Project Summary The development of new synthetic methods has the potential to transform how pharmaceutical drugs are made and even what types of compounds will be designed as potential targets. The synthetic accessibility is a crucial component in the design of drugs and entirely new synthetic strategies open up new vistas of potential targets for consideration. A transformation that has generated considerable recent interest is C-H functionalization, because it represents a different logic for how to join molecules together. One of the major challenges is to control the site selectivity in substrates containing multiple C-H bonds. A promising approach has been the rhodium-catalyzed reactions of donor/acceptor carbenes, which by using the right catalyst, will allow selective reactions to occur at either primary, secondary of tertiary C-H bonds. A major, limitation associated with this approach, however, is the narrow range of donor/acceptor carbenes that are currently used, primarily limited to carbenes derived from vinyl- aryl- and heteroaryldiazoacetates. This proposal focuses on the development of new types of donor/acceptor carbenes, which will greatly enhance the synthetic versatility of this promising methodology to access new chemical space. This will be achieved by expanding the range of functionality that can be associated with the donor/acceptor carbene chemistry, designing a new class of high symmetry bowl-shaped chiral catalysts, and illustrating new strategic opportunities for catalyst-controlled C-H functionalization applied to pharmaceutically relevant targets.