Synthesis of Five-Membered Halo Enol Lactone Analogues of α-Amino Acids: Potential Protease Suicide Substrates

Aryl-substituted halo enol lactones can act as enzyme-activated irreversible inhibitors of serine proteases. We have developed synthetic routes to five-membered halo enol lactone analogues of α-amino acids, in order to extend these inactivators to more highly selective peptide substrate analogues. All of these methods involve the conversion of a propargyl-substituted amino acid derivative (i.e., a 4-pentynoic acid) into a 5(E)-halomethylidenetetra-hydro-2-furanone by a halolactonization process. The parent system, 3-benzamido-5(E)-(iodomethylidene)-tetrahydro-2-furanone, a halo enol lactone analogue of glycine, was prepared from N-benzoylpropargylglycine, which itself was prepared by propargyl alkylation of diethyl benzamidomalonate. The phenylalanine analogue, 3-amino-3-benzyl-5(E)-(bromomethylidene)tetrahydro-2-furanone, was prepared from N-protected propargyl-phenylalanine derivatives, which were themselves prepared by three methods: an indirect propargyl alkylation of the 2-phenyloxazolone derived from phenylalanine by using the 2-bromo-2-propenyl group as a propargyl synthon, successive propargyl and benzyl alkylation of a STÁBASE-protected glycine derivative, and direct propargyl substitution of a benzylidine-protected phenylalanine. The phenylglycine analogue, 3-benzamido-3-phenyl-5-(E)-(bromomethylidene)tetrahydro-2-furanone, was prepared by propargyl alkylation of the 2-phenyloxazolone of phenylglycine, which itself was prepared from N-benzoylphenylglycine. These methods provide satisfactory approaches to several five-membered halo enol lactone analogues of amino acids.