The authors found that in the nickel-catalyzed coupling of aceto-α-bromo-D-glucose with MeZn–I, nonpolar solvents accelerated competing elimination events, and oligomeric baseline products were produced without adding a nickel catalyst. They also found that the smaller ligand furnished higher yields, presumably due to steric effects in the catalyst. Notably, during the process of ligand screening exclusive β-selectivity was observed when using terpy (terpyridine) as a ligand (211a ), while the diastereomeric ratio modestly favored the β-anomer in other cases. The results suggest that catalyst-controlled selectivity in the synthesis of C-glycoside might be achievable. The developed conditions were also extended to other alkyl zinc reagents and glycosyl halides. Notably, “fully armed” benzyl-protected sugars were best matched to chloride-leaving groups, and “disarmed” acetyl-protected sugars worked best as the bromide (the chlorides were unreactive). Moreover, glucosides produced a modest β-selectivity (211a, 211b, 211l, 211m, 211n ), while mannosides uniformly afforded high α-selectivity (211c, 211e–211k ), presumably owing to anchimeric assistance or additional steric effects exerted by the proximal axial OAc or OBn group.
Later, the same group reported a nickel-catalyzed Giese glycosyl radical addition, which enabled the synthesis of α-alkyl C-glycosides (Scheme 29). [39] The reaction features a low alkene loading and obviates toxic heavy metals. In this protocol, both ligands and nickel catalysts played an essential role in promoting the desired reactivity in favor of background elimination. The reactions of glucosyl bromides with three different acylates proceeded smoothly under the reaction conditions, affording desired alkyl C-glycosides as α-anomers in good yields. Notably, electron-poor styrene derivatives were also amenable to this method, whereas only a trace amount of products were formed from styrene (214d ) and 4-methoxystyrene (214e ). Moreover, other glycosyl bromides were also suitable substrates. Not surprisingly, 5-dealkylated C-arabinoside (214p ) was produced with a diminished stereoselectivity. To increase the diastereoselectivity of coupling glucosyl bromides with methyl methacrylate, the authors examined a range of proton sources where i-Pr2CHOH afforded 5:1 of d.r. as the best result. The optimal conditions then were applied to various geminally disubstituted alkenes, which afforded the desired products in moderate-to-good diastereoselectivities. (214s–214n ). Mechanistically, the authors suggested that glycosyl radical could be involved while a mechanism relying on olefin insertion into a nickel-glycosyl intermediate followed by transmetalation to zinc cannot be rigorously ruled out.
Scheme 29 Nickel-mediated Giese glycosyl radical addition toward alkyl C-glycoside