Emerging Capabilities of Nonclassical Noncovalent Interactions and Asymmetric Catalysis in Stereoselective Glycosylations and Carbohydrate Functionalizations.

ConspectusDeriving inspiration from frontier catalytic paradigms has emerged as a major force to tackle long-standing stereoselectivity issues in carbohydrate synthesis. In particular, there is a strong momentum in the harnessing of and the use of in the functionalization of carbohydrate polyols.In this Account, we describe our pioneering contributions to advancing these two major directions. First, we introduce our early work whereby halogen bonding (XB) interactions could be harnessed catalytically on sugars. We realized that the polyoxygenated motifs embedded in different regions of the carbohydrate scaffold offered multiple anchoring points where the XB-catalyst could iteratively interact via halogenO interactions. As a consequence, a counterintuitive multistage XB-activation concept was discovered. In our XB-catalyzed strain-release glycosylation, we intriguingly observed substantial elevation of anomeric selectivity over a wide array of glycosyl substrates as compared with thiourea catalysis. In XB-catalyzed 2-deoxyglycosylations, the multistaged XB-activation phenomena was also operative. Apart from the broader tolerance of glycosyl donors/acceptors compared to thiourea catalysis, we demonstrated the halogen tunability concept, where a halogen swap on the catalyst enabled tolerance of sensitive pentose-based donors.Next, we discovered that the two σ-holes per chalcogen property of phosphonochalcogenide (PCH) catalysts imparted unique benefits in glycoside activation. This opened up an unknown bifurcated chalcogen bonding (ChB) activation concept that paved a stereoselective entry into 7-ring sugars through either an internal nucleophilic substitution (Si) type mechanism or an intramolecular aglycone transposition strategy. - and -glycosylations of indoles with glycals were realized through conformational distortion by a network of ChB and π-interactions. The exclusively α-selective - and -iminoglycosylation of iminoglycals was further developed through an unprecedented multistep ChB-activation manifold.Second, our investigations revealed that multiple stereoselectivity challenges in site-selective carbohydrate functionalizations can be concomitantly tackled by an asymmetric catalytic system. Departing from the classical use of asymmetric catalysis to create chiral centers on achiral substrates, we advanced stereochemical complexity generation on sugars by simultaneously addressing the site-, diastereo-, and enantioselectivity challenges when carbohydrate polyols react with prochiral electrophiles. Additionally, rarely observed dynamic kinetic resolution type glycosylations on reducing sugars were unravelled when chiral Rh(I) and chiral copper catalytic systems were employed. We also discovered that the multiple stereoselectivity control by chiral Pd/organoboron-catalyzed site-selective functionalization of carbohydrate polyols can be attributed to the vital stereocontrolling role of NCIs such as CH-π interactions and hydrogen bonding.