Design of α-Selective Glycopyranosyl Donors Relying on Remote Anchimeric Assistance

Abstract

Oligosaccharides have a variety of versatile biological effects, but unlike peptides and oligonucleotides, investigation of the roles of oligosaccharides is not easy. Since biosynthesis of oligosaccharides does not comply with direct genetic control, their isolation from natural sources and biotechnological preparation are complicated, due to the heterogeneous composition of raw carbohydrates. Oligosaccharide synthesis is needed for the establishment or confirmation of the structure of natural glycocompounds. Also, synthetically prepared, defined oligosaccharides and their derivatives are becoming increasingly important tools for many biological and immunological research projects. The key step of oligosaccharide synthesis involves glycosylation, a reaction that builds glycosidic bonds. Usually, construction of 1,2-trans-bonds is easy, and therefore, this reaction can even be included into automated syntheses. At this time, installation of the 1,2-cis-bond remains simultaneously frustrating and compelling. In our and other laboratories, a strategy of α-selective (1,2-cis) glycosylation, relying on remote anchimeric assistance with acyl groups, is studied. The state of the art in this work is summarized in this review.

The Cyclic Nitronate Route to Pharmaceutical Molecules: Synthesis of GSK’s Potent PDE4 Inhibitor as a Case Study

“…It is noteworthy that an anchimeric-assisted epimerization in 1,2-oxazine series has not been reported previously. Moreover, to our knowledge, this is the first reported example of a remote neighboring group participation from the 1,4-position in a six-membered ring confirmed by DFT calculations [38][39][40]. The formation of an eight-membered ring in this case may be driven by an unusual secondary anchimeric interaction involving the nitrogen atom of the 1,2-oxazine ring leading to an unusual tricyclic oxazolo(1,2)oxazinium cation C4.…”

The Experimental Evidence in Support of Glycosylation Mechanisms at the SN1–SN2 Interface

“…In this latter vein, Boons and coworkers computationally located a hydrogen bond from the incoming acceptor to the carbonyl group of an equatorial ester at O3 in their α-glucosylation system (Figure 21) thereby providing a possible explanation for the greater selectivity observed with the ester protected systems, 163 and, incidentally, the high levels of α-selectivity previously observed by numerous investigators with donors carrying esters at the 3-position. 313–316 As physical organic studies beyond the computational work have yet to be conducted and as the area has been recently reviewed 306 it is not covered further here.…”

Mechanisms of Stereodirecting Participation and Ester Migration from Near and Far in Glycosylation and Related Reactions

“…Stereodirecting participation by remote esters has been invoked frequently in glycosylation reactions. The subject has been reviewed recently, 26,27 and examples continue to be advanced in the context of a wide variety of glycosyl donors. 150,161,162,[235][236][237][238][239][240][241][242] Unfortunately, in most cases the reports are limited to observations of changes in selectivity, often relatively minor, when switching between a remote ether type protecting group and an ester.…”

“…[8][9][10][11][12][13][14][15][16][17][18][19][20][21] It has been practiced as a tool in glycosylation reactions since the discovery of the Koenigs-Knorr reaction 22 and as such the number of examples of its use, even in a single year, 23 are far too numerous to list here. Stereodirecting participation by more remote groups has also been very widely invoked in glycosylation reactions, since its introduction in the 1970's, 24,25 and has been reviewed in recent years, 16,26,27 such that, again, no attempt is made to comprehensively treat all implied examples of it.…”