Chemistry Reference
In-Depth Information
6.5.6. Transamination
Besides amino acid dehydrogenases, further catalysts suitable for the transformation
of carbonyl functionality into an amine moiety are transaminases. Notably, depending
on the type of transaminase, both
α
-keto acids and ketones are tolerated as substrates,
thus leading to
α
-amino acids and amines with a stereogenic center in
α
- position,
respectively.
The synthesis of chiral
-amino acid starting from keto acids by means of a transami-
nation has been developed by NSC Technologies [273,274]. This process can be used for
the synthesis of both L- and D-amino acids and is based on the transfer of an amino
group from an inexpensive amino donor, for example, L-glutamic acid or L-aspartic acid,
to the carbonyl moiety of the keto acid substrate. This reaction is catalyzed by a trans-
aminase (aminotransferase) and requires pyridoxal phosphate as a cofactor (which is
bound to the transaminase). A broad substrate range has been observed and enantiose-
lectivities are excellent in general, thus leading to the desired D- or L-amino acids in
enantiomerically pure form [275]. For example, starting from pyruvic acid (
162
) the
desired product L - alanine (L -
164
) is formed in an effi cient transamination process with
an impressive space - time yield of 4.8 kg/(L · d) when using L - glutamic acid (L -
164
) as an
amino donor (Scheme 6.71). Furthermore, several nonproteinogenic
α
- amino acids such
as L - phosphinothricine, L - homophenylalanine, and L -
tert
- leucine have been produced
as well using transamination.
α
O
NH
2
NH
2
O
Transaminase
Me
CO
2
H
+
HO
2
C
CO
2
H
Me
CO
2
H
+
HO
2
C
CO
2
H
165
162
L-
163
L-
164
Scheme 6.71.
A drawback of transaminations is incomplete reactions (with yields typically around
50% in “standard” processes) due to thermodynamic reasons [275,276]. This problem
has been overcome by coupling the transamination reaction with a subsequent reaction,
which consumes the synthesized α-keto acid (as an undesired side product) in an irre-
versible step. For example, decarboxylation of oxaloacetate, which is the keto acid side
product when using L-aspartate as amino donor, turned out to be such a suitable sub-
sequent irreversible step [277].
Other effi cient approaches to shift the equilibrium in the desired direction have been
developed by the Geffl aut group [278].These methods are based on a coupling of the
transaminase process with either an irreversible aspartate aminotransferase-catalyzed
transamination process using cysteine sulfi nic acid (
166
) as an amino donor or an amino
dehydrogenase-catalyzed reaction under
in situ
cofactor recycling. In the latter method-
ology, the applied cofactor recycling is based on the use of formate in combination with
an FDH. In the presence of a branched chain aminotransferase from
E. coli
, these types
of transaminations turned out to be suitable for the synthesis of various types of non-
natural, 3- or 4-substituted glutamic acid analogues, for example, (2
S
,3
R
) -
168
. A selected
example is shown in Scheme 6.72.
