Diastereoselective synthesis of highly substituted, amino- and pyrrolidino-tetrahydrofurans as lead-like molecular scaffolds

Wales, Steven M.; Merisor, Elena; Adcock, Holly; Pearce, Christopher A.; Strutt, Ian; Lewis, William; Hamza, Daniel; Moody, Christopher J.

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.

Citation

Wales, S. M., Merisor, E., Adcock, H., Pearce, C. A., Strutt, I., Lewis, W., …Moody, C. J. (2018). Diastereoselective synthesis of highly substituted, amino- and pyrrolidino-tetrahydrofurans as lead-like molecular scaffolds. Chemistry - A European Journal, 24(32), 8233-8239. https://doi.org/10.1002/chem.201801046

• Journal Article Type: Article
• Acceptance Date: Apr 10, 2018
• Online Publication Date: Apr 14, 2018
• Publication Date: Jun 7, 2018
• Deposit Date: May 10, 2018
• Publicly Available Date: Apr 15, 2019
• Journal: Chemistry - A European Journal
• Print ISSN: 0947-6539
• Electronic ISSN: 1521-3765
• Publisher: Wiley
• Peer Reviewed: Peer Reviewed
• Volume: 24
• Issue: 32
• Pages: 8233-8239
• DOI: https://doi.org/10.1002/chem.201801046
• Keywords: tetrahydrofurans; pyrrolidines; heterocycles; drug discovery; lead-oriented synthesis
• Public URL: https://nottingham-repository.worktribe.com/output/925224
• Publisher URL: https://onlinelibrary.wiley.com/doi/10.1002/chem.201801046
• Additional Information: This is the peer reviewed version of the following article: S. M. Wales, E. G. Merisor, H. V. Adcock, C. A. Pearce, I. R. Strutt, W. Lewis, D. Hamza, C. J. Moody, Chem. Eur. J. 2018, 24, 8233., which has been published in final form at https://dx.doi.org/10.1002/chem.201801046. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Use of Self-Archived Versions.