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Enantioselective synthesis of a tricyclic, sp³‐rich diazatetradecanedione: an amino acid‐based natural product‐like scaffold

Bischoff, Matthias ; Mayer, Peter ; Meyners, Christian ; Hausch, Felix (2020)
Enantioselective synthesis of a tricyclic, sp³‐rich diazatetradecanedione: an amino acid‐based natural product‐like scaffold.
In: Chemistry – A European Journal, 26 (21)
doi: 10.1002/chem.201905144
Article, Bibliographie

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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 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.

Item Type: Article
Erschienen: 2020
Creators: Bischoff, Matthias ; Mayer, Peter ; Meyners, Christian ; Hausch, Felix
Type of entry: Bibliographie
Title: Enantioselective synthesis of a tricyclic, sp³‐rich diazatetradecanedione: an amino acid‐based natural product‐like scaffold
Language: English
Date: 2020
Place of Publication: Weinheim
Publisher: Wiley-VCH
Journal or Publication Title: Chemistry – A European Journal
Volume of the journal: 26
Issue Number: 21
DOI: 10.1002/chem.201905144
Corresponding Links:
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.

Alternative Abstract:
Alternative abstract Language

sp³-Enriched scaffolds: Using simple amino acids, an elaborated synthesis was designed to construct a rigid tricyclic scaffold consisting of six-, seven- and eight-membered rings.

English
Uncontrolled Keywords: amino acids, diastereoselective epoxidation, FK506-binding protein, natural products, sp³−sp² Negishi coupling
Classification DDC: 500 Science and mathematics > 540 Chemistry
Divisions: 07 Department of Chemistry
07 Department of Chemistry > Clemens-Schöpf-Institut > Fachgebiet Biochemie
Date Deposited: 24 Jan 2024 07:26
Last Modified: 24 Jan 2024 07:26
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