Synthesis of multicyclic peptides via CLiPS and oxime ligations

Abstract

Cyclic and multicyclic peptides are ubiquitous in Nature. They show interesting biological activities as for example antibacterial agents. Due to their constrained nature, they show improvements compared to their linear counterparts, such as higher metabolic stabilities, specificities and oral availabilities. Several methods have been developed to synthesize monocyclic peptides. Methods to further constrain peptides to bicyclic peptides have even found application in high-throughput library-based synthesis methods, such as phage display. While these advances have shown the importance of constraining a peptide to increase activity, there is still room for improvement. Adding peptide cycles, yielding tricyclic, or even higher multicycles, is a challenging objective where the current methodologies may fall short. In this thesis, the scaffold-assisted synthesis of tri-, tetra-, and pentacyclic peptides is described, using the sequential combination of CLiPS and oxime ligation as orthogonal ligation techniques. The CLiPS reaction is a well-known constraining technology, whereby nucleophilic cysteine thiolates react with scaffold-bound arylmethyl bromide electrophiles. Oxime ligation is a click-type reaction between an electrophilic aldehyde or ketone and a nucleophilic aminooxy group, forming an oxime linkage that can exhibit E/Z isomerism. There are two possible strategies to combine CLiPS with oxime ligation. In the first, the scaffold bears all electrophiles, while the peptides bear all nucleophiles. In the second strategy, the oxime groups are reversed, meaning that both the peptides and scaffolds contain both nucleophilic and electrophilic groups. Within this framework, our aim was to develop a one-pot procedure, to access isomerically pure multicyclic peptides