Stereoselective synthesis of novel uracil polyoxin C conjugates as substrate analogues of chitin synthase.
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.
Plant
Andrew
A
Centre for Chemical Biology, Richard Roberts Building, Department of Chemistry, University of Sheffield, Sheffield, UK. andrew.plant@syngenta.com
Thompson
Peter
P
Williams
David M
DM
D002687:Chitin Synthase / Q000737:chemistry*; D008968:Molecular Conformation; D011741:Pyrimidine Nucleosides / Q000138:chemical synthesis* / Q000737:chemistry; D013237:Stereoisomerism; D014498:Uracil / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry
D011741:Pyrimidine Nucleosides; C414026:uracil polyoxin C; D014498:Uracil; D002687:Chitin Synthase