A Tetra-Orthogonal Strategy for the Efficient Synthesis of Scaffolds Based on Cyclic Peptides

We have developed a straightforward and robust strategy for synthesizing a family of cyclic peptide scaffolds for the presentation of defined moieties in a wide range of orientations. Specifically we are exploring quinoxaline as the moiety, as a potential nucleic acid binding motif. The method requires the use of four degrees of orthogonality, which in turn allow the extension of the main chain, incorporation of the target side chains, on-resin cyclization, and the revelation of an amino group upon cleavage to increase solubility. We show that related approaches fail for a range of reasons, including the failure of cyclization. Following the optimization of the approach with a single cyclic peptide, we synthesized a family of all possible bis and tris quinoxaline adducts showing by ESI–MS that the desired full length cyclic product is produced in a majority of cases. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s10989-017-9642-0) contains supplementary material, which is available to authorized users.