Click Chemistry: A Straightforward Route to Decorated Prolines

Abstract

The synthesis of α-substituted prolines has been accomplished by microwave-assisted Huisgen 1,3-dipolar cycloaddition between azides and orthogonally protected α-propynyl proline in the presence of Cu(I).

Key words

alkynes - amino acids - azides - α-substituted prolines - 1,2,3-triazoles

References and Notes

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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. Peredukov AS. Osipov SN. Synlett  2007,  136 
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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. Kugo Y. Kondo Y. Yamazaki T. Sato T. J. Chem. Soc., Perkin Trans. 1  1997,  3339 
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16

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-H_a), 3.59 (br s, 3 H, OMe), 3.51 (dt, J = 7.3, 10.2 Hz, 1 H, 5-H_b), 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-H_a), 2.15 (m, 1 H, 3-H_b), 1.97-2.07 (m, 1 H, 4-H_a), 1.89-1.96 (m, 1 H, 4-H_b). Anal. Calcd for C₁₇H₁₉NO₄: C, 67.76; H, 6.36; N, 4.65. Found: C, 67.57; H, 6.63; N, 4.93.

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-H_a], 3.23 [d, J = 14.6 Hz, 1 H, C(2)CHH], 3.02-3.10 (m, 1 H, 5-H_b), 2.24-2.32 (m, 1 H, 3-H_a), 2.27 (t, J = 7.3 Hz, 2 H, CH ₂CO₂Et), 2.02-2.10 (m, 3 H, 3-H_b + CH ₂CH₂CO₂Et), 1.67-1.79 (m, 1 H, 4-H_a), 1.29-1.41 (m, 1 H, 4-H_b), 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.