Chemistry at Princeton

Chemistry at PRINCETON C E L E B R AT I N G T H E F R I C K C H E M I S T R Y L A B O R ATO R Y

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“For our chemistry faculty, this building is a dream come true, a long-awaited opportunity to transform their workplace, to attract new talent in such areas as organic synthesis, inorganic chemistry, chemical biology, and physical chemistry, and to pursue the complex questions that lie at the intersection of the sciences more effectively than ever before.�

SHIRLEY M. TILGHMAN, PRESIDENT OF PRINCETON UNIVERSITY

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A New World in Chemistry David MacMillan

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A Renaissance for Chemistry at Princeton A. J. Stewart Smith

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New Frontiers of Research

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Teaching Chemistry at Princeton

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New Growth

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A Story of Discovery Edward C. Taylor

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“Studying chemistry at Princeton is an invaluable experience as a result of the department’s dedication toward providing an intellectually stimulating environment as well as a hands-on approach to scientific discovery.”

Yici Zheng (Sarah), chemistry major, Class of 2011

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Some days, when I walk into the new Frick Chemistry Laboratory and take in all the architectural and scientific splendor, I wonder if I am dreaming.

Imagine—just at the time I have been asked to chair the Department of Chemistry, Princeton has constructed the greatest academic building for chemistry in the world. In addition, the University has strongly encouraged us to expand by attracting outstanding new faculty to conduct research and to teach and inspire. It’s a wonderful time to be involved with leading a department.

A NEW WORLD IN CHEMISTRY DAVID MACMILLAN, A. BARTON HEPBURN PROFESSOR OF ORGANIC CHEMISTRY AND CHAIR, DEPARTMENT OF CHEMISTRY

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hat we want is for Princeton to be the best place to

In his classic text, General Chemistry, Pauling concluded: “It is

conduct chemical research and to learn chemistry on a

hard to draw a line between chemistry and other sciences.”

global level. We are going to get there by doing what Princeton does best, which is to concentrate on excellence and to focus on the best people, from professors at the height of their careers to undergraduate students taking their first major steps toward realizing their potential.

Precisely. Chemistry itself, my intellectual love since I was introduced to it as a boy, always has been at the center of revolutionary thinking, and remains so. We know that it will ever be the branch of the natural sciences dealing with the composition of substances and their properties and reactions. Yet we

In looking forward, we envision many exciting new challenges.

We will start by understanding what we mean by “chemistry.”

also understand that we must expand beyond the more classical areas of organic, inorganic, and physical chemistry so that the discipline encompasses more of what it should. With

Chemistry, known as “the central science,” has wielded a strong

their special way of viewing and understanding the world,

influence on many other scientific and technological fields.

chemists are in a unique position to tackle some of the major

Likewise, it has been shaped by other disciplines.

scientific challenges of the century, including the need for new

So what is it? Linus Pauling, who won the 1954 Nobel Prize in Chemistry for his work on the nature of the chemical bond, said, “Chemistry is the science of substances—their structure, their

“biological” medicines, alternative energies, new processes to produce new chemicals, and new materials powering advanced imaging technologies and high-speed electronics.

properties, and the reactions that change them into other

How can we make sure that we are properly taking advantage of

substances.”

the opportunity granted us through the existence of our

Pauling, one of the most influential chemists in history, acknowledged that his definition was far from perfect, being

world-class facilities and deep support at Princeton to sow the seeds for greatness?

both too narrow and overly broad. Chemists, he argued, must

We will do so by focusing on areas where chemistry mixes

know how energy interacts with matter, know how the color of

directly and significantly with other disciplines, such as

substances can be produced by the absorption of light, and

biology, physics, and engineering, and, notably, where they are

must understand the atomic structures of substances. On the

expected to produce solutions with a pronounced, beneficial

other hand, he said, almost all of science can be included within

impact on society.

chemistry, broadly defined.

key research areas

These four areas represent the bulk of what chemists will be researching over the next 20 years. At Princeton, we are actively seeking the best people in these sectors.

Catalysis and Chemical Synthesis

Chemical Biology

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Chemistry intersects with many subjects in biology, such as biophysics and bioinorganics, and the goal is to create or aid the development of new biological medicines.

Energy

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The focus will be projects that expand the capability of alternative energies, such as designing capacitors to store photons from sunlight, using hydrogen and oxygen bonds.

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Researchers will pursue plans to develop new forms of chemical reactions that ultimately will undergird the development of new substances for medicines and materials.

Materials

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Chemists will research new materials with the ability to convey electrons and photons at higher speeds and capacities that will intensify as the demand for faster computers and high-quality imaging systems grows.

A new home for chemistry The Frick Chemistry Laboratory is a worldclass facility from which the Princeton chemistry department is well positioned to move scientific inquiry into the future. David MacMillan, chair of the department, said the completion of the building in 2010 “coincides with a revitalization of the department and the recruitment of top-tier faculty members.”

The modern building is a light-filled 265,000-square-foot single structure that has two wings—one housing laboratories and the other housing offices and conference rooms— spanning a central atrium that is 75 feet high.

Sustainability features are central to the design of the building.

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“This is and will continue to be one of the best infrastructures for chemistry in the world. We have a wonderful home that provides a stimulating environment for teaching and research.”

David MacMillan

We are aware of how deeply chemistry has expanded into the

where she made seminal contributions in the development of

life sciences and will continue to do so. Similarly, chemists

two new catalysis concepts. One, asymmetric alkylation, had

must be at the center of alternative energy developments,

been viewed for a long time as a “holy grail” in the field of

integrally involved in future efforts to convert energy-poor

catalysis.

molecules to energy-rich molecules by employing sunlight as the energy source. Catalysis will be vastly important, acting as a key because it can produce compounds economically and in energy-saving ways. And the ability to study individual atoms and explore interactions granted us by the next generation of scientific instruments not only assures knowledge about the behavior of materials, but will assuredly help produce new varieties.

At Princeton, we are seeking the best people in these research areas. Recently, our faculty has grown with the addition of researchers actively engaged in work at the scientific frontier.

has joined the faculty from Rockefeller University. He combines tools of organic chemistry, biochemistry, and cell biology in his efforts to develop a suite of new technologies that provide fundamental insight into how proteins work. The chemistry-driven approaches Muir has developed will have widespread applications for studying protein function in the postgenomic era.

Haw Yang joined the faculty from the University of CaliforniaBerkeley in 2009. His research is at the forefront of physical chemistry, materials chemistry, and the biophysics of single biological macromolecules. His interdisciplinary work exempli-

For example, Paul Chirik, previously a professor at Cornell

fies the new chemistry, and his talents make him a welcomed,

University, is one of the foremost organometallic chemists on

pivotal force at Princeton.

the planet. He works at the intersection of the traditional disciplines of organic and inorganic chemistry and is seeking to develop chemical reactions that are energy efficient.

Abigail Doyle joined the faculty in 2008 as an assistant professor. As a graduate student at Harvard University, Doyle’s research concentrated on organic synthesis and catalysis, 8

Thomas Muir, one of the world’s premier chemical biologists,

We are ecstatic that these brilliant minds have joined us.

We will enlist many more innovative thinkers as members of Princeton’s chemistry faculty.

In our 265,000-square-foot building, we have a wonderful home that provides a stimulating environment for teaching and

research. It houses outstanding facilities in nuclear magnetic

and Princeton’s U.S. patent has yielded royalties that supported

resonance imaging and catalysis and also will contain stellar

the construction of our wonderful building.

services in mass spectroscopy and protein biochemistry resources. This is and will continue to be one of the best infrastructures for conducting chemistry in the world. In addition, Frick’s location at the heart of the University’s emerging science neighborhood illustrates the centrality of the subject as well as its close ties to many disciplines.

We are fortunate in that we have a rich past upon which to build, including the work of Princeton scientists such as Kurt Mislow, the Hugh Stott Taylor Professor of Chemistry Emeritus, and Edward C. Taylor, the A. Barton Hepburn Professor of Organic Chemistry Emeritus. Mislow, a longtime National Academy of Sciences member, developed key theoretical concepts in stereochemistry, emphasizing the study of molecular chirality in organic, inorganic, and biochemical systems. Taylor’s research

Our roots run deep. Princeton’s ambitions in chemistry stem from a productive past that includes early leadership in this field. Physician John Maclean established the first undergraduate chemistry laboratory on an American campus in Nassau Hall after being appointed a professor of chemistry at Princeton in 1795.

It is fitting then to close with the words of the eminent chemist and Princetonian Hugh Stott Taylor, who chaired the Department of Chemistry from 1926 to 1951. Taylor, a leader in the field of catalysis, looked to the legacy of Maclean for inspiration at the dedication of the old Frick chemistry building in 1929: “May the vivifying influence of Maclean in the early days of science at Princeton be an inspiration to those who follow him in tasks of teaching and seeking in chemistry,” he said.

led to the development of the anti-cancer drug Alimta in

We echo his wish in vowing that we will continue to teach and

cooperation with the pharmaceutical company Eli Lilly and Co.,

to seek.

Art on display in the atrium Suspended from the ceiling is Resonance, a sculpture consisting of multiple ovoid forms covered in semitransparent white cloth. The work is by artist Kendall Buster, who studied microbiology before pursuing an education in art. It was commissioned specifically for the new building and was inspired by models employed to represent molecular structures.

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Connecting the sciences Located on Washington Road, the building is an integral part of the University’s natural sciences neighborhood that connects disciplines such as genomics, neuroscience, physics, geosciences, environmental science, and molecular biology. The new Streicker Bridge spans Washington Road and allows for easy access to the building by foot.

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A RENAISSANCE FOR CHEMISTRY AT PRINCETON A. J. STEWART SMITH, DEAN FOR RESEARCH AND THE CLASS OF 1909 PROFESSOR OF PHYSICS

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he new Frick Chemistry Laboratory, with its state-of-the-

math complex and the Lewis Library, and linked via the graceful

art facilities, is launching a renaissance of chemistry at

Streicker Bridge over Washington Road to homes of molecular

Princeton University. More broadly, the laboratory

biology, genomics, ecology and evolutionary biology, and before

represents the excitement, strength, and forward momentum of

long, the neuroscience and psychology complex. The science

science and engineering research at Princeton today.

neighborhood is a testament to Princeton’s recognition that the

The building’s design, featuring teaching and research laboratories in close proximity, advances Princeton’s dual mission— first established in Woodrow Wilson’s day—to serve as a leading

scientific disciplines are inextricably intertwined, and the physical proximity of the scientists working at the forefront of these disciplines will catalyze path-breaking research.

research university and to provide the best education to

With a single faculty and a lack of barriers among schools and

undergraduate and graduate students. The world-class

academic departments, Princeton is ideally configured for

scholar-teachers on our faculty simultaneously devote them-

innovation and continues to break new ground, as befits its

selves to deepening our understanding of the world and sharing

standing as one of the world’s top research universities.

the knowledge they create with their students, engaging their minds and inciting in them a passion for discovery.

Explorations of the unknown entail risks by their very nature, making it essential for the University to support and encourage

With Frick’s cutting-edge facilities and exciting spaces to add

its extraordinary scholars with world-class laboratories and

to the equation, we can now compete for the best scholars.

instruments as they extend the frontiers of knowledge. Frick’s

From the date of its approval in 2006, the building has been a

spectacular nuclear magnetic resonance suite and the Merck

magnet for recruiting exceptional faculty. There is no doubt

Center for Catalysis are but two of the facilities that demon-

the facility also will enhance the transition of knowledge from

strate the University’s deep commitment to providing the most

generation to generation, from research laboratories to

fertile environment for discovery. But Princeton cannot do this

the classroom.

alone—the generous support of dedicated alumni and friends,

Frick’s location is perfect. Chemistry now joins Princeton’s burgeoning science neighborhood, adjacent to the physics-

corporations, foundations, and federal sponsors has been, and will remain, crucial to ensuring the University’s ongoing excellence in research.

Key building spaces

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Administrative and faculty spaces

Student teaching labs

Amenities

Research facilities

On the west side of the building facing Washington Road are faculty and administrative offices in interconnecting pods, arranged by research area. The building contains offices and adjoining group rooms for all faculty members, plus offices for administrative staff. Each floor has two conference rooms that seat 20 to 25 people.

On the east wing, the atrium level contains introductory and organic teaching labs, accommodating 120 to 140 students in daily sessions.

The upper three floors incorporate research labs with 200 highefficiency fume hoods installed at work areas. Below grade on the B level of the building is a 260-seat auditorium.

The atrium includes study tables, and lounge and café seating. Social spaces on upper levels are intended as interaction zones for faculty and students. Shared conference rooms on upper levels are designated for faculty and research group use.

Research functions that require very low vibration conditions are located on the B level, such as dedicated space for laser tables and the nuclear magnetic resonance (NMR) equipment lab. The NMR equipment sits on 10-foot-thick monolithic concrete blocks founded on bedrock and isolated by perimeter joints from the building structure.

The ideas and equipment in Frick and its neighborhood will be

future scientific leaders who will be trained and inspired in

brought to bear upon the largest problems facing society

these halls. But we cannot forget that the buildings, and the

today—including energy supply, climate change, cancer, and

evolution of science at Princeton, are possible only because of

national security. Solving these problems will require broad

Princeton’s longstanding research excellence and the scientists

interdisciplinary collaborations, especially with the School of

whose extraordinary accomplishments and contributions

Engineering and Applied Science, and often also with experts in

helped bring the University to this point.

the realms of policy and the social sciences in the Woodrow Wilson School of Public and International Affairs.

And so, it could not be more fitting that the building itself was made possible in large part by royalties from Alimta, the

This is representative of the increasing thrust toward multidis-

blockbuster Eli Lilly and Co. anti-cancer drug that developed

ciplinary research that is taking place at the leading research

from the insight and hard work over many years of Edward

institutions around the globe. Princeton already is graced with

C. Taylor, the A. Barton Hepburn Professor of Organic Chemistry

many flourishing research enterprises, including the Center for

Emeritus. Ted, as I’ve known him for some 40 years, is an

Quantitative Biology, the Carbon Mitigation Initiative, the

exemplar of the Princeton ideal, an extraordinary scholar with

Princeton Center for Complex Materials, the Mid-Infrared

an insatiable appetite for knowledge who tirelessly shared his

Technologies for Health and the Environment Center, the

ideas, enthusiasm, and time with the generations of students he

Princeton Physical Sciences-Oncology Center, the Energy

taught at Princeton for more than four decades. How marvelous

Frontier Research Center on Combustion, and the Center for

to see the new laboratory emerge from the chrysalis of its

Information Technology Policy.

construction site into an object of awe and beauty, not unlike the

It is important to contemplate the future discoveries and inventions that Frick and its neighboring science buildings will

beautiful butterflies that inspired Ted’s curiosity and led so serendipitously to the wonderful success we celebrate today.

enable, and exhilarating to imagine the accomplishments of the

Sustainability features integrated into the new building • High-performance exterior glazing with sunscreens to optimize ambient daylighting of interior spaces while controlling heat gain.

• Photovoltaic panels that generate power while providing shading for the glazed atrium roof.

Glazed atrium roof with embedded array of solar cells

• Integrated mechanical systems that enable optimal transfer of cooled and heated air from offices through the atrium and into the laboratories, reducing the amount of outside air that must be conditioned to meet the ventilation demands of the labs.

• High-efficiency fume hoods with automatic sash closers that reduce both air supply and exhaust requirements, and heat recovery systems that capture energy from lab exhaust.

• Radiators that heat the individual offices, and ceiling-mounted chilled beams—linked to the room’s thermostat—that directly cool the office air by passive convection currents.

• Graywater system, including a 12,000-gallon rainwater collection cistern, that collects and recycles stormwater for nonpotable uses.

• Landscaped rain gardens and biofiltration areas that retain and filter additional building and site stormwater.

• Occupancy and daylight sensors for control of dimmable fluorescent lighting systems.

• Sustainable energy monitoring display in the atrium.

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NEW FRONTIERS OF RESEARCH The new Frick Chemistry Laboratory provides a nexus for chemistry at Princeton that expands the discipline into new fields, as well as brings together research across the life sciences and engineering.

Building out of four main faculty research groups— chemical biology; inorganic; organic; and physical and theoretical chemistry—researchers delve into cross-disciplinary work that allows new knowledge to flourish. Research also is conducted by graduate students and postdoctoral fellows, who work closely with faculty members. Supporting this inquiry for all researchers—from faculty to undergraduate students—are world-class research facilities and instrumentation.

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“The new Frick Chemistry Laboratory contains dedicated mass spectrometry facilities that we use to probe the chemical reactions of cellular metabolism and explore how they can go awry in cancer and viral infections.�

Joshua Rabinowitz, associate professor of chemistry and the Lewis-Sigler Institute for Integrative Genomics 15

Chemical Biology Group The 20th-century discoveries of crucial biological molecules

For example, understanding the structure and function of

such as DNA and proteins, and identification of their struc-

proteins was, in the past, limited to studying proteins in their

tures on a molecular level, offered an exciting promise of a

natural state; synthesizing these large molecules remained

new era of science. Biologists and biochemists believed,

outside the capacity of chemistry. Yet now, the development

toward the end of the last century, that knowing these

of genetic techniques to alter protein structure, as well as

structures would allow them to understand all the chemical

breakthrough chemical techniques, allow protein fragments

processes of life. Now, however, it is clear that while revolu-

to be stitched together at specific points. This discovery has

tionary breakthroughs in medical science trace their roots to

opened the door to an unprecedented appreciation of

many of these early discoveries, research in the related fields

molecular structure and chemical function.

of chemical biology and molecular biology have only explored the “tip of the iceberg.�

The chemical biology research conducted at Princeton takes the observation of important biological molecules beyond the

Researchers at Princeton are striving to better understand

scale of a single cell. Here, advances in physical chemistry in

the chemistry of fundamental life processes from all possible

the area of spectroscopy have allowed single proteins to be

angles. Advances in analytical techniques such as mass

observed independently. Researchers are exploring how the

spectrometry have allowed the behavior of small metabolites

precise conformation and dynamic behavior of a protein

in cells to be accurately measured in real time. While the role

influences its function in the body. And on the other end of

of the fundamental biochemical molecules has long been

the spectrum, Princeton researchers are discovering how

recognized in maintaining health or causing disease states,

cellular proteins regulate the distribution of metal in cells

the subtle interplay of numerous other small molecules is

and in the body, which has implications that go beyond the

just now beginning to be explored. The search for new

single organism to the entire species, and how they respond

signaling pathways in cells will further allow chemists to

to environmental pressures such as epidemic diseases and

understand how seemingly disconnected systems in biology

climate change.

influence one another.

Chemical biology group (left to right): Michael Hecht, Dorothea Fiedler, Joshua Rabinowitz (not shown: Jannette Carey, Thomas Muir, Clarence Schutt)

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Inorganic group (left to right): Jeffrey Schwartz, Paul Chirik, Andrew Bocarsly, Robert Cava

Inorganic Group The field of inorganic chemistry, centered on metal-containing

widely overlooked in favor of studying primarily organic biologi-

compounds, has its roots in medieval alchemy, but today the

cal problems, research of bioinorganic systems now is uncover-

products developed by inorganic chemists are arguably worth

ing a rich understanding of what roles metals can and will play

more than gold. Inorganic compounds are key participants in

in future medical developments.

the development of both pharmaceutical drugs and new materials that are improving the quality of human lives in countless respects. In addition to tackling unique challenges, inorganic chemists also are developing methods and techniques that quickly become widely distributed throughout other divisions of chemistry.

Undoubtedly, one of the greatest challenges facing the entire field of chemical sciences in the next century is the development of alternative sources of fuel that can replace conventional fossil fuels. Although renewable energy sources, like wind and solar power, have been studied for decades, they are not yet widely available because these technologies are both

Many of the members of Princeton’s inorganic group contribute

expensive and are not easily combined with the current

to the Princeton Institute for the Science and Technology of

American energy infrastructure built on chemical fuels. Now,

Materials (PRISM), where they collaborate with scientists across

however, chemists at Princeton as part of the new Andlinger

the campus community. They add their chemical expertise to

Center for Energy and the Environment and the Princeton

projects that explore everything from how materials are

Environmental Institute, are exploring ways to develop

assembled on the molecular level to what microscopic interac-

clean-burning alternatives to oil and gasoline by harnessing

tions enable a material to exhibit unique optical and structural

energy from sunlight. And by developing unique methods

properties. Furthermore, a number of Princeton’s inorganic

whereby waste carbon dioxide is converted into useful

chemists are dedicated to gaining a better understanding of how

transportation fuels, Princeton scientists are helping to both

both natural and artificial metal-containing chemicals are

rethink the chemical energy sector and mitigate growing

incorporated into biological systems. As an area that once was

human-generated carbon dioxide emissions.

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Organic Group Organic chemistry, and specifically the synthesis of carbon-

But the field of organic chemistry is not limited to drug

containing chemical compounds, is as fundamental to the

discovery; the same innovative principles chemists have applied

entire field of chemistry today as it was over a century ago when

to making medicines will lead to new materials with never-

it first became widely recognized as a unique discipline. During

before-seen properties and will help develop new clean-energy

the past 60 years, organic chemistry research has focused

alternatives. The chemical reactivity that underpins the funda-

primarily on identifying molecules with pharmaceutical and

mental processes of life is being explored with a level of detail

materials potential and on finding unique methods to make

unimaginable in the recent past. Inspired by nature, the current

these molecules. Today, more than ever, organic chemists are

state of organic chemistry allows us even to contemplate

exploring fundamentally new technology for making drugs that

building biomaterials, such as new joint ligaments,

will combat diseases that don’t yet have a cure.

from scratch.

With its established excellence in drug discovery, the chemistry

The Merck Center for Catalysis in the new Frick Chemistry

department at Princeton is embarking on numerous collabora-

Laboratory is a vital component for this work, enabling practitio-

tive research projects with biochemists and molecular biolo-

ners of organic synthesis—whatever their research goal—to

gists just across Washington Road. Cutting-edge techniques for

greatly accelerate the discovery of important new reactions. A

testing the ability of molecules to bind to proteins implicated in

Chemspeed robotic platform, along with numerous high-speed

diseases such as malaria, HIV, and cytomegalovirus may lead to

analytic devices, allow graduate students and postdoctoral

the development of another new medicine, following in the

fellows to acquire quantities of data in a single day that would

footsteps of the Princeton-discovered anticancer drug Alimta.

otherwise take weeks.

Organic group (left to right): Martin Semmelhack, Abigail Doyle, Erik Sorensen, John Groves, David MacMillan

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Physical and theoretical group (left to right): Annabella Selloni, Zoltan Soos, Steven Bernasek, Herschel Rabitz, Haw Yang, Salvatore Torquato, Roberto Car

Physical and Theoretical Group The roots of physical and theoretical chemistry are humble and

interactions between molecules in real systems as they occur

centered on the simplest possible chemical system—the

over time. Within this realm, Princeton chemists have excelled

hydrogen atom. After beginning with little more than a math-

in using molecular dynamics to describe the crucial properties

ematical description of this minimalistic structure, followed by

of materials. These range from predicting when and where a

countless experiments to confirm their models, the first

building material will crack, to how materials will interact with

theoretical chemists dedicated decades of work and refinement

light and electricity.

to their field before they were able to move on to even moderately more complicated problems. Only then could they begin to understand the delicate but predictable way in which chemical compounds assemble and persist. Following breakthroughs in both quantum mechanics and experimental methods, however, physical and theoretical chemists now are applying their theories to highly complex systems. Now scientists are able to answer crucial questions about the structure and function of biomolecules, catalysts, and new materials by studying them in silico—that is, starting from mathematical principles with computers.

The classical description of chemical compounds actually ignored any interactions that may have occurred between two neighboring molecules; because these interactions were constantly changing, they were difficult to account for. But that viewpoint was naive, and recently the field of molecular dynamics has emerged, whereby chemists can monitor all the

Often, the inspiration for a new theoretical model comes from an unexpected observation of a natural system. Complementary to their studies of molecular dynamics, physical chemists also are interested in making observations of the fundamental properties of known chemical molecules. Recent advances in the use of lasers have allowed chemists to make observations at amazing speeds—as quickly as one millionth of one billionth of a second—and to observe the behavior of systems as small as a single molecule. These achievements are helping Princeton chemists to better understand some of the key chemical processes that occur on surfaces, such as those used in the chemical industry to promote chemical reactions.

Physical chemists also are using laser technology to exert their influence on new molecules. By using perfectly tuned pulses of light, chemical bonds can be broken and formed in specific and unexpected ways.

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Graduate Program The graduate program in chemistry offers a stimulating

A variety of departmental activities play important roles in the

educational and research environment within a community of

Ph.D. process. In the second year, students encounter the

highly regarded researchers and scholars. The program has

University-wide requirement of the Generals Exam, which, in

approximately 150 graduate students. Chemistry research

chemistry, takes the form of evaluating research progress and

involves relatively large groups of graduate students and

defending the proposed thesis research. In the third year, each

postdoctoral associates working with each professor. Among

student gives a formal seminar to the department on their

the organic chemistry faculty, for example, it is common to see

results and future directions. Before the dissertation is evalu-

groups of eight to 12 graduate students and a comparable num-

ated, an independent research proposal is defended before a

ber of postdocs. This organization leads to a strong sense of

committee of faculty. The overall goal is to nurture the develop-

group identity and a spirit of cooperation and collaboration.

ment of a scientifically mature, creative, and productive Ph.D.

Research ideas develop in many ways, but a primary source is

candidate.

the discussion at group meetings, which allows for give-andtake among graduate students, postdocs, and the faculty leader.

Such meetings also give the students a chance to present their work and defend their interpretations of their data.

Chemistry does a large amount of “service teaching,” and this effort is carried out by the graduate students. Typically, each student serves as a laboratory teaching assistant (TA) for two semesters, usually in the second year, in the freshman chemis-

Research is the overarching activity of the graduate program,

try or organic chemistry courses. In addition, there are special

which now is further bolstered by the new work spaces in the

teaching functions, such as serving as head TA, precepting, and

Frick building that encourage collaboration. Graduate re-

supervising the core lab, that attract advanced graduate

searchers are encouraged to pursue a cross-disciplinary

students and provide a strong experience relevant to an

approach to their work, collaborating with researchers in

academic future.

science and engineering departments and institutes at Princeton. Such research is well supported by the range of instruments and equipment housed in Frick.

There is a strong national competition for the best chemistry graduate students, and Princeton has been exceptionally successful in recent years. The process includes campus visits by prospective students, with scheduled visits with faculty and informal gatherings with current students. A facilities tour is a part of the visit, and the Frick Chemistry Laboratory is a major new advantage in attracting outstanding students. It is easy to show that the facilities, from the individual lab stations to the departmental instrumentation, is equal to or better than what is available at other universities.

“Princeton is a special place, with ample resources and a friendly, collaborative atmosphere, which makes it a great place to learn and carry out cutting-edge research.”

DAVID NAGIB, CHEMISTRY PH.D. CANDIDATE

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Research facilities housed in Frick include a collection of seven nuclear magnetic resonance machines, as well as a new mass spectrometry facility. The instruments and the specialists who operate them, such as Istvan Pelczer, help scientitsts across campus conduct research.

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Research Facilities Chemistry research depends on machines for analysis and

Mass spectrometry has a long history as an analytical tool in

purifications, as well as specialists to operate them. In many

chemistry and has enjoyed a renaissance in the last decade or

cases, the specialists are true collaborators on research

so with exceedingly versatile and powerful instruments being

projects, working closely with students and postdoctoral

developed every year. The new facility at Frick accommodates

researchers. While some of the instruments at the Frick

the several machines acquired in recent years in a spacious,

Chemistry Laboratory are dedicated to particular research

open setting. As with the NMR machines, most of the instru-

groups led by faculty, there are four shared facilities that house

ments are hands-on and are available to all researchers on

the more sophisticated machines and are overseen by the

campus. The design of the space allows for incorporation of

research professionals. Most of this equipment can be seen in

new instruments without serious disruption. The director of the

the basement of Frick, very visible in all its complexity behind

facility trains and supervises students to use the facility, and

glass walls. The facilities are critical to the research work of

also carries out collaborative experiments.

undergraduates, graduate students, and postdoctoral fellows, all of whom have equal access to the technology.

The Merck Catalysis Center and the Separations Facility share another all-glass enclosure and provide services that are

The workhorse for determining the structures of organic

unique to Princeton. The Catalysis Center focuses on the

molecules is nuclear magnetic resonance (NMR) spectroscopy.

development of new catalysts through efficient screening

The collection of seven NMR machines serves the whole

technology with automated analysis and robotic operation. The

campus and is visited by many academic collaborators, as well

result of generous collaborative funding from Merck & Co., Inc.

as users from local industry. The new facility is designed with

and the University, it is open for research to all faculty, and is

support areas such as a data-handling room, a sample

supervised by the center’s director. The Separations Facility

preparation room with a sterile hood, and a meeting room for

makes available to the campus the most sophisticated technol-

educational activities and senior thesis students. The instru-

ogy and expertise for purification of organic compounds, with a

ments are largely hands-on and can be operated by students

focus on chiral separations using liquid carbon dioxide as a

and postdocs for their own experiments, although lab directors

solvent. The director of the facility and two staff members carry

are available for consultation and collaboration on more sophis-

out purifications primarily for the chemistry and molecular

ticated applications.

biology departments, as well as outside users from the pharmaceutical industry.

“Chemistry research depends on machines for analysis and purifications, as well as specialists to operate them.

These machines are the workhorses for determining the structures of organic molecules.�

MARTIN SEMMELHACK, PROFESSOR OF CHEMISTRY

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New dimensions for chemistry • The Frick Chemistry Laboratory, with two wings and a central atrium, was designed to foster cross-disciplinary collaboration.

• It has an occupied basement and four stories above grade, plus a mechanical penthouse.

• The penthouse roof is 86 feet above grade.

Its various exhaust stacks extend another 14 feet to 100 feet above grade.

• The central atrium is 27 feet wide and 75 feet high.

• The Frick Chemistry Laboratory is the biggest academic building on campus after Firestone Library.

• Occupants of the building include up to 30 faculty, 30 departmental staff, and 250 to 300 graduate students, postdoctoral fellows, and research staff. The teaching laboratories and auditorium regularly accommodate several hundred undergraduates.

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Teaching chemistry at princeton “Chemistry is the central science.� This is not a sound bite but a description that helps define both research and teaching in chemistry. The other natural sciences draw heavily on an understanding of the world at the level of atoms and molecules, essentially of chemistry.

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“There are many fantastic things about Princeton’s chemistry department, including amazing advisers, a collaborative environment, and the friendly and relaxed attitude of the department as a whole.”

Karolina Brook, chemistry major and alumna, first-year student at Harvard Medical School

t Princeton, teaching chemistry at the undergraduate

to introduce chemical concepts in the guise of “The Chemistry

level brings together three learning environments and

of Magic” and “From the Bronze Age to the Plastic Age: A

approaches: foundational courses, specialist courses,

History of Chemistry Through Experiments.” One of the most

and research projects for chemistry majors.

The foundational courses—freshman chemistry, organic chemistry, physical chemistry, and inorganic chemistry—have evolved in recognition that teaching in chemistry today is designed to do much more than create chemists. In concert

which ranges from the mechanics of modern medicinal chemistry through biological evaluation to some of the policy issues that factor into considering the impact of the pharmaceutical industry.

with Princeton’s general goal of producing educated men and

There is a growing number of undergraduate and graduate

women, these courses are taken by one-third of the undergrad-

courses that are cross-listed with other departments, consis-

uates as part of a program to infuse a scientific literacy in our

tent with the central role of chemical concepts in other disci-

students. The several flavors of freshman chemistry offered

plines. The list includes geosciences, molecular biology,

include “Advanced Materials Chemistry,” with the interdisciplin-

chemical and biological engineering, physics, the materials

ary merging of chemistry and engineering. The organic

science and engineering program, and the Princeton Environ-

chemistry program now includes a course with a biological

mental Institute, all adding up to almost a dozen courses.

emphasis, using the processes of biological systems to exemplify the basic concepts of organic chemistry.

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popular new courses is “Drug Discovery in the Genomics Era,”

In the junior year, chemistry majors deepen their focus on the work of the department, while building a strong sense of

A key component to freshman chemistry and organic chemis-

teamwork that is a hallmark of chemistry research. The “core

try is the laboratory, and it is here, in particular, that the new

lab” for chemistry majors occupies Floor B in the Frick labora-

building will enhance the undergraduate experience. The

tory, in beautiful new space outfitted with the instruments of

visitor to the new undergraduate labs will see row after row of

analytical and physical chemistry. What was traditionally called

chemical hoods (the isolated space with high airflow to allow

analytical chemistry has merged into physical chemistry, while

safe work with all manner of chemicals), arranged so that

retaining the strong emphasis on measurement, error analysis,

each student has his or her own hood for the lab period.

and quantitative techniques. Now spectrometers, lasers, and

This contrasts with the old labs with perhaps six hoods to be

computer screens have replaced burettes and balances.

shared by 100 students while they did most of their work on

Collaboration is encouraged in the core lab, where students

the open bench.

complete problem sets and lab reports as a group.

The specialist courses broaden and deepen the teaching of

In the fall semester, each junior prepares three junior indepen-

chemistry. Freshman seminars reach out to non-scientists

dent papers under the supervision of three faculty members.

The form can differ from one professor to another, but the

there is a senior person in the group, the postdoctoral mentor,

papers generally involve a deep review of the literature on a

who also helps guide the undergraduate progress, especially in

clearly defined topic and present an analysis of the state-of-

the day-to-day details of lab work.

the-art, including open questions and possible future directions. The papers are designed to give the students a chance to organize the original literature and, especially, to evaluate the data, analysis, and conclusions in the articles. The three papers are assigned partly based on the students’ interests, but also to let them encounter a range of topics. In parallel, most of the faculty present 30-minute research talks to introduce the juniors to all the various research projects in the department.

From the experience of the junior paper and the research talks, each student selects a professor with whom to do the spring term junior independent work. This is usually a prelude to the senior thesis, and involves the preparation of a research proposal as well as experimental work; it is the beginning of truly independent research and access to frontier chemistry research technology. In the chemistry department, the research is done as part of a group, with a strong group identity and organization. This extends from the day-to-day work in the

About half of the chemistry majors stay for the summer between the junior and senior years, doing full-time research and functioning exactly like graduate students. Each will have an independent project that is expected to develop into the senior thesis topic. The summer is a beautiful time on campus, and having an open schedule for research can be a wonderful experience, with the camaraderie of the research group and weekly gatherings of the undergraduate researchers from all groups.

The senior year is a contrast between the intensity of moving forward on the thesis experimental work and then writing the thesis itself, and the freedom to explore special topics in the final coursework. It is not unusual for chemistry majors to enjoy two or three graduate specialty courses in the company of graduate students, such as advanced organic synthesis, quantum chemistry, and electrochemistry.

laboratory, where each group member can consult and advise

Overall, the chemistry program can be characterized as flexible,

others in the group, to weekly research discussion meetings as

with relatively few rigid requirements, and a wide variety of

well as occasional social events outside of the lab. Typically

options in coursework and research.

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“In choosing a place to begin my career, I was drawn to Princeton for its commitment to excellence in research and teaching, and for the chance to be a part of a department looking toward the future of the field. The research taking place in the chemistry department spans a number of disciplines, highlighting the central role that chemistry occupies in the natural sciences.�

Abigail Doyle, assistant professor of chemistry 30

NEW GROWth

As it settles into its new home, the chemistry department is building a preeminent faculty that engages in deep scholarship and enables ideas to reach fruition and expand knowledge. Faculty describe the chemistry environment at Princeton with words such as: “collaborative, exciting, forwardlooking, supportive, and stimulating.� Much of this momentum is connected to the new direction of the department and the opportunities faculty bring to helping it reach its goals from within its physical home. Recent faculty members include the following individuals who span a range of research expertise and bring excitement to the future of chemistry at Princeton.

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PAUL CHIRIK Edward S. Sanford Professor of Chemistry

DOROTHEA FIEDLER Assistant Professor

Main research: Organic and inorganic chemistry Previous position: Professor at Cornell University Ph.D.: California Institute of Technology

Main research: Elucidating signaling functions of small molecule second messengers Previous position: Postdoctoral fellow at the University of California-San Francisco Ph.D.: University of California-Berkeley

ABIGAIL DOYLE Assistant Professor

DAVID MACMILLAN A. Barton Hepburn Professor of Organic Chemistry

Main research: Organic and organometallic chemistry Previous position: Graduate study at Harvard University Ph.D.: Harvard University

Main research: Organic synthesis and catalysis Previous position: Professor at the California Institute of Technology Ph.D.: University of California-Irvine

THOMAS MUIR Van Zandt Williams Jr. Class of 1965 Professor of Chemistry

ERIK SORENSEN Arthur Allan Patchett Professor in Organic Chemistry

Main research: Organic chemistry, biochemistry, and cell biology Previous position: Professor at Rockefeller University Ph.D.: University of Edinburgh

Main research: Synthesis of biologically active natural products Previous position: Associate professor at the Scripps Research Institute Ph.D.: University of California-San Diego

JOSHUA RABINOWITZ Associate Professor of Chemistry and the Lewis-Sigler Institute for Integrative Genomics

HAW YANG Associate Professor

Main research: Biochemical kinetics, cellular metabolism, and chemical basis of complex biological processes Previous position: Co-founder and vice president for research, Alexza Pharmaceuticals Ph.D.: Stanford University

Main research: Molecular reactivity in complex systems Previous position: Assistant professor at the University of California-Berkeley Ph.D.: University of California-Berkeley

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A sTORY OF DISCOVERY E D W A R D C . TAY L O R , A . B A R T O N H E P B U R N P R O F E S S O R O F O R G A N I C C H E M I S T R Y E M E R I T U S

I have often been asked how an interest in the lovely white, yellow, and red pigments in the wings of butterflies could have led to the discovery of Alimta. For an answer, we have to go back to the fall of 1946, when I entered graduate school at Cornell University to major in organic chemistry. In searching for a possible thesis topic, I ran across an article in Science describing the isolation, properties, and structure of a strange compound that the researchers from the pharmaceutical company Lederle had isolated from human liver.

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t had the totally unexpected property of being necessary for

years before the structure of even the simplest of the butterfly

the growth of a number of microorganisms. During their

wing pigments could be elucidated, for these compounds were

structural investigations of this compound, they found that

not easy to work with. Their solubility, for example, rivaled that

its core was made up of two fused six-membered rings that

of Vermont granite, so that spectroscopic studies were difficult,

constituted six carbon atoms and four nitrogen atoms, a core

and combustion analysis to determine molecular composition—

that had only been observed before as pigments in the wings of

the ratios of carbon, hydrogen, nitrogen, and oxygen—was

butterflies, and in the skins of tropical fish.

seldom reliable because of the reluctance of these compounds to burn. (There was even a patent granted at that time for the use of related compounds as furnace liners.)

As it turned out, my choice of this area of organic chemistry for study proved to be extremely fortunate, for it led to a lifelong fascination with heterocyclic chemistry, and proved to be an

The Pterin Ring System

The Yellow Wing Pigment from the Brimstone Butterfly

invaluable training in the techniques of working in this experimentally challenging field.

At the same time that I was pursuing my thesis work at Cornell, the scientists at Lederle Laboratories reasoned that it might be possible to develop a new group of antibacterial agents. If the structure of the liver compound could be modified, they reasoned that bacteria might treat the modified compounds as if they were essential for its growth. Bacterial growth, however,

The Growth Factor from Human Liver Folic Acid

Top left: Pterin core that Edward Taylor studied during his Ph.D. work. Top right: Structure described in Purrmann’s paper in 1941. Below: Compound isolated from liver by Lederle scientists and reported in Science.

Shortly before I began my scientific studies, Robert Purrmann, a young organic chemist at the University of Munich, had taken up a problem that had frustrated some of the best organic

would not function in the same way as the original. An analogy might be a key that fits a lock but is unable to turn the tumblers.

This argument was known as the “antimetabolite theory.” So Lederle made a change in the structure of the liver compound by substituting one nitrogen atom for an oxygen atom to give a compound called aminopterin, and replacing a hydrogen by a methyl group in the latter compound to give methotrexate.

These new compounds indeed proved to be powerful antibacterial agents.

chemists in Europe over a period of 50 years. This was the

The compound isolated from human liver was shown to be the

elucidation of the structures of the white and yellow pigments

same substance that, albeit not identified structurally, had

in butterfly wings. Purrmann finally managed to identify and

earlier been found in various leafy vegetables such as spinach,

subsequently synthesize both the white pigment of the white

and therefore named “folic acid” in 1941. Derivatives of “folic

cabbage butterfly and the gorgeous yellow pigment of the

acid” are sometimes referred to as “folates.”

brimstone butterfly, and he published these results in Liebig’s Annalen der Chemie in 1941.

In 1948, it was found by others that aminopterin and methotrexate were effective in bringing about remissions in acute

Purrmann’s paper came to the attention of the Lederle

lymphoblastic leukemia in children. This startling revelation of

chemists who were struggling with the structure of the

the antitumor effects of blocking the action of folic acid immedi-

compound from human liver. To their amazement, the two-ring

ately excited worldwide interest, for both the antibacterial and

core of the Lederle compound was almost identical to the

the antitumor activity of aminopterin and methotrexate were

butterfly wing pigments described by Purrmann. This coinci-

shown to be due primarily to blocking the action of a specific

dence of structure between the butterfly wing pigments and the

enzyme dihydrofolic acid reductase (DHFR) essential for the

core of the liver compound that was essential for the growth of

ultimate biosynthesis of both DNA and RNA in cells. These

bacteria struck me as stunningly bizarre, and I decided at that

discoveries are considered to be the beginning of modern

moment to devote my Ph.D. thesis to a study of the so-called

cancer chemotherapy.

pterin heterocyclic core and related heterocycles—where they come from in nature, their properties, both physical and biological, and methods for their preparation.

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should actually be inhibited because the modified structure

A fundamental problem associated with this approach to cancer chemotherapy was the lack of specificity (for cancer cells rather than normal cells) of any of the DHFR inhibitors thus far

I therefore spent the next three years working with these

discovered, and this held true for a number of newer DHFR

fascinating, frustrating compounds. It was abundantly obvious

inhibitors that were found during the following several decades.

from the beginning of this project why it had taken more than 50

During this time, however, much was learned about the multiple

roles of folate-derived coenzymes in cellular metabolism, and it became increasingly clear that a better approach might be to search for inhibitors of some of the other folate-dependent enzymes involved in other aspects of cellular biosynthetic processes. By this time some 20 such processes had been identified. One indication that this was a fertile area for potential drug development was the discovery in 1957 of 5-fluorouracil (5-FU), which blocked an enzyme known as thymidylate synthase that is key to the biosynthesis of DNA. Further insights included the discovery of the essential role of a different enzyme that catalyzes the conversion of monoglutamates such as folic acid itself, as well as aminopterin and methotrexate, to polyglutamates.

My own role in these decades-long developments from the 1946–48 discoveries was minor. After receiving my Ph.D. from Cornell, I spent a year in Zurich, Switzerland, studying with Nobelist Professor Leopold Ruzicka under a National Academy of Sciences postdoctoral fellowship. In 1950, I studied at the University of Illinois as a postdoctoral fellow, where I was appointed to the faculty in 1951. I accepted a position at Princeton in 1954, and have been here ever since. Although I retained my fascination with the folic acid arena, and continued to work with the heterocyclic ring systems that had so fascinated me in graduate school, I spent most of the following several decades enjoying myself hugely in explorations of many diverse areas of chemistry such as photochemistry, organometallic chemistry, synthetic methodology, and the total synthesis of natural products, most of them quite unrelated to butterfly wing pigments.

It was not until the middle 1970s that I returned to cancer chemotherapy as a specific research goal. The incentive was the accumulation by others of much additional information on the complex pathways by which drugs such as methotrexate enter

as a pseudo substrate for the enzymes involved in one-carbon

the cell, undergo activation and deactivation, and can be retained

atom transfers in cellular metabolism. Its structure, however,

in or eliminated from the cell, as well as an understanding of the

precluded its possible function as a one-carbon acceptor; i.e., it

other multiple roles played by folate-dependent enzymes.

could not participate in any of the one-carbon transfer reactions

One of my first major new projects in this field involved the synthesis of 5,10-dideazaaminopterin (A), 5,10-dideazafolic acid

known to be critical for the syntheses, inter alia, of purines and thymidylate, and therefore both DNA and RNA.

(B), and the corresponding tetrahydro derivatives C and D (see

At this time, I had been for many years a consultant to both the

diagrams at right). Compound D, 5,10-dideazatetrahydrofolic

medicinal chemistry and the process development programs at

acid, subsequently became known by its acronym DDATHF. The

Eli Lilly and Co. in Indianapolis, Indiana. As a consequence, we

deletion of two of the nitrogen atoms of aminopterin, folic acid,

knew each other well, and they readily agreed to subject these

and their tetrahydro derivatives would be expected both to

new potential antitumor candidates to initial evaluation. So I

lower basicity and increase lipophilicity (the ability of a sub-

sent samples of these compounds to them, and crossed

stance to dissolve in fats, oils, and lipids), and we therefore

my fingers.

anticipated that these compounds would have different biological properties as a result. Of particular potential interest was D because, as a variant of tetrahydrofolic acid and not aminopterin, it might satisfy the requirements of a new type of inhibitor. For one thing, this new inhibitor would have to be accepted by the cell as a “normal substrate� for all of the

The first response I received was a curious one. Lilly reported that something appeared to be amiss with their tests, and they asked if I could send them an additional sample of D. Fortunately, there was a bit more, but not much more, of the compound, and I sent it to Lilly.

transport and activation processes that were now understood to

Their next response, however, was a very excited apology. It

be essential for inhibitory activity. In addition, it had to function

appeared that nothing had been wrong with the first tests, but

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Lilly could not believe them and assumed that the tests were

itself proved to be one of the two most active compounds,

faulty. My compound D was one of the most active antitumor

another being a variation of DDATHF in which a thiophene ring

agents they had ever seen, and brought about 95-100 percent

replaced a benzene ring.

inhibition of growth in a broad range of tumors in mice and in human tumor xenografts. In addition, it was fully active against tumors that were resistant to methotrexate, indicating that it was acting to block tumor growth by a totally different mechanism. Further examination of this compound by Lilly showed convincingly that it killed tumor cells by blocking de novo purine biosynthesis within cells, thus preventing DNA and RNA biosynthesis.

was required next. One unavoidable step in the synthesis of both of these compounds was reduction of a substituted pyridine ring. As we had carried it out, the hydrogen addition was not stereospecific, meaning that hydrogen adds to the pyridine ring of the substrate, at the point of attachment of the sidechain, to both sides of the ring. This generates two compounds known as isomers (in this case diastereomers)

It was clear that we had an extraordinarily exciting compound

structurally identical in every way except for the orientation in

on our hands, and that we might be on the brink of a major

space of those new hydrogen atoms. Because we wanted to

breakthrough. Princeton does not have a medical school and

evaluate the pharmacological properties of the individual

thus could not provide a base for various aspects of the drug

diastereomers, the two diastereomers of DDATHF (and of the

development process, let alone for clinical trials. We needed an

second, thiophene-containing candidate) had either to be

active collaboration with a partner with extensive experience in

separated and evaluated separately, or individually synthesized.

drug development and with an active cancer program in place.

In discussions with Lilly, it was decided that Lilly would

A Princeton/Lilly collaboration was a natural one to investigate

undertake the separation challenge, while Princeton would

this exciting lead, and this was quickly agreed upon. I was to

tackle the synthesis challenge.

head up the chemistry effort, while Lilly took on the basic

At Lilly, my principal chemical collaborator Joe Shih succeeded

biochemical and pharmacological studies that are so critical for guiding the synthetic work, as well as the overall organization of this collaborative effort.

It seemed highly unlikely that DDATHF (compound D), whose extraordinary activity served to launch this collaborative program, would prove to be the ultimate structure of choice. We therefore embarked on what amounted to a classical SAR, or

in the separation of the two diastereomers of DDATHF. The yields were extremely low: diastereomer A was obtained only in 3–5 percent yield, and diastereomer B was obtained in 15 percent yield. The latter was chosen to be the clinical candidate and was named lometrexol. Some time later, the two diastereomers of the thiophene-containing candidate were also separated by Shih, and one of the two, named LY309887, was also

structure-activity-relationship study, where structural changes

chosen for clinical trial.

are made systematically, and each new compound emerging

However, preparing sufficient quantities of these materials for

from this work is then evaluated. In this way, it may become apparent that certain changes decrease or eliminate activity, while other changes may increase activity. Every portion of the structure of the initial compound (in this case DDATHF) is probed,

clinical trials appeared to be a herculean task, since the reduction step, followed by the mandatory separation of diastereomers (in very low yield), occurred late in a multistep total synthesis. Although the single diastereomer B indeed

and a picture of what was hoped to be an optimal structure may

went into clinical trial, an alternative approach to its prepara-

emerge. We had to bear in mind that every change in structure

tion was a high priority.

can affect solubility, absorption, bioavailability, metabolism, partition coefficients, toxicity, possible activity against other biological targets, stability (pharmacokinetic and biochemical properties), as well as resonance, inductive effects, electronic distribution, chemical reactivity and stability, shape, size and bond angles, pKa and hydrogen bonding capacity (chemical properties). Furthermore, the effect of a change in one part of the molecule can modify or cancel what might have appeared to be a potentially useful change in another part of the molecule.

Success in such an enterprise is hardly assured!

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I must delve into a bit of chemistry at this point to explain what

While Lilly was struggling with the separation problems, I tried at Princeton one approach after another to devise a stereospecific strategy; i.e., a synthesis of diastereomer B alone. After many, many failures, I decided to dodge the problem entirely by designing a new candidate that could not exist in two diastereomeric forms. In chemical terms, this approach required the design of a compound that did not possess the stereogenic carbon atom (see arrow in earlier depiction on the previous page of DDATHF, compound D) that was responsible for the two diastereomers resulting from the pyridine reduction step. To

For me, this program proved to be a veritable playground for

accomplish this, I focused on a new ring system that retained

explorations of heterocyclic chemistry, since it called for the

as many of the structural features of DDATHF as possible so I

synthesis of many new ring systems and required the discovery

could assess the impact of the new ring system on activity.

of many new chemical transformations. Over the next four

However, there was no way one could predict the consequence

years, at least 800 new antitumor candidates were designed

of what amounted to a very significant change in the structure

and synthesized, at Princeton and at Lilly, and each compound

of DDATHF, and the abandonment of features that we had

had to be thoroughly evaluated. To our astonishment, DDATHF

already determined to be critically important for activity.

Certain fragments of our projected new target compound were

Everyone was ecstatic when early clinical trials showed that

already in hand, and this facilitated the design and implementa-

almost all solid tumors examined responded to Alimta.

tion of its synthesis. Dietmar Kuhnt joined my group at that

Perhaps the most remarkable of all the responses was that

time as a postdoc, and I asked him to prepare the compound.

with malignant pleural mesothelioma, the devastating lung

And to our amazement and delight, this new compound proved

cancer caused primarily by exposure to asbestos. No clinically

to be a veritable bombshell when it was evaluated at Lilly.

effective treatment for mesothelioma was previously known.

After extensive attempts by both Princeton and Lilly to improve

The results of clinical trials in mesothelioma were so promis-

on this compound, we found that this was still the most active

ing that even before the drug was approved, the FDA allowed

compound in the series, and it was chosen for clinical trials.

Lilly to provide it free of charge to more than 1,000 medically

This compound is now known as Alimta.

eligible patients through a compassionate use program.

Most striking was its remarkable activity against thymidylate

Many obstacles lay ahead. For instance, in the last phase of

synthase (TS). This folate-dependent enzyme is required for the

stability testing, glass particles appeared in the vials of Alimta.

biosynthesis of thymidine, and thus DNA, and finding an

These particles were caused by a totally unexpected interac-

effective inhibitor of TS was considered the holy grail for cancer

tion of liquid Alimta and the glass. Lilly scientists quickly

researchers. Furthermore, our new compound also proved to

reconstituted the drug into a new powdered formulation. In

be an inhibitor of several other folate-dependent enzymes

addition, during a Phase I clinical trial, some patients reacted

including dihydrofolate reductase and glycinamide ribonucleo-

to Alimta administration with skin rash. Lilly found that this

tide N-formyltransferase. It was therefore, in essence, and all

effect could be mitigated by the addition of a low dose of oral

by itself, the equivalent of a cocktail of antitumor agents, with

steroids to the treatment regimen.

the advantages of the usual antitumor cocktail (a combination of different drugs with different targets of action) but without its disadvantages (a combination of the toxicities of each drug in the mixture).

In 2004, Alimta, in combination with cisplatin, received its first FDA approval for the treatment of malignant pleural mesothelioma when surgery was not an option. Within five years, Alimta received three more approvals for the treatment of

The transformation of Princeton’s new clinical candidate

advanced nonsquamous non-small cell lung cancer (NSCLC).

compound into an effective and successful cancer drug has

Through these clinical trials, researchers have shown that

been described as possessing all of the elements of a great

tumor histology can be used to determine which NSCLC

action movie—overcoming obstacles, detective work, persever-

patients may benefit from Alimta treatment.

ance and, ultimately, a triumph for patients. It was the result of the remarkable scientific collaboration between Princeton and Lilly that should stand as a model of what can be possible when academia and industry truly work together.

Today, Lilly continues to study Alimta in combination with other therapies and in new tumor types at cancer centers around the world.

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Produced by the Office of Communications Contributing writers: Alyson Kenward, Kitta MacPherson, Hilary Parker, Martin Semmelhack, and Ruth Stevens Edited by Karin Dienst Designed by Phillip Unetic, UneticDesign.com Photography by Denise Applewhite and Brian Wilson, with Morley Von Sternberg (back cover) Nondiscrimination Statement In compliance with Title IX of the Education Amendments of 1972, Section 504 of the Rehabilitation Act of 1973, and other federal, state, and local laws, Princeton University does not discriminate on the basis of age, race, color, sex, sexual orientation, gender identity, religion, national or ethnic origin, disability, or veteran status in any phase of its employment process, in any phase of its admission or financial aid programs, or other aspects of its educational programs or activities. The vice provost for institutional equity and diversity is the individual designated by the University to coordinate its efforts to comply with Title IX, Section 504 and other equal opportunity and affirmative action regulations and laws. Questions or concerns regarding Title IX, Section 504 or other aspects of Princeton’s equal opportunity or affirmative action programs should be directed to the Office of the Vice Provost for Institutional Equity and Diversity, Princeton University, 205 Nassau Hall, Princeton, NJ 08544 or (609) 258-6110.

Copyright © 2011 by The Trustees of Princeton University In the Nation’s Service and in the Service of All Nations

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Department of Chemistry Princeton University Princeton, NJ 08544

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