Ammonium Chloride Promoted Ugi Four-Component, Five-Center Reaction of alpha -Substituted alpha -Isocyano Acetic Acid: A Strong Solvent Effect

Conditions have been developed for the multicomponent synthesis of di- and tetrapeptide based on the unique reactivity of alpha -isocyanoacetic acids (including its alpha -substituted derivs.) by an Ugi four-component, five-center reaction. Simply mixing an alpha -isocyanoacetic acid, a carbonyl compd. (aldehyde or ketone), and a secondary amine (ratio: 1:1:2, resp.) in toluene in the presence of 1.5 equiv of ammonium chloride afforded the desired product in good to excellent yield as a mixt. of two diastereomers. For example, peptide deriv. Me2NCH(C6H13)CONHCH(CH2Ph)CONMe2 was prepd. in 96% yield from Ugi reaction of isonitrile C==NCH(CH2Ph)CO2K, aldehyde C6H13CHO and amine Me2NH.HCl. [on SciFinder (R)]