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DOI: 10.1055/s-2006-950255
Synthesis and Solid-Phase Applications of N-Tetrachlorophthaloyl (TCP) Side-Chain-Protected Amino Acids
Publication History
Publication Date:
09 October 2006 (online)
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.
Key words
tetrachlorophthaloyl - side-chain protection - amino acids - cyclic peptides - solid-phase synthesis
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References and Notes
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.
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).