Taming Nitrene Reactivity with Silver Catalysts

Nitrene transfer (NT) is a convenient strategy to directly transform C–H bonds into more valuable C–N bonds and exciting advances have been made to improve selectivity. Our work in silver-based NT has shown the unique ability of this metal to enable tunable chemo-, site-, and stereoselective reactions using simple N-dentate ligand scaffolds. Manipulation of the coordination environment and noncovalent interactions around the silver center furnish unprecedented catalyst control in selective NT and provide insights for further improvements in the field.1 Introduction1.1 Strategies for Nitrene Transfer1.2 Brief Summary of Chemocatalyzed Nitrene Transfer1.3 Focus of this Account2 Challenges in Chemocatalyzed Nitrene Transfer2.1 Reactivity Challenges2.2 Selectivity Challenges2.3 Chemoselective Nitrene Transfer2.4 Site-Selective Nitrene Transfer2.5 Enantioselective Nitrene Transfer3 Summary and Perspective3.1 Future Opportunities and Challenges3.2 Conclusion

Bifunctional Small Molecule Ligands of K-Ras Induce Its Association with Immunophilin Proteins

Here we report the design, synthesis and characterization of bifunctional chemical ligands that induce the association of Ras with ubiquitously expressed immunophilin proteins such as FKBP12 and cyclophilin A. We show this approach is applicable to two distinct Ras ligand scaffolds, and that both the identity of the immunophilin ligand and the linker chemistry affect compound efficacy in biochemical and cellular contexts. These ligands bind to Ras in an immunophilin-dependent fashion and mediate the formation of tripartite complexes of Ras, immunophilin and the ligand. The recruitment of cyclophilin A to GTP-bound Ras blocks its interaction with B-Raf in biochemical assays. Our study demonstrates the feasibility of ligand-induced association of Ras with intracellular proteins and suggests it as a promising therapeutic strategy for Rasdriven cancers.