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Biocatalytic Synthesis of α,β-Unsaturated 2-Keto Acids and Derivatives Using the Promiscuous Aldolase, NahE

Type I aldolases catalyze carbon-carbon bond-forming reactions to form a diverse set of products in nature but often display high selectivity for their natural substrates. One such aldolase, NahE, is known to catalyze the condensation of pyruvate with a wide range of aldehydes to give trans-4-phenyl-2-oxo-3-butenoic acids under mild aqeuous conditions. These ,-unsaturated 2-oxo acids are versatile intermediates for synthetic transformations. NahE has also been used for the synthesis of α-fluoro-β-hydroxy esters, β-hydroxy esters, and quinaldic acids. However, a thorough study of the substrate scope on a practical scale has not been performed for the native NahE-catalyzed aldol condensation reaction. Here we report that NahE can accept >35 (hetero)aromatic and aliphatic aldehydes. Most condensation products derived from substituted benzaldehydes were isolated in >95% yield without need for further purification, while non-benzaldehyde substrates gave the corresponding products in isolated yields between 26 and 98%. Reactions could be performed on gram scale. These products could be converted to α,β-unsaturated carboxylic acids in up to 93% yield over two steps. This reaction sequence was also performed using whole cells in up to 79% yield. This work demonstrates that NahE is a robust, efficient, and versatile catalyst for organic synthesis.