Glycosyl ortho-(1-Phenylvinyl)benzoates as Donors for Streamlined One-Pot Assembly of Carbohydrates from Oligosaccharides to Polysaccharides.

ConspectusCarbohydrates are essential and the most abundant biomolecules, with pivotal roles in numerous biological processes. However, in comparison with proteins and DNA, the biosynthesis of carbohydrates is not a template-driven process but instead a stepwise process, which results in heterogeneous and complex carbohydrate structures. The accessibility of well-defined, pure, and sufficient glycans remains a bottleneck in carbohydrate chemistry, impeding the in-depth biological and functional studies and development of carbohydrate-based therapeutics. To address this issue, we have developed new glycosylation reactions with glycosyl ortho-(1-phenylvinyl)benzoates (PVBs) as versatile donors and new one-pot glycan assembly strategies on the basis of PVB glycosylation for the streamlined synthesis of carbohydrates from oligosaccharides to polysaccharides.The advantages of this new glycosylation reaction protocol include the following: (1) glycosyl PVB donors are readily prepared and shelf-stable, (2) promoters such as NIS and TMSOTf are cheap and readily available, (3) glycosylation yields are generally good to excellent with few side reactions, (4) substrate scopes are broad, (5) the operation of the method is simple, and (6) the method is suitable for the one-pot assembly of glycans. Different from traditional carbohydrate synthesis that is stepwise, tedious, and time-consuming, new one-pot glycan assembly strategies based on PVB donors not only accelerated the synthesis and reduced chemical wastes but also precluded potential issues such as aglycone transfer, undesired interferences of the departing species, and unpleasant odor inherent to one-pot glycosylation with thioglycosides. These one-pot glycan assembly strategies mainly include four tactics: (1) by utilizing the orthogonality of PVB donors, orthogonal one-pot glycosylation could construct diverse glycosidic bonds, including the challenging 1,2-cis-glycosidic linkages, through strategic combinations of PVB donors with the other donors such as glycosyl trichloroacetimidate, N-phenyltrifluoroacetimidate, and ortho-alkynylbenzoates; (2) by utilizing the high reactivity of PVB donors, reactivity-based one-pot glycosylation could achieve efficient glycan assembly via the combinations of PVB donors with thioglycosides or n-Pen glycosides; (3) through preactivation of PVB donors, preactivation-based one-pot glycosylation could achieve the efficient assembly of different glycosidic linkages, especially 1,2-cis-glycosidic bonds; and (4) through utilizing the orthogonality and reactivity of PVB donors, orthogonal and reactivity-based one-pot glycosylation could construct at least four different glycosidic bonds simultaneously. Indeed, one-pot glycan assembly strategies on the basis of PVB glycosylation method have been successfully applied to the streamlined total synthesis of diverse and complex carbohydrates with important biological activities, including plants glycans such as the undecasaccharide from Dendrobium huoshanense and tridecasaccharide from Angelica sinensis, fungi glycans such as nonadecasaccharide from Ganoderma sinense and tetradecasaccharide from Lentinus giganteus, nucleosides such as capuramycin, mucin-related tumor associated carbohydrate antigens, bacterial glycans such as lipopolysaccharide from Bacteroides vulgatus, and mannose-capped lipoarabinomannan up to 101-mer from Mycobacterium tuberculosis.