Nitrogen-bridged, natural product-like octahydrobenzofurans and octahydroindoles: scope and mechanism of bridge-forming reductive amination via caged heteroadamantanes

Wales, Steven M.; Adcock, Holly V.; Lewis, William; Hamza, Daniel; Moody, Christopher J.

Abstract

The biological significance of sp3-rich synthetic scaffolds with natural product-like features yet distinct global frameworks is being increasingly recognised in medicinal chemistry and biochemistry. Taking inspiration from the vast array of bioactive, bridged alkaloids, we report the synthesis of unique, densely functionalised tricyclic scaffolds based on nitrogen-bridged, octahydrobenzofurans and octahydroindoles. These heterocycle-rich frameworks were assembled by a one-pot, two-step bridge-forming reductive amination process, which was shown to proceed via caged, heteroadamantane intermediates that thermodynamically drive an exo–endo epimerisation, enabling intramolecular azaMichael addition over the concave face of the fused bicyclic precursors. In addition to evaluating the scope of this aza bridge-forming reaction, further stereochemical complexity was introduced by subsequent diastereoselective ketone reductions and other manipulations. Finally, strategic diversity points (amino, carboxy) were decorated with common medicinal chemistry fragments, providing a set of exemplar derivatives with Lipinski compliant physicochemical properties.

Citation

Wales, S. M., Adcock, H. V., Lewis, W., Hamza, D., & Moody, C. J. (2018). Nitrogen-bridged, natural product-like octahydrobenzofurans and octahydroindoles: scope and mechanism of bridge-forming reductive amination via caged heteroadamantanes. European Journal of Organic Chemistry, 2018(34), 4696-4704. https://doi.org/10.1002/ejoc.201800962

• Journal Article Type: Article
• Acceptance Date: Jun 21, 2018
• Online Publication Date: Jun 25, 2018
• Publication Date: Sep 16, 2018
• Deposit Date: Jul 12, 2018
• Publicly Available Date: Jun 26, 2019
• Journal: European Journal of Organic Chemistry
• Print ISSN: 1434-193X
• Electronic ISSN: 1099-0690
• Publisher: Wiley
• Peer Reviewed: Peer Reviewed
• Volume: 2018
• Issue: 34
• Pages: 4696-4704
• DOI: https://doi.org/10.1002/ejoc.201800962
• Keywords: aza-Michael addition; bridged compounds; drug discovery; heterocycles; reductive amination
• Public URL: https://nottingham-repository.worktribe.com/output/941816
• Publisher URL: https://onlinelibrary.wiley.com/doi/abs/10.1002/ejoc.201800962
• Additional Information: This is the peer reviewed version of the following article: Wales, S. M., Adcock, H. V., Lewis, W. , Hamza, D. and Moody, C. J. (2018), Nitrogen‐Bridged, Natural Product Like Octahydrobenzofurans and Octahydroindoles: Scope and Mechanism of Bridge‐Forming Reductive Amination via Caged Heteroadamantanes. Eur. J. Org. Chem., 2018: 4696-4704, which has been published in final form at https://doi.org/10.1002/ejoc.201800962. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Use of Self-Archived Versions.
• Contract Date: Jul 12, 2018