A guide to bullvalene stereodynamics †

Ives, Robert A.; Maturi, William; Gill, Matthew T.; Rankine, Conor; McGonigal, Paul R.

Abstract

Here, we analyze the stereodynamic properties of bullvalenes using principal moments of inertia and exit vector plots to draw comparisons with commonly used ring systems in medicinal chemistry. To aid analyses, we first classify (i) the four elementary rearrangement steps available to substituted bullvalenes, which (ii) can be described by applying positional descriptors (α, β, γ, and δ) to the substituents. We also (iii) derive an intuitive equation to calculate the number of isomers for a given bullvalene system. Using DFT-modelled structures for di-, tri-, and tetrasubstituted bullvalenes, generated using a newly developed computational tool (bullviso), we show that their 3D shapes and the exit vectors available from the bullvalene scaffold make them comparable to other bioisosteres currently used to replace planar aromatic ring systems in drug discovery. Unlike conventional ring systems, the shapeshifting valence isomerism of bullvalenes gives rise to numerous shapes and substituent relationships attainable as a concentration-independent dynamic covalent library from a single compound. We visualize this property by applying population weightings to the principal moments of inertia and exit vector analyses to reflect the relative thermodynamic stabilities of the available isomers.

Citation

Ives, R. A., Maturi, W., Gill, M. T., Rankine, C., & McGonigal, P. R. (2024). A guide to bullvalene stereodynamics †. Chemical Science, 15(36), 14608-14617. https://doi.org/10.1039/d4sc03700f

• Journal Article Type: Article
• Acceptance Date: Aug 23, 2024
• Online Publication Date: Aug 23, 2024
• Publication Date: Sep 28, 2024
• Deposit Date: Sep 9, 2024
• Publicly Available Date: Sep 9, 2024
• Journal: Chemical Science
• Print ISSN: 2041-6520
• Electronic ISSN: 2041-6539
• Publisher: Royal Society of Chemistry
• Peer Reviewed: Peer Reviewed
• Volume: 15
• Issue: 36
• Pages: 14608-14617
• DOI: https://doi.org/10.1039/d4sc03700f
• Public URL: https://durham-repository.worktribe.com/output/2777800