Stereoselective assembly of C-oligosaccharides via modular difunctionalization of glycals

Abstract

C-oligosaccharides are found in natural products and drug molecules. Despite the considerable progress made during the last decades, modular and stereoselective synthesis of C-oligosaccharides continues to be challenging and underdeveloped compared to the synthesis technology of O-oligosaccharides. Herein, we design a distinct strategy for the stereoselective and efficient synthesis of C-oligosaccharides via palladium-catalyzed nondirected C1–H glycosylation/C2-alkenylation, cyanation, and alkynylation of 2-iodoglycals with glycosyl chloride donors while realizing the difunctionalization of 2-iodoglycals. The catalysis approach tolerates various functional groups, including derivatives of marketed drugs and natural products. Notably, the obtained C-oligosaccharides can be further transformed into various C-glycosides while fully conserving the stereochemistry. The results of density functional theory (DFT) calculations support oxidative addition mechanism of alkenyl-norbornyl-palladacycle (ANP) intermediate with α-mannofuranose chloride and the high stereoselectivity of glycosylation is due to steric hindrance.

Reactivity Switch in Glycal Dienes toward Different Nucleophiles: Mechanistic Insight and Applications toward the Synthesis of Naphthalene-Fused Pyran Derivatives

“…Glycals, the enol-ethers of sugars, are crucial in constructing intricate organic molecules and serve as valuable chiral pool starting materials. − A common Ferrier rearrangement is often employed to explore the synthetic potential of these sugars, leading to the stereoselective formation of various glycosides. − Recent advancements have introduced strategies to functionalize the C2 position of glycals, enabling the synthesis of branched sugars through either metal-catalyzed C–H functionalization or cross-coupling reactions. − The distinctive reactivity of glycals arises from an enol-ether that imparts altered reactivity to both carbons. The selection of an external reactant becomes crucial, determining whether the attack occurs at the C1 or C2 position.…”

Synthesis of 1,2-Disubstituted C-Aryl Glycosides via Palladium/Norbornene Cooperative Catalysis

“…At present, the research mainly focuses on monosubstitutional derivatization and cyclization structure, but the limited availability of 1,2-disubstituted glycals has rarely been explored, and the previous research needed directional group assistance to realize disubstitutions . However, the method of C-aryl glycosylation directly by one-step construction of 1,2-disubstituted glycosides has not been reported . Meanwhile, synthesis of all-carbon tetrasubstituted enolate has faced significant challenges, particularly when doing this transform in the electron-rich, unstable, and highly functionalized glycals in a regioselective manner.…”