5,7,3'',4''-Tetra-O-benzylepicatechin synthesis

2H-1-Benzopyran-3(4H)-one, 2-[3,4-bis(phenylmethoxy)phenyl]-5,7-bis(phenylmethoxy)-, (2R)-

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Yield:87292-49-7 81%

Reaction Conditions:

Stage #1: (+)-(2R)-5,7-bis(benzyloxy)-2-[3,4-bis(benzyloxy)phenyl]chroman-3-onewith L-Selectride;lithium bromide in tetrahydrofuran at -78; for 3.08333 h;
Stage #2: with sodium hydroxide;dihydrogen peroxide in tetrahydrofuran;ethanol;water at 20;

Steps:

1.C

A 1 M solution of lithium tri-sec-butylborohydride in tetrahydrofuran, herein after THF, (100 mL, L-Selectride, sold by the Aldrich Chemical Co, Inc., Milwaukee, Wis.) was added, under an argon atmosphere, to a stirred, 0° C. solution of anhydrous lithium bromide, LiBr, (34.9 g, 402 mmol) in 100 mL anhydrous THF. The resulting mixture was cooled to -78° C., using an acetone/CO₂bath, followed by dropwise addition of a solution of the flavanone according to Part B (50.1 g, 77.2 mmol) in 400 mL of anhydrous THF, over a period of 50 min. Stirring was continued at -78° C. for 135 min. The cooling bath was removed and 360 mL of 2.5 M aqueous sodium hydroxide (NaOH) was added to the reaction mixture. The reaction flask was placed in a room temperature water bath and a mixture of 35% aqueous H₂O₂(90 mL) and ethanol (270 mL) was added over a period of 130 min. Stirring was continued overnight. Chloroform (700 mL) was added to dissolve the crystallized product, the phases were separated, the aqueous phase was extracted with CHCl₃(50 mL), the combined organic phases were dried over MgSO₄, evaporated and dried in vacuo to provide 56.6 g of crude product. This material was dissolved in 600 mL of a boiling mixture of ethyl acetate (EtOAc) and ethanol (EtOH) (2:3), and allowed to crystallize at room temperature, then in the refrigerator. The product was isolated by suction filtration, washed with 2×50 mL of cold (-20° C.) EtOAc/EtOH (1:3), and dried in vacuo first at room temperature, then at 80° C. to obtain 35.4 g (70%) of a light yellow solid. The evaporated mother liquor was filtered over silica gel, SiO₂, (14×6.5 cm, CHCl₃, then CHCl₃/EtOAc 12:1), the eluate concentrated to 40 mL, and the residue diluted with 60 mL of ethanol, to obtain an additional 5.5 g (11%) of the O-benzylepicatechin as a yellowish solid: mp 129.5-130° C. (from EtOAc/EtOH); [α]_D-27.7° [α]₅₄₆-33.4° (EtOAc, c 21.6 g/L); ¹H NMR (CDCl₃) δ 7.48-7.25 (m, 20 H), 7.14 (s, 1 H), 7.00, 6.97 (ABq, 2 H. J=8.5 Hz, A part d with J=1.5 Hz), 6.27 (s, 2 H), 5.19 (s, 2 H), 5.18 (s, 2 H), 5.02 (s, 2 H), 5.01 (s, 2 H), 4.91 (s, 1 H), 4.21 (br s, 1 H), 3.00, 2.92 (ABq, 2 H, J=17.5 Hz, both parts d with J=1.5 and 4 Hz, resp.), 1.66 (d, 1 H, J=5.5 Hz); Anal. Calcd. for C₄₃H₃₈O₆: C, 79.36; H, 5.89. Found: C, 79.12: H, 5.99.