Iron-catalyzed stereoselective glycosylation for 1,2-cis-aminoglycoside assembly.

Abstract

Complex carbohydrates are essential to life processes, but it is challenging to isolate these molecules from natural sources in high homogeneity. Therefore, complex-glycan synthesis becomes critical to improving our understanding of their important functions. Due to their complexity, synthesis is still difficult for nonexperts. One of the key challenges is to search for general solutions for highly 1,2-cis-selective glycosylation, which will directly assemble 1,2-cis-2-aminoglycosides that are incorporated in numerous biologically important complex glycans and glycoconjugates. Here we describe an iron-catalyzed, chemical glycosylation method for rapid assembly of 1,2-cis-aminoglycosidic linkages. The iron catalyst is commercially available, and the bench-stable supporting ligand and amination reagents are easily prepared from abundant, readily available starting materials. This catalytic, exclusively 1,2-cis-selective glycosylation is effective for a broad range of glycosyl donors and acceptors, and it can be operated in a continuous fashion and scaled up to the multigram scale. The reactivity of this glycosylation is tunable for both electron-rich and electron-deficient substrates by modulating amination reagents. The glycosylation proceeds through a unique mechanism in which the iron catalyst activates a glycosyl acceptor and an oxidant when it facilitates the cooperative atom transfer of both moieties to a glycosyl donor in an exclusively cis-selective manner. This glycosylation protocol takes several hours to operate. It complements the existing 1,2-cis-selective glycosylation methods and effectively addresses the challenge of achieving both generality and high stereoselectivity in the 1,2-cis-selective aminoglycosylation.