A Convergent Enantioselective Synthesis of the Anti-Malarial Agent (+)-Febrifugine

Abstract

Chiral pool derived 3-benzyloxy-3,4,5,6-tetrahydropyridine N-oxide underwent regio- and diastereoselective 1,3-dipolar cycloaddition with N-allylquinazolone to give a cycloadduct that was elaborated to (+)-febrifugine a potent anti-malarial alkaloid.

Key words

alkaloids - piperidines - nitrones - cycloadditions - reductive ring-opening

References

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Solid N-allylquinazolone 5 (0.34 g, 1.83 mmol) was added to a solution of nitrone 4 (0.38 g, 1.85 mmol) in toluene. The mixture was stirred under reflux for 24 h and solvent was then removed under reduced pressure. The crude product was purified by column chromatography on silica gel using Et₂O-MeOH 49:1 as eluent to give isoxazolidine 3 as a colourless oil (0.35 g, 48%). [α]_D ²⁰ -41.4 (c 1.0, CHCl₃). IR (neat): ν_max = 3062, 2944, 1674, 1610 cm^-1. ¹H NMR (300 MHz, DMSO-d ₆, 90 °C): δ = 1.20-1.32 (m, 1 H), 1.45-1.60 (m, 1 H), 1.64-1.74 (m, 1 H), 2.00 (dddd, 1 H, J = 4.0, 4.0, 4,0, 12.7 Hz), 2.12-2.22 (m, 1 H), 2.24-2.31 (m, 1 H), 2.55-2.70 (m, 2 H), 3.12 (ddd, 1 H, J = 1.8, 4.0, 4.0 Hz), 3.35-3.45 (m, 1 H), 4.05 (dd, 1 H, J = 7.5, 13.9 Hz), 4.22 (dd, 1 H, J = 3.9, 13.9 Hz), 4.39 (m, 1 H), 4.48 (d, 1 H, J = 12.0 Hz), 4.57 (d, 1 H, J = 12.0 Hz), 7.22-7.36 (m, 5 H), 7.54 (ddd, 1 H, J = 1.1, 7.1, 8.1 Hz), 7.67 (d, 1 H, J = 7.7 Hz), 7.81 (ddd, 1 H, J = 1.6, 7.2, 8.5 Hz), 8.20 (dd, 1 H, J = 1.4, 8.1 Hz), 8.22 (s, 1 H). ¹³C NMR (75 MHz, DMSO-d ₆, 90 °C): δ = 19.8, 27.5, 38.6, 48.4, 51.1, 66.3, 69.5, 72.5, 76.0, 121.0, 125.5, 126.21, 126.5, 126.6, 126.8, 127.4, 133.5, 138.3, 147.4, 147.5, 159.6. HRMS (EI): m/z calcd for [C₂₃H₂₅N₃O₃]⁺: 391.1896. Found: 391.1893.

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The specific rotation and spectral data of this compound was in agreement with the reported values; see ref. [4j]