Journal article
Diastereoselective Synthesis of Highly Substituted, Amino‐ and Pyrrolidino‐Tetrahydrofurans as Lead‐Like Molecular Scaffolds
Chemistry : A European Journal, Vol.24(32), pp.8233-8239
2018
PMID: 29656543
Abstract
A series of highly substituted tetrahydrofurans (THFs), decorated with modifiable 2‐aryl, 3‐carboxy and 4‐amino substituents, has been prepared for biological evaluation within the European Lead Factory. Diastereoselective reductive amination of pre‐functionalised 4‐oxofurans, readily prepared from cinnamate esters via oxa‐Michael/Dieckmann annulation, provided the requisite THF cores on gram scale with three contiguous stereocentres, including full substitution at C‐3. In a second series, a pyrrolidine ring was fused to the same oxofuran scaffold via an intramolecular reductive amination, inverting the configuration at C‐4 relative to the other ring substituents. The resulting compounds, which displayed desirable physical properties as lead‐like scaffolds, were derivatised into a small library of 24 compounds, demonstrating their ability to serve as starting points for drug discovery. Ultimately, this chemistry enabled the preparation of 1948 THF‐containing compounds for inclusion in the Joint European Compound Library.
Highly substituted tetrahydrofurans (THFs) and pyrrolidino‐THFs with three contiguous stereocentres in the form of orthogonally modifiable 2‐aryl, 3‐carboxy and 4‐amino substituents have been prepared. Divergent routes were developed to access these mono‐ and bicyclic scaffolds via a 4‐oxofuran intermediate, from which inter‐ and intramolecular reductive aminations, respectively, forged the key C−4−N bond. The resulting compounds exhibit desirable physical properties as lead‐like scaffolds for drug discovery.
Details
- Title
- Diastereoselective Synthesis of Highly Substituted, Amino‐ and Pyrrolidino‐Tetrahydrofurans as Lead‐Like Molecular Scaffolds
- Authors
- Steven M. Wales (Author) - University of NottinghamElena G. Merisor (Author) - Sygnature Discovery Ltd, BiocityHolly V. Adcock (Author) - Sygnature Discovery Ltd, BiocityChristopher A. Pearce (Author) - Sygnature Discovery Ltd, BiocityIan R. Strutt (Author) - Sygnature Discovery Ltd, BiocityWilliam Lewis (Author) - University of NottinghamDaniel Hamza (Author) - Sygnature Discovery Ltd, BiocityChristopher J. Moody (Corresponding Author) - University of Nottingham
- Publication details
- Chemistry : A European Journal, Vol.24(32), pp.8233-8239
- Publisher
- Wiley-VCH Verlag GmbH & Co. KGaA
- DOI
- 10.1002/chem.201801046
- ISSN
- 1521-3765
- PMID
- 29656543
- Organisation Unit
- Student Services and Engagement; School of Science, Technology and Engineering
- Language
- English
- Record Identifier
- 99707484302621
- Output Type
- Journal article