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

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. A convergent synthesis of a series of mono‐ and bifunctional 6‐fluoro‐spiro[3.3]heptanes‐advanced fluorine‐labelled conformationally rigid building blocks for medicinal chemistry is developed. The target products were obtained on a multigram scale (up to 302 g), characterized (pKa, LogP, and Sw), and assessed with the lead‐likeness criteria.