Chemoenzymatic Production of Enantiocomplementary 2‐Substituted 3‐Hydroxycarboxylic Acids from l‐α‐Amino Acids

Abstract

A two‐enzyme cascade reaction plus in situ oxidative decarboxylation for the transformation of readily available canonical and non‐canonical l‐α‐amino acids into 2‐substituted 3‐hydroxycarboxylic acid derivatives is described. The biocatalytic cascade consisted of an oxidative deamination of l‐α‐amino acids by an l‐α‐amino acid deaminase from Cosenzaea myxofaciens, rendering 2‐oxoacid intermediates, with an ensuing aldol addition reaction to formaldehyde, catalyzed by metal‐dependent (R)‐ or (S)‐selective carboligases namely 2‐oxo‐3‐deoxy‐l‐rhamnonate aldolase (YfaU) and ketopantoate hydroxymethyltransferase (KPHMT), respectively, furnishing 3‐substituted 4‐hydroxy‐2‐oxoacids. The overall substrate conversion was optimized by balancing biocatalyst loading and amino acid and formaldehyde concentrations, yielding 36–98% aldol adduct formation and 91–98% ee for each enantiomer. Subsequent in situ follow‐up chemistry via hydrogen peroxide‐driven oxidative decarboxylation afforded the corresponding 2‐substituted 3‐hydroxycarboxylic acid derivatives.

Biocatalysis making waves in organic chemistry

“…In particular combinations with other aldolases allow for highly stereoselective syntheses (Scheme 12). [141][142][143] 2.1.2.5. Pictet-Spenglerases.…”

Tailored Particle Catalysts for Multistep One‐pot Chemoenzymatic Cascade in Pickering Emulsions

“…[2] Therefore, chemoenzymatic cascades have been increasingly used for value-added synthesis. [3] Despite immense attractiveness, the practical applications of chemoenzymatic reactions generally suffer from three inherent limitations. [4] The first one is the difficulty of recycling two catalysts in one system.…”

“…The merit of this combination is to minimize purification steps and shift reactions equilibrium to the final product, thus saving time and cost [2] . Therefore, chemoenzymatic cascades have been increasingly used for value‐added synthesis [3] . Despite immense attractiveness, the practical applications of chemoenzymatic reactions generally suffer from three inherent limitations [4] .…”

Hot off the press

“…A biocatalytic cascade process has been developed for the direct synthesis of optically active 3-hydroxycarboxylic acids from L-aamino acids. 30 Oxidative deamination using an L-amino acid deaminase (PmaLAAD) was followed by aldol reaction of the resulting a-keto acid with formaldehyde, catalysed by metaldependent (R)-or (S)-selective carboligases (Scheme 4). Finally, oxidative decarboxylation by hydrogen peroxide allowed the synthesis of a wide range of 3-hydroxycarboxylic acids in good yields and high enantiomeric excess.…”