Process for Producing Optically Active (R)‑Tetrahydrothiophene-3-ol with High Optical Purity and High Purity: Bioconversion and Crystallization

(R)-Tetrahydrothiophene-3-ol (1) is a key intermediate in the synthesis of penem-based antibiotics. However, it is a viscous liquid at room temperature, which makes it impossible to purify the (R)-isomer especially in the presence of the (S)-isomer. In this study, we successfully developed a process for producing (R)-alcohol 1 with high optical purity by combining bioconversion and crystallization. (R)-Alcohol 1 was prepared by enantioselective bioreduction which used tetrahydrothiophene-3-one (2) as the substrate, and the optical purity was 70–92% ee. The (R)-alcohol 1 liquid was collected from incubation solution and purified to furnish (R)-alcohol 1 with 98.7% ee by cooling crystallization from organic solvents. The scale-up using common crystallization process was difficult, but we developed a crystallization process that employed a jacketed pressure filtration vessel equipped with an agitator which can be operated under low temperature from crystallization to filtration. This led to the establishment of a process for producing (R)-alcohol 1 with high optical purity, and the validity of this process was proved by the scale-up test.