Chemoenzymatic Oxosulfonylation-Bioreduction Sequence for the Stereoselective Synthesis of beta-Hydroxy Sulfones

A series of optically active beta-hydroxy sulfones has been obtained through an oxosulfonylation-stereoselective reduction sequence in aqueous medium. Firstly, beta-keto sulfones were synthesized from arylacetylenes and sodium sulfinates to subsequently develop the carbonyl reduction in a highly selective fashion using alcohol dehydrogenases as biocatalysts. Optimization of the chemical oxosulfonylation reaction was investigated, finding inexpensive iron(III) chloride hexahydrate (FeCl3 . 6H(2)O) as the catalyst of choice. The selection of isopropanol in the alcohol-water media resulted in high compatibility with the enzymatic process for enzyme cofactor recycling purposes, providing a straightforward access to both (R)- and (S)-beta-hydroxy sulfones. The practical usefulness of this transformation was illustrated by describing the synthesis of a chiral intermediate of Apremilast. Interestingly, the development of a chemoenzymatic cascade approach avoided the isolation of beta-keto sulfone intermediates, which allowed the preparation of chiral beta-hydroxy sulfones in high conversion values (83-94 %) and excellent optical purities (94 to >99 % ee).