Synlett 2015; 26(16): 2272-2276
DOI: 10.1055/s-0034-1378877
letter
© Georg Thieme Verlag Stuttgart · New York

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

Gints Smits
Latvian Institute of Organic Synthesis, Aizkraukles 21, Riga 1006, Latvia   Email: ronalds@osi.lv
,
Ronalds Zemribo*
Latvian Institute of Organic Synthesis, Aizkraukles 21, Riga 1006, Latvia   Email: ronalds@osi.lv
› Author Affiliations
Further Information

Publication History

Received: 07 May 2015

Accepted after revision: 03 July 2015

Publication Date:
01 September 2015 (eFirst)

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.

Supporting Information

 
  • 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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