Abstract
The enzyme aryl/alkenyl malonate decarboxylase (AMDase) catalyses the enantioselective decarboxylative protonation (EDP) of a range of disubstituted malonic acids to give homochiral carboxylic acids that are valuable synthetic intermediates. AMDase exhibits a number of advantages over the non-enzymatic EDP methods developed to date including higher enantioselectivity and more environmentally benign reaction conditions. In this report, AMDase and engineered variants have been used to produce a range of enantioenriched heteroaromatic α-hydroxycarboxylic acids, including pharmaceutical precursors, from readily accessible α-hydroxymalonates. The enzymatic method described here represents an improvement upon existing synthetic chemistry methods that have been used to produce similar compounds. The relationship between the structural features of these new substrates and the kinetics associated with their enzymatic decarboxylation is explored, which offers further insight into the mechanism of AMDase.
Highlights
In this study we further explore the biocatalytic potential of AMDases, and improved mutants from directed evolution, for the chemoenzymatic synthesis of a series of heteroaryl a-hydroxy acids, which include a number of key intermediates re
We have described an efficient enzymatic synthesis of homochiral heteroaryl a-hydroxy acetic acids
KGaA, Weinheim anyl malonates were on the whole higher with the AMDase mutant M159V, whilst the wild-type AMDase gave the highest rates with the other heteroaromatic substrates
Summary
The aryl/alkenyl malonate decarboxylase (AMDase) catalyses the decarboxylation of a-aryl and a-alkenyl malonic acids 1 to produce enantioenriched carboxylic acids 2 (Figure 1A).[1,2,3,4,5,6,7] AMDase belongs to the Asp/Glu racemase superfamily of enzymes that are widespread across bacteria and include glutamate,[8,9,10,11] aspartate[12] and hydantoin racemases[13,14] as well as maleate isomerases.[15,16] the natural metabolic function of AMDases is not known, these enzymes can effect the stereoselective decarboxylation of a range of disubstituted malonic acids 1, provided that one a-substituent is aryl or alkenyl and the other is a small functional group, for example, methyl, hydroxy or amino.[2]Recently we solved X-ray crystal structures of the Bordetella bronchiseptica AMDase (3DG9 and 3IP8).[1,2] These were the first structures of this class of enzyme and revealed a “dioxyanion hole” motif that we suggest donates six hydrogen bonds required to stabilise a putative high-energy enediolate inter-[b] Dr M. The stereochemistry of the a-hydroxy acid products 9 a– e, 19, 23, 26 and 29 are assigned based on: the stereochemical course of AMDase-catalysed decarboxylation reaction as determined previously by detailed labelling experiments and high resolution X-ray structures of AMDase (Figure 1);[1,2] the configuration of many AMDase products as determined previously;[1,2,3,4,5,6,7] preparation phenyl malonic acid (1, L = Ph & S = H), with both substrates exhibiting similar Km values.
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