A synthetic strategy to xylose-containing thioglycoside tri- and tetrasaccharide building blocks corresponding to Cryptococcus neoformans capsular polysaccharide structures

Abstract

As part of an ongoing project aimed at developing vaccine candidates against Cryptococcus neoformans the preparation of tri- and tetrasaccharide thioglycoside building blocks, to be used in construction of structurally defined part structures of C. neoformans GXM capsular polysaccharide, was investigated. Using a naphthalenylmethyl (NAP) ether as a temporary protecting group and trichloroacetimidate donors in optimized glycosylations the target building blocks, ethyl 6-O-acetyl-2,4-di-O-benzyl-3-O-(2-naphthalenylmethyl)-α-D-mannopyranosyl-(1→3)-[2,3,4-tri-O-benzyl-β-D-xylopyranosyl-(1→2)]-4,6-di-O-benzyl-1-thio-α-D-mannopyranoside (16) and ethyl 2,3,4-tri-O-benzyl-β-D-xylopyranosyl-(1→2)-4,6-di-O-benzyl-3-O-(2-naphthalenylmethyl)-α-D-mannopyranosyl-(1→3)-[2,3,4-tri-O-benzyl-β-D-xylopyra-nosyl-(1→2)]-6-O-acetyl-4-O-benzyl-1-thio-α-D-mannopyranoside (21), were efficiently prepared. These synthesized thiosaccharide building blocks were then used as donors in high-yielding (∼90%) DMTST promoted glycosylations to a spacer-containing acceptor to, after deprotection, afford GXM polysaccharide part structures ready for protein conjugation to give vaccine candidates. Also, the NAP groups in the building blocks were removed to obtain tri- and tetrasaccharide acceptors suitable for further elongation towards larger thiosaccharide building blocks.