Preparation of Optically Active l,2-Diols and a-Hydroxy Ketones Using Glycerol Dehydrogenase as Catalyst: Limits to Enzyme-Catalyzed, Synthesis due to Noncompetitive and Mixed Inhibition by Product

Glycerol dehydrogenase (GDH, EC 1.1.1.6, from Enterobacter aerogenes or Cellulomonas sp.) catalyzes the interconversion of analogues of glycerol and dihydroxyacetone. Its substrate specificity is quite different from that of horse liver alcohol dehydrogenase (HLADH), yeast alcohol dehydrogenase, lactate dehydrogenase, and other alcohol dehydrogenases used in enzyme-catalyzed organic synthesis and is thus a useful new enzyrnic catalyst for the synthesis of enantiomerically enriched and isotopically labeled organic molecules. This paper illustrates syrthetic applications of GDH as a reduction catalyst by the enantioselective reduction of 1-hydroxy-2-propanone and 1-hydroxy-2-butanone to the corresponding fi 1,2-diols (ee = 95-98%). (R)-1,2-Butanediol-2-d1 was prepared by using formate-d1 as the ultimate reducing agent. Comparison of (R)-1,2-butanediol prepared by reduction of 1-hydroxy-2-butanone enzymatically and with actively' fermenting bakers' yeast indicated that yield and enantiomeric purity were similar by the two procedures. Reactions prcrceeding in the direction of substrate oxidation usually suffer from slow rates and incomplete conversions due to product inhibition. The kinetic consequences of product inhibition (competitive, noncompetitive, and mixed) for practicai synthetic applications of GDH, HLADH, and other oxidoreductases are analyzed. In general, product inhibition seems the most serious limitation to the use of these enzymes as oxidation catalysts in organic synthesis.