Chemistry Reference
In-Depth Information
“ standard ” method in
-amino acid synthesis. Besides natural substrates, this method
turned out to be very suitable also for (non-natural)
α
- amino acid pharma intermediates.
For example, recently, researchers at Boehringer Ingelheim Pharmaceuticals, Inc.
reported the synthesis of the non-natural
α
- amino acid (
S
) -
65
, a key building block in
the synthesis of a protease inhibitor [83]. In the presence of an amino acylase I, the reso-
lution proceeds in aqueous buffer at pH 7.0 under the formation of (
S
) - 2 - amino - 8 -
nonenoic acid, (
S
) -
65
, in
α
≥
45% yield and with
>
99% ee (Scheme 6.25 ).
O
O
HN
CH
3
NH
2
HN
CH
3
L-aminoacylase I
rac
+
CO
2
H
CO
2
H
CO
2
H
Water
pH 7.5-7.7
rac
-
64
(
S
)-
65
45% yield
>99% ee
(
R
)-
64
Scheme 6.25.
D-enantioselective amino acylases are available for the analogous synthesis of the
corresponding D-amino acids [84,85]. Furthermore, dynamic kinetic resolution based on
the combination of an aminoacylase and an
N
-acetyl amino acid racemase has been
successfully developed by the Tokuyama group and Kula group [86,87]. This type of
dynamic kinetic resolution has been applied in a continuous synthesis of optically active
methionine using a recombinant
N
-acylamino acid racemase from
Amycolatopsis
sp. and
an L- and D-aminoacylase, respectively [88]. The dynamic kinetic resolution in the pres-
ence of an L-amino acylase gave enantiomerically pure L-methionine in a continuous
production process in
99% yield.
Starting with
N
-phenylacetyl amino acids as substrates, a penicillin acylase, which is
a highly effi cient enzyme used in the large-scale manufacture of 6-amino penicillanic
acid (6-APA) for side-chain cleavage, is a suitable enzyme [89]. The corresponding L-
>
α
-amino acids are obtained with excellent enantioselectivities. Although the phenylace-
tyl group is the preferred acyl-substituent, the synthetically useful Z-protecting group
(Z = benzyloxycarbonyl) is also tolerated by penicillin acylase [90] . An impressive appli-
cation of penicillin acylase for the highly enantioselective synthesis of both aliphatic and
aromatic
-amino acids has been reported by Soloshonok and coworkers [91]. Besides
the broad substrate range, high conversion and excellent enantioselectivities make this
route particularly attractive. Accordingly, most
β
β
-amino acids are obtained in enantio-
merically pure form (
>
99% ee). A selected example is shown in Scheme 6.26. The use
O
O
Ph
Ph
NH
O
NH
2
O
NH
O
Penicillin acylase
buffer, pH 7.0
rac
OH
OH
OH
+
+H
2
O
rac
-
66
-PhCH
2
CO
2
H
(
S
)-
66
(
R
)-
67
>99% ee
Scheme 6.26.
