Synthesis of C-Oligosaccharides through Versatile C(sp3 )-H Glycosylation of Glycosides

Abstract

C-oligosaccharides are pharmacologically relevant because they are more hydrolysis-resistant than O-oligosaccharides. Despite indisputable advances, C-oligosaccharides continue to be underdeveloped, likely due to a lack of efficient and selective strategies for the assembly of the interglycosidic C-C linkages. In contrast, we, herein, report a versatile and robust strategy for the synthesis of structurally complex C-oligosaccharides via catalyzed C(sp³ )-H activations. Thus, a wealth of complex interglycosidic (2→1)- and (1→1)-C-oligosaccharides becomes readily available by palladium-catalyzed C(sp³ )-H glycoside glycosylation. The isolation of key palladacycle intermediates and experiments with isotopically-labeled compounds identified a trans-stereoselectivity for the C(sp³ )-H glycosylation. The glycoside C(sp³ )-H activation manifold was likewise exploited for the diversification of furanoses, pyranoses and disaccharides.

Keywords: 2-Deoxyglycosides; C(sp3)−H Activation; C-Disaccharide Synthesis; Palladium Catalysis.

Scheme 1

C‐oligosaccharides synthesis via C(sp³)−H glycosylation of glycosides. a) Natural products featuring interglycosidic C‐linkages. b) Methodologies for C‐disaccharide synthesis. c) C‐glycosyl acceptor design and C−H glycosylation of glycosides.

Scheme 2

β‐Elimination of various glycosides.

Scheme 3

Key mechanistic studies.

Scheme 4

Versatility and robustness of C(sp³)−H glycosides glycosylation.

Scheme 5

Late‐stage diversification and quinoline amide transformation. General conditions: a) Pd/C, H₂ (1.0 atm), EtOAc/MeOH, 16 h. b) LiAlH₄, N₂, 0 °C 2 h. c) K₂CO₃, MeOH, 12 h. d) N‐methylmaleimide, toluene, 110 °C, 3 h.