Practical non-enzymatic synthesis of propargyl sialyl-α-(2-3')-lactosamine trisaccharide using minimal protecting groups manipulation

Abstract

The trisaccharide, prop-2-ynyl 5-acetamido-3,5-dideoxy-d-glycero-α-d-galacto-2-nonulopyranosylonic acid-(2 → 3)-β-d-galactopyranosyl-(1 → 4)-2-acetamido-2-deoxy-β-d-glucopyranoside (9) has been efficiently synthesized in a few steps without the need of conformationally constrained glycosyl donors and acceptors or enzymes. First, using the known prop-2-ynyl 2-acetamido-2-deoxy-6-O-tert-butyldiphenylsilyl-β-d-glucopyranoside as acceptor (2) and the peracetylated galactosyl trichloroacetimidate (3) as glycosyl donor, followed by protecting groups manipulation, prop-2-ynyl (6-O-tert-butyldiphenylsilyl-β-d-galactopyranosyl)-(1 → 4)-2-acetamido-2-deoxy-6-O-tert-butyldiphenylsilyl-β-d-glucopyranoside (6) was synthesized with exclusive O-4 regioselectivity due to steric hindrance of the upper face of the acceptor at O-3. Sialylation with the thiophenyl glycosyl donor (7) afforded the desired trisaccharide with the shortest number of steps and in higher overall yield than previously reported methodologies. The direct use of minimally protected N-acetyl-lactosamine acceptor (6) was critical for the efficient synthesis of the title compound. The propargylic aglycone is suitable for chemical ligation using click chemistry as reported for its (2 → 6) sialylated analog.

Keywords: Lactosamine; Sialic acid; TACAs; Trisaccharide.