Unraveling the promoter effect and the roles of counterion exchange in glycosylation reaction.

The stereoselectivity of glycosidic bond formation continues to pose a noteworthy hurdle in synthesizing carbohydrates, primarily due to the simultaneous occurrence of SN1 and SN2 processes during the glycosylation reaction. Here, we applied an in-depth analysis of the glycosylation mechanism by using low-temperature nuclear magnetic resonance and statistical approaches. A pathway driven by counterion exchanges and reaction byproducts was first discovered to outline the stereocontributions of intermediates. Moreover, the relative reactivity values, acceptor nucleophilic constants, and Hammett substituent constants (σ values) provided a general index to indicate the mechanistic pathways. These results could allow building block tailoring and reaction condition optimization in carbohydrate synthesis to be greatly facilitated and simplified.

Thiocarbonyl as a Switchable Relay-Auxiliary Group in Carbohydrate Synthesis.

A multifunctional O-phenyl thiocarbonyl (O(C═S)OPh) group was introduced in glycosylation reactions. This auxiliary group exhibits three features (1) C6-long-range participation effect, (2) relay activation, and (3) switchable promoter-controlled carbonylation, which enables the facile synthesis of both 6-deoxy glucoside and 6-alcohol glucoside. In addition, we successfully quantified the extent of the C6-acyl participation effect and developed its application toward the α-trisaccharide motif.

Mapping Mechanisms in Glycosylation Reactions with Donor Reactivity: Avoiding Generation of Side Products.

The glycosylation reaction, which is key for the studies on glycoscience, is challenging due to its complexity and intrinsic side reactions. Thioglycoside is one of the most widely used glycosyl donors in the synthesis of complex oligosaccharides. However, one of the challenges is its side reactions, which lower its yield and limits its efficiency, thereby requiring considerable effort in the optimization process. Herein, we reported a multifaceted experimental approach that reveals the behaviors of side reactions, such as the intermolecular thioaglycon transformation and N-glycosyl succinimides, via the glycosyl intermediate. Our mechanistic proposal was supported by low temperature NMR studies that can further be mapped by utilizing relative reactivity values. Accordingly, we also presented our findings to suppress the generation of side products in solving this particular problem for achieving high-yield glycosylation reactions.