The overall objective of this research program is to develop and apply state-of-the-art computation methods to understand stereoselectivity, chemoselectivity, and reactivity at the molecular level with the aim of designing new, more effective reagents, catalysts, and biological ligands. The control of selectivity and reactivity ar essential features of efficient synthesis, yet our molecular level understanding of how fundamental interactions perturb these aspects is only rudimentary. Further, many aspects of how these same fundamental interactions govern binding in a biological context are incompletely understood. This program seeks to quantitate these fundamental interactions to explain observed results and to build on this foundation. In addition to developing improved computational and analytical tools, a primer will be constructed tabulating the prevalence and strength of these widespread, fundamental interactions. We have identified three overall goals. In the first, transition state calculations will be used to probe mechanism, understand control elements, and quantitate fundamental interactions. In the second, empirical modeling tools will be developed and used to identify the key control factors governing reactivity and selectivity. This knowledge, in turn, focuses the studies in aim 1 to the most important elements. In the third, a new experimental measure of hydrogen-bonding is outlined, which is an important component of the interaction primer that is being built and also addresses timely questions in the selectivity and strength of biological binding. Relevance: The fundamental hallmark of this proposal is the ability to design new reactions and catalysts via computation to construct important organic structures in an efficient and rational manner. New synthetic methods greatly increase access to untapped chemical space, leading to materials and pharmaceuticals that benefit society. To achieve this goal, investigations will focus on obtaining an improved understanding of the fundamental interactions governing reactivity and selectivity. These same interactions govern biological systems, and further understanding will enable the design of enzymatic inhibitors and agents targeting other biomolecules to disrupt biological functions. Invaluable training will be afforded to undergraduate students, graduate students, and postdoctoral researchers involved in this proposal.
This proposal will use computation to understand the mechanism and selectivity of key organic and organometallic synthetic processes, as well as interactions in biologically relevant systems. New synthetic methods greatly increase access to new materials and pharmaceuticals that benefit society. The understanding of how small molecules bind to biomacromolecules is a key driver in drug design.
|Kim, Byeong-Seon; Gutierrez, Osvaldo; Kozlowski, Marisa C et al. (2018) A Simple Procedure for the Synthesis of ?-Hydroxyallenamides via Homoallenylation of Aldehydes. Adv Synth Catal 360:1426-1432|
|Hu, Chen; Hong, Gang; He, Yuchen et al. (2018) Lewis Acid-Controlled Regioselective Phosphorylation of 2-Indolylmethanols with Diarylphosphine Oxides: Synthesis of Highly Substituted Indoles. J Org Chem 83:4739-4753|
|Zatolochnaya, Olga V; Rodríguez, Sonia; Zhang, Yongda et al. (2018) Copper-catalyzed asymmetric hydrogenation of 2-substituted ketones via dynamic kinetic resolution. Chem Sci 9:4505-4510|
|Gutierrez, Osvaldo; Hendrick, Charles E; Kozlowski, Marisa C (2018) Divergent Reactivity in Pd-Catalyzed [3,3]-Sigmatropic Rearrangement of Allyloxy- and Propargyloxyindoles Revealed by Computation and Experiment. Org Lett 20:6539-6543|
|Patel, Nitinchandra Dahyabhai; Sieber, Joshua D; Tcyrulnikov, Sergei et al. (2018) Computationally Assisted Mechanistic Investigation and Development of Pd-Catalyzed Asymmetric Suzuki-Miyaura and Negishi Cross-Coupling Reactions for Tetra-ortho-Substituted Biaryl Synthesis. ACS Catal 8:10190-10209|
|Sha, Sheng-Chun; Tcyrulnikov, Sergei; Li, Minyan et al. (2018) Cation-? Interactions in the Benzylic Arylation of Toluenes with Bimetallic Catalysts. J Am Chem Soc 140:12415-12423|
|Kang, Houng; Herling, Madison R; Niederer, Kyle A et al. (2018) Enantioselective Vanadium-Catalyzed Oxidative Coupling: Development and Mechanistic Insights. J Org Chem :|
|Tcyrulnikov, Sergei; Curto, John M; Gilmartin, Philip H et al. (2018) Lewis Acid-Promoted Enantioselective Dearomative Spirocyclizations of Allenes. J Org Chem 83:12207-12212|
|Qu, Bo; Mangunuru, Hari P R; Tcyrulnikov, Sergei et al. (2018) Enantioselective Synthesis of ?-(Hetero)aryl Piperidines through Asymmetric Hydrogenation of Pyridinium Salts and Its Mechanistic Insights. Org Lett 20:1333-1337|
|Zou, Yike; Gutierrez, Osvaldo; Sader, Avery C et al. (2017) A Computational Investigation of the Ligand-Controlled Cu-Catalyzed Site-Selective Propargylation and Allenylation of Carbonyl Compounds. Org Lett 19:6064-6067|
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