Although many synthetic and biological transformations involve oxocarbenium ion intermediates, details about the structure and reactivity of these highly reactive species remain unknown. For example, debate continues about the preferred conformation of the mannosyl cation, although drugs targeting this cation have been tested to treat genetic and viral diseases as well as cancer. In other cases, inconsistencies in the literature remain, such as the nature of anchimeric assistance in stereoselective glycosylation. This proposal builds upon our work during the last funding period that demonstrates the influence of heteroatom substituents on the conformations of oxocarbenium ions and thus the stereoselectivity of their reactions. We have devised an approach to solving the structure of the mannosyl cation, and we will gain insight into the nature of anchimeric assistance. We have also devised new stereoselective synthetic methods based upon oxocarbenium and peroxocarbenium ion intermediates. This proposal will have considerable implications for public health. For example, our studies on the three- dimensional structures of carbohydrate-derived intermediates will impact the design of drugs for the treatment of diabetes, hepatitis, HIV, and cancer. In addition, our studies on the structure and reactivity of these intermediates will enable chemists to prepare those drugs more efficiently.

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)
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Lees, Robert G
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New York University
Schools of Arts and Sciences
New York
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; 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; 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
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
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
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
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
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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