One-Step Preparation of Pyrrolo[1,4]benzodiazepine Dilactams: Total Synthesis of Oxoprothracarcin, Boseongazepines B and C

Abstract

A one-step synthesis of pyrrolo[1,4]benzodiazepine dilactams has been developed. The high yielding method involves direct coupling of unprotected anthranilic acids with proline esters. This transformation was successfully applied in the first total syntheses of boseongazepines B and C as well as oxoprothracarcin and limazepine E.

Key words

pyrrolo[1,4]benzodiazepine - dilactams - total synthesis - oxoprothracarcin - boseongazepine

• References and Notes

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• 8 General Procedure for Synthesis of PBD Dilactams: To a stirred solution of anthranilic acid (2.2 mmol, 2 equiv), BOP reagent (2.2 mmol, 2 equiv) and HOBt hydrate (2.2 mmol, 2 equiv) in anhyd DMF (10 mL) was added Et₃N (10.9 mmol, 10 equiv). After stirring for 15 min, proline ester hydrochloride (1.1 mmol, 1 equiv) was added and the resultant mixture was stirred for 16 h. The volatiles were removed in vacuo and the residue was partitioned between CH₂Cl₂ and brine. The organic phase was dried over anhyd Na₂SO₄, filtered and concentrated in vacuo. The residue was purified by flash column chromatography (EtOAc–MeOH) or reversed-phase flash column chromatography (MeOH + 0.5% HCOOH–H₂O + 0.5% HCOOH). (S)-9-Bromo-2,3-dihydro-1H-benzo[e]pyrrolo[1,2-a][1,4]-diazepine-5,11(10H,11aH)-dione (23): colorless solid; [α]_D +423 (c = 0.1, MeOH). ¹H NMR (300 MHz, CDCl₃): δ = 7.95 (d, J = 7.9 Hz, 1 H), 7.69–7.81 (m, 2 H), 7.14 (t, J = 7.9 Hz, 1 H), 4.05 (d, J = 6.2 Hz, 1 H), 3.76–3.91 (m, 1 H), 3.50–3.70 (m, 1 H), 2.67–2.86 (m, 1 H), 1.92–2.18 (m, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 170.0, 164.4, 136.0, 133.1, 130.9, 129.2, 126.0, 115.5, 56.8, 47.5, 26.4, 23.5. HRMS–ESI: m/z [M + H] calcd for C₁₂H₁₂N₂O₂Br: 295.0082; found: 295.0090. (S)-8-(Trifluoromethyl)-2,3-dihydro-1H-benzo[e]pyrrolo-[1,2-a][1,4]diazepine-5,11(10H,11aH)-dione (24): yellowish solid; Lit. 9: [α]_D +41 (c = 0.1, MeOH). ¹H NMR (400 MHz, DMSO): δ = 7.93 (dd, J = 7.9, 1.5 Hz, 1 H), 7.76 (br s, 1 H), 7.73 (dd, J = 7.9, 1.5 Hz, 1 H), 7.12 (t, J = 7.9 Hz, 1 H), 4.03 (d, J = 6.0 Hz, 1 H), 3.72–3.88 (m, 1 H), 3.52–3.69 (m, 1 H), 2.66–2.85 (m, 1 H), 1.95–2.14 (m, 3 H). ¹³C NMR (100 MHz, DMSO): δ = 170.7, 163.4, 137.1, 131.9, 131.9 (q, J = 32.2 Hz), 129. 8, 123.5 (q, J = 272.8 Hz), 119.9, 118.1, 56.1, 47.0, 25.7, 23.0. HRMS–ESI: m/z [M + H] calcd for C₁₃H₁₂N₂O₂F₃: 285.0851; found: 285.0855. (S,E)-2-Ethylidene-10-{[2-(trimethylsilyl)ethoxy]methyl}-2,3-dihydro-1H-benzo[e]pyrrolo[1,2-a][1,4]diazepine-5,11(10H,11aH)-dione (21): To a stirred solution of oxoprothracarcin (140 mg, 0.6 mmol, 1 equiv) in anhyd DMF (1.5 mL) under an argon atmosphere was added NaH (80% in mineral oil, 21 mg, 0.7 mmol, 1.2 equiv) at 0 °C. After stirring for 30 min SEM-Cl (118 mg, 0.7, 1.2 equiv) was added and the mixture was allowed to warm to r.t. overnight and then partitioned between CH₂Cl₂ and brine. The organic phase was dried over anhyd Na₂SO₄, filtered and concentrated in vacuo. The residue was purified by flash column chromatography (EtOAc–PE, 9:1 → 1:1). The title compound was isolated as a yellowish oil (170 mg, 79%); [α]_D +333.00 (c = 0.1, CHCl₃). ¹H NMR (300 MHz, CDCl₃): δ = 7.90 (dd, J = 7.8, 1.6 Hz, 1 H), 7.69 (dd, J = 7.8, 1.6 Hz, 1 H), 7.48–7.57 (td, J = 7.8, 1.6 Hz, 1 H), 7.34 (td, J = 7.8, 1.6 Hz, 1 H), 5.46–5.60 (m, 2 H), 4.72 (d, J = 9.8 Hz, 1 H), 4.24–4.40 (m, 2 H), 4.17 (d, J = 15.7 Hz, 1 H), 3.59–3.82 (m, 2 H), 3.48 (d, J = 16.3 Hz, 1 H), 2.55–2.70 (m, 1 H), 1.74 (d, J = 6.6 Hz, 3 H), 0.99 (t, J = 8.6 Hz, 2 H), 0.02 (s, 9 H). ¹³C NMR (100 MHz, CDCl₃): δ = 170.0, 165.3, 139.9, 133.1, 132.4, 130.0, 129.5, 126.4, 122.7, 118.5, 78.1, 67.1, 57.6, 51.1, 28.2, 18.4, 14.6, –1.3. HRMS–ESI: m/z [M + Na] calcd for C₂₀H₂₈N₂O₃SiNa: 395.1767; found: 395.1758. Boseongazepine C: To a stirred solution of 21 (150 mg, 0.4 mmol, 1 equiv) in MeOH (3 mL) was added NaBH₄ (46 mg, 1.2 mmol, 3 equiv) at 0 °C. The mixture was then stirred at r.t. and then an additional 2 equiv of NaBH₄ were added. The process of addition (2 equiv of NaBH₄) was repeated three times to achieve full consumption of 21. The reaction mixture was then partitioned between CH₂Cl₂ and brine. The organic phase was separated and the aq phase was extracted with CH₂Cl₂ (2 ×). The combined organic extracts were dried over anhyd Na₂SO₄, filtered and concentrated in vacuo. The residue was purified by preparative LC–MS (MeOH + 0.5% HCOOH–H₂O + 0.5% HCOOH). The collected prothracarcin was used in the next step without further purification. The obtained material was dissolved in a mixture of MeOH (1 mL) and CH₂Cl₂ (0.3 mL) and treated with NaBH₄ (46 mg, 1.208 mmol, 3 equiv). The process was repeated several times to achieve full consumption of the prothracarcin. The reaction mixture was then partitioned between CH₂Cl₂ and brine. The organic phase was separated and the aq. Phase was extracted with CH₂Cl₂ (2 ×). The combined organic extracts were dried over anhyd Na₂SO₄, filtered and concentrated in vacuo. The residue was purified by flash column chromatography (EtOAc–PE, 1:1 → 1:0). The title compound was isolated as a yellowish solid (25 mg, 27%). See the Supporting Information for compound characterization.
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