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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.

Authors

Steven M. Wales

Holly V. Adcock

William Lewis

Daniel Hamza

Christopher J. Moody



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. doi: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 http://eprints.nottingham.ac.uk/id/eprint/52907
Publisher URL https://onlinelibrary.wiley.com/doi/abs/10.1002/ejoc.201800962
Copyright Statement Copyright information regarding this work can be found at the following address: http://eprints.nottingham.ac.uk/end_user_agreement.pdf
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.

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Copyright Statement
Copyright information regarding this work can be found at the following address: http://eprints.nottingham.ac.uk/end_user_agreement.pdf





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