Abstract
Arylmalonate decarboxylase (AMDase) catalyzes the cofactor‐free asymmetric decarboxylation of prochiral arylmalonic acids and produces the corresponding monoacids with rigorous R selectivity. Alteration of catalytic cysteine residues and of the hydrophobic environment in the active site by protein engineering has previously resulted in the generation of variants with opposite enantioselectivity and improved catalytic performance. The substrate spectrum of AMDase allows it to catalyze the asymmetric decarboxylation of small methylvinylmalonic acid derivatives, implying the possibility to produce short‐chain 2‐methylalkanoic acids with high optical purity after reduction of the nonactivated C=C double bond. Use of diimide as the reductant proved to be a simple strategy to avoid racemization of the stereocenter during reduction. The developed chemoenzymatic sequential cascade with use of R‐ and S‐selective AMDase variants produced optically pure short‐chain 2‐methylalkanoic acids in moderate to full conversion and gave both enantiomers in excellent enantiopurity (up to 83 % isolated yield and 98 % ee).
Highlights
2-methylbutanoic acid derivatives are present in a wide range of fermented products such as bread, cheese, and several alcoholic beverages, contributing to their complex flavor.[3] (S)-2-methylbutanoic acid is a precursor for the synthesis of the cholesterol-lowering drug pravastatin.[4] (R)-2-Methylbutanoic acid is part of the sex pheromone of the invasive species Acutaspis albopicta.[5] (S)-2-Methylhexanoic acid is a constituent of the cytotoxic marine natural compound palau’imide.[6]
This substrate specificity of AMDase suggests the potential applicability of AMDase and its variants to produce both enantiomers of short-chain 2-methylalkanoic acids
Considering that AMDase does not accept substrates without a delocalized p-electron system,[10,15] we envisioned a cascade by combining the enzymatic synthesis of intermediary 2-methylalk-3-enoic acids followed by a chemical C=C double bond reduction
Summary
Enantiopure 2-methyl-substituted carboxylic acids are widely used as active pharmaceutical ingredients, building blocks, and fragrance and aroma compounds.[1,2] For instance, 2-methylbutanoic acid derivatives are present in a wide range of fermented products such as bread, cheese, and several alcoholic beverages, contributing to their complex flavor.[3] (S)-2-methylbutanoic acid is a precursor for the synthesis of the cholesterol-lowering drug pravastatin.[4] (R)-2-Methylbutanoic acid is part of the sex pheromone of the invasive species Acutaspis albopicta.[5] (S)-2-Methylhexanoic acid is a constituent of the cytotoxic marine natural compound palau’imide.[6]. We report a chemoenzymatic cascade reaction to produce optically pure short-chain 2-methylalkanoic acids by combining the enzymatic asymmetric decarboxylation of methylvinylmalonic acid derivatives 1 and the chemical reduction of the nonactivated C=C double bond (Scheme 1).
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