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Synthesis of meta-substituted arene bioisosteres from [3.1.1]propellane

Nature volume 611, pages 721–726 (2022)Cite this article

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Abstract

Small-ring cage hydrocarbons are popular bioisosteres (molecular replacements) for commonly found para-substituted benzene rings in drug design1. The utility of these cage structures derives from their superior pharmacokinetic properties compared with their parent aromatics, including improved solubility and reduced susceptibility to metabolism2,3. A prime example is the bicyclo[1.1.1]pentane motif, which is mainly synthesized by ring-opening of the interbridgehead bond of the strained hydrocarbon [1.1.1]propellane with radicals or anions4. By contrast, scaffolds mimicking meta-substituted arenes are lacking because of the challenge of synthesizing saturated isosteres that accurately reproduce substituent vectors5. Here we show that bicyclo[3.1.1]heptanes (BCHeps), which are hydrocarbons for which the bridgehead substituents map precisely onto the geometry of meta-substituted benzenes, can be conveniently accessed from [3.1.1]propellane. We found that [3.1.1]propellane can be synthesized on a multigram scale, and readily undergoes a range of radical-based transformations to generate medicinally relevant carbon- and heteroatom-substituted BCHeps, including pharmaceutical analogues. Comparison of the absorption, distribution, metabolism and excretion (ADME) properties of these analogues reveals enhanced metabolic stability relative to their parent arene-containing drugs, validating the potential of this meta-arene analogue as an sp3-rich motif in drug design. Collectively, our results show that BCHeps can be prepared on useful scales using a variety of methods, offering a new surrogate for meta-substituted benzene rings for implementation in drug discovery programmes.

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Fig. 1: Comparison of para- and meta-substituted arene bioisosteres, and synthesis of [3.1.1]propellane.
Fig. 2: Theoretical analysis of [1.1.1] and [3.1.1]propellane reactivity and synthesis of BCHeps from [3.1.1]propellane.
Fig. 3: BCHep functionalization and topological analysis of crystalline derivatives.
Fig. 4: Synthesis of BCHep pharmaceutical analogues and comparison of pharmacokinetic profile and metabolic stability.

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Acknowledgements

N.F. thanks Studienstiftung des Deutschen Volkes e.V. for a scholarship. J.N. thanks the Marie Skłodowska-Curie actions for an Individual Fellowship (GA No 786683). E.A.A. and A.J.S. thank the EPSRC for support (grant nos EP/S013172/1 and EP/T517811/1). B.R.S., A.J.S. and H.D.P. thank the EPSRC Centre for Doctoral Training in Synthesis for Biology and Medicine for studentships (EP/ L015838/1). T.Z.-T., T.G. and P.E.B. thank Alzheimer’s Research UK for support (grant no. ARUK-2021DDI-OX). P.R. thanks the Deutsche Akademie für Naturforscher Leopoldina for a fellowship.

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Authors and Affiliations

  1. Chemistry Research Laboratory, Department of Chemistry, University of Oxford, Oxford, UK

    Nils Frank, Jeremy Nugent, Bethany R. Shire, Helena D. Pickford, Patrick Rabe, Alistair J. Sterling, Amber L. Thompson, Christopher J. Schofield, Fernanda Duarte & Edward A. Anderson

  2. Alzheimer’s Research UK Oxford Drug Discovery Institute, Centre for Medicines Discovery, Nuffield Department of Medicine, Oxford, UK

    Tryfon Zarganes-Tzitzikas, Thomas Grimes & Paul E. Brennan

  3. Abbvie Drug Discovery Science & Technology (DDST), North Chicago, IL, USA

    Russell C. Smith

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Contributions

E.A.A., N.F., J.N. and A.J.S. conceived the project. Experimental work was carried out by N.F., J.N., B.R.S., P.R., T.Z.-T. and T.G. H.D.P. and A.L.T. collected the crystallographic data. N.F. and A.J.S. carried out the computational analysis. The project was supervised by E.A.A., F.D., P.E.B. and C.J.S. E.A.A., N.F., J.N. and F.D. wrote the initial manuscript which was reviewed and edited by E.A.A., N.F., J.N., R.C.S., P.E.B. and F.D.

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Correspondence to Edward A. Anderson.

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Supplementary Information

Supplementary Sections 1–18 containing materials and methods, procedures, crystallographic data, further computational analysis, peptide labelling studies, evaluation of ADME properties, unsuccessful reactions, coordinates and spectra data.

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Physicochemical and pharmacokinetic property data. Deposited in the Oxford Research Archive.

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Frank, N., Nugent, J., Shire, B.R. et al. Synthesis of meta-substituted arene bioisosteres from [3.1.1]propellane. Nature 611, 721–726 (2022). https://doi.org/10.1038/s41586-022-05290-z

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