Polyoxin C

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 N-(2-{[(tert-butyldimethylsilyl)oxy]methyl}phenyl)carbonitrile. Following the Ugi reaction, treatment with HCl in MeOH achieves deprotection of the isopropylidene group and the N-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.

Carbocyclic uracil polyoxin C analogs are prepared from an acylnitroso-derived hetero Diels-Alder cycloadduct in fewer than nine steps. Pd(0)/InI-mediated allylation of 4-acetoxy-2-azetidinone is used to install the beta-amino acid side chain at the C-5' position of the carbocycle.

Stereoselective syntheses of both the natural (C5'- S) and unnatural (C5'- R) diastereoisomers of uracil polyoxin C methyl ester have been developed. The key stereocontrolled step involves nucleophilic addition of trimethylsilyl cyanide to the appropriate chiral sulfinimine derived from 2',3'-protected 5'-formyluridine and (S)-(-)-tert-butanesulfinamide or (R)-(+)-tert-butanesulfinamide, respectively. A variety of substrate mimics designed to function as inhibitors of chitin synthase have been synthesized by conjugation of the methyl ester of uracil polyoxin C (UPOC) with activated isoxazole carboxylic acids. Amide bond formation was accomplished via coupling of the amino functionality of UPOC methyl ester with a free isoxazole acid using HBTU or alternatively an isoxazole pentafluorophenyl ester. The substrate mimics incorporate features of the nucleoside-peptide antibiotics, the polyoxins and the nikkomycins, as well as features of the transition state structure expected during polymerization of the natural chitin synthase substrate uridine diphosphoryl-N-acetylglucosamine (UDP-GlcNAc), namely, a metal-binding site and glycosyl oxocarbenium ion mimic.