Unnatural Amino Acid Derivatives through Click Chemistry: Synthesis of Triazolylalanine Analogues

Published as part of the ISHC Conference Special Section

Abstract

A novel tert-butyl 2-(1-oxoisoindolin-2-yl)acetate derivative is selectively alkylated with propargyl bromide in the presence of lithium hexamethyldisilazide. After removal of the tert-butyl protecting group, the resulting N-isoindolinyl (ethynylalanine) derivative is reacted with a series of azides under ‘click conditions’. The click reactions afford an array of N-isoindolinyl- 1,2,3-triazolylalanine derivatives as the free carboxylic acids. Following esterification, the N-isoindolinone protecting group is then transformed into the more easily removable phthaloyl group by selective oxidation at the benzylic position.

Key words

amino acids - click chemistry - histidine - metal complexes - peptides - triazoles

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• 13 General Procedure for the Synthesis of Click Compounds 4–10 2-(1-Oxoisoindolin-2-yl)pent-4-ynoic acid (3, 50 mg, 0.22 mmol, 1 equiv ) was dissolved in THF followed by the addition of CuSO₄·5H₂O (5.44 mg, 0.022 mol, 0.1 equiv) and the corresponding azides (0.24 mmol, 1.1 equiv) at r.t. A freshly prepared solution of sodium ascorbate (21.6 mg, 0.11 mmol, 0.5 equiv) in H₂O (1 mL) was added to the reaction mixture and stirring was continued (16 h). After completion of reaction, the mixture was concentrated and the resulting crude residue was purified by gravity column chromatography (CHCl₃/MeOH, 3:1) to provide pure triazoles 4–10. 3-(1-Hexyl-1H-1,2,3-triazol-4-yl)-2-(1-oxoiso-indolin-2-yl)propanoic Acid (4) Off-white solid; 67 mg (86%); mp 138–140 °C; R_f = 0.44 (MeOH/CHCl₃, 2.5:7.5). FT-IR (neat): 3383, 2929, 2859, 1705, 1659, 1602, 1398, 1215 cm^–1. ¹H NMR (400 MHz, DMSO-d ₆): δ = 7.77 (s, 1 H), 7.61–7.56 (m, 3 H), 7.47–7.43 (m, 1 H), 4.83 (d, J = 9.2 Hz, 1 H), 4.76 (d, J = 17.2 Hz, 1 H), 4.42 (d, J = 17.2 Hz, 1 H), 4.23 (t, J = 6.8 Hz, 2 H), 3.50 (dd, J = 4.0 Hz, 15.6 Hz, 1 H), 3.11 (dd, J = 12.0 Hz, 14.8 Hz, 1 H), 1.70–1.62 (m, 2 H), 1.17–1.10 (m, 4 H), 1.08–1.05 (m, 2 H), 0.80 (t, J = 7.6 Hz, 3 H) ppm. ¹³C NMR (125 MHz, DMSO-d ₆): δ = 173.9, 168.2, 145.2, 142.8, 133.3, 131.3, 127.8, 123.6, 122.9, 122.5, 56.5, 49.5, 47.3, 30.9, 30.1, 27.4, 25.8, 22.3, 14.3 ppm. HRMS: m/z calcd for C₁₉H₂₄N₄O₃ [M + H]: 357.1921; found: 357.1919.
• 14 General Procedure for the Preparation of Esters 11–17 The corresponding click acids 4–10 were dissolved in MeOH (20 mL) followed by the addition of a catalytic amount of acetyl chloride. The reaction mixture was stirred overnight at r.t. After completion of the reaction, the reaction mixture was concentrated, and the oily residue was partitioned between CH₂Cl₂ (20 mL) and H₂O (15 mL). The CH₂Cl₂ layer was separated, dried over Na₂SO₄, and then concentrated to provide the corresponding esters 11–17 as clear colorless oils. Methyl 3-(1-Hexyl-1H-1,2,3-triazol-4-yl)-2-(1-oxoisoindolin-2-yl)propanoate (11) Colorless oil; 50 mg (84%); R_f = 0.70 (CHCl₃/MeOH, 8:2). FT-IR: 2954, 2930, 1740, 1683, 1469, 1210 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 7.74 (d, J = 7.2 Hz, 1 H), 7.49 (t, J = 7.2 Hz, 1 H), 7.41–7.37 (m, 3 H), 5.35 (dd, J = 4.8 Hz, 10.8 Hz, 1 H), 4.48 (d, J = 2.8 Hz, 2 H), 4.18 (td, J = 1.2 Hz, 7.2 Hz, 14.4 Hz, 2 H), 3.73 (s, 3 H), 3.50–3.44 (m, 2 H), 1.72 (q, J = 7.6 Hz, 2 H), 1.16–1.09 (m, 6 H), 0.78 (t, J = 6.8 Hz, 3 H) ppm. ¹³C NMR (175 MHz, CDCl₃): δ = 170.7, 169.2, 143.2, 141.8, 131.6, 128.0, 123.9, 123.7, 123.2, 121.4, 53.4, 52.7, 50.3, 47.5, 31.0, 30.1, 26.6, 25.9, 22.3, 13.8 ppm. HRMS: m/z calcd for C₂₀H₂₆N₄O₃ [M + H]: 370.2005; found: 370.2003.
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• 17 General Procedure for the Benzylic Oxidation of Isoindolinone-Protected Click Compounds 11–17 Giving Phthalimides 18–23 To a solution of isoindolinones 11–17 (1 equiv) in MeCN/H₂O (9:1) was added Oxone (5.0 equiv) and KBr (0.5 equiv). The resulting reaction mixture was allowed to reflux (16 h). After completion of the reaction, the reaction mixture was concentrated and the residue was partitioned between H₂O (15 mL) and CH₂Cl₂ (15 mL). The organic layer was separated, dried over anhydrous Na₂SO₄, and evaporated to obtain a crude residue which was further purified by column chromatography on silica gel (CHCl₃/MeOH, 9.5:0.5) to afford pure phthalimides 18–23. 2-(1,3-Dioxoisoindolin-2-yl)-3-(1-hexyl-1H-1,2,3-triazol-4yl)propanoic Acid (18) Colorless oil; 38 mg (91%); R_f = 0.57 (hexane/EtOAc, 1:1). FT-IR: 2925, 2856, 1775, 1744, 1711, 1386, 718, cm^–1. ¹H NMR (700 MHz, CDCl₃): δ = 7.80 (dd, J = 2.8 Hz, 5.6 Hz, 2 H), 7.70 (dd, J = 2.8 Hz, 5.6 Hz, 2 H), 7.32 (s, 1 H), 5.19 (dd, J = 4.9 Hz, 9.8 Hz, 1 H), 4.22–4.20 (m, 2 H), 3.76 (s, 3 H), 3.69–3.64 (m, 2 H), 1.77–1.74 (m, 2 H), 1.24–1.17 (m, 6 H), 0.83 (t, J = 7.0 Hz, 3 H) ppm. ¹³C NMR (175 MHz, CDCl₃): δ = 169.1, 167.3, 143.1, 134.1, 131.7, 123.5, 121.7, 52.9, 51.7, 50.2, 31.0, 30.1, 25.9, 25.4, 22.3, 13.9 ppm. HRMS: m/z calcd for C₂₀H₂₄N₄O₄ [M + H] 384.1798; found: 384.1608.

The spectral properties of 24 were identical with those previously reported:
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For a unique N-Boc-protected triazolyl alanine methyl ester derivative, see:
• 18b Boibessot T. Benimelis D. Jean M. Benfodda Z. Meffre P. Synlett 2016; 27: 2685