Palladium-Catalyzed Stereocontrolled Synthesis of C-Glycosides by Stereoretentive C(sp3)–C(sp2) Cross-Coupling
Year: 2025
Type: preprint
Abstract: C-glycosides represent a valuable class of biomolecules owing to their exceptional hydrolytic stability, diverse biological activities, and broad applications in natural product synthesis and glycomimetic design. Despite their importance, achieving stereo-controlled chemical synthesis of C-glycosides remains a significant challenge in organic chemistry. In this work, we present a novel and efficient method for the stereo-controlled synthesis of C-glycosides via C(sp3)–C(sp2) Suzuki-Miyaura type cross-coupling, introducing sugar aryl thioether as an electrophilic coupling partner. Our strategy focuses on developing an easily accessible and bench-stable S-linked tetrazole glycosyl donor via a one-pot synthesis from free sugar, which subsequently serves as a strong electrophilic coupling partner with boronic acid. Interestingly, this robust technique has a significant level of stereospecificity, allowing for the selective synthesis of both anomeric configurations directly from their respective glycosyl donors. The reactivity and versatility of this reaction are demonstrated in over 40 examples, including different monosaccharides and disaccharides. Furthermore, the synthetic utility of the method was highlighted by the synthesis of different sugar analogues of the antidiabetic drug Ipragliflozin. Mechanistic studies show that oxidative addition occurs at the anomeric centre by polarizing the C-S bond with the S-linked 1-phenyl-tetrazole group and lowering the activation barrier for the rate-determining step. The distinct reactivity of aryl thio-ether as an electrophilic cross-coupling partner may open new possibilities for the straightforward asymmetric C-C bond formation reactions in organic synthesis.
Source: ChemRxiv
Authors: Adrita `Nandy, Soumyadip Dey, Debabrata Giri, Shubhi Dwivedi, Abhijit Sau
Institution: Indian Institute of Technology Hyderabad
Language: English
Subfield: Organic Chemistry
Field: Chemistry
Domain: Physical Sciences
Open Access status: green
Awards: G3685609169, G5250394363
OpenAlex ID: W4413850243