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CC BY-ND-NC 4.0 · Synlett 2018; 29(09): 1229-1231
DOI: 10.1055/s-0036-1591556
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Synthesis of Nepetoidin B

Vitaliy Timokhin
a   Department of Energy Great Lakes Bioenergy Research Center and Department of Biochemistry, the Wisconsin Energy Institute, University of Wisconsin, Madison, WI, 53726, USA   Email: jralph@wisc.edu
,
Matthew Regner 
a   Department of Energy Great Lakes Bioenergy Research Center and Department of Biochemistry, the Wisconsin Energy Institute, University of Wisconsin, Madison, WI, 53726, USA   Email: jralph@wisc.edu
,
Yukiko Tsuji
a   Department of Energy Great Lakes Bioenergy Research Center and Department of Biochemistry, the Wisconsin Energy Institute, University of Wisconsin, Madison, WI, 53726, USA   Email: jralph@wisc.edu
,
John Grabber
b   U.S. Dairy Forage Research Center, USDA-ARS, 1925 Linden Drive West, Madison, WI, 53706, USA
,
John Ralph*
a   Department of Energy Great Lakes Bioenergy Research Center and Department of Biochemistry, the Wisconsin Energy Institute, University of Wisconsin, Madison, WI, 53726, USA   Email: jralph@wisc.edu
› Author AffiliationsThe project was funded by Stanford University’s Global Climate and Energy Program (GCEP), with analytical facilities (primarily NMR) funded in part by the DOE Great Lakes Bioenergy Research Center (DOE Office of Science BER DE-FC02-07ER64494).
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Publication History

Received: 16 February 2018

Accepted after revision: 26 February 2018

Publication Date:
28 March 2018 (online)

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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

Supporting Information

    Supporting information for this article is available online at https://doi.org/10.1055/s-0036-1591556.
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  • 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%). Rf = 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): δH = 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): δH = 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