Amino Acids and Peptides. L. Development of a Novel Nπ-Protecting Group for Histidine, Nπ-2-Adamantyloxymethylhistidine, and Its Application to peptide Synthesis

Nα-tert-Butyloxycarbonyl-Nπ-2-adamantyloxymethylhistidine, Boc-His(Nπ-2-Adom)-OH, was prepared by the reaction of Boc-His (Nτ-Boc)-OMe with 2-adamantyloxymethyl chloride (2-Adom-Cl), followed by saponification. The 2-Adom group was stable to trifluoroacetic acid (TFA), 1 N NaOH and 20% piperidine/DMF and easily removed by 1 M trifluoromethanesulfonic acid-thioanisole/TFA and HF. This new protecting group suppressed recemization during peptide synthesis and exhibited high solubility in organic solvents. It was applied to the synthesis of thyrotropin-releasing hormone (TRH) using both solution and solid-phase methods. The Nπ-2-Adom group can be used for peptide synthesis in combination with the tert-butyloxycarbonyl group as the Nd-protecting group in both solution and solid-phase methods.