An Efficient Synthesis of (±)-Epigallocatechin Gallate by Reductive ­Intramolecular Etherification

Abstract

The synthesis of (±)-epigallocatechin gallate by direct cyclization to the cis-3-acyloxy-2-arylbenzopyranee is described. α-Acyloxylketones, possessing a 2-hydroxylphenyl group at the β-position, underwent intramolecular reductive etherification to give cis-3-acyloxy-2-arylbenzopyran due to neighboring group participation of the acyloxyl group at the α-position. Using this method, we accomplished the stereoselective synthesis of (±)-epigallo­catechin gallate.

catechin - cyclizations - natural products - neighboring group effects

References and Notes

1

Current Address: Cancer Research Lab. Hanno Advanced Research Lab., Taiho Pharmaceutical Co., Ltd. 1-27, Misugidai, Hanno-shi, Saitama, 357-8527, Japan.

2

Current Address: Fukaya Plant Tokyo Kasei Kogyo Co., LTD. 725 Kashiai Fukaya-shi, Saitama 366-0816, Japan.

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10

Procedure for the reductive cyclization to give (2R*,3R*)-3,4-dihydro-5,7-dimethoxy-2-(3,4,5-trimethoxyphenyl)-2H-chromen-3-yl 3,4,5-trimethoxybenzoate (14a): To a stirred solution of 2a (17 mg, 0.024 mmol) in CH₂Cl₂ (0.5 mL) was added a solution of triethylsilane (10%) and trifluoroacetic acid (25%) in CH₂Cl₂ at 0 °C. The reaction mixture was then warmed to r.t. for 4 h. Toluene (5 mL) was added to the reaction mixture and the volatile components were removed by evaporation in vacuo. The product was purified using column chromatography on silica gel, eluting with hexane-EtOAc (5:1 → 2:1) to afford 2a (12 mg, 0.021 mmol, 88%) as a white solid; mp 155-157 °C; IR (solid) 2940, 2839, 1717, 1621, 1592 cm^-1; ¹H NMR (400 MHz, CDCl₃): δ = 7.17 (s, 2 H), 6.70 (s, 2 H), 6.25 (d, J = 1.9 Hz, 1 H), 6.12 (d, J = 1.9 Hz, 1 H), 5.67 (m, 1 H), 5.09 (s, 1 H), 3.86 (s, 3 H), 3.81 (s, 6 H), 3.80 (s, 3 H), 3.79 (s, 3 H), 3.78 (s, 3 H), 3.72 (s, 6 H), 3.05 (d, J = 3.4 Hz, 2 H); ¹³C NMR (100 MHz, CDCl₃): δ = 165.1, 159.7, 158.8, 155.5, 153.1, 152.8, 142.5, 137.9, 133.3, 125.1, 107.2, 103.9, 100.1, 93.2, 91.9, 77.7, 68.6, 60.9, 60.8, 56.2, 56.0, 55.4, 25.9.

11

(±)-Epigallocatechin gallate(1): mp 220 °C (dec); ¹H NMR [400 MHz, acetone-d ₆-D₂O (2:1)]: δ = 6.89 (s, 2 H), 6.53 (s, 2 H), 5.90 (d, J = 2.4 Hz, 1 H), 5.89 (d, J = 2.4 Hz, 1 H), 4.89 (s, 1 H), 5.28 (s, 1 H), 2.87 (dd, J = 17.5, 4.4 Hz, 1 H), 2.78 (dd, J = 17.5, 1.6 Hz, 1 H); ¹³C NMR [100 MHz, acetone-d ₆-D₂O (2:1)]: δ = 212.2, 167.2, 157.3, 156.8, 146.2, 145.9, 139.3, 133.1, 130.6, 121.3, 110.2, 106.8, 98.9, 96.6, 95.7, 78.1, 70.3, 26.6. The analytical data (¹H and ¹³C NMR) of 1 was identical to the commercially available authentic sample [(-)-EGCG, Wako Pure Chemical industries, Ltd.].