Tandem resolution and skeletal extension of racemic β-amino alcohols via cooperative chemoenzymatic catalysis

ABSTRACT Kinetic resolution serves as a valuable method for producing enantioenriched compounds in pharmaceutical and pesticide industries but is inherently limited to a theoretical 50% yield, whereas dynamic kinetic resolution reaches full conversion yet generates only a single enantiomer, restricting the molecular diversity essential for accelerating drug discovery. Divergent resolution of racemic mixtures addresses these limitations but often disrupts the substrate skeleton. Herein, we present a tandem resolution strategy that directs the two enantiomers along divergent pathways, recovering one in enantiopure form while converting the other into a structurally distinct heteroaromatic product. Through cooperative catalysis of alcohol dehydrogenase (ADH) and artificial flavin (SBFA), we resolve racemic primary β -amino alcohols as key pharmaceutical motifs, wherein ADH enantioselectively oxidizes one enantiomer while SBFA simultaneously regenerates NAD + and transforms the aminoacetone by-product into structurally distinct pyrazine derivatives. This strategy has been demonstrated across a series of substrates, delivering resolved amino alcohols with 90%–99% enantiomeric excess and pyrazine products in up to ∼73% of the theoretical maximum.