Electronic complementarity permits hindered butenolide heterodimerization and discovery of novel cGAS/STING pathway antagonists

Although biaryl rings can be easily formed via cross coupling, their tetrahedral, high-fraction sp(3) equivalents cannot. Now the scope, mechanism and biological profile of a general attached-ring synthesis has been probed. This provides direct access to full bridgehead substitution via sp(3)-sp(3) coupling and enables rapid entry to natural product space. sp(3)-hybridized attached-rings are common motifs in secondary metabolites and represent tetrahedral equivalents to the biaryl substructures that overpopulate synthetic libraries. Few methods are available that can link fully substituted carbon atoms of two rings with stereocontrol. Here we have developed a stereoselective, heteroselective butenolide coupling that exhibits an unusually fast rate of C-C bond formation driven by exquisite complementarity of the reacting pi systems. Heterodimerization generates a compound collection with topological complexity and diverse principal moments of inertia. The special status of the sp(3)-sp(3) attached-ring motif is demonstrated in a high-throughput screen for inhibitors of the cyclic GMP-AMP synthase/stimulator of interferon genes pathway, which recruited these butenolide heterodimers from a field of 250,000 compounds. The driving forces underlying this general attached-ring coupling identify a novel paradigm for the accession of wider natural product chemical space, accelerating the discovery of selective lead compounds.