
O
O
rac
+
CRL
buffer
E
8
91
E >150
rac
+
CRL
buffer
R
H
CH 3
Scheme 2.55 Enzymatic resolution of cyclic esters by Candida rugosa lipase
2.1 Hydrolytic Reactions
93