One-Pot Synthesis of Nuevamine Aza-Analogues by Combined Use of an Oxidative Ugi Type Reaction and Aza-Diels–Alder Cycloaddition

Abstract

A rapid and efficient one-pot synthesis of a series of four novel nuevamine aza-analogues is described based on the oxidative Ugi-type reaction and aza-Diels–Alder reaction as post-functionalization. A simple IBX-mediated oxidation of a secondary amine followed by isonitrile α-addition and finally an aza-Diels–Alder cycloaddition provides the desired compounds in excellent overall yields considering the short reaction time, atom economy, and the molecular complexity of the final products. This protocol presents a highly attractive procedure for the rapid generation of fused polyheterocycles.

Key words

one-pot synthesis - natural products - oxidation - oxidative Ugi reaction - aza-Diels–Alder cycloaddition

• References and Notes

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• 35 Synthesis of 2a-d; Typical Procedure: To a stirred solution of 1,2,3,4-tetrahydroisoquinoline (3; 0.885 mmol, 1.0 equiv) in THF at reflux, IBX (4; 1.77 mmol, 2.0 equiv) was added. After 30 min, 2-isocyano-1-morpholino-3-phenylpropan-1-one (6a; 0.885 mmol, 1.0 equiv) was added. Finally, after 60 min, maleic anhydride (9; 1.062 mmol, 1.2 equiv) was added. After 30 min, the reaction mixture was filtered and the solvent was removed under reduced pressure. The crude material was dissolved in CH₂Cl₂ (5.0 mL) and washed with sat. aq NaHCO₃ (3 × 15 mL) followed by an excess of brine. The crude product was immediately purified by silica-gel column chromatography (hexane–EtOAc, 2:1 v/v) to afford the desired nuevamine aza-analogue 2a (42% yield) as a white solid. Mp 63 °C; R_f = 0.18 (hexane–EtOAc, 2:1). ¹H NMR (500 MHz, CDCl₃): δ = 8.10–8.06 (m, 1 H, ArH), 7.83 (s, 1 H, ArH), 7.35–7.32 (m, 3 H, ArH), 7.30–7.27 (m, 1 H, ArH), 7.23–7.19 (m, 3 H, ArH), 7.16–7.13 (m, 1 H, ArH), 5.58 (s, 1 H, CH), 4.61–4.56 (m, 1 H, CHH), 4.46 (d, J = 14.2 Hz, 1 H, CHH), 4.32 (d, J = 14.2 Hz, 1 H, CHH), 3.85–3.80 (m, 4 H, 2 × CH₂), 3.48–3.42 (m, 1 H, CHH), 3.10–3.02 (m, 1 H, CHH), 2.87–2.82 (m, 4 H, 2 × CH₂), 2.81–2.76 (m, 1 H, CHH). ¹³C NMR (125 MHz, CDCl₃): δ = 166.6 (C=O), 161.4 (ArC), 159.1 (ArC), 148.0 (ArC), 139.7 (ArC), 133.8 (ArC), 132.8 (ArC), 129.4 (ArC), 129.2 (ArC), 128.5 (ArC), 127.6 (ArC), 127.1 (ArC), 126.6 (ArC), 126.4 (ArC), 124.8 (ArC), 123.7 (ArC), 67.4 (CH₂), 59.4 (CH), 53.2 (CH₂), 40.2 (CH₂), 37.9 (CH₂), 29.5 (CH₂). FTIR (film in CH₂Cl₂): 1692 (C=O) cm^–1. HRMS: m/z calcd. for C₂₆H₂₅N₃O₂: 411.1947; found: 411.1949.
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