Preparation of the N ‐Acetylglucosaminidase Inhibitor 1‐Acetamido‐1,2,5‐trideoxy‐2,5‐imino‐ D ‐glucitol from Methyl α‐ D ‐Mannopyranoside

Fragmentation of methyl 3‐ O ‐benzyl‐6‐bromo‐2‐ O ‐( tert ‐butyldimethylsilyl)‐6‐deoxy‐4‐ O ‐(4‐methoxybenzyl)‐α‐ D ‐mannopyranoside ( 2 ) and in situ reductive amination give (3 R ,4 S ,5 R )‐6‐benzylamino‐4‐benzyloxy‐5‐( tert ‐butyldimethylsilyloxy)‐3‐(4‐methoxybenzyloxy)hexene ( 3 ) which is converted by intramolecular aminomercuration into an epimeric mixture of the bromomercuriopiperidine derivatives 4 and 5 . The minor D ‐ manno epimer 4 is transformed into mesylate 10 which, upon reaction with LiN 3 in DMF, suffers a piperidine‐pyrrolidine ring contraction to give azidomethylpyrrolidine 11 . Reductive acetylation by means of thioacetic acid affords the fully protected pyrrolidine aza sugar derivative 12 . The major L ‐ gulo epimer 5 is transformed into the mesylate 15 which, again, upon reaction with LiN 3 in DMF undergoes piperidine‐pyrrolidine ring contraction to give the 1‐azido‐3‐ O ‐benzyl‐2,5‐benzylimino‐6‐bromomercurio‐1,2,5,6‐tetradeoxy‐4‐ O ‐(4‐methoxybenzyl)‐ L ‐iditol ( 16 ). Eliminative dehalomercuration by means of Zn powder is accompanied by in situ reduction of the azido group to give amino alkene 17 . Intramolecular aminomercuration of 17 followed by N ‐acetylation yields the protected 1,2,5,6‐tetradeoxy‐2,5‐imino‐ D ‐glucitol derivative 20 as the major epimer. Reductive oxygenation of 20 leads to pyrrolidine 22 which is deprotected to give title compound 1 . Selective cleavage of the PMB group of 22 leads to 24 . Benzylation of 22 affords again 12 from which the OH group at C‐4 is liberated by selective cleavage of the PMB ether to give pyrrolidine 13 . Compound 1 inhibits NAGase from bovine kidney.