Stereoselective Synthesis of C-Aryl-α-Glycosides by Reductive C(sp²)–C(sp³) Cross-Coupling Reaction

Abstract

C-Aryl glycosides have attracted considerable interest as biologically active natural products and as O-aryl glycoside mimetics in drug discovery. Here, we describe a straightforward synthesis of C-aryl glycosides by photoredox/Ni dual-catalyzed reductive cross-coupling between glycosyl bromides and aryl bromides. This methodology enables a highly α-stereoselective synthesis of C-aryl glucosides, galactosides, and mannosides.

Key words

glycosides - photoredox catalysis - nickel catalysis - cross-coupling - stereoselectivity - conformational restriction

Publication History

Received: 12 May 2024

Accepted after revision: 25 June 2024

Accepted Manuscript online:
25 June 2024

Article published online:
19 July 2024

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• 30 C-Aryl-α-Glycosides 3aa–co; General Procedure A 10 mL vial was charged with NiCl₂·DME (11.0 mg, 50.1 μmol), dtbbpy (16.0 mg, 59.6 μmol), and MeCN (5.0 mL) in air, and the mixture was sonicated to give a blue solution of the ligated Ni complex (10 mM in MeCN stock solution). This solution (500 μL, 5.0 μmol, 10 mol%) was added to a 4 mL vial, concentrated by blowing N₂, and dried in vacuo. To the vial were sequentially added the appropriate glycosyl bromide 1 (75.0 μmol, 1.5 equiv), (het)aryl bromide 2 (50.0 μmol, 1.0 equiv), {Ir[dFCF₃ppy]₂(dtbbpy)PF₆} (2.8 mg, 2.5 μmol, 5 mol%), DME (500 μL), 2,4,6-collidine (13 μL, 100 μmol, 2.0 equiv), and TMSSiOH (23 μL, 75 μmol, 1.5 equiv). The vial was sealed and the mixture was stirred and irradiated by a blue LED for 12 h at 28–30 °C. The mixture was then exposed to air, filtered through Celite (rinsed with 1:1 hexane–EtOAc), then concentrated. The residue was purified by recycling GPC (CHCl₃) and short-column chromatography (silica gel). 3aa Prepared by the general procedure from 1a (26.5 mg, 75.0 μmol, 1.5 equiv) and p-2a (10.8 mg, 50.0 μmol, 1.0 equiv), and purified by GPC and short-column chromatography [silica gel, hexane–EtOAc (9:1 to 2:1)] to give a white solid; yield: 10.8 mg (53%), [α]_D ²⁰ = 119.5 (c 1.0, CHCl₃). ¹H NMR (500 MHz, CDCl₃): δ = 8.11 (d, J = 8.5 Hz, 2 H), 7.58 (d, J = 7.9 Hz, 2 H), 5.64 (d, J = 5.5 Hz, 1 H), 5.37 (t, J = 9.6 Hz, 1 H), 4.80 (dd, J = 11.9, 5.8 Hz, 1 H), 4.33 (dd, J = 11.9, 9.8 Hz, 1 H) , 4.29 (dd, J = 12.5, 5.2 Hz, 1 H), 4.25 (dd, J = 12.5, 2.4 Hz, 1 H), 3.94 (s, 3 H), 3.85 (ddd, J = 9.2, 4.9, 2.8 Hz, 1 H), 2.16 (s, 3 H), 2.06 (s, 3 H). ¹³C{¹H} NMR (126 MHz, CDCl₃): δ = 170.6, 169.0, 166.4, 152.6, 138.4, 130.7, 130.6 (2C), 126.5 (2C), 78.1, 77.7, 72.7, 72.3, 69.0, 62.1, 52.5, 20.9, 20.6. HRMS-ESI: m/z [M + Na]⁺ calcd for C₁₉H₂₀NaO₁₀: 431.0954; found: 431.0943.