Above and beyond Organic Synthesis

Room 319 of Conant Building at Harvard University is a good place to learn much in a short time about Elias J. Corey, this year’s recipient of the Priestley Medal. The outer office is lined with shelves filled with manila folders and books, chemical and medical. In one compartment, medals are arrayed, like in a shrine. On one wall are anchored strings from which molecular structure models hang, like clothes drying on a line. Three empty bottles of champagne stand in a row on a low table by the window, reminders of celebrations past. In the inner space are more shelves built like library stacks. More molecular structure models cascade from the ceiling to the floor like decorative garlands. One shelf wall is covered with greeting cards featuring Mount Fuji.

Photographs are everywhere. There are pictures of, among others, Claire, Corey's wife; the Corey grandchildren, Sara and Katherine; colleagues from the University of Illinois, Urbana-Champaign, where Corey began his independent research career in 1951; the chemistry faculty at Harvard when Corey joined in 1959, including Paul D. Bartlett, Mary and Louis F. Fieser, Frank H. Westheimer, and Robert B. Woodward; and scenes from the Nobel Prize ceremonies.

The Priestley Medal is the American Chemical Society's highest honor. It is awarded for distinguished service to chemistry. Corey, Harvard's Sheldon Emery Professor of Chemistry, has performed distinguished service in three major ways: as a scientist, as a teacher, and as an adviser to the pharmaceutical industry.

As a scientist, Corey--or E. J., as family, friends, and colleagues call him--has been working on a wide range of problems in the chemical sciences. His contributions not only have empowered synthetic organic chemistry but also have had a profound impact on biology and medicine.

Corey has a "broad and eclectic view" and has never been one to "focus on a narrow piece of the intellectual landscape," says Jeremy R. Knowles, a longtime Harvard colleague. "While you may think of him as having transformed organic synthesis, he has done much more than that by relating synthesis to other parts of chemistry. He continues to make fiercely penetrating intellectual contributions all the way from mechanistic organic chemistry to the biomedical sciences."

AS A TEACHER, Corey has been instilling in students and coworkers the value of setting high standards, of executing experiments with rigor, of conducting research ethically, and of caring for coworkers. Former members of the Corey group are sometimes referred to as "graduates of the E. J. Corey School of Chemistry." They include Nobel Laureates Ryoji Noyori (2001, Chemistry) and Bengt I. Samuelsson (1982, Physiology or Medicine), as well as numerous industry leaders and academics.

"I am grateful for the learning experience I gained in his laboratories," says J. Michael Fitzpatrick, a former postdoc and now president and chief operating officer of Rohm and Haas. "That time was pivotal in my career as a chemist and has been invaluable to me throughout my years in the industry."

Corey's "approach to science is supplemented with a strict discipline, a systematic approach to learning, and the courage to plunge into uncharted areas," says K. C. Nicolaou, a former postdoc and now a chemistry professor at Scripps Research Institute. "These attributes have made him a role model to students and admirers who value his science, integrity, and advice."

As an adviser to pharmaceutical companies, Corey has been serving humanity in ways that are not obvious and may never be disclosed. What can be said is that the breadth and depth of knowledge of chemistry, biology, and medicine that he brings to his role as adviser are "unmatched," says Paul A. Da Silva Jardine, a former graduate student and now a senior director for chemistry at Pfizer.

Superstar that he may be in the world of chemistry, Corey leads a simple, well-organized life. His days are predictable: rising at around 7 AM, listening to classical music while exercising and then getting dressed for breakfast at around 8 AM, reading the New York Times after breakfast, and out the door to be in his office by 9:30 AM. He is back home for dinner at 7 PM and then spends the rest of the evening reading and listening to more classical music.

His home being only about one mile from Harvard, Corey regularly walks to and from his office. One of his former walking companions was the late Edward M. Purcell, the Harvard physicist who was a codiscoverer of nuclear magnetic resonance absorption and who shared the 1952 Nobel Prize in Physics. He was Corey's hero.

They taught each other about their subjects during the daily walks. They sat together in committees, including some advising President John F. Kennedy. Corey says that Purcell expressed his thoughts and analyses much more clearly than anybody else on the committees, which included many Nobel Laureates. The qualities of Purcell that Corey admires--clarity of thought, breadth of scholarship, and conscientiousness as a teacher--are qualities of Corey himself.

The morning of Oct. 17, 1990, began as usual for Corey, except that on his way to Harvard, he detoured to the Charles Hotel to fetch a visitor. As the two were entering Conant Building, a graduate student congratulated Corey--for what reason Corey did not know. Approaching the third floor, they were greeted by a crowd abuzz with the news that the 1990 Nobel Prize in Chemistry had been awarded to Corey "for his development of the theory and methodology of organic synthesis."

Corey was being recognized for retrosynthetic analysis, the logical deconstruction of synthetic targets. He formalized the principles in the 1960s, but the ideas had been percolating in his mind since he was an 18-year-old undergraduate in Arthur C. Cope's advanced organic synthesis course at Massachusetts Institute of Technology. Cope distributed problem sets consisting of structures for which synthetic routes had to be derived. Corey soon realized that he could find solutions very rapidly, but he couldn't figure out how.

At the time, synthetic routes were determined by available starting materials. But by the 1950s, natural products with unusual structures began to appear in the literature. It was not obvious what starting materials might be used to prepare them. So Corey began analyzing targets without concern for starting materials but by looking for disconnections that simplified the target. "It was working for me. I knew what strategies I was applying."

Corey laid out the principles of strategic disconnections in the 1989 book "The Logic of Chemical Synthesis," which he wrote with Xue-Min Cheng. But he had been teaching the approach to graduate students since the 1960s. "The logic is so powerful that after one semester students are producing plans comparable with what was coming from the very best labs," he says.

Some people did not believe that logic could be applied to synthesis. Partly to convince them, in 1966 Corey embarked on research to harness computers for retrosynthetic analyses. A program that a machine could use to generate synthetic routes validates the logic, he says.

The idea was way ahead of its time. Like dinosaurs, computers then were big machines but with only kilobytes of memory. Graphical representation of molecular structures did not exist. And Corey did not have the resources to go after such an ambitious goal.

Despite the limitations, the Corey group developed the software called Organic Chemical Simulation of Synthesis–Logic and Heuristics Applied to Synthetic Analysis. Given a chemical structure drawn with a stylus on an electrostatic tablet hooked to a computer, the software suggests starting materials and reactions to prepare the compound.

This achievement in human-machine communication in chemistry was first reported in Science in 1969. Corey followed up in 1972 with three papers published back-to-back in the Journal of the American Chemical Society. But shortly after the papers were published, Corey was told that the journal would not accept any more papers of that ilk. The work was so radical that it bothered people, Corey believes. He recalls being chided by John Cornforth, Nobel Laureate bioorganic chemist, that such a program would render synthetic chemists useless.

The computer research was also part of a grand vision--a global database of all the chemical information that can be brought to bear on a synthesis problem coupled to the logic of synthetic analysis. That such an infrastructure does not exist is "a real tragedy," Corey says. It would have been extremely difficult to achieve in the 1960s, but now would be an auspicious time to try again, he says. "I am convinced that within the next century computers will be used by synthetic chemists interactively to assist in problem solving. The benefits could be comparable to those of the Human Genome Project."

The explosion in the number of total syntheses in the past five decades testifies to the power of retrosynthetic analysis. By 1960, fewer than 50 total syntheses had been achieved; by 2001, the number had jumped to 25,000, Corey says. Retrosynthetic analysis is powerful in another sense: By revealing gaps in synthetic methods, it spurs the invention of new reactions and reagents. Corey regards his contributions in this area as even more important than retrosynthetic analysis.

"IN MY OWN RESEARCH, I always strive to do things that are useful to other people," Corey says. As an example, he pulls out a slide outlining a concise synthesis of the hormone estrone in which the key step is a Diels-Alder reaction catalyzed by a "little molecule that I'm just so proud of and excited about." Since 1938, it had been thought that an enantioselective Diels-Alder reaction of what is known as Dane's diene would efficiently yield the required ring system. People tried and failed, Corey says.

In the method he developed recently with postdoctoral fellows Qi-Ying Hu and Pankaj D. Rege, the required ring system is obtained in 92% yield and 94% enantiomeric excess. One recrystallization renders the Diels-Alder product enantiomerically pure. A few more manipulations convert the product to estrone. The third-generation oral contraceptive desogestrel has been prepared in a similar way.

The "little molecule" that catalyzes the key step is a boron-containing organic cation that can be traced back to Corey's landmark work on the synthesis of prostaglandins. Corey had developed a route in which simple reagents form a key intermediate in 99% enantiomeric excess through a Diels-Alder reaction. The catalyst, a chiral oxazaborolidine, was designed on the basis of a deep understanding of the reaction mechanism. The synthesis of prostaglandins, also called eicosanoids, is widely cited as a major contribution of Corey's because it not only advanced organic synthesis but also allowed biomedical investigations to proceed by making the scarce hormones available to investigators.

Syntheses of hormones such as estrone and the prostaglandins are but a few of Corey's innumerable achievements that have accelerated medical research. In fact, Corey says, organic chemistry's relevance to medicine was what hooked him on chemistry in the first place.

Born on July 12, 1928, in Methuen, Mass., a town 30 miles north of Boston, Corey was the youngest child of Elias and Fatina (née Hasham) Corey. When Corey was only 18 months old, his father died of pneumonia. Shortly thereafter, Fatina Corey changed her son's name from William to Elias. Corey himself caught pneumonia when he was four years old. He recalls the family doctor saying that he might not make it.

Corey's extraordinary capacity to learn was evident from his early childhood. At age five, he attended St. Laurence O'Toole Elementary School, a Catholic school in the next city, Lawrence. He went straight to first grade, skipping kindergarten because he could already recite poems and perform additions. By the end of seventh grade, he had learned everything he would have studied in eighth grade. He spent much of his eighth-grade year playing football and baseball and memorizing the Bible.

The nuns at St. Laurence encouraged Corey to take the scholarship examination for St. John's Preparatory School, in Danvers, Mass. Despite finding the tests easy, he didn't get a scholarship, so he attended Lawrence Public High School. Later, he found out that St. John's was for boys who wanted to be priests. "They must have figured I wasn't the right material. I think that was my greatest good fortune," he says.

At 16, Corey entered MIT to study engineering. However, a course in qualitative analysis sparked his interest in chemistry. He so enjoyed the problem solving and calculations involved that he solved four times the number of required unknowns. But it was organic chemistry that hooked him.

"Remember, I almost died of pneumonia," he explains. "Penicillin, sulfonamide antibiotics--terrific medicines came along in the early 1940s. They were magic bullets, and they were discussed in the early organic chemistry course."

Corey's teachers at MIT included John D. Roberts, C. Gardner Swain, and John C. Sheehan. For his undergraduate thesis, he joined Sheehan's group, which was then working on the synthesis of penicillin. He completed his undergraduate work in three years and continued working with Sheehan for the Ph.D. degree.

In November 1950, at the beginning of his third year in graduate school, Corey was offered a teaching position at the University of Illinois, Urbana-Champaign, by Roger Adams, the greatest organic chemist at that time, according to Corey. He had to be in Illinois in January 1951, which meant he had only a few weeks to write his thesis.

Corey was at Illinois from 1951 to mid-1959. In 1954, he was offered a full professorship at the University of Chicago. Illinois matched the offer, and Corey stayed. But when Harvard called in 1959, it was no contest. For Corey, having grown up in the Boston area, where all his family lived, moving to Harvard was like going home. It also meant a lot that Harvard offered him--at age 30--a full professorship. To this day, he considers that offer "the most gratifying of my professional honors."

Nevertheless, leaving Illinois was painful. "For years I had this recurring dream that I was back at Illinois, that I had made a mistake. I had dreams of looking for an apartment in Urbana-Champaign because I wanted to be with my friends," Corey says.

In September 1961, Corey and Claire Higham were married. The two met at Illinois, where Claire had earned a bachelor's degree in chemistry and where she had been working as an analytical chemist. "I didn't understand his chemistry, but the graduate students were saying he will one day win the Nobel Prize. This was in the mid-1950s," she recalls. What she noticed was "his fabulous memory and ability to connect things and grasp situations quickly." Their home life has always been quiet, simple, and ordinary, she adds.

The Coreys have three children: David Reid (born in 1963 and now a professor of biochemistry at the University of Texas Southwestern Medical Center, Dallas), John (born in 1965 and now a classical composer and teacher at the Conservatory of Fontenay-aux-Roses, in France), and Susan (born in 1967 and now retraining for a career change after years of teaching in the Boston public school system). Corey is an engaged father, Claire says.

When David was about six years old, he began tagging along to the lab, where he would play with the molecular models or watch his father experiment with dry ice or phenolphthalein. One summer in high school, at his father's suggestion, David worked as an assistant in the lab. That was the most that Corey engaged David in chemistry. That David decided to become a chemist was a surprise because Corey never encouraged him to do so. "David may just have seen how much joy I get from what I do," he says.

With the Corey children all independent these days, the Coreys dote on David's daughters--five-year-old Sara and two-year-old Katherine--as often as they can. Corey "has an absolute love affair with his family and with chemistry," according to Brian M. Stoltz, a former postdoc of Corey's and now an assistant professor of chemistry at California Institute of Technology. "And because chemistry involves a group, he treats his group as his family. That's his life."

Corey is beloved by former students and coworkers. The Japanese branch of the "Corey School" feted him with symposia on his 60th and 70th birthdays, which in Japan are milestones to be marked by special festivities. During these celebrations, Corey delivered his talk in only slightly accented Japanese, which he learned partly by watching television during visits to Japan.

In the U.S., Corey's 70th birthday was marked by a bound compilation of greetings from Corey School graduates worldwide, a project initiated and executed by Nicolaou. The letters--some handwritten and many accompanied by then-and-now photos, as well as structures and reaction schemes--give a glimpse of Corey as a teacher of chemistry.

Corey works only on difficult problems, expects his coworkers to pour their hearts into seeking solutions just as he does, and is satisfied only with innovative solutions. Failure is not possible because even unsuccessful experiments yield lessons and insights. Precise experimentation is paramount; researchers must pay attention and "know what is happening in the flask."

It would be easy to imagine Corey as a ruthless taskmaster if all one knew about him were his prolific output and the intense focus of coworkers on the tasks at hand. What is not well known is that Corey is extraordinarily compassionate and always available for discussion, reachable in times of deep personal trials, promoting his coworkers' welfare and advancement, and acknowledging their scientific contributions.

"I always had a good personal relationship with him," says Hans-Jürgen Hess, one of Corey's first postdocs at Illinois. With Corey's support, Hess joined Pfizer and rose through the ranks to vice president for medicinal products research, from which he retired recently. "I could talk to him about anything, not only science."

Many people also don't know that Corey has a funny, lighthearted side. Back in 1969, for example, prominently displayed on Corey's desk was a quotation from Dr. Seuss: "Today is done. Today was fun. Tomorrow is another one. Every day from here to there, funny things are everywhere."

Many people also are not aware that Corey is an intensely caring person. In his greetings to Corey on the occasion of Corey's 70th birthday, Andrew G. Myers, a former graduate student and now a Harvard colleague, wrote, "It seems somewhat ironic that someone who was denied a father himself would prove to be a sterling example of what a father is meant to be."

Until he turned 70, Corey taught an organic synthesis course, Chemistry 115. He prepared meticulously for the lectures, wanting them to be as good as they could be. Except for one time when he was severely ill after a trip overseas, he never missed a class, not even on the day that he learned of his Nobel Prize.

William R. Roush, a chemistry professor at the University of Michigan, Ann Arbor, took the course in 1974. The class would begin with Corey putting up a structure, which would be the theme of the day's lectures, he recalls. And it would conclude with Corey putting up references to review articles on the chemistries that would be discussed next.

One of Roush's research areas now is intramolecular Diels-Alder reactions. He was drawn to the area by a lecture on the synthesis of dendrobine, a major component of a Chinese drug. When Corey showed the structure, Roush recalls, "I jotted down a retrosynthetic analysis. But he didn't talk about the analysis I generated." After the lecture, Roush showed Corey his notes and asked if the route had been tried. No, but somebody should, was Corey's response. With Corey's encouragement, Roush synthesized dendrobine as his Ph.D. thesis project, under the direction of Woodward.

"I'm still working on intramolecular Diels-Alder reactions today," Roush says. "I credit that to Corey. Even though I was not a member of his group, I felt free to ask him questions at any time. He defines what a faculty mentor should be."

Although he retired from classroom teaching in 1998, Corey cannot imagine retiring from research. "I love solving problems. Discovery is in my blood. It's hard for me to turn away from that," he says.

His group now consists only of postdoctoral fellows. He no longer competes for government grants, and he no longer holds a staff position at Harvard. He has taken these steps to make way for young people because he believes in the American way of giving young people the chance to do independent research early.

Corey's funding now comes exclusively from private sources. A major supporter is Pfizer, the pharmaceutical company that he has been advising since the 1950s. Because of the imperatives of confidentiality, the world may never know what new drug discovery programs, or indeed new lifesaving drugs, are the fruits of Corey's advice. What's clear is that, in advising what is now the world's largest pharmaceutical company, Corey goes far beyond the challenges of synthesis.

Corey "always started from the desire to understand the larger context of a problem before engaging you on the narrow solution," says George M. Milne Jr. Milne has known Corey for 32 years, since Milne began his career at Pfizer as a chemist until his retirement in 2002 as executive vice president for global research and development. "That is so he could bring to bear his medical and biochemical understanding and from that context design an elegant, fully comprehensive solution."

IT HAS ALWAYS been important for Corey that people grasp the centrality of chemistry in advancing the biomedical sciences, Milne says. Chemists are the one group that can envision what a comprehensive solution to a biomedical challenge ought to look like and that has the skills and tools to create molecules to test their ideas.

Corey also "has a profound sense of stewardship, both of the science and the people," Milne says. During the past two decades when molecular biology and the biological sciences have been attracting most of the interest and support in drug discovery, Corey "worried a lot about the role of chemistry and ensuring its impact," he explains. "It would not be uncommon for him to talk about the big biomedical problems and how chemistry might be redirected to bring it to bear on the key challenges and also be concerned about the morale of chemistry staff and their ability to contribute to the field and be rewarded for their contribution."

Back in Harvard's chemistry department, Corey's stewardship and enthusiasm for chemistry have been inspiring colleagues. Corey has "a remarkable sense of citizenship," always looking for ways to better the department's future and encouraging younger faculty to shape the department, says David R. Liu, a former undergraduate member of the Corey group and now an associate professor of chemistry. "During the 13 years that I have known him, E. J. has consistently placed the welfare of his colleagues and students as the highest priority in his tireless efforts."

Corey's enthusiasm for chemistry is "both infectious and uplifting," says Knowles, a colleague since 1974. "He isn't just somebody who has a broad interest in the subject; he catalyzes it in the rest of us. He exudes a wonderful enthusiasm all the time."

"When you talk to [Corey] about chemistry, he still gets a youthful gleam in his eyes," says M.Christina White, an assistant professor and much younger colleague. "It's inspiring to see someone who has been doing chemistry for as long as he has and still is mesmerized by it and loves it."