Opposite Enantioselectivity in the Bioreduction of (Z)-β-Aryl-β-cyanoacrylates Mediated by the Tryptophan 116 Mutants of Old Yellow Enzyme 1: Synthetic Approach to (R)- and (S)-β-Aryl-γ-lactams

The Trp 116 mutants of Old Yellow Enzyme 1 that catalyse the reduction of (Z)-beta-aryl-beta-cyanoacrylates give the opposite enantioselectivity according to the nature of the amino acid in position 116. Small amino acids (e.g., alanine) make the substrate bind to the enzyme's active site in a classical orientation, affording the (S)-enantiomer of the reduced product. When the size of the amino acid increases (e.g., leucine), a flipped binding mode is adopted by the substrate, which is converted into the corresponding (R)-derivative. With bulky amino acids (e.g., tryptophan in the wild-type) the reduction does not occur. The enantiomerically enriched cyanopropanoates thus prepared can be converted into the corresponding (S)- and (R)-beta-aryl-gamma-lactams, precursors of inhibitory neurotransmitters belonging to the class of gamma-aminobutyric acids, by a simple functional group interconversion in a sequential one-pot procedure.