Synthesis of Difficult Cyclic Peptides by Inclusion of a Novel Photolabile Auxiliary in a Ring Contraction Strategy

Abstract

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.

Contemporary strategies for peptide macrocyclization

“…Another ring-contraction strategy involving lactones was developed by Meutermans, Smythe and co-workers and was applied to the head-to-tail cyclization of small peptides 75 . A salicylaldehyde-derived auxiliary is attached to the N-terminus of the peptide chain through reductive amination.…”

The cyclization of peptides and depsipeptides

“…A very interesting challenge to the conventional and orthogonal coupling strategy was set by the attempted synthesis [61] of all-L cyclo (Ala-Phe-LeuPro-Ala) from its linear precursor. Using conventional conditions, e.g.…”

A Gradient Descent Algorithm for Minimizing Amino Acid Coupling Reactions when Synthesizing Cyclic-Peptide Libraries

“…We have been interested in establishing solid-phase chemistries including new linkers, peptide cyclization auxiliaries, and synthetic strategies [8,[14][15][16] that allow the synthesis of libraries of cyclic peptides (head-to-tail) in a practical and versatile manner. This paper presents a gradient descent method for minimizing the number of coupling reactions required to synthesize the cyclic peptide library.…”