Kyung Woon Jung
Associate Professor of Chemistry
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.
Synthesis of Chiral g-Lactams
Intramolecular C-H Insertion of Diazoamides
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.
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.
Asymmetric Synthesis of Tetrahydroisoquinolines
Formal Aromatic C-H Activation
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
Synthesis of Tetrahydroisoquinoline Alkaloids
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.
Oxygen Promoted Palladium Catalysis
Oxidative Palladium(II) Catalysis and Its Synthetic Applications
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.
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.
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.
Double Heck Reaction and Its Synthetic Applications
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.
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.
Bioorganic and Medicinal Chemistry
Inhibition of PKC-i
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.
Synthesis of Artificial Biomolecules
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.
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.
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.
Binding-Based Proteome Profiling (BBPP)
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.
Synthesis of Building Blocks and Libraries
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.