A Formal Synthesis of (±)-Tylophorine Based on an Atom Transfer Radical Addition Reaction

Abstract

A short, formal synthesis of (±)-tylophorine was achieved using a radical–ionic sequence for the preparation of epoxides as the key step. This sequence, carried out between a phenantrenic allylic alcohol and iodoacetonitrile, provided an advanced intermediate containing most of the required elements for the final construction of the indolizidine scaffold.

Key words

tylophorine - total synthesis - free radicals - ATRA - epoxidation

• References and Notes

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• 17 Synthesis of 11 from 10b To a solution of 10b (0.1 g, 0.2 mmol) on Et₃N (0.04 mL, 0.4 mmol) in CH₂Cl₂ (5 mL) was added dropwise MsCl (0.03 mL, 0.4 mmol). The resulting mixture was stirred for 1 h at r.t. and then H₂O was added. The reaction was extracted with CH₂Cl₂ (3 × 20 mL), the organic phase was dried with Na₂SO₄, and the solvent removed in vacuo. The product was used without purification for the next reaction. The crude was dissolved in DMF (1 mL) and transferred via cannula to a suspension of NaH (0.008g, 0.34 mmol, of 60% dispersion in mineral oil). The reaction mixture was stirred for 4 h at r.t. Then, H₂O was added, and the reaction was extracted with Et₂O (3 × 20 mL). The organic phase was dried with Na₂SO₄, and the solvent was removed in vacuo to yield the colorless solid 11. The product was purified by flash chromatography with hexane–EtOAc (9:1). All spectroscopic data for compound 11 fully matched with those reported by Fürstner.¹⁰ H NMR (400 MHz, CDCl₃): δ = 1.26 (s, 9 H), 1.60–1.74 (m, 1 H), 1.75–1.90 (m, 2 H), 1.92–2.10 (m, 1 H), 2.55–2.65 (m 1 H), 3.27–3.37 (m, 1 H), 3.45–3.52 (m, 1 H), 3.90–3.97 (m, 1 H), 4.03 (s, 3 H), 4.11 (s, 3 H), 4.12 (s, 3 H), 4.21 (s, 3 H), 4.23–4.32 (m, 1 H), 7.17 (s, 1 H), 7.37 (s, 1 H), 7.79 (s, 1 H), 7.82 (br s, 1 H), 8.31 (br s, 1 H) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 22.7, 28.6, 29.7, 37.1, 46.8, 55.9, 56.0, 56.2, 56.7, 57.4, 79.0, 102.9, 106.8, 107.9, 123.9, 124.7, 125.2, 126.2, 126.3, 131.8, 148.7, 148.9, 149.0, 149.1, 154.7 ppm. MS (EI) m/z (%) = 481 (45) [M⁺], 311 (78), 170 (20), 114 (100), 70 (58), 57 (40). HRMS–FAB: m/z calcd for C₂₈H₃₅NO₆ [M⁺]: 481.2464; found: 481.2459.