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Abstract

Directed evolution of an enzyme as catalyst for a given stereoselective transformation provides a mutant for that particular reaction, but organic chemists need catalysts that are characterized by broad substrate acceptance. In a previous study we succeeded in evolving a set of variants of the thermally robust alcohol dehydrogenase TbSADH from Thermoanaerobacter brockii as a catalysts in the (R)- and (S)-selective reduction of tetrahydrofuran-3-one, this difficult-to-reduce compound being a sterically small substrate. These mutants were now tested in the asymmetric reduction of seven structurally unrelated and sterically more demanding substrates, including acetophenone, benzyl methyl ketone, 4-phenyl-2-butanone, and 2-oxo-4-phenyl-butanoic acid ethyl ester. The variants clearly out-perform WT TbSADH, but overly bulky substituted benzophenone derivatives are not accepted by WT or mutants.