im-Trityl protection of histidine

Abstract

A rational attempt to prepare FmocHis(piTrt)OH regiospecifically gave in fact the well-known tau-trityl isomer, and experiments with model systems indicate that the prospects for access to pi-trityl histidine derivatives, which would be of great value for the racemization-free synthesis of histidine-containing peptides, are poor.

Racemisation of Amino Acids: From Synthetic Challenge to Biological Significance

“…Histidine (His) is among the most racemisation-prone residues in peptide synthesis, in both Boc-and Fmoc-based strategies [22,[33][34][35]. Beyond the common oxazol-5(4H)-one-mediated pathway, His racemisation arises from its imidazolyl side chain, which contains two nitrogens (Nτ and Nπ) capable of intramolecular base catalysis.…”

“…Modern His building blocks typically protect Nτ, leaving Nπ partially reactive. The unshielded Nπ can catalyse α-proton abstraction during activation, forming cationic intermediates that tautomerise to enolates or reprotonate to yield racemates (Figure 6A) [22].…”

“…Additionally, certain electron withdrawing side chains, such as Cys, can facilitate intramolecular proton transfer, further promoting racemisation [21]. Basic conditions, including those encountered during ester hydrolysis, may also enhance α‐proton abstraction and contribute to racemisation at the stereogenic centre [22].…”