Solid-phase synthesis of C-terminal peptide amides using a photoremovable α-methylphenacylamido anchoring linkage

Abstract

Polymer-supported solid-phase synthetic procedures have been developed for the synthesis of C-terminal peptide amides using a new photolytically removable α-methylphenacylamido anchoring linkage between the polymeric support and the growing peptide. The preparation of this new polymeric support involves a four-step polymer-analogous reaction starting from 2%-divinylbenzene-crosslinked polystyrene resin. The steps involved are (i) Friedel-Crafts reaction with 2-bromopropionyl chloride to give the 2-bromopropionyl resin, (ii) reaction of the 2-bromopropionyl resin with potassium phthalimide to give the phthalimidomethyl resin, (iii) hydrolysis with alcoholic potash to give the partially hydrolysed phthalamido resin and (iv) treatment with alcoholic HCl to give the 2-aminopropionyl resin. N-protected amino acids undergo coupling with this amino resin by the dicyclohexylcarbodiimide-mediated coupling. The acylated resins on irradiation at 350 nm in DMF released the attached carboxyl function in the C-terminal amide form. The mechanism of the photolytic deprotection involves a radical scission of the amide linkage adjacent to the phenacyl group. The synthetic utility of the new resin has been illustrated by the preparation of several N-protected amino acid amides and the C-terminal peptide amides, Boc-Pro-Val-NH₂, Boc-Gly-Phe-Pro-NH₂ and Boc-Leu-Ala-Gly-Val-NH₂ in 70–74% yield.