Efficient Synthesis of 2,5-Diketopiperazines by Staudinger-Mediated Cyclization

Abstract

Solution- and solid-phase Staudinger-mediated cyclizations were assessed to efficiently prepare hetero-2,5-diketopiperazines from their protected azido dipeptide thioesters under microwave irradiation. Short reaction time, good yields and ease of purification are the main assets of this methodology.

Key words

azides - cyclization - cyclic peptides - Staudinger - methodology

• References

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• 43 General Procedure for the Solution-Phase Synthesis of 2,5-Diketopiperazines from Azido Peptide Thioesters 1a–c: To a stirred solution of 1a–c (1 mmol) in anhyd CH₂Cl₂ (4 mL), tributylphosphine (0.37 mL, 1.5 mmol) was added and stirring was continued for 5 min at r.t. H₂O (0.1 mL, 5 mmol) was added and stirring was continued again for 5 min. The vial was then subjected to microwave irradiation (50 W, 50 °C, 5 min). Hexanes (4 mL) was added to the reaction to induce crystallization and placed in the freezer. The reaction mixture was filtered and the remaining solid was washed with CH₂Cl₂ (5 mL) and hexanes (15 mL) and dried under vacuum to yield pure 2a–c. General Procedure for the Solid-Phase Synthesis of 2,5-Diketopiperazines from Supported Azido Peptide Thioesters 1d–f: To a stirred suspension of 1d–f (1 mmol) in anhyd CH₂Cl₂ (4 mL), tributylphosphine (0.37 mL, 1.5 mmol) was added and stirring was continued for 5 min at r. t. H₂O (0.1 mL, 5 mmol) was added and stirring was continued again for 5 min. The vial was then subjected to microwave irradiation (50 W, 50 °C, 5 min). The solids were filtered and washed with CH₂Cl₂, the remaining solid was treated with hot MeOH and the resulting mother liquor was collected. The mother liquor was cooled in the freezer and the precipitate was collected and dried under vacuum to yield pure 2a–c. (S)-3-Isobutylpiperazine-2,5-dione (2a): Yield: 78% (0.13 g); white microcrystals; mp 248.0–250.0 °C. ¹H NMR (300 MHz, DMSO-d ₆): δ = 8.26 (br s, 1 H), 7.99 (br s, 1 H), 3.79–3.89 (m, 1 H), 3.56–3.70 (m, 2 H), 1.69–1.84 (m, 1 H), 1.49–1.56 (m, 2 H), 0.89 (d, J = 6.7 Hz, 3 H), 0.87 (d, J = 6.6 Hz, 3 H). ¹³C NMR (75 MHz, CDCl₃): δ = 168.8, 166.3, 52.9, 44.2, 42.1, 23.6, 22.9, 21.8. Anal. Calcd for C₈H₁₄N₂O₂: C, 56.45; H, 8.29; N, 16.46. Found: C, 56.63; H, 8.41; N, 16.28. (S)-3-Benzylpiperazine-2,5-dione (2b): Yield: 74% (0.15 g); white microcrystals; mp 251.0–252.0 °C. ¹H NMR (300 MHz, DMSO-d ₆): δ = 8.11–8.18 (m, 1 H), 7.84–7.90 (m, 1 H), 7.21–7.32 (m, 3 H), 7.10–7.18 (m, 2 H), 4.02–4.09 (m, 1 H), 3.26–3.42 (m, 2 H), 3.08 (dd, J = 13.5, 4.4 Hz, 1 H), 2.87 (dd, J = 13.5, 4.9 Hz, 1 H). ¹³C NMR (75 MHz, CDCl₃): δ = 167.4, 166.0, 136.1, 130.2, 128.3, 127.0, 55.7, 43.8. Anal. Calcd for C₁₁H₁₂N₂O₂: C, 64.49; H, 5.92; N, 13.72. Found: C, 64.43; H, 6.06; N, 13.65. (S)-3-Methylpiperazine-2,5-dione (2c): Yield: 78% (0.10 g); white microcrystals; mp 236–238 °C. ¹H NMR (300 MHz, DMSO-d ₆): δ = 8.17 (br s, 1 H), 7.99 (br s, 1 H), 3.88 (dq, J = 0.6, 6.9 Hz, 1 H), 3.76 (s, 2 H), 1.30 (d, J = 6.9 Hz, 3 H). ¹³C NMR (75 MHz, CDCl₃): δ = 168.8, 166.2, 49.7, 44.5, 18.6. HRMS (ESI): m/z [M + H] calcd for C₅H₉N₂O₂: 129.0795; found: 130.1637