A Concise Enantiodivergent Synthesis of Equol

Abstract

Equol, a nonsteroidal estrogen produced from the metabolism of the isoflavonoid phytoestrogen daidzein, has been synthesized as both enantioenriched forms based on MacMillan’s α-arylation of carbonyl compound mediated by amino acid derived indazolidinones and copper precatalysts. The natural form of (S)-equol and its enantiomer (R)-equol have been synthesized in 8 steps from 2,4-dimethoxybenzaldehyde with good enantiomeric purity (90% ee and 90% ee, respectively).

Key words

equol - asymmetric synthesis - isoflavan - α-arylation - ­MacMillan’s catalyst

• References and Notes

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• 17 General Procedure for the Synthesis of (S)-3-(2,4-Dimethoxyphenyl)-2-(4-methoxyphenyl)propan-1-ol (9)^16a To an oven-dried round-bottom flask was added crude diaryliodonium salt 4 (65–70% purity determined by ¹H NMR; 3.24 g, 4.34 mmol) and CuBr (122 mg, 0.85 mmol), and then toluene (6.4 mL) and Et₂O (3.2 mL) were added. Afterwards, (2R,5R)-5 (334 mg, 0.844 mmol) and NaHCO₃ (1.62 g, 19.3 mmol) were added to the suspension. Under argon atmosphere, a solution of aldehyde 3 (823 mg) in toluene/Et₂O (2:1, 4.8 mL) was added. The reaction mixture was stirred at room temperature for 44 h. The resulting mixture was diluted with CH₂Cl₂ (10 mL) and cooled to –23 °C. After adding NaBH₄ (1.64 g, 43.3 mmol), cold MeOH (8 mL) was gradually added to the solution, and the mixture was stirred for 1 h at –23 °C. The reaction mixture was quenched with water (8 mL) and extracted with EtOAc (3 × 30 mL). The combined organic layer was washed with sat. NH₄Cl aq. (2 × 30 mL), dried over Na₂SO₄, and the solvent was removed in vacuo. The resulting yellow oil was purified by silica gel column chromatography using hexane/EtOAc (7:3) as an eluent to give (S)-3-(2,4-dimethoxyphenyl)-2-(4-methoxyphenyl)propan-1-ol (9) including inseparable 3-(2,4-dimethoxyphenyl)propyl alcohol (8) as a pale yellow oil (630 mg, (S)-9/8 = 71:29 estimated by ¹H NMR analysis).