Stability of Side‐Chain Protecting Groups in Solid‐Phase Peptide Synthesis

Abstract The relative first‐order rates of deprotection of N∈‐benzyloxycarbonyllysine in 2%, 10%, and 50% trifluoroacetic acid in dichloromethane at 20° are 1, 50, and 1000, respectively. The N∈‐2‐chlorobenzyloxycarbonyl group is at least 60 times more stable than the N∈‐benzyloxycarbonyl group under solid‐phase conditions, because no branched peptides (< 0.2 mole%) were formed during synthesis of decalysylvaline using Nα‐tert‐butyloxycarbonyl‐N∈‐2‐chlorobenzyloxycarbonyllysine. Since O‐2‐chlorobenzylserine, Nim‐tosylhistidine, Nim‐2,4‐dinitrophenylhistidine and S‐4‐methylbenzylcysteine were completely stable in 50% trifluoroacetic acid–dichloromethane for over 200 h, these side‐chain protecting groups should be suitable for the solid‐phase synthesis of large peptides.