(Principal Investigator's) The objective of this research program is to invent and/or discover efficient chemical synthesis methods that will allow structurally complex nitrogen-containing molecules to be prepared in a practical way from commercially-available building blocks. Our ultimate goal i to develop sufficiently versatile and efficient synthesis tools so that any desired molecule could be synthesized in a commercially viable manner. In this endeavor we target structurally novel, complex chemical structures for which there is no existing road map, or obvious strategy, for their synthesis. Our intent is not just to make the target compounds, but to evolve new synthesis strategies and to learn about the chemical peculiarities of novel chemical structures. In the long term, the availability of these new organic synthesis tools will facilitate the future development of new chemical agents for treating cardiovascular and other diseases. Many of our current natural produc synthesis targets exhibit promising medicinal properties, yet are not sufficiently accessible for in vivo evaluation. In these areas, our proposed investigations could have immediate practical application by making these compounds, and analogs, available for biomedical investigation. A variety of complex guanidine and polyamine alkaloids have been selected for investigation. These structures are targeted for two reasons: (1) guanidine an polyamine functional group arrays are found in a high percentage of recently-isolated, pharmacologically-active, natural products, and (2) methods for chemical synthesis of compounds containing many nitrogen atoms are less developed than other organic synthesis tools. Among our synthesis targets are (a) the crambescidin alkaloids, for which a variety of pharmacological activities have been reported, most significantly in vitro anticancer activity inhibition of calcium channels, inhibition of Na(+), K(+) and Ca(2+)-ATPases, (b) the batzelladine alkaloids, which inhibit protein-protein interactions tha are important for immunological responses, (c) palau'amine, a relatively non-toxic immunomodulator, (d) styloguanidine, a chitinase inhibitor, and (e) aloperine, an active component of traditional Chinese medicines used for treating heart arrhythmias and inflammatory disorders. The proposed investigations are founded on discoveries made during the current project period of new strategies for preparing complex guanidine alkaloids by cyclocondensation and cycloaddition reactions.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Medicinal Chemistry Study Section (MCHA)
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University of California Irvine
Schools of Arts and Sciences
United States
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Canham, Stephen M; Hafensteiner, Benjamin D; Lebsack, Alec D et al. (2015) Stereocontrolled enantioselective total synthesis of the [2+2] quadrigemine alkaloids. Tetrahedron 71:6424-6436
Quasdorf, Kyle W; Overman, Larry E (2014) Catalytic enantioselective synthesis of quaternary carbon stereocentres. Nature 516:181-91
Overman, Larry E; Roberts, Scott W; Sneddon, Helen F (2008) Catalytic asymmetric synthesis of allylic thiol derivatives. Org Lett 10:1485-8
Lanman, Brian A; Overman, Larry E; Paulini, Ralph et al. (2007) On the structure of palau'amine: evidence for the revised relative configuration from chemical synthesis. J Am Chem Soc 129:12896-900
Becker, Michael H; Chua, Peter; Downham, Robert et al. (2007) Total synthesis of (-)-sarain A. J Am Chem Soc 129:11987-2002
Gergely, Joshua; Morgan, Jeremy B; Overman, Larry E (2006) Stereocontrolled synthesis of functionalized cis-cyclopentapyrazolidines by 1,3-dipolar cycloaddition reactions of azomethine imines. J Org Chem 71:9144-52
Nilsson, Bradley L; Overman, Larry E (2006) Concise synthesis of guanidine-containing heterocycles using the Biginelli reaction. J Org Chem 71:7706-14
Garg, Neil K; Hiebert, Sheldon; Overman, Larry E (2006) Total synthesis of (-)-sarain A. Angew Chem Int Ed Engl 45:2912-5
Cohen, Frederick; Overman, Larry E (2006) Evolution of a strategy for the synthesis of structurally complex batzelladine alkaloids. Enantioselective total synthesis of the proposed structure of batzelladine F and structural revision. J Am Chem Soc 128:2594-603
Cohen, Frederick; Overman, Larry E (2006) Enantioselective total synthesis of batzelladine F and definition of its structure. J Am Chem Soc 128:2604-8

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