Enantioselective Chemoenzymatic Synthesis of Chiral α-hydroxycarboxylic acids

by Mussa

ABSTRACT

---

Chiral α-hydroxycarboxylic acids (AHA) are useful building blocks for the asymmetric synthesis of complex natural products, yet their chemical synthesis remains challenging with the known synthetic routes achieving either racemic mixtures by classical methods or enantio-enriched AHAs (only by using complex catalysts). In this work, we demonstrate efficient enantioselective synthesis of chiral AHAs from the corresponding glyoxal derivatives by type III glyoxalases. Glyoxal substrates were derived from the corresponding methyl ketones by using selenium dioxide as an oxidizing agent. Four type III glyoxalases Homo sapiens DJ-1 (hDJ-1), Arabidopsis thaliana DJ-1d (atDJ-1d), Escherichia coli heat shock protein 31 (Hsp31) and Candida albicans Glx3 were screened for the conversion of purified glyoxal derivatives to AHAs. Chiral HPLC analysis revealed the production of enantiopure L-isomers of AHAs by hDJ-1 glyoxalase and near-racemic mixtures of AHAs by Hsp31. Glyoxalases were capable of converting 100 mg glyoxal derivatives to corresponding acids while preserving enantioselectivity at room temperature. Furthermore, AHAs with electron-withdrawing groups attached to α-carbon, which are unavailable by common synthetic routes, were synthesized in either enantiopure or racemic form employing the same glyoxalases. Combined, our results suggest that type III glyoxalases, especially hDJ-1, are efficient catalysts for a simple enantioselective synthesis of a range of AHAs at synthetically reasonable scales.