Synthesis of 2-(N-Acetylamino)-2-deoxy-C-glucopyranosyl nucleosides as potential inhibitors of chitin synthases.
The C-glucopyranosyl nucleosides (1-4) containing the N-acetyl glucosaminyl and uridine units have been synthesized as nonhydrolyzable substrate analogues of UDP-GlcNAc aimed to inhibit the chitin synthases. The key intermediate, 4-(2'-(N-acetylamino)-3', 4',6'-tri-O-benzyl-2'-deoxy-alpha-D-glucopyranosyl)but-2-enoic acid (5), was prepared from the perbenzylated (N-acetylamino)-alpha-C-allylglucoside (7), by successive oxidative cleavage, Wittig olefination, and ester deprotection. The coupling of the acid 5 with the hydroxyl or amine function of the uridine derivatives (6a or 6b) afforded, respectively, the ester 12 and amide 14. The dihydroxylation of the conjugated double bond in ester 12 or amide 14 was better achieved with osmium tetraoxide/barium chlorate, leading to the expected diols 13 and 15 as a mixture of two diastereoisomers. The desired compounds 1-4 were obtained after catalytic hydrogenation of compounds 12-15.
Grugier
J
J
Laboratoire de Chimie des Glucides, CNRS UMR 7613, Université Pierre et Marie Curie, 4 Place Jussieu, 75005 Paris, France.
Xie
J
J
Duarte
I
I
Valéry
J M
JM
D000117:Acetylglucosamine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism; D002687:Chitin Synthase / Q000037:antagonists & inhibitors*; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D006865:Hydrogenation; D009682:Magnetic Resonance Spectroscopy; D011741:Pyrimidine Nucleosides / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D013379:Substrate Specificity; D014529:Uridine / Q000031:analogs & derivatives / Q000378:metabolism; D014537:Uridine Diphosphate N-Acetylglucosamine / Q000031:analogs & derivatives / Q000378:metabolism
D004791:Enzyme Inhibitors; D011741:Pyrimidine Nucleosides; D014537:Uridine Diphosphate N-Acetylglucosamine; D002687:Chitin Synthase; D000117:Acetylglucosamine; D014529:Uridine