We have investigated new routes for the synthesis of acid-sensitive amino acids using N-fluorenylmethoxycarbonyl amino acids and mild acid labile side chain protection in order to avoid HF cleavage as final step. The 4-(benzyloxy)benzylamine resin, applied successfully by Pietta and Brenna, proved to be unsuitable for the synthesis of peptide amides since we have found that trifluoroacetic acid treatment of peptide-resins yielded the peptide still bearing a p-hydroxybenzyl group on the carboxamide nitrogen. We have successfully used the 2,4-dimethoxybenzhydrylamine support for the synthesis of peptide amides. Cholecystokinin octapeptide and GnRH were synthesized on the 2,4-dimethoxybenzhydrylamine resin and cleaved from the polymer with trifluoroacetic acid-thioanisole (4:1), and 95% trifluoroacetic acid containing phenol (2.5%) and dimethyl sulfide (2.5%), respectively. The final cleavage conditions had to be optimized in order to obtain good yields, suggesting that side chain protections of certain amino acids, possibly arginine and tryptophan, may have to be further refined.
ASJC Scopus subject areas
- Organic Chemistry