A New Tri-Orthogonal Strategy for Peptide Cyclization

A solid phase tri-orthogonal protection/cleavage strategy that uses acidic, basic, and neutral conditions is described. Strategically protected α-azido-γ-9-fluorenylmethyl-l-glutamate (1) and α-azido-ε-N-Fmoc-l-lysine (2) were incorporated into growing peptides on Wang resin using a novel azide protection strategy. These residues, separated by 1−3 monomers, were deprotected at the side chains and cyclized via lactam formation. The N-terminus was further functionalized to extend the chain. This method represents a straightforward protocol for peptide cyclization on solid support.