Chemistry Reference
In-Depth Information
NH
2
O
NH
2
HO
2
S
HO
2
C
CO
2
H
HO
2
C
CO
2
H
CO
2
H
Ph
166
165
(2
S
,3
R
)-
168
38% yield
>98% de
Branched chain
aminotransferase
from
E. coli
Aspartate
aminotransferase
O
O
NH
2
Me
CO
2
H
+SO
2
HO
2
C
CO
2
H
HO
2
C
CO
2
H
rac
162
Ph
L-
163
rac
-
167
Scheme 6.72.
Furthermore, ω-transaminases turned out to be capable for the transformation of a
range of prochiral ketones into the corresponding enantiomerically pure amines (bearing
a primary amino moiety).
A highlight in this fi eld is the highly effi cient synthesis of (
S
) - methoxyisoproylamine
((
S
) -
171
), which is an intermediate for the production of the herbicide metolachlor [279].
Based on a recombinant whole-cell catalyst overexpressing a transaminase, which was
optimized through directed evolution, an impressive synthesis of this molecule was
developed by Celgene researchers. A key feature is the high substrate concentration of
2.08 M, corresponding to 183 g/L. The desired (
S
) - enantiomer (
S
) -
171
was obtained with
excellent >99% ee (Scheme 6.73). Isopropylamine (
170
) was used as an amine donor.
The high conversion of 93% was achieved through removal of acetone in vacuo. Besides
this process, Celgene also applied this transaminase technology for numerous other
types of chiral (
S
) - and (
R
)-amines. Furthermore, this transamination technology has
been scaled up to the production of chiral amines on a > 500 - kg scale [280] .
Recombinant
whole-cell catalyst
containing
transaminase
O
NH
2
NH
2
O
MeO
MeO
Me
+
Me
Me
Me
+
Me
Me
169
(183 g/L
substrate input)
170
(
S
)-
171
93% conversion
>99% ee
172
Scheme 6.73.
Besides the use of isopropylamine as an amine source, L-amino acids also represent
suitable cosubstrates. The use of L-alanine as an alternative amino donor has been
investigated by the Kim group [281]. To make this process synthetically useful, biocata-
lytic removal of the pyruvic acid formed as a result of the oxidation of the cosubstrate
L-alanine was required. Thus, the equilibrium is shifted in the desired direction, leading
