Enantioselective Photocatalytic Synthesis of Bicyclo[2.1.1]hexanes as Ortho-disubstituted Benzene Bioisosteres with improved Biological Activity

Title: Enantioselective photocatalytic synthesis of bicyclo[2.1.1]hexanes as ortho-disubstituted benzene bioisosteres with improved biological activity
Authors: Pablo Garrido-García, Irene Quirós, Paula Milán-Rois, Silvia Ortega-Gutiérrez, Mar Martín-Fontecha, Luis A. Campos, Álvaro Somoza, Israel Fernández, Thomas Rigotti and Mariola Tortosa
Journal: Nature Chemistry
Year: 2025
DOI: 10.1038/s41557-025-01746-7

1,5-Disubstituted bicyclo[2.1.1]hexanes are bridged scaffolds with well-defined exit vectors that are becoming increasingly popular building blocks in medicinal chemistry because they are saturated bioisosteres of ortho-substituted phenyl rings. Here we have developed a Lewis-acid-catalysed [2 + 2] photocycloaddition to obtain these motifs as enantioenriched scaffolds, providing an efficient approach for their incorporation in a variety of drug analogues. Retention of the biological activity of the bicyclo[2.1.1]hexane-containing analogues in the specific proteins targeted by the original drugs has confirmed the suitability of this moiety to serve as a bioisostere of ortho-substituted phenyl rings. Moreover, we have studied the potential of the different enantiomers of the drug analogues to selectively induce cytotoxicity in a panel of tumour cell lines, observing markedly differential effects for the two enantiomers and a substantial improvement over the corresponding sp2-based drugs. This showcases that the control of the absolute configuration and tridimensionality of the drug analogue has a large impact on its biological properties.