Synthesis of a C₃-Symmetric Nanoscale Molecular Platform Based on Marine Cyclopeptides

Abstract

Efficient synthesis of a conformationally preorganized, C₃-symmetric molecular platform is reported. The rigid scaffold is based on the structure of marine cyclopeptides and presents three functional groups pointing in the same direction. The bicyclic imidazole building blocks were synthesized in seven steps from trans-4-hydroxy-(S)-proline.

amino acids - condensation - cyclizations - heterocycles - peptides

References

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Preparation of Compounds 12, 13, 22 and 23. To a solution of the amidoketone (11 or 21; 8.40 mmol) in xylenes (200 mL) were added TFA (3.1 mL, 40.0 mmol) and a solution of NH₃ in MeOH (7 M, 5.7 mL, 40.0 mmol) at r.t. The solution was stirred at 150 °C with azeotropic removal of water for 6 h and then cooled to r.t. The mixture was concentrated and the residue was dissolved in EtOAc, then washed with sat. NaHCO₃ solution and brine. The organic layer was dried over MgSO₄ and concentrated in vacuo. Purification was accomplished by flash chromatography on silica gel (CH₂Cl₂-EtOAc-MeOH, 75:25:5). Data for 12: ¹H NMR (300 MHz, CDCl₃): δ = 0.09 (s, 6 H), 0.87 (s, 9 H), 2.94 (dd, J = 4.2, 17.0 Hz, 1 H), 3.31 (dd, J = 6.6, 17.0 Hz, 1 H), 3.77-3.89 (m, 4 H), 4.20 (dd, J = 6.2, 11.6 Hz, 1 H), 4.37 (d, J = 6.1 Hz, 2 H), 4.97-5.12 (m, 3 H), 5.57 (m, 1 H), 7.24-7.36 (m, 5 H). ¹³C NMR (75 MHz, CDCl₃): δ = -4.99, -4.87, 17.9, 25.6, 34.7, 37.6, 51.4, 53.6, 67.0, 75.7, 123.9, 128.0, 128.1, 128.5, 136.1, 140.7, 142.8, 156.3, 163.4. HRMS (FAB+): m/z [M + H⁺] calcd for C₂₃H₃₄N₃O₅Si: 460.2268; found: 460.2260. Data for 13: Mp 148-150 °C. ¹H NMR (300 MHz, DMSO-d ₆): δ = 2.77 (dd, J = 2.3, 17.1 Hz, 1 H), 3.18 (dd, J = 6.1, 17.1 Hz, 1 H), 3.70 (s, 3 H), 3.80 (dd, J = 2.1, 11.8 Hz, 1 H), 4.09 (dd, J = 5.3, 11.8 Hz, 1 H), 4.21 (d, J = 5.9 Hz, 2 H), 4.88 (s, 1 H), 5.05 (s, 2 H), 5.57 (d, J = 4.3 Hz, 1 H), 7.25-7.40 (m, 5 H), 7.88 (t, J = 5.9 Hz, 1 H). ¹³C NMR (75 MHz, DMSO-d ₆): δ = 34.0, 37.2, 50.6, 53.4, 65.5, 74.1, 122.2, 127.6, 127.7, 128.2, 136.9, 141.0, 143.7, 156.1, 162.8. HRMS (FAB+): m/z [M + H⁺] calcd for C₁₇H₂₀N₃O₅: 346.1403; found: 346.1384. Data for 22: ¹H NMR (300 MHz, CDCl₃): δ = 0.10 (s, 6 H), 8.85 (d, J = 6.7 Hz, 3 H), 0.88 (s, 9 H), 0.98 (d, J = 6.7 Hz, 3 H), 2.15-2.30 (m, 1 H), 2.95 (dd, J = 4.2, 17.0 Hz, 1 H), 3.34 (dd, J = 6.6, 17.0 Hz, 1 H), 3.85 (s, 3 H), 3.86-3.94 (m, 1 H), 4.07-4.18 (m, 1 H), 4.46 (t, J = 8.7 Hz, 1 H), 4.98-5.14 (m, 3 H), 5.56 (d, J = 9.1 Hz, 1 H), 7.25-7.37 (m, 5 H). ¹³C NMR (75 MHz, CDCl₃): δ = -5.0, -4.9, 17.9, 18.5, 19.4, 25.6, 32.8, 34.7, 51.5, 53.4, 54.0, 66.8, 75.5, 124.1, 127.9, 128.0, 128.4, 136.3, 141.8, 143.9, 156.2, 163.6. HRMS (FAB+): m/z [M + H⁺] calcd for C₂₆H₄₀N₃O₅Si: 502.2737; found: 502.2736. Data for 23: ¹H NMR (300 MHz, CDCl₃): δ = 0.85 (d, J = 6.7 Hz, 3 H), 0.98 (d, J = 6.7 Hz, 3 H), 2.14-2.28 (m, 1 H), 3.00-3.11 (m, 1 H), 3.32 (dd, J = 5.9, 17.5 Hz, 1 H), 3.84 (s, 3 H), 4.08 (m, 2 H), 4.44 (t, J = 8.7 Hz, 1 H), 5.00-5.13 (m, 3 H), 5.76 (d, J = 9.3 Hz, 1 H), 7.25-7.37 (m, 5 H). ¹³C NMR (75 MHz, CDCl₃): δ = 18.7, 19.4, 32.8, 34.5, 51.5, 53.6, 54.2, 66.9, 75.3, 124.1, 127.9, 128.0, 128.5, 136.3, 142.1, 144.2, 156.4, 163.5. HRMS (FAB+): m/z [M + H⁺] calcd for C₂₀H₂₆N₃O₅: 388.1872; found: 388.1858.

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Data for 25: Mp 136 °C. ¹H NMR (500 MHz, CDCl₃): δ = 0.06 (s, 9 H), 0.07 (s, 9 H), 0.84 (s, 27 H), 1.02 (d, J = 6.7 Hz, 9 H), 1.03 (d, J = 6.7 Hz, 9 H), 2.06-2.15 (m, 3 H), 2.94 (dd, J = 3.7, 16.9 Hz, 3 H), 3.35 (dd, J = 6.4, 16.9 Hz, 3 H), 3.74 (dd, J = 3.7, 11.2 Hz, 3 H), 4.08 (dd, J = 5.8, 11.2 Hz, 3 H), 4.93 (dd, J = 6.1, 8.7 Hz, 3 H), 5.02 (m, 3 H), 8.32 (d, J = 8.7 Hz, 3 H). ¹³C NMR (125 MHz, CDCl₃): δ = -5.0, -4.8, 17.9, 18.4, 19.3, 25.7, 34.1, 35.0, 51.3, 53.3, 76.1, 126.5, 138.2, 142.6, 162.8. HRMS (FAB+): m/z [M + H⁺] calcd for C₅₁H₈₈N₉O₆Si₃: 1006.6165; found: 1006.6116.

<A NAME="RG02204ST-12">12</A>

Data for 26: Mp >250 °C. ¹H NMR (500 MHz, CDCl₃): δ = 0.92 (d, J = 6.7 Hz, 9 H), 1.04 (d, J = 6.7 Hz, 9 H), 1.92-2.01 (m, 3 H), 3.22-3.30 (m, 6 H), 3.78 (dd, J = 4.4, 11.5 Hz, 3 H), 4.41 (d, J = 11.5 Hz, 3 H), 4.64 (dd, J = 8.1, 9.6 Hz, 3 H), 5.09 (m, 3 H), 5.38 (s, 3 H), 8.19 (d, J = 9.8 Hz, 3 H). ¹³C NMR (125 MHz, CDCl₃): δ = 18.9, 19.3, 34.1, 35.6, 50.8, 53.3, 75.6, 125.5, 139.2, 142.8, 163.2. HRMS (FAB+): m/z [M + H⁺] calcd for C₃₃H₄₆N₉O₆: 664.3571; found: 664.3578.

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