Oxocarbenium ions are important reactive intermediates in both bioorganic and synthetic organic chemistry. The goal of our research is to deepen our understanding of how steric and electronic effects govern the selective reactions of oxocarbenium and iminium ions and to use these effects to accomplish stereoselective transformations. During the proposed funding period, we will accomplish the following goals: (1) We will demonstrate that the powerful electronic effect exerted by heteroatom substituents on six-membered ring oxocarbenium and iminium ions will control the stereochemical outcomes of both intermolecular and intramolecular nucleophilic attack. (2) We will also show that a variety of heteroatom substituents can be used to control stereoselectivity in these reactions, and we will explore how several substituents interact to reinforce or oppose each other. These experiments will deepen our understanding of electronic influences on stereoselectivity as well as introduce new methods for forming various heteroatom-substituted oxygen and nitrogen heterocycles. (3) We will demonstrate that reactions of medium-ring oxocarbenium and iminium ions will also be controlled by the electronic nature of substituents, therefore leading to new approaches for remote asymmetric induction. (4) With a detailed knowledge of electronic effects on reactions of carbocations, we will demonstrate that this phenomenon can be used as a guiding principle for retrosynthetic analysis. We will complete syntheses of the alkaloid vincarodine, which has been shown to reverse multi-drug resistance in leukemia cells, and laurefucin, a marine natural product with a substitution pattern that will be a demonstration of the powerful influences of electronic effects on oxocarbenium ion conformation.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Medicinal Chemistry Study Section (MCHA)
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Schwab, John M
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University of California Irvine
Schools of Arts and Sciences
United States
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Beaver, Matthew G; Buscagan, Trixia M; Lavinda, Olga et al. (2016) Stereoelectronic Model To Explain Highly Stereoselective Reactions of Seven-Membered-Ring Oxocarbenium-Ion Intermediates. Angew Chem Int Ed Engl 55:1816-9
Garcia, Angie; Sanzone, Jillian R; Woerpel, K A (2015) Participation of alkoxy groups in reactions of acetals: violation of the reactivity/selectivity principle in a Curtin-Hammett kinetic scenario. Angew Chem Int Ed Engl 54:12087-90
Otte, Douglas A L; Woerpel, K A (2015) Evidence that Additions of Grignard Reagents to Aliphatic Aldehydes Do Not Involve Single-Electron-Transfer Processes. Org Lett 17:3906-9
Garcia, Angie; Otte, Douglas A L; Salamant, Walter A et al. (2015) Acceleration of acetal hydrolysis by remote alkoxy groups: evidence for electrostatic effects on the formation of oxocarbenium ions. Angew Chem Int Ed Engl 54:3061-4
Garcia, Angie; Otte, Douglas A L; Salamant, Walter A et al. (2015) Influence of alkoxy groups on rates of acetal hydrolysis and tosylate solvolysis: electrostatic stabilization of developing oxocarbenium ion intermediates and neighboring-group participation to form oxonium ions. J Org Chem 80:4470-80
Kendale, Joanna C; Valentín, Elizabeth M; Woerpel, K A (2014) Solvent effects in the nucleophilic substitutions of tetrahydropyran acetals promoted by trimethylsilyl trifluoromethanesulfonate: trichloroethylene as solvent for stereoselective C- and O-glycosylations. Org Lett 16:3684-7
Lavinda, Olga; Tran, Vi Tuong; Woerpel, K A (2014) Effect of conformational rigidity on the stereoselectivity of nucleophilic additions to five-membered ring bicyclic oxocarbenium ion intermediates. Org Biomol Chem 12:7083-91
Otte, Douglas A L; Borchmann, Dorothee E; Lin, Chin et al. (2014) 13C NMR spectroscopy for the quantitative determination of compound ratios and polymer end groups. Org Lett 16:1566-9
Tran, Vi Tuong; Woerpel, K A (2013) Nucleophilic addition to silyl-protected five-membered ring oxocarbenium ions governed by stereoelectronic effects. J Org Chem 78:6609-21
Dibble, David J; Ziller, Joseph W; Woerpel, K A (2011) Spectroscopic and X-ray crystallographic evidence for electrostatic effects in 4-substituted cyclohexanone-derived hydrazones, imines, and corresponding salts. J Org Chem 76:7706-19

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