Ni-Catalyzed Intramolecular Reductive 1,2-Dicarbofunctionalization of Alkene: Facile Access to Podophyllum Lignans Core

In memory of Prof. Xuan Tian

Abstract

The facile access to the tetracyclic skeleton of podophyllotoxin, a medicinally important lignan natural product, was efficiently achieved via a unique intramolecular alkylarylation of the tethered alkene in a dihalide under mild conditions using reductive nickel catalysis.

Key words

nickel - reductive coupling - intramolecular - cyclization - synthesis

Publication History

Received: 17 May 2020

Accepted: 16 June 2020

Article published online:
17 July 2020

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• 10 In a 100 mL round-bottom flask, enol ether 7 (1.50 g, 3.1 mmol) was dissolved in anhydrous CH₂Cl₂ (35 mL) and cooled to 0 °C. To this solution was added TBCD (97%, 1.57 g, 3.7 mmol, 1.2 equiv) portionwise, and the mixture was stirred for 30 min at 0 °C. A solution of allyl alcohol (3.6 mL, 62 mmol, 20.0 equiv) in CH₂Cl₂ (5 mL) was then added dropwise, and the resulting mixture was gradually warmed to room temperature and stirred further for 9 h. The reaction was quenched with saturated aqueous NaHCO₃ (3 mL), Na₂SO₃ (3 mL), and stirred further for 30 min. The resulting mixture was extracted with CH₂Cl₂ (2 × 50 mL), and the combined organic layers were washed with water (2 × 15 mL) and brine (15 mL), respectively, dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The crude product was purified by flash column chromatography (petroleum ether/EtOAc = 10:1 → petroleum ether/EtOAc = 4:1) on silica gel to afford 8 (1.519 g, 79% yield) as a yellow oil. R_f = 0.36 (petroleum ether/EtOAc = 2:1). IR (film): ν_max = 2930, 2838, 1590, 1504, 1479, 1461, 1422, 1383, 1326, 1265, 1229, 1128, 1037, 929, 845, 792, 736, 701, 685, 582 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ (major isomer) = 7.19 (s, 1 H), 6.99 (s, 1 H), 6.52 (s, 2 H), 5.93 (s, 1 H), 5.89 (s, 1 H), 5.86–5.80 (m, 1 H), 5.35 (dd, J = 17.2, 1.6 Hz, 1 H), 5.13 (dd, J = 10.8, 1.6 Hz, 1 H), 4.76 (d, J = 10.8 Hz, 1 H), 4.55 (dd, J = 11.2, 2.8 Hz, 1 H), 4.26 (dd, J = 13.2, 4.8 Hz, 1 H), 4.00 (d, J = 2.4 Hz, 1 H), 3.88 (dd, J = 12.8, 5.2 Hz, 1 H), 3.76 (s, 6 H), 3.74 (s, 3 H), 3.31 (s, 3 H) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 153.3 (2 C), 148.7, 147.3, 137.23, 137.17, 135.6, 133.8, 119.0, 116.7, 107.0, 105.3 (2 C), 102.0, 101.8, 90.5, 69.7, 60.8, 57.7, 57.3, 56.21 (2 C), 56.17 ppm. HRMS (ESI): m/z calcd for C₂₃H₂₆O₇ ⁷⁹BrINa⁺ [M + Na]⁺: 642.9799; found: 642.9791.
• 11 Xiao J, Nan G, Wang Y.-W, Peng Y. Molecules 2018; 23: 3037