ENZYMES IN ORGANIC-SYNTHESIS .16. HETEROCYCLIC KETONES AS SUBSTRATES OF HORSE LIVER ALCOHOL-DEHYDROGENASE - STEREOSPECIFIC REDUCTIONS OF 2-SUBSTITUTED TETRAHYDROTHIOPYRAN-4-ONES

Horse liver alcohol dehydrogenase (HLADH) has been shown to have the ability to effect efficient and stereospecific reductions of S-heterocyclic ketone analogues of its good carbocyclic substrates. This extends considerably the asymmetric synthesis potential of the enzyme. Preparative scale (~2 g) H LADH-catalyzed reductions of racemic 2-substituted tetrahydrothiopyran-4-ones arc cnantioselectivc. Reductions of each pair of enantiomers occur in the same absolute configuration sense to give the corresponding cis-and trans-2-substituted tetrahydrothiopyran-4-ols of 100% enantiomeric purity and with 5 configurations at each alcohol center. The tolerance by HLADH of the presence of the sulfide function in its substrates adds significantly to the versatility and flexibility of this enzymic synthesis method. For example, enantiomerically pure acyclic secondary alcohols of predetermined absolute configurations cannot be obtained directly by HLADH-mediated reductions of their precursor ketones. This previous disadvantage has now been overcome by exploiting the sulfur atom as a “lock” to maintain a desirable cyclic substrate configuration during the reduction step, followed by Raney nickel removal of the sulfur from the (4S)-cis-and-trans-thiopyranols obtained to give the corresponding acyclic 3S alcohols in good yields. The stereospecificities of the reductions, including the influence of the C-2 substituent on the degree of enantioselectivity, are all interpretable in terms of the enzyme's active-site characteristics. © 1979, American Chemical Society. All rights reserved.