Synthesis of difficult cyclic peptides by inclusion of a novel photolabile auxiliary 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 reactions of the C- and N- termini under high dilution conditions. Yields of such processes are highly dependent on the size of the ring being formed and on the particular amino acids of the linear precursor, giving rise to the well-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-Ala, which does not generate monocyclic product under conventional cyclization conditions, was used as a model to probe a range of auxiliaries. This has led to the development of a new photolabile peptide cyclization auxiliary. The 6-nitro-2-hydroxybenzyl group is readily and quantitatively introduced at the N-terminus via a reductive alkylation. Cyclization of the auxiliary-peptide initially proceeds through a cyclic nitrophenyl ester that preorganizes the peptide for lactamization. As the C- and N- termini are in close proximity, lactamization is achieved via an intramolecular O-N acyl transfer step to produce the N-substituted target cycle. The auxiliary is then removed by mild photolysis to produce the target cyclic peptide, cyclo-[Ala-Phe-Leu-Pro-Ala], in good yield. This strategy should find further useful applications in the assembly of libraries of small cyclic peptides.