Synthesis of fluoro derivatives of 2-amino-2-deoxy-D-galactose and -D-glucose

Abstract

Selective fluoride displacement of the 6-mesyloxy group of methyl 2-benzamido-3-O-benzyl-2-deoxy-4,6-di-O-mesyl-α-D-glucopyranoside 4 gave the 6-fluoride 5. Subsequent removal of the blocking substituents afforded 2-amino-2,6-dideoxy-6-fluoro-D-glucose, isolated as its hydrochloride 11 and its N-acetyl derivative 12. Nucleophilic displacement of the remaining 4-mesyloxy group of the intermediary 6-fluoro-4-mesylate 5, by benzoate anion afforded derivatives of 2-amino-2,6-deoxy-6-fluoro-D-galactose (18). An interplay of similar substitutions on 4 gave, after deprotection, methyl 2-acetamido-4,6-difluoro-2,4,6-trideoxy-α-D-galactopyranoside (22), methyl 2-acetamido-3-O-acetyl-4,6-difluoro-2,4,6-trideoxy-α-D-glucopyranoside (27), and methyl 2-benzamido-3-O-benzyl-6-fluoro-2,4,6-trideoxy-β-L-threo-hex-4-enopyranoside(28).Methyl 2-acetamido-2,4-dideoxy-4-fluoro-α-D-glucopyranoside diacetate (31) was synthesized from the 4-O-mesyl-6-O-trityl-galactopyranoside 29.

Synthesis of multiply fluorinated N-acetyl-D-glucosamine and D-galactosamine analogs via the corresponding deoxyfluorinated glucosazide and galactosazide phenyl thioglycosides

“…Palladium-catalyzed hydrogenolytic debenzylation of 49-58 then yielded the target fluoro analogs 61-70. To complete the series of fluorinated analogs for the purpose of comparing their NMR spectra, the known C6 monodeoxyfluorinated compounds 71 [27,28] and 72 [29] were prepared by published procedures [27,29]. The magnitudes of the vicinal 3 J H-H , 3 J H-F , 3 J C-F , geminal 2 J H-F , 2 J C-F , and one-bond 1 J C-F coupling constants confirmed the expected fluorination pattern and ᴅ-gluco or ᴅ-galacto con-figuration for all fluoro analogs 59-72.…”

“…Unprotected multiply-deoxyfluorinated N-acetyl-ᴅ-glucosamine (GlcNAc) and N-acetyl-ᴅ-galactosamine (GalNAc) have not yet been described except for a 4,6-difluoro-GalNAc analog [22], although GlcNAc is the most abundant monosaccharide component of mammalian glycans [23], and GalNAc occurs in important glycan structures including the T N and T antigen and their sialylated forms [24]. A complete series of O-protected monofluorinated [22,[25][26][27][28][29][30][31][32] and several difluorinated [22,26,33,34] GlcNAc/GalNAc analogs have been prepared. Some acylated mono-and difluorinated analogs have potential in biomedical applications due to their ability to inhibit the glycan and glycosaminoglycan biosynthesis [34][35][36][37].…”

The Synthesis and Glycoside Formation of Polyfluorinated Carbohydrates

“…466 Protection of OH-3 as benzyl ether 1023 was followed by benzylidene acetal hydrolysis to allow activation to the 4,6-di-O-mesylate 1025. 467 Fluoride substitution to give 1026 could be achieved with TBAF in refluxing acetonitrile or with KF in refluxing ethylene glycol, the latter having a much shorter reaction time. Replacing the 3-Obenzyl group with an acetate and the benzamide with acetamide gave, after acetate methanolysis, methyl 2,4,6-trideoxy-2acetamido-4,6-difluorogalactoside 1029.…”

Synthesis of multiply fluorinated N-acetyl-D-glucosamine and D-galactosamine analogs via the corresponding deoxyfluorinated glucosazide and galactosazide thiodonors

“…Palladium-catalyzed hydrogenolytic debenzylation of 39-48 then yielded the target fluoro analogs 51-60. To complete the series of fluorinated analogs for the purpose of comparing their NMR spectra, the known C6 monodeoxyfluorinated compounds 61 [27,28] and 62 [29] were prepared by published procedures [27,29]. The magnitudes of the vicinal 3 JH-H, 3 JH-F, 3 (tg) conformations to a significant degree ( 3 JH5-F6 = 12.7-14.6 Hz).…”

“…Unprotected multiply-deoxyfluorinated N-acetyl-D-glucosamine (GlcNAc) and N-acetyl-Dgalactosamine (GalNAc) have not yet been described except for 4,6-difluoro-GalNAc analog [22], although GlcNAc is the most abundant monosaccharide component of mammalian glycans [23], and GalNAc occurs in important glycan structures including TN and T antigen [24] and their sialylated forms [25]. A complete series of O-protected monofluorinated [22,[26][27][28][29][30][31] and several difluorinated [22,26,32,33] GlcNAc/GalNAc analogs have been prepared. Some acylated mono-and difluorinated analogs have potential in biomedical applications due to their ability to inhibit glycan and glycosaminoglycan biosynthesis [33][34][35][36][37].…”