Small-ring containing molecules have recently seen increased interest as building blocks for drug design. Indeed, the movement of “escaping from flatland” has highlighted the usefulness of polycyclic molecules such as bicyclo[1.1.1]pentanes or bicyclo[2.2.2]octanes, to mimic para-substituted benzene rings.[1] While such aromatic replacements have been extensively studied, analogous approaches to rigidify flexible saturated counterparts remain largely underexplored. This led us to investigate whether bicyclo[2.1.0]pentanes, commonly known as housanes, could serve as replacements for cyclopentanes. Here, the isostere aims to rigidify the less stable conformer of the original scaffold, fixing it in the potentially more active geometry.[2]

Current methodologies for housane synthesis are limited either by the accessibility of starting materials (e.g. in diazine homolysis), or by the presence of electron withdrawing groups (e.g. in the transannular alkylation of cyclopentanes).[3] To overcome these limitations, we developed a carbo-metalation-cyclization sequence on carbonyl-substituted cyclopropenes.[4] The carbo-metalation step was rendered regioselective using electronically biased cyclopropenes and diastereoselective through chelation with the carbonyl species. The transient metal complex could then perform 4-exo-trig cyclization to afford the desired bicyclic scaffold.[5]

Key achievements of this work include: (1) high diastereoselectivity (d.r. > 20:1); (2) broad functional group tolerance as substituents (e.g. alcohols, amines, halides, nitriles); (3) gram-scalable applicability. Finally, we calculated geometrical parameters to demonstrate that our housane scaffold closely mimics di-substituted cyclopentanes and performed ring-opening reactions with nucleophiles to highlight their potential as covalent binders. 

[1] N. A. Meanwell. J. Med. Chem. 2011, 54, 2529-2591.
[2] R. C. Epplin, S. Paul, L. Herter, M. K. Brown. Nat. Commun. 2022, 13, 6056.
[3] D. Coto, D. Suárez-García, R. Vicente. Angew. Chem. Int. Ed. 2024, 63, e202409226.
[4] V. Smyrnov, J. Waser. Angew. Chem. Int. Ed. 2024, 63, e202404265.
[5] C. Tanguy, V. Smyrnov, M. Wodrich, J. Waser. J. Am. Chem. Soc. 2026, https://doi.org/10.1021/jacs.6c03013.