University of Nebraska-Lincoln
809B/810 Hamilton Hall
Lincoln, NE 68588-0304
1. Synthesis of Organic Peroxides
Each year, malaria infects hundreds of millions of people, resulting in one to three million deaths. In many parts of the world, malaria has become resistant to traditional antimalarials such as chloroquine. The discovery of the peroxide artemisinin provided an effective method for treatment of drug-resistant Plasmodium falciparum, the most serious form of malaria. However, the apparent emergence of artemisinin-resistant strains of malaria has resulted in an increased focus on the development of structurally diverse classes of peroxide antimalarials. In collaboration with Prof. Jon Vennerstrom (Pharmaceutical Sciences, UNMC and the Swiss Tropical and Public Health Institute) we are pursuing bis-peroxyspiroketals and 3-alkoxy-1,2-dioxolanes as new classes of antimalarials which are readily prepared, stable, and have promising activity in blood cell cultures (Figure 1, Publication 1-2).
Synthesis of peroxide natural products:
We have described the first syntheses of members of the plakinic acid and peroxyacarnoate families of peroxides, as well as the first asymmetric approach to the core of the peroxyplakoric acids (Figure 2, Publication 3-5).
New Methods for peroxide synthesis:
An Improved Synthesis of 1,1-dihydroperoxides and 1,2,4,5-Tetroxanes: Re(VII) catalysts allow a mild and broadly applicable approach to 1,1-dihydroperoxides, important intermediates previously available only for selected skeletons. We also discovered that a simple change in conditions allowed condensation of the 1,1-dihydroperoxides with an added aldehyde or ketone to form 1,2,4,5-tetraoxanes, important skeletons in antimalarial research. Our method greatly extends the range of tetraoxanes which can be prepared and, for known tetraoxanes, offers a major improvement in yields compared with existing methods (Figure 3, Publication 6-7).
2. New Approaches to Alkene Ozonolysis
Ozonolysis is the most commonly applied method for conversion of alkenes to aldehydes and ketones. However, the utility of this transformation is limited by the formation of peroxide intermediates (e.g., ozonides) that must normally be decomposed in a separate step. We are expanding the synthetic scope and utility of ozonolysis based upon reagents that take advantage of the reactivity of the intermediate carbonyl oxides.
Reductive ozonolysis in the presence of amine oxides: We recently discovered a highly efficient method for "reductive" ozonolysis in the presence of amine oxides. Our mechanistic hypothesis predicts that the anionic peroxyacetal derived from trapping of the carbonyl oxide by the amine oxide undergoes a Grob-like fragmentation to generate the carbonyl and a molecule of the singlet excited state of oxygen (Figure 4A, Publication 8-10). This hypothesis is supported by our work with decomposition of 1,1-dihydroperoxides, which is discussed under "New Reactions of Organic Peroxides".
Reductive ozonolysis in the presence of solubilized water: More recently we found that ozonolysis in acetone or acetonitrile containing as little as 1-2% water directly furnishes aldehydes or ketones by trapping of the carbonyl oxide and decomposition of the resulting tetrahedral intermediate (Figure 4B, Publication 8-10).
3. New Reactions of Peroxides
A new fragmentation of hydroperoxyacetals: Reaction of hydroperoxyacetals with hypochlorite results in a high-yielding dehydration to form esters. The reaction appears to involve a novel heterolytic chain reaction involving formation and fragmentation of secondary chloroperoxides (Figure 5, Publication 11).
Chemical generation of singlet oxygen (1O2): Singlet molecular oxygen (1O2) is an important oxidant in chemistry, biology, and medicine. Recent work from our lab exploited the central mechanistic hypothesis of one of our reductive ozonolysis procedures (see above), to come up with a new and highly efficient chemical generation of 1O2 based upon a new fragmentation of readily prepared peroxide derivatives (Figure 6, Publication 12).
4. Center for Nanohybrid Functional Materials(CNFM)
Center for Nanohybrid Functional Materials: We are part of the Center for Nanohybrid Functional Materials, a group of fourteen investigators from UNL Chemistry, UNL Electrical Engineering, and four other Nebraska colleges or universities. The activities of the Center focus on interdisciplinary approaches to discovery and application of new sensing and separation principles at the surfaces of functionalized nanomaterials. Our research in this area will focus on methods for synthesis of functionalized nanomaterials.
Bioanalytical Linkers: In individual collaborations with several groups, including Prof. Rebecca Lai (UNL Chemistry), and Prof. Craig Eckhardt/Prof. Christine Ericsson (UNL Chemistry/Wartburg College, IA), we have been investigating the synthesis of functionalized amphiphiles with unique chemical or physical properties (Publication 13).
5. Chemical Biology and Nutrigenomics
Phytosterols: Plant sterols, aka phytosterols, are of growing interest as dietary additives able to reduce serum cholesterol. In collaboration with Prof. Tim Carr (UNL Nutrition Sciences) through the Nebraska Gateway for Nutrigenomics, we are exploring the influence of molecular structure on the cholesterol-lowering effect (Figure 7, Publication 14-16).
(1) “A Nonhydrolyzable Biotin-AMP Analog is a Potent Inhibitor of Holocarboxylase Synthetase” Sittiwong, W.; Cordonnier, E.; Zempleni, J.*; Dussault, P. H.* Biorg. Med. Chem Lett. 2014, 24 5568–5571.
(2) C. Schwartz and P.H. Dussault (2014) "1,1-Dihydroperoxides" in The Chemistry of Peroxides, Volume 3, edited by A. Greer and J.F. Liebman. John Wiley & Sons, Ltd: Chichester, UK, pp. 87-124
(3) “Self-Healing Gels based on Constitutional Dynamic Chemistry and Their Potential Applications” Wei, Z.; Yang, J. H.’ Zhou, J. X.; Xu, F.; Chen, Y. M.’ Zrinyi, M.; Dussault, P. H.; Osada, Y. Chem. Soc. Rev. 2014, 43, 8114-31.
(4) “Synthesis of S,S,O-Orthoesters and difluoroalkyl ethers via reaction of peroxide electrophiles with lithiated 1,3-dithianes” Kyasa, S. K.; Dussault, P. H. Org. Lett., 2014, 5235–5237.
(5) “Development of cyclobutene- and cyclobutane-functionalized fatty acids with inhibitory activity against Mycobacterium tuberculosis.” Sittiwong, W.; Zinniel, D. K., Fenton, R. J.; Marshall, D. Story, C. B.; Kim, B.; Lee, J-Y.; Powers, R.; Barletta, R. G.; Dussault, P. H.*, ChemMedChem 2014, 9, 9, 1838 – 1849.