Page 321 - Cascade_Biocatalysis_Integrating_Stereoselective_and_Environmentally_Friendly_Reactions

297

14
Enzymatic Stereoselective Synthesis of -Amino Acids

Varsha Chhiba, Moira Bode, Kgama Mathiba, and Dean Brady

14.1
Introduction

The β-hydroxy and β-amino acid structural motif occurs commonly in compounds
of pharmaceutical importance [1]. Examples include the β-substituted β-adrenergic
agents, used in the treatment of cardiovascular and psychiatric disorders [2–4], and
the biologically active molecules cispentacin [5], sitagliptin [6] (Figure 14.1), taxol
[7], and otamixaban [8].
Although in the past many of these compounds have been used in racemic form,
the current trend in the pharmaceutical industry is toward enantiomerically pure
drugs. The enantioselective synthesis or the chiral separation of racemic mixtures
is often difficult, and synthetic chemistry is increasingly looking toward the use of
enzymes for the preparation of single enantiomer compounds to be used for the
generation of β-substituted pharmaceutical intermediates [9, 10], an area that our
group has also focused on [11, 12].
The traditional use of peptides as therapeutic compounds has often been prob-
lematic for a number of reasons. Small peptides often display a great degree of
flexibility, which enables changes in conformation that adversely affect the activity
of the peptide in vivo. Similarly, susceptibility to protease activity, aggregation of
the peptides, poor absorption through the cell membrane, as well as poor solubility
contribute to poor efficacy of peptide based therapeutics [13, 14].
Of particular interest in medicinal chemistry is the inclusion of non-standard
amino acids in therapeutic peptides or peptidomimetics [15] to overcome these
problems. Peptidomimetic approaches employing β-amino acids (Figure 14.2) have
shown potential in recent years since β-amino acids are similar enough to their
α-analogs to function as required while reducing the rate of peptide hydrolysis
by proteases and consequently improving the pharmacokinetic properties of these
compounds [16].
Peptidomimetics typically function as antimicrobial compounds [15, 17], but new
functions are being discovered. Wolin et al. [18] found that β-amino acid derivatives
act as glycine transport inhibitors, whereas Zhu et al. [19] have identified others
that function as proteasome inhibitors. Armour et al. [20] incorporated them into

Cascade Biocatalysis: Integrating Stereoselective and Environmentally Friendly Reactions, First Edition.
Edited by Sergio Riva and Wolf-Dieter Fessner.
c 2014 Wiley-VCH Verlag GmbH & Co. KGaA. Published 2014 by Wiley-VCH Verlag GmbH & Co. KGaA.