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