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 PhPAuNTf and PhPAuOTf. 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, S2-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 ...

Convergent Synthesis of Linear and Branched β(1,3)‐Glucans and Evaluation of their Binding Affinities to Dectin‐1

“…The multiple‐branched tetradecasaccharide 9 can be prepared by the gold‐catalyzed, multiple glycosylation of the undecasaccharide 10 with the glycosyl 2‐alkynylbenzoate 11 , followed by global deprotection. The acid‐labile p ‐methoxybenzyl (PMB) ethers and benzylidene acetals would remain intact under the mild gold‐catalyzed glycosylation conditions . At the global deprotection step, these protecting groups can be readily removed by hydrolysis under acidic conditions to give the tetradecasaccharide 9 possessing an azido group.…”

“…The subsequent glycosylation of the diol 14 with the donor 15 , followed by acetylation of the remaining hydroxyl group and removal of tert ‐butyldimethylsilyl (TBS) ethers would provide the undecasaccharide 10 possessing three hydroxyl groups. TBS ethers would be intact under these gold‐catalyzed glycosylation conditions . The trisaccharide 15 can be prepared by the regio‐ and chemo‐selective glycosylation of the 6‐ O ‐TBS‐D‐glucal 16 with the donor 17 , followed by transformation of the enol ether to the glycosyl benzoate 15 .…”

1‐Picolinyl‐5‐azido Thiosialosides: Versatile Donors for the Stereoselective Construction of Sialyl Linkages

“…To probe the proposed reaction mechanisms, systematic control reactions were conducted with 3 as acceptor (Table ). Donor 69 a containing a p ‐picolinyl (PPic) group at C‐1 was coupled with 3 under the standard conditions affording 70 a in a 7:1 α/β stereoselectivity (entry 1); meanwhile sialyl o ‐alkynylbenzoate donors 2′ and 2′′ with Pic and PPic groups at C‐1, respectively, afforded moderate but almost the same stereoselectivity (entries 2 and 3). These results clearly indicate that route a can be ruled out as a prominent mechanism in 2 sialylation.…”

1‐Picolinyl‐5‐azido Thiosialosides: Versatile Donors for the Stereoselective Construction of Sialyl Linkages

“…To probe the proposed reaction mechanisms,s ystematic control reactions were conducted with 3 as acceptor ( Table 6). Donor 69 a containing a p-picolinyl (PPic) group at C-1 was coupled with 3 under the standard conditions affording 70 a in a7 :1 a/b stereoselectivity (entry 1);m eanwhile sialyl oalkynylbenzoate donors [31] 2' ' and 2' '' ' with Pic and PPic groups at C-1, respectively,a fforded moderate but almost the same stereoselectivity (entries 2a nd 3). These results clearly indicate that route ac an be ruled out as ap rominent mechanism in 2 sialylation.…”