A Single Enzyme in Enantiocomplementary Synthesis of ß-Nitroalcohols: Bidirectional Catalysis by Hydroxynitrile Lyase.

A single enzyme, Baliospermum montanum hydroxynitrile lyase (BmHNL), without alteration, enabled bidirectional catalysis in enantiocomplementary synthesis of chiral ß-nitroalcohols. BmHNL catalyzed promiscuous Henry (24 examples) and retro-Henry reaction (22 examples) provided up to >99% and 50% conversion to (S)- and (R)-ß-nitroalcohols respectively, while both cases displayed up to >99% ee. The broad substrate scope and high stereoselectivity of BmHNL represents its synthetic applications in sustainable production of diverse chiral ß-nitroalcohols. Kinetic parameters of BmHNL was determined for Henry and retro-Henry reaction, which reveals poor catalytic efficiency for both the promiscuous transformations, however, the former has better efficiency than the latter. Practical applicability of the biocatalyst and transformation was illustrated by preparative scale synthesis of chiral intermediates of (S)-Tembamide, and (S)-Micanozole.

Hydroxynitrile lyase engineering for promiscuous asymmetric Henry reaction with enhanced conversion, enantioselectivity and catalytic efficiency.

Arabidopsis thaliana hydroxynitrile lyase (AtHNL) engineering has uncovered variants that showed up to 12-fold improved catalytic efficiency than the wild-type towards asymmetric Henry reaction. The AtHNL variants have displayed excellent enantioselectivity, up to >99%, and higher conversion in the synthesis of 13 different (R)-ß-nitroalcohols from their corresponding aldehydes. Using cell lysates of Y14M/F179W, we demonstrated a preparative scale synthesis of (R)-1-(4-methoxyphenyl)-2-nitroethanol, a tembamide chiral intermediate, in >99% ee and 52% yield.

Biocatalytic approaches for enantio and diastereoselective synthesis of chiral ß-nitroalcohols.

Chiral ß-nitroalcohols find significant application in organic synthesis due to the versatile reactivity of hydroxyl and nitro functionalities attached to one or two vicinal asymmetric centers. They are key building blocks of several important pharmaceuticals, bioactive molecules, and fine chemicals. With the growing demand to develop clean and green methods for their synthesis, biocatalytic methods have gained tremendous importance among the existing asymmetric synthesis routes. Over the years, different biocatalytic strategies for the asymmetric synthesis of ß-nitroalcohol stereoisomers have been developed. They can be majorly classified as (a) kinetic resolution, (b) dynamic kinetic resolution, (c) Henry reaction, (d) retro-Henry reaction, (e) asymmetric reduction, and (f) enantioselective epoxide ring-opening. This review aims to provide an overview of the above biocatalytic strategies, and their comparison along with future prospects. Essentially, it presents an enzyme-toolbox for the asymmetric synthesis of ß-nitroalcohol enantiomers and diastereomers.