Formation and degradation of urea derivatives in the azide method of peptide synthesis. Part 2. Acidolytic degradation of urea derivatives

Abstract

Treatment of Boc-Gly-Tyr-Ser-NH·CH(CH₂·CH₂·SMe)·NH·CO-Glu(OBu^t)-His-Phe-Arg-Trp-Gly-Lys-(Boc)-Pro-Val-Gly-Lys(Boc)-Lys(Boc)-Arg-Arg-NH₂ with trifluoroacetic acid for deprotection yielded not the desired octadecapeptide-related urea but an N^α-blocked tetradecapeptide. This unexpected degradation has been studied with Z-Gly-NH·CH(CH₂Ph)·NH·CO-Gly-OBu^t as a model compound to demonstrate that the urea derivative of general formula R¹CO·NH·CHR²·NH·CO·NHR³ decomposes to give R¹CO·NH₂ and NH₂·CO·NHR³ in the absence of scavenger and to give R¹CO·NH·CHR²R⁴ and NH₂·CO·NHR³ in the presence of scavenger R⁴H (anisole or 2-mercaptoethanol) when treated with an acid reagent, such as formic acid, trifluoroacetic acid, hydrogen fluoride, or hydrogen bromide in acetic acid. The urea derivative, which is a side product in the azide method of peptide synthesis, is thus degraded to smaller fragments which usually differ in size and nature from the desired peptide, so that the danger of contamination of peptide with urea may be eliminated if the coupling product is treated with acid before purification.