A concise synthesis of (±)-7-O-galloyltricetiflavan

(±)-7-O-galloyltricetiflavan (1a) was synthesized successfully in five steps from the commercially available trihydroxyacetophenone (2) and trimethoxybenzoyl chloride (3). The flavone 4a was prepared in a one-pot reaction and it gave hex-O-methylflavan 6 followed by acylation and reduction. However, the demethylation of flavan 6, 5-O-acetylflavan 10 and 5-O-phenylacetylflavan 11 by BBr3 gave all the hydrolyzed fragments 7 and 8 as the major products. By contrast, in the same condition, hept-O-methylflavan 9 could provide the desired product (±)-7-O-galloyltricetiflavan (1a) in 91% yield. The additional 5-O-B-Br2 complex may stabilize the ester bond during the demethylation process.

3][4][5] To date, the preparation of (À)-7-O-galloyltricetiavan (1)  still requires extraction and purication of plant material, and only a few synthetic examples of this type of avan have been reported. 6,7Herein we report the rst total synthesis of (AE)-7-O-galloyltricetiavan (1a) in ve steps as well as an interesting discovery during the demethylation process.
The synthesis of (AE)-7-O-galloyltricetiavan (1a) was started from the preparation of the avone derivative 4a as shown in Scheme 1. Buckle's group reported an efficient one-pot synthesis of avones by the treatment of 2-hydroxyacetophenones with the corresponding aroyl chloride in wet K 2 CO 3 /acetone (1% w/w water), 8 but the reaction proceeded very slowly because the trihydroxyacetophenone (2) was insoluble in acetone.With water-toluene as the solvent, in the presence of K 2 CO 3 and tetrabutylammonium hydrogen sulfate, 9 the reaction could provide avone 4a in 30% yield and 3-acylated product 4b in 50% yield in one-pot in about two hours.Many efforts to improve the yield of 4a failed, but 4b could be converted into 4a by hydrolysis in 50% yield. 10Aerwards, acylation of 4a with trimethoxybenzoyl chloride (3) and K 2 CO 3 gave 7-O-galloylavone 5 in 91% yield, which was then reduced to the avan 6 by hydrogenation with palladium on carbon as the catalyst for 3 days in 62% yield. 11en avan 6 was treated with BBr 3 in dichloromethane at À40 C or À78 C, 12 the desired product 1a was generated in only 3% yield (based on HPLC-MS analysis), accompanied with 4-O-methyl gallic acid (7) and avan 8 as the major products, indicating the ester bond of hex-O-methylavan 6 is highly unstable under acidic conditions (Scheme 1).
Then, 5-O-methylavan 9, 5-O-acetylavan 10 and 5-O-phe-nylacetylavan 11 were prepared as substrates to explore if they provided different results (Scheme 2).Similarly, 5-O-acetylavan 10 and 5-O-phenylacetylavan 11 were not tolerated under these reaction conditions, which gave the hydrolyzed products 7 and 8 as major products.In contrast, when avan 9 was treated with BBr 3 in dichloromethane at À40 C to room temperature, the desired product (AE)-7-O-galloyltricetiavan (1a) was generated in 91% yield and no hydrolyzed product was detected aer 24 h.The structure of (AE)-7-O-galloyltricetiavan (1a) were conrmed by 1 H NMR, 13 C NMR, and HR-MS spectrum, and they are consistent with the literature's report. 1 We presumed that when BBr 3 was added to the additional 5-O-methyl group to form the 5-O-B-Br 2 complex, it may stabilizes the ester bond of 7-phenolic hydroxyl group.By contrast, the 5-O-acetyl or 5-O-phenylacetyl groups was more easily hydrolyzed and could not help stabilize the ester bond.

General experimental procedures
All reactions were performed in glassware containing a Teoncoated stir bar.Solvents and chemical reagents were obtained from commercial sources and used without further purication. 1H and 13 C NMR spectra were recorded on Varian Mercury 500 MHz or 400 MHz, and the data were recorded using DMSO-d 6 , CDCl 3 and CD 3 OD as the solvents.Chemical shis (d) are reported in ppm downeld from an internal TMS standard.The reactions and products were analyzed by HPLC-MS.Highresolution mass spectra were obtained in ESI mode on a hybrid IT-TOF mass spectrometer.Flash column chromatography on silica gel (200-300 mesh) was used for the routine purication of reaction products.The column output was monitored by TLC on silica gel (100-200 mesh) precoated on glass plates (15 Â 50 mm), and spots were visualized by a 5% vanillin sulfuric acid/ethanol solution.
Synthesis of compounds 4a and 4b.The two-phase mixture of a trihydroxyacetophenone (2, 4.0 g, 21.06 mmol) and an aroyl chloride (3, 13.34 g, 56.14 mmol) in toluene (100 mL) and saturated aqueous K 2 CO 3 (100 mL) was vigorously stirred at 60 C for 30 min.Tetrabutylammonium hydrogen sulfate (7.3 g, 21.5 mmol) was added, and the mixture was stirred at 75 C for an additional two hours.During this period, the organic layer turned orange, and an orange-brown liquid separated at the interface.The toluene layer was separated, and the orangebrown liquid was extracted with CHCl 3 (50 mL).The toluene and CHCl 3 solutions were washed with water (2 Â 90 mL), dried with Na 2 SO 4 , ltrated and concentrated to give a brown oil (15.2 g).The mixture was redissolved in methanol (60 mL), CH 3 ONa (2.32 g) was added, the solution was then stirred for 30 min at r.t. until 2 M HCl (aq, 18 mL) was added to adjust the pH to 6-7.The resulting yellow solid was isolated by ltration and washed with 40 mL CHCl 3 to give compound 4a as a canary yellow solid (2.19 g) in 30% yield.The CHCl 3 solution was concentrated to give compound 4b as a yellow solid (5.76 g) in 50% yield.6).To a solution of compound 5 (2.03 g, 3.77 mmol) in 150 mL of CH 2 Cl 2 was added palladium on carbon (5%, 1.00 g), and the mixture was stirred for 72 h under H 2 at 0.40 MPa pressure at r.t.The solution was ltrated, concentrated, and then puried by silica gel column chromatography to give compound 6 (1.23 g) as a white foam solid in 62% yield. 1   (9).To a solution of compound 6 (600 mg, 1.14 mmol) in 5 mL of dry acetone was added dimethyl sulfate (238 mL, 2.51 mmol) and anhydrous K 2 CO 3 (472 mg, 3.42 mmol), and the mixture was stirred for 5 h at 56 C. The solution was concentrated, redissolved in EtOAc washed with water, dried with Na 2 SO 4 , ltered, and then concentrated to give a brown oil.Aer purication by ash silica gel column chromatography, compound 9 (0.62 g) was obtained as a white solid in 99.0% yield. 1  Synthesis of (AE)-7-O-galloyltricetiavan (1a).Compound 9 (0.48 g, 0.88 mmol) was dissolved in dry CH 2 Cl 2 (20 mL), then BBr 3 (15.4mL, 1.0 M in CH 2 Cl 2 ) was added dropwise at À40 C. The resultant red-brown solution was warmed to r.t. and stirred for 12 h under N 2 .Upon completion, the reaction contents were quenched by the addition of ice water (20 mL), the CH 2 Cl 2 was removed, and the water layer was extracted twice with ethyl acetate (50 mL).The combined organic extracts were then washed with water (25 mL) and brine (15 mL), dried with Na 2 SO 4 , ltered, and concentrated.The residue was puried over Sephadex LH-20 gel to give (AE)-7-O-galloyltricetiavan (0.36 g) as a brown solid in 91% yield and in 98% purity (from HPLC-MS).(10).To a solution of compound 6 (100 mg, 0.19 mmol) in 5 mL of dry acetone was added acetyl chloride (25 mL) and anhydrous K 2 CO 3 (52 mg, 0.38 mmol), and the mixture was stirred for 2 h and adjusted to pH ¼ 5 with 2 M HCl (aq).The solution was concentrated, redissolved in EtOAc washed with water, dried with Na 2 SO 4 , ltered and concentrated to give a brown oil.Aer purication by silica gel column chromatography, compound 10 (91 mg) was obtained as a colorless oil in 85% yield. 1