Synthesis of difficult cyclic peptides by inclusion of a novel photolabileauxiliary in a ring contraction strategy

Cyclic peptides comprise a large and important class of biologically active molecules. They are generally synthesized through amide bond-forming react ions of the C- and N- termini under high dilution conditions. Yields of suc h processes are highly dependent on the size of the ring being formed and o n the particular amino acids of the linear precursor, giving rise to the we ll-known sequence-dependent effect of cyclization. To overcome this problem , we have developed a peptide cyclization strategy that proceeds through a ring closure/ring contraction process. The linear peptide Ala-Phe-Leu-Pro-A la, which does not generate monocyclic product under conventional cyclizati on conditions, was used as a model to probe a range of auxiliaries. This ha s led to the development of a new photolabile peptide cyclization auxiliary . The 6-nitro-2-hydroxybenzyl group is readily and quantitatively introduce d at the N-terminus via a reductive alkylation. Cyclization of the auxiliar y-peptide initially proceeds through a cyclic nitrophenyl ester that preorg anizes the peptide for lactamization. As the C- and N- termini are in close proximity, lactamization is achieved via an intramolecular O-N acyl transf er step to produce the N-substituted target cycle. The auxiliary is then re moved by mild photolysis to produce the target cyclic peptide, cyclo-[Ala-P he-Leu-Pro-Ala], in good yield. This strategy should find further useful ap plications in the assembly of libraries of small cyclic peptides.