Synlett 2018; 29(09): 1203-1206
DOI: 10.1055/s-0036-1591547
letter
© Georg Thieme Verlag Stuttgart · New York

A Concise Total Synthesis of (±)-Mesembrine

Hyoungsu Kim
a  College of Pharmacy and Research Institute of Pharmaceutical Science and Technology(RIPST), Ajou University, Suwon 16499, R. of Korea
,
Hosam Choi
b  Department of Chemistry, The Catholic University of Korea, Bucheon 14662, R. of Korea   Email: [email protected]
,
Kiyoun Lee*
b  Department of Chemistry, The Catholic University of Korea, Bucheon 14662, R. of Korea   Email: [email protected]
› Author Affiliations
This work was supported by the Basic Science Research Program from the National Research Foundation of Korea (NRF-2016R1C1B1008816) funded by the Ministry of Education and the 2017 Research Fund of the Catholic University of Korea.
Further Information

Publication History

Received: 02 January 2018

Accepted after revision: 28 January 2018

Publication Date:
16 February 2018 (online)


Abstract

A concise total synthesis of (±)-mesembrine has been successfully accomplished in seven steps and 24% overall yield from commercially available 3-ethoxy-2-cyclohexen-1-one. Central to the assembly of the skeleton of mesembrine are a Johnson–Claisen rearrangement for the formation of the benzylic quaternary stereocenter and direct allylic oxidation to generate the substrate for the amidation/transannular aza-conjugate addition reaction.

Supporting Information

 
  • References and Notes

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  • 17 Procedure for the Preparation of Compound 3 A sealed tube charged with alcohol 5 (205 mg, 0.876 mmol) in triethyl orthoacetate (17.5 mL, 0.05 M) was treated with 2-nitrophenol (3.65 mg, 0.026 mmol, 3 mol%). After stirring for 20 h at 140 °C, the resulting mixture was cooled to room temperature and quenched with the addition of sat. aq NaHCO3 and diluted with H2O and EtOAc. The layers were separated, and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with sat. aq NaCl, dried over anhydrous Na2SO4, and concentrated in vacuo. The residue was purified by column chromatography (SiO2, 10% EtOAc/hexanes) to provide 3 (193 mg, 73%) as a yellow oil. 1H NMR (300 MHz, CDCl3): δ = 6.89–6.83 (m, 2 H), 6.80–6.76 (m, 1 H), 6.13–6.05 (m, 1 H), 5.92 (dt, J = 10.2, 3.5 Hz, 1 H), 3.96 (dq, J = 7.1, 0.7 Hz, 1 H), 3.86 (s, 3 H), 3.84 (s, 3 H), 2.76 (d, J = 14.1 Hz, 1 H), 2.65 (d, J = 14.2 Hz, 1 H), 2.06–1.95 (m, 2 H), 1.95–1.78 (m, 2 H), 1.60–1.47 (m, 1 H), 1.44–1.26 (m, 1 H), 1.08 (t, J = 7.1 Hz, 3 H). 13C NMR (125 MHz, CDCl3): δ = 171.2, 148.2, 147.0, 139.4, 132.2, 128.3, 119.1, 110.4, 110.3, 59.8, 55.8, 55.7, 46.9, 41.5, 37.1, 25.0, 18.6, 14.0. IR (film): νmax = 2934, 2834, 1730, 1517, 1255, 1149, 1029, 467 cm–1. HRMS (ESI): m/z calcd for C18H24O4: 304.1675; found: 304.1677 [M+].
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  • 20 Procedure for the Synthesis of Mesembrine (1) A cooled (0 °C) solution of ketal 11 (252 mg, 0.726 mmol) in THF (9 mL, 0.08 M) was treated with LiAlH4 (3.6 mL, 1.0 M in THF, 3.63 mmol, 5 equiv). After refluxing for 5 h, the resulting mixture was quenched with the addition of MeOH and cooled to room temperature. The resulting mixture was added 1 M HCl (9 mL, 0.08 M) and stirred at reflux. After stirring for 4 h, the resulting mixture was basified with the addition of 1 M NaOH and diluted with EtOAc. The layers were separated, and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with sat. aq NaCl, dried over anhydrous Na2SO4, and concentrated in vacuo. The residue was purified by flash chromatography (SiO2, 2% Et3N gradient elution: 5% MeOH/CH2Cl2 to 10% MeOH/CH2Cl2) to provide (±)-mesembrine (1, 204 mg, 97%) as a white foam. 1H NMR (500 MHz, CDCl3): δ = 6.93 (dd, J = 8.4, 2.1 Hz, 1 H), 6.89 (d, J = 1.9 Hz, 1 H), 6.84 (d, J = 8.4 Hz, 1 H), 3.90 (s, 3 H), 3.88 (s, 3 H), 3.16–3.10 (m, 1 H), 2.94 (t, J = 3.4 Hz, 1 H), 2.60 (t, J = 3.1 Hz, 2 H), 2.48–2.38 (m, 1 H), 2.37–2.28 (m, 1 H), 2.31 (s, 3 H), 2.26–2.03 (m, 5 H).13C NMR (125 MHz, CDCl3): δ = 211.5, 149.0, 147.4, 140.2, 117.9, 110.9, 109.9, 70.4, 56.0, 55.9, 54.8, 47.5, 40.5, 40.1, 38.8, 36.2, 35.2. IR (film): νmax = 3468, 2941, 2835, 2782, 1716, 1519, 1254, 1148, 1027 cm–1. HRMS (ESI): m/z calcd for C17H23NO3: 289.1678; found: 289.1677 [M+].