Fluorine-Labelled Spiro[3.3]heptane-Derived Building Blocks: Is Single Fluorine the Best?

Article abstract of DOI:10.1002/ejoc.202100804

A reliable methodology for constructing 6-fluoro-spiro[3.3]heptane scaffold is developed. A vast library of 2-mono- and 2,2-difunctionalized 6-fluoro-spiro[3.3]heptane-derived building blocks were obtained in a multigram scale (up to 302 g) though the convergent synthetic strategy. This class of compounds was designed for medicinal chemistry as fluorine-labelled conformationally restricted isosteres of cyclohexane framework. The structure was confirmed by X-ray diffraction study, and the physico-chemical properties (acidity, lipophilicity and water solubility) were characterized. Finally, the generation of virtual compound libraries using the LLAMA software showed that the monofluorinated spiro[3.3]heptane-derived building blocks demonstrated the highest propensity to populate the lead-like chemical space as compared to non- and difluorinated counterparts, as well as cyclohexane derivatives, while retaining similar three-dimensionality features.