Electronic complementarity permits hindered butenolide heterodimerization and discovery of novel cGAS/STING pathway
Benjamin J Huffman1, Shuming Chen2, J Luca Schwarz1
1Department of Chemistry, Scripps Research, La Jolla, CA, USA.
Abstract:
sp3-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 π systems. Heterodimerization generates a compound collection with topological complexity and diverse principal moments of inertia. The special status of the sp3-sp3 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.
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