Enantioselective Synthesis of a Tricyclic,sp3-Rich Diazatetradecanedione: an Amino Acid-Based Natural Product-Like Scaffold |
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Authors: | Dr Matthias Bischoff Dr Peter Mayer Dr Christian Meyners Prof?Dr Felix Hausch |
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Institution: | 1. Compound Management and Screening Center (COMAS), Max Planck Institute of Molecular Physiology, Otto-Hahn-Strasse 11, 44227 Dortmund, Germany;2. Department of Chemistry, Ludwig-Maximilians-University München, Butenandtstrasse 5–13, 81377 München, Germany;3. Department of Chemistry, Institute of Chemistry and Biochemistry, Darmstadt University of Technology, Alarich-Weiss-Strasse 4, 64287 Darmstadt, Germany |
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Abstract: | 6-, 7-, and 8-membered rings are assembled from a linear precursor by successive cyclisation reactions to construct a tricyclic diazatricyclo6.5.1.04, 9]-tetradecanedione scaffold. Advanced building blocks based on d -aspartic acid and l -pyroglutamic acid were combined by a sp3?sp2 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, sp3-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. |
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Keywords: | amino acids diastereoselective epoxidation FK506-binding protein natural products sp3?sp2 Negishi coupling |
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