Reversible-Hydrogen-Transfer-Mediated Anomerization of Azaheterocyclyl 2-Deoxy-C-glycosides and Mechanistic Studies

Abstract

Mutarotation of O-glycans and O-glycosides has long been well-established and exploited in the stereocontrolled chemical synthesis of O-glycosides, while few examples of C-glycoside anomerization are known to date. During the development of a simple iridium catalyst-promoted α-stereoselective C-glycosylation of 2-indoly-pyridine with glycal donors, we serendipitously discovered the occurrence of 2-deoxy-C-glycoside anomerization, enabling α-to-β configuration conversion. Control experiments and density functional theory calculations were performed to explore the mechanistic details of the anomerization of the C-glycosylation products, which could tolerate C-aryl and C-alkyl-glycosides. The anomerization reaction plausibly proceeds through the pathway involving the activation of the C­(sp3)–H bond mediated by the iridium catalyst and reversible hydrogen transfer, rather than the classical anomerization mechanisms involving the endocyclic cleavage of the C1–O5 bond or exocyclic cleavage of the glycosidic bond.

Recent Advances and Strategies towards Synthesis of Indolyl and Tryptophan‐C‐Glycoside Scaffolds

“…In this relation, the catalytic anomerization emerges as a powerful tool that represents an efficient protocol for the direct stereoselective formation of 2-deoxy-C-glycosides. Recently, Mu and Lui research [72] group explored iridium-catalyzed anomerization of azaheterocyclyl 2-deoxy-C-glycosides involving reversible hydrogen transfer via classic Chalk-Harrod-type mechanism (Scheme 28). Iridiumcatalyzed hydrogen atom transfer (HAT) strategy was applied for the epimerization of 2-deoxy-C-glycoside with a good conversion ratio.…”

Diversification of Glycosyl Compounds via Glycosyl Radicals

“…[6c, 19c] Among these, glycosyl sulfoxides and sulfones enabled unprecedented protecting-group-free glycosyl radical diversification pushing the frontiers of radical-based glycosylation. Furthermore, new catalytic technologies have allowed for the non-anomeric radical functionalization on the sugar scaffold, such as the C1 epimerization of heteroaryl α-C-glycosyl compounds demonstrated by the Liu group, [22] C2-functionalization of carbohydrates reported by the Ngai group, [23] and the epimerization of the sugar unit within glycosyl compounds developed by the Wendlandt [24] and the MacMillan [25] labs. These advances have been covered in recent reviews [26] and will not be highlighted here.…”

Stereoselective Synthesis of Indolyl-C-glycosides Enabled by Sequential Aminopalladation and Heck Glycosylation of 2-Alkynylanilines with Glycals

“…C -Glycosides have received a great deal of attention in carbohydrate chemistry over the past decades because of their attractive biological activities and high stability toward chemical and enzymatic hydrolysis. , Indolyl- C -glycosides, as a privileged class of C -glycosides, are widely found in various natural products, biologically important proteins, and drug candidates (Scheme a) . Accordingly, remarkable efforts have been devoted to providing efficient methods for the preparation of these cores . The traditional routes, including the reaction of lithioindoles with glycolactone or 1,2-anhydro sugars, , cyclization of glycosyl alkynes, and Friedel–Crafts glycosylation, , always suffered from limitations such as the utilization of prefunctionalized glycosyl precursors or indolyl partners, poor selectivity, and harsh reaction conditions.…”