Organic Synthesis with Enzymes. 3.₁ TBADH-Catalyzed Reduction of Chloro Ketones. Total Synthesis of (+)-(S,S)-(cis-6-Methyltetrahydropyran-2-yl)acetic Acid: A Civet Constituent

Highly enantioselective reduction of aliphatic chloro ketones catalyzed by Thermoanaerobium brockii alcohol dehydrogenase (TBADH) afforded the corresponding S chloro alcohols, which are new and useful chiral bifunctional building blocks. The synthetic potential of these compounds was illustrated by syntheses of several optically pure cyclic ethers. In particular, (S)-(+)-5-chloropentan-2-ol was used for the total synthesis of (+)-(S,S)-(cis-6-methyltetrahydropyran-2-yl) acetic acid, a natural constituent of the perfume material civet. Two of the key steps in the synthesis involve organopalladium chemistry: a Pd(0)-catalyzed intramolecular allylic etherification followed by a Pd(II)-catalyzed Wacker oxidation of the disubstituted olefin.