An Approach to the Synthesis of Tetrahydroisoquinoline Alkaloids by Alkene Hydroamination: Synthesis of Coralydine

Dedicated to the memory of Professor Jean-Louis Namy

Abstract

The protoberberine alkaloid coralydine was synthesized in a short sequence by a strategy including an intramolecular alkene hydroamination as the key step, followed by a Pictet–Spengler ­cyclization.

Key words

alkaloids - total synthesis - nitrogen - heterocycles

• References and Notes

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• 13 The use of other chiral bisoxazoline ligands gave similar results.
• 14 Synthesis of Coralydine (2) and O-Methylcorytenchirine (3): To a solution of compound 13 (52 mg, 0.15 mmol) in toluene (3 mL) were added at r.t. 4 Å molecular sieves (200 mg) and orthophosphoric acid (50 mg). The solution was stirred for 5 min at r.t. and 1,1-dimethoxyethane was added (0.2 mL). After 4 h at 70 °C, the solution was cooled, filtered and evaporated to dryness. The residue was dissolved in CH₂Cl₂ (20 mL) and neutralized with an aq 10% Na₂CO₃ solution (20 mL). The organic layer was dried (Na₂SO₄), filtered and concentrated in vacuo. The residue was purified by chromatography (20% EtOAc–Et₂O) to give 2 (17 mg) and 3 (17 mg) as colorless oils that solidify on standing (combined yield: 61%). Data for coralydine (2; natural product numbering): R_f 0.55 (20% EtOAc–Et₂O). ¹H NMR (400 MHz, CDCl₃): δ = 1.51 (d, J= 6.3 Hz, 3 H, C19-H), 2.40–2.46 (m, 1 H, C6-H_a), 2.66–2.70 (m, 1 H, C5-H_a), 2.84 (m, 1 H, C13-H_b), 3.09 (dd, J _1,13a= 16 Hz, J _13a,13b= 2.5 Hz, 1 H, C13-H_a), 3.11 (m, 1 H, C5-H_b), 3.35 (m, 1 H, C6-H_b), 3.66–3.69 (m, 2 H, C8-H, C18-H), 3.83 (s, 3 H, OMe), 3.84 (s, 6 H, 2 × OMe), 3.85 (s, 3 H, OMe), 6.60 (s, 1 H, C4-H), 6.63 (s, 1 H, C12-H), 6.66 (s, 1 H, C9-H), 6.73 (s, 1 H, C1-H). ¹³C NMR (100 MHz, CDCl₃): δ = 22.2 (C19), 29.9 (C5), 36.8 (C13), 47.3 (C6), 56.0 (OMe), 56.3 (OMe), 59.2, 59.5 (C8, C18), 109.1 (C1), 109.8 (C9), 111.3, 111.5 (C4, C12), 127.0, 127_.2 (C15, C20), 130.7 (C14), 131.6 (C21), 147.6, 147.7 (C2, C3, C10, C11). HRMS (ESI⁺): m/z [M + H]⁺ calcd for [C₂₂H₂₈NO₄ ⁺]: 370.2013; found: 370.2016. Data for O-methylcorytenchirine (3): see Supporting Information.