Structure-activity relationships of derivatives of the prototypical calcitonin gene-related peptide (CGRP) antagonist, CGRP(8-37), revealed benzylation of the histidyl residue in position 10 increases antagonistic potency 10-100-fold. The benzyl group was introduced in a 45% yield by global benzylation of resin-bound peptides after assembly on the MBHA-resin by solid phase peptide synthesis. Long-range coupling constants from 1H NMR experiments suggest benzylation occurred on the 4(5)-carbon of the histidyl's imidazole ring. In order to confirm the spectroscopically derived structure and improve isolated yields of the CGRP antagonists, attempts to prepare protected derivatives of 4(5)-benzyl-L-histidine that are suitable for SPPS will be reported. Specifically, a failed synthesis of N-a-Fmoc-(N-im-trityl)-4-benzyl-L-histidine (1  ) for SPPS using a Fmoc-protection strategy, will be presented. Ongoing efforts to prepare N-a-Boc-(N-t-BOM)-4-benzyl-L-histidine (2 ) for SPPS using a Boc/benzyl-protection strategy, will also be presented.

Preparation of protected derivatives of 4(5)-benzyl-L-histidine

248th National Meeting (2014)

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