Conformationally Armed 3,6-Tethered Glycosyl Donors: Synthesis, Conformation, Reactivity, and Selectivity

Abstract

The reactivity and selectivity of 3,6-tethered glycosyl donors have been studied using acceptors with different steric and electronic characteristics. Eight (four anomeric pairs) 3,6-bridged-glycosyl donors were synthesized in high yields from their common parent sugars. The glycosylation properties were tested using at least three different acceptors and several promoter systems. Thiophenyl 2,4-di-<i>O</i>-benzyl-3,6-<i>O</i>-(di-<i>tert</i>-butylsilylene)-α-d-glucopyranoside gave α/β mixtures with standard NIS/TfOH mediated activation, whereas the corresponding fluoride was found to be highly β-selective, when using SnCl₂/AgB­(C₆F₅)₄ as the promoter system. Mannosyl donors were highly α-selective despite the altered conformation. Galactosylations using NIS/TfOH were generally α-selective, but more β-selective using the galactosyl fluoride and depending on the acceptor used. Thiophenyl 2-azido-2-deoxy-4-<i>O</i>-benzyl-3,6-<i>O</i>-(di-<i>tert</i>-butylsilylene)-α-d-glucopyranoside was found to be α-selective . The reactivity of the donors was investigated using competition experiments, and some but not all were found to be highly reactive. Generally it was found that the α-thioglycosides were significantly more reactive than the β; this difference in reactivity was not found for 3,6-anhydro-, armed-(benzylated), or the classic super armed (silylated) donors. A mechanism supporting the unusual observations has been suggested