How we drifted into peptide chemistry and where we have arrived at

Abstract

The history of peptide chemistry in our group is described. It all started with the cyclic undecapeptide cyclosporin, the immunosuppressive compound, which is commercialised as Sandimmune ®/Neoral ® by Sandoz/Novartis, and which has revolutionized transplant medicine. The discovery that cyclosporin can be deprotonated to a hexalithio derivative, and thus C-alkylated on a sarcosine moiety, led us into a research project on peptide modifications. We defined structural prerequisites for the use of peptide enolates and for electrolytic decarboxylation of peptides. Parallel to these activities, the group was engaged in developing synthetic methodologies aimed at stereoselective preparations of α-, β-, and γ-amino acid derivatives (cf. diastereoselective alkylations, self regeneration of stereogenic centers, axially chiral enolates). A third avenue into peptide chemistry originated from our investigations on the biopolymer PHB (poly-3-hydroxybutanoic acid); the question arose ‘what happens upon replacement of chain-bound O by NH in the polyester?’ A brief summary is given of the results obtained in our ensuing discovery tour of β-peptides built of homologated proteinogenic amino acids. They form secondary structures with short chain lengths and they have unexpected physiological properties, rendering them candidates for peptidic drugs. The synthesis of β 3-peptides is straightforward, and in the meantime most of the Fmoc-protected building blocks are commercial. The β 2-homoamino acids are less readily available. Their preparation and the assembly of a β 2-eicosapeptide with the twenty proteinogenic side chains are discussed herein. The reasons for the chosen sequence and the strategy of what turned out to be a 159-step synthesis are described. Full experimental details are given for the preparation of the dimeric Fmoc-β 2hXaa(PG)-β 2hXaa(PG)-OH building blocks used, for their solid-phase coupling to two β 2-decapeptide segments, for the thioligation, and for the purification, isolation and spectroscopic characterization of the resulting 20mer. An outlook to future projects in the exciting field of β- and γ-peptide chemistry and biology is given.