Preparation of head-to-tail cyclic peptides via side-chain attachment: implications for library synthesis.

Cyclic peptide mixtures represent a promising approach for drug lead discovery. Diversity can be expanded via changes in ring size, amide bond replacements, D- and L-natural and unnatural amino acids, and by the incorporation of beta-turn mimics and related conformational constraints. We expand the scope of our side-chain attachment/resin-bound cyclization strategy first developed using aspartic acid, asparagine, and elated acid-based attachments. In this report, we describe the preparation and use of Boc-Lys-OFm, Boc-Orn-OFm, and Boc-Dab-OFm. The synthetic strategies were verified by the independent synthesis of two small RGD-based cyclic mixtures, cyclo(Pro-Xxx-Lys-Arg-Gly-Asp), where Xxx = Ala, Ser, Leu, Tyr, using Boc-Asp-OFm, and then Boc-Lys-OFm for the initial resin-bound side-chain linkage. A new orthogonal synthetic approach to cyclic peptides, based on the use of the paranitrobenzyl (ONB) ester for alpha-carboxyl protection (selectively cleaved via SnCl2 reduction), was developed. It led to the successful synthesis of individual cyclic pentapeptides using serine (Boc-Ser-ONB), and tyrosine (Fmoc-Tyr-ONB) as the side chain-linked residues.