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

Abstract The disaccharide donor O -[2,3,4,6-tetra- O -acetyl-β- d -galactopyranosyl)-(1→4)-3,6-di- O -benzyl-2-deoxy-2-dimethylmaleimido-α,β- d -glucopyranosyl] trichloroacetimidate ( 7 ) was prepared by reacting O -(2,3,4,6-tetra- O -acetyl-α- d -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-β- d -galactopyranosyl)-(1→4)-2,3,6-tri- O -benzyl-β- d -glucopyranoside ( 8 ) as acceptor afforded the desired tetrasaccharide benzyl (2,3,4,6-tetra- O -acetyl-β- d -galactopyranosyl)-(1→4)-(3,6-di- O -benzyl-2-deoxy-2-dimethylmaleimido-β- d -glucopyranosyl)-(1→3)-(2,4,6-tri- O -benzyl-β- d -galactopyranosyl)-(1→4)-2,3,6-tri- O -benzyl-β- 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-β- d -galactopyranosyl)-(1→3)-4,6- O -benzylidene-2-deoxy-2-dimethylmaleimido-α,β- d -glycopyranosyl] trichloroacetimidate as donor with 8 as acceptor afforded the desired tetrasaccharide benzyl (2,3,4,6-tetra- O -acetyl-β- d -galactopyranosyl)-(1→3)-(4,6-benzylidene-2-deoxy-2-dimethylmaleimido-β- d -glucopyranosyl)-(1→3)-(2,4,6-tri- O -benzyl-β- d -galactopyranosyl)-(1→4)-2,3,6-tri- O -benzyl-β- 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-β- d -galactopyranosyl)-(1→3)-4,6- O -benzylidene-2-deoxy-2-dimethylmaleimido-β- d -glucopyranoside was transformed into O- [2,3,4,6-tetra- O -acetyl-β- d -galactopyranosyl)-(1→3)-4,6-di- O -acetyl-2-deoxy-2-dimethylmaleimido-α,β- 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 .