Gram-Scale Synthesis of (±)-Tylophorine

Abstract

We report a practical scalable synthesis of the natural product (±)-tylophorine by using an operationally simple protecting-group-free route from readily accessible starting materials. Synthesis of a cyclic N-acetyl diester compound through cyclization, followed by two key steps (decarboxylation and a Clemmensen reduction), provides access to the target molecule.

Key words

gram-scale synthesis - tylophorine - alkaloids - decarboxylation - Clemmensen reduction

• References and Notes

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• 16 (±)-Tylophorine (1); Gram-Scale Procedure A solution of compound 10 (1.3 g, 3.190 mmol, 1.0 equiv) in THF (50 mL) was added dropwise to a stirred solution of LiAlH₄ (605.4 mg, 15.95 mmol, 5.0 equiv) in anhyd THF (70 mL) at 0 °C, and the mixture was refluxed for 1 h then cooled to 0 °C. Excess LiAlH₄ was quenched with 20% aq KOH (15 mL), and the resulting mixture was filtered through Celite, then washed with CHCl₃ (100 mL) and MeOH (50 mL), dried (Na₂SO₄), and concentrated in vacuo. The crude product was crystallized from CHCl₃ and Et₂O to give a light-yellow solid; yield: 1.2 g (96%); R_f = 0.48 (CH₂Cl₂–MeOH, 9:1). IR (film): 3397, 2926, 1616, 1512, 1251, 1040 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 7.84 (s, 1 H), 7.83 (s, 1 H), 7.32 (s, 1 H), 7.17 (s, 1 H), 4.63 (d, J = 14.6 Hz, 1 H), 4.12 (s, 6 H), 4.06 (s, 3 H), 4.06 (s, 3 H), 3.68 (d, J = 14.6 Hz, 1 H), 3.48 (td, J = 8.5, 1.9 Hz, 1 H), 3.38 (dd, J = 15.8, 2.5 Hz, 1 H), 2.95–2.89 (m, 1 H), 2.54–2.44 (m, 2 H), 2.30–2.21 (m, 1 H), 2.21–1.89 (m, 2 H), 1.83–1.73 (m, 1 H). ¹³C NMR (125 MHz, CDCl₃): δ = 148.7, 148.5 (2), 126.4, 126.1, 125.9, 124.4, 123.7, 123.5, 104.0, 103.5, 103.4, 103.2, 60.3, 56.1, 56.0 (2), 55.3, 54.2, 33.9, 31.4, 21.7. HRMS (ESI): m/z [M + H]+ calcd for C₂₄H₂₈NO₄ 394.2012; found: 394.2002.