Synthesis of lacto-N-neotetraose and lacto-N-tetraose using the dimethylmaleoyl group as amino protective group

摘要

The disaccharide donor O-[2, 3, 4, 6-tetra-O-acetyl-#beta#-D-galactopyranosyl)-(1 -> 4)-3, 6-di-O-benzyl-2-deoxy-2-dimethylmaleimido-#alpha#, #beta#-D-glucopyranosyl] trichloroacetimidate (7) was prepared by reacting O-(2, 3, 4, 6-tetra-O-acetyl-#alpha#-galactopyranosyl) trichloroacetimidate with tert-butyldimethylsilyl 3, 6-di-O-benzyl-2-deoxy-2-dimethylmaleoylamido-glucopyranoside to give the corresponding disaccharide 5. Deprotection of the anomeric center and then reaction with trichloroacetonitrile afforded 7. Reaction of 7 with 3'-O-unprotected benzyl (2, 4, 6-tri-O-benzyl-#beta#-D-galactopyranosyl)-(1 -> 4)-2, 3, 6-tri-O-benzyl-#beta#-D-glucopyranoside (8) as acceptor afforded the desired tetrasaccharide benzyl (2, 3, 4, 6-tetra-O-acetyl-#beta#-D-galactopyranosyl)-(1 -> 4)-(3, 6-di-O-benzyl-2-deoxy-2-dimethylmaleimido-#beta#-D-glucopyranosyl)-(1 -> 3)-(2, 4, 6-tri-O-benzyl-#beta#-D-galactopyranosyl)-(1 -> 4)-2, 3, 6-tri-O-benzyl-#beta#-D-glucopyranoside. Replacement of the N-dimethylmaleoyl group by the acetyl group, O-debenzylation and finally O-deacetylation gave lacto-N-neotetraose. Similarly, reaction of O-[(2, 3, 4, 6-tetra-O-acetyl-#beta#-D-galactopyranosyl)-(1 -> 3)-4, 6-O-benzylidene-2-deoxy-2-dimethylmaleimido-#alpha#, #beta#-D-galactopyranosyl] trichloroacetimidate as donor with 8 as acceptor afforded the desired tetrasaccharide benzyl (2, 3, 4, 6-tetra-O-acetyl-#beta#-D-galactopyranosyl)-(1 -> 3)-(4, 6-benzylidene-2-deoxy-2-dimethylmaleimido-#beta#-D-glucopyranosyl)-(1 -> 3)-(2, 4, 6-tri-O-acetyl-#beta#-D-galactopyranosyl)-(1 -> 4)-2, 3, 6-tri-O-benzyl-#beta#-D-glucopyranoside. Removal of the benzylidene group, replacement of the N-dimethylmaleoyl group by the acetyl group and then O-acetylation afforded tetrasaccharide intermediate 15, which carries only O-benzyl and O-acetyl protective groups. O-Debenzylation and O-deacetylation gave lacto-N-tetraose (1). Additionally, known tert-butyldimethylsilyl (2, 3, 4, 6-tetra-O-acetyl-#beta#-D-galactopyranosyl)-(1 -> 3)-4, 6-O-benzylidene-2-deoxy-2-dimethylmaleimido-#beta#-D-glucopyranoside was transformed into O-[2, 3, 4, 6-tetra-O-acetyl-#beta#-D-galactopyranosyl)-(1 -> 3)-4, 6-di-O-acetyl-2-deoxy-2-dimethylmaleimido-#alpha#, #beta#-D-glucopyranosyl] trichloroacetimidate as glycosyl donor, to afford with 8 as acceptor the corresponding tetrasaccharide 22, which is transformed into 15, thus giving an alternative approach to 1.