A General Synthesis of Phenanthridinone Alkaloids

Abstract

We report a general synthesis of the phenanthridinone skeleton using functionally rich, bridged bicyclic lactones obtained from the Diels-Alder cycloadditions of 3-bromo-2(H)-pyran-2-one.

Diels-Alder cycloadditions - stereoselectivity - regio­selectivity

References and Notes

1

Previous address: Department of Chemistry, King’s College London, Strand, London WC2R 2LS, UK.

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9

Compound 7
A sealed pressure tube (Aldrich Chemical Co Cat No Z18, 109-9) was charged with 3-bromo-2 (H)-pyran-2-one (617 mg, 3.53 mmol), 3,4-dimethoxystyrene (2.5 g, 15.2 mmol), a few crystals of 2,6-di-tert-butyl-4-methylphenol (anti-polymerization agent), and a small magnetic stirrer bar. The pressure tube was sealed and heated at 80 °C for 5 d. Removal of all volatile materials followed by silica gel chromatography using 20-40% v/v EtOAc in PE afforded the endo-isomer (1.16 g, 97%). ¹H NMR: δ = 6.80 (1 H, aromatic), 6.72 (2 H, aromatic), 6.67 (dd, 1 H, J _1,7 = 5.2 Hz, J _7,8 = 7.8 Hz, H-7), 6.46 (dm, 1 H, J _7,8 = 7.8 Hz, H-8), 5.39 (m, 1 H, H-1), 3.87 (s, 3 H, OCH₃), 3.86 (s, 3 H, OCH₃), 3.33 (ddd, 1 H, J _5,8 = 0.9 Hz, J _5,6endo = 4.5 Hz, J _5,6exo = 9.7 Hz, H-5), 2.95 (ddd, 1 H, J _1,6exo = 4.2 Hz, J _5,6exo = 9.7 Hz, J _6exo,endo = 13.8 Hz, H-6_exo), 2.10 (ddd, 1 H, J _1,6endo = 1.3 Hz, J _5,6endo = 4.5 Hz, J _6endo,6exo = 13.8 Hz, H-6_endo). ¹³C NMR: δ = 168.97 (C-3), 148.80 (aromatic C), 148.42 (aromatic C), 136.21 (C-8), 132.13 (C-7), 132.05 (aromatic C), 121.24 (aromatic CH), 112.74 (aromatic CH), 110.66 (aromatic CH), 73.90 (C-1), 64.58 (C-4), 55.95 (OCH₃), 55.83 (OCH₃), 44.51 (C-5), 37.28 (C-6). MS: m/z = 340 (4) [M⁺ for ⁸¹Br], 338 (4) [M⁺ for ⁷⁹Br], 184 (4), 165 (14), 164 (100), 149 (16), 128 (4), 103 (4), 108 (5), 77 (4). ESI-HRMS: m/z calcd for C₁₅H₁₅ ⁸¹BrO₄Na: 363.00255; found: 363.00247.

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12

Compound 8 A round-bottomed flask was charged with a solution of compound 7 (339 mg, 1 mmol) in anhyd MeOH (15 mL) and Pd/C (10% w/w, 60 mg). The reaction mixture was stirred at r.t. under H₂ atmosphere for 45 h. The mixture was filtered through Celite^® and the solid residue washed with EtOAc. The solvent was removed under reduced pressure and the residue was purified by silica gel chromatography using 40% EtOAc in PE to give compound 8 (272 mg, 93%). ¹H NMR: δ = 6.76 (3 H, aromatic), 4.30 (m, 1 H, H-4), 3.86 (s, 3 H, OCH₃), 3.85 (s, 3 H, OCH₃), 3.45 (s, 3 H, CO₂CH₃), 3.38 (dt, 1 H, J _1,2 = J _2,3a = 4.3 Hz, J _2,3e = 12.1 Hz, H-2), 2.91 (q, 1 H, J = 4.5 Hz, H-1), 2.61 (ddd, 1 H, J _3e,4 = 2.9 Hz, J _2,3e = 12.0 Hz, J _3e,3a = 13.5 Hz, H-3e), 2.20 (tdd, 1 H, J _1,6e = 4.0 Hz, J _6e,5a = 5.0 Hz, J _6e,5e = J _6e,6a = 13.2 Hz, H-6e), 2.09 (tdd, 1 H, J _4,5e = 3.0 Hz, J _5e,6a = 4.0 Hz, J _5e,5a = J _5e,6e = 13.2 Hz, H-5e), 1.83 (m, 2 H, H-3a and H-6a), 1.64 (dddd, 1 H, J _4,5a = 1.5 Hz, J _5a,6e = 5.0 Hz, J _5a,6a = 6.5 Hz, J _5e,5a = 13.7 Hz, H-5a), 1.46 (br, 1 H, OH). ¹³C NMR: δ = 174.94 (CO₂), 148.90 (aromatic C), 147.79 (aromatic C), 136.57 (aromatic C), 119.87 (aromatic CH), 111.41 (aromatic CH), 111.21 (aromatic CH), 66.74 (C-4), 56.17 (OCH₃), 56.15 (OCH₃), 51.42 (CO₂CH₃), 46.04 (C-1), 38.21 (C-2), 34.76 (C-3), 29.09 (C-5), 23.28 (C-6). MS: m/z 295 (20) [MH⁺], 294 (100) [M⁺], 276 (13) [M⁺ - H₂O], 217 (9), 216 (25), 193 (10), 165 (9), 164 (11), 151 (24). ESI-HRMS: m/z calcd for C₁₆H₂₂O₅Na: 317.13594; found: 317.13557.

13 Mehta G. Mohal N. Tetrahedron Lett.  1998,  39:  3281 

14

Compound 10
DPPA (0.2 mL, 0.94 mmol) was added to a stirred solution of compound 8 (210 mg, 0.75 mmol) and Et₃N (0.2 mL, 1.5 mmol) in anhyd benzene (20 mL) at 0 °C. After 30 min, the solution was brought to r.t. and then after 2 h was set to reflux for 45 h. Solvent was removed and the residue was dissolved in CH₂Cl₂ (3 mL). This was added to a stirred suspension of AlCl₃ in CH₂Cl₂ (5 mL) at 0 °C. After 30 min, the solution was brought to r.t. and was stirred for 24 h. The reaction mixture was poured into H₂O and was extracted with EtOAc (3 × 20 mL). The combined organic extracts were washed with aq NaHCO₃ and dried over Na₂SO₄. Evaporation of solvent and silica gel chromatography (20-60% v/v EtOAc in PE) afforded compound 10 as a yellow gum (49 mg, 24%). ¹H NMR: δ = 6.61 (s, 1 H, aromatic), 6.63 (s, 1 H, aromatic), 4.18 (m, 1 H, H-4), 3.81 (s, 3 H, OCH₃), 3.79 (s, 3 H, OCH₃), 3.31 (dt, 1 H, J _d = 8.3 Hz, J _t = 4.0 Hz, H-2), 2.85 (dm, 1 H, J = 3.2 Hz, H-1), 1.40-2.30 (m, 6 H, 3 × CH₂). ¹³C NMR: δ = 156.47 (aromatic C), 148.45 (aromatic C), 133.47 (aromatic C), 119.05 (aromatic C), 111.15 (aromatic CH), 111.21 (aromatic CH), 76.21 (C-4), 56.30 (OCH₃), 56.26 (OCH₃), 51.56 (C-1), 38.28 (C-2), 31.15 (C-3), 26.03 (C-5), 25.03 (C-6). MS: m/z = 278 (20)[ MH⁺]. ESI-HRMS: m/z calcd for C₁₅H₁₉NO₄Na: 300.12118; found: 300.1212.

15 Hakogi T. Monden Y. Taichi M. Iwama S. Fujii S. Ikeda K. Katsumura S. J. Org. Chem.  2002,  67:  4839