A Bidirectional Synthesis of (+)-Terreusinone

Abstract

An efficient, bidirectional synthesis of the photoprotecting dipyrrolobenzoquinone (+)-terreusinone has been accomplished. Key steps include a copper- and amine-free double Sonogashira reaction of an electron-rich 1,4-dibromide with a protected propargylic alcohol followed by pyrrolo[2,3-f]indole formation by double hydroamination catalyzed by Echavarren’s cationic gold(I) complex. This new route to (+)-terreusinone complements the original synthesis and offers advantages over its predecessor.

Key words

terreusinone - pyrroloindole - Sonogashira coupling - hydroamination - natural product

• References and Notes

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• 10 Subjecting 7 to the reaction conditions shown in Scheme 4 leads to slow degradation (ca. 12 h) and not the formation of pyrroloindole 5
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• 13 3-Methoxy-2,5-bis{(R)-4-methyl-3-[(triisopropylsilyl)-oxy]pent-1-yn-1-yl}benzene-1,4-diamine (7) In a 4-dram vial equipped with a stirring bar and Teflon-lined screwcap, N-methyl-2-pyrrolidone (15 mL) was purged with nitrogen for 1 h. Pd(OAc)₂ (5.84 mg, 0.026 mmol), 1,1′-bis(di-tert-butylphosphino)ferrocene (14.8 mg, 0.031 mmol), K₂CO₃ (180 mg, 1.3 mmol), 2,5-dibromo-3-methoxy-1,4-dianiline (2, 76 mg, 0.26 mmol) and (R)-triisopropyl[(4-methylpent-1-yn-3-yl)oxy]silane [(R)-4, 330 mg, 1.3 mmol] were added, and the reaction mixture was heated at 138 °C for 2 h. After cooling to r.t., the reaction mixture was filtered through a pad of Celite, and the cake was washed with EtOAc (100 mL). The filtrate was washed with H₂O (80 mL), brine (80 mL), dried (Na₂SO₄), filtered, and concentrated in vacuo. The residue was purified with flash chromatography using hexanes–EtOAc (19:1) as eluent to yield the title compound (67.6 mg, 0.105 mmol, 40%) as an orange oil; [α]_D ²⁰ +54.4 (c 1.0, EtOAc). IR (neat): ν_max = 2943, 2866, 1598, 1459, 1431, 1384, 1366, 1304, 1239, 1156, 1088, 1055, 996 cm^–1. ¹H NMR (400 MHz, acetone-d ₆): δ = 1.05 (6 H, d, J = 6.4 Hz, 2 × Me), 1.08 (6 H, t, J = 6.4 Hz, 2 × Me), 1.12–1.15 (36 H, m, 12 × TIPSMe), 1.19–1.24 (6 H, m, 6 × TIPSCH), 1.96–2.03 [2 H, m, 2 × (CH₃)₂CH], 3.82 (3 H, s, OMe), 4.13 (2 H, br s, NH₂), 4.40 (2 H, br s, NH₂), 4.69 (1 H, d, J = 5.2 Hz, CH), 4.77 (1 H, d, J = 4.8 Hz, CH), 6.51 (1 H, s, Ar-H). ¹³C NMR (100 MHz, acetone-d ₆): δ = 13.1 (6 × CH), 17.5 (2 × Me), 17.7 (2 × Me), 18.5 (6 × TIPSMe), 18.6 (6 × TIPSMe), 36.5 (CH), 36.6 (CH), 60.0 (OMe), 69.7 (CH), 69.9 (CH), 79.2 (C), 82.7 (C), 96.3 (C), 100.3 (C), 104.9 (C), 110.6 (C), 112.8 (CH), 134.3 (C), 142.1 (C), 148.9 (C). ESI-MS: m/z (%) = 665 (90) [M + Na]⁺, 650 (100). ESI-HRMS: m/z calcd for [C₃₇H₆₆N₂O₃Si₂ + Na]⁺: 665.4504 [M + Na]⁺; found: 665.4482
• 14 4-Methoxy-2,6-bis{(R)-2-methyl-1-[(triisopropylsilyl)-oxy]propyl}-1,5-dihydropyrrolo[2,3-f]indole (5) To a solution of 2,5-dialkynyl-1,4-dianiline 7 (26 mg, 0.04 mmol) in toluene (5 mL) was added (acetonitrile)- [(2-biphenyl)di-tert-butylphosphine]gold(I) hexafluoro-antimonate (8, 4.65 mg, 0.006 mmol, 15 mol%), and the reaction mixture was heated to 60 °C for 4 h. The reaction mixture was concentrated in vacuo, and the crude residue was purified by flash chromatography using hexanes–EtOAc (9:1) as eluent to yield the title compound (19.6 mg, 0.03 mmol, 76%) as a yellow oil; [α]_D ²⁰ +73.5 (c 0.65, EtOAc). IR (neat): ν_max = 3484, 2942, 2866, 1462, 1383, 1342, 1297, 1223, 1080, 1057, 1013, 919 cm^–1. ¹H NMR (400 MHz, acetone-d ₆): δ = 0.88 (6 H, d, J = 2.0, 2 × Me), 1.00 (6 H, d, J = 2.0 Hz, 2 × Me), 1.01–1.08 (36 H, m, 12 × TIPSMe), 1.09–1.12 (6 H, m, 6 × TIPSCH), 2.12–2.80 [2 H, m, 2 × (CH₃)₂CH], 4.08 (3 H, s, OMe), 4.80 (1 H, J = 6.4 Hz, CH), 4.86 (1 H, d, J = 6.0 Hz, CH), 6.27 (1 H, d, J = 2.4 Hz, H-2), 6.45 (1 H, d, J = 1.6 Hz, H-2′), 7.17 (1 H, s, Ar-H), 9.21 (1 H, br s, NH), 9.59 (1 H, br s, NH). ¹³C NMR (100 MHz, acetone-d ₆): δ = 13.3 (6 × CH), 18.2 (Me), 18.3 (Me), 18.4 (6 × TIPSMe), 18.5 (6 × TIPSMe), 19.4 (Me), 19.6 (Me), 36.7 (2 × CH), 60.3 (OMe), 76.2 (CH), 76.3 (CH), 95.4 (CH), 96.8 (CH), 100.0 (CH), 117.4 (C), 124.9 (C), 128.6 (C), 136.3 (CH), 136.8 (C), 140.4 (C), 141.7 (C). ESI-MS: m/z (%) = 665 (34) [M + Na]⁺, 491 (100), 469 (42). ESI-HRMS: m/z calcd for [C₃₇H₆₆N₂O₃Si₂ + Na]⁺: 665.4504 [M + Na]⁺; found: 665.4499
• 15 (3R,3′R)-1,1′-(2,5-Diamino-3-methoxy-1,4-phenylene)bis(4-methylpent-1-yn-3-ol) (10) To a solution of 2,5-dialkynyl-1,4-dianiline 7 (25 mg, 0.038 mmol) in THF (7 mL) at 0 °C was added TBAF (0.06 mL, 0.06 mmol, 1 M solution in THF), and the reaction mixture was stirred at 0 °C for 20 min. The solvent was removed under reduced pressure, and the crude residue was purified with flash chromatography using hexanes–EtOAc (1:1, 0.5% Et₃N) as eluent to give the title compound as a yellow oil (11.7 mg, 0.035 mmol, 92%); [α]_D ²⁰ +28.1 (c 0.3, EtOAc). IR (neat): ν_max = 3334, 2960, 2927, 1603, 1554, 1459, 1430, 1289, 1194, 1153, 1027, 864 cm^–1. ¹H NMR (400 MHz, acetone-d ₆): δ = 1.02–1.05 (6 H, m, 2 × Me), 1.06–1.10 (6 H, m, 2 × Me), 1.88–1.97 [2 H, m, 2 × (CH₃)₂CH], 3.82 (3 H, s, OMe), 4.16 (2 H, br s, NH₂), 4.36–4.44 (6 H, m, 2 × CH, 2 × OH, NH₂), 6.47 (1 H, s, ArH). ¹³C NMR (100 MHz, acetone-d ₆): δ = 18.1 (Me), 18.2 (Me), 18.69 (Me), 18.72 (Me), 35.60 (CH), 35.64 (CH), 60.0 (Me), 68.3 (CH), 68.5 (CH), 78.7 (C), 82.1 (C), 97.0 (C), 101.2 (C), 104.8 (C), 110.5 (C), 112.6 (CH), 134.2 (C), 141.9 (C), 148.6 (C-O). ESI-MS: m/z (%) = 331 (10) [M + H]⁺, 313 (18), 295 (26), 280 (100), 264 (23), 241 (12), 226 (11). ESI-HRMS: m/z calcd for [C₁₉H₂₆N₂O₃ + H]⁺: 331.2016 [M + H]⁺; found: 331.2022
• 16 (1R,1′R)-1,1′-(4-Methoxy-1,5-dihydropyrrolo[2,3-f]indole-2,6-diyl)bis(2-methylpropan-1-ol) (9) Path A To a solution of pyrroloindole 5 (15 mg, 0.023 mmol) in THF (7 mL) at 0 °C was added TBAF (0.047 mL, 0.047 mmol, 1 M solution in THF), and the reaction mixture was stirred at 0 °C for 20 min. The solvent was removed under reduced pressure, and the crude residue was purified with flash chromatography using hexanes–EtOAc (1:1, 0.5% Et₃N) as eluent to give the title compound as a crimson oil (4.3 mg, 0.013 mmol, 56%); [α]_D ²⁰ +63 (c 0.18, EtOAc) {lit.⁴ [α]_D ²⁰ +45.9 (c 0.17, EtOAc)}; spectroscopic data are consistent with literature data.⁴ Path B To a solution of 2,5-dialkynyl-1,4-dianiline 10 (3 mg, 0.009 mmol) in toluene (6 mL) was added (acetonitrile)[(2-biphenyl)di-tert-butylphosphine]gold(I) hexafluoro-antimonate (8, 1.05 mg, 0.0014 mmol, 15 mol%), and the reaction mixture was heated to 60 °C for 1 h. The reaction mixture was concentrated in vacuo, and the crude residue was purified by flash chromatography using hexanes–EtOAc (1:1, 0.5% Et₃N) as eluent to yield the title compound as a yellow oil (0.7 mg, 0.0022 mmol, 24%), data as obtained for path A above
• 17 Terreusinone [(+)-1] Pyrroloindole 9 was oxidized as described in ref. 4 to give the title compound (2.26 mg, 0.0064 mmol, 59%) as an orange solid; mp 223 °C (decomp.) [lit.¹ 230 °C (decomp.); lit.⁴ 216 °C (decomp.)]; [α]_D ²¹ +49.6 (c 0.19, MeOH) {lit.¹ [α]_D +47 (c 0.3, MeOH)}, {lit.⁴ [α]_D ²⁰ +43.7 (c 0.16, MeOH)}; spectroscopic data are consistent with literature data⁴