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-hydroxy-carboxylic 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.
Highlights
The high selectivity of biocatalysts in functionalization reactions facilitates the transformation of bio-based molecules into intermediates that lead to the production of high value chemicals.[1]
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 4hydroxy-2-oxoacids
In a previous work we developed an effective chemoenzymatic method for the synthesis of enantiomerically pure 2-substituted 3-hydroxycarboxylic esters.[9b]. The key step was an enzymatic stereoselective aldol addition of chemically synthetized 2oxoacids to formaldehyde catalyzed by two enantiocomplementary Type II 2-oxoacid aldolases, 2-keto-3deoxy-l-rhamnonate aldolase (YfaU, EC 4.1.2.53) fused with maltose binding protein from E. coli (MBP) (MBP-YfaU), and 3-methyl-2-oxobutanoate hydroxymethyltransferase (KPHMT, EC 2.1.2.11) and variants thereof
Summary
The high selectivity of biocatalysts in functionalization reactions facilitates the transformation of bio-based molecules into intermediates that lead to the production of high value chemicals.[1]. Asc.wiley-vch.de formaldehyde catalyzed by MBP-YfaU and KPHMT, furnishing both enantiomers of 3-substituted 4hydroxy-2-oxoacids, and iii) in situ transformation into 2-substituted 3-hydroxycarboxylic acids by oxidative decarboxylation. This strategy represents a complementary approach for the synthesis of 3-hydroxycarboxylic acids using widely available and diverse canonical and non-canonical l-α-amino acids as starting materials. In a previous work we developed an effective chemoenzymatic method for the synthesis of enantiomerically pure 2-substituted 3-hydroxycarboxylic esters.[9b] The key step was an enzymatic stereoselective aldol addition of chemically synthetized 2oxoacids to formaldehyde catalyzed by two enantiocomplementary Type II 2-oxoacid aldolases, 2-keto-3deoxy-l-rhamnonate aldolase (YfaU, EC 4.1.2.53) fused with maltose binding protein from E. coli (MBP) (MBP-YfaU), and 3-methyl-2-oxobutanoate hydroxymethyltransferase (KPHMT, EC 2.1.2.11) and variants thereof. Our ongoing work on the synthesis of 2-substituted 3-hydroxycarboxylic acids and derivatives has prompted us to develop an enzymatic cascade strategy for their preparation comprising: i) an enzymatic deamination reaction of l-α-amino acids rendering 2oxoacids; ii) an ensuing aldol addition of 2-oxoacid to
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