Page 186 - Cascade_Biocatalysis_Integrating_Stereoselective_and_Environmentally_Friendly_Reactions

162 7 Synergies of Chemistry and Biochemistry for the Production of -Amino Acids

R R R
H N H N H 2 N
2
2
H 2 N COOH COOH COOH COOH
R R
3
2
α- β - β - β 2,3 -
Figure 7.1 General structure types of α-and β-amino acids.
recently been shown to reduce body weight in mice and it has been postulated as
an attractive pharmacological strategy in order to prevent (and/or treat) obesity and
related metabolic disorders in some individuals [13].
2
2,3
3
Substituted β-amino acids can be denominated β , β ,and β , depending on
the position of the side chain/s (R) on the amino acid skeleton, as shown in
Figure 7.1 [14, 15]. Until recently, methods for the synthesis of β-amino acids relied
predominantly on classical resolution, stoichiometric use of chiral auxiliaries, or
homologation of α-amino acids [3, 16]. In the last decade, chemical synthesis
of β-amino acids has received considerable research attention, and a number of
reviews on catalytic asymmetric synthesis strategies can be found in the literature
[2, 17–19]. The search for environmentally friendly methods that do not require
high catalyst loadings have led to the emergence of biocatalysis as a new strategy for
β-amino acids production [2, 16, 20, 21]. Both chemical and biocatalytic strategies
2
have allowed the production of β-amino acids, but the resolutions of β -amino acids
2,3
3
have not yet been studied to the same extent as their β -and β -counterparts [16].
3
Almost all β -amino acids with proteogenic side chains are available commercially,
2,3
and the synthesis of both these and β -amino acids is relatively straightforward
2
whatever the method. However, β -amino acids must be prepared using multi-step
procedures [22].
β-Alanine and 3-AiBA are natural catabolites of uracil and thymine acting through
the reductive catabolism of pyrimidines [23]. The final part of this degradation
involved in the breakdown of the cyclic amide ring to the corresponding β-
amino acid is catalyzed by the enzymes dihydropyrimidinase (hydantoinase, E.C.
3.5.2.2) and N-carbamoyl-β-alanine amidohydrolase (NCβAA) (β-alanine synthase,
ureidopropionase, E.C. 3.5.1.6). The ‘‘hydantoinase process’’ is an enzymatic
cascade made up of the enzyme hydantoinase (E.C.3.5.2.2), the enantioselective N-
carbamoyl-α-amino acid hydrolase (d-carbamoylase, E.C. 3.5.1.77; l-carbamoylase,
E.C. 3.5.1.87), and hydantoin racemase (E.C. 5.1.99.5) that allows successful
industrial-scale production of optically pure α-amino acids from racemic mixtures of
5-monosubstituted hydantoins (example for d-amino acids in Figure 7.2a) [24, 25].
As we understand it, there is a conceptual similarity between the ‘‘hydantoinase
2
process’’ and the way β-amino acids are produced (example for β -amino acids
in Figure 7.2b). This similarity, together with the fact that some hydantoinase
enzymes also hydrolyze different 5- and 6-monosubtituted dihydrouracils (DHUs)
(or dihydropyrimidines) [26–28], might allow the development of a new route
for β-amino acid synthesis [16]. Very recently, a commercial hydantoinase with
dihydropyrimidinase activity in combination with nitrous acid has yielded free