N-tetrachlorophthaloyl (TCP) protection for solid-phase peptide synthesis

The N-tetrachlorophthaloyl-(TCP-)amino protecting group has been evaluated for use in solid-phase peptide synthesis. The TCP group was unaffected by exposure to either piperidine or N,N-diisopropylethylamine (DIEA), which suggests compatibility with both Fmoc and Boc solid-phase synthesis protocols. Quantitative TCP removal was achieved by treatment with hydrazine/DMF (3:17) at 35 °C for 30 min or with ethylenediamine/DMF (1:200) at 50 °C for 30 min. Several C-terminal peptide amides were synthesized successfully by following protocols that use hydrazine/DMF (3:17) at 40 °C for 1 h for repetitive deprotection. Treatment of TCP-amines with methylamine or with diamines did not give the corresponding amines (deprotected), but rather the appropriate N,N′-disubstituted tetrachlorophthalamides, which corresponds to a single ring-opening step. This observation was harnessed to prepare linear and macrocyclic peptide-arene hybrids based on the mild reaction of the parent TCP compound with 1,3-diaminopropane/DMF (1:49) at 25 °C for 5 min.