An Inverse Electron-Demand Diels-Alder-Based Total Synthesis of Urolithin M7

Abstract

Urolithin M7 was synthesized from 2-hydroxy-4-methoxybenzaldehyde in 8 steps and 48% overall yield. The key step was an inverse electron demand Diels-Alder (IEDDA) reaction between diene 10 and the enamine (7) derived from dimethoxyacetaldehyde and pyrrolidine, which generated the 6H-dibenzo[b,d]pyran-6-one skeleton.

Key words

inverse electron demand Diels-Alder - domino reaction - dibenzopyranone - urolithin M7

References and Notes

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1

Present address: Department of Chemistry, Mount St. Vincent University, Halifax, NS, B3M 2J6, Canada.

9

Experimental Procedure for 9
A solution of dimethoxyacetaldehyde (60 wt% solution in H₂O, 19.6 mL, 0.130 mol) and pyrrolidine (9.76 mL, 0.117 mol) in benzene (150 mL) was heated at reflux with azeotropic removal of H₂O for 1 h. The resulting mixture was allowed to cool for 10 min, and solid 10 (3.38 g, 13.0 mmol) was added in one portion. The resulting mixture was heated at reflux for 7 d. The reaction mixture was cooled to r.t. and then concentrated under reduced pressure. The residue was taken up in CH₂Cl₂ (150 mL) and washed with aq 1 M HCl solution (5 50 mL), dried over MgSO₄, gravity filtered, and concentrated under reduced pressure to afford 9 (4.08 g, 100%) as a tan solid: mp 195-196 ˚C. IR (Nujol): ν = 1735 (s), 1715 (s), 1607 (m), 1121 (s) cm^-¹. ^¹H NMR (500 MHz, CDCl₃): δ = 8.76 (d, J = 9.3 Hz, 1 H), 8.57 (d, J = 1.1 Hz, 1 H), 7.80 (d, J = 1.0 Hz, 1 H), 6.81 (dd, J = 9.6, 3.0 Hz, 1 H), 6.76 (d, J = 2.6 Hz, 1 H), 4.08 (s, 3 H), 3.96 (s, 3 H), 3.87 (s, 3 H). ^¹³C NMR (125.8 MHz, CDCl₃): δ = 165.6, 161.3, 160.7, 156.4, 152.7, 130.0, 129.1, 128.0, 124.0, 121.3, 116.1, 111.7, 110.0, 101.3, 56.1, 55.3, 52.4. MS (EI): m/z (%) = 314 (100) [M⁺], 299 (53), 283 (13), 212 (4), 157 (4). Anal. Calcd for C₁₇H₁₄O₆: C, 64.97; H, 4.49. Found C, 65.03; H, 4.61.