Alcohol NADP(+)-dependent oxidoreductases (EC 1.1.1.2) (secondary alcohol dehydrogenases) are useful catalysts in the synthesis of novel chiral building blocks, particularly those that cannot be easily synthesized via chemical means. Secondary alcohol dehydrogenases (sec-ADHs) from the thermophilic glycolytic anaerobes such as Thermoanaerobium and Thermoanaerobacterium can reduce a broad range of aliphatic ketones to the corresponding secondary alcohols with excellent enantioselectivity.(1,2) The stereoselective reduction of diketones to diols has been demonstrated by a number of workers,(3-5) but the products are typically the homo-(S) isomers. Work performed within this laboratory and elsewhere has demonstrated that the addition of nonreactive cosolvents to thermostable sec-ADH-catalyzed transformations can have a marked effect on the stereoselectivity of the reaction and that this effect is temperature-dependent.(6,7) More recent studies have demonstrated that the addition of organic solvents provides a mechanism for controlling the enantioselectivity of such reactions.(8-10) We have undertaken a study of the thermostable sec-ADH-catalyzed reduction of alpha-and beta-diketones to chiral diols. The inherent stability of these enzymes has allowed us to apply a wide range of biotransformation temperature and solvent conditions. This, in addition to the use of diketone substituent groups, may provide us with a means of shifting the stereoselectivity of the reduction in favor of the desired diol product. This technology may then be applied to the biosynthesis of chiral intermediates or products with pharmaceutical importance.
