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TCI Practical Example: The Synthesis of the C-Aryl Glycoside through the Cross-Coupling of the Glycosyl Dihydoropyridinecarboxylic Acid Precursor

We are proud to present the synthesis of the C-aryl glycoside catalyzed by a photoredox catalyst. The glycosyl ester was prepared by condensation dihydropyridinecarboxylic acid and alcohol and utilized as radical precursors. C-aryl glycoside was synthesized via the cross-coupling reaction using a glycosyl radical which was generated from the precursor by a photoredox catalyst.

Used Chemicals

• 3,5-Bis(ethoxycarbonyl)-2,6-dimethyl-1,4-dihydropyridine-4-carboxylic Acid [B6316]
• 2,3,5-Tri-O-benzyl-α/β-D-ribofuranose (1)
• 4-Dimethylaminopyridine (= DMAP) [D1450]
• 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide Hydrochloride (= EDCI) [D1601]
• Dichloromethane
• Sodium Carbonate [S0560]
• 1,2,3,5-Tetrakis(carbazol-9-yl)-4,6-dicyanobenzene (= 4CzIPN)
• Methyl 4-Bromobenzoate [B0556]
• 2,2'-Bipyridyl (= bpy) [B0468]
• Nickel(II) Bromide Ethylene Glycol Dimethyl Ether Complex (= NiBr₂·DME) [N1050]
• 1,4-Dioxane

Procedure

A four-neck round bottom flask was charged with 2,3,5-tri-O-benzyl-α/β-D-ribofuranose (1) (2.165 g, 5.15 mmol, 1 eq.) and dichloromethane (26 mL). The solution was cooled under 5 ˚C, then DMAP (0.063 g, 0.51 mmol, 0.1 eq.), EDCI (1.38 g, 7.21 mmol, 1.4 eq.), 3,5-bis(ethoxycarbonyl)-2,6-dimethyl-1,4-dihydropyridine-4-carboxylic acid (1.684 g, 5.66 mmol, 1.1 eq.) were added. The reaction mixture was allowed to warm to ambient temperature and stirred for 46 h. After the reaction, the reaction mixture was quenched with ion-exchanged water (35 mL). The solution was transferred into a separatory funnel, and the aqueous layer was extracted with dichloromethane (10 mL, twice). The combined organic layers were washed with brine, dried over sodium sulfate (10 g) for about 30 minutes and then filtered. The solvent was removed in vacuo, giving crude as a blown oil (3.91 g), which was purified by silica gel column chromatography (hexane:ethyl acetate = 1:1, Rf = 0.45) to give compound 2 as a light yellow oil (2.99 g, 66% yield).
30 mL sealed vessel was charged with 4CzIPN (0.0158 g, 0.020 mmol, 0.1 eq.), methyl 4-bromobenzoate (0.0858 g, 0.399 mmol, 2.0 eq.), sodium carbonate (0.0443 g, 0.418 mmol, 2.1 eq.), 2,2’-bipyridine (0.0086 g, 0.055 mmol, 0.28 eq.) at rt under N₂. A solution of NiBr₂・DME (0.012 g, 0.040 mmol, 0.20 eq.) in 1,4-dioxane (5 mL) and the solution of 1 (0.14 g, 0.20 mmol, 1.0 eq.) in 1,4-dioxane (5 mL) were added to the sealed vessel. The mixture was placed in a preheated oil bath whose temperature was set to 120 ˚C, and placed at a distance of 2-3 cm from Blue LED lamp. After irradiation for 46 h, the reaction mixture was cooled to room temperature and filtered through Celite pad (1 cm). The solvent was removed in vacuo and the crude was given as a yellow oil (0.23 g). The crude was purified by silica gel column chromatography (hexane:ethyl acetate = 10:2, Rf = 0.30) to give compound 3 as a colorless oil (0.053 g, 49% yield).

Experimenter's Comments

• NiBr₂·DME was weighed in a nitrogen-filled glove box and dissolved in 1,4-dioxane completely using a sonication.
• 1,4-Dioxane was degassed with nitrogen for 30 min before use.
• Irradiation of visible light was performed with Kessil A160WE Tuna Blue 40W x 2.
• The reaction mixture was monitored by ¹H NMR and UPLC.
• The α/β selectivity of 3 was 1:17.

Analytical Data

Compound 3

¹H NMR (270 MHz, CDCl₃); δ 7.96 (d, J = 8.2 Hz, 2H), 7.46 (d, J = 8.2 Hz, 2H), 7.40-7.30 (m, 11H), 7.26-7.23 (m, 2H), 7.18-7.15 (m, 2H), 5.05 (d, J = 6.9 Hz, 1H), 4.71-4.44 (m, 6H), 4.39-4.34 (m, 1H), 4.01 (dd, J = 5.3, 3.3 Hz, 1H), 3.92 (s, 3H), 3.77 (dd, J = 6.9, 5.3 Hz, 1H), 3.65 (qd, J = 10.6, 3.9 Hz, 2H).

Lead Reference

• Diastereoselective Synthesis of Aryl C-Glycosides from Glycosyl Esters via C-O Bond Homolysis
• • Y. Wei, B. Ben-zvi, T. Diano, Angew. Chem. Int. Ed. 2021, 60, 9433.

Other References

• Highly stereoselective synthesis of aryl/heteroaryl-C-nucleosides via the merger of photoredox and nickel catalysis
• • Y. Ma, S. Liu, Y. Xi, H. Li, K. Yang, Z. Cheng, W. Wang, Y. Zhang, Chem. Commun. 2019, 55, 14657.