C-H bond activation followed by carbon-carbon bond formation will become one of the most important new methods in synthesis. In contrast to many carbon-carbon bond-forming methods, C-H activation can be highly functional group tolerant and therefore should be applicable to the efficient synthesis of an enormous number of drugs and natural products that incorporate a variety of functionality. In addition, because almost every compound has a carbon-hydrogen bond, in terms of substrate availability, C-H activation cannot be surpassed.
Over the past few years we have collaborated with the Bergman group to develop new synthetic methods based upon C-H activation chemistry and are applying this chemistry to the efficient synthesis of natural products and drug candidates. For example, we have developed methods for the rapid construction of important multicyclic compounds by the intramolecular hydroarylation of alkenes (Figure 1).
Figure 1. Rapid preparation of complex, multicyclic compounds using C-H activation methods
In these efforts we have uncovered a novel mechanism for C-H activation and functionalization of nitrogen heterocyles whereby a rhodium carbene intermediate serves as the resting state of the catalyst (Figure 2). A representative structure of a rhodium carbene intermediate is shown in the Main Page graphic. We have subsequently applied our new catalyst system to the intermolecular alkylation and direct arylation of a wide range of aromatic and nonaromatic nitrogen heterocycles. These methods are noteworthy due to their high level of functional group compatibility and increasingly are being used by the pharmaceutical industry.
Figure 2. Novel rhodium carbene C-H functionalization intermediate
We have also identified very efficient catalysts for highly enantioselective intramolecular hydroarylation reactions (Figure 3). In ongoing efforts, we are applying the C-H activation methods that we have developed to the synthesis of important drugs and complex, bioactive natural products, including the first total synthesis of lithospermic acid and the efficient synthesis of potent new inhibitors of JNK3 kinase for the potential treatment of neurodegenerative diseases (Figure 4).
Figure 3. Highly enantioselective C-H activation and functionalization
Figure 4. Natural products and drug candidates synthesized by C-H activation methods