Stereoselective alkyl C-glycosylation of glycosyl esters via anomeric C-O bond homolysis: efficient access to C-glycosyl amino acids and C-glycosyl peptides

Abstract

C-Glycosyl peptides possess excellent metabolic stability and therapeutic properties and thus play critical roles in biological studies as well as drug discoveries. However, the limited accessibility of C-glycosyl amino acids has significantly hindered the broader research of their structural features and mode of action. Herein, for the first time we disclose a novel visible-light-driven radical conjugate addition of 1,4-dihydropyridine (DHP)-derived glycosyl esters with dehydroalanine derivatives, generating C-glycosyl amino acids and C-glycosyl peptides in good yields with excellent stereoselectivities. Redox-active glycosyl esters, as readily accessible and bench-stable radical precursors, could be easily converted to glycosyl radicals via anomeric C(sp³)-O bond homolysis under mild conditions. Importantly, the generality and practicality of this transformation were fully demonstrated in >40 examples including 2-dexosugars, oligosaccharides, oligopeptides, and complex drug molecules. Given its mild reaction conditions, robust sugar scope, and high anomeric control and diastereoselectivity, the method presented herein could find widespread utility in the preparation of C(sp³)-linked sugar-based peptidomimetics.

Fig. 1. Selected bioactive C-alkyl glycopeptides and their synthetic strategies.

Fig. 2. Scope of C-alkyl glycosylation with DHP-derived glycosyl esters. (a) Scope of furanoses. (b) Scope of pyranoses. (c) Scope of oligosaccharides. (d) Scope of pharmacophore-coupled monosaccharides. 19b–19f, 19h, 19o, and 19p used conditions A; 19g, 19i–19n, and 19q–19aa used conditions B; ^a20 h was used; ^b24 h was used; ^c17 (0.15 mmol), 18 (0.10 mmol), 1,4-dioxane (1.5 mL), and 20 h was used; ^d17 (0.15 mmol), 18 (0.10 mmol), 1,4-dioxane (3.0 mL), and 24 h. d.r. was determined by ¹H NMR analysis of crude reaction mixtures.

Fig. 3. Scope of Dha amino acids and peptides. General reaction conditions: 17a (0.30 mmol), 20 (0.20 mmol), PC1 (2.0 mol%), 1,4-dioxane (3.0 mL), blue LEDs (6 W), 85 °C, 10 h, N₂, and isolated yields; ^a20h; ^b20o (0.10 mmol) and 24 h. d.r. was determined by ¹H NMR analysis of crude reaction mixture.

Fig. 4. Synthetic applications and downstream transformations. (a) Gram scale reaction of 17a. (b) Derivatization of (+)-sclareolide. (c) Radical glycosylation of thiazolines for preparing β-thiolated amino acids. (d) Deprotection of glycosyl amino acids and preparation of glycopeptides via a peptide coupling reaction. (e) Comparison of glycosyl chlorides and glycosyl DHP esters. Reaction details are shown in ESI notes 7.

Fig. 5. Mechanistic studies. (a) Radical-trapping experiment. (b) Deuterium labeling studies. (c) Light on-off experiments. (d) Control experiment supporting the essential role of α-heteroatoms. Reaction details are shown in the ESI notes 8 Mechanistic studies.

Fig. 6. Computational studies of the mechanistic aspects of the reaction. Computational analysis of addition reactions for cyclohexane (blue) and tetrahydropyran (yellow) DHP esters calculated at the ωB97XD/6-31+G(d,p)-SDM(dichloromethane)//ωB97XD/6-311+G(d,p)-SDM(dichloromethane) levels of theory. Gibbs free energy (298 K, 1 atm) and enthalpy (in brackets) are reported in kcal mol⁻¹.

Fig. 7. Proposed reaction mechanism for alkyl C-glycosylation via C–O bond homolysis.