In 2018, Gong and co-workers disclosed a stereoselective method of
preparing α-C-vinyl/aryl glycosides via nickel-catalyzed reductive
coupling of glycosyl halides with vinyl and aryl halides (Scheme 2).[10] In their report, three different reaction
conditions were developed. Method A, which used pyridine as the ligand,
enabled the coupling of a variety of E -vinyl bromides with
various α-glycosyl bromides, yielding vinyl C-glycosides in high yields
with moderate-to-good α-selectivities. Styrene-derived vinyl bromides,
dienyl bromides, and alkyl-decorated vinyl bromides were all
glycosylated successfully under method A (21a–21f ). Notably,Z -vinyl bromide is also amenable to the reaction, although
affording the corresponding products as a mixture of E/Z isomers
(21a ). Moreover, the reaction displayed high α-selectivities
when applied to galactosides (21d ), mannosides (21e ),
and maltosides (21f ).
The authors developed method B when they failed to prepare aryl
C-glycoside using method A. Method B employed DMAP as a ligand and
per-O-acetyl glycosyl bromide as an effective glycosyl partner, with a
small amount of HBr necessary to initiate the reaction. They then found
aryl iodides bearing electron-withdrawing groups are more effective than
iodobenzene and other electron-rich aryl iodides in yielding
corresponding aryl C-glucosides (21g–21j ). Good
diastereoselectivity was also observed in galactosides (21k )
and maltoside (21m ), but not for arabinoside (21l ). To
further improve the glycosylation of electron-rich arenes, method C was
developed, which utilized dtbBpiy (4,4‘-di-tert-butyl-2,2‘-bipyridine)
as a ligand. Notably, 6-indole (21q ) and 3-thiophenyl groups
(21p ) were well-tolerated and good-to-high α-selectivities were
observed for galactosides (21q, 21r ) and mannosides
(21s ).
The authors proposed a radical chain mechanism involving an aryl-Ni(II)
intermediate, which intercepts a glycosyl radical generated from the
corresponding glycosyl halide. [11] The role of
MgCl2 was also examined (Scheme 2-B), and the authors
suggested that DMAP and Cl– may exchange to form
Ni(II)-Cl bond (24 ) by releasing a DMAP ligand, presumably
accounting for the authentic intermediate for intercepting a glycosyl
radical. Moderate α-selectivities are generally observed with glucoside
products, likely owing to the more stable nature of the boat conformer
of the glucopyranosyl radical intermediate (25 , Scheme 2-C).
However, in this study, the use of pyridine/DMAP ligands resulted in a
significant enhancement of α-selectivities. The authors suggested that
the enhanced α-selectivity could be attributed to the dissociation of
the ligand from the nickel center upon formation of the α-Ni-C bond,
thus reducing the repulsive steric interaction via α-attack.
Additionally, the high α-selectivity for C-mannosides can be explained
by the chair-like mannosyl radical, which leads to a preferential
formation of α-products due to less steric hindrance of the α-face. Both
catalysts and substrate structure play an important role in determining
the stereoselective outcomes of the developed reactions.
In 2019, Gong and co-workers developed a ligand-controlled β-selective
glycosylation via a nickel-catalyzed reductive coupling of glycosyl
halides with aryl/vinyl halides (Scheme 3). [12]The combination of Ni/t Bu-Terpy/Zn was proved to be optimal. The
reaction conditions feature a wide scope of aryl iodides, yielding the
corresponding aryl C-glycosides in moderate-to-good yields with high β-
Selectivities (29a–29s ). Notably, meta -bromo
substitutes in aryl iodides were found to be intact in the reaction.
(29i ) Remarkably, the use of MgCl2 improved the
yields of reactions with electron-rich and -neutral arenes. The authors
reasoned that MgCl2 is essential to activate Zn and
reduce Ni(II) to Ni(0), which was validated by the control experiment
that showed no reaction in the absence of MgCl2. It was
also discovered that the formation of glucal and hydrodehalogenation
byproducts accounted for the low-yielding reactions. The utility of the
developed methods was further highlighted by the successful synthesis of
Salmochelin derivatives 29n and the precursor of the commercial
drug canagliflozin for type-2- diabetes 29o . Additionally, the
developed coupling protocol was also extended to synthesize β-C-vinyl
glycosides (29t–29ac ). Preliminary mechanistic studies
revealed that the developed glycosylation process involves a radical
mechanism. The authors proposed that the stereochemistry of the
developed approach is largely dependent on a favorable β-attack of a
glycosyl radical to a bulky Terpy-Ni(II)-Ar intermediate, and in the
case of mannoside, α-configured product was favored due to substrate
control.
Scheme 3 Nickel-catalyzed β-selective preparation of aryl/vinyl
C-glycosides