One-pot glycosylations in the synthesis of human milk oligosaccharides

Human milk oligosaccharides contain a well-defined core structure that makes them interesting synthetic targets for one-pot glycosylation strategies. In this investigation, a one-pot procedure was studied in which a galactose thioglycoside is coupled chemoselectively to a phthalimide-protected glucosamine thioglycoside, and the resulting disaccharide is then coupled to the 3′-position in lactose. Very high yields of the tetrasaccharide product can be obtained when a protected lactosamine thioglycoside is formed in the first coupling. In contrast, it was not possible to extend the one-pot process to the synthesis of the corresponding 3″-linked structures, due to an inefficient synthesis of the lacto-N-biose thioglycoside in the first glycosylation. This is explained by the reactivity difference between the 3- and 4-positions in phthalimide-protected glucosamine. The one-pot procedure has been applied in an efficient synthesis of the pentasaccharide lacto-N-neofucopentaose I, which is composed of N-acetyllactosamine, lactose, and fucose. On the other hand, a stepwise approach was found to be the preferred synthetic pathway for preparation of the isomeric lacto-N-fucopentaose I, which contains a lacto-N-biose moiety. Copyright © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.