Asymmetric C1 Extension of Aldehydes through Biocatalytic Cascades for Stereodivergent Synthesis of Mandelic Acids

Author:

Liu Yanqiong12,Fu Zunyun3,Dong Haihong2,Zhang Jingxuan24,Mao Yingle2ORCID,Zheng Mingyue134ORCID,Liao Cangsong124ORCID

Affiliation:

1. School of Chinese Materia Medica Nanjing University of Chinese Medicine Nanjing 210023 China

2. Chemical Biology Research Center, Shanghai Institute of Materia Medica Chinese Academy of Science Shanghai 201203 China

3. Drug Discovery and Design Center State Key Laboratory of Drug Research, Shanghai Institute of Materials Medica Chinese Academy of Sciences Shanghai 201203 China

4. University of Chinese Academy of Sciences Beijing 100049 China

Abstract

AbstractThe development of mild, efficient, and enantioselective methods for preparing chiral building blocks from simple, renewable carbon units has been a long‐term goal of the sustainable chemical industry. Mandelate derivatives are valuable pharmaceutical intermediates and chiral resolving agents, but their manufacture relies heavily on highly toxic cyanide. Herein, we report (S)‐4‐hydroxymandelate synthase (HmaS)‐centered biocatalytic cascades for the synthesis of mandelates from benzaldehydes and glycine. We show that HmaS can be engineered to perform R‐selective hydroxylation by single‐point mutation, empowering the stereodivergent synthesis of both (S)‐ and (R)‐mandelate derivatives. These biocatalytic cascades enabled the production of various mandelate derivatives with high atom economy as well as excellent yields (up to 98 %) and ee values (up to >99 %). This methodology offers an effective cyanide‐free technology for greener and sustainable production of mandelate derivatives.

Funder

National Natural Science Foundation of China

Natural Science Foundation of Shanghai

Publisher

Wiley

Subject

General Medicine

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