Organic Peroxides: Synthesis, Reactivity, and Applications
New reactions of peroxides: C-O bond formation:
Recent work in our lab has demonstrated that peroxides can be used as effective "RO+" synthons enabling synthesis of ethers through both intramolecular and intermolecular transfer of alkoxy electrophiles to carbanions. We are continuing to investigate the use of this reaction for synthesis of otherwise challenging targets, including hindered, spirocyclic, and alkynyl ethers.
Reductive cleavage of peroxides :
Despite the seemingly fragile nature of the O-O bond (bond dissociation energies typically in the range of 30-36 kcal/mol), reactions of peroxides with nucleophiles and reductants often display surprisingly high activation barriers. This is exemplified by the "acetone" peroxides, shock sensitive high explosives that are almost inert to reaction with metal hydrides, Fe(II) salts, or phosphines. We have identified catalysts that facilitate reductive cleavage of these and other hindered peroxides.
Ozonolysis: Our lab has a long history of developing new methodology based upon ozonolysis (recent review) and we continue to investigate methods for selective ozonolysis.
(taken from Fisher and Dussault, Tetrahedron, 2017, 73, 4233)
Antimycobacterials: Mycobacterium tuberculosis, the causative agent of human tuberculosis (TB), infects billions with latent (dormant) stage disease. Five to ten percent of those with latent infections will progress at some point to active (and infectious) TB, which is responsible for over a millions deaths annually. Activation can be triggered by malnutrition, age, HIV co-infection, or treatment with immunosuppressants. Treatment remains problematic due to the increasing prevalence of drug resistant (and multi-drug resistant) strains. There is an urgent need for new antimycobacterials with novel mechanisms of action. In collaboration with Prof. Raul Barletta (UNL Veterinary and Biomedical Sciences) and Prof. Robert Powers, we recently found that analogs of natural fatty acids incorporating four-membered ring carbocycles offer potent and selective growth inhibition of Mycobacterium tuberculosis. (Sittiwong, et al, ChemMedComm, 2014, 9, 1838; DOI: 10.1002/cmdc.201402067) Our ongoing research seeks to:
1) Apply the "click" capability of the cyclobutenes (see the following section on Chemical Biology) to identification of the molecular targets of the modified fatty acids; and,
2) Identify optimal structures for inhibition of M. tb.
Chemically enhanced biosynthesis of antibiotics: In collaboration with Prof. Liangcheng Du, we are partnering chemical synthesis with biosynthesis to explore promising activity in a new class of antibiotics derived from a common bacteria (see the following section).Acute Radiation Sickness: In collaboration with several groups at the University of Nebraska Medical Center to develop molecules and formulations able to serve as both prophylactic and therapeutic agents for Acute Radiation Sickness.
Chemical Biology and Nutrigenomics
Expanding the range of click-capable functionality:
Recent work in our lab established cyclobutene-containing fatty acids as excellent substrates for electron-demand Diels-Alder (IEDDA) "click" cycloadditions [Sittiwong, Wantanee, "Synthesis and Application of Four-Membered Carbocycle Amphiphiles" (2014).] A recent collaboration with Prof. Jiantao Guo and coworkers (illustrated at right) demonstrated application of this platform, via unnatural amino acid chemistry, within modified proteins that will undergo click labeling within cells: Liu, et al, Chem. Sci. 2017. In collaboration with Prof. Robert Powers, we are also using the cyclobutene click reaction to follow the metabolic fate of the new class of antimycobacterials described under Medicinal Chemistry.
An ongoing collaboration with Prof. Liangcheng Du partners organic synthesis with biosynthesis to explore biosynthesis of analogs of the WAP family of antibiotics, which have demonstrated strong activity against Methicillin-resistant S. aureus. (Chen, et al RSC Advances, 2015, 5, 105753).
A separate collaboration involving Prof. Du and Prof. Yiqi Yang (UNL Textiles) will exploit bacterial biosynthetic machinery to generate a unexplored class of functionalized monomers anticipated to form the basis for high performance and high value polymers.
Surface Functionalization and Bioanalytical Chemistry
A long-standing collaboration with Prof. Rebecca Lai has explored the development and application of functionalized amphiphiles with unique chemical or physical properties. Recent projects have included development of new multivalent amphiphiles in support of more robust electrochemical sensors (illustrated at right), development of sensors that can operate on metal oxide surfaces, and simple strategies for reducing surface fouling of sensors. We are currently interested in applying new types of "click" ligation to functionalization of surfaces, and in the generation of reactive surface elements.
Safety: peroxides and ozone
Based upon our work with peroxides and ozone, we have prepared a brief introduction to work with these reagents in academic labs:
The overview includes three documents:
Safe Use of Hydrogen Peroxide in the Organic Lab (downloaded 951 times through 16 Feb 2018)
Working with organic peroxides in the academic lab (342 downloads)
Alkene Ozonolysis in the Academic Lab (1187 downloads)
Topics include classes of peroxides and hydroperoxides, reactivity of organic peroxides, hazard identification (including the concept of active oxygen content), hazard minimization, reaction monitoring using peroxide-sensitive strips and TLC dips, an introduction to the safe use of ozone in organic synthesis, and references to further reading on peroxide safety.