Synthesis of N‐tert.‐butoxycarbonyl(α‐phenyl)aminomethylphenoxyacetic acid for use as a handle in solid‐phase synthesis of peptide α‐carboxamides

Abstract

N-tert-butoxycarbonyl-aminomethyl(.alpha.-phenyl)phenoxyacetic acid was synthesized and found to be suitable for use as a handle in the solid-phase synthesis of peptide .alpha.-carboxamides. This handle was prepared with an 82% yield when N-tert-butoxycarbonyl-(p-hydroxy)benzhydrylamine was treated with with excess sodium iodoacetate under alkaline conditions. In stability studies the linkage between the C-terminal amino acid and the handle was resistant to acidolysis in 50% trifluoroacetic acid/CH2Cl2 (< 1% loss after 10 h). Upon treatment for 30 min with HF:anisole(9:1) at 0.degree. C, 92% cleavage of glycinamide from Gly-handle-resin was obtained. In a test synthesis of a peptide .alpha.-carboxamide, pyroglutamylhistidylprolinamide [TRH] was synthesized in 83% yield. Two other handles, tert-butoxycarbonyl-aminomethylphenoxyacetic acid and N-tert-butoxycarbonyl-aminomethylphenyloxymethylphenoxyacetic acid, were also synthesized but were unsuitable for carboxamide synthesis under the same conditions of solid-phase synthesis.