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Synthesis of bicyclo[3.1.1]heptanes, meta-substituted arene isosteres, from [3.1.1]propellane

Nature Protocols volume 20, pages 2056–2082 (2025)Cite this article

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Abstract

The use of saturated small-ring bridged hydrocarbons as bioisosteres for aromatic rings has become a popular tactic in drug discovery. Perhaps the best known of such hydrocarbons is bicyclo[1.1.1]pentane, for which the angle between the exit vectors of the bridgehead substituents is identical to that of a para-substituted arene (180°). The development of meta-arene (bio)isosteres is much less explored due to the challenge of identifying an accurate geometric mimic (substituent exit vector angle ~120°, dihedral angle ~0°). To address this, we recently reported straightforward access to bicyclo[3.1.1]heptanes (BCHeps), which exactly meet these geometric properties, via radical ring-opening reactions of [3.1.1]propellane. This required the development of a scalable synthesis of [3.1.1]propellane, as well as the implementation of various ring-opening reactions and derivatizations. Here we describe methodology for a multigram scale synthesis of [3.1.1]propellane in five steps from commercially available ethyl 4-chlorobutanoate, which proceeds in an overall yield of 26–37%. We also describe the functionalization of [3.1.1]propellane to three key classes of BCHep iodides by photocatalyzed-atom transfer radical addition reactions using 456 nm blue light. We further report protocols for the elaboration of these products to other useful derivatives, via iron-catalyzed Kumada coupling with aryl Grignard reagents and conversion of a pivalate ester to a carboxylic acid through hydrolysis/oxidation. The total times required to synthesize [3.1.1]propellane, the BCHep iodides and the BCHep carboxylic acid are ~53, 6–8 and 40 h, respectively, requiring an average level of synthetic chemistry expertise (for example, masters and/or graduate students).

Key points

  • The bioisosteric replacement of benzene rings with saturated small ring bridged hydrocarbons is a rapidly evolving field of drug design due to, for example, improved solubility, membrane permeability and metabolic stability.

  • The bicyclo[3.1.1]heptane framework is an effective bioisostere for meta-substituted aromatic compounds. This protocol describes the synthesis of [3.1.1]propellane and its conversion to various bicyclo[3.1.1]heptane derivatives.

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Fig. 1: Small-ring bridged hydrocarbons as disubstituted benzene bioisosteres.
Fig. 2
Fig. 3: Overview of the protocol content.
Fig. 4
Fig. 5: ATRA reactions of [3.1.1]propellane.
Fig. 6: General photochemical experimental setup for small-scale reaction in a screw-cap vial.
Fig. 7: Overview of Procedure 3.

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Data availability

The authors declare that additional data related to this protocol are available in the ‘Key references using this protocol’. Analytical data for the different compounds described here are taken directly from the primary paper (see ‘Related links’) and are included in Supplementary Information (Supplementary Figs. 1–22).

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Acknowledgements

B.P. thanks the Marie Skłodowska-Curie actions for an Individual Fellowship (grant no. 101020227). N.F. thanks Studienstiftung des Deutschen Volkes e.V. for a scholarship. J.N. thanks the Marie Skłodowska-Curie actions for an Individual Fellowship (grant no. 786683). A.D. and E.A.A. thank the EPSRC for support (EP/S013172/1).

Author information

Authors and Affiliations

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

    Bhaskar Paul, Ayan Dasgupta, Nils Frank, Jeremy Nugent & Edward A. Anderson

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  1. Bhaskar Paul
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  2. Ayan Dasgupta
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  3. Nils Frank
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Contributions

B.P., A.D., N.F., J.N. and E.A.A. contributed intellectually and practically to the development of this protocol. The manuscript was written by B.P., A.D. and E.A.A. with input from all authors.

Corresponding author

Correspondence to Edward A. Anderson.

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Competing interests

The authors declare no competing interests.

Peer review

Peer review information

Nature Protocols thanks Pavel Mykhailiuk, Masanobu Uchiyama, Xiaheng Zhang and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Key references

Frank, N. et al. Nature 611, 721–726 (2022): https://doi.org/10.1038/s41586-022-05290-z

Nugent, J. et al. ACS Catal. 9, 9568–9574 (2019): https://doi.org/10.1021/acscatal.9b03190

Nugent, J. et al. Angew. Chem. Int. Ed. 59, 11866–11870 (2020): https://doi.org/10.1002/anie.202004090

Extended data

Extended Data Fig. 1 Synthesis of compound 3.

a) Initial experimental setup, b) Reaction flask with reagents, c) Dropwise addition of EtMgBr at 0 °C, d) At the end of EtMgBr addition (see TLC plate, inset), e) Reaction mixture in a separating funnel after quenching with H2SO4, and f) After extraction, drying of solution over MgSO4.

Extended Data Fig. 2 Synthesis of compound 4.

a) Addition of substrate to the nitrogen filled flask (see TLC plate, inset), b) Transfer of solvent through cannula, c) During the addition of MeSO2Cl, d) At the end of MeSO2Cl addition, e) At the end of rection (after 30 minutes stirring), and f) After quenching the reaction mixture with water.

Extended Data Fig. 3 Synthesis of compound 5.

a) Reaction flask on a stirrer plate, b) Flask with substrate (4) and CH2Cl2, c) After few drops addition of TiCl4, d) During addition of TiCl4, e) End of reaction (after 3 h stirring), (see TLC plate, inset) and f) After quenching the reaction mixture with water.

Extended Data Fig. 4 Synthesis of compound 6.

a) Reaction flask with substrate (5), TBAI, and CHBr3, b) Addition of NaOH at the beginning, c) After the addition of NaOH, d) Reaction mixture after 12 h stirring, e) Reaction mixture after extraction, and f) Purified compound 6 in a round-bottomed flask (see TLC plate, inset).

Extended Data Fig. 5 Synthesis of [3.1.1]propellane (1).

a) Nitrogen filled flask with stirrer bar, b) After addition of substrate (6), c) After the addition of Et2O, d) Reaction mixture −78 °C in a dry ice/acetone cooling bath, e) Syringing out PhLi solution (1.9 M in nBu2O), and f) Addition of PhLi solution to the reaction mixture, g) Reaction mixture after the addition of PhLi solution, and h) Reaction mixture after 7 h stirring.

Extended Data Fig. 6 Distillation of [3.1.1]propellane (1).

a) Dry-ice cold finger of rotary evaporator, b) Full setup of the distillation, c) After distillation of Et2O, d) After distillation of [3.1.1]propellane in nBu2O, e) Syringe out of [3.1.1]propellane solution from collection flask, and f) Storing of [3.1.1]propellane solution (1) in a acro-seal bottle.

Extended Data Fig. 7 Handling of [3.1.1]propellane solution (1).

a) [3.1.1]Propellane bottle held by a clamp, b) After removing the screw cap, c) Syringing out the solution with a nitrogen inlet attached, d) After resealing the bottle.

Extended Data Fig. 8 Experimental setup for compound 7 (section 1). a-e) Small-scale reaction in a screw cap vial.

a) Screw cap vial with a magnetic stirrer bar, iodomethyl pivalate and fac-Ir(ppy)3 catalyst, b) Reaction vial connected to the Schlenk line by a needle, c) Purging of the reaction mixture, d) Reaction vial on a photo reactor, and e) After the reaction (~5 h stirring). f-i) Preperative-scale reaction in a one-neck round-bottomed flask. f) Flask, magnetic stirrer bar, and Subaseal, g) Flask connected to the Schlenk line by a needle, h) After addition of [3.1.1]propellane solution and pivalonitrile, and i) After the photochemical reaction.

Extended Data Fig. 9 Grignard synthesis and Kumada coupling.

Panels a-b show Grignard; panels c-f for Kumada coupling. a) Reaction mixture after addition of I2, b) During heating of the reaction mixture, c) During addition of Grignard reagent 11 to the reaction mixture (for small-scale reaction in a screw cap vial), d) Flask with a stirrer bar, and Fe(acac)3, e) Stirring of reaction mixture after the addition of substrate (7), TMEDA, and THF under N2, and f) During addition of Grignard 11 to the reaction mixture.

Extended Data Fig. 10 Hydrolysis and oxidation reactions.

Panels a-c show hydrolysis; panels d-f show oxidation. Preparative-scale synthesis (a-b, and d-e), and small-scale synthesis (c and f). a) Flask with a magnetic stirrer, substrate (12), aq. NaOH solution and methanol, b) During heating of the reaction mixture, c) Heating of the reaction mixture in a screw cap vial. d) Flask with a magnetic stirrer, NaIO4, and solvent, e) After addition of RuCl3.xH2O, and f) Reaction mixture after 3 h stirring.

Supplementary information

Supplementary Information

This section contains 1H and 13C NMR spectra (Supplementary Figs. 1–20) of the key compounds described in this protocol.

Reporting Summary

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Paul, B., Dasgupta, A., Frank, N. et al. Synthesis of bicyclo[3.1.1]heptanes, meta-substituted arene isosteres, from [3.1.1]propellane. Nat Protoc 20, 2056–2082 (2025). https://doi.org/10.1038/s41596-024-01109-5

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