Bioinspired Formal Synthesis of Pancracine via Selective Hydro­genation of an Indole Derivative

Abstract

A bioinspired formal synthesis of the montanine-type Amaryllidaceae alkaloid pancracine through selective hydrogenation of a 3-arylindole derivative is disclosed. The key features of this synthesis include a hexahydroindole synthesis by a chemoselective hydrogenation of an aryl-substituted indole and a diastereoselective silyl hydride reduction of an iminium intermediate generated from an enaminone through Tf₂O activation. The eight-step assembly of the 5,11-methanomorphanthridine framework represents a novel and efficient strategy that permits one of the shortest syntheses of pancracine reported so far.

Key words

bioinspired synthesis - hydrogenation - chemoselectivity - indole alkaloids - pancracine

Publication History

Received: 07 January 2023

Accepted after revision: 28 January 2023

Accepted Manuscript online:
28 January 2023

Article published online:
28 February 2023

• References and Notes

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• 62 Procedure for the Selective Hydrogenation of 11c A solution of compound 11c (100 mg, 0.29 mmol, 1.0 equiv) in 50:1 HFIP–TFA (2.5 mL) was stirred in the presence of 50 wt % Pd/C at 50 ℃ under H₂ at atmospheric pressure for 24 h. The mixture was then cooled to r.t. and filtered through Celite. The filtrate was basified with sat. aq NaHCO₃, and the mixture was extracted with CH₂Cl₂ (×3). The combined organic layer was washed with brine, dried (Na₂SO₄), and concentrated under reduced pressure to give a crude residue that was purified by column chromatography (silica gel, 0.5–5% MeOH–CH₂Cl₂) to give 14c as a light-red solid; yield: 36 mg (48%). ¹H NMR (400 MHz, DMSO-d ₆): δ = 7.30 (s, 1 H), 6.76 (d, J = 7.9 Hz, 1 H), 6.64 (d, J = 1.5 Hz, 1 H), 6.59 (dd, J = 8.0, 1.6 Hz, 1 H), 5.94 (s, 2 H), 4.06 (dd, J = 11.0, 4.5 Hz, 1 H), 3.87 (t, J = 10.9 Hz, 1 H), 3.22 (dd, J = 10.7, 4.7 Hz, 1 H), 2.43 (t, J = 5.8 Hz, 1 H), 2.38 (t, J = 6.6 Hz, 1 H), 2.11–2.03 (m, 2 H), 1.89 (p, J = 6.3 Hz, 2 H). ¹³C NMR (101 MHz, DMSO-d ₆): δ = 188.86, 169.32, 147.10, 145.22, 139.92, 119.67, 110.98, 107.81, 107.30, 100.54, 54.99, 43.12, 36.31, 23.24, 22.20. Procedure for the Tf₂O-Induced Diastereoselective Activation/Reduction Tf₂O (28 mg, 0.1 mmol, 2.0 equiv) and EtMe₂SiH (8.8mg, 0.1 mmol, 2.0 equiv) were added successively to a stirred solution of compound 21 (21 mg, 0.05 mmol, 1.0 equiv) in anhydrous CH₂Cl₂ (4 mL) at r.t. The mixture was stirred at r.t. for 24 h then quenched with sat. aq NaHCO₃ and extracted with CH₂Cl₂ (×3). The combined organic layer was washed with brine, dried (Na₂SO₄), and concentrated under reduced pressure. The residue that was purified by column chromatography (silica gel, 1–5% EtOAc–PE) to give compound 22 (79 mg, 36% yield) and dia-22 (108 mg, 49% yield) in a combined 85% yield. 22 ¹H NMR (400 MHz, CDCl₃): δ = 7.57 (d, J = 8.2 Hz, 2 H), 7.21 (d, J = 8.4 Hz, 2 H), 6.53 (d, J = 8.0 Hz, 1 H), 6.34 (dd, J = 8.0, 1.8 Hz, 1 H), 6.22 (d, J = 1.7 Hz, 1 H), 5.90 (d, J = 0.8 Hz, 2 H), 4.16–4.04 (m, 1 H), 3.90 (dd, J = 10.7, 7.5 Hz, 2 H), 3.35 (dd, J = 10.7, 4.0 Hz, 1 H), 2.65 (dq, J = 12.1, 3.9 Hz, 1 H), 2.41 (s, 3 H), 2.39–2.37 (m, 2 H), 2.09 (d, J = 14.1 Hz, 1 H), 1.79–1.63 (m, 1 H), 1.50 (dd, J = 25.6, 11.5 Hz, 1 H). ¹³C NMR (101 MHz, CDCl₃): δ = 147.76, 146.53, 144.08, 143.92, 133.13, 132.99, 129.58, 127.47, 120.20, 118.0 (q, J _C–F = 308.2 Hz), 108.24, 107.08, 101.02, 59.91, 56.39, 42.85, 29.11, 26.44, 21.46, 20.36. ¹⁹F NMR (376 MHz, CDCl₃): δ = –74.74. dia-22 ¹H NMR (400 MHz, CDCl₃) δ = 7.68 (d, J = 8.3 Hz, 2 H), 7.39 (d, J = 7.9 Hz, 2 H), 6.75 (d, J = 1.0 Hz, 1 H), 6.70 (dd, J = 2.3, 1.0 Hz, 2 H), 5.94 (dd, J = 3.4, 1.5 Hz, 2 H), 3.80 (d, J = 8.1 Hz, 1 H), 3.48 (dd, J = 9.8, 2.4 Hz, 1 H), 3.39–3.35 (m, 1 H), 3.17 (dd, J = 9.8, 8.3 Hz, 1 H), 2.75–2.70 (m, 1 H), 2.47 (s, 3 H), 2.33–2.30 (m, 2 H), 2.15–2.09 (m, 1 H), 1.71–1.65 (m, 2 H). ¹³C NMR (101 MHz, CDCl₃): δ = 147.84, 146.68, 144.46, 143.30, 135.17, 134.99, 130.82, 129.88, 128.18, 121.22, 118.0 (q, J _C–F = 321.6 Hz), 107.98, 107.62, 100.99, 61.27, 57.25, 43.36, 28.09, 26.63, 21.57, 20.48. ¹⁹F NMR (376 MHz, CDCl₃): δ = –74.68.