Overview


Research in the Lewis group focuses on identifying solutions to challenging synthetic 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. 

Developing these new functional materials requires a dynamic and highly interdisciplinary research environment. There are opportunities for rigorous training in organic and organometallic synthesis, protein engineering and evolution, molecular biology, structural and biophysical characterization of proteins, and computational modeling. Students are encouraged to exploit all of these tools to develop new catalysts for fundamentally important chemical transformations. 

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Project Areas


1) Protein Engineering and Directed Evolution. Enzymes are increasingly employed for chemical synthesis 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 (Fig. 1A). 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 (Fig. 1B/C). We are using structure-guided and directed evolution schemes to expand the substrate scope and improve the practicality of these valuable catalysts. We then explore structure function relationships in improved enzymes to help rationalize mechanisms for the observed improvements and to inform subsequent engineering efforts.

Fig. 1. A) General scheme for directed enzyme evolution.

B) Work-flow for structure-guided and directed evolution of halogenases.
C) Representative substrate scope of the halogenase RebH.

We are also pursuing several other enzymatic solutions for new C-H bond hetero-functionalization reactions. These efforts include genome mining for new halogenases and exploring non-native atom transfer reactions of various metalloenzymes. As part of these efforts, we also develop new evolution and mutagenesis methodologies, including continuous evolution, in collaboration with the Dickinson lab. Ultimately, we hope to port these enzymatic transformations into living organisms to facilitate chemical production in vivo.


2) Artificial Metalloenzymes. Many powerful reactions, particularly those catalyzed by non-biological metals, are not found in nature, so systems that combine the reactivity of metal catalysts with the evolvability and specificity of enzymes are highly sought after. To expand the scope of reactions are developing new classes of artificial metalloenzymes (ArMs), hybrid constructs comprised of protein scaffolds and metal catalysts (Fig. 2A).  Optimization of ArMs using directed evolution is being used to produce highly active enzymes for in vitro and in vivo transition metal catalysis.  We are focusing on incorporating privileged transition metal catalysts into protein scaffolds to generate bioorthogonal variants of known reactions.  This is illustrated by our recent work on dirhodium tetracarboxylate and manganese terpyridine ArMs (Fig. 2B/C). 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.

Fig. 2. A) General scheme for ArM formation, and B) Representative cofactors.


Fig. 3. Representative dirhodium ArM and ArM-catalyzed enantioselective cyclopropanation.


In parallel with our ArM design and evolution efforts, we are pursuing detailed mechanistic studies on the systems developed in our laboratory to date. These studies involve steady state kinetics, biophysical experiments (e.g. FRET, LC-MS/MS, NMR, UV/Vis, etc.), and computational simulation (MD, QM/MM in collaboration with the Roux group at Chicago). Beyond shedding light on the function of these complex and fascinating systems, these studies are intended to inform future design efforts aimed at improving ArM activity and selectivity for synthetic applications.


3) Transition Metal Catalysis. 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 (Fig. 1A).  Ultimately, we envision designing catalysts that can be incorporated into proteins to control metal reactivity and selectivity. As part of this program, we are exploring the transmetallation of organic fragments between discrete late metal complexes (Fig. 1B) and the compatibility of these relatively unexplored elementary reactions with various dual catalytic C-C bond-forming reactions (Fig. 1C/D), such as direct arylation and olefin hydroarylation. We have also begun investigating the mechanisms of complexes known to promote non-directed C-H functionalization. By understanding the nature of these systems, we hope to identify discrete complexes that can be incorporated into proteins in order to override the substrate control typically relied upon to provide selectivity in reactions catalyzed by these complexes.


Fig. 3. A) General scheme for dual catalytic functionalization of unactivated C-H bonds. B) Transmetallation of ligands between Ir and Pt complexes. C) Pd-catalyzed cross-coupling of organoiridium complexes and aryl iodides. D) Pd-catalyzed, Ir-promoted direct arylation of unactivated arenes.