One-Pot Enzyme Cascade Catalyzed Asymmetrization of Primary Alcohols: Synthesis of Enantiocomplementary Chiral β-Nitroalcohols

Biocatalytic asymmetrization of inexpensive and stable primary alcohols to prepare enantioenriched beta-nitroalcohols is an important development in green chemistry for the production of chiral pharmaceutical intermediates. Herein, we report a one-pot, two-step cascade reaction sequence in which first benzylic alcohols were oxidized to produce corresponding benzaldehydes using horse liver alcohol dehydrogenase (HLADH). The in situ generated aldehydes were then reacted in a biphasic medium with nitromethane by Arabidopsis thaliana hydroxynitrile lyase (AtHNL) or Baliospermum montanum HNL (BmHNL) catalyzed Henry reaction to produce stereoselective beta-nitroalcohols with (R) or (S) configuration, respectively. Using HLADH-AtHNL, (R)-beta-nitroalcohols were obtained in up to 64% conversion, and HLADH-BmHNL, (S)-beta-nitroalcohols in up to 70% conversion, while in both cases excellent stereoselectivity (up to > 99% ee) was achieved. The concept was proven by functionalization of sp(3) C-H bond of ten simple achiral benzylic alcohols to enantiocomplementary chiral beta-nitroalcohols.

Automated summary

"In this study, a one-pot, two-step cascade reaction sequence was developed to convert benzylic alcohols to enantioenriched beta-nitroalcohols. By utilizing specific enzymes, high conversion rates and excellent stereoselectivity were achieved, demonstrating a new method for producing chiral pharmaceutical intermediates."