Gold(I)-Catalyzed Glycosylation with Glycosyl o-Alkynylbenzoates as Donors.

Abstract

Naturally occurring glycans and glycoconjugates have extremely diverse structures and biological functions. Syntheses of these molecules and their artificial mimics, which have attracted the interest of those developing new therapeutic agents, rely on glycosylation methodologies to construct the various glycosidic linkages. In this regard, a wide array of glycosylation methods have been developed, and they mainly involve the substitution of a leaving group on the anomeric carbon of a glycosyl donor with an acceptor (a nucleophile) under the action of a particular promoter (usually a stoichiometric electrophile). However, glycosylations involving inherently unstable or unreactive donors/acceptors are still problematic. In those systems, reactions involving nucleophilic, electrophilic, or acidic species present on the leaving group and the promoter could become competitive and detrimental to the glycosylation. To address this problem, we applied the recently developed chemistry of alkynophilic gold(I) catalysts to the development of new glycosylation reactions that would avoid the use of the conventional leaving groups and promoters. Gratifyingly, glycosyl o-alkynylbenzoates (namely, glycosyl o-hexynyl- and o-cyclopropylethynylbenzoates) turned out to be privileged donors under gold(I) catalysis with Ph3PAuNTf2 and Ph3PAuOTf. The merits of this new glycosylation protocol include the following: (1) the donors are easily prepared and are generally shelf-stable; (2) the promotion is catalytic; (3) the substrate scope is extremely wide; (4) relatively few side reactions are observed; (5) the glycosylation conditions are orthogonal to those of conventional methods; and (6) the method is operationally simple. Indeed, this method has been successfully applied in the synthesis of a wide variety of complex glycans and glycoconjugates, including complex glycosides of epoxides, nucleobases, flavonoids, lignans, steroids, triterpenes, and peptides. The direct glycosylation of some sensitive aglycones, such as dammarane C20-ol and sugar oximes, and the glycosylation-initiated polymerization of tetrahydrofuran were achieved for the first time. The gold(I) catalytic cycle of the present glycosylation protocol has been fully elucidated. In particular, key intermediates, such as the 1-glycosyloxyisochromenylium-4-gold(I) and isochromen-4-ylgold(I) complexes, have been unambiguously characterized. Exploiting the former glycosyloxypyrylium intermediate, SN2-type glycosylations were realized in specific cases, such as β-mannosylation/rhamnosylation. The protodeauration of the latter vinylgold(I) intermediate has been reported to be critically important for the gold(I) catalytic cycle. Thus, the addition of a strong acid as a cocatalyst can dramatically reduce the required loading of the gold(I) catalyst (down to 0.001 equiv). C-Glycosylation with silyl nucleophiles can proceed catalytically when moisture, which is sequestered by molecular sieves, can serve as the H+ donor for the required protodeauration step. Indeed, the unique mechanism explains the merits and broad applicability of the present glycosylation method and provides a foundation for future developments in glycosylation methodologies that mainly involve improving the diastereoselectivity and catalytic efficiency of glycosylations.