Synthetic Studies on Acochlearine: Construction of the A/B/C/E/F Ring System

Abstract

Synthetic studies on acochlearine are described. The pentacyclic A/B/C/E/F ring system of acochlearine was constructed from a bicyclic enone via chemoselective reductive amination, one-pot bromination–intramolecular Mannich reaction cascade, and 6π-electrocyclization.

Key words

alkaloids - halogenation - lactams - domino reaction - ­Mannich reaction - C–H functionalization

• References and Notes

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• 12 (4aR,7R,11aR,11bR,13aR,14S)-6-Ethyl-9-(hydroxymethyl)-2,2-dimethyl-6a,7,11,11a,13,13a-hexahydro-4H,12H-4a,11b,7-{epiethane[1,1,2]triyl}[1,3]dioxino[4,5-f]indeno[2,1-b]azocin-5(6H)-one (7) A 10 mL screw-top test tube equipped with a Teflon-coated magnetic stirring bar was charged with 24 (10.8 mg, 30.3 μmol) and toluene (0.6 mL) under an Ar atmosphere. To the solution was added vinyl magnesium bromide (1 M in THF, 91 μL, 90.7 μmol) at r.t. The resulting reaction mixture was stirred at reflux for 11 h. The reaction was quenched with sat. aq NH₄Cl at r.t., and stirred for an additional 0.5 h. The aqueous layer was extracted with CH₂Cl₂ three times. The combined organic extracts were dried over Na₂SO₄ and filtered. The organic solvents were removed under reduced pressure to give a crude material, which was purified by preparative TLC (EtOAc) to afford diene 7 (9.7 mg, 25.2 μmol, 83%) as a colorless oil. R_{f =} 0.30 (EtOAc). ¹H NMR (600 MHz, CDCl₃): δ = 5.70–5.67 (m, 2 H), 4.33 (d, 1 H, J = 12.0 Hz), 4.11 (d, 1 H, J = 13.2 Hz), 4.07 (d, 1 H, J = 12.6 Hz), 3.77 (dd, 1 H, J = 12.0, 4.2 Hz), 3.62 (dq, 1 H, J = 13.2, 6.6 Hz), 3.50 (d, 1 H, J = 12.0 Hz), 3.27 (dq, 1 H, J = 13.8, 7.2 Hz), 3.26 (s, 1 H), 2.79 (d, 1 H, J = 4.8 Hz), 2.09–1.97 (m, 3 H), 1.83 (m, 1 H), 1.77–1.64 (m, 4 H), 1.62–1.56 (m, 2 H) 1.52 (s, 3 H), 1.41 (s, 3 H), 1.25 (d, 1 H, J = 12.0 Hz), 1.16 (t, 3 H, J = 7.2 Hz). ¹³C NMR (150 MHz, CDCl₃): δ = 169.1, 145.5, 137.4, 119.8, 112.5, 99.7, 72.4, 70.3, 65.4, 64.4, 49.5, 48.6, 47.1, 44.7, 44.6, 42.0, 28.5, 26.7, 26.0, 25.7, 23.8, 22.1, 13.6. IR (neat): 3422, 2936, 2241, 1644, 1195, 1089, 729, 516 cm^–1. ESI-HRMS: m/z calcd for C₂₃H₃₁NNaO₄: 408.2145 [M⁺ + Na]; found: 408.2141
• 13 We considered that the cyclization took place through α face to give the diene 7 since the α face (exo face) of cyclohexene was sterically less hindered than the β face (endo face).