Jared Lewis Assistant Professor
Born Effingham, Illinois, 1980.
University of Illinois at Urbana Champaign, B.S., 2002.
University of California, Berkeley, Ph.D., 2007.
California Institute of Technology, Postdoctoral Fellow, 2007-2010.
University of Chicago, Assistant Professor, 2011-.
2013, Chicago Biomedical Consortium Catalyst Award
2011, David and Lucile Packard Foundation Fellowship in Science and Engineering.
2011, Searle Scholar Award.
2010, NIH Pathways to Independence Award.
2007-2010, NIH National Research Service Award.
OFFICE: SCL 302, 5735 South Ellis Avenue, Chicago, IL 60637
PHONE: (773) 702-3546
FAX: (773) 702-0805
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, wasteful protection and deprotection steps, and low catalyst activity are particularly notable. Research in the Lewis group focuses on identifying solutions to these problems through the development of new catalysts 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.
1) 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.
2) 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 regio- and stereoselectivity, and extremely 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. Thus, while the activity of a given enzyme may or may not be particularly general (with respect to substrate scope for example), this activity is highly generalizable such that activity toward a desired substrate can be rapidly improved using successive rounds of mutagenesis and screening. 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.
3) 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.
Students can look forward to a dynamic and highly interdisciplinary group with a focus on developing new catalysts for fundamentally important chemical transformations. There will be opportunities for rigorous training in disciplines ranging from molecular biology to air-free organometallic synthesis, and students will be encouraged to exploit all of these tools in order to devise innovative approaches to chemical problems.
1. Yang, H.; Srivastava, P.; Zhang, C.; Lewis, J. C. A General Method for Artificial Metalloenzyme Formation via Strain-Promoted Azide-Alkyne Cycloaddition. ChemBioChem. In Press.
2. Lewis, J. C. Artificial Metalloenzymes and Metallopeptide Catalysts for Organic Synthesis. ACS Catal. 2013, 3, 2954-2975.
3. Durak, L. J. and Lewis, J. C. Transmetallation of Alkyl and Hydride Ligands From Cp*(PMe3)IrR1R2 to (cod)Pt/PdR3X. Organometallics 2013, 32, 3153-3156.
4. Payne, J. T.; Andorfer, M. C.; Lewis, J. C. Regioselective Arene Halogenation Using the FAD-Dependent Halogenase RebH. Angew. Chemie. Int. Ed. 2013, 125, 5379-5382.
5. Zhong, Z.; Yang, H.; Zhang, C.; Lewis, J. C. Synthesis and Catalytic Activity of Amino Acids and Metallopeptides with Catalytically Active Metallocyclic Side Chains. Organometallics, 2012, 31, 7328-7331.
6. McIntosh, J. A.; Coelho, P. S.; Farwell, C. C.; Wang, Z. J.; Lewis, J. C.; Brown, T. R.; Arnold, F. H. Enantioselective Intramolecular C-H Amination Catalysed by Engineered Cytochrome P450 Enzymes in vitro and in vivo. Angew. Chem. Int. Ed. 2013, 52, 9309-9312.
7. Lewis, J. C.; Coelho, P. S.; Arnold, F. H. Enzymatic Functionalization of Carbon-Hydrogen Bonds. Chem. Soc. Rev. 2011, 40, 2003-2021.
8. Lewis, J. C.; Mantovani, S. M.; Fu, Y.; Snow, C. D.; Komor, R. S.; Wong, C. H.; Arnold, F. H. Combinatorial Alanine Substitution Enables Rapid Optimization of Cytochrome P450BM3 for Selective Hydroxylation of Large Substrates. ChemBioChem. 2010, 11, 2502-2505.
9. Lewis, J. C.; Bastian, S.; Bennett, C. S.; Fu, Y.; Mitsuda, Y.; Chen, M. M.; Greenberg, W. A.; Wong, C.-H.; Arnold, F. H. Chemoenzymatic Elaboration of Monosaccharides Using Engineered Cytochrome P450 BM-3 Demethylases. Proc. Natl. Acad. Sci. U.S.A. 2009, 106, 16550-16555.
10. Lewis, J. C.; Bergman, R. G.; Ellman, J. A. Direct Functionalization of Nitrogen Heterocycles via Rh-Catalyzed C-H Bond Activation. Acc. Chem. Res. 2008, 41, 1013-1025.