Synthesis of N-β-d-glucopyranosyluronate derivatives of barbital, phenobarbital, metharbital, and mephobarbital

The synthesis and characterization of barbital, phenobarbital, metharbital, and mephobarbital glucuronides is reported. The condensation of per(trimethylsilyl)-barbital and -phenobarbital with methyl 1,2,3,4-tetra-O-acetyl-β-d-glucopyranuronate in the presence of trimethylsilyl trifluoromethanesulfonate gave moderate yields of the N1-(β-d-glucopyranosyluronate) barbiturate derivatives. The diastereomers of the phenobarbital derivatives were resolved by use of C18 reversed-phase HPLC. The homologous N3-methyl barbiturate N1-glucuronates were prepared by reaction of the barbital and phenobarbital N1-glucuronate derivatives with diazomethane. The absolute configuration of the phenobarbital N1-β-d-glucopyranuronate epimers was determined by oxidative removal of the glycon from the mephobarbital N1-β-d-glucopyranuronate epimers to give the optical isomers of mephobarbital. The spectroscopic data for this series of compounds will facilitate the characterization of N-glycosylated imide xenobiotics that may be detected as mammalian metabolites in biodisposition studies.