Templated Oligosaccharide Synthesis: The Linker Effect on the Stereoselectivity of Glycosylation

Abstract

A new method for intramolecular oligosaccharide synthesis that is conceptually related to the general molecular clamp approach is introduced. Exceptional α-selectivity has been achieved in a majority of applications. Unlike other related concepts, this approach is based on the bisphenol A template, which allows one to connect multiple building blocks to perform templated oligosaccharide synthesis with complete stereoselectivity. This principle was demonstrated by the synthesis of an α,α-linked trisaccharide.

Templated Oligosaccharide Synthesis: Driving Forces and Mechanistic Aspects

“…For this purpose, we obtained a template with succinoyl linkers for both the glycosyl donor and acceptor attachment ( 7 – 9 ). As summarized in Table 2, complete α -stereoselectivity was still maintained in all reactions involving glycosylations of secondary glycosyl acceptors 7 and 8 7 (entries 1–4). Herein, we also tested the use of dimethyl(thiomethyl)sulfonium triflate (DMTST), 22 another popular promoter for glycosidation of thioglycosides 23 (entry 2).…”

“…The preliminary results indicate that the rigidity of the template is essential for the stereoselection. The first series of conjugates 1 – 3 7 were designed to deliver the glycosyl acceptor from the bottom face (linker L1 is shorter than L2, succinoyl vs glutaryl, respectively). The results of this study are summarized in Table 1.…”

“…The results of this study are summarized in Table 1. When per-benzylated donor tethered with 3-OH acceptor 1 was activated with NIS/TfOH followed by the ester bond cleavage under Zemplen conditions (NaOMe) and standard acetylation (Ac 2 O/pyridine), disaccharide 4 7 was isolated in 60% yield (entry 1). The most encouraging outcome of this test reaction is that glycoside 4 was obtained with complete α -selectivity, and no traces of the β -linked diastereomer could be detected.…”

“…With optimized reaction conditions, the protocol was applied to glycosylation of tethered 4-OH acceptor 2 , and disaccharide 5 7 was obtained in 81% yield and complete α -selectivity (entry 3). Glycosylation of tethered 6-OH acceptor 3 provided disaccharide 6 7 in 63% yield.…”

“…Glycosylation of tethered 6-OH acceptor 3 provided disaccharide 6 7 in 63% yield. Again, the preference was given to the formation of α -linked product, although the presence of the other diastereomer was also evident ( α / β = 9.2/1, entry 4).…”