3-Oxabicyclo[3.1.1]heptanes as Isosteres of <i>meta</i> -Substituted Benzene Rings

Replacement of the aromatic rings in drug candidates with isosteric rigid sp³-rich scaffolds can improve physicochemical properties, increase the chance of progressing the molecule in development, and open new chemical space. Isosteres of <i>meta</i>-substituted benzenes remain challenging due to the difficulty of mimicking the exit vector angles and bond distances. Herein, we report the synthesis of 1,5-disubstituted 3-oxabicyclo[3.1.1]heptanes (oxa-BCHeps), which can serve as saturated isosteres of <i>meta</i>-substituted phenyl rings with a similar geometric arrangement. This structural motif can be obtained under mild reaction conditions via acid-mediated isomerization of (2-oxaspiro[3.3]heptan-6-yl)methanols using catalytic quantities of pyridinium chloride (PyrHCl). We demonstrate the utility of this methodology by preparing various building blocks for use in medicinal chemistry and incorporating 3-oxa-BCHep into the anticancer drug sonidegib, improving its physicochemical properties, such as permeability, metabolic stability, and solubility.