Charles Bessey Professor
Ph.D. California Institute of Technology
B.Sc. University of California at Irvine
Organic synthesis, synthetic methods, proxides, oxidations and ozonolysis, antimalarials, chemical biology, cell-cell signaling
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).
For more information, please visit the Dussault Research Group Homepage.
“The Synthesis of spiro-Bisperoxyketals” Ghorai, P.; Dussault, P. H.*, Hu, C. Org. Lett., 2008, 10, 2401; “3-Alkoxy-1,2-Dioxolanes: Synthesis and Evaluation as Potential Antimalarial Agents” Schiaffo, C. E.; Rottman, M.; Wittlin, S.; Dussault, P. H.* ACS Med. Chem. Lett. 2011, Web-published as ASAP article.
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).
“Asymmetric Synthesis of 1,2-dioxanes: Approaches to the Peroxyplakoric Acids” Xu, C.; Schwartz, C.; Raible, J. D.; Dussault, P. H.* Tetrahedron, 2009, 65, 9680; “Asymmetric Synthesis of 1,2-Dioxolane-3-acetic acids: Structural Elucidation of Plakinic Acid A” P. Dai, T. K. Trullinger, X. Liu, and P. H. Dussault*; J. Org. Chem. 2006, 71, 2283; “Total Synthesis of Peroxyacarnoates A and D: Metal-Mediated Couplings as a Convergent Approach to Polyunsaturated Peroxides” Xu, C.; Raible, J.; Dussault, P. H.* Org. Lett. 2005, 7, 2509.
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).
“A broadly applicable synthesis of 1,2,4,5-tetraoxanes” Ghorai, P.; Dussault, P. H.* Org. Lett., 2009, 11, 213-216; “A mild and efficient Re(VII)–catalyzed synthesis of 1,1-dihydroperoxides”, Ghorai, P.; Dussault, P. H.* , Org. Lett., 2008 10, 4577.
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). 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).
“Ozonolysis in solvent/water mixtures; direct conversion of alkenes to aldehydes and ketones” Schiaffo, C. E., Dussault, P. H.* J. Org. Chem. 2008, 73, 4688. “Reductive Ozonolysis” via a new fragmentation of carbonyl oxides” Schwartz, C.; Raible, J.; Mott, K.; Dussault, P. H. Tetrahedron, 2006, 62, 10747; “Fragmentation of Carbonyl Oxides by N-oxides: An Improved Approach to Alkene Ozonolysis” C. Schwartz, J. Raible, K. Mott and P. H. Dussault* Organic Letters, 2006, 8, 3199.
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).
Fragmentation of chloroperoxides; hypochlorite-mediated dehydration of hydroperoxyacetals to esters“ Fisher, T. J.; Dussault, P. H.* Tetrahedron Letters, 2010, 51, 5615-5617.
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).
“A new peroxide fragmentation: efficient chemical generation of 1O2 in organic media.” Ghorai, P.; Dussault, P. H.* Org. Lett. 2009, 11, 4572–4575
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.
“Reversible collapse of the Langmuir films of a series of triphenylsilyl ether-terminated amphiphiles” Christine A. DeVries, James J. Haycraft , Qiang Han, Farhana Noor-e-Ain, Joseph Raible, Patrick H. Dussault, and Craig J. Eckhardt, Thin Solid Films 2011, 519, 2430-2437.Nebraska Gateway for Nutrigenomics, we are exploring the influence of molecular structure on the cholesterol-lowering effect (Figure 7).
“Phytosterol ester constituents affect micellar cholesterol solubility in model bile.” Brown, A. W.; Hang, J.; Dussault, P. H.; Carr, T. P.* Lipids, 2010, 45, 855; “A concise synthesis of beta-sitosterol and other phytosterols” Hang, J.; Dussault, P.* Steroids, 2010, 75, 879; “Sterol and stanol substrate specificity of pancreatic cholesterol ester lipase” A. W. Brown, J.Hang, P. H. Dussault, T. Carr,* J.Nutr. Biochem., 2010, 21, 736.
Fungal and bacterial biosynthesis: An ongoing collaboration with Prof. Liangcheng Du (UNL Chemistry), investigates biosynthetic processes intermediates in both fungal and bacterial systems:
“Biosynthesis of HSAF, a Tetramic Acid-containing Macrolactam from Lysobacter enzymogenes” L. Lou, G. Qian, Y. Xie, J. Hang, H. Chen, K. Zaleta-Rivera, Y. Li, Y. Shen, P. H Dussault, F. Liu and L. Du*, J. Am. Chem. Soc. 2011, 133, 643; “A Bi-domain Nonribosomal Peptide Synthetase Encoded by FUM14 Catalyzes the Formation of Tricarballylic Esters in the Biosynthesis of Fumonisins” K. Zaleta-Rivera, C. Xu, F. Yu, R. A. E. Butchko, R. H. Proctor, M. E. Hidalgo-Lara, A. Raza, P. H. Dussault, and L. Du* Biochemistry 2006, 45, 2561.
Patrick H. Dussault
Charles Bessey Professor
An undergraduate, graduate, or postdoctoral student in my group can expect to receive training in:
For more information, please visit the Dussault Research Group website.
If you are seeking an exciting graduate career that helps you develop research skills at the interface of chemistry and biology, and are a self-motivated and creative individual, please email a letter of interest or resume to Prof. Dussault at email@example.com.