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Enantioselective Synthesis of a Tricyclic, sp3 -Rich Diazatetradecanedione: an Amino Acid-Based Natural Product-Like Scaffold.


ABSTRACT: 6-, 7-, and 8-membered rings are assembled from a linear precursor by successive cyclisation reactions to construct a tricyclic diazatricyclo[6.5.1.04,?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.

SUBMITTER: Bischoff M 

PROVIDER: S-EPMC7187416 | biostudies-literature | 2020 Apr

REPOSITORIES: biostudies-literature

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Enantioselective Synthesis of a Tricyclic, sp<sup>3</sup> -Rich Diazatetradecanedione: an Amino Acid-Based Natural Product-Like Scaffold.

Bischoff Matthias M   Mayer Peter P   Meyners Christian C   Hausch Felix F  

Chemistry (Weinheim an der Bergstrasse, Germany) 20200219 21


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<sup>4, 9</sup> ]-tetradecanedione scaffold. Advanced building blocks based on d-aspartic acid and l-pyroglutamic acid were combined by a sp<sup>3</sup> -sp<sup>2</sup> Negishi coupling. A carbamate-guided syn-diastereoselective epoxidation followed by an intramolecular epoxide opening allowed the construction of the piperidine ring. An efficient on  ...[more]

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