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