Gold(I)-Catalyzed 2-Deoxy-β-glycosylation via 1,2-Alkyl/Arylthio Migration: Synthesis of Velutinoside A Pentasaccharide

2-Deoxy-beta-glycosides are essential components of natural products and pharmaceuticals; however, the corresponding 2-deoxy-beta-glycosidic bonds are challenging to chemically construct. Herein, we describe an efficient catalytic protocol for synthesizing 2-deoxy-beta-glycosides via either IPrAuNTf2-catalyzed activation of a unique 1,2-trans-positioned C2-S-propargyl xanthate (OSPX) leaving group or (PhO)3PAuNTf2-catalyzed activation of a 1,2-trans-C2-ortho-alkynylbenzoate (OABz) substituent of the corresponding thioglycosides. These activation processes trigger 1,2-alkyl/arylthio-migration glycosylation, enabling the synthesis of structurally diverse 2-deoxy-beta-glycosides under mild reaction conditions. The power of this strategy is demonstrated by the first synthesis of the pentasaccharide chain corresponding to velutinoside A, which features gold(I)-catalyzed construction of four successive beta-l-oleandrosidic bonds in both a convergent and a one-pot glycosylation manner. Mechanistic studies, including control experiments and deuterium-labeling experiments, emphasize the crucial role of the OSPX and the involvement of the gold(I)-activated C equivalent to C triple bond during the glycosylation process. The low-temperature NMR experiments unveiled a unique dual-coordination pattern of the gold(I) catalyst to the thiocarbonyl group and the alkynyl group of the OSPX, initiating a 5-exo-dig cyclization process. Furthermore, density functional theory (DFT) simulations reveal the ligand-induced match-mismatch effect between leaving groups OSPX and OABz and gold catalysts IPrAuNTf2 and (PhO)3PAuNTf2. The DFT simulations also suggest that the formation of 2-deoxy-beta-glycosidic bonds occurs via the bottom-face attack of the acceptor to the oxocarbenium intermediate, which adopts a 4 H 3 half-chair conformation, leading to an energetically favored, 4 C 1-conformed intermediate D beta that is stabilized by a hydrogen bonding interaction.