Siteselective and Enantiocomplementary C(sp³)–H Oxyfunctionalization for Synthesis of α-Hydroxy Acids

Abstract

Oxyfunctionalization of abundant carboxylic acids represents a direct approach to synthesizing α-hydroxy acids, which are valuable intermediates of various active pharmaceutical ingredients. Although ideal, the transformation is yet to be accomplished. Herein, enantiocomplementary C(sp 3 )−H oxyfunctionalization for the synthesis of α-hydroxy acids was realized by a cooperative strategy of substrate engineering, homologue screening and protein engineering of αketoglutarate-dependent nonheme iron aryloxyalkanoate dioxygenases. The reaction provided concise synthetic routes toward three types of 67 α-hydroxy acids with high efficiency and selectivity (yield up to 90% and ee up to >99%). The distinctive complementary reactions add to a growing repertoire of biocatalytic oxyfunctionalization reactions.

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“…Enantiocomplementary methods for the synthesis of α-hydroxy acids via C–H hydroxylation of carboxylic acid substrates has been achieved via homologue screening, as well as substrate and protein engineering of α-ketoglutarate-dependent non-haem iron aryloxyalkanoate dioxygenases (AADs) (Scheme 3). 31 The optimised AADs showed broad substrate scope and performed highly regio- and enantioselective hydroxylations at preparative scale. The enantioselective synthesis of α-hydroxy acids has also been reported using an enzymatic intramolecular Cannizzaro reaction of aryl and heteroaryl-substituted glyoxals.…”