A Trfbute to Carl Djensssi: Reflections on a Remarkable Scientific Entrepreneur Number 42 October 18,1982 There has been much said about the Djerassi is best known to the public for scientflc entrepreneur. Ordinarily the h~ contribution to the development of term is applied to the scientist who has the birth control pill. But research in con- been successful in business, One thinks traception is only one aspect of his multi- of Thomas Edison or Edwin Land, faceted career. He is one of the giants of founder of Polaroid, among others, But modern organic chemistry. Carl has been there are also scientific entrepreneurs in a leader in analyzing or “elucidating” the the academic community. Many Cur- structures of complex organic molecules rent Contents@ (G@’ ) readers fall into and in applying these discoveries to the this category so I will not belabor the synthesis of pharmaceutically important point. My reason for mentioning these compounds. He is also responsible for two meanings of scientific entrepreneur major advances in the methodologies is to emphasize that we rarely find both used by organic chemists. Analytical kinds in one person. To maintain a cred- techniques which he helped develop, ible academic existence one needs enor- such as optical rotatory dispersion, circu- mous dedication and energy. To func- lar dichroism, and mass spectrometry, tion in a scientifically oriented business are now among the most widely used you need these qualities as well as signifi- took in organic chemistry. cant managerial competence. That rare I first met Djerassi back in 1959. We combination of qualities is found in my were introduced by Joshua Lederberg, friend Carl Djerassi. who refers to Carl as one of the “wonders I recently had the honor of speaking of nature. ”I In 1960, when lS1° began informally at a very unusual event. The publishing Index Chemicus@ (Z@), now numerous friends and collaborators of Current Abstracts of Chemistry and Djerassi attended a party celebrating the Index Chemicus” (CA C&IC@ ), Carl publication of his 1,000th paper. My ad- served on the editorial advisory board. lib comments on that occasion left me He also lent his enthusiastic support to somewhat frustrated. In the euphoria of our next project, Science Citation In- the moment I failed to state so many of dex” (SCP ). Carl became one of the the more relevant facts about his many first memberx of the edkorial advisory accomplishments that I wished I had board of CC/Space, Electronic & Phys- come prepared with an appropriate ora- icai Sciences, a predecessor of CC/ tion, which I now belatedly provide. PhysicaL Chemical & Earth Sciences Perhaps only Carl and his closest friends (CC/PC&ES). In addition to his profes- will understand the special sympathies sional advice and encouragement, Carl we share, not the least of which is his ap- has shared with me his friendship and preciation of art and humanistic studies. joie de vivre. 721 of industrial experience he grew restless and eager for a position in academe, but he could not find one. Then, in the spring of 1949, D jerassi received a call from chemist George Rosenkranz. Ro- senkranz was the director of a small Mexican company called Syntex, and he invited Djerassi to head a research team there.z The job was appealing in that it would allow Carl to continue his investi- gation into the chemistry of steroids. Steroids were of interest to Djerassi and others because of their complicated structures and their prominent role in regulating such physiological processes as reproduction, digestion, and calcium metabolism. As more and more was un- derstood about the function of steroids in the body, their importance as phar- maceutical agents increased dramatical- Carl Djerassi ly. Steroid chemistry had been the sub- ject of Djerassi’s PhD thesis, but at Ciba Djerassi was bo~ in Vienna in 1923. it was difficult to keep working in this His Bulgarian-born father and Austrian area. Company policy confined most mother were both physicians. After the steroid research to the laboratories at outbreak of World War II, he emigrated Ciba’s Swiss headquarters. to the US with only $30 in his pocket. He It is of interest to mention that during spent two semesters at a now defunct this period the work on steroid chemis- junior college in Newark, New Jersey, try was almost frantic. In fact, the back- before accepting a scholarship from log of applications at the US Patent Of- Tarkio College, a small school in Tarkio, fice was eventuaUy so large that the Missouri. He later transferred to Ken- Pharmaceutical Manufacturers Associa- yon College, Ohio, and graduated sum- tion financed a steroid literature coding ma cum laude before his nineteenth project. Eugene Garfield Associates, birthday. Our foreign readers should re- predecessor of 1S1, received the con- alize that most Americans graduate at tract to do this work in 1958. We encod- the age of 22. ed over 20,000 steroid compounds and At this point, he joined a research established a precedent for the widely team at the Ciba Pharmaceutical Com- used fragment coding system employed pany, Summit, New Jersey. Within a in the Index Chemicus Registry System@ year, he and hk co-workers developed (ICR.S” ) and other systems. one of the first successful antihista- At the end of the 1940s, much of the mines, tnpelannamine. This compound, excitement centered around the dis- marketed by the Ciba-Geigy Corpora- covery that a steroid hormone, corti- tion as Pyribenzamine, is still used to sone, could aUeviate arthritis symptoms. treat a variety of allergy symptoms. The chemical could be derived from In 1943, Carl enrolled in the graduate animal bile, but initially not in amounts program at the University of Wisconsin. large enough to be of use in treating this He earned a PhD in organic chemistry chronic, widespread disease. Scientists before his twenty-second birthday and around the world were racing to find a returned to Ciba. After four more years more practical method for synthesizing 722 cortisone. The team Djerassi was invited the kind described earlier were rarely to head at Syntex was in fact attempting performed, “Natural products,” or natu- to develop a new synthesis. Djerassi ac- rafly occurring organic substances, can cepted the job, and in 1951, his team be used as models for synthetic com- won the race. They found away to make pounds. However, many natural prod- cortisone relatively simply, using a ucts consist of molecules so large, com- readily available raw material, the Mex- plex, and delicate that relationships be- ican yam. 3 tween their structure and function—and That same year, Djerassi’s team syn- in some cases, the structures them- thesized another compound which re- selves—are often obscure. At the time ceived much less attention at the time. when Djerassi was beginning his career, They named it “norethisterone,” and it it was still not uncommon for a natural was to become the active ingredient in products chemist using traditional ana- the birth control pill. Today it is known lytical methods to spend a lifetime eluci- as norethlndrone. dating the structure of a single sub- The work began with the female stance.4 hormone progesterone. Among other It was to a persistent problem, the in- things, progesterone prevents women adequacy of physical methods available from ovulating during pregnancy, thus for assessing organic structures, that acting as a natural contraceptive. Djer- Djerassi now turned his attention. He assi’s team found that by making a very was offered a professorship at Wayne spectilc change in progesterone’s chemi- State University, Detroit, in 1952. The cal structure, they could increase its following year he and his colleagues potency eightfold. This “analog” or syn- began to investigate optical rotatory thetic version of progesterone was dispersion. strong enough to work when injected, Optical rotatory dispersion and opti- but it lost its potency when administered cal circular dichroism, which Djerassi orally. The Syntex group needed a and others developed a decade later, use chemical which would be absorbed by polarized light to take an “impression” of the oral route. A breakthrough came a molecule’s three-dimensional shape. when they “rediscovered” a compound Both techniques operate on a principle synthesized more than a decade earlier known as the “Cotton effect,” named for but largely ignored because of its ap- a nineteenth-century French physicist, parent lack of medicinal value.z It was Fran~ois Cottons Cotton observed that called ethisterone and its activity in the polarized light can undergo changes body was not udlke that of progester- when it passes through certain sub- one. Moreover, its activity persisted stances. Dj erassi was able to transform even when taken orally. Djerassi’s group thk phenomenon into a practical tool devised a way to make the same chemi- for analyzing molecular structures. He cal modification in ethisterone which found that many organic substances, they had earlier made in progesterone. notably those containing a carbonyl The result was synthetic noreth~terone, group, produced the Cotton effect, and which prevented ovulation, was orally that the intensity of the effect vaned active, and could be incorporated into a with the wavelength of the light. He pill.z graphed these changes as “Cotton effect It is, of course, more efficient to me- curves,” and determined that many mo- thodically rearrange molecules, enhanc- lecular structures produced their own ing or creating desirable chemical prop- distinctive curves. By using these curves erties, than it is to randomly synthesize as “fingerprints” of molecules, he could compounds for biological testing. But make comparisons between molecules until recently, specific manipulations of never before possible. The “stereochem- 723 ish-y” or three-dimensionality of un- ples.