After that, Walczak and co-workers reported a light-induced cross-coupling of anomeric trifluoroborates (Scheme 14).[23] A wide range of aryl iodides and 2-deoxyglycosyl trifluoroborates was well-tolerant with the developed method, affording corresponding products as exclusive α-anomers in moderate-to-excellent yields. The authors found that aryl units with electron-withdrawing groups furnish better yields likely because of increasing the rate of reductive elimination and the ability to stabilize the generated aryl radical. Moreover, free hydroxy groups of substrates were compatible with the reaction conditions (101d, 101f ). Pyridine moiety (101j, 101k ), aldehyde group (101e ), and phenylalanine moiety (101l ) were also tolerated. Notably, diminished α-selectivities were observed when carbohydrate substrates bearing C2-substituents were used as coupling partners (101s, 101t ).
Yu and co-workers recently developed a method for the preparation of vinyl C-glycosyl amino acids/peptides via nickel-catalyzed reductive hydroglycosylation of alkynes (Scheme 15). [24]Inspired by works of NiH-catalyzed hydrocarbonation of unsaturated bonds, a reaction pathway was proposed by the authors, as shown in Scheme 15-A. Initially, the branch-selective insertion of NiH species to terminal alkyne 103 to furnish the vinyl nickel species107 . Subsequently, this intermediate is oxidized by glycosyl bromide 102, leading to the formation of a high-valent Ni(II) complex 108 and a glycosyl radical. The glycosyl radical recombines with the nickel species to give the nickel species109 which undergoes the process of reductive elimination, furnishing the desired vinyl C-glycoside 104 and nickel catalyst 105 . Lastly, the active NiH species 106 is regenerated through a hydride transfer event.
In this report, two types of optimal conditions were developed for mannose- and glucosamine-type saccharides, and these reactions tolerate a wide scope of terminal alkyne-containing amino acid derivatives and glycosyl bromides, affording corresponding C-glycosides104a–104y in good efficiencies (Scheme 15-B). Notably, no epimerization of amino acid residue was observed. Additionally, the method could also be extended to internal acetylenic amino acids (104z, 104aa , Scheme 15-C). The authors suggested that the observed stereoselectivity could be governed by the predominant conformation of glycosyl radical intermediate, which is stabilized by the anomeric effect. [25] For mannose-type bromides, the anomeric radical is predominantly in the4C1 conformation, leading to the 1,2-trans (α-selectivity) product. For glucose-type bromides, a shift between α- and β-anomer is observed, owing to a flexible B2,5 conformation adopted by glucosyl radical; however, the moderate-to-good β-selective glycosylation can be obtained when the C2-substituent is a bulky substituent, such as NPhth group (104l–104o, 104s, 104t, 104v, 104w ). For xylose-type bromides, lacking C5 substituent, a moderate 1,2-trans selectivity was observed since xylosyl radical can adopt both B2,5 conformation and 1C4 conformation, as suggested by the authors (104p ). Lastly, the potential utilities of the current method were further demonstrated by convergent C-glycosylation of complex saccharides (104ab, 104ac , Scheme 15-D).
Goddard-Borger and co-workers developed a method for the synthesis of C-mannosylated glycopeptide via nickel-catalyzed photoreductive cross-coupling reactions (Scheme 16). [26] The reaction using HE as a photoreductant enabled the coupling of per-acetyl protected α-D-mannosyl bromide with a range of halogenated (hetero)arenes, delivering desired products in good yields. Both electron-rich and -deficient systems were effective substrates in the reaction (112a-112c ), with the only exception of thiazole (112d ), which decomposed under the reaction. Notably, C-mannosylation of peptides was successfully achieved (112e ). Interestingly, the authors found that during the process, the typical4C1 conformation was adopted by simple α-C-mannosylated arene products (112a-112d ), whereas complex, bulky α-C-mannosylated glycopeptides favored the1C4 conformation (112e ). As suggested by the authors, this could be attributable to the role of tryptophan in driving a shift in the pyranose’s preferred conformation from 4C1 to1C4. Furthermore, the synthesis of Fmoc-protected Trp(Man) (113 ), which is an essential building block for SPPS (solid-phase peptide synthesis), was successfully realized on a gram-scale, which facilitated the first automated SPPS of α-C-mannosylated glycopeptides (116 , Scheme 16-B). Notably, during this process, the authors found Trp(Man) derivatives underwent facile acid-mediated anomerization. The preliminary mechanistic studies suggested that such an anomerization most likely occurred as a result of the protonation of the endocyclic pyranose oxygen and the formation of a stabilized acyclic benzylic cation (118a , Scheme. 16-C). Although the developed reaction condition enabled the formation of glycopeptides, the solubility of peptide substrates in organic solvent precluded the further expansion of peptide scope, especially the utility in late-stage mannosylation. To complement the method, the authors also developed a photocatalytic variation of this cross-coupling reaction that operates in polar aprotic solvents and tolerates water (Scheme 17). The reaction provided efficient access to late-stage mannosylation of larger complex peptides. For example, a range of complex peptides bearing a 2-bromo-L-tryptophan residue was successfully C-mannosylated, affording the desired products in synthetically useful yields (123a-123f ). Lastly, a mechanism was proposed for the nickel-catalyzed cross-coupling of mannosyl bromide 110 and Trp-derived bromide 121a with Hantzsch ester acting as a photoreductant (Scheme 17).
Scheme 16 Nickel-catalyzed synthesis of C-mannosylated glycopeptide bearing 2-bromo-L-tryptophan residue