Hexafluoro-2-propyl Esters in Peptide Synthesis^1a

The use of hexafluoro-2-propanol and its esters for peptide coupling reactions was investigated. Hexafluoro- 2-propyl esters of N-protected amino acids and peptides may be prepared without racemization by carbodiimide-mediated coupling of the carboxyl component with hexafluoro-2-propanol (HFP). In peptide coupling reactions HFP esters are about 10³ 4times less reactive than the corresponding p-nitrophenyl esters. In HFP, which is a powerful peptide solvent, more reactive acyl components are converted to HFP esters under base catalysis. Coupling in HFP is much slower than in dimethoxyethane or dimethylformamide. HFP esters are stable to conditions for removal of benzyloxycarbonyl protecting groups.