A stereodivergent multicomponent approach for the synthesis of C–N atropisomeric peptide analogues

Roper, Natalie J.; Campbell, Aaron D. G.; Waddell, Paul G.; Brown, Alistair K.; Ermanis, Kristaps; Armstrong, Roly J.

Abstract

A four-component Ugi reaction is described for the stereoselective synthesis of novel C–N atropisomeric peptide analogues. Using this approach, a combination of simple, readily available starting materials (ortho-substituted anilines, aldehydes, carboxylic acids and isocyanides) could be combined to access complex products possessing both central and axial chirality in up to 92% yield and >95 : 5 d.r. Variation of the reaction temperature enabled the development of stereodivergent reactions capable of selectively targeting either diastereoisomer of a desired product from a single set of starting materials with high levels of stereocontrol. Detailed experimental and computational studies have been performed to probe the reaction mechanism and stereochemical outcome of these reactions. Preliminary studies show that novel atropisomeric scaffolds prepared using this method display inhibitory activity against M. tuberculosis with a significant difference in activity observed between different atropisomers.

Citation

Roper, N. J., Campbell, A. D. G., Waddell, P. G., Brown, A. K., Ermanis, K., & Armstrong, R. J. (2024). A stereodivergent multicomponent approach for the synthesis of C–N atropisomeric peptide analogues. Chemical Science, 15(40), 16743-16751. https://doi.org/10.1039/d4sc04700a

• Journal Article Type: Article
• Acceptance Date: Sep 15, 2024
• Online Publication Date: Sep 16, 2024
• Publication Date: Oct 28, 2024
• Deposit Date: Oct 22, 2024
• Publicly Available Date: Oct 22, 2024
• Journal: Chemical Science
• Print ISSN: 2041-6520
• Electronic ISSN: 2041-6539
• Publisher: Royal Society of Chemistry
• Peer Reviewed: Peer Reviewed
• Volume: 15
• Issue: 40
• Pages: 16743-16751
• DOI: https://doi.org/10.1039/d4sc04700a
• Public URL: https://nottingham-repository.worktribe.com/output/40250016
• Publisher URL: https://pubs.rsc.org/en/content/articlelanding/2024/sc/d4sc04700a