Synthesis of Theaflavins via Biomimetic Oxidative Coupling Reactions

Abstract

Biomimetic synthesis of theaflavins from catechins was accomplished by using 2-nitrobenzenesulfonyl (Ns) as a protecting group for phenols to minimize undesired side reactions of the ­electron-rich aromatic rings. This enabled the construction of the complex benzotropolone core in a single-step oxidative coupling ­reaction.

Key words

theaflavins - 2-nitrobenzensulfonyl group - polyphenol - biomimetic synthesis - benzotropolone

• References and Notes

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• 11 Synthetic Procedure for 2: To a solution of 12 (1.0 g, 1.5 mmol) in MeCN (15 mL) was added Pb(OAc)₄ (806 mg, 4.5 mmol) at 0 °C. The resulting suspension was stirred for 10 min at 0 °C. The reaction mixture was added to benzene, and then the mixture was filtered through a pad of Celite. Then the filtrate was evaporated under reduced pressure, and the resulting crude product 15 was dissolved in MeCN–CH₂Cl₂ (1:4, 25 mL). To the solution of 15 were added MS 3A (1.0 g) and 14 (342 mg, 505 μmol) in MeCN–CH₂Cl₂ (1:4, 10 mL) at 0 °C. The resulting suspension was stirred for 20 min at 0 °C. After the addition of H₂O the mixture was stirred for 5 min at r.t. The reaction mixture was filtered, and the filtrate was extracted with EtOAc, the organic phase was washed with H₂O, and evaporated under reduced pressure. The residue was purified by silica gel flash column chromatography (CH₂Cl₂–MeOH, 98:2) to afford 16 (327 mg, 50%) as an orange amorphous solid. To a suspension of Cs₂CO₃ (501 mg, 0.17 mmol) and thiophenol (0.17 mL, 1.7 mmol) in MeCN–DMF (1:2, 2.7 mL) was added the solution of 16 (223 mg, 0.17 mmol) in MeCN (3.0 mL) at 0 °C After stirring at 0 °C for 2 h, the reaction was quenched with aq 1 M HCl and extracted with EtOAc. The organic phase was evaporated under reduced pressure. The residue was purified by preparative TLC (CH₂Cl₂–MeOH, 9:1) to afford 2 (53 mg, 55%) as an orange amorphous solid. Spectral Data for 2: [α]_D ²⁰ –122.1 (c = 0.20, acetone). ¹H NMR (500 MHz, acetone-d ₆): δ = 8.83 (br s, 1 H), 8.27 (s, 1 H), 7.77 (s, 1 H), 7.67 (s, 1 H), 6.08 (s, 1 H), 6.04 (s, 1 H), 5.96 (s, 1 H), 5.95 (s, 1 H), 5.62 (d, J = 5.0 Hz, 1 H), 5.02 (s, 1 H), 4.38 (br s, 1 H), 4.10–4.16 (m, 1 H), 2.75–3.00 (m, 3 H), 2.66 (dd, J = 16.0, 9.0 Hz, 1 H). HRMS (ESI): m/z [M + Na]⁺ calcd for C₂₉H₂₄O₁₂Na: 587.1159; found: 587.1130
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