Acknowledgement I would like to thank my advisor Prof. Zachary T. Ball for teaching me everything I know in synthetic skills during my first year and guiding me through the rest of my time here at Rice. He has helped me better myself through constant constructive criticism, both in research and writing. I would also like to thank past and present Ball group members, Dr. Brian Popp, Dr. Alex Zaykov, Dr. Jessica Herron, Vincenzo Russo, Ramya Sambasivan, Cara Bovet, Zhen Chen, Dr. Jane Coughlin, Farrukh Vohidov, Matt Minus, Rob Ferguson, Julian Cooper. They have been a very good support in discussing research, exchanging ideas, and have become great pals in the last few years. Especially, Brian and Ramya’s encouragement in tough times is really valued. I thank my friends Rajkishore Barik and Meenu Adhikari for making Houston a second home. Again, Ramya Sambasivan for being a very good friend and always a willing ear to vent out frustrations associated with the graduate life and Avani Verma for bringing all kinds of fun in life and being so encouraging during my panic moments in thesis writing process. I would like to take this opportunity to express my gratitude and respect for my father Kuru Ram, and mother Amita Kundu, for the confidence and faith they always had in me, my sister Aruna Hajra who always supported me in my endeavors. I would like to thank my fiancée Soumya Sarkar, for his never wavering trust, love and support throughout my Ph.D in our 6 yr long, long- distance relation. Last but not least thanks to everyone who cared! -Rituparna Kundu Abstract Developing Dirhodium-Complexes for Protein Inhibition and Modification & Copper-Catalyzed Remote Chlorination of Alkyl-Hydroperoxides by Rituparna Kundu The work describes the development of a new class of protein-inhibitors for protein-protein interactions, based on metallopeptides comprised of a dirhodium metal center. The metal incorporation in the peptide sequence leads to high increase in binding affinity of the inhibitors. The source of this strong affinity is the interaction of histidine on the protein surface with the rhodium center. In addition to this work, rhodium-based small molecule inhibitors for FK-506 binding proteins are investigated. Also, methodology for rhodium-catalyzed modification of proteins containing surface cysteine has been developed where a simple rhodium(II) complex catalyzes cysteine modification with diazo reagents. The reaction is marked by clean cysteine selectivity and mild reaction conditions. The resulting linkage is significantly more stable in human plasma serum, when compared to common maleimide reagents. Apart from this body of work in chemical-biology, the thesis contains the discussion of development of copper-catalyzed remote chlorination of alkyl hydroperoxides. The atom transfer chlorination utilizes simple ammonium chloride salts as the chlorine source and the internal redox process requires no external redox reagents. Table of Content Chapter 1 Rational Design of Metal-Based Inhibitors for Proteins .............................................................. 1 1.1. Introduction ....................................................................................................................................... 1 1.2. Rational design of metal-based protein-inhibitors ............................................................................ 2 1.2.1. Improving target specificity by fine tuning ligand exchange reactions at metal center............. 2 1.2.2. Improving potency and drug residence time by fine tuning metal and chelator combination .. 4 1.2.3. Kinetically inert metal complexes for highly selective inhibition of protein kinases .................. 7 1.2.4. Affinity enhancement of an inhibitor by combining two weak interacting fragments ............ 12 1.2.5. Inducing selectivity by incorporating a biological recognition sequence in a metal inhibitor . 15 1.2.6. Altering target and action of a drug by incorporating a metal-fragment ................................. 16 1.2.7. Other examples ......................................................................................................................... 17 1.3. Conclusions ...................................................................................................................................... 18 1.4. References ....................................................................................................................................... 18 Chapter 2 Metal catalyzed directed sp3 C–H bond activation .................................................................... 22 2.1. Introduction ..................................................................................................................................... 22 2.2. Functionalizing sp3 C–H bonds using proximal-directing groups ..................................................... 23 2.2.1. Rh-catalyzed amination of sp3 C–H bonds ................................................................................ 24 2.2.2. Pt-mediated directed sp3 C–H activation .................................................................................. 26 2.2.3. Pd-catalyzed directed sp3 C–H activation ................................................................................. 28 2.3. Conclusions ...................................................................................................................................... 31 2.4. References ....................................................................................................................................... 31 Chapter 3 Copper–Catalyzed Remote sp3 C–H Chlorination of Alkyl Hydroperoxide ................................ 33 3.1. Introduction ..................................................................................................................................... 33 3.2. Development of copper-catalyzed C-H chlorination ....................................................................... 35 3.2.1. Substrate synthesis ................................................................................................................... 35 3.2.2. Preliminary assumptions ........................................................................................................... 37 3.2.3. Substrate-dependent optimization of copper-catalyzed C-H chlorination............................... 39 3.2.4. Substrate-scope of copper-catalyzed C-H chlorination ............................................................ 44 3.3. Conclusions ...................................................................................................................................... 47 3.4. Experimental .................................................................................................................................... 48 3.4.1. General Considerations ............................................................................................................. 48 3.4.2. Synthesis of Alkyl-hydroperoxides ............................................................................................ 50 3.4.3. Copper-Catalyzed C-H chlorination of Alkyl hydroperoxides:................................................... 64 3.5. References ....................................................................................................................................... 76 Chapter 4 Hybrid Organic-Inorganic inhibitors for PDZ Domain ................................................................ 79 4.1. Introduction ..................................................................................................................................... 79 4.2. Dirhodium‒histidine interaction ...................................................................................................... 81 4.3. Design of metallopeptide based inhibitors ...................................................................................... 85 4.4. Screening the potency of metalated inhibitors for CALP ................................................................. 91 4.5. Developing dirhodium metallopeptide inhibitors for N1P1 ............................................................ 95 4.6. Conclusions ...................................................................................................................................... 98 4.7. Experimental .................................................................................................................................... 99 4.7.1. General Considerations. ............................................................................................................ 99 4.7.2. Synthetic Procedures. ............................................................................................................. 102 4.7.3. Characterization data .............................................................................................................. 103 4.8. References ..................................................................................................................................... 116 Chapter 5 Designing Dirhodium-Ligated Small Molecule Inhibitors for FK506-Binding Proteins ............ 120 5.1. Introduction ................................................................................................................................... 120 5.2. Designing small-molecule metalated inhibitors ............................................................................ 121 5.2.1. Synthesis of compound B .......................................................................................................