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DOI: 10.1055/s-2004-822906
Synthesis of a C3-Symmetric Nanoscale Molecular Platform Based on Marine Cyclopeptides
Publication History
Publication Date:
01 April 2004 (online)
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.
Key words
amino acids - condensation - cyclizations - heterocycles - peptides
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References
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.
11Data 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.
12Data 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.