N (π)-2-Naphthylmethoxymethyl-Protected Histidines: Scalable, Racemization-Free Building Blocks for Peptide Synthesis

Histidine (His) racemizes with relative ease during peptide synthesis. One strategy to suppress this racemization is to protect the nitrogen atom of the imidazole moiety in His with a suitable protecting group. Among the numerous protecting groups that have already been tested, the p -methoxybenzyloxymethyl (PMBOM) group on the π-nitrogen atom effectively suppresses the racemization. However, a large-scale synthesis of N (π)-PMBOM-protected derivatives has hitherto been hampered by the requirement of a freshly prepared unstable reagent. Herein we report the synthesis of N (π)-2-naphthylmethoxymethyl (NAPOM)-protected His derivatives, which can be prepared on a gram scale and do not suffer from the aforementioned instability problems. Furthermore, these NAPOM-protected His derivatives suppress the racemization in Boc- and Fmoc-based peptide synthesis.