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.

Public Health Relevance

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.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Synthetic and Biological Chemistry A Study Section (SBCA)
Program Officer
Lees, Robert G
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University of Pennsylvania
Schools of Arts and Sciences
United States
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Lassalas, Pierrik; Gay, Bryant; Lasfargeas, Caroline et al. (2016) Structure Property Relationships of Carboxylic Acid Isosteres. J Med Chem 59:3183-203
VanGelder, Kelsey F; Wang, Melinda; Kozlowski, Marisa C (2015) Route to α-Aryl Phosphonoacetates: Useful Synthetic Precursors in the Horner-Wadsworth-Emmons Olefination. J Org Chem 80:10288-93
Curto, John M; Kozlowski, Marisa C (2015) Chemoselective activation of sp(3) vs sp(2) C-H bonds with Pd(II). J Am Chem Soc 137:18-21
Gutierrez, Osvaldo; Metil, Dattatray; Dwivedi, Namrata et al. (2015) Practical, asymmetric route to sitagliptin and derivatives: development and origin of diastereoselectivity. Org Lett 17:1742-5
Liu, Lei; Carroll, Patrick J; Kozlowski, Marisa C (2015) Vanadium-catalyzed regioselective oxidative coupling of 2-hydroxycarbazoles. Org Lett 17:508-11
VanGelder, Kelsey F; Kozlowski, Marisa C (2015) Palladium-Catalyzed α-Arylation of Aryl Nitromethanes. Org Lett 17:5748-51
Gutierrez, Osvaldo; Tellis, John C; Primer, David N et al. (2015) Nickel-catalyzed cross-coupling of photoredox-generated radicals: uncovering a general manifold for stereoconvergence in nickel-catalyzed cross-couplings. J Am Chem Soc 137:4896-9
Walvoord, Ryan R; Kozlowski, Marisa C (2015) Cinchonidinium acetate as a convenient catalyst for the asymmetric synthesis of cis-stilbenediamines. Tetrahedron Lett 56:3070-3074
Metz, Alison E; Ramalingam, Kailasham; Kozlowski, Marisa C (2015) Xanthene-4,5-diamine derivatives: a study of anion-binding catalysis. Tetrahedron Lett 56:5180-5184
Curto, John M; Dickstein, Joshua S; Berritt, Simon et al. (2014) Asymmetric synthesis of α-allyl-α-aryl α-amino acids by tandem alkylation/π-allylation of α-iminoesters. Org Lett 16:1948-51

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