We will develop a new synthetic methodology where high yielding photochemical key reactions are incorporated into a diversity-oriented split-and-pool combinatorial synthesis. Photochemical reactions hold unparalleled promise for building complex polycyclic scaffolds. They offer a number of synthetic shortcuts and concise pathways to complex synthetic targets. Yet, photochemistry never became a sought-after tool by synthetic chemists and its utilization in high-throughput synthesis is simply non-existent. Specifically, we aim to develop a new photoassisted synthetic methodology for rapid access to topologically diverse N,O,S-polyheterocycles, containing a large fraction of sp3 hybridized carbon atoms and stereogenic centers, and decorated by various functional groups and carbo/heterocyclic pendants rigidly or semi-rigidly held in a unique spatial configuration by these novel core frameworks with a minimal number of rotatable bonds. The synthetic strategy will involve key photochemical steps and their combination with ground state reactions, most prominently our recently discovered intramolecular cycloadditions of azaxylylenes photogenerated via excited state proton transfer from the amido or amino-group to the carbonyl group or imine. Achieving a well-defined three-dimensional relationship within an assortment of functional groups and/or heterocyclic moieties is central to synthetic medicinal chemistry. The broad objective is to generate potential pharmacophores by systematically sampling the chemical space with diversified core structures augmented with a range of peripheral functionalities. From the high throughput chemistry standpoint this task can only be achieved with a diverse set of distinctive core scaffolds suspending a variety of functional pendants in a unique 3D pattern. High throughput synthetic methods are blamed for """"""""steering discovery efforts toward achiral, aromatic compounds"""""""" while natural products, possessing a broad spectrum of bioactivity, look nothing like the sp2-dominated aromatic heterocycles. Our photoassisted synthetic methodology will produce a variety of unique (poly)heterocyclic core scaffolds containing high number of saturated, i.e. sp3, carbons quantified by Lovering's Fsp3 saturation parameter.

Public Health Relevance

Photochemical reactions initiated by light hold unparalleled promise for building unusual molecular frameworks and offer expeditious access to difficult synthetic targets. Yet, with the exception of a few landmark syntheses, synthetic organic photochemistry remains underutilized by synthetic organic chemists. This is especially true for diversity-oriented synthesis (DOS) and its split-and-pool implementation, which is most relevant to the high-throughput synthesis of small molecules and the discovery of new promising therapeutic agents. We are developing novel synthetic methodologies, enabling us to gain rapid access to a massive number of new drug-like molecules, primarily complex nitrogen, oxygen, and sulfur-containing heterocycles, which will be available for biological screening. Not unimportant is the fact that photochemical steps use light as a reagent, and therefore could be environmentally friendly.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Academic Research Enhancement Awards (AREA) (R15)
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Synthetic and Biological Chemistry A Study Section (SBCA)
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Lees, Robert G
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University of Denver
Schools of Arts and Sciences
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Umstead, Weston J; Mukhina, Olga A; Kutateladze, Andrei G (2016) Photoassisted access to complex polyheterocycles containing a ?-lactam moiety. J Photochem Photobiol A Chem 329:182-188
Mukhina, Olga A; Kutateladze, Andrei G (2016) Oxazolines as Dual-Function Traceless Chromophores and Chiral Auxiliaries: Enantioselective Photoassisted Synthesis of Polyheterocyclic Ketones. J Am Chem Soc 138:2110-3
Kuznetsov, Dmitry M; Mukhina, Olga A; Kutateladze, Andrei G (2016) Photoassisted Synthesis of Complex Molecular Architectures: Dearomatization of Benzenoid Arenes with Aza-o-xylylenes via an Unprecedented [2+4] Reaction Topology. Angew Chem Int Ed Engl 55:6988-91
Mukhina, Olga A; Kuznetsov, Dmitry M; Cowger, Teresa M et al. (2015) Amino Azaxylylenes Photogenerated from o-Amido Imines: Photoassisted Access to Complex Spiro-Poly-Heterocycles. Angew Chem Int Ed Engl 54:11516-20
Umstead, Weston J; Mukhina, Olga A; Bhuvan Kumar, N N et al. (2015) Photoinduced Cycloadditions in the Diversity-Oriented Synthesis Toolbox: Increasing Complexity with Straightforward Postphotochemical Modifications. Aust J Chem 68:1672-1681
Tong, Qiong; Mazur, Sharlyn J; Rincon-Arano, Hector et al. (2015) An acetyl-methyl switch drives a conformational change in p53. Structure 23:322-31
Umstead, Weston J; Mukhina, Olga A; Kutateladze, Dr Andrei G (2015) Conformationally Constrained Penta(hetero)cyclic Molecular Architectures via Photoassisted Diversity-Oriented Synthesis. European J Org Chem 2015:2205-2213
Mukhina, Olga A; Kumar, N N Bhuvan; Cowger, Teresa M et al. (2014) Photoassisted diversity-oriented synthesis: accessing 2,6-epoxyazocane (oxamorphan) cores. J Org Chem 79:10956-71
Kumar, N N Bhuvan; Mukhina, Olga A; Kutateladze, Andrei G (2013) Photoassisted synthesis of enantiopure alkaloid mimics possessing unprecedented polyheterocyclic cores. J Am Chem Soc 135:9608-11
Valiulin, Roman A; Arisco, Teresa M; Kutateladze, Andrei G (2013) Photoinduced intramolecular cyclopentanation vs photoprotolytic oxametathesis in polycyclic alkenes outfitted with conformationally constrained aroylmethyl chromophores. J Org Chem 78:2012-25

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