N‐Tetrachlorophthaloyl (TCP) Protection for Solid‐Phase Peptide Synthesis

Abstract

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. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2004)

An Optimized Protocol for the Synthesis of Peptides Containing trans‐Cyclooctene and Bicyclononyne Dienophiles as Useful Multifunctional Bioorthogonal Probes

“…Removal of TCP with EDA partially deprotected the Fmoc group as well, which is not an issue if both groups are detached at the final step from the solid support. However, and in contrast to literature, [20,22] in our hands the TCP functionality turned out to be unstable towards nucleophilic amines, such as piperidine or morpholine used during Fmoc and Alloc groups removal. Based on HPLC-MS results, the side product structure was proposed to derive from the nucleophilic attack of such amines to the phthalimide moiety (see ESI, Section 4d, Scheme S1).…”

“…Interestingly, the use of hydrazine (H2NNH2•H2O) for TCP deprotection was not suitable as both click groups were affected, mainly by reduction (see ESI, Section 4c). [20] During Alloc deprotection using Pd(0), the TCO group remained untouched when nucleophilic scavengers such as morpholine or dimethyl barbituric acid (DBA) were present, while other scavengers (SiHPr3, Me2N•BH3) led to decomposition of the click group (reduction was observed, among other side reactions). [21] On the other hand, the BCN group was not stable toward Pd(0) (partial reduction), regardless of the nature of the scavenger.…”

Protection Reactions

“…In fact, this cyclization has been used as the basis for the development of a mild protocol for preparation of phthalimides. Tetrachlorophthaloyl group is an improved analog of Phth and can be removed under mild conditions by treatment with 15% hydrazine in N,N 0 -dimethylformamide (DMF) for 1 h at room temperature [13].…”

Solid-Phase-Supported Approach for the Preparation of Bioresponsive and Multifunctional MRI Probes

“…If utilized, the most popular deprotection conditions involve hydrazine. 18 On the other hand, ethylene diamine is one attractive alternative due to its less harsh nature, increased reactivity, and overall safer use. 19 Procedures describing this method typically employ an excess of ethylene diamine in butanol or isopropanol at reflux.…”