Synthesis of Nonnatural Amino Acid Derivatives with Ni Complexes and Investigation of the Antifungal Activity of Their Dipeptide Derivatives

Abstract

A convenient synthesis of optically pure (S)-2-amino-3-(1-benzyl-1H-1,2,3-triazol-5-yl)-2-methylpropanoic acids via propargylated amino acids is reported. An (S)-2-amino-2-methylpent-4-ynoic acid–Ni–N-(2-benzoylphenyl)-1-benzyl-l-prolinamide complex was prepared and then functionalized by click-coupling reactions to give the corresponding (S)-2-amino-3-(1-benzyl-1H-1,2,3-triazol-5-yl)-2-methylpropanoic acid Ni complexes. Subsequently, these Ni complexes were cleaved to obtain the free (S)-2-amino-3-(1-benzyl-1H-1,2,3-triazol-5-yl)-2-methylpropanoic acids with excellent optical purities. Next, by using the activated ester method for peptide synthesis, N-Fmoc-(S)-(2-amino-3-(1-benzyl-1H-1,2,3-triazol-4-yl)-2-methylpropanoyl)glycine dipeptide was prepared. The nonnatural amino acids and dipeptides were tested for their biological activity and showed a selective high inhibitory activity against fungi.

Key words

nickel complexes - asymmetric alkylation - amino acids - antifungal agents

Publikationsverlauf

Eingereicht: 18. Januar 2025

Angenommen nach Revision: 10. Februar 2025

Accepted Manuscript online:
10. Februar 2025

Artikel online veröffentlicht:
26. März 2025

• References and Notes

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• 28 Complexes 4a–e; General Procedure CuI (0.109 mmol) and i-Pr₂NH (5.45 mmol) were added to a solution of the appropriate benzylic azide (1.3 mmol) in DMSO (4 mL), and the mixture was stirred for 20–30 min at r.t. Ni complex 3 (1.09 mmol) was then added, and the mixture was stirred at 80 °C under an inert atmosphere for 7–8 h until the starting material was consumed (TLC). The mixture was cooled to r.t., diluted with CH₂Cl₂, and washed with H₂O (×2). The organic layer was dried (Na₂SO₄), filtered, and concentrated under reduced pressure, and the residue was purified by column chromatography [silica gel, EtOAc–acetone (5:1)]. Amino Acids 5a–e; General Procedure The appropriate nickel complex 4a–e (0.4–1.1 mmol) was dissolved in MeOH (10–15 mL) and H₂O (5.0 mL) and 12 M aq HCl (1.50 mL) were added. The resulting mixture was stirred and heated at 60 °C for 40 min, while its color changed from red to green. The mixture was cooled to r.t., diluted with H₂O, and extracted with CH₂Cl₂ (×4). The aqueous layer was treated with 6% aq NH₃ to adjust its pH to 1. The amino acid was separated from the mixture by using a cation-exchange column (Dowex+) to give a white solid. (2S)-2-Amino-3-(1-benzyl-1H-1,2,3-triazol-4-yl)-2-methylpropanoic Acid (5a) Prepared from 4a (520 mg, 0.761 mmol) as a white solid; yield: 170 mg (0.653 mmol, 86%; ee > 99%); mp 155–157 °C, [α]_D ²⁰ +14.569 (c 0.151, 6 M aq HCl). ¹H NMR (300 MHz, DMSO): δ = 7.92 (s, 1 H), 7.36–7.25 (m, 5 H), 5.53 (s, 2 H), 3.29 (d, J = 15.0 Hz, 1 H), 3.23 (d, J = 15.0 Hz, 1 H), 1.58 (s, 3 H). ¹³C NMR (75 MHz, DMSO): δ = –171.63, 135.49, 128.41, 127.84, 124.43, 116.54, 112.74, 58.69, 53.0, 32.37, 21.8. Anal. Calcd for C₁₃H₁₆N₄O₂ (260.29): C, 59.99; H, 6.20; N, 21.52. Found: C, 60.05; Н, 59.98; N, 21.40.