Two Southern California research teams joined efforts to reveal the mechanistic underpinnings of an unusually efficient carbon-carbon bond formation.
The reaction allowed drug-like molecules to be accessed with exquisite control over the stereochemistry.
High failure rates of drug candidates is partly responsible for the prevalent high cost of therapeutic drugs today. Medicinal chemistry studies have shown that current drug candidate pools are overpopulated by planar sp2-sp2 carbon-carbon bonds, leading to multiple relatively non-discriminant binding and toxicity. Natural-product-like molecules with more sp3-hybridized carbons and defined stereochemistry, on the other hand, are more likely to make it through the pipeline. Efficient synthetic methods that furnish sp3-sp3 carbon-carbon bonds with stereocontrol therefore stand to improve the “druglike-ness” of the candidate pools.
The Shenvi group at The Scripps Research Institute showed that unusually fast formation of sp3-sp3 carbon bonds can be achieved between two butenolide molecules under strongly basic conditions even at low temperature. This bond formation reaction is so efficient that it outcompetes proton transfer, which are among the fastest chemical processes known. In addition, the reaction creates two new fully substituted carbon stereocenters with good diastereoselectivity, which endows the synthesized molecules with diverse three-dimensional shapes as measured by their principal moments of inertia (PMI). A high-throughput screen found these synthesized molecular candidates to be selective and non-toxic inhibitors for the cGAS/STING cytosolic DNA sensing pathway, signaling their potential for the treatment of autoimmune disorders.
Using modern and robust computational chemistry methods, Houk and Cram Teacher-Scholar Dr. Shuming Chen (pictured right) at UCLA were able to identify the driving forces underlying the efficiency of this reaction. Their work revealed the exquisite electronic complementarity of the two reacting partners, showing that the carbon-carbon bond formation barrier was lowered due to excellent alignment of secondary orbitals and stabilizing π–π stacking. The novel synthetic method and mechanistic insight in this study provides a powerful paradigm for exploring the chemical space of natural-product-like molecules and accelerating the discovery of new life-saving drugs.
a, The carbon-carbon bond-forming transition state is stabilized by electronic complementarity and π–π stacking. Bond distances are shown in ångströms. b, A comparison of the principal moments of inertia (PMI) between a representative section of ChEMBL database and the molecules synthesized in this study.