Application of the Ugi Reaction for the One-Pot Synthesis of Uracil Polyoxin C Analogues

A simple, two-step synthesis of amide derivatives of uracil polyoxin C (UPOC) methyl ester using the Ugi reaction is described. The four components employed in the Ugi reaction are 2′,3′-isopropylidine-protected uridine-5′-aldehyde, 2,4-dimethoxybenzylamine, an isoxazolecarboxylic acid, and the convertible isonitrile <i>N</i>-(2-{[(<i>tert</i>-butyldimethylsilyl)oxy]methyl}phenyl)carbonitrile. Following the Ugi reaction, treatment with HCl in MeOH achieves deprotection of the isopropylidene group and the <i>N-</i>benzyl group and conversion of the isonitrile-derived amide (the Ugi product) into the corresponding methyl ester. The procedure is amenable to automated multiparallel synthesis of novel compounds related to the polyoxin and nikkomycin nucleoside−peptide antibiotics.