Abstract
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 aqueous conditions. These α,β-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 into 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.
Key words
aldolase - NahE - biocatalysis - chemoenzymatic synthesis - aldol condensation - cinnamic
acids
