Unifying Scheme for the Biosynthesis of Acyl-Branched Sugars: Extended Substrate Scope of Thiamine-Dependent Enzymes

Thiamine diphosphate (ThDP) dependent enzymes are useful catalysts for asymmetric C-C bond formation through benzoin-type condensation reactions that result in alpha-hydroxy ketones. A wide range of aldehydes and ketones can be used as acceptor substrates; however, the donor substrate range is mostly limited to achiral alpha-keto acids and simple aldehydes. By using a unifying retro-biosynthetic approach towards acyl-branched sugars, we identified a subclass of (myco)bacterial ThDP-dependent enzymes with a greatly extended donor substrate range, namely functionalized chiral alpha-keto acids with a chain length from C-4 to C-8. Highly enantioenriched acyloin products were obtained in good to high yields and several reactions were performed on a preparative scale. The newly introduced functionalized alpha-keto acids, accessible by known aldolase-catalyzed transformations, substantially broaden the donor substrate range of ThDP-dependent enzymes, thus enabling a more general use of these already valuable catalysts.