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12 During our study, the preparation of racemic α-trifluoro-methyl azahistidine analogues using the same approach has been reported: Shchetnikov GT.
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15 A related compound of 5 (NBoc instead of NCbz) has been previously prepared in racemic form by propargylation of Boc-Pro-OMe: Ikeda M.
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1-Benzyl 2-Methyl (2
R
)-2-Prop-2-ynylpyrrolidine-1,2-dicarboxylate (4): To a solution of compound 5 (0.56 mmol, 197 mg) in MeOH (3 mL) in a microwave reaction tube was added TMSCl (2.89 mmol, 365 µL). The mixture was stirred for 2.5 h at 40 °C using an irradiation power of 150 W with simultaneous cooling of the reaction vessel with a stream of compressed air. The solvent was removed under reduced pressure, and a sat. solution of NaHCO3 (3 mL) was added followed by carbobenzyloxy chloride (CbzCl, 0.62 mmol, 87 µL) at 0 °C. The reaction mixture was allowed to warm to r.t., stirred overnight at r.t., and diluted with EtOAc. The two layers were separated, the aqueous layer was extracted with EtOAc and the combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by chromatography on silica gel (eluent: PE-Et2O, 1:1) to give pure 7 (154 mg, 73%; mixture of two rotamers at r.t.) as a colourless oil. TBAF (1 M, 0.62 mmol, 0.6 mL) was added dropwise to a solution of proline 7 (0.41 mmol, 154 mg) in THF (10 mL). The mixture was stirred at r.t. for 2 h, and then the solvent was removed at reduced pressure. The residue was dissolved in CH2Cl2 and H2O and the two layers were separated. The aqueous layer was extracted with CH2Cl2 and the combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by chromatography on silica gel (eluent: PE-Et2O, 1:1) to give pure 4 (67 mg, 55%; mixture of two rotamers at r.t.) as a colourless oil. Compound 4: R
f
0.37. 1H NMR (400 MHz, DMSO-d
6, 110 °C): δ = 7.28-7.40 (m, 5 H, Ph), 5.09 (br s, 2 H, CH
2Ph), 3.66 (ddd, J = 5.3, 7.8, 10.2 Hz, 1 H, 5-Ha), 3.59 (br s, 3 H, OMe), 3.51 (dt, J = 7.3, 10.2 Hz, 1 H, 5-Hb), 3.05-3.17 (m, 1 H, CHHCº), 2.81 (dd, J = 2.6, 17.0 Hz, 1 H, CHHCº), 2.64 (t, J = 2.6 Hz, 1 H, ºCH), 2.32 (m, 1 H, 3-Ha), 2.15 (m, 1 H, 3-Hb), 1.97-2.07 (m, 1 H, 4-Ha), 1.89-1.96 (m, 1 H, 4-Hb). Anal. Calcd for C17H19NO4: C, 67.76; H, 6.36; N, 4.65. Found: C, 67.57; H, 6.63; N, 4.93.
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19
General Procedure: To a mixture of proline 4 (1 equiv) and azide 8 (1.2 equiv) in a mixture of H2O and t-BuOH (1:1) in a microwave reaction tube were added copper turnings (0.2 equiv) and copper sulfate (0.7 equiv). The mixture was stirred for 15-20 min at 125 °C, using an irradiation power of 100 W with simultaneous cooling. It was then diluted with H2O and CH2Cl2 and the two layers were separated. The aqueous layer was extracted with CH2Cl2 and the combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by chromatography on silica gel to afford analytically pure proline 9.
20
1-Benzyl 2-Methyl (2
R
)-2-{[1-(4-Ethoxy-4-oxobutyl)-1
H
-1,2,3-triazol-4-yl]methyl}pyrrolidine-1,2-dicarboxylate (9c): R
f
0.28 (PE-Et2O, 1:1). 1H NMR (400 MHz, DMSO-d
6, 110 °C): δ = 7.52 (s, 1 H, triazole), 7.29-7.41 (m, 5 H, Ph), 5.12 (s, 2 H, CH
2Ph), 4.34 (t, J = 6.9 Hz, 2 H, NCH
2CH2CH2CO2Et), 4.08 (q, J = 7.1 Hz, 2 H, CH
2CH3), 3.63 (br s, 3 H, OMe), 3.46-3.58 [m, 2 H, C(2)CHH + 5-Ha], 3.23 [d, J = 14.6 Hz, 1 H, C(2)CHH], 3.02-3.10 (m, 1 H, 5-Hb), 2.24-2.32 (m, 1 H, 3-Ha), 2.27 (t, J = 7.3 Hz, 2 H, CH
2CO2Et), 2.02-2.10 (m, 3 H, 3-Hb + CH
2CH2CO2Et), 1.67-1.79 (m, 1 H, 4-Ha), 1.29-1.41 (m, 1 H, 4-Hb), 1.20 (t, J = 7.1 Hz, 3 H, CH2CH
3). Anal. Calcd for C23H30N4O6: C, 60.25; H, 6.59; N, 12.22. Found: C, 59.98; H, 6.90; N, 11.98.
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21a
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