Dr.

Iwao Ojima
Distinguished Professor of Chemistry
Director, the Institute of Chemical Biology & Drug Discovery
State University of New York at Stony Brook
Iwao Ojima was born in Yokohama, Japan in 1945. He received his B.S. (1968), M.S. (1970), and Ph.D.
(1973) degrees from the University of Tokyo, Japan. He joined the Sagami Institute of Chemical Research
and held a position as Senior Research Fellow until 1983. He joined the faculty at the Department of
Chemistry, State University of New York at Stony Brook first as Associate Professor (1983), was promoted
to Professor (1984), Leading Professor (1991), and then to Distinguished Professor (1995). He served as the
Department Chairman from May 1997 through October 2003. Since early 2003 he has been the founding
Director of the Institute of Chemical Biology and Drug Discovery at Stony Brook.
He has a wide range of research interests in synthetic organic, organometallic and medicinal chemistry,
including asymmetric synthesis, organic synthesis based on homogeneous catalysis, peptide and peptide
mimetics, β-lactam chemistry, enzyme inhibitors, anticancer agents, antithrombotic agents, and medicinally
relevant organofluorine compounds.
He is a recipient of the E. B. Hershberg Award (for Important Discovery of Medicinally Active Substances)
(2001) and the Arthur C. Cope Scholar Award (1994) from the American Chemical Society; the Chemical
Society of Japan Award (for distinguished achievements) (1999) and National Young Investigator’s Award
from the Chemical Society of Japan (1976). He is a Fellow of the J. S. Guggenheim Memorial Foundation
(1995), the American Association for the Advancement of Science (1997), and The New York Academy of
Sciences (2000). He also received the Outstanding Inventor Award from The Research Foundation of the
State University of New York in 2002, and a NYSTAR Faculty Development Award in 2003 from the
Governor of the State of New York.
He has served as an advisory committee member for the National Institutes of Health, National Science
Foundation and the U.S. Department of Energy. He has served or currently serves as Editorial Advisory
Board member of Journal of Organic Chemistry, Organometallics, Journal of Molecular Catalysis, Current
Topics in Medicinal Chemistry (current), Medicinal Chemistry (current), and Letters in Drug Design &
Discovery (current).
He has published more than 340 papers and reviews in leading journals as well as edited 5 books. He
currently holds or has applications pending for more than l40 patents. SciFinder lists more than 600
publications to his credits. Since he started his career in the U.S. at Stony Brook unversty in 1983, he has
given more than 400 invited lectures at universities, research institutes, and industries. Also, he has given
more than 70 Plenary and Invited Lectures at international conferences and symposia.
 Stony Brook Symposium on
New Horizons in Organic Chemistry
September 29-30, 2005
The Charles B. Wang Center

Thursday, September 29
8:00 AM – 1:00 PM Registration
9:00 AM – 11:40 AM SBU Alumni Symposium
11:45 AM- 1:00 PM Buffet Lunch for Registered Participants and Poster Setup

Opening Lecture (1:00-2:00 PM)

Greetings: Dr. Robert L. McGrath, Provost

Moderator: Professor Michael G. White, Chair, Department of Chemistry

Professor Ryoji Noyori

(Nobel Laureate in Chemistry, 2001; President, RIKEN, Japan)
“Asymmetric Hydrogenation: Science and Opportunities”

Session I: Medicinal Chemistry and Drug Discovery (2:00-5:30 PM)

Moderator: Professor Frank W. Fowler

2:00 – 2:30 Professor Gunda I. Georg (University of Kansas)

“Taxol: Brain Delivery”

2:30 – 3:00 Dr. Alain Commerçon (Sanofi-Aventis, France)

“New Generation Taxoids: Discovery and Development of RPR109881”

3:00 – 3:30 Dr. John Piwinski (Schering-Plough Research Institute, NJ))

“Utilizing SAR and SBDD to Discover Novel Antiviral Agents”

3:30 – 4:00 Coffee break, Poster Session

Moderator: Professor Joseph W. Lauher

4:00 – 4:30 Dr. Ezio Bombardelli (Indena, SpA, Italy)

“Colchicine and its analogues as potential anticancer drugs”

4:30 – 5:00 Dr. Ralph J. Bernacki (Roswell Park Cancer Institute)

“IDN 5390, a novel seco-taxane with anti-angiogenic activity, inhibits
endothelial cell motility at sub-cytotoxic concentrations”
5:00 – 5:30 Professor David G. I. Kingston (Virginia Tech.)
“The shape of things to come: Structural and synthetic studies of Taxol and
related compounds”

5:30 – 6:15 Short talks by poster presenters

6:15 – 7:00 Reception, Student Activity Center Ballroom B

(Registered Participants Only)

7:00 – 9:30 Symposium Banquet, Student Activity Center Ballroom A

(Registered Participants Only)

Friday, September 30
8:00 – 8:40 Continental Breakfast, Charles B. Wang Center
8:40 Greetings: Dr. James V. Staros, Dean, College of Arts and Sciences,

Session II: Synthetic Methodology and Organic Synthesis (8:45-12:30)

Moderator: Professor Kathlyn A. Parker

8:45 – 9:15 Professor Eiichi Negishi (Purdue University)

“ZACA Reaction: Zr-Catalyzed Asymmetric Carboalumination of Alkenes”

9:15 – 9:45 Professor Masahiro Murakami (Kyoto University, Japan)

“Torque Control by Metal-Orbital Interactions”

9:45 – 10:15 Professor Hisashi Yamamoto (University of Chicago)

“Designer Acid Catalysis for Selective Organic Transformation”

10:15-10:30 Short Coffee Break

Moderator: Professor Nancy S. Goroff

10:30 – 11:00 Professor Michael P. Doyle (University of Maryland)

“New Advances in Catalysis with Dirhodium(II) Compounds”

11:00 – 11:30 Professor Gary A. Molander (University of Pennsylvania)

“Expanding Organoboron Chemistry with Organotrifluoroborates”

11:30 – 12:00 Professor Thomas W. Bell (University of Nevada, Reno)

“Synthesis and Photochemistry in Pursuit of a Light-Driven Molecular Motor”

12:00 – 12:30 Professor Eiichi Nakamura (University of Tokyo)

“Organic Synthesis: The Key Science for the Future”

12:30 – 1:30 Lunch, Poster Session

Session III: Bioorganic Chemistry and Chemical Biology (1:30-5:30 PM)

Moderator: Professor Dale G. Drueckhammer

1:30 – 2:00 Professor Koji Nakanishi (Columbia University)

“Bioorganic studies on gingkolides”

2:00 – 2:30 Professor Peter J. Tonge (Stony Brook University)

“Mycolic Acid, Menaquinone and Mycobactin Biosynthesis: Mining the Magic
Mountain for Novel Tuberculosis Chemotherapeutics”

2:30 – 3:00 Professor Scott M. Sieburth (Temple University)

“Silicon as a Central Drug Design Component”

3:00 – 3:30 Coffee Break, Poster Session

Moderator: Professor Daniel P. Raleigh

3:30 – 4:00 Professor Nicole S. Sampson (Stony Brook University)

“Multivalent and Stereoregular Polymers to Probe Fertilinβ Function in
Fertilization”

4:00 – 4:30 Professor Steven Rokita (University of Maryland)

“Selective Alkylation of DNA through a Recognition-Dependent Process”

4:30 – 5:00 Professor Cynthia J. Burrows (University of Utah)

“Heterocyclic Chemistry leading to Mutagenesis via Oxidation of DNA Bases”

5:00 – 5:30 Professor Glenn D. Prestwich (University of Utah)

“Injectable synthetic extracellular matrix for tissue engineering and repair”

5:30 Closing Remarks: Robert C. Kerber, Associate Chair, Department of Chemistry

 SBU Alumni Symposium
September 29 (9:00 – 11:40 AM), 2005

8:30 – 9:00 Coffee and Danish, Charles B. Wang Center

Greetings: Dr. Donna M. Iula, Chair of Organizing Committee, Pfizer

Moderator: Dr. Seung-Yub Lee, ICB & DD

9:00 – 9:20 Dr. Scott D. Kuduk (Merck Research Laboratories, PA)

“2,3-Diaminopyridine Bradykinin B1 Receptor Antagonists”

9:20 – 9:40 Dr. An T. Vu (Wyeth Research, PA)

“2-Phenylquinolines as Potent and Selective Estrogen Receptor beta (ERβ)
Ligands”

9:40 – 10:00 Professor Thierry Brigaud (Université de Cergy-Pontoise, France)

“Chiral fluorinated imines and oxazolidines: synthons for organofluorine
chemistry and asymmetric synthesis”

10:00 – 10:20 Dr. Joseph Zhu (Amgen, Inc., CA)

“Design and Synthesis of Conformationally Constrained TRPV1 Antagonists”

10:20 – 10:40 Dr. Matthew M. Zhao (Merck Research Laboratories, NJ)

“Development of the Manufacturing Process to Emend® (Aprepitant), Winner
of 2005 Presidential Green Chemistry Challenge Award”

10:40 – 11:00 Dr. Ivan Habuš (Ruđer Bošković Institute, Croatia)

“Diels-Alder reactions on imines derived from 3-amino-β-lactams”

11:00 – 11:20 Dr. Masakatsu Eguchi (Institute for Chemical Genomics, WA)
“Design, Synthesis, and Application of Peptide Secondary Structure Mimetics”

11:20 – 11:40 Professor Elke Schoffers (Western Michigan University)

“Looking for a Ligand with a New Twist? Chiral Phenanthrolines for Organic
Chemistry”

11:40 Greeting and Remarks: Professor Iwao Ojima

Asymmetric Hydrogenation: Science and Opportunities
Asymmetric catalysis is four-dimensional chemistry. High efficiency can be achieved only by using a
combination of both an ideal three-dimensional structure (x, y, z) and suitable kinetics (t). Although H-
H bonds are readily cleaved by transition metal complexes, truly useful asymmetric hydrogenations are
limited. BINAP-transition metal complexes are shaped in a manner that is beneficial for chiral
recognition, and these complexes can act as hydrogenation catalysts. However, their efficiency highly
depends on the metal and the auxiliary anionic or neutral ligands, and the reaction conditions. No
universal catalysts exist because of the diversity of unsaturated organic compounds. The means of
developing efficient asymmetric hydrogenations is discussed from a mechanistic point of view.

Professor Ryoji Noyori (President, RIKEN, Japan)

Nobel Laureate in Chemistry, 2001
Ryoji Noyori was born in 1938 in Japan, was educated at Kyoto University and became an Instructor in
Hitosi Nozaki's group at the same university in 1963. He was appointed Associate Professor at Nagoya
University in 1968, spent a postdoctoral year at Harvard with E.J. Corey in 1969–1970 and, shortly
after returning to Nagoya, was promoted to Professor in 1972. In 2003, he was appointed President of
RIKEN and also University Professor at Nagoya. Noyori is a Member of the Japan Academy and the
Pontifical Academy of Sciences, and a Foreign Member of the National Academy of Sciences, USA,
the Russian Academy of Sciences, and the Royal Society, UK. His research has long focused on the
fundamentals and applications of molecular catalysis based on organometallic chemistry, particularly
asymmetric catalysis and what is now known as "green chemistry”. In 2001, he received the Wolf
Prize in Chemistry and the Roger Adams Award, and also shared the Nobel Prize in Chemistry with W.
S. Knowles and K. B. Sharpless.
 Professor Gunda I. Georg
(University of Kansas)
Gunda I. Georg is a University Distinguished Professor in the Departme
nt of Medicinal Chemistry at the University of Kansas. She also is the
Director of the Center for Drug Discovery and the Director of the Exper
imental Therapeutics Program of the Kansas Masonic Cancer Institute.
She is the PI of a statewide NIH COBRE Center for Cancer Experiment
al Therapeutics. She received the Dr. rer. nat. degree in Medicinal Che
mistry from the University of Marburg in Germany in 1980 and was a p
ostdoc in the Department of Chemistry at the University of Ottawa, Can
ada. She has over 130 publications in the area of organic medicinal che
mistry with a focus on the synthesis and structure-activity studies of anti
cancer natural products and male contraceptive agents. She is the co-inv
entor of Aquavan®, a water-soluble anesthetic, which is in phase III cli
nical trails. She has served on various scientific advisory boards, for ex
ample for the NIH, the American Cancer Society, and the Institute for t
he Study of Aging. She is an AAAS Fellow and has received the Sato
Memorial International Award of the Pharmaceutical Society of Japan a
mong other honors.

Taxol: Brain Delivery

Taxol, commonly used for the treatment of breast, ovarian, and lung cancer, is not significantly
absorbed across the gastrointestinal epithelium after oral administration and does not cross the blood-
brain-barrier. A primary mechanism limiting taxol distribution into the brain is active efflux by the
multi-drug resistant gene product 1 (MDR1) or P-glycoprotein (Pgp) localized on the blood side of the
microcerebrovascular endothelium comprising the BBB. We hypothesized that specific modifications
of the taxol molecule could reduce binding or recognition by Pgp, resulting in improved BBB
permeability. Our approach is based on Seelig’s suggestion that clusters of hydrogen bond acceptors
(electron donating groups), arranged in fixed spatial distances from each other, are required for
recognition by Pgp binding sites. The recognition elements are formed either by two or by three
electron donating groups. It was also hypothesized that the number and strength of the hydrogen bonds
present in a molecule determine Pgp affinity. This implies that one could remove recognition elements
from the molecule that are not necessary for biological activity and improve BBB penetration. It was
further observed that certain functional groups with a negative charge do not interact with Pgp. We
investigated a number of taxol analogues that were modified at the 3’-amide group, at C9, C10, and C7
to test this hypothesis. The analogues were analyzed for cytotoxicity against the MCF7 breast cancer
cell line and the drug resistant breast cancer cell line NCI/ADR-RES. They were also investigated for
their influence on rhodamine 123 uptake into brain microvessel endothelial cells to assess interaction
with Pgp. One of the derivatives, the C10 hemisuccinate analogue of Taxol (Tx-67), was also examined
in an in situ rat brain perfusion experiment (J. Med. Chem. 2005, 48, 832). Several of the taxol
analogues, including Tx-67 showed reduced interaction with Pgp in the BBB.
 Dr. Alain Commerçon
(Sanofi-Aventis, France)
2005-present : Currently head of Natural Products Chemistry at
Sanofi-Aventis
2004-2005 : Senior Director at Aventis. Head of HTMC (High Throu
put Medicinal Chemistry) and Coordinator of NPCT (Nat
ural Product Chemistry Team)

Member of the National Commissions of ARC – French Association for

Cancer Research (2000-2004).
Member of the board of SFC (Société Française de Chimie)
Member of the board of SCT (Société de Chimie Thérapeutique)
Member of the Scientific Board of Ariana Pharmaceuticals

Sanofi-aventis New Generation Taxoids:

Discovery and Development of RPR109881

Cancer is still the leading cause of death throughout the world. Although chemotherapy plays the key
role for treating advanced cancer, results of currently available chemotherapy regimens are still
disappointing. Recently, several new compounds, such as taxanes and camptothecines, have
demonstrated promising activities. Among these compounds, the taxanes, paclitaxel and docetaxel, have
the same mechanism of action and have broad antitumor activity on solid tumors (e.g. breast, ovarian,
lung, prostate) . These compounds interact with polymerized tubulin to promote the formation of
microtubules, to prevent their disassemble, and, thus, to block cell division at the G2-M phase.
At present taxanes are key compounds in chemotherapy treatment. However recurrences are common
and new agents active after taxanes failure are necessary. As part of our research program on new
generation taxoids, a main objective has been the targeting of resistant / refractory tumor cells. Our
efforts led to the discovery of new generation compounds. Within this set of promising molecules was
RPR109881, a new modified taxane generated by a serendipitous chemical rearrangement. The initial
approach leading to RPR109881 will be disclosed along with preclinical data. This compound is
currently undergoing clinical trials. Phase I data led to 90 mg/m2 as the recommended dose with 1h
infusion duration. Recent data from Phase II against MBC (metastatic breast cancer) showed that
patients tolerability was acceptable in taxotere non-resistant and taxoid resistant strata, and was similar
to that reported in Phase I studies. Neutropenia was the main hematological toxicity and diarrhea the
most frequent non-hematological toxicity. Efficacy data showed nearly 20% response rate for the
resistant stratum.
These results support the on-going evaluation of RPR109881 versus standard therapy in a randomized
Phase III study of patients with MBC.
 Professor David G. I. Kingston
(Virginia Tech.)
1960 B.A.(Chemistry) Cambridge University, England
1964 Ph.D. (Organic Chemistry) Cambridge University, England
(Advisors: Lord Todd and D.W. Cameron)
1963-1964 Research Associate, M.I.T. Cambridge, Massachusetts
1964-1966 NATO Fellow, Cambridge University
1966-1971 Assistant Professor of Chemistry, SUNY Albany
1971-present Associate Professor - University Distinguished Professor,
Virginia Polytechnic Institute and State University, Blacksburg,
Virginia.
1999 Research Achievement Award, American Society of
Pharmacognosy
2002 Virginia Scientist of the Year, April 2002.
1983-1998 Associate Editor of the Journal of Natural Products
2000-2004 Member of NIH Bioorganic and Natural Products Chemistry
Study Section.

The shape of things to come: Structural and synthetic studies

of Taxol and related compounds.

Paclitaxel (TaxolTM, 1) and its semisynthetic analog docetaxel (2) are two of the most important
anticancer agents developed over the last 30 years, and Professor Ojima has made major contributions
to their chemistry and biology. The compounds continue to excite interest as new activities are
discovered for them and their analogs. Their primary mechanism of action is by interaction with the
cellular protein tubulin, causing irreversible polymerization to microtubules. A detailed knowledge of
this crucial interaction is thus of paramount importance in the design and development of highly potent
analogs and also for the development of “non-taxane” tubulin polymerization agents. The lecture will
review our work on discovering the tubulin-binding conformation of paclitaxel by a combination of
REDOR NMR and fluorescence spectroscopic studies, and by molecular modeling combined with the
results of electron crystallographic studies. This work has resulted in the design and synthesis of
bridged paclitaxel analogs such as 3 that have tubulin-assembly and cytotoxic activities equal to or
better than those of paclitaxel. The implications of this work for the future development of paclitaxel-
like compounds will be discussed, and the synthesis of the simplified analog 4 will be described.

R2O O OH AcO O OH O
O
HO
O O
R1 NH O
O X BzO
Ph O O HO O O Ph N
H O
OH HO OAc HO O
OCOPh PhCOO
1 2
1 R = Ph, R = Ac PhCONH O O
2 R1 = Me3CO, R2 = H 4
3
 Dr. Ezio Bombardelli
(Indena SpA)
Dr. Bombardelli is President of the Scientific Board for Research and
Development of Natural Products, Indena SpA, Milan Italy. He
received his B.Sc. in Biology from the University of Pavia in 1962,
and completed a 5 year postdoctoral role of Assistant Professor at the
Biochemistry Institute at the University of Milan, 1962-1966. In
1962 he went on to join Inverni Della Beffa SpA, Milan, Italy, as
Deputy Director of Research and Development, 1962-1985. Main
duties were conducting chemical research on natural products of
natural semi-synthetic origin, isolation, structure elucidation,
synthesis and medicinal chemistry. From 1986 he became Scientific
Director of Indena SpA before becoming President. Special research
interests have been Botanical Derivatives, Anti-tumour, Anti-
inflammatory, Anti-microbial, Anti-viral and CNS compounds. Over
390 research papers have been published and about 120 patents. He
has been an active participant to many conferences and symposia,
where he has presented numerous scientific papers.

Colchicine and its analogues as potential anticancer drugs

Colchicine is an alkaloid extracted from the seeds of Colchicum autumnale, a plant native of the
Caucasian area and reported since the Greek Antiquity for the treatment of joints-pain.
Curiously neglected in Europe for centuries, the plant was introduced in the States by Benjamin
Franklin after a trip to United Kingdom where he got relief from gout by application an extract of
Colchicum.
The demand of colchicine in the world is today appreciably high not only because of its use in the
treatment of the gout, but also because of its importance as starting material for the manufacturing its 3-
O-glucosyl thio-analogue, thiocolchicoside, widely used in Europe for the treatment of spasticity and
muscular contractures.
Colchicine is also known as an antimitotic agent and its citotoxic properties were discovered in 1889,
when the Italian scientist Pernice described the influence of such an alkaloid on tissues proliferation.
Nevertheless the compound is probably the oldest citotoxic drug known still lacking of any clinical
application. A colchicine analogue, known with the trademark of Colcemid®, has been in use for a
fairly limited period for the treatment of Hodgkin’s lymphoma.
The major limiting factors of the class of colchinoids were the appreciable toxicity and the development
of resistance.
Believing in the potentiality of this class we kept on re-examining many natural and semisynthetic
derivatives, together their thio-analogues, focusing our attention particularly on the activity against
platinum resistant, taxane resistant and MDR tumours. After an extensive SAR study we found that
appreciable result in vitro were obtained by modification of ring B and derivatization of nitrogen. In
particular we found that dimeric derivatives of thiocolchicine, whose IDN 5404 is the lead, were
extremely active against colon tumor platinum-resistant cell lines. Furthermore it has been found that
those dimers, besides their classical ability to inhibit the polymerization of tubulin, are able to interact
with topoisomerase I with a mechanism different from that peculiar to camptothecin.
Recently, dosage formulations of IDN 5404 with human serum albumin demonstrated a consistent
reduction in toxicological effects, enhancing therefore the therapeutic index of the class and opening
new possibilities in the treatment of colon cancer.
 Dr. Ralph J. Bernacki
(Roswell Park Cancer Institute)
Pharmacology & Therapeutics Dept.
Grace Cancer Drug Center,
Roswell Park Institute
Buffalo, NY 14263

1972-1974 Cancer Research Scientist I

1974-1976 Cancer Research Scientist II
1976-1977 Senior Cancer Research Scientist
1977-1980 Cancer Research Scientist IV
1981-1993 Cancer Research Scientist V
1993-2000 Cancer Research Scientist VI
2000-present Member

IDN 5390, a novel seco-taxane with anti-angiogenic activity,

inhibits endothelial cell motility at sub-cytotoxic concentrations

The protracted low-dose administration of conventional chemotherapeutic agents, including the taxanes
paclitaxel and docetaxel, has been shown to inhibit tumor growth by an anti-angiogenic mechanism. However,
the feasibility of these two clinical agents for protracted scheduling is limited by host toxicity and poor oral
bioavailibility. IDN 5390, a novel seco-taxane derivative with demonstrated anti-tumor activity, has improved
oral bioavailability and a toxicity profile suitable for daily administration, rendering it an excellent candidate for
protracted dosing in vivo to achieve an anti-angiogenic effect. The aims of these studies were to evaluate the in
vitro activity of IDN 5390 on endothelial cell functions relevant to angiogenesis, namely endothelial cell
proliferation, motility and microcapillary formation, and to compare the efficacy of IDN 5390 to paclitaxel and
docetaxel. In a modified Boyden chamber migration assay, a monolayer “wound” closure assay and a capillary
tube formation assay, IDN 5390 inhibited human umbilical vein endothelial cell (HUVEC) migration and
capillary formation in a dose-dependent manner at concentrations that did not compromise cell viability. In
contrast, paclitaxel and docetaxel, although more potent inhibitors of endothelial cell proliferation, did not
exhibit selectivity for inhibition of cell migration or capillary tube formation. Further evaluation of these agents
revealed that while paclitaxel, docetaxel and IDN 5390 all potently polymerized purified tubulin in vitro, IDN
5390 did not stabilize microtubules against depolymerization as potently as paclitaxel or docetaxel, suggesting
that the dynamic instability of microtubules of these agents may be differentially regulated in a cellular context.
Indeed, treatment of HUVEC with IDN 5390, even at high concentrations, resulted in only a transient G2/M
arrest, while paclitaxel and docetaxel induced sustained G2/M arrest to an overall greater extent than IDN 5390.
The in vivo anti-angiogenic activities of IDN 5390 and docetaxel were compared in a subcutaneous Matrigel
plug assay of neovascularization. Docetaxel administered intravenously to mice Q3D x 3 doses at 20, 10 and 5
mg/kg/dose was compared to IDN 5390 adminstered orally, QD at 120, 60 and 30 mg/kg/dose. The anti-
angiogenic effect of docetaxel even at the highest dose of 20mg/kg/dose was only equal to that of IDN 5390 at
the lowest dose, as determined by microvessel density in the CD31 immunnostained plug. Additionally, greater
toxicity, as determined by animal weight loss, was observed among docetaxel-treated animals compared to IDN
5390-treated animals. Thus, the selective anti-motility activity on endothelial cells and the differential
regulation of microtubule dynamics by IDN 5390 represent a novel mechanism of taxane drug action and a new
paradigm in anti-angiogenic taxane drug development. (Supported in part by funds from Indena SpA, Milan,
Italy.)
 Dr. John Piwinski
(Schering-Plough Research Institute, NJ)
John J. Piwinski received his B.S. degree in Chemistry and Biochemistry
from the State University of New York at Stony Brook in 1976. As an
undergraduate, he received his first exposure to research by working
under the direction of Professor Frank W. Fowler. In 1980 he received
his Ph.D. in Organic Chemistry from Yale University working with
Professor Frederick E. Ziegler. He joined Revlon Health Care (USV
Laboratories) in 1980 as a Senior Scientist working in the cardiovascular
diseases area. In 1983 he moved to Schering-Plough where he worked in
the respiratory diseases group. He was promoted to Director of Chemistry
for Allergy and Immunology in 1992, to Vice President of Chemical
Research in 1999 and most recently Group Vice President of Chemical
Research in 2004. He also has approximately 120 published research
papers, abstracts and approved U.S. patents. He is a member of the
Scientific Advisory Board for the New Jersey Academy of Sciences since
1996, a member of the American Chemical Society since 1975 and most
recently serves as a member for the Institute of Chemical Biology & Drug
Discovery Advisory Board at SUNY at Stony Brook.

Utilizing SAR and SBDD to Discover Novel Antiviral Agents

Over the past century medicinal chemistry has played a pivotal role in the discovery of new therapeutic
agents for the treatment of disease. The fundamental role of organic synthesis for investigating
structure-activity relationships (SAR) to attain a desired pharmacological profile for a therapeutic agent
has not changed much during this time. However, as we gained a better understanding of how
therapeutic agents work at the molecular level, a new direction in the drug discovery process emerged
towards the latter half of the century. Simultaneously, new methods and technologies emerged that
improved the drug discovery process, such as tools to aid in structure-based drug design (SBDD).
These new technologies enabled the medicinal chemist to design more potent and selective agents with
improved pharmacokinetic and in vivo profiles. As a result, new medicines are being approved today
that are very safe and treat diseases that previously had no cures. This presentation will illustrate how
scientists have been integrating many of these new technologies to discover modern medicines. Efforts
at Schering-Plough have resulted in a series of CCR5 antagonists and HCV protease inhibitors, which
have resulted in compounds that are currently in clinical development for the treatment of HIV and
Hepatitis C.
 Professor Eiichi Negishi
(Purdue University)
H. C. Brown Distinguished Professor of Chemistry, Purdue University,
grew up in Japan and received his Bachelor’s degree from the University
of Tokyo (1958). He then joined a chemical company, Teijin. In 1960 he
came to the University of Pennsylvania on a Fulbright Scholarship and
obtained his Ph.D. degree in 1963. He returned to Teijin but joined
Professor H. C. Brown’s Laboratories at Purdue as a Postdoctoral
Associate in 1966. He was appointed Assistant to Professor Brown in
1968. It was during the following few years that he began to see the need
for some catalytic ways of promoting organoborane reactions. Negishi
went to Syracuse University as Assistant Professor in 1972 and was
promoted to Associate Professor in 1976. In 1979 he was invited back to
Purdue University as Full Professor. In 1999 he was appointed the
inaugural H. C. Brown Distinguished Professor of Chemistry. Various
awards he has received include the Guggenheim Fellowship (1987), the
1996 A. R. Day Award, a 1997 Chemical Society of Japan Award, the
1998 ACS Organometallic Chemistry Award, a Humboldt Senior
Researcher Award, Germany (1998 – 2001), and the 2000 RSC Sir E.
Frankland Prize Lectureship. At Purdue University, he was the recipient
of the 1998 McCoy Award and the 2003 Sigma Xi Award.

ZACA Reaction:
Zr-Catalyzed Asymmetric Carboalumination of Alkenes

The Zr-catalyzed asymmetric carboalumination of alkenes (ZACA reaction) was discovered a decade
ago. (i) R3Al, cat. (-)-(NMI)2ZrCl2 R
(ii) O2 R = Me, 70-80% ee
R1 OH
R1 R = Et or higher alkyl, 90-95% ee

The ZACA reaction represents a prototypical example of enantioselective carbon-carbon bond-forming

reactions of alkenes of one-point binding. It is catalytic in both Zr and a chiral auxiliary, e.g., NMI. The
enantioface selectivity of methylalumination has only been 70-80% ee, although that of ethyl- and
higher alkylmetalation has been 90-95% ee. Despite the less than satisfactory enantioselectivity for
methylalumination, a highly efficient asymmetric method for the synthesis of a wide range of
stereochemically pure chiral organic compounds including (i) deoxypolypropionates, and (ii) reduced
terpenoids, such as vitamins E and K, has been developed. The current status of the ZACA-based
asymmetric method will be discussed with emphasis on several methodological breakthroughs. Some of
the noteworthy transformations are shown below. In cases where the products cannot be readily purified
by simple means, such as chromatography and recrystallization, the lipase-catalyzed selective
acetylation may be used to produce stereoisomerically pure compounds in 60-80% recovery.
(i) Et3Al, IBAO
(ii) cat. (-)-(NMI)2ZrCl2
H 3 O+
90% ee
OH 92% OH
(i) Zn(OTf)2, DMF
Me3Al
cat. (-)-(NMI)2ZrCl2 (ii) vinyl bromide, cat. PdLn
1 1 AlMe2 R1
R R 71% overall 75% ee
(i) Me3Al t
cat. (+)-(NMI)2ZrCl2 (i) BuLi then ZnBr2
(ii) I2, (iii) TBSCl, base (ii) vinyl bromide, cat. PdLn
HO
TBSO I TBSO

"One-pot" "One-pot"
(-)-ZACA-Pd-cat. vinyl. (+)-ZACA-Pd-cat. vinyl.
etc.
 Professor Masahiro Murakami
(Kyoto University, Japan)
1984 Doctor of Science The University of Tokyo
(Prof. Mukaiyama)
1984 – 1987 Assistant, The University of Tokyo
1987 – 1993 Assistant, Kyoto University
1991 – 1992 Postdoctoral Fellow, ETH Zürich, Switzerland
(Prof. Eschenmoser)
1993 – 2001 Associate Professor, Kyoto University
2002 – Present Professor, Kyoto University

Contrasteric Torque Control by Metal-Orbital Interactions

The electrocyclic ring-opening of cyclobutenes is a classical textbook example of concerted pericyclic

reactions that proceed under the control of the Woodward–Hoffmann rules. Substituents located at the
3- and 4-positions can move either inward or outward during the thermal ring opening reaction. Rondan
and Houk proved that the selectivity of the rotational direction, termed torquoselectivity, is subject to
electronic control. We discovered the interesting preference of silyl groups to rotate inward,
contradicting intuitive expectation for outward rotation based on steric grounds. The antibonding 　*
orbital of a silicon–carbon linkage is energetically low-lying and able to accept electron density from
the HOMO of the opening cyclobutene skeleton, stabilizing the inward transition state.
H H 110 　
C C C
C C H H + PhMe2Si H
PhMe2Si H PhMe2Si H H H
Si
77 : 23
The following reaction of trans-3,4-bis(trimethylsilyl)cyclobutene presents a striking exam¬ple of
contrasteric behaviors.1 In addition, exclusive inward rotation was experimentally identified with 3-
borylcyclo-butene.2

H SiMe3 110 　
C H H + E,E-isomer
Me3Si H Me3Si SiMe3
78 : 22
1. Murakami M., Hasegawa, M. Angew. Chem. Int. Ed.
H H 92 　
C 2004, 43, 4874.
H H
(pin)B H
2. Murakami M., Usui I., Hasegawa M., Matsuda T. J. Am.
(pin)B H Chem. Soc. 2005, 127, 1366.
(pin)B = pinacolatoboryl exclusive
 Professor Hisashi Yamamoto
(University of Chicago)
Hisashi Yamamoto received his Bachelor from Kyoto University and Ph.
D. from Harvard under the mentorship of Professor E. J. Corey. His first
academic position was as Assistant Professor and lecturer at Kyoto
University, and in 1977 he was appointed Associate Professor of
Chemistry at the University of Hawaii. In 1980 he moved to Nagoya
University where he became Professor in 1983. In 2002, he moved to
United States as Professor at the University of Chicago. He has been
honored to receive the Prelog Medal in 1993, the Chemical Society of
Japan Award in 1995, the Max-Tishler Prize in 1998, Le Grand Prix de la
Fondation Maison de la Chimie in 2002, National Prize of Purple Medal
(Japan) in 2002, and Yamada Prize in 2004.
His current interests are mainly development of new synthetic reactions
in the filed of acid catalysis including designer Lewis acids, designer
Brønsted acids, and combination of these two acid systems. Recently he
is also interested in a new field on Niroso aldol reactions.

Designer Acid Catalysis for Selective Organic Transformation

Lewis and Brønsted acids can be utilized as more effective tools for chemical reactions by sophisticated
engineering as “designer acids”. Needless to say, the ultimate goal of such “designer acids” is to achieve
high reactivity, selectivity, and versatility as a useful tool o f organic synthesis. The full potential of acid
catalysts has not yet been realized. One possible way to take advantage of such abilities may be to apply a
“combined acids system” to the catalyst design. The concept of combined acids, which can be classified
into Brønsted acid assisted Lewis acid (BLA), Lewis acid assisted Lewis acid (LLA), Lewis acid assisted
Brønsted acid (LBA), and Brønsted acid assisted Brønsted acid (BBA), can be a particularly useful tool for
the design of asymmetric catalysis,
because combining such acids will bring out
their inherent reactivity by associative
interaction, and also provide more
organized structure, which will allow an
effective asymmetric environment to be
secured.(1) Table 1 summarizes the
representative examples for each acid
catalysts. The other way to generate highly
reactive acid catalysis is designing super
Lewis acid catalysis based on super
Brønsted acid systems. Several new
Brønsted acids are introduced and used for
selective organic transformations. The
lecture will include these new trends of acid
catalysis in organic synthesis.
1. H. Yamamoto and K. Futatsugi, Angew. Chem. Int.
Ed. Engl., 2005, 44, 1924-1942; See also the following
general introduction of acid catalysis: a) Lewis Acids in
Organic Synthesis, Vols. 1 and 2 (Ed. H. Yamamoto),
Wiley-VCH, Weinhelm, 2000; b) Lewis Acid Reagents:
A Practical Approach (Ed. H. Yamamoto), Oxford
University Press, Oxford, 1999.
 Professor Michael P. Doyle
(University of Maryland)
Michael P. Doyle received his B.S. degree from the College of St.
Thomas in St. Paul, MN, and his Ph.D. degree from Iowa State University.
Following a postdoctoral engagement , he joined the faculty at Hope
College in 1968. In 1984, he moved to Trinity University in San Antonio,
TX, as the Dr. D. R. Semmes Distinguished Professor of Chemistry, and
in 1997 he came to Tucson, AZ, as Vice President, then President, of
Research Corporation and Professor of Chemistry at the University of
Arizona. In 2003 he moved to the University of Maryland, College Park,
where he is Professor and Chair of the Department of Chemistry and
Biochemistry. Among the awards that he has received are a Camille and
Henry Dreyfus Teacher-Scholar Award (1973), a Chemical
Manufacturers Association Catalyst Award (1982), the American
Chemical Society Award for Research at Undergraduate Institutions
(1988), Doctor Honoris Causa from the Russian Academy of Sciences
(1994), Alexander von Humboldt Senior Scientist Award (1995), the
James Flack Norris Award for Excellence in Undergraduate Education
(1995), the George C. Pimentel Award for Chemical Education (2002),
and the Arthur C. Cope Scholar Award (2006). He has written or
coauthored ten books, including Basic Organic Stereochemistry, 20 book
chapters, and he is the co-author of more than 250 journal publications.

New Advances in Catalysis with Dirhodium(II) Compounds

The challenge of development of catalysts that are effective for a broad range of transformations has
been met with dirhodium carboxamidates. With high turnover numbers and selectivities, they are
highly effective for catalytic reactions with diazo esters, as Lewis acids in catalytic processes, and as
oxidation catalysts. Chiral catalysts for metal carbene transformations have been developed.
Dirhodium(II) carboxamidate catalysts that possess four chiral pyrrolidone, oxazolidinone, azetidinone,
or imidazolidinone ligands with pendent ester substituents are highly effective. Optical yields of greater
than 95% have been achieved in intramolecular cyclopropanation reactions in alkyne cyclopropenation
reactions, in gamma-lactone production from carbon-hydrogen insertion reactions of diazoacetate esters.
New applications of these catalysts as Lewis acids (hetero-Diels-Alder and ketene cycloaddition
reactions) and for chemical oxidations will be presented.
 Professor Gary A. Molander
(University of Pennsylvania)
Consultant, Hauser Chemical Research, 1991-1999. NIH Medicinal
Chemistry Study Section, 1993-1997. Associate Chair, Department of
Chemistry and Biochemistry, University of Colorado, 1992-1995. Elected
Member-at-Large, ACS Division of Organic Chemistry Executive
Committee, 1999. Executive Director, 37th National Organic Symposium,
1999-2001. Editorial Advisory Board, Organometallics, 2000-2003.
Chair-Elect, Philadelphia Organic Chemists’ Club, 2000. Chair,
Philadelphia Organic Chemists’ Club, 2001. Alternate Councilor,
Philadelphia Section of the American Chemical Society, 2001-2003.
Associate Editor, Organic Letters, 2002-.
Editorial Advisory Board, Current Topics in Medicinal Chemistry, 2002-.
Associate Editor, Comprehensive Organic Functional Group
Transformations II, Pergamon Press, 2003-2004. Board of Consulting
Editors, Tetrahedron and Tetrahedron Letters, 2003-2008. Director,
Philadelphia Section of the American Chemical Society, 2004-2006.
Volume Editor, Science of Synthesis, Thieme Publishers, 2004-2005.
Editor, Encyclopedia of Reagents for Organic Synthesis, Wiley, 2004-
present. Secretary/Treasurer, ACS Division of Organic Chemistry, 2005-
present. Vice Chair, Department of Chemistry, University of
Pennsylvania, 2005- presnet.

Expanding Organoboron Chemistry with Organotrifluoroborates

Organotrifluoroborates have emerged as complementary boron reagents for Suzuki-Miyaura type cross-
coupling reactions. For many years, boronic acids, boronate esters or organoboranes have been
employed as the principle organoboron partners in these transformations. However, these reagents
possess many limitations. Boronic acids are notorious for the difficulty involved in their purification as
well as their uncertain stoichiometry. Even though the use of boronate esters is more attractive from
this point of view, these reagents lack atom economy and are more expensive to employ.
Organoboranes are limited by the inherent characteristics of the in situ hydroboration reaction used to
create them. These latter reagents also suffer from high sensitivity to air and poor functional group
compatibility in some cases. In contrast, organotrifluoroborates are unique compounds that have been
shown to overcome these limitations. These reagents can be easily prepared from inexpensive materials.
They are stable to air and moisture, allowing storage for long periods of time without noticeable
degradation. In fact, their high versatility and stability has made them excellent partners in Suzuki-
Miyaura type coupling reactions.
The presentation will outline the utility and versatility of organotrifluoroborates in cross-coupling
reactions. Additionally, the ability of these reagents to resist chemical oxidation will be highlighted.
This feature of organotrifluoroborates offers the unique opportunity to preserve the carbon-boron bond
in the oxidation of remote functionality within the same molecule.
 Professor Thomas W. Bell
(University of Nevada, Rino)
Thomas Bell, born in 1951, received his PhD from University College,
London in 1980, having conducted his thesis research with F. Sondheimar
and D.J. Cram (UCLA). He worked with J. Meinwald as an NIH
Postdoctoral Fellow at Cornell University, then joined the State
University of New York at Stony Brook as an Assistant Professor in 1982.
There, he reached the rank of Professor in 1991, then moved to his
current position as Professor of Chemistry at the University of Nevada,
Reno, in 1995. He has been a Fellow of the American Association of the
Advancement of Science since 1994; in 1990 and 1996 he was appointed
Visiting Professor at Université Louis Pasteur in Strasbourg, France. His
current interests include advanced materials, antiviral and
immunomodulatory drugs, nanoscale molecular assemblies and devices,
and supramolecular chemistry, as well as hiking, mountain biking, skiing
and snowboarding.

Synthesis and Photochemistry

in Pursuit of a Light-Driven Molecular Motor

A multidisciplinary team at UNR has planned the synthesis of a light-driven molecular motor of
potential use in nanotechnology. Design and modeling of a molecular motor based on “sterically
geared” 9-(2,2,2-triphenylethylidene)fluorene (1)[1] are discussed. Several substituted analogs of 1,
such as the 2-tert-butyl derivative (2), have been synthesized to investigate photoisomerization
efficiency. This first photoisomerization study of a dibenzofulvene reveals significant quantum yields (4
9%), despite theoretical prediction of inefficient or negligible isomerization of the parent hydrocarbon,
fulvene. Polar substituents increase absorption wavelengths and can greatly enhance
photoisomerization quantum yields. The current status of our efforts to synthesize the target molecular
motor is also described.

Ph3C
CPh3

(E)-6
(Z)-6
1

[1] T.W. Bell, V. J. Catalano, M.G.B. Drew, D. J. Phillips, Chem. Eur. J., 2002, 8, 2219.
 Professor Eiichi Nakamura
(University of Tokyo)
Eiichi Nakamura received his first degree in chemistry with Prof. T.
Mukaiyama and his Ph.D. degree in 1978 with Prof. I. Kuwajima both at
Tokyo Institute of Technology. After two postdoctoral years with Prof. G.
Stork at Columbia University, he started his academic career at Tokyo
Institute of Technology in 1980, and in 1995, he moved to the University
of Tokyo as a Professor of Physical Organic Chemistry. He is currently
the Project Leader of "Nakamura Functional Carbon Cluster" ERATO
Project (Japan Agency for Science and Technology) and a Senior Science
Officer at the Japan Society for Promotion of Science. He is a recipient of
The Japan IBM Science Prize (1993), Nagoya Medal in Organic
Chemistry, Silver Meal (2001) and The Chemical Society of Japan Award
(2003). He is a Fellow of the American Association for Advancement of
Science and a Fellow of the Royal Society of Chemistry.

Organic Synthesis: The Key Science for the Future

Carbon clusters remain to be the subject of 2000 papers every year. While a majority of these reports
are concerned with the materials per se, it is our belief that the future science of carbon clusters depends
on chemically modified carbon cluster complexes and control of their nano architectures-a new
challenge for synthetic chemists.
Some time ago, we discovered that addition of an organocopper reagent to [60]fullerene takes place
regioselectiviely to give penta-addition product.[1] The reaction is completely regioselective, often
quantitative and can be carried out on a multi-gram scale with minimum synthetic skill. The adduct can
be converted to a variety of metal complexes, where the fullerene cyclopentadienide (FCp) serves as a
　5-ligand to the metal, an intriguing example being "bucky ferrocene".[2] We also found that metal
atoms can be introduced also in a "ship-in-bottle" way into carbon nanotubes to make endohedral
metallonanotubes.[3] Such engineered carbon clusters can then be transformed into one- or two-
dimensional nano-architectures.[4]

[1] M. Sawamura, H. Iikura, and E. Nakamura, J. Am. Chem. Soc., 118 (1996) 12850-12851.
[2] A. Hashimoto, H. Yorimitsu, K. Ajima, K. Suenaga, H. Isobe, J. Miyawaki, M. Yudasaka, S. Iijima, E. Nakamura, Proc.
Natl. Acad. Sci., 101 (2004) 8527-8530.
[3] M. Sawamura, Y. Kuninobu, M. Toganoh, Y. Matsuo, M. Yamanaka and E. Nakamura, J. Am. Chem. Soc., 124 (2002)
9354-9355.
[4] S. Zhou, C. Burger, B. Chu, M. Sawamura, N. Nagahama, M. Toganoh, U. E. Hackler, H. Isobe, and E. Nakamura,
Science, 291, (2001) 1944-1947; M. Sawamura, K. Kawai, Y. Matsuo, K. Kanie, T. Kato and E. Nakamura, Nature, 419,
(2002) 702-705; E. Nakamura and H. Isobe Acc. Chem. Res. 36, (2003) 807-815.
 Professor Koji Nakanishi
(Columbia University)
Born in Hong Kong, and brought up in Lyon, London, and Alexandria, he
graduated from Nagoya University, 1947 with Fujio Egami. After 2 years
of post-graduate work with Louis Fieser, Harvard University, he returned
to Nagoya University where he completed his Ph.D. in 1954 with
Yoshimasa Hirata He was Assistant Professor at Nagoya until 1958 and
then Professor of Chemistry at Tokyo Kyoiku University. In 1963 he
moved to Tohoku Univeersity, Sendai, and in 1969 joined Columbia
University, becoming Centennial Professor in 1980.
He was a founding member and research director of the International
Centre of Insect Physiology and Ecology (ICIPE) in Kenya, 1969-1977,
and 1978-1991, Director of Suntory Institute for Bioorganic Research,
and was a director at Biosphere 2, Arizona, Columbia University, from
April 2001, until its termination in December 2003.
His research covers isolation and structural studies of natural products,
vision and chiroptical spectroscopy. He discovered NMR NOE in
structure determinations, determined structures of 200 natural products,
published 800 papers. He has received awards from 12 countries. A
Nakanishi Prize of the Am. Chem. Society and the Chem. Soc. Japan
started in 1996 and is awarded in alternate years in Japan and the U.S.

Bioorganic studies on gingkolides

The tree Ginkgo biloba was mentioned in the Chinese Material Medica 5000 years. Fossil records show
that the Ginbkgo genus was present 180 millionsa years ago with many widespread species. However,
today only one species , G. biloba , has survived. The morphology of the Ginkgo tree appears to have
changed very little for over 100 milion years and hence the name the fossil tree. The standardized
extract, containing 21% flavonoids and 7% terpene trilactones (TTL), is the best selling herb selling 1
billion dollars in 1997, the main reputed activity being prevention of dementia and memory
enhancement. The TTL consist of the diterpenoid ginkgolides and the sesquiterpenoid bilobalide,(1) all
having tight cage structures.
The TTL has attracted immense interest when it
was found to be antagonists of PAFR (patelet
activating factor receptor) in 1986; it has since
been found that they are also ligands for several
other receptors.(2,3)
Despite the intense interests, their mode of action on a molecular structure level is hardly known.
With such clarifications in mind, we have been performing studies on chemical conversions,
preparation of photoaffinity probes and bioactivities.(4) These aspects including the finding that TTL
inhibit progress of Alzheimer’s disease(5) will be presented.
(1). a) M. Maruyama, A. Terahara, Y. Nakadaira, M.C. Woods, Y. Takagi, K. Nakanishi, Tetrahedron Lett., 315
(1967). b) M.C. Woods, I. Miura, Y. Nakadaira, A. Terahara, M. Maruyama, K. Nakanishi, Tetrahedron Lett., 321
(1967). (discovery of NOE).
(2). K. Stromgaard and K. Nakanishi. Angew. Chem. Int. Ed. 43, 1640 (2004)
(3). S. Jaracz, K. Nakanishi,A.A.Jensen, K.Stromgaard. Chem. Eur. J, 10,150 (2004).
(4). K. Nakanishi, Bioorg. Med. Chem., 13, 4987 (2005).
(5). O. Vitolo, B.Gomg. Z. Cao, H. Ishii, S. Jaracz, K. Nakanishi, O. Arancio, S. Dzyuba, M. Shelanski, submitted.
 Professor Peter J. Tonge
(Stony Brook University)
1988-1993 Research Associate, Institute for Biological Sciences, NRC,
Ottawa, Canada.
1993-1994 Research Officer, Institute for Biological Sciences, NRC,
Ottawa, Canada.
1995-1995 Staff Investigator, The Picower Institute for Medical
Research, Manhasset, NY
1996-2000 Assistant Professor, Department of Chemistry, SUNY at
Stony Brook.
2000-2004 Associate Professor, Department of Chemistry, SUNY at
Stony Brook.
1996-present Member, Biophysics Graduate Program, Stony Brook.
1997-present Member, Molecular and Cellular Biology Graduate
Program, Stony Brook.
1999-present Member, Biochemistry and Structural Biology Graduate
Program, Stony Brook.
1999-present Member, Center for Infectious Diseases, Stony Brook.
1999-present Member, Molecular Genetics and Microbiology Graduate
Program, Stony Brook.
1999-present Member, Molecular and Cellular Pharmacology Graduate
Program, Stony Brook.
2004-present Member, Institute for Chemical Biology & Drug Discovery

Mycolic Acid, Menaquinone and Mycobactin Biosynthesis:

Mining the Magic Mountain for Novel Tuberculosis
Chemotherapeutics

Novel chemotherapeutics for treating multi-drug resistant (MDR) strains of Mycobacterium

tuberculosis (MTB) are required to combat the spread of tuberculosis, a disease that kills more than two
million people annually. Using structure-based drug design we have developed a series of alkyl-
substituted diphenyl ethers that are uncompetitive inhibitors of InhA, the MTB fatty acid enoyl
reductase. The most potent compound has a Ki’ value of 1 nM for InhA and MIC99 values of 1-3 μM
for both drug sensitive and drug resistant strains of MTB.
In addition to fatty acid biosynthesis, we are using structural and mechanistic approaches to characterize
enzyme targets involved in the biosynthesis of the electron carrier menaquinone and the siderophore
mycobactin, compounds that are essential for MTB viability. Current studies are focused on MenB, the
dihydroxynapthoyl-CoA synthase in menaquinone biosynthesis, as well as MenF the first enzyme in
this pathway which converts chorismate into isochorismate. The mechanism of MenF is being
compared with that of MbtI, the first enzyme in the mycobactin pathway which converts chorismate
into salicylate. Finally we are also studying the tubulin homolog FtsZ, which plays an essential role in
mycobacterial cell division.
 Professor Scott M. Sieburth
(Temple University)
Scott Sieburth grew up in Rhode Island and graduated from Worcester
Polytechnic Institute in 1977. He was awarded his Ph.D. from Harvard
University after studying with Paul Wender there and at Stanford
University. In 1982 he joined the Agricultural Chemicals Group of FMC
Corporation in New Jersey. After seven years with FMC he moved to the
State University of New York at Stony Brook where he was promoted to
Associate Professor in 1996. In 2001 he moved to Temple University in
Philadelphia where he continues to study organosilicon chemistry and
biological activity, synthetic photochemical methods, and total synthesis.

Silicon as a Central Drug Design Component

Organosilanes can be incorporated into peptides and peptide-like molecules as a substituent (e.g., 1) or
in a central position such as silanediol 2. Alpha-silyl amino acid derivatives 1 are relatively new and
can suffer from hydrolytic instability in which the bond between silicon and the peptide chain is broken.
Silanediols such as 2 are potentially unstable toward polymerization reactions (silicone formation). In
both cases, stability is readily achieved by appropriate choice of the silicon environment. Recent
advances in the preparation of 1 and 2, as well as applications of this chemistry toward biologically
active molecules, will be described.

O
H H HO OH H
N N Si N
N
H
O Si O O
1 2
 Professor Nicole S. Sampson
(Stony Brook University)
Nicole S. Sampson was born in Indianapolis, Indiana in 1965 and
acquired her B.S. degree in chemistry at Harvey Mudd College in 1985.
She obtained her Ph.D. in the laboratory of Paul A. Bartlett at UC
Berkeley in 1990 and then carried out postdoctoral research in the
laboratory of Jeremy R. Knowles at Harvard University. Nicole joined
the faculty at Stony Brook University in 1993 and is currently a Professor
of Chemistry, as well as a member of the graduate programs in
Pharmacology, Biochemistry & Structural Biology, and Biophysics. Her
research interests are in the areas of mechanistic enzymology and
chemical biology. Her work presently focuses on catalysis by
cholesterol–modifying enzymes, how they modify the lipid bilayer and
their role in bacterial pathogenesis, investigating the role of protein
segmental dynamics in catalysis, and probing protein–protein interactions
in mammalian fertilization using synthetic molecules.

Multivalent and Stereoregular Polymers

to Probe Fertilinβ Function in Fertilization

In the post-genomic era, understanding protein function is a critical focus of chemical biology research.
The sperm protein fertilinβ, a member of the ADAM family of proteins is implicated in sperm-egg
binding in all mam¬mals studied to date. The three-amino acid sequence ECD is the essential egg-
binding element of fertilinβ. We present the synthesis and mechanistic investigation of polymers that
display the ECD motif in multivalent fashion to probe fertilinβ-egg interactions.
 Professor Steven Rokita
(University of Maryland)
Steven E. Rokita (b.1957), Professor, Department of Chemistry and
Biochemistry, University of Maryland, College Park, MD. B.S., 1979,
University of California at Berkeley; Ph.D., 1983, Massachusetts Institute
of Technology (mentor: Christopher T. Walsh); NIH Postdoctoral
Fellowship, 1984-1986, Rockefeller University (mentor: E. Thomas
Kaiser). Catacosinos Young Investigator for Cancer Research, 1988.
Molecular Biochemistry Advisory Panel, NSF 1993-1996; Bioorganic
and Natural Products Study Section, NIH, 1997-2001. Advisory Board of
Bioconjugate Chemistry, 1997-1999. Vice-Chair (1998) and Chair (1999),
Bioorganic Chemistry Gordon Conference. Nominating Committee,
Biological Chemistry Division, American Chemical Society, 2000.
Alternative Councilor, Biological Chemistry Division, American
Chemical Society, 2002- 2004. Awards (Univ. of Maryland) include
Outstanding Invention (2001) and Faculty Excellence in Research (2005).
Area of Research. Bioorganic/biochemistry. Nucleic acid structure and
reactivity; target promoted alkylation of DNA, excess electron transfer in
DNA; biological and biomimetic reactions of nickel and copper; enzyme
mechanisms of dehalogenation.

Selective Alkylation of DNA

through a Recognition-Dependent Process

Highly electrophilic quinone methides are generated during metabolism of numerous compounds
ranging from food preservatives to anti-cancer drugs. These species readily alkylate the most
nucleophilic sites of DNA. Reaction is reversible, however, and the major adducts act as a reservoir for
continually regenerating quinone methides over an extended period. The consequence of this
reversibility is evident in the evolution of DNA products generated by a simple model quinone methide
as well as quinone methides that have been conjugated to DNA binding ligands. In particular,
oligodeoxynucleotide-quinone methide conjugates appear to form instrastrand adducts with all
nucleotides except for T. Intrastrand reaction remains reversible and yet is not sensitive to trapping by
external agents such as non-complementary DNA, thiols or water. The alternative interstrand reaction
is only observed after association with complementary DNA. Once the self-adduct spontaneously
regenerates the quinone methide, further base pairing with the target strand is allowed. This additional
recognition in turn inhibits reformation of the intrastrand self-adduct and promotes interstrand
alkylation of the chosen target. This overall process represents a
O type of safety catch mechanism for
HO
delivering a highly reactive
intermediate to a precise target and
reversible self-adduct formation
may ultimately provide a general
approach to gene specific reactions in
vivo.
HO

O
OH

quinone methide regeneration target promted alkylation of a

and full target recognition chosen nucleobase sequence
 Professor Cynthia J. Burrows
(University of Utah)
Cindy Burrows studied physical organic chemistry at the University of
Colorado (B. A. 1975) and Cornell University (Ph. D. with B. K.
Carpenter, 1982) before becoming an NSF-CNRS postdoctoral fellow
with Nobelist J.-M. Lehn in Strasbourg, France. From 1983-1995, she
held the positions of Assistant through Full Professor of Chemistry at
Stony Brook and was the western neighbor of the Ojima group. In 1995,
she returned to the West, along with her husband (Prof. Scott Anderson)
and triplets (now age 13), as Professor of Chemistry at the University of
Utah. Research in the Burrows lab ranges from the identification of new
heterocyclic compounds and the mechanisms by which they are formed
during DNA oxidation to the investigation of the biological effects of
these lesions on DNA replication and repair. Prof. Burrows has been a
member of numerous editorial boards and review panels; she also served
as Associate Editor of Organic Letters from its inception until 2002 and is
currently Senior Editor of the Journal of Organic Chemistry. She is a
Fellow of the AAAS and the recipient of the Robert Parry Teaching
Award at the University of Utah; her research was recently recognized
with the ACS Utah Award and the U of U’s Distinguished Creative and
Scholarly Research Award.

Heterocyclic Chemistry leading to Mutagenesis

via Oxidation of DNA Bases

DNA in under constant assault by reactive oxygen species generated endogenously as a byproduct of
respiration and exogenously under conditions of oxidative stress or radiation. Prolonged oxidative
stress forms part of the etiology of cancer, atherosclerosis, neurological diseases and aging. The
guanosine heterocycle is a principal target of oxidation leading to 8-oxoguanosine as well as newly
characterized spirocyclic and guanidinium-derived products. The latter products have been the subject
of some controversy concerning structural characterization and mechanism of formation, and the use of
13C, 15N, and 18O labeling has helped resolve some of these issues. Clues to the mechanism of
formation have suggested parallel pathways for elucidation of adducts formed in oxidative polyamine
and protein cross-linking to DNA. Synthetic methods for generation of new DNA lesions permit
biochemical studies of DNA polymerases and DNA repair enzymes. These studies, in conjunction with
in vivo mutagenesis analysis, suggest that these unusual oxidation products of guanosine may be highly
detrimental to the integrity of the genome due to the formation of unusual base pairs that proliferate and
escape repair.
 Professor Glenn D. Prestwich
University of Utah
Dr. Prestwich graduated with a B.Sc. (Honors) in Chemistry from the
California Institute of Technology in 1970, he earned a Ph.D. in
Chemistry from Stanford University in 1974, followed by three years as
an NIH postdoctoral fellow, first at Cornell University and then at the
International Centre for Insect Physiology and Ecology in Nairobi,
Kenya. From 1977 to 1996, he was at The University at Stony Brook in
New York, as Professor of Chemistry, Professor of Biochemistry & Cell
Biology, and Director of the New York State Center for Advanced
Technology in Medical Biotechnology. He co founded Clear Solutions
Biotechnology, Inc. (Stony Brook, New York) to commercialize
hyaluronan biomaterials. He is a recipient of Alfred P. Sloan Research
and Dreyfus Teacher-Scholar Awards, and was honored with the 1998
Paul Dawson Biotechnology Award of the American Association of
Colleges of Pharmacy. He was elected as a Fellow of the American
Institute for Medical and Biological Engineering in 2005 and was
selected as a V100 Top 100 Venture Entrepreneurs in Utah in 2005.

Injectable synthetic extracellular matrix

for tissue engineering and repair

We recently developed a novel approach to the creation of a fully synthetic, covalently crosslinked
extracellular matrix (sECM). This material may be crosslinked in situ in the presence of cells to
provide an injectable cell-seeded hydrogel for tissue repair, or with drugs in a controlled-release format.
Chemical modification of hyaluronan (HA), other glycosaminoglycans (GAGs), proteins, or other
carboxylate-containing polymers with thiol residues creates macromonomers that can be crosslinked
with biocompatibile polyvalent electrophiles. In the first section of this overview, we present the vision
and strategy for creating sECMs. In the second section, we highlight selected in vitro and in vivo
applications of this technology. Among the applications, we first show in vitro and in vivo growth of
healthy cellularized tissues using films, sponges, and hydrogels based on the sECM technology. We
then extend the use of the in situ crosslinkable sECM to the growth for the in vivo repair of cartilage
defects and healing of tympanic membrane perforations. Next, we describe the use of biointeractive,
crosslinked heparin-containing GAG dressings for controlled release of bFGF and re-epithelialization of
full-thickness wounds in a diabetic mouse model of chronic wound healing. Finally, we illustrate the
use of in situ crosslinkable HA hydrogels, with and without covalently linked antiproliferatives, for
prevention of abdominal surgical adhesions and maintenance of sinus ostia in vivo.
 Dr. Scott D. Kuduk
(Merck Research Laboratories, PA)
Scott Kuduk was born in Long Island, NY. He obtained his B.S. and
Ph.D. degrees at the State University of New York Stony Brook under
the guidance of Professor Iwao Ojima. He joined the Merck Research
Laboratories in 1999 after completing postdoctoral studies with
Professor Samuel Danishefsky at the Sloan-Kettering Institute for
Cancer Research. He is currently a Research Fellow at Merck where his
research has dealt with organofluorine chemistry and with the design of
novel therapeutic agents for the treatment of pain.

2,3-Diaminopyridine Bradykinin B1 Receptor Antagonists

The quest for improved treatments of chronic pain and inflammation continues to be an area of intense
research. Human bradykinin B1 receptor antagonists embody a novel approach for the treatment of
these disease states. A series of 2,3-diaminopyridine based BK B1 receptor antagonists was optimized
to have sub-nanomolar affinity for the human B1 receptor and good pharmacokinetic properties. The
optimization was achieved by blocking a number of potential metabolic pathways, particularly through
the use of various ester isosteres. Lead compounds were shown to exhibit good efficacy in rabbit in
vivo models of pain and inflammation.

R1
H R2
H N
N
O
O
N NH
N NH
R3
CO2Me

R4
 Dr. An T. Vu
(Wyeth Research, PA)
An Vu was born and raised in Saigon, Vietnam. During his youth, he
emigrated along with his parents to the United States and settled in a
small town in Georgia where he continued his secondary education. In
1992 he obtained his B.S. in Chemistry from Mercer University in
Macon, GA. He received his Ph.D. in Organic Chemistry in 1997 from
Emory University in Atlanta, GA, where he studied the transition metal-
mediated reductive cyclization reactions under the direction of Professor
William E. Crowe. He then worked with Professor Iwao Ojima as an
NIH Postdoctoral Research Fellow at the State University of New York
at Stony Brook, where he developed useful catalytic synthetic processes
involving rhodium-catalyzed silylcarbocyclization (SiCaC),
heterosilylcarbocyclization and silylcarbotricyclization (SiCaT)
reactions. In 1999 he joined Wyeth Research in Collegeville, PA where
he is currently a Senior Research Scientist and working in the areas of
women’s health, cardiovascular and metabolic diseases. He is the author
of a number of scientific articles, book chapter, abstracts, presentations,
and patent publications.

2-Phenylquinolines as Potent and Selective

Estrogen Receptor beta (ERβ) Ligands.

The discovery in 1996 of a second subtype of estrogen receptor, estrogen receptor beta (ERβ), with its
unique tissue distribution patterns and transcriptional properties from those of ERα, has prompted
intense research to elucidate its physiological functions and identify its potential therapeutic targets.
Our approach toward this goal has been to utilize highly selective ERβ agonists. Recently, we have
designed and developed a series of 2-phenylquinolines as a new class of ERβ selective ligands. A
number of substituted 2-phenylquinolines displayed low nanomolar affinity and as high as 100 fold
ERβselectivity. A select group of compounds were profiled as either full or partial ERβ agonists in a
cell-based functional assay measuring the transcription of KRT19 mRNA. The uterine weight
estrogenic bioassay of the most selective compounds showed no significant uterine stimulation, thus
indicating no activation of ERα in this sensitive estrogen target organ. The design, synthesis, biological
evaluation, and potential binding modes within the ligand binding pocket of this class of compounds
will be discussed.

R1
OH
R6
N
R2

HO R3
R5 R4
 Professor Thierry Brigaud
(Université de Cergy-Pontoise, France)
Born 16 August 1962 in Paray-le-Monial (France). Ph.D in organic
chemistry in 1990 at the Université Claude Bernard, Lyon I (France)
under the direction of Prof. E. Laurent: Nucleophilic fluorination in α-
position of an aromatic ring or a thioether. Postdoc at the State
University of New York at Stony Brook (USA) in 1990-1991 under the
supervision of Prof. I. Ojima : Asymmetric synthesis of non-protein
amino acids. In 1991, appointed maître de conférences of the Université
de Reims Champagne-Ardenne (France). From 2002, appointed
professor of the université de Cergy-Pontoise (France). Main domain of
interest: Organofluorine chemistry, asymmetric synthesis, Synthesis of
fluorinated analogs of natural products (carbohydrates, terpenes, amino
acids).

Chiral fluorinated imines and oxazolidines:

synthons for organofluorine chemistry and asymmetric synthesis

Fluorinated imines, hydrazones and oxazolidines derived from chiral amino alcohols are very useful
synthons for the stereoselective synthesis of 　-fluoroalkylated amino compounds.1,2
The Strecker and the Mannich-type reactions with chiral fluorinated iminium constitute a powerful
method for the synthesis of enantiopure fluorinated 　 and 　-amino acids, 　-amino ketones, amino
alcohols and diamines in a few steps. NH2

F3C CO2H NH2 O

R1
F3C R
α-amino acids
* β-amino acid and ketones
R
N

F3C R1 NH2 NH2

R2-M NH2
2
or R F3C R F3C 1
ou R2SiMe3 R1 R
H N O Diamines
*

F3C R1
NH2 OH
NH2
OH F3C
F3C 1
R
Amino alcohols
Recent results about the use of fluorinated oxazolidines as chiral auxiliaries will also be presented. The
oxazolidines derived from fluoral hemiacetal and (R)-phenylglycinol are very stable to hydrolysis.
Therefore these oxazolidines can be used as highly efficient chiral auxiliaries for amide enolates alkylation.
R O R O

N Ph 1) Base R' N Ph
F3C F3C
O 2) R'X O
High diastereoselectivity
(1) Lebouvier, N.; Laroche C., Huguenot, F.; Brigaud, T. Tetrahedron Lett. 2002, 43, 2827.
(2) Fries, S.; Pytkowicz, J.; Brigaud, T. Tetrahedron Lett. 2005, 46, 4761.
 Dr. Joseph Zhu
(Amgen, Inc., )
Joseph (Jiawang) Zhu, Ph.D. is currently a Senior Scientist in the
Department of Chemistry Research & Discovery at Amgen, Inc. His
research interests are design and syntheses of biologically and
therapeutically interesting molecules, and studying their
pharmacokinetics, pharmacodynamics, and other properties. He has
published more than 10 articles and co-authored more than 10 patents.
He holds a B.S. in Chemistry from Nanjing University, China, and a
Ph.D. in Chemistry from Colorado State University at Fort Collins under
the supervision of Professor Louis S. Hegedus, and Pursued Post-doc
research in Professor Iwao Ojima’s laboratories at SUNY-Stony Brook.

Design and Synthesis of Conformationally

Constrained TRPV1 Antagonists

The vanilloid receptor-1 (VR1 or TRPV1) belongs to the family of transient receptor potential (TRP)
cation channels and is activated by heat, acid, and plant irritants such as capsaicin. TRPV1 is
predominantly expressed in primary sensory neurons and is involved in the transmission process of
noxious pain stimuli to the brain. Blockade of the cell signaling with a TRPV1 antagonist offers a
potential for the development of novel analgesics.
Recently, we have discovered and reported a series of N-aryl cinnamides as potent, selective, and
competitive TRPV1 antagonists. Probing the antagonist-binding pocket of TRPV1 via studies of its
ligands of (E)-3-(4-tert-butylphenyl)-N-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)acrylamides have lead to
the hypothesis of that the bioactive conformations, the receptor-binding modes, of the N-aryl
cinnamides are the co-planar, s-cis conformation with respect to the carbonyl group. The synthesis,
conformational analysis, and biological properties of these analogs will be presented.
Furthermore, the synthesis and biological activities of conformationally constrained pharmacophores
will be addressed.
 Dr. Matthew M. Zhao
(Merck Research Laboratories, NJ)
Born in 1965, Xingtai, Hebei Province, China. He obtained his BS in
chemistry from Lanzhou University in 1985. He was awarded CGP
scholarship in 1986 to pursue graduate study in the US. He joined
professor Ojima’s group in 1987 and obtained his PhD degree in 1991.
He then went on to Professor Leo Paquette group for postdoctoral
research and was awarded Merck Postdoctoral Fellowship. He joined
Process Research Department in Merck Research Laboratories in 1993
focusing on the development of efficient, robust and environmentally
benign process for the production of novel Merck drug candidates. He
has worked on numerous projects highlighted by the development of
manufacture processes for two successful Merck drugs, Singulair® and
Emend®. He has over 25 publications and hold more then ten patents.
He is currently a Senior Research Fellow.

Development of the Manufacturing Process to Emend®

(Aprepitant), Winner of 2005 Presidential Green Chemistry
Challenge Award

Aprepitant (1), an antagonists of the neurokinin-1 (NK-1) receptor is a new therapeutic agents for the
treatment of chemotherapy-induced emesis. The first generation synthesis allowed us to made multi-
kilogram quantities of the drug substance. Search for better alternatives synthesis of aprepitant
ultimately lead to discovery of a much more efficient manufacturing route with over 80% reduction in
cost, energy and raw material volumes.

CF3
O O

N
H CF3
N F
O
N
N 1
H
 Dr. Ivan Habuš
(Ruđer Bošković Institute, Croatia)
Ivan Habus, Associate Professor, Rudjer Boskovic Institute (RBI,
Zagreb, Croatia), Division of Physical Chemistry, Laboratory for
Analytical Chemistry – Head of the Laboratory. He was born in 1956
and received his Ph.D. in 1988 at RBI. Research project was involved in
the transformations of monosaccharides into new chiral bidentate
ligands, bis-diphenyl-phosphinites and phosphines, and development of
their rhodium(I) complexes as the catalysts for the homogeneous
catalytic hydrogenation of various prochiral substrates. From 1988 to
1990 he was engaged in postdoctoral research with Prof. Iwao Ojima at
SUNY at Stony Brook, NY, USA. He was involved in asymmetric
synthesis of various non-protein amino acids by applying “β-Lactam
Synthon Method”. From 1990 to 1992 he spent with Prof. Francis
Johnson as postdoctoral fellow at SUNY at Stony Brook. At Hybridon,
Inc., Cambridge, MA, USA, he was appointed as research scientist
(1992-1997) and senior research scientist (1997-1998) in the field of
oligonucleotide synthesis. From 1998 to 2000 he was employed as
principal scientist at ArQule, Inc., Woburn, MA, USA, working in the
field of combinatorial chemistry. Currently at RBI, he is supervising the
custom service activities: Organic Elemental Microanalysis (C, H, N, S,
halogens) and FT-IR Spectroscopic Analysis of Urinary/Gall Calculi.
Based on the analysis of urinary calculi in the Laboratory is followed the
presence of urolitiase in the Republic of Croatia dependent on region,
sex, and age of the patients.

Diels-Alder reactions on imines derived from 3-amino-β-lactams

Synthesis of diversily substituted monocyclic β-lactams have been of considerable interest to the
synthetic community in the past few decades [1]. Because of the recent developments using β-lactams
as synthons for several biologically active compounds, research on this topic has gained tremendous
attention [2,3]. Hetero Diels – Alder reactions involving imino-dienes or imino-dienophiles are widely
used for the construction of nitrogen-containing compounds [4,5]. Our interest in the use of 3-amino-β-
lactams [6,7] as starting substrates for the preparation of potentially bioactive products prompted us to
evaluate the combination of the aza-Diels – Alder reaction of 2-azetidinone-tethered imines I with
siloxydienes as a route to the asymmetric synthesis of 5,6-dihydro-γ-pyridones II using β-lactams as
chiral building blocks (Scheme 1) [8,9]. Effects of various dienes and substituents on dienophile, Lewis
acids, and solvents on the product formation and diastereoselectivity of the reactions will be discussed.

R3 O O 1. G.S. Singh, Tetrahedron, 59 (2003) 7631.

R3 R3
2. H.C. Neu, Science, 257 (1992) 1064.
OTMS
N R2 3. A.K. Bose, B.K. Banik, C. Mathur, D.R. Wagle, M.S. Manhas,
Lewis acid
N R2 N R2 Tetrahedron, 56 (2000) 5603.
N
+ CH3CN, -20 oC
+ 4. P. Buonora, J.-C. Olsen, and T. Oh, Tetrahedron, 57 (2001)
O R1 OMe
N N 6099.
O R1 O R1 5. K.A. Jorgensen, Angew. Chem. Int. Ed., 39 (2000) 3558.
I II 6. I. Ojima and I. Habuš, Tetrahedron Lett., 31 (1990) 4289.
R1 = H, Aryl
R1 = H, Aryl
R2 = Fc, Aryl R2 = Fc, Aryl
7. I. Habuš et al., J. Mol. Struct., (2005).
R3 = Fc, Aryl, Alkyl R3 = Fc, Aryl, Alkyl 8. J.F. Kerwin, Jr. and S. Danishefsky, Tetrahedron Lett., 23
(1982) 3739.
9. B. Alcaide, P. Almendros, J.M. Alonso, and M.F. Aly, Chem.
Eur. J., 9 (2003) 3415.
 Dr. Masakatsu Eguchi
(Institute for Chemical Genomics, WA)
Masakatsu Eguchi received his B.S. degree in 1981 and M.S. degree in
1983 in pharmaceutical science from Tokyo College of Pharmacy (now
Tokyo University of Pharmacy and Life Science). His Ph.D. degree was
granted from Brigham Young University, department of chemistry in
1990, where he worked under the late Prof. Bryant Rossiter.
Subsequently, he did postdoctoral work at State University of New York
at Stony Brook with Prof. Iwao Ojima ('90-'93) and Sandoz (now
Novartis). In 1994, he joined Molecumetics Ltd. as a senior scientist and
was promoted to senior research fellow in 1999 working on the design
and combinatorial synthesis of peptidomimetics. He moved to Pacific
Northwest Research Institute as a staff scientist with Prof. Michael Kahn
in 2000. In 2004, Prof. Kahn's research group established a new non-
profit research organization, Institute for Chemical Genomics. Masa has
been actively involved in drug discovery efforts for 10 years.

Design, Synthesis, and Application of Peptide

Secondary Structure Mimetics

Secondary structure elements in proteins play a key role in molecular recognition events in biological
systems through their characteristic three-dimensional presentation of functional groups on their
surfaces. Cytokine-receptor interaction and many protein-DNA interactions are mediated through α-
helical structure, many peptide ligand-receptor interactions and antigenantibody interactions are
mediated through reverse turns, and proteases, kinases, most SH2 domains, and MHC recognize their
substrates through β-strand structures. Most of these proteinprotein interactions are initiated or
mediated by a key local secondary structure element in the protein; therefore, small molecules bearing a
similar local structural feature can effectively mimic the ligand binding function of a protein or peptide.
A successful peptidomimetic must be able to present the correct pharmacophoric residues in the proper
three-dimensional space. Conformationally constrained analogs of such peptidomimetics pay a lower
entropy cost upon binding to their receptor or enzymes. The rapid generation of secondary structure-
templated chemical libraries through solid-phase synthesis is a key technology to develop novel
pharmaceutical agents effectively.
We have developed β-turn and β-strand scaffolds readily accessible through solid phase synthesis from
commercially available diversity components and applied these scaffolds for the preparation of
biologically active compounds such as protease inhibitors, opioid receptor agonists, or transcription
factor modulators. Design and synthesis of these chemical libraries and some preliminary biological
data will be presented.
 Professor Elke Schoffers
(Western Michigan University)
Prof. Schoffers started her academic career at the Johannes Gutenberg
University in Mainz, Germany, and continued graduate studies in the
United States under the supervision of Professors I. Ojima (SUNY Stony
Brook, M.S., 1991), C.R. Johnson (WSU, Ph.D., 1996), and A.J. Pearson
(CWRU, postdoc, 1996-98). Her expertise is in the area of
stereoselective synthesis with background in organometallic,
heterocyclic, and biochemistry. Specific projects address the
development of N-containing ligands for asymmetric catalysis and the
synthesis of metabolites that influence biological signals. This includes
the preparation of inosamines that have been proposed to be nutritional
mediators for nitrogen fixation in legume plants. Over the last 5 years,
Professor Schoffers has worked with 7 graduate and 9 undergraduate
students (8 female, 2 minorities) on various research projects.

Looking for a Ligand with a New Twist?

Chiral Phenanthrolines for Organic Chemistry

1,10-Phenanthroline has long been known for its complexes with metals and non-metals and has thus
found numerous applications in analytical chemistry since the 1930’s. More recently, there has been a
renewed interest in 1,10-phenanthroline and its derivatives for their potential applications in asymmetric
catalysis.
O

O N NH HN
Ph Ph Ph

N N N N N N
(1,10-Ph en) (1) (2)

Herein we report our progress towards functionalizing the 1,10-phenanthroline template, and give
details about the preparation and application of novel optically active derivatives (1, 2). Among others,
we tested these new ligands in asymmetric alkylation, aminohalogenation, reduction and Aldol
reactions
 Biomedical innovation
Through Multidisciplinary
and Translational Research
– From Bench to Bed Side –