Synthesis of type I LacNAc (Galβ1 → 3GlcNAc) oligosaccharides usually suffers from low yields. We herein report the efficient synthesis of type I LacNAc oligosaccharides by chemoselective glycosylation. With 16 relative reactivity values (RRVs) measured thiotoluenyl-linked disaccharide donors and acceptors, chemoselective glycosylations were investigated to obtain optimal conditions. In these reactions, the RRV difference between the donors and acceptors had to be more than 6311 to obtain type I LacNAc tetrasaccharides in 72–86% yields, with minimal occurrence of aglycon transfer. The threshold of RRV difference was further applied to plan the synthesis of longer glycans. Because it is challenging to measure the RRVs of tetrasaccharides, anomeric proton chemical shifts were utilized to predict the corresponding RRVs, which consequently explained the outcome of glycosylations for the synthesis of type I LacNAc hexasaccharides. The result supported the idea that elongation of glycan chains has to proceed from the reducing to the nonreducing end for a better yield.

We recently developed a facile synthesis to yield orthogonally protected mannose‐ and Gal‐β1,3/4‐GlcNAc‐containing oligosaccharides. With optimized reaction conditions, the protection/glycosylation steps were carried out in a successive manner, without purification of intermediate products. The entire development sequence is herein described in detail, including each installation and removal of protecting groups, the optimization of glycosylation reactions, the successive operation of reaction steps, and further applications for glycan synthesis. We also discuss the unsolved problems and current challenges.

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