Novel Bowl-shaped Catalysts for Selective C-H Functionalization

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. Particularly important in the current era is the development of new strategies to access chiral scaffolds as it is generally recognized that there are has been an overreliance on the use of planar scaffolds for drug candidates. Enantioselective C-H functionalization is the central focus of this proposal. It represents an exciting new approach but a major challenge has been how to control site-selectivity in substrates containing multiple C-H bonds. The Davies group pioneered the rhodium-catalyzed chemistry of donor/acceptor carbene intermediates and found that these carbenes are exceptionally effective as selective C-H functionalization. In order to maximize their synthetic potential, Davies designed chiral catalysts of different shapes and sizes to control the three dimensional shape of the products and which C-H bond will be functionalized. His first generation catalyst was effective at reacting at activated C-H bonds. His second generation catalysts were sterically demanding and could distinguish between primary, secondary and tertiary C-H bonds at unactivated site. The third generation catalysts described in this proposal are bowl-shaped catalysts and are capable of subtle site selectivity between very similar C-H bonds. The secondary structure of the bowl plays a critical role in the selectivity. The program over the next five years will evaluate four series of bowl-shaped catalysts with a range of challenging substrates. In addition, the systems will be optimized so that it can operate under extremely low catalyst loadings. Many of the targets are related to compounds of pharmaceutical interest and the Davies group will work closely with companies to ensure the new methodology is impactful in drug discovery and large scale process chemistry.