Page 91 - Cascade_Biocatalysis_Integrating_Stereoselective_and_Environmentally_Friendly_Reactions

4.2 General Features of -Transaminases 67

(a) Kinetic resolution
Thermodynamically favored (in general)
O
NH 2 NH 2
ω-TA, PLP + Easy to perform
R R 1 R R 1 R R 1 Only one enzyme required
Racemate Limited to 50% product yield
Amine- Co-
acceptor product ee of product depends on conversion
(b) Asymmetric reductive amination
Theoretically 100% yield possible
O ω-TA, PLP NH 2
ee independent from conversion
R R 1 R R 1 In general thermodynamically unfavored
Amine- Co- (for most amine donors)
donor product
Often additional enzymes are required
(c) Deracemization

Theoretically 100% yield possible
Two enantiocomplementary
NH 2
ω-TAs, PLP NH 2 Broad applicabillity
R R 1 Recycling of 1 Enantiocomplementary ω-TAs necessary
Racemate acceptor and donor R R
Two sequential steps required
Additional PLP/PMP recycling enzmyes required
Scheme 4.2 Different techniques to prepare enantiomerically pure amines employing
ω-transaminases (ω-TAs) including the advantages and drawbacks of each method.

a combination of the first two strategies. Regarding the overall efficiency, the latter
two are preferred since both techniques are theoretically able to generate 100%
yield in contrast to 50% for kinetic resolution (KR) (Scheme 4.2). Unfortunately, the
amination of ketones suffers from a counterproductive thermodynamic equilibrium
favoring in general the substrate ketone rather than the desired product amine;
moreover, product inhibition has been reported for synthetic transformations of
various non-natural substrates [14]. Thus, first applications for the enantioselective
preparation of chiral amines employing ω-TAs exploited the thermodynamically
favored KR, despite the limitation of 50% yield [15].
Shifting the amination reaction to the product side has been a major challenge
for a long time; as more methods for equilibrium shifting were developed, more
research groups from industry and academia started to investigate the scope and
potential of this enzyme class. Today, fairly well working methodologies for the
amination have been established, enabling the use of ω-TAs as a routine technique
for asymmetric synthesis to produce a wide range of enantiomerically pure amines
and building blocks [10] as well as pharmaceuticals [16].

4.2.1
Cascades to Shift the Equilibrium for Amination
The nonfavorable thermodynamic equilibrium for the asymmetric amination of
ketones as well as the frequent occurrence of coproduct inhibition turns the