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Kyung W. Jung

Associate Professor of Chemistry
Organic Chemistry

Ph.D., 1994, University of Wisconsin - Madison
M.S., 1987, Seoul National University
B.S., 1985, Seoul National University
Office: LHI 218
Phone: (213) 740-8768
Fax: (213) 821-4096
Email: kwjung@usc.edu


Research Focus

 

Our research area targets two important applications.

1. Alternative future fuels & energy.

Overview on Future Fuels & Energy
Recently, we have successfully developed novel N-heterocyclic carbene (NHC)-amidate ligands and their corresponding metal complexes which possess a highly electron-rich metal center, due to the strong σ- donating and π-electron donating abilities of the NHC and amidate ligands. We found that these properties of the NHC-amidate ligands have generated stable and reactive catalysts with transition metals (cf. Pd, Ir, Pt, Ni, and Fe) to facilitate 1) direct oxidative degradation of carbohydrate biomass, 2) C-H activation of less-reactive hydrocarbons, and 3) C-O activation of CO2. In particular, the increased stability of these metal complexes in nucleophilic solvents such as water and alcohols allows for conditions amenable to green chemistry and possibility for use in hydrothermal processes. Based upon the research results, we herein plan to extend this chemistry to a new direct oxidation/reduction process of unreactive abundant resources to obtain useful feedstocks as listed below:

Biomass (Generation of Formic Acid)
Biomass is still increasing interest in converting them into more convenient and valuable fuels and other value-added products. Especially, formic acid, one of value-added production from biomass, is primarily used in preservation of animal feed and in tanning of leather in the leather industry. More importantly, recent
research has demonstrated that formic acid could be used as a safe and easy-to-transport source of hydrogen to power fuel cells for electricity generation and automobiles. Therefore, if carbohydrate biomass could be converted readily into formic acid efficiently at mild conditions, this should provide the basis for new green processes. Although some researchers have demonstrated hydrothermal conversion of carbohydrate biomass into value-added products, few studies have shown targeted yields for conversion of carbohydrate biomass into commodity chemicals such as formic acid. Our research has demonstrated direct oxidative degradation process with hydrogen peroxide in the presence of our noble catalyst, and then the generation of formic acid from the biomass (cf. grass) reached approximately 4% conversion based on grass powder weight.

Methane and Carbon Dioxide (Generation of Value-added Products)
The continued consumption of fossil fuels, one of the world’s major supplies of energy, has led to an increased concentration of CO2 in the atmosphere and has prompted concerns over global warming and exhaustion of natural resources. Much of the effort to control such problems focuses on advancing technologies towards alternative fuels (methanol, ethanol, and biofuel) and enhancement of natural sinks for CO2 sequestration. As shown in left scheme, although it is an initial stage, we found that our catalyst could be used as a core substance in environmentally friendly process. As a contribution to this research, the project expands the development of economical and environmentally friendly recyclable processes, which may be used to produce chemical feedstocks from abundant resources (CH4 and CO2).
A successful outcome of these projects will be immediately applicable for use as environmentally friendly commercial protocols because current technologies, which convert abundant low-cost feedstocks to energy, fuel, and other useful chemicals, operate at high temperatures and utilize multiple steps that lead to inefficient, capital-intensive processes. Our demonstrated protocols will provide effective technologies to satisfy worldwide energy demands and to allow for continued development of operations in an environmentally responsible manner.

2. Drug discovery.

Medicinal Chemistry Projects
Our lab is currently involved in two medicinal chemistry projects in collaboration with the School of Pharmacy. We are synthesizing a variety of small molecules which may disrupt protein-protein interactions, and also creating compounds through SAR studies in order to optimize their activity towards the proteins of interest.

First Generation of Bcl-2/Bcl-xL Inhibitor
A feature of cancer is its ability to evade physiological signals that would allow for cell death, and Bcl-2 related proteins comprise a class of gene products which are associated with inhibition of apoptosis. Our current study is focused on targeting the BH3 binding domain of Bcl-2 and Bcl-xL using nonpeptidic small molecule inhibitors. The goal of this project is to synthesize a library of novel analogues of Bcl-2/Bcl-xL inhibitors to optimize their ADMET properties and binding affinities. Based upon a pharmacophore model, analogues containing a 2-phenyl-1H-benzimidazole backbone are being synthesized. Analogues containing carboxamide linkers with various flexible side chains have been positioned to provide access to the hydrophobic pocket of the binding groove of Bcl-2 and Bcl-xL. Preliminary tests suggest these compounds demonstrate efficacy in vitro.

Second Generation of HIV-1 Integrase Inhibitor
The integrase enzyme, one of the three key enzymes of HIV-1, is accountable for the key event of viral DNA infection of the host DNA. Through inhibition of this enzyme, the HIV
transfection cycle from cell to cell should be halted, and consequently, may eradicate the immunodeficiency disease. Although there is already one known FDA approved drug targeting this key enzyme, the need for development of a second generation arsenal drug is still urgent due to the high mutation rate of this retrovirus. Our lab has identified one hit compound that is currently being pursued for lead optimization. Through the use of computational modeling we are developing analogues to improve current inhibitory activity.

In order to achieve these goals, we make three approaches.

1. Design & synthesis of novel organometallic catalysts.

Novel NHC-Amidate-Pd(II) Complex
We have designed and synthesized a number of organometallic catalysts for more efficient reactions and for unprecedented reactions compared to known catalysts and their reactions. The most recent example includes novel NHC-amidate ligands and their metal complexes as generally depicted in the structure below. While developing the ligand design, we decided to utilize two heteroatom ligands, in addition to NHCs, based on previous studies. We hoped this would ultimately offer a “Pd(OAc)2 mimic”. In our general ligand design, we include one oxygen as a donor ligand to replace one of the AcO? ligands in Pd(OAc)2. Inclusion of an amidate nitrogen ligand could also induce stronger coordination and/or chelation. Our designed NHC-amidate-Pd(II) complexes have a highly electron- rich Pd center, due to the strong σ-donating ability of the NHC. This in turn would furnish a stronger trans effect to allow the catalyst to react efficiently. In addition, an amidate ligand, which has strong σ-donating and possible π-electron donating abilities, can produce a more electron rich Pd center. Alkoxide or ether moieties at the trans position to the NHC are capable of coordinating to the metal, contributing to higher stability of the incipient and reacting catalysts. We believe that these properties of the NHC ligands will generate stable and reactive catalysts to facilitate the activation of less-reactive hydrocarbons when they form complexes with Pd metal.

2. Development of synthetic methodologies.

Our projected studies focus on the development of synthetic methodologies, which can be either improvements over the existing methods or novel reactions. Some examples are shown here.

C-H Activation, Oxidation, Cross-Couplings via Novel NHC-Amidate Catalysts
Using our newly designed NHC-amidate metal complexes, we have been engaged in the development of novel catalytic reactions, which are challenging to carry out by utilizing known methods or catalyts. For example, we have demonstrated efficient C-H activation methods including activation of methane to acetic acid as shown above. A number of new reactions including methane activation, carbon dioxide utilization, and biomass conversion have been explored in an effort to mitigate current energy and environment problems. We approach these problems by inventing new reactions and new mechanisms as exemplified in the selective conversion of methane to acetic acid.

Oxidative Palladium(II) Catalysis
Using oxidative Pd(II) catalysis, we have developed new synthetic methodologies, which include a modified Heck reaction as shown above. Under mild conditions, our boron-Heck reactions are highly efficient, giving rise to the stereoselective synthesis of various alkenes. Asymmetric catalysis has also been achieved to effect both intra- and intermolecular couplings. These methods are useful in the synthesis of medicinal compounds and natural products.

3. Organic synthesis.

Our synthetic efforts are directed towards biologically important natural products as well as structurally novel artificial biomolecules. Here are some examples.

Synthesis of Bioactive γ-Lactam Natural Products
Chiral γ-lactams, prepared from natural amino acids by our cyclization procedure, have been used for the synthesis of various natural products, requiring efficient synthetic routes for mass production. Our synthetic targets encompass lactacystin, pramanicin, statine, rolipram, epolactaene, and kainic acid. These compounds and their structural analogs hold great promise as chiral drug candidates to fight numerous diseases such as cancer, Alzheimer's disease, epilepsy, and cardiovascular diseases. Due to their scarcity in natural sources and difficulties in total syntheses, biological studies have been hampered and further clinical trials are also far from reality. Our efficient pathways aim to address the limited availability of these compounds. Moreover, these novel methodologies in γ-lactam synthesis will provide new perspectives in discovery of structurally related chiral drugs. We believe this new synthetic protocol will help to advance organic synthesis, as well as to enhance the progress of related fields such as biology and medicinal chemistry, culminating in drug discovery.

Synthesis of Artificial Biomolecules
We have embarked on medicinal chemistry to optimize hit molecules for better potency, efficacy, and pharmacological properties. In particular, we are interested in disrupting protein-protein interaction such as Bak-Bcl-2 interaction, Fas-FAP-1 binding and MDM2-p53 interaction. Lately, we extended this concept to HIV proteins and acquired promising initiatives. In these approaches, we designed small molecules in order to bind strongly to the targeted proteins, hoping that these new molecules can replace the natural binding proteins. These compounds intrinsically contain a few heteoatoms in their structures, thereby we have carried out a number of heterocyclic syntheses while we have developed our own expertise and experience in heteroatom chemistry, cross-coupling methods, and analytical evaluation.

 

Selected publications

 
1Oxidative Palladium(II) Catalysis: A Highly Efficient and Chemoselective Cross-Coupling Method for Carbon-Carbon Bond Formation under Base-Free and Nitrogenous-Ligand Conditions. Yoo, K. S.; Yoon, C. H.; Mishra, R. K.; Jung, Y. C.; Yi, S. W.; Jung, K. W. J. Am. Chem. Soc., 2006, 128, 16384.
2Stereogenic Evolution of clasto-Lactacystin β-Lactone from (L)-Serine. Yoon, C. H.; Flanigan, D. L.; Yoo, K. S.; Jung, K. W. Eur. J. Org. Chem., 2007, 37.
3Asymmetric Intermolecular Heck-Type Reaction of Acyclic Alkenes via Oxidative Palladium(II) Catalysis. Yoo, K. S.; Park, C. P.; Yoon, C. H.; Sakaguchi, S.; O'Neill, J.; Jung, K. W. Org. Lett., 2007, 9, 3933.
4Total Syntheses of (-)-α-Kainic Acid and (+)-α-Allokainic Acid via Stereoselective C-H Insertion and Efficient 3,4-Stereocontrol. Jung, Y. C.; Yoon, C. H.; Turos, E.; Yoo, K. S.; Jung, K. W. J. Org. Chem. 2007, 72, 10114.
5Chiral PdII Complexes Possessing Tridentate NHC-Amidate-Alkoxy Ligand: Access to Oxygen- Bridging Dimer Structure. Sakaguchi, S.; Yoo, K. S.; O'Neill, J.; Lee, J. H.; Stewart, T.; Jung, K. W. Angew. Chem. Int. Ed. 2008, 47, 9326.
6Chemoselective Three-Component Coupling via A Tandem Pd Catalyzed Boron-Heck and Suzuki Reaction. O'Neill, J.; Yoo, K. S.; Jung, K. W. Tetrahedron Lett. 2008, 49, 7307.
7Highly Regioselective Heck-Coupling Reactions of Aryl Halides and Dihydropyran (DHP) in the Presence of NHC-Pyridine Ligand. Jarusiewicz, J.; Yoo, K. S.; Jung, K. W. Synlett, 2009, 482.
8Air/Water-Stable Tridentate NHC-PdII Complex; Catalytic C-H Activation of Hydrocarbons via H/D Exchange Process in D2O. Lee, J. H.; Yoo, K. S.; Park, C. P.; Olsen, J. M.; Sakaguchi, S.; Prakash, G. K. S.; Mathew, T.; Jung, K. W. Adv. Synth. Cat. 2009, 351, 563.
9Efficient Three-Component Strecker Reaction of Aldehydes/Ketones via NHC-Amidate Palladium(II) Complex Catalysis. Jarusiewicz, J.; Choe, Y.; Yoo, K. S.; Park, C. P.; Jung, K. W. J. Org. Chem., 2009, 74, 2873.
10Expeditious Enyne Construction from Alkynes via Oxidative Pd(II) Catalyzed Heck-Type Coupling. Hadi, V.; Yoo, K. S.; Jeong, M.; Jung, K. W. Tetrahedron Lett. 2009, 50, 2370.
11Formal Aromatic C-H Insertion for Stereoselective Isoquinolinone Synthesis and Studies on Mechanistic Insights into the C-C Bond Formation. Park, C. P.; Nagle, A. S.; Yoon, C. H.; Chen, C.; Jung, K. W. J. Org. Chem. 2009, 74, 6231.
12Tridentate, anionic tethered N-heterocyclic carbene of Pd(II) complexes. Sakaguchi, S.; Kawakami, M.; O'Neill, J.; Yoo, K. S.; Jung, K. W. J. Organometal. Chem. 2010, 695, 195.
13 Asymmetric Intermolecular Boron-Heck Type Reactions via Oxidative Palladium(II) Catalysis with Chiral Tridentate NHC-Amidate-Alkoxide Ligands. Yoo, K. S.; O'Neill, J.; Sakaguchi, S.; Giles, R.; Lee, J. H.; Jung, K. W. J. Org. Chem. 2010, 75, 95.
14Efficient Diacetoxylation of Alkenes via Pd(II)/Pd(IV) Process with Peracetic Acid and Acetic Anhydride. Park, C. P.; Lee, J. H.; Yoo, K. S.; Jung, K. W. Org. Lett. 2010, 12, 2450.
15Development of the Next Generation of HIV-1 Integrase Inhibitors: Pyrazolone as a Novel Inhibitor Scaffold. Hadi, V.; Koh, Y.-H.; Sanchez, T.; Barrios, D.; Neamati, N.; Jung, K. W. Bioorg. Med. Chem. Lett, 2010, 20, 6854.
16 Oxidative Degradation of Reducing Carbohydrates to Formic Acid with H2O2 and NH4OH. Pullanikat, P.; Jung, S. J.; Yoo, K. S.; Jung, K. W. Tetrahedron Lett. 2010, i, 6192.

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