Jared C. Lewis
Department of Chemistry
The University of Chicago
5735 South Ellis AvenueChicago, IL 60637
2011 Searle Scholar
New Catalyst Systems for Efficient Chemical Synthesis
The practice of chemical synthesis has matured to a discipline capable of providing compounds of amazing complexity for biological, medical, and materials research, but the efficiency by which molecules are prepared, and thus the speed at which they are applied toward societal problems, is limited by a number of factors. Of these, extended synthetic sequences, isolation of intermediates, and low catalyst activity are particularly notable. Our research focuses on identifying solutions to these problems through the development of new catalyst systems for a variety of key chemical transformations. Small molecule transition metal catalysts, enzymes, and artificial metalloenzymes are being explored toward this end and comprise the three major areas of emphasis within the group.
New catalytic methods to functionalize C-H bonds continue to emerge at a rapid pace due to the potential improvements in both atom and step efficiency that these transformations could exhibit over traditional synthetic approaches. We are investigating the use of dual catalyst systems to enable remote functionalization of unactivated C-H bonds with regioselectivity imposed by supramolecular scaffolds. As part of this program, we are exploring the transmetallation of organic fragments between discrete late metal complexes and the compatibility of these relatively unexplored elementary reactions with various dual catalytic C-C bond-forming reactions, such as direct arylation and olefin hydroarylation.We are also pursuing a variety of enzymatic solutions for C-H bond hetero-functionalization. Enzymes are increasingly employed in large-scale syntheses of fine chemicals due to their high catalytic efficiency, high selectivity, and mild operating conditions. Perhaps the most attractive feature of these catalysts however, is their ability to be systematically optimized for a particular application using directed evolution. We are exploiting this property to engineer various halogenases for use in organic synthesis due to the importance of halogenated compounds as both building blocks and active pharmaceutical ingredients. We are using various rational and random mutagenesis schemes in order to expand the substrate scope and improve the practicality of these valuable catalysts.
Finally, we are developing new classes of artificial metalloenzymes, hybrid constructs comprised of protein scaffolds and metal catalysts, that can be expressed directly in E. coli. Optimization of artificial metalloenzymes using directed evolution will thus be possible for the first time, and this capability will be used to produce highly active enzymes for in vitro and in vivo transition metal catalysis. Initially, we will focus on incorporating privileged transition metal catalysts into protein scaffolds to generate bioorthogonal variants of known reactions. We then hope to demonstrate that scaffolds can be used to augment the reactivity of metal catalysts in order to access new reactions not possible in the absence of the scaffold protein. Ultimately, these enzymes will be utilized in metabolic engineering efforts for the biosynthesis of natural product derivatives and even completely synthetic compounds. Such an approach would greatly facilitate the synthesis of complex molecules and enable exciting collaborations to explore the biological activity of these compounds.
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