Facile and Efficient Solid-Phase Synthesis of DNA-Interactive Pyrrolo[2,1-c][1,4]benzodiazepines

Abstract

The solid-phase synthesis of pyrrolo[2,1-c][1,4]benzodiazepines is described. Isatoic anhydrides attached to chloromethyl Wang resin are coupled with proline and the polymer-bound tricyclic compounds are reduced using very mild conditions, and successively cleaved from the resin to afford the desired imine-containing heterocyclic compounds. Reactions were monitored by FT-IR spectroscopy on the resin beads.

Key words

pyrrolo[2,1-c][1,4]benzodiazepines - solid-phase synthesis - chloromethyl Wang resin - isatoic anhydrides

References

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14

Preparation of Compound 5a: The isatoic anhydride (1a, 0.815 g, 5 mmol) and NaH (0.12 g, 5 mmol) were taken in dry DMF (15 mL) and were stirred at r.t. for 1 h, followed by the addition of chloromethyl Wang resin (1 g, 1 mmol), which was allowed to stir at the same temperature for 24 h. The derivatized resin was filtered, rinsed with DMF (4×), CH₂Cl₂ (4×) and THF (2×), and dried in vacuo to give 1.115 g of 2a. The two C=O functional groups showed their absorption bands in the IR spectrum at 1782 cm^-1 and 1729 cm^-1. A mixture of isatoic resin (1.11 g) and l-proline (0.575 g, 5 mmol) in DMF (3 mL) at 50 °C was sonicated for 1 h to give polymer-bound PBD-5,11-dione (3a). Alternatively, this mixture in DMF (15 mL) was stirred at 100 °C for 8 h to give 3a. The resin was sequentially washed with DMF (4×), CH₂Cl₂ (4×), MeOH (4×), THF (4×) and dried in vacuo to give 1.10 g of 3a. These two C=O functional groups showed their absorption bands in the IR spectrum at 1748 cm^-1 and 1609 cm^-1. To a suspension of 3a (0.3 g) in dry THF (10 mL) at -10 °C was added LiBH₄ (0.021g, 1 mmol) in portions and stirred at -10 °C for 6 h. Alternatively, to a suspension of 3a (0.3 g) in MeOH-THF (7:3) at 0 °C was added NaBH₄ (0.037g, 1 mmol) in portions and stirred at 0 °C for 6 h. The resin 4a was filtered and rinsed with THF (4×), MeOH (4×), CH₂Cl₂ (4×) and MeOH (4×). One of the C=O band disappeared and an OH group appeared at 3400 cm^-1 while the C=O showed the absorption at 1611 cm^-1 in the IR spectrum. Finally, the product 4a was cleaved from the solid support using TFA-H₂O to yield the crude product 5a, which was further purified by column chromatography. ¹H NMR (200 MHz, CDCl₃): δ = 2.02-2.16 (2 H, m), 2.26-2.38 (2 H, m), 3.36-3.94 (3 H, m), 7.28-7.38 (2 H, m), 7.53 (1 H, t, J = 6.69 Hz), 7.79 (1 H, d, J = 4.46 Hz), 8.05 (1 H, d, J = 7.43 Hz). MS (EI): m/z = 200 [M⁺]; [α]_D ²⁶ +343 (c 0.4, CHCl₃) [lit. [16] [α]_D ²² +319 (c 0.147, CHCl₃)].

15

Preparation of Compound 6a: The suspension of 3a (0.5 g) in TFA-H₂O (9:1, 6 mL) was allowed to stir at r.t. for 4 h. The resin was filtered and washed with CH₂Cl₂ (3×). The combined filtrate was evaporated to afford the crude product (6a). This was further purified by column chromatography. ¹H NMR (200 MHz, CDCl₃): δ = 1.92-2.06 (3 H, m), 2.70-2.80 (1 H, m), 3.47-3.64 (1 H, m), 3.71-3.84 (1 H, m), 4.00-4.08 (1 H, m), 7.01 (1 H, d, J = 8.06 Hz), 7.22 (1 H, t, J = 7.32 Hz), 7.43 (1 H, t, J = 7.32 Hz), 7.95 (1 H, d, J = 8.06 Hz), 9.03 (1 H, s). MS (SI): m/z = 216 [M⁺]; [α]_D ²⁶ +489 (c 0.5, MeOH) [lit. [17] [α]_D ²⁵ +523 (c 1.0, MeOH)].