Application of a Ruthenium-Catalyzed Allylation–Cycloisomerization Cascade to the Synthesis of (±)-Herbindole A

Abstract

A short and efficient total synthesis of the cytotoxic cyclopent[g]indole alkaloid (±)-herbindole A from dihydromesitylene has been achieved by incorporating a ruthenium-catalyzed allylation–cycloisomerization cascade reaction as the key step. The protocol has also been applied to the synthesis of the unnatural trans-epimer of the marine natural product.

Key words

alkaloids - domino reaction - homogeneous catalysis - ruthenium - total synthesis.

• References

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• 8 Procedure for the Ruthenium-Catalyzed Key Step: 2-(cis-3,5-Dimethylcyclopent-1-en-1-yl)but-3-yn-2-ol (2; 150 mg, 0.91 mmol) and catalyst A (9 mg, 0.018 mmol) were dissolved in toluene (2 mL) and pyrrole (65 mg, 0.97 mmol) and a solution of TFA in toluene (0.04 M, 0.45 mL) were subsequently added. The mixture was heated for 5 min at 200 °C using microwave irradiation. Evaporation of the solvent and flash chromatography on silica (pentane/Et₂O) furnished the purified product 1 (148 mg, 76%) as a slightly yellow powder. ¹H NMR (600 MHz, CDCl₃): δ = 1.34 (d, J = 7.1 Hz, 3 H), 1.44 (d, J = 7.2 Hz, 3 H), 1.54 (dt, J = 13.0, 2.1 Hz, 1 H), 2.32 (s, 3 H), 2.47 (s, 3 H), 2.69 (dt, J = 13.0, 9.1 Hz, 1 H), 3.38–3.43 (m, 1 H), 3.43–3.49 (m, 1 H), 6.54 (dd, J = 3.2, 2.1 Hz, 1 H), 7.12 (dd, J = 3.2, 2.3 Hz, 1 H), 7.92 (br. s, NH). ¹³C NMR (150 MHz, CDCl₃): δ = 15.5 (CH₃), 15.8 (CH₃), 23.0 (CH₃), 24.0 (CH₃), 37.3 (CH), 39.3 (CH), 42.0 (CH₂), 101.8 (CH), 123.0 (CH), 123.4 (C), 126.6 (C), 126.8 (C), 127.9 (C), 130.7 (C), 142.2 ppm (C). IR: 3410 (w), 2955 (m), 2925 (m), 2865 (m), 1692 (w), 1655 (m), 1598 (w), 1447 (m), 1372 (w), 1316 (w), 1278 (m), 1073 (w), 723 (m), 701 (s), 638 (m) cm^–1. MS (EI): m/z (%) = 214 (38) [M⁺ + 1], 213 (45) [M⁺], 199 (75), 198 (100), 183 (30), 182 (32), 105 (29). HRMS: m/z [M⁺] calcd for C₁₅H₁₉N: 213.1517; found: 213.1517.