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Enantioselective Synthesis of a Tricyclic, sp 3 ‐Rich Diazatetradecanedione: an Amino Acid‐Based Natural Product‐Like Scaffold
Author(s) -
Bischoff Matthias,
Mayer Peter,
Meyners Christian,
Hausch Felix
Publication year - 2020
Publication title -
chemistry – a european journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.687
H-Index - 242
eISSN - 1521-3765
pISSN - 0947-6539
DOI - 10.1002/chem.201905144
Subject(s) - chemistry , stereochemistry , intramolecular force , enantioselective synthesis , piperidine , amide , stereoisomerism , ring (chemistry) , epoxide , combinatorial chemistry , natural product , molecule , organic chemistry , catalysis
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.