A Practical and Efficient Synthesis of (±)-Anatabine

Abstract

A new efficient synthesis of racemic anatabine is reported. The title target was obtained in an excellent overall yield of 70%, by a five-step synthesis, using cheap reagents and mild reaction conditions.

Key words

anatabine - heterocycles - total synthesis - tobacco alkaloids - ring closure

• References

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• 12 Compound 11; colorless oil. IR (neat): 712, 661, 1136, 1187, 1448, 1685, 3043 cm^–1. The NMR spectra show a mixture of two rotamers (ratio 2:1) as result of hindered rotation of the amide bond. ¹H NMR (400 MHz, CDCl₃): δ = 2.64–2.89 (m, 3 H), 3.24 (br d, J = 18.7 Hz, 0.5 H), 3.53 (m, 2 H), 4.23 (br d, J = 18.2 Hz, 1 H), 4.65 (br d, J = 18.7 Hz, 0.5 H), 5.39 (br d, J = 5.7 Hz, 0.5 H), 5.68 (m, 1.5 H), 5.95 (m, 0.5 H), 6.07 (m, 2 H), 7.31 (m, 1.5 H), 7.66 (m, 1.5 H), 8.59 (m, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 26.3, 27.9, 40.1, 41.1, 48.5, 52.1, 116.6 (q, ¹ J _C,F = 287.9 Hz), 116.8 (q, ¹ J _C,F = 287.9 Hz), 122.8, 123.0, 123.7, 123.8, 124.0, 124.3, 133.3, 134.0, 134.8, 135.5, 148.3, 148.7, 149.3, 149.4, 156.0 (² J _C,F = 36.3 Hz), 156.6 (² J _C,F = 36.3 Hz). ¹⁹F NMR (376 MHz, CDCl₃): δ = –68.3 (s, 1.5 F), –69.5 (s, 3 F). MS (EI): m/z = 256 (M⁺), 255, 187, 159 (100%), 105, 78, 54. Anal. Calcd for C₁₂H₁₁F₃N₂O (256.23): C, 56.25; H, 4.33; N, 10.93. Found: C, 56.21; H, 4.30; N, 10.90.
• 13a The hydrolysis reaction was even tested using 2-MeTHF and CPME instead THF; however, only traces of 6 (<3% by GC) were detected after 2 h.
• 13b The N-Boc anatabine 5 can be directly converted into 6 in lower yield (72%) and longer reaction time (8 h) working at 0 °C in a 0.06 M TFA/CH₂Cl₂ (1:1) solution.