Collective synthesis of 1,2,4-trisubstituted, meta- and ortho-substituted arene bioisosteres from bicyclobutanes.

Replacing benzene rings with C(sp3)-rich bioisosteres to yield compounds with improved drug-like properties is an attractive strategy in medicinal chemistry. While many caged hydrocarbons have been validated as bioisosteres of ortho- and meta-disubstituted benzenes, 3D analogues of 1,2,4-trisubstituted benzenes-the second most prevalent benzenoid pattern in drugs-remain elusive because vector fidelity and enantioselective access are still formidable challenges. Here we report a practical route to (enantiomerically pure) 2-thiabicyclo[3.1.1]heptanes (thia-BCHeps) by cycloadditions of bicyclo[1.1.0]butanes with 1,4-dithiane-2,5-diol. This method produces cycloadducts with two and three exit vectors, which serve as promising bioisosteres for ortho-substituted and 1,2,4-trisubstituted benzenes, respectively. Moreover, the cycloadducts can be transformed into a diverse chemical space, including 1,5-disubstituted thiabicyclo[3.1.1]heptenes. Crystallographic analysis and a comparison of the pharmacokinetic properties, along with an evaluation of the biological activity of diflunisal, salicylanilide and the anticancer drug sonidegib, in relation to their 3D thia-BCHep analogues, demonstrate that the thia-BCHeps obtained can provide new surrogates for 1,2,4-trisubstituted, meta- and ortho-substituted benzene rings in drug discovery programmes.