Carl Djerassi: Chemist and Entrepreneur

Carl Djerassi: Chemist and entrepreneur Eugene Garfield 534 CHEMTECH SEPTEMBER 1983 Much has been said about the scientific entrepreneur. established a precedent for the widely used fragment coding Although the term ordinarily is applied to the person who system employed in the Index Chemicus Registry System has been successful in business—one thinks of Thomas (ICRS) and other systems. Edison or Edwin Land, among others—there also are At the end of the 1940s, much of the excitement centered scientific entrepreneurs in the academic community. It is on the discovery that cortisone could alleviate arthritis not often that one finds a scientist who can fit both symptoms. The chemical was derived from animal bile, but descriptions. To maintain a credible academic existence one initially in amounts too small for treating this chronic, needs enormous dedication and energy; to function in a widespread disease. Scientists around the world were racing scientifically oriented business these qualities as well as to find a more practical method of synthesis. In 1951, significant managerial competence are needed. That rare Djerassi and his team at Syntex won the race; they found a combination of qualities is found in my friend Carl relatively simple way to make cortisone using a readily Djerassi. available raw material, the Mexican yam (2). I recently had the honor of speaking informally at an That same year, Djerassi's team synthesized another unusual event. The numerous friends and collaborators of compound, which received much less attention at the time. Djerassi attended a party celebrating the publication of his They named it "norethisterone," and it was to become the thousandth paper. My ad-lib comments on that occasion left active ingredient in the birth control pill. Today it is known me somewhat frustrated—in the euphoria of the moment as norethindrone. I failed to state so many of the more relevant facts about his The work began with the female hormone progesterone. accomplishments that I wished I had come prepared with Among other things, progesterone prevents women from an appropriate oration, which I now belatedly provide. ovulating during pregnancy, thus acting as a natural Perhaps only Carl and his closest friends will understand the contraceptive. Djerassi's team found that they could change special sympathies we share, not the least of which is his the structure of progesterone to increase its potency appreciation of art and humanistic studies. eightfold. This progesterone analogue was strong enough Djerassi is best known to the public for his contribution to work when injected, but lost its potency when to the development of the birth control pill, but research in administered orally. The Syntex group needed a chemical contraception is only one aspect of his multifaceted career. that could be absorbed orally. A breakthrough came when He is one of the giants of modern organic chemistry. Carl they rediscovered a compound that, although synthesized has been a leader in elucidating the structures of complex more than a decade earlier, had largely been ignored organic molecules and in applying these discoveries to the because of its apparent lack of medicinal value (1). It was synthesis of pharmaceutically important compounds. He also called ethisterone and its activity in the body was not unlike is responsible for major advances in the methodologies used that of progesterone. Moreover, its activity persisted even by organic chemists. Analytical techniques which he helped when taken orally. Djerassi's group made the same chemical develop, such as optical rotatory dispersion, circular modification in ethisterone that they had earlier made in dichroism, and mass spectrometry are now used widely. progesterone. The result was synthetic norethisterone, which Djerassi was born in Vienna in 1923. His Bulgarian-born prevented ovulation, was orally active, and could be father and Austrian mother were both physicians. After the incorporated into a pill (1). outbreak of World War II, he emigrated to the U.S. with $80 It is, of course, more efficient to methodically rearrange in his pocket. He spent two semesters at a now-defunct junior molecules, enhancing or creating desirable chemical college in Newark, N.J., before accepting a scholarship from properties, than it is to randomly synthesize compounds for Tarkio College, a small school in Tarkio, Mo. In 1948, Carl biological testing. Natural products can be used as models enrolled in the graduate program at the University of for synthetic compounds. However, many natural products Wisconsin, where he earned a Ph.D. in organic chemistry consist of molecules so large, complex, and delicate that before his twenty-second birthday. After four years of relationships between their structures and functions—and in industrial experience at Ciba, he grew restless and eager for some cases, the structures themselves—are often obscure. a position in academe, but could not find one. At the time that Djerassi was beginning his career, it was still In the spring of 1949, Djerassi received a call from chemist not uncommon for a natural-products chemist using George Rosenkranz--who was director of a small Mexican traditional analytical methods to spend a lifetime analyzing company called Syntex--inviting Djerassi to head a research the structure of a single substance (8). team there (1). The job was appealing in that it would allow Carl to continue his investigation into the chemistry of New tools steroids. Steroids were of interest to Djerassi and others It was to the inadequacy of physical methods available because of their complicated structures and their prominent for assessing organic structures that Djerassi now turned his role in regulating such physiological processes as attention. In 1952, he was offered a professorship at Wayne reproduction, digestion, and calcium metabolism. Steroid State University in Detroit. The following year he and his chemistry had been the subject of Djerassi's doctoral colleagues began to investigate optical rotatory dissertation, but at Ciba most steroid research was done in dispersion. the laboratories at Ciba's Swiss headquarters. Optical rotatory dispersion and optical circular dichroism, It is of interest to mention that during this period work on which Djerassi and others developed a decade later, use steroid chemistry was almost frantic. In fact, the backlog of polarized light to take an impression of a molecule's applications at the U.S. Patent Office eventually was so large three-dimensional shape. Both techniques operate on the that the Pharmaceutical Manufacturers Association financed principle of the Cotton effect; wherein polarized light a steroid literature coding project. Eugene Garfield changes as it passes through certain substances (4). Djerassi Associates, predecessor of the Institute for Scientific transformed this phenomenon into a practical tool for Information (ISI), received the contract to do this work in analyzing molecular structures. He found that many organic 1958. We encoded more than 20 000 steroid compounds and substances, notably those containing carbonyl groups, CHEMTECH SEPTEMBER 1983 535 produced the Cotton effect and that the intensity of the to interpret the mass spectra of organic molecules. I effect varied with the wavelength of the light. He graphed remember the early days of Carl's interest in mass these changes as "Cotton effect curves," and by using them spectrometry because we considered creating a new as fingerprints of molecules, made comparisons between molecular weight index for Index Chemicus, derived molecules that never before were possible. The automatically from the molecular formula. Since then, some stereochemistry of unknown structures could be deduced of Carl's most important discoveries and influential from known structures and subtle differences between publications have been buih on that earlier research, making similar molecules discerned (5). it possible for him to use and interpret mass spectral data Optical rotatory dispersion and circular dichroism (16-24). measure two different components of the Cotton effect. The former detects a rotation in the light waves. The latter measures a change in the way the waves oscillate, a transition In areas such as pest control from a strictly back-and-forth to an elliptical motion. Both techniques have opened new fields in organic chemistry (5). and birth control, Djerassi has In addition to enormously speeding up the process of argued that the problems of the stereochemical elucidation, they have made it possible for chemists to work with minute quantities of compounds. less developed countries should Moreover, unlike the analytical techniques previously in be given more priority in the use, Djerassi's inventions made it possible for chemists to establish the absolute configuration of molecules. Thus, scientific community, chemists may effectively distinguish among enantiomorphs, crucial because mirror-image molecules often have entirely different biological properties. Although optical rotatory dispersion and circular During the past 10 years, Djerassi has continued his efforts dichroism quickly became part of the standard vocabulary to develop and refine the tools used for structural of organic chemistry, some of the most important discoveries elucidation. Together with Joshua Lederberg and Edward involving these techniques have been made in Djerassi's Feigenbaum, Djerassi undertook a major collaborative laboratorv. During the 1950s, much of his work involved the

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