Biocatalytic Asymmetric Michael Additions of Nitromethane to α,β-Unsaturated Aldehydes via Enzyme-bound Iminium Ion Intermediates

The enzyme 4-oxalocrotonate tautomerase (4-OT) exploits an N-terminal proline as main catalytic residue to facilitate several promiscuous C-C bond-forming reactions via enzyme-bound enamine intermediates. Here we show that the active site of this enzyme can give rise to further synthetically useful catalytic promiscuity. Specifically, the BOA mutant of 4-OT was found to efficiently promote asymmetric Michael additions of nitromethane to various alpha,beta-unsaturated aldehydes to give gamma-nitroaldehydes, important precursors to biologically active gamma-aminobutyric acids. High conversions, high enantiocontrol, and good isolated product yields were achieved. The reactions likely proceed via iminium ion intermediates formed between the catalytic Pro-1 residue and the alpha,beta-unsaturated aldehydes. In addition, a cascade of three 4-OT(FSOA)catalyzed reactions followed by an enzymatic oxidation step enables assembly of gamma-nitrocarboxylic acids from three simple building blocks in one pot. Our results bridge organo- and biocatalysis, and they emphasize the potential of enzyme promiscuity for the preparation of important chiral synthons.