The C-Disaccharide α-C(1→3)-Mannopyranoside of N-Acetylgalactosamine Is an Inhibitor of Glycohydrolases and of Human α-1,3-Fucosyltransferase VI. Its Epimer α-(1→3)-Mannopyranoside of N-Acetyltalosamine Is Not

The radical C-glycosidation of (−)-(1S,4R,5R,6R)-6-endo-chloro-3-methylidene-5-exo-(phenylseleno)-7-oxabicyclo[2.2.1]heptan-2-one ((−)-4) with 2,3,4,6-tetra-O-acetyl-α-d-mannopyranosyl bromide gave (+)-(1S,3R,4R,5R,6R)-6-endo-chloro-5-exo-(phenylseleno)-3-endo-(1‘,3‘,4‘,5‘-tetra-O-acetyl-2‘,6‘-anhydro-7‘-deoxy-d-glycero-d-manno-heptitol-7‘-C-yl)-7-oxabicyclo[2.2.1]hept-2-one ((+)-5) that was converted into (+)-(1R,2S,5R,6R)-5-acetamido-3-chloro-2-hydroxy-6-(1‘,3‘,4‘,5‘-tetra-O-acetyl)-2‘,6‘-anhydro-7‘-deoxy-d-glycero-d-manno-heptitol-7‘-C-yl)cyclohex-3-en-1-yl acetate ((+)-10) and into (+)-(1R,2S,5R,6S)-5-bromo-3-chloro-2-hydroxy-6-(1‘,3‘,4‘,5‘-tetra-O-acetyl-2‘,6‘-anhydro-7‘-deoxy-d-glycero-d-manno-heptitol-7‘-C-yl)cyclohex-3-en-1-yl acetate ((+)-19). Ozonolysis of (+)-10 and further transformations provided 2-acetamido-2,3-dideoxy-3-C−(2‘,6‘-anhydro-7‘-deoxy-d-glycero-d-ma nno-heptitol-7‘-C-yl)-d-galactose (α-C(1→3)-d-mannopyranoside of N-acetylgalactosamine (α-d-Manp-(1→3)CH2-d-GalNAc): 1). Displacement of the bromide (+)-19 with NaN3 in DMF provided the corresponding azide ((−)-20) following a SN2 mechanism. Ozonolysis of (−)-20 and further transformations led to 2-acetamido-2,3-dideoxy-3-C−(2‘,6‘-anhydro-7‘-deoxy-d-glycero-d-ma nno-heptitol-7‘-C-yl)-d-talose (α-C(1→3)-d-mannopyranoside of N-acetyl d-talosamine (α-d-Manp-(1→3)CH2-d-TalNAc): 2). The neutral C-disaccharide 1 inhibits several glycosidases (e.g., β-galactosidase from jack bean with K i = 7.5 μM, α-l-fucosidase from human placenta with K i = 28 μM, β-glucosidase from Caldocellum saccharolyticum with K i = 18 μM) and human α-1,3-fucosyltransferase VI (Fuc-TVI) with K i = 120 μM whereas it 2-epimer 2 does not. Double reciprocal analysis showed that the inhibition of Fuc-TVI by 1 displays a mixed pattern with respect to both the donor sugar GDP-fucose and the acceptor LacNAc with K i of 123 and 128 μM, respectively.