University of Southern California Wed. Oct. 22, 2014 
 
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Kyung Woon Jung

  
Associate Professor of Chemistry

Office: LHI 105
Phone: (213) 740-8768
Fax: (213) 821-4096
Email: kwjung@usc.edu
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Research Focus

 

Our projected studies focus on the development of synthetic methodologies and their utilization towards the syntheses of biologically important natural products as well as structurally novel artificial biomolecules.  The projects described herein include only the ongoing projects in our labs. 

I.          Synthesis of Chiral g-Lactams

Scheme A

I-A.      Intramolecular C-H Insertion of Diazoamides

In our laboratories, we have discovered an efficient synthetic protocol for preparing chiral g-lactams (pyrrolidinones) via a stereo- and regioselective intramolecular C-H insertion of an a-diazo-(a-sulfonyl)acetamide as delineated in Scheme A.  This work extends the current methodology to various systems including amino acid derivatives, and these substrates should demonstrate the feasibility, generality, and stereoselectivity of this methodology.  Since our well-designed templates are expected to avert most shortcomings found in the previously known methods, this research will give rise to an efficient synthetic protocol for chiral pyrrolidinones.  Since pyrrolidine and pyrrolidinone skeletons are prevalent in biologically active natural products, our developed methodology will prove useful for construction of crucial intermediates for syntheses. 

I-B.      Synthesis of Bioactive g-Lactams

Chiral g-lactams, prepared from natural amino acids by our cyclization procedure, will be 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 g-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.

Scheme B

II.        Asymmetric Synthesis of Tetrahydroisoquinolines

Scheme C

II-A.    Formal Aromatic C-H Activation

Recently, we discoved a useful method to make chiral isoquinolones and tetrahydroisoquinolines.  As shown in scheme C, the diazoamide can be converted to the corresponding isoquinolone through formal aromatic C-H insertion.  Since the cyclization precursors are derived from chiral amino alcohols, the resulting tetrahydroisoquinolines are prepared in optically pure forms, thus facilitating the targeted asymmetric syntheses (vide infra).  We plan to probe the feasibility, limitations, and benefits of this methodology by varying substituents in the cyclization substrates.  Mechanistic insight is also a goal of this study.  Based upon our data, we now believe this reaction may be actually aromatic C-H insertion and our study can open a doorway to a new avenue in organic chemistry. 

Scheme D

II-B.    Synthesis of Tetrahydroisoquinoline Alkaloids

A variety of alkaloid natural products exhibit significant biological activities and interesting structural features as selectively shown in Scheme D.  Especially, ecteinascidin 743 is under clinical trials as an anticancer agent.  Using our developed protocol, we will pursue the total synthesis of this target molecule, which has three similar tetrahydroisoquinoline scaffolds.  We have successfully completed the syntheses of the mono-tetrahydroisoquinoline alkaloids such as calycotomine and praziquantel.  Coupling of tetrahydroisoquinoline building blocks is underway, hopefully leading to the synthesis of the target natural product in the near future.  We believe successful development of the asymmetric method to generate the key isoquinoline scaffolds would facilitate the designed synthesis. 

III.       Oxygen Promoted Palladium Catalysis

Scheme E

III-A.   Oxidative Palladium(II) Catalysis and Its Synthetic Applications

The first objective is to continue current studies regarding our synthetic methodology, which includes a modified Heck reaction (Scheme E).  As presented above, aryl stannanes were found to react with various olefins to generate disubstituted olefins, reminiscent of Heck reaction.  The couplings took place smoothly under mild conditions such as room temperature, no additives, and neutral conditions.  Boron variants have also been studied to effect the same transformations, which can be of great significance in organic synthesis.  Thus, this protocol would constitute a complimentary method to the existing Heck, Stille, and Suzuki couplings. 

Scheme F

Substrate limitations, reaction conditions, and stereoselectivities will be examined by introducing differently functionalized olefins, stannanes, and boron derivatives.  Thus far, we have observed efficient conversions with both aryl and olefinic substrates.  A double tin-Heck catalysis could become a versatile method for the synthesis of natural products containing conjugated olefins (Scheme E).  As delineated above, various Heck variants including double Heck catalysis will be used to synthesize trienes and higher order polyenes.  The developed protocols will also be applied to the synthesis of various natural products including palmerolide A illustrated in Scheme F. 

Palmerolide A was isolated by Professor Bill Baker from the Antarctic tunicate Synoicum adareanum.  This novel polyketide natural product displays selective cytotoxicity in the NCI’s 60 cell line panel, exhibiting great inhibition of melanoma (LC50 = 18 nM).  Relative and absolute stereochemistries were determined mostly by NMR studies.  We have embarked on the total synthesis of this novel anticancer agent to mitigate supply problem for further biological studies as well as to unambiguously elucidate the structure.  Our cross-coupling methodology can be applied to the synthesis to enhance its efficiency.  In particular, the oxidative cross-coupling reaction is suitable for the stereoselective preparation of trisubstituted olefins, thus shortening the number of steps. 

III-B.   Double Heck Reaction and Its Synthetic Applications

Likewise, a double Heck reaction will be investigated in pursuit of the total synthesis of a novel marine alkaloid, lamellarin I, which is a multidrug resistance reversal agent.  The feasibility of the intramolecular double Heck reaction will be determined, where two C-C bonds between aryls and pyrroles would be installed simultaneously to secure the pentacyclic skeleton.  Utilizing our oxygen promoted Heck reaction, we will efficiently accomplish the total synthesis of lamellarin a 20-sulfate, which is known as the inhibitor of human HIV integrase.

Scheme G

With the synthesis near completion, we aim to synthesize a variety of structural analogs as well as combinatorial libraries on the solid phase.  Successful polymer supported oxidative Heck and double Heck reactions would enable the preparation of combinatorial libraries of drug-like compounds, which will contain aryls, heterocyclics, and polyenes. 

IV.       Bioorganic and Medicinal Chemistry

IV-A.   Inhibition of PKC-i

We have recently embarked on the desigining of possible inhibitors of PKC-i to find lead compounds, which target cancer and rare diseases such as neurofibromatosis.  One of our collaborators has discovered indirect evidence suggesting that PKC-i activates CAK (cdk7), regulating cell cycle progression.  Inhibition of this pathway depletes Rb/E2f, resulting in antiproliferative activity.  In addition, NF-kB can also be suppressed to regulate the cell survival mechanism.  Thus, we can find an alternative candidate for the cure of cancer, especially brain malignancies, if we can identify specific inhibitors and validate the biological mechanism.  Our drug targets include small molecule inhibitors with pyrrolidine structural motifs as well as peptidomimetic scaffolds.

IV-B.   Synthesis of Artificial Biomolecules

The projected study includes the synthesis of novel artificial biomolecules using carbonates and carbamates as backbone skeletons by utilizing our cesium methodologies.  The first objective is to prepare and characterize promising macrolides used in molecular recognition and biochemical modeling.  An unprecedented class of macrolides, namely crown carbonates, will be synthesized as delineated below, then subjected to structural investigation as well as complexation studies.  The second objective is to synthesize carbamate containing peptidomimetics for investigation of their structural features in pursuit of an organized conformation such as an a-helix.  As depicted below, various oxapeptoids and carbamatoids will be prepared from substituents with varying lengths and sequences.  These peptidomimetic compounds will also be utilized to disrupt oncoprotein binding such as in Bak-Bcl-2 interaction, Fas-FAP-1 binding and MDM2-p53 interaction.  Since these biological interactions are crucial for cell growth and death, discovery of small binding molecules should expedite the ongoing research in drug discovery for various diseases.

Scheme H

We have prepared a few macrolides and peptidomimetic compounds, which have been subjected to biological assays.  We have found in collaboration with biologists at the H. Lee Moffitt Cancer Center and Research Institute that some of our designed peptidomimetic compounds exhibited antitumor activities.  With more structural analogs and biological screening, we will be able to explore another interesting field of research to its full potential. 

Similarly, we will prepare synthetic oligonucleotides, carbonate and carbamate nanomolecules, and carbonate polymers for the discovery of new materials.  These new materials are anticipated to be utilized for various purposes.  Oligonucleotides with carbonate backbones can be an inhibitor of human telomerase with the appropriate sequence and also can be good antisense compounds.  Nanomolecules and polymers can be utilized as drug delivery agents, artificial skins, and so forth.  We believe this project can be extended to numerous fields with the appropriate collaborations.

IV-C.   Binding-Based Proteome Profiling (BBPP)

Professor David Merkler and we have designed a new project using mostly his enzymatic expertise.  The aim of our collaborative research is to design a set of activity-based profiling reagents to identify CoA-dependent proteins and then use our newly designed ABPP (activity-based protein profiling) probes to profile CoA-dependent proteins in human disease-related proteomes.  This concept stems simply from the fact that CoA-dependent proteins are ubiquitous and the aberrant expression of CoA-dependent enzymes correlates to major human health problems, including cancer, cardiovascular disease, diabetes, and obesity.  Our improvement over the known ABPP methods is to design ABPP probes that have the tag attached to CoA.  Such probes take advantage of the high affinity that most CoA-dependent proteins and enzymes exhibit for their CoA ligands to form isolable ABPP-protein complexes.  We would like to call this new approach Binding-Based Proteome Profiling.  We can apply the concept to various applications including protein-protein interaction.

IV-D.   Synthesis of Building Blocks and Libraries

We have worked on the synthesis of novel building blocks for medicinal purpose.  These building blocks have been used for our own drug discovery projects as well as for collaborative projects with industry.  Our expertise is to develop novel and efficient synthetic methods to facilitate the synthesis of crucial building blocks, which in turn benefit the design of new compound libraries for appropriate biological assays.  Due to our strength, we have been able to collaborate with industry actively, and spin off a couple of companies for the past four years or so.

(c) 2014 Loker Hydrocarbon Institute