Enantioselective Synthesis of a Tricyclic, sp(3)-Rich Diazatetradecanedione: an Amino Acid-Based Natural Product-Like Scaffold

Bischoff, Matthias; Mayer, Peter; Meyners, Christian und Hausch, Felix (2020): Enantioselective Synthesis of a Tricyclic, sp(3)-Rich Diazatetradecanedione: an Amino Acid-Based Natural Product-Like Scaffold. In: Chemistry-A European Journal, Bd. 26, Nr. 21: S. 4677-4681

Abstract

6-, 7-, and 8-membered rings are assembled from a linear precursor by successive cyclisation reactions to construct a tricyclic diazatricyclo[6.5.1.0(4, 9)]-tetradecanedione scaffold. Advanced building blocks based on d-aspartic acid and l-pyroglutamic acid were combined by a sp(3)-sp(2) Negishi coupling. A carbamate-guided syn-diastereoselective epoxidation followed by an intramolecular epoxide opening allowed the construction of the piperidine ring. An efficient one-pot hydroxyl-group protection twofold deprotection reaction prepared the ground for the cyclisation to the bicycle. A final deprotection of the orthogonal protecting groups and lactamisation led to the novel, sp(3)-rich tricycle. The final compound is a substrate mimic of peptidyl-prolyl cis-trans isomerases featuring a locked trans-amide bond. Cheminformatic analysis of 179 virtual derivatives indicates favourable physicochemical properties and drug-like characteristics. As proof of concept we, show a low micromolar activity in a fluorescence polarisation assay towards the FK506-binding protein 12.

• Dokumententyp: Zeitschriftenartikel
• Fakultät: Chemie und Pharmazie > Department Chemie
• Themengebiete: 500 Naturwissenschaften und Mathematik > 540 Chemie
• ISSN: 0947-6539
• Sprache: Englisch