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Scholarly Interest Report
         
Zachary T. Ball
Associate Professor
Associate Professor of Chemistry
 
e-mail:Zachary.Ball@rice.edu
 
  • A.B. Chemistry (1999) Harvard University, Cambridge, MA
  • Ph.D. Chemistry (2004) Stanford University, Stanford, CA
 
Primary Department
   Department of Chemistry
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Department Affiliations
 
  • Center for Biological and Environmental Nanotechnology
  • Institute of Biosciences and Bioengineering
  • Smalley Institute for Nanoscale Science and Technology
  •  
    Websites
     Ball Group Website
     Ball Lab home page
     Ball Research Group
     
    Research Areas
     organic chemistry, catalysis, transition-metal chemistry, biological chemistry
     

    Research Statement

     

    1.   Rhodium metallopeptides.


    Polypeptides are the biological solution to ligand design for transition-metal catalysis. Metal cofactors within protein folds achieve reactivity that is generally inaccessible to traditional transition-metal catalysts. Efforts to understand these capabilities and apply them to new reactivity have been extensive: work by numerous groups has resulted in tremendous capabilities to build new metalloproteins with novel structure, spectroscopy, and other physical characteristics. However, designing new and useful reactivity and catalytic function has proven a daunting challenge. We have focused on designing metallopeptides with new catalytic capabilities that combine features of enzymes and traditional transition-metal catalysts. One crucial feature of biological catalysis that we have sought to emulate is the ability to override inherent chemical reactivity, performing site-specific chemistry in a functional-group-rich environment. From a practical perspective, exploring peptides as ligands for transition-metal catalysis facilitates (A) efficient screening of ligand diversity and (B) design of large-length-scale (nanometer) structure necessary for molecular recognition.


    Metallopeptide synthesis and structure. The lab has developed methods for direct metalation of carboxylate side chains of fully deprotected peptides. The resulting rhodium metallopeptides are stable in serum and are readily purified by RP–HPLC. We have developed protecting-group methods for the synthesis of metallopeptides with multiple carboxylates and demonstrated the ability of rhodium metalation to create or destroy helical structure.


    2. Rhodium metallopeptides that interact with proteins. A fundamental concept of our work in this area is the use of peptides as molecular recognition units to deliver a rhodium center to a specific site in a complex environment (Fig. 1). Localization allows both catalysis and metal-ligand interactions with peripheral side chains leading to stabilization of a protein-peptide interface.


    Proximity-driven modification of polypeptides. We set out to combine peptide-based molecular recognition with rhodium-based catalysis to allow site-specific modification of polyfunctional substrates such as peptides and proteins. Initial examinations focused on coiled-coil peptide substrates as models for protein interactions. We observed remarkable rate accelerations for tryptophan modification (>103). The true potential of this approach was revealed upon discovering that many other side chains—wholly unreactive with Rh2(OAc)4—are efficient substrates for proximity-driven modification.


    A new tool for site-specific protein modification. Initial peptide work has been extended to modification of whole proteins. In recombinant systems, we developed recognition elements that allow orthogonal modification of multiple proteins in lysate by judicious choice of catalyst. The ability to modify specific proteins in lysate is a remarkable and enabling attribute that speaks to the utility and robustness of our methods. These results have been extended to  entirely natural protein sequences, first with modification of the Myc bZip, and more recently with the Fyn SH3 domain. SH3 domains are a large class of medically relevant recognition motifs, and this result offers a new tool for site-specific functionalization of similar peptide-recognition domains.


    Potent hybrid organic–inorganic inhibitors. The other major goal of localization-induced metal function has been templating reversible metal-ligand with peripheral histidine, methionine, or cysteine near the binding site. This stabilizing interaction has enabled us to discover the most potent inhibitors yet reported for PDZ domains regulating CFTR function, and to demonstrate successful function in lysate.


    3.   Small-molecule catalysis. The ability to synthesize ligand diversity quickly and efficiently makes polypeptides an ideal platform for the discovery of new rhodium(II) catalysts. More recently, our efforts have focused on the role of axial ligands, peptides with non-traditional axial–equatorial coordination modes, and high-throughput catalyst discover methods.


     4.   Copper catalysis and other research. The group has developed novel copper catalysts for C–Si and C–H activation. For C–Si activation, we developed stable copper(I) fluoride complexes that efficiently transmetalate with silanes to afford organocopper compounds, in the first direct evidence of copper–silicon transmetallation from simple sp2silanes. This discovery has been extended to the development of catalytic methods employing silane activation. For C–H activation, we demonstrated a radical method based on atom-transfer ideas to achieve remote functionalization of unactivated sp3 C–H bonds. We have also received funding for two separate projects involving the synthesis of small molecules and responsive polymers for use in upstream oil research.

     
    Teaching Areas
     organic and biological chemistry
     
    Selected Publications
     Refereed articles
     

    Vohidov, F.; Knudsen, S. E.; Leonard, P. G.; Ohata, J.; Wheadon, M. J.; Popp, B. V.; Ladbury, J. E.; Ball, Z. T. "Potent and selective inhibition of SH3 domains with dirhodium metalloinhibitors." Chem. Sci., 6: 4778-4783.

     
     

    Ball, Z. T. "Molecular recognition in protein modification with rhodium metallopeptides." Curr. Opin. Chem. Biol. , 25: 98-102.


    doi:http://dx.doi.org/10.1016/j.cbpa.2014.12.017
     
     

    Minus, M. B.; Liu, W.; Vohidov, F.; Kasembeli, M. M.; Long, X.; Krueger, M.; Stevens, A.; Kolosov, M. I.; Tweardy, D. J.; Redell, M. S.; Ball, Z. T. "Rhodium(II) proximity-labeling identifies a novel target site on STAT3 for inhibitors with potent anti-leukemia activity." Angew. Chem. Int. Ed., 54: 13085-13089.

     
     

    Ohata, J.; Vohidov, F.; Aliyan, A.; Huang, K.; Marti, A. A.; Ball, Z. T. "Luminogenic iridium azide complexes." Chem. Commun., 51: 15192-15195.

     
     

    Ohata, J.; Vohidov, F.; Ball, Z. T. "Convenient analysis of protein modification by chemical blotting with fluorogenic "click" reagents." Mol. Biosyst. , 11: 2846-2849.

     
     

    Popp, B. V.; Miles, D. H.; Smith, J. A.; Fong, I. M.; Pasquali, M.; Ball, Z. T. "Stabilization and Functionalization of Single-Walled Carbon Nanotubes with Polyvinylpyrrolidone Copolymers for Applications in Aqueous Media." Polym. Sci., Part A: Polym. Chem. , 53: 337-343.


    doi:10.1002/pola.27365
     
     

    Vohidov, F.; Coughlin, J. M.; Ball, Z. T. "Rhodium(II) Metallopeptide Catalyst Design Enables Fine Control in Selective Functionalization of Natural SH3 Domains." Angew. Chem. Int. Ed., 54: 4587-4591.

     
     

    Vohidov, F.; Popp, B. V.; Ball, Z. T. "Designing enzyme-like catalysts: A rhodium(II) metallopeptide case study." Proceedings of the 24th American Peptide Symposium, 2015: 24-26.

     
     

    Coughlin, J. M.; Kundu, R.; Cooper, J. C.; Ball, Z. T. "Inhibiting prolyl isomerase activity by hybrid organic–inorganic molecules containing rhodium(II) fragments." Bioorg. Med. Chem. Lett. , 24: 5203-5206.


    doi:http://dx.doi.org/10.1016/j.bmcl.2014.09.068
     
     

    Kinzurik, M. I.; Hristov, L. V.; Matsuda, S. P. T.; Ball, Z. T. "Mixed Bioengineering–Chemical Synthesis Approach for the Efficient Preparation of Δ7-Dafachronic Acid." Org. Lett. , 16: 2188-2191.


    doi:10.1021/ol5006642
     
     

    R. Sambasivan; W. Zheng; S. J. Burya; B. V. Popp; C. Turro; C. Clementi; and Z. T. Ball "A tripodal peptide ligand for asymmetric Rh(II) catalysis highlights unique features of on-bead catalyst development." , ASAP (2014) : 1401–1407.


    http://dx.doi.org/10.1039/C3SC53354A
     
     

    Vohidov, F.; Coughlin, J. M.; Ball, Z. T. "Rhodium(II) Metallopeptide Catalyst Design Enables Fine-Control in Selective Functionalization of Natural SH3 Domains." Angew. Chem. Int. Ed.In Press


    doi:10.1002/anie.201411745
     
     

    R. Kundu, Z. T. Ball "A rhodium-catalyzed method for serum-stable cysteine modification." Chem. Commun., 49 (2013) : 4166-4168.


    http://dx.doi.org/10.1039/C2CC37323H
     
     

    R. Sambasivan and Z. T. Ball "Studies of asymmetric styrene cyclopropanation with a rhodium(II) metallopeptide catalyst developed with a high-throughput screen." , 25 (2013) : 493-497.


    http://dx.doi.org/10.1002/Chir.22144
     
     

    B. V. Popp, Z. Chen and Z. T. Ball "Sequence-specific Inhibition of a Designed Metallopeptide Catalyst." Chem. Commun., 48 (2012) : 7492-7494.

     
     

    R. Kundu, P. R. Cushing, B. V. Popp, Y. Zhao, D. R. Madden, and Z. T. Ball "Hybrid Organic-Inorganic Inhibitors of a PDZ Interaction that Regulates the Endocytic Fate of CFTR." Angew. Chem. Int. Ed., 51 (2012) : 7217-7220.


    http://dx.doi.org/10.1002/anie.201202291
     
     

    R. Sambasivan and Z. T. Ball "Determination of orientational isomerism in rhodium(II) metallopeptides by pyrene fluorescence." Org. Biomol. Chem., 10 (2012) : 8203-8206.


    http://dx.doi.org/10.1039/C2OB26667A
     
     

    R. Sambasivan and Z. T. Ball "Screening Rhodium Metallopeptide Libraries 'On Bead': Asymmetric Cyclopropanation and a Solution to the Enantiomer Problem." Angew. Chem. Int. Ed., 51 (2012) : 8568-8572.


    http://dx.doi.org/10.1002/anie.201202512
     
     

    R. Sambasivan, Z. T. Ball "Studies of asymmetric styrene cyclopropanation with a rhodium(II) metallopeptide catalyst developed with a high-throughput screen." Chirality, 25 (2013) : 493-497.In Press

     
     

    Z. Chen, F. Vohidov, J. M. Coughlin, L. J. Stagg, S. T. Arnold, J. E. Ladbury, and Z. T. Ball "Catalytic Protein Modiication with Dirhodium Metallopeptides: Specificity in Designed and Natural Systems." J. Am. Chem. Soc., 134 (2012) : 10138-10145.

     
     

    Z. T. Ball "Designing enzyme-like catalysts: a rhodium(II) metallopeptide case study." Acc. Chem. Res., 46 (2013) : 560–570.


    http://dx.doi.org/10.1021/ar300261h
     
     

    A. N. Zaykov and Z. T. Ball "A general synthesis of dirhodium metallopeptides as MDM2 ligands." Chem. Commun., 47 (2011) : 10927-10929.

     
     

    A. N. Zaykov, Z. T. Ball "Kinetic and stereoselectivity effects of phosphite ligands in dirhodium catalysts." Tetrahedron, 67 (2011) : 4397-4401.

     
     

    B. V. Popp, Z. T. Ball "Proximity-Driven Metallopeptide Catalysts: Remarkable Side-Chain Scope Enables Modification of the Fos bZip Domain." Chem, Sci., 2 (2011) : 690-695.

     
     

    Z. Chen, B. Popp, C. L. Bovet, Z. T. Ball "Site-specific protein modification with a dirhodium metallopeptide catalyst." ACS Chem. Biol., 6 (2011) : 920-925.

     
     

    Kundu, R.; Ball, Z.T. "Copper-Catalyzed Remote sp3 C–H Chlorination of Alkyl Hydroperoxides." Org. Lett., 12 (2010) : 2460–2463.

     
     

    Popp, B.V.; Ball, Z.T. "Structure-Selective Modification of Aromatic Side Chains with Dirhodium Metallopeptide Catalysts." J. Amer. Chem Soc, 132 (2010) : 6660–6662.

     
     

    Sambasivan, R.; Ball, Z.T. "Metallopeptides for Asymmetric Dirhodium Catalysis." J. Amer. Chem Soc, 132 (2010) : 9289-9291.

     
     

    V. Russo, J. R. Herron, Z. T. Ball "Allylcopper Intermediates with N-Heterocyclic Carbene Ligands: Synthesis, Structure, and Catalysis." Org. Lett., 12 (2010) : 220-223.

     
     

    Zaykov, A.N.; Popp, B.V.; Ball, Z.T. "Helix Induction by Dirhodium: Access to Biocompatible Metallopeptides with Defined Secondary Structure." Chem.—Eur. J., 16 (2010) : 6651 - 6659.

     
     

    A. N. Zaykov, K. R. MacKenzie, Z. T. Ball "Controlling Peptide Structure with Coordination Chemistry: Robust and Reversible Peptide-Dirhodium Ligation." Chem. Eur. J., 15 (2009) : 8961-8965.

     
     

    B. M. Trost, J. D. Sieber, W. Qian, R. Dhawan, Z. T. Ball "Asymmetric Total Synthesis of Soraphen A: A Flexible Alkyne Strategy." Angew. Chem. Int. Ed., 48 (2009) : 5478-5481.

     
     

    J. R. Herron, V. Russo, E. J. Valente, Z. T. Ball "Catalytic Organocopper Chemistry from Organosiloxane Reagents." Chem. Eur. J., 15 (2009) : 8713-8716.

     
     

    V. Russo, J. Allen, Z. T. Ball "Synthesis and isotopic labeling of a naturally occurring alkyl-thiadiamondoid." Chem. Commun. (2009) : 595-596.

     
     

    Jessica R. Herron and Zachary T. Ball "Synthesis and Reactivity of Functionalized Arylcopper Compounds by Transmetalation of Organosilanes." J. Amer. Chem. Soc., 130 (2008) : 16486-16487.

     
     Book chapters
     Ball, Z.T. Hydrosilylation of Alkynes and Related Reactions. In Comprehensive Organometallic Chemistry III; Crabtree, R. H. and Mingos, D. M. P., Eds.; Elsevier: Oxford 2006; vol. 10; pp 789-814.
     
     Other
     

    J. A. Gladysz, Z. T. Ball, G. Bertrand, S. A. Blum, V. M. Dong, R. Dorta, F. E. Hahn, M. G. Humphrey, W. D. Jones, J. Klosin, I. Manners, T. J. Marks, J. M. Mayer, B. Rieger, A. P. Sattelberger, J. M. Schomaker, and V. W.-W. Yam "Organometallics Roundtable 2011." Organometallics, 31 (2012) : 1-18.

     
    Presentations
     Invited Talks
     

    "Designing enzyme-like catalysts: A rhodium(II) metallopeptide case study." University of Virginia, Department of Chemistry, Charlottesville, VA. (Feb 2013)

     
     

    "Designing enzyme-like catalysts: A rhodium(II) metallopeptide case study." Trinity University, Department of Chemistry, San Antonio, TX. (Apr 2013)

     
     

    "Designing enzyme-like catalysts: A rhodium(II) metallopeptide case study." The Ohio State University, Department of Chemistry, Columbus, OH. (Feb 2013)

     
     

    "Designing enzyme-like catalysts: A rhodium(II) metallopeptide case study." Purdue University, Department of Medicinal Chemistry and Molecular Pharmacology, West Lafayette, IN. (Feb 2013)

     
     

    "Designing enzyme-like catalysts: A rhodium(II) metallopeptide case study." University of Georgia, Athens, GA. (Sep 2013)

     
     

    "Inhibiting protein–protein interactions with hybrid inorganic-organic rhodium complexes." ACS Southwest Regional Meeting, Waco, TX. (Nov 2013)

     
     

    "Catalysis with rhodium metallopeptides." Department of Chemistry, University of Wisconsin, Madison, Wisconsin. (February, 2012)

     
     

    "Catalysis with rhodium metallopeptides." Department of Chemistry, Brigham Young University, Provo, Utah. (March, 2012)

     
     

    "Catalysis with rhodium metallopeptides." Department of Chemistry, Texas Christian University, Fort Worth, Texas. (April, 2012)

     
     

    "Catalysis with rhodium metallopeptides." Department of Chemistry, Texas A&M University, College Station, Texas. (April, 2012)

     
     

    "Catalysis with rhodium metallopeptides." Department of Chemistry, University of Houston, Houston, Texas. (March, 2012)

     
     

    "Catalysis with rhodium metallopeptides." Department of Chemistry, University of Texas, Austin, Texas. (April, 2012)

     
     

    "Catalysis with rhodium metallopeptides." School of Pharmacy, University of Wisconsin, Madison, Wisconsin. (March, 2012)

     
     

    "Catalysis with rhodium metallopeptides." Twelfth International Conference on New Aspects of Organic Chemistry, Kyoto, Japan. (November, 2012)

     
     

    "Catalysis with rhodium(II) metallopeptides." Gordon Research Conference on Chemistry & Biology of Peptides, Ventura, California. (February, 2012)

     
     

    "Designing enzyme-like catalysts: A rhodium(II) metallopeptide case study." Department of Chemistry, University of Texas-San Antonio, San Antonio, Texas. (September, 2012)

     
     

    "Designing enzyme-like catalysts: A rhodium(II) metallopeptide case study." Department of Chemistry, University of Delaware, Newark, Delaware. (October, 2012)

     
     

    "Designing enzyme-like catalysts: A rhodium(II) metallopeptide case study." Department of Chemistry, University of Houston, Houston, Texas. (October, 2012)

     
     

    "Designing enzyme-like catalysts: A rhodium(II) metallopeptide case study." Department of Chemistry, University of West Virginia, Morgantown, West Virginia. (September, 2012)

     
     

    "Designing enzyme-like catalysts: a rhodium(II) metallopeptide case study." Department of Applied Chemistry, Osaka University, Osaka, Japan. (November, 2012)

     
     

    "Rhodium(II) metallopeptides for asymetric catalysis." Young Investigators Symposium, Chirality 2012 Conference, Fort Worth, Texas. (June, 2012)

     
     

    "Catalysis with rhodium(II) metallopeptides." University of Illinois at Chicago, Chicago, Illinois. (October, 2011)

     
     

    "Catalysis with rhodium(II) metallopeptides." Arizona State University, Tempe, Arizona. (September, 2011)

     
     

    "Catalysis with rhodium(II) metallopeptides." University of Arizona, Tucson, Arizona. (September, 2011)

     
     

    "Catalysis with rhodium(II) metallopeptides." 67th Southwest Regional Meeting of the American Chemical Society, Austin, Texas. (November 9, 2011)

     
     

    "Catalysis with rhodium(II) metallopeptides." University of Pittsburgh, Pittsburgh, Pennsylvania. (October, 2011)

     
     

    "Catalysis with rhodium(II) metallopepties." University of Illinois at Urbana-Champaign, Urbana, Illinois. (November, 2011)

     
     

    "Designing enzyme-like reactivity with dirhodium metallopeptides." International Conference on Biological Inorganic Chemistry ICBIC 15, Vancouver, Canada. (August 8, 2011)

     
     

    "Dirhodium metallopeptides as protein ligands." 242nd National Meeting of the American Chemical Society, Denver, Colorado. (August 28-September 1, 2011) With A. Zaykov

     
     

    "Diverse structures and functions of dirhodium metallopeptides." University of Maryland, College Park, Maryland. (May, 2011)

     
     

    "Diverse structures and functions of dirhodium metallopeptides." FGA Stone Symposium, Baylor University, Waco, Texas. (April 27, 2011)

     
     

    "Diverse structures and functions of dirhodium metallopeptides." Syracuse University, Syracuse, New York. (April, 2011)

     
     

    "Diverse structures and functions of dirhodium metallopeptides." SUNY - Buffalo, Buffalo, New York. (April, 2011)

     
     

    "Diverse structures and functions of dirhodium metallopeptides." Georgetown University, Washington, DC. (May, 2011)

     
     

    "Diverse structures and functions of dirhodium metallopeptides." Ohio State University, Columbus, Ohio. (March, 2011)

     
     

    "Structures and functions of dirhodium metallopeptides." Young Investigators Symposium, 242nd National Meeting of the American Chemical Society, Denver, Colorado. (August 29, 2011)

     
     

    "Proteins as substrates: Selective catalysis in complex environments." Department of Chemistry, University of South Florida, Tampa, Florida. (September, 2010)

     
     

    "Proteins as substrates: Selective catalysis in complex environments." Keith Fagnou Memorial Lectureship, Department of Chemistry, Ottawa University, Ottawa, Ontario, Canada. (November, 2010)

     
     

    "Proteins as substrates: Selective catalysis in complex environments." National Science Foundation Workshop on Organic Synthesis and Natural Products Chemistry, Squam Lake, New Hampshire. (July, 2010)

     
     

    "Proteins as substrates: Selective catalysis in complex environments." Department of Chemistry, Gonzaga University, Spokane, Washington. (October, 2010)

     
     

    "Amphiphillic Polyvinylpyrollidone-based Copolymers for Single-Walled Carbon Nanotube Wrapping." 2009 Fall Meeting of the Materials Research Society, Boston, Massachusetts. (December, 2009)

     
     

    "Dirhodium Metallopeptides." Department of Chemistry, Mesa State College, Grand Junction, Colorado. (December, 2009)

     
     

    "Copper Complexes for Carbon-Silicon Bond Activation." Gordon Research Conference on Organometallic Chemistry, Newport, Rhode Island. (July 6-11, 2008)

     
     

    "Synthesis and Reactivity of Organocopper Complexes from Organosilane Transmetallation." Southwest Catalysis Society Spring Meeting, Houston, Texas. (April 4, 2008)

     
     Keynote Speaker
     

    "Designing Enzyme-like Catalysts: A Rhodium(II) Metallopeptide Case Study." 2nd International Symposium on Molecular Activation, Nara, Japan. (November, 2012)

     
     Posters
     

    "Hybrid organic-inorganic inhibitors of PDZ interactions that regulate CFTR activity." Gordon Research Conference on Metals in Medicine, Andover, New Hampshire. (June, 2012)

     
     

    "Designed metallopeptides for protein functionalization and inhibition." Gordon Research Conference on Bioorganic Chemistry, Andover, New Hampshire. (June 8-11, 2011)

     
     Seminar Speaker
     

    “Designing enzyme-like catalysts: A rhodium(II) metallopeptide case study,” University of New Mexico, Albuquerque, NM.

     
     

    “Designing enzyme-like catalysts: A rhodium(II) metallopeptide case study,” Tufts University, Department of Chemistry, Medford, MA.

     
     Workshops
     

    “Peptides ligands and biological inspiration for selective chemical catalysis,”  The Future of Asymmetric Catalysis Workshop, Telluride CO.

     
    Supervised Theses & Dissertations
     Jessica Herron, Ph.D. Catalytic Organosilane Activation with Copper Complexes. (2012) (Thesis Director)

     Alexander Zaykov, Ph.D. Synthesis and Applications of Dirhodium Metallopeptides. (2012) (Thesis Director)

     Julian Cooper, B.S. "Strategic Design and Synthesis of Inhibitor Analogues for Signal Transducer and Activator of Transcription 3 (STAT3)". (2014) (Thesis Director)

     Ramya Sambasivan, Ph.D. Peptide ligands for asymmetric Rh(II) catalysis. (2015) (Thesis Director)

     Lachezar Hristov, B.S. A mixed bioengineering–chemical synthesis approach for the efficient preparation of ∆7-dafachronic acid. (2015) (Thesis Director)

     Rituparna Kundu, Ph.D. Developing Dirhodium-Complexes for Protei Inhibition and Modification & Copper-Catalyzed Remote Chlorination of Alkyl-Hydroperoxides. (Thesis Director)

    Awards, Prizes, & Fellowships
     CAREER Award, National Science Foundation, National Science Foundation (2011-2016)

     John L. Margrave Junior Faculty Innovation Award, Department of Chemistry, Rice University (2008)