Synlett 2017; 28(14): 1729-1732
DOI: 10.1055/s-0036-1588510
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© Georg Thieme Verlag Stuttgart · New York

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

Pravin C. Patil
Department of Chemistry, University of Louisville, 2320 South Brook Street, Louisville, Kentucky 40292, USA   Email: Faluzz01@louisville.edu
,
Frederick A. Luzzio*
Department of Chemistry, University of Louisville, 2320 South Brook Street, Louisville, Kentucky 40292, USA   Email: Faluzz01@louisville.edu
› Author Affiliations
This work was financially supported by the NIH/NIDCR through grant 1RO1DEO23206
Further Information

Publication History

Received: 08 May 2017

Accepted after revision: 26 June 2017

Publication Date:
24 July 2017 (online)


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.

Supporting Information

 
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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 410. 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; Rf = 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 410 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 1117 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%); Rf = 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 1117 (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 1823. 2-(1,3-Dioxoisoindolin-2-yl)-3-(1-hexyl-1H-1,2,3-triazol-4yl)propanoic Acid (18) Colorless oil; 38 mg (91%); Rf = 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.

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