N-Glycosylation is a widespread posttranslational modification of eukaryotic proteins. N-Glycans are functional constituents of glycoproteins and serve to control the intra-and intercellular distribution and three-dimensional structure of glycoproteins and also protect them against degradation. Furthermore, N-glycans are involved in important biological processes including cell differentiation, cell adhesion, and malignant transformation. [1] Here we report the synthesis of undecasaccharide 1 (see Scheme 2), one of the prototypical structures of complex-type N-glycans of mammalian origin. [2] This represents the first purely chemical synthesis of 1 achieved with strict stereochemical control. [3] With the aim of constructing this complex molecule in a stereocontrolled fashion, our initial investigation centered around the use of tetrasaccharide 2 [4a] (Scheme 1), obtainable by p-methoxybenzylassisted intramolecular aglycon delivery (IAD), as the key intermediate, which was eventually transformed into the fully protected undecasaccharide 3. However, deprotection of 3 turned out to be highly challenging, mainly due to the difficulty of manipulating sialic acid methyl ester in the presence of a 4,5dichlorophthaloyl (DCPhth) group, and vice versa.
In our revised synthetic plan (Scheme 2), the core trisaccharide 12 was designed as the key intermediate on the basis of the following considerations: First, acetamido groups were masked as azides in the hope that problems associated with the potential nucleophilicity of acetamido groups and/or the base lability of phthalimide (or DCPhth) can be largely eliminated at the stage of critical glycoside bond forming reactions and/or manipulation of the protecting groups. Additionally, to maximize the efficiency of b-mannosylation, cyclohexylidene-protected 8 [5a] was adopted as the mannosyl donor; it has proved to be the most suitable glycosyl donor for such purposes.
In practice, preparation of trisaccharide 12 was executed with monosaccharide components 4, [5b,c] 5, [5d] and 8 [5a] (Scheme 3) and commenced with the high-yield preparation [*] Dr.