Synthesis of Nepetoidin B

Abstract

The first synthesis of nepetoidin B in an overall yield of 17% was achieved in two steps through Baeyer–Villiger oxidation of commercially available 1,5-bis(3,4-dimethoxyphenyl)-1,4-pentadien-3-one with oxone to produce the tetramethylated nepetoidin B, followed by demethylation using boron tribromide.

Key words

Baeyer–Villiger oxidation - demethylation - medicinal chemistry - natural products

• References and Notes

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• 34 Synthesis of 2-(3,4-Dihydroxyphenyl)ethenyl-3-(3,4-dihydroxyphenyl)-2-propenoate (1) To a stirred solution of (E,E)-3 (1.341 g, 3.620 mmol, 1.0 equiv) in dry CH₂Cl₂ (20 mL) under argon was added neat BBr₃ (2.09 mL, 21.722 mmol, 6.0 equiv) dropwise at −78 °C. The solution was stirred at the same temperature for another 30 min, at which point the mixture was allowed to warm to 0 °C over the course of 1 h, and then to warm to r.t. over the course of 1 h. After once again cooling the mixture to −78 °C, it was quenched by addition of saturated aqueous NaHCO₃ (18 mL) and then allowed to warm to r.t. over 20 min. The mixture was partitioned between EtOAc (120 mL) and H₂O (150 mL), and the aqueous layer was extracted with EtOAc (2 x 50 mL). The combined organic layers were washed with brine (50 mL), then dried over anhydrous Na₂SO₄, and the solution was concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (MeOH/CH₂Cl₂ 10:90) to furnish nepetoidin B, compound 1, as a yellow solid (490 mg, 43%). R_f = 0.58 (MeOH/CH₂Cl₂ 15:85). The ratio of isomers (E,E)-1/(Z,E)-1 is 94:6, as determined by ¹H NMR spectroscopic analysis (signals at 5.67 (d, J = 7.4 Hz, H-7) and 6.36 (d, J = 15.8 Hz, H-8) for the (Z,E)-1 and (E,E)-1 isomers, respectively). HPLC Separation of the Isomers of Nepetoidin B [(E,E)-1 and (Z,E)-1] The mixture of the isomers of nepetoidin B [(E,E)-1 94% and (Z,E)-1 6%] obtained from the demethylation of (E,E)-3 was separated by HPLC. To collect a sufficient quantity for ¹H and ¹³C NMR analysis, 1 (12 mg) was dissolved in MeOH (350 μL), and the method described above was run five times using 50 μL injections of the solution. The appropriate fractions were combined and concentrated in vacuo to afford each purified isomer for further analysis. (E,E)-1 (7 mg): ¹H NMR (500 MHz, acetone-d ₆): δ_H = 6.36 (d, J = 15.8 Hz, H-8), 6.38 (d, J = 12.8 Hz, H-7'), 6.77−6.78 (m, H-6' and H-5), 6.89 (d, J = 8.2 Hz, H-5'), 6.93 (d, J = 1.8 Hz, H-2), 7.11 (dd, J = 8.2, 2.1 Hz, H-6), 7.22 (d, J = 2.1 Hz, H-2'), 7.68 (d, J = 15.9 Hz, H-7), 7.81 (d, J = 12.8 Hz, H-8'), 8.21 (br. s, 4 x OH). The obtained NMR spectroscopic data for (E,E)-1 matched literature values.^10,15,19 (Z,E)-1 (0.3 mg): ¹H NMR (500 MHz, acetone-d ₆): δ_H = 5.67 (d, J = 7.4 Hz, H-7'), 6.51 (d, J = 15.9 Hz, H-8), 6.81 (d, J = 8.2 Hz, H-5'), 6.90 (d, J = 8.2 Hz, H-5), 7.00 (dd, J = 8.2, 2.1 Hz, H-6'), 7.13 (dd, J = 8.2, 2.1 Hz, H-6), 7.26 (d, J = 2.0 Hz, H-2), 7.26 (d, J = 7.3 Hz, H-8'), 7.37 (d, J = 2.1 Hz, H-2'), 7.73 (d, J = 15.9 Hz, H-7), 8.05 (br. s, 4 x OH).^{1,10,15,19,30}