Synthesis and Solid-Phase Applications of N-Tetrachlorophthaloyl (TCP) Side-Chain-Protected Amino Acids

Abstract

The synthesis of Boc-Lys(TCP)-OH, Boc-d-Lys(TCP)-OH and Boc-Orn(TCP)-OH, and their application to the solid-phase synthesis of cyclic peptides and cyclic peptide-arene hybrids are described.

tetrachlorophthaloyl - side-chain protection - amino acids - cyclic peptides - solid-phase synthesis

References and Notes

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<A NAME="RD22706ST-9">9</A>

General Procedure for the Synthesis of TCP Side-Chain-Protected Amino Acids: A mixture of the corresponding N ^α-Boc protected amino acid (1 mmol), tetrachlorophthalic anhydride (1 mmol), Et₃N (4 mmol) and toluene (45 mL) was heated under reflux in a flask fitted with a Dean-Stark receiver for 6-9 h. Reactions were followed by TLC. The solvent was evaporated in vacuo and the residue was taken up in CHCl₃, washed with 5% aq citric acid, water, and brine. The organic solution was dried over anhyd MgSO₄ and concentrated in vacuo. Products were isolated by column chromatography and characterized by NMR, mass spectrometry, and elemental analysis. Their specific rotation was also determined. Selected compound Boc-Lys(TCP)-OH was obtained as a white powder; [α]²⁵ _D -9.6 (c = 1.0 DMF); mp 272.9-274.5 °C. ¹H NMR (200 MHz, CDCl₃): δ = 1.36 (s, 9 H), 1.36-1.55 (m, 2 H), 1.65-2.10 (m, 4 H), 3.63 (t, J = 7.0 Hz, 2 H), 4.20 (br s, 1 H), 4.99-5.03 (m, 1 H). ¹³C NMR (50 MHz, CDCl₃): δ = 22.5, 27.7, 28.2, 31.8, 38.3, 53.1, 80.2, 127.6, 129.6, 140.0, 155.0, 163.5, 176.9.
ESI-MS: m/z (%) = 510.8 (85), 512.8 (100), 514.7 (52)
[M - H]^-. Anal. Calcd for C₁₉H₂₀Cl₄N₂O₆: C, 44.38; H, 3.92; N, 5.45. Found: C, 44.00; H, 3.98; N, 5.37.

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<A NAME="RD22706ST-11">11</A>

As described in ref. 4, after Pd(PPh₃)₄ treatment, the peptidyl resins are washed with THF (3 × 2 min), DMF (3 × 2 min), CH₂Cl₂ (3 × 2 min), DIPEA-CH₂Cl₂ (1:19, 3 × 2 min), CH₂Cl₂ (3 × 2 min), sodium N,N-diethyldithiocarbamate (0.03 M in DMF, 3 × 15 min), DMF (5 × 2 min), and CH₂Cl₂ (3 × 2 min).