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

Abstract

The 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.

Enantiospecific Analysis of Carboxylic Acids Using Cinchona Alkaloid Dimers as Chiral Solvating Agents

“…In addition, biocatalytic cascades consisting of multiple enzymatic reactions in one pot are efficient and enantioselective methods for preparing chiral mandelate. On the basis of Prof. Cangsong Liao group’s findings (Figure b), , we have also verified the enantipurity of optically pure ( R )-3-chloro-MA, which was manufactured by E. coli whole cells harboring PpLTA, RpLTD, and AoHmaS S201V from aldehyde. In view of these results, the dimers (DHQ) 2 PHAL and (DHQD) 2 PHAL were utilized to successfully determine the potential enantiopurity for the resolution of various substituted carboxylic acids (Figures S36–S40).…”

Siteselective and Enantiocomplementary C(sp3)–H Oxyfunctionalization for Synthesis of α-Hydroxy Acids

“…9−13 Different cyanide-free asymmetric C 1 -extension strategies were also developed for the stereodivergent synthesis of mandelic acids. 14,15 Alternatively, the production of mandelates by the functionalization of styrene was achieved by enzyme cascades. 16,17 Nonetheless, the scopes of C 1 -extension strategies and functionalization of styrene were limited to the production of mandelates from aromatic substrates.…”

“…b). Asymmetric reduction of the corresponding α-keto acids is a classic and efficient method, but α-keto acids are costly materials. , Therefore, biocatalytic cascades have been designed to provide access to α-hydroxy acids from α-amino acids and low-cost achiral starting materials, such as aldehydes and glycine. , Hydroxynitrile lyases (HNL) have been used and already established in industrial chemistry for the production of chiral mandelic acid and derivatives for many years. − Different cyanide-free asymmetric C 1 -extension strategies were also developed for the stereodivergent synthesis of mandelic acids. , Alternatively, the production of mandelates by the functionalization of styrene was achieved by enzyme cascades. , Nonetheless, the scopes of C 1 -extension strategies and functionalization of styrene were limited to the production of mandelates from aromatic substrates.…”