Human carbonic anhydrase II as a versatile biocatalyst for the synthesis of chiral aryl-1,2-diols

Abstract Human carbonic anhydrase II (hCAII) is a reported biocatalyst for stereoselective reduction of aryl-alkyl-substituted ketones using phenylsilane as an abiotic hydride ion source. During studies investigating the substrate scope of hCAII/PhSiH 3 , we examined the reduction of 1-phenyl-1,2-propanedione under different conditions. In the presence of 2–6 equivalents of PhSiH 3 , we unexpectedly observed exclusive formation of enantiopure anti / syn -1-phenylpropane-1,2-diols (PPDs). The hCAII/PhSiH 3 -catalyzed reduction of racemic and enantiopure forms of 2-hydroxy-1-phenylpropan-1-one (HPP) and phenylacetylcarbinol (PAC) intermediates to give 1,2-diols is described. Experimental studies on 2-, 3-, and 4-substituted phenyl-1,2-propanediones and two heteroaromatic analogs revealed substituent effects on the regio- and stereoselectivity of the reduction, which were rationalized by computational studies on the unsubstituted and 4-substituted phenyl derivatives. The preparative utility of the optimized biocatalytic production of 1,2-diols is demonstrated. The combined results reveal how mechanistic knowledge of hCAII/PhSiH 3 -catalyzed reduction enabled the development of a scalable method for the synthesis of chiral 1,2-diols.