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Percy Lavon Julian
Pioneer of Medicinal Chemistry Synthesis

Bryan A. Wilson, Monte S. Willis MD, PhD
DOI: http://dx.doi.org/10.1309/LM4M5FESPE3KDPTR 688-692 First published online: 1 November 2010

Percy Lavon Julian (1899–1975)

The contributions of Dr. Julian to the field of medicinal chemistry began humbly at the turn of the century in the segregated American South. Percy Lavon Julian was born on April 11, 1899, in Montgomery, AL. His formal public education was limited, while his secondary education ended at the eighth grade which was the norm for African Americans at that time. His father, who had been denied the opportunity to go to college, made it a priority to ensure that his children received this opportunity.14 Julian went on to complete two years of teacher training at the State Normal School for Negroes in Montgomery. In 1916, Julian became the first in his family to attend college when he was admitted to DePauw University in Green-castle, IN. During his first two years of college, Julian took remedial classes in addition to his college courses to make up for the academic deficiencies resulting from his limited primary education. Despite this, Julian was an excellent student in college and was elected as a member of both the Phi Beta Kappa and Sigma Xi honor societies. In 1920, Julian earned a bachelor’s degree in chemistry and was named valedictorian of his class.

DePauw University circa 1916. A few African American students had been accepted to DePauw before Julian arrived; however, the culture was far from accepting. When he arrived, Julian was taken to off-campus housing because the dorms on campus were for “whites only.” Furthermore, it took a day and a half for Julian to find a diner that would serve him. This would be the beginning of many unwelcoming environments Julian would overcome and thrive in.

Despite overcoming the barrier of obtaining a college education denied to his father, there were many more obstacles for Julian to overcome in his quest to become a distinguished chemist. After graduation, Julian taught at Fisk University in Nashville, TN, until 1922. However, if he was to achieve his goal of becoming a leader in chemistry, he recognized the need to earn a PhD in chemistry. Such an opportunity was largely unavailable to African Americans at that time. In 1922, Saint Elmo Brady was the only African American who had earned a PhD in chemistry in the United States.

Harvard circa 1922. As Julian arrived in 1922, the President of Harvard had just banned black students from the dorms in Harvard yard.14

In 1923, Julian was awarded an Austin fellowship in biophysics and organic chemistry at Harvard University, where he earned his master’s degree a year later. With the aid of a minor fellowship, he remained at Harvard studying biophysics and organic chemistry until 1926.11 Subsequently, he spent 1 year at West Virginia State College as Professor of Chemistry, where he was the only member of his department.11 He then went on to teach at Howard University, another historically black college, until 1929. In 1930, he was awarded a fellowship from the Rockefeller Institute, which gave him the financial support needed to earn his PhD degree. He took a leave of absence from Howard to earn his PhD degree under Dr. Ernst Späth, a giant in the field of natural products chemistry with a special interest in alkaloids, at the University of Vienna in Austria.

Even with his desire to continue his studies at Harvard, there were a number of barriers preventing him from continuing his work on a PhD in chemistry. Despite earning his MA in 1923, Harvard did not extend him a position as a teaching assistant, an essential position to becoming a PhD candidate. It has been reported this position was not offered because of the fear it might offend the southern students he would be teaching.11

In 1929, Vienna’s Chemische Institut was one of the premier institutions for the study of natural products chemistry.14 At that time, there were many individuals who understood there were chemicals in plants that had profound effects on a variety of human physiological functions. For example, coffee could wake you up and tobacco had soothing effects. Therefore, the goal of natural product chemistry in the 20th century was to identify the specific chemicals that cause these effects, in order to isolate them for use in various applications. Among these chemicals, alkaloids were of particular interest because they had powerful pharmacological effects and included substances such as caffeine, nicotine, cocaine, strychnine, and morphine. Julian’s thesis work sought to isolate and structurally identify the active alkaloids in the Austrian plant, Corydalis cava, extracts of which were known to be effective in treating pain and tachycardia. Julian completed his PhD in 2 years after successfully identifying tetrahydrocoptisin, hydro-hydrastinin, and canadine as the key alkaloids found in Corydalis cava.1

Ernst Späth described Julian by saying, “Ein ausserordentlicher Student wie ich in meiner Laufbahn noch nie gehabt habe,” which translates to “an extraordinary student, the likes of which I have never had before in my career as a teacher.”

Just outside the laboratory Julian found an exciting world to explore in Vienna, Austria. With fellow student Edwin Mosettig, Julian joined the Mossettig family for swims in the Danube, ski trips, and the opera. Edwin’s mother was a famous musician, making the Mossettig house a point of social activity. It was there Julian experienced the layers of society largely inaccessible to minorities at the time in the United States. Since dark-skinned persons were rare in Europe, he was of great interest to many.14

Synthesis of Physostigmine

Dr. Julian returned to the United States in the fall of 1931 with his fellow student, Joseph Pikl, from Dr. Späth’s laboratory. One of their first goals was to synthesize the drug physostigmine, an alkaloid found in the calabar bean of the West African plant, Physostigma venosum. Their interest in doing this was physostigmine’s use as an anti-glaucoma agent in promoting fluid drainage in the eye. The race to synthesize physostigmine was a competitive and bold undertaking. Several individuals in research laboratories around the world were working hard to unravel the complexity of synthesizing this compound, including Dr. Robert Robinson, one of England’s premier chemists and a Nobel Prize laureate. Dr. Robinson published a number of reports on the partial synthesis of physostigmine, which in parallel with publications from Dr. Julian and Pikl’s lab, led to an understanding of the final steps in the synthesis of physostigmine.25 Despite Dr. Robinson’s papers from 1935 suggesting, an “apparent” complete synthesis pathway for physostigmine,17,18 Dr. Julian realized the final product in this pathway did not have the correct melting temperature. In Dr. Julian’s subsequent manuscript, entitled “Studies in the indole series, V: The complete synthesis of physostigmine (eserine)”,6 Dr. Julian pointed out this error, along with a description of his pathway for the complete synthesis of physostigmine with the expected melting temperature. Recent publications have discussed in detail how Drs. Robinson and Julian came up with such different answers to synthesizing physostigmine.15 The primary difference between their conclusions resulted from the different strategies they each took to synthesize d,l-eserethole, a key intermediate formed 2 steps prior to the final product in the synthesis of physostigmine (Figure 1). Dr. Robinson reported the synthesis of d,l-eserethole, which was not d,l-eserethole at all but the eserethole-b isomer.15,19 It took several subsequent publications to identify the subtle yet significant differences between Drs. Robinson’s and Julian’s syntheses (reviewed by Ault, 200815). Dr. Julian’s correct full synthesis of physostigmine was recognized by the American Chemical Society (ACS) as one of the 25 most important achievements in chemistry,12 resulting in the ACS’s designation of Dr. Julian’s laboratory as a National Historic Chemical Landmark. The significance of this achievement is also recognized by Dr. Julian’s eventual election to the National Academy of Sciences.

Figure 1

Overview of Dr. Julian’s complete synthesis of physostigmine. Considered a milestone, in 1999 the American Chemical Society recognized Dr. Julian’s synthesis of the glaucoma drug physostigmine as 1 of the top 25 achievements in the history of American chemistry. This represents a “total synthesis”; that is, an assembly of a complex compound from basic intermediates. Compound 9 represents formation of d,l-eserethole, a key intermediate needed for the successful synthesis of physostigmine.6

Despite his stunning international academic success, Dr. Julian’s ability to ascend the academic ranks eluded him. Both DePauw and the University of Minnesota denied him appointments because of his race.10 Even after leaving academics for industry, he continued to face discrimination. For example, after accepting a research position at the Institute of Paper Chemistry in Wisconsin, he was barred from working because Appleton, WI city statutes stated, “No negro should be bedded or boarded in Appleton overnight.”13 He was subsequently hired by Glidden Paint Company in Chicago, IL, as its director of research. During his 18 years at Glidden, Dr. Julian was responsible for filing more than 100 patents and increased the value of the company considerably with his inventions.

Synthesis of Sex Hormones

In 1935, Dr. Julian was hired as director of research in the Soya Products Division of the Glidden Company, one of the largest paint manufacturers in the United States. His first assignment was to develop a process for the isolation and preparation of a soybean protein to be used in cold weather paints. His success in achieving this goal led to an increase in the profits from these specific products from $35,000 to $135,000 in a 1-year time span.11 Dr. Julian had first learned about soybeans during his training in Dr. Späth’s lab in Vienna. It was there he discovered that German scientists had used them to prepare steroid hormones (eg, progesterone) and in the manufacturing of physostigmine. Progesterone (or progestational steroidal ketone) had been discovered in 1933 along with its role in supporting pregnancy. The ability to manufacture progesterone had obvious medical applications. Steroids are naturally produced by both plants and animals and consist of compounds containing a basic 4 cyclic hydrocarbon ring structure, cyclopentanoperhydrophenanthrene. Therefore, Dr. Julian investigated using soybean steroids to synthesize progesterone.

While Dr. Julian was at DePauw, he discovered that mixing water and Calabar bean oil resulted in the formation of steroid crystals containing stigmasterol. In a fateful series of events, water leaked into 100,000 gallons of soybean oil scheduled for use by the Durkee Famous Foods plant, a subsidiary of Glidden. Glidden would have been out $200,000 as a result of this accident, so Dr. Julian rushed to see the damage. He noticed there was white sludge throughout the tank, which he recognized as similar to the stigmasterol crystals he had seen previously. Thus, he felt confident the main process for isolating steroids from soybean oil was through the addition of water. Subsequently, he devised an industrial synthesis process for converting stigmasterol into progesterone by scaling up the process developed by the German group of Butenandt and Fernholz 5 years earlier.7,8 Using this process, the Glidden Company suddenly became a major manufacturer of human sex hormones. By 1940, progesterone produced by Glidden was shipped to the Upjohn pharmaceutical company as the first commercial shipment of sex hormones in the United States. The development of testosterone and birth control pills were soon to follow based on the high throughput synthesis of steroids developed by Dr. Julian and his co-workers at Glidden.

Synthesis of Cortisone

Dr. Julian continued his research on steroids by investigating manufacturing methods to produce cortisone. Cortisone had recently been shown effective in the treatment of arthritis, an autoimmune disease causing the destruction of cartilage and bone within specific joints. Dr. Philip Hench, of the Mayo Clinic, presented data showing how arthritis patients responded positively to the drug, cortisone.16 However, the drug was expensive and essentially impossible to obtain for clinical application. Dr. Hench had received small quantities of cortisone that had been synthesized from the bile of slaughtered oxen. However, given the need for thousands of cattle and the more than 30 chemical reactions necessary to make a 1-year supply of cortisone for a single patient, a more efficient and economical industrial process was needed for the large scale synthesis of cortisone.

Dr. Julian became interested in making cortisone more widely available for the public. He devised a plan to create large quantities of cortisone by synthesizing it in the same fashion as progesterone, using an almost identical compound called Reichstein’s Substance S, the cortisone precursor found in the cortex of the adrenal glands. Dr. Julian published a paper on a new synthetic pathway for the steroid, Reichstein’s Substance S, from soybeans.9 The only difference was that compared to cortisone, Substance S lacked an oxygen on carbon number 11. Many investigators, including Dr. Julian, searched to no avail for ways to synthesize cortisone by chemically placing an oxygen atom on carbon-11 of Substance S. The price of cortisone topped $4,000 an ounce, 100 times the value of gold at the time.14 Although, by the summer of 1951, 4 teams of investigators announced new ways to synthesize cortisone, the process took 15 steps. However, scientists from Upjohn discovered a common mold that could effortlessly insert an oxygen atom specifically at the carbon 11 position of Substance S. This was the breakthrough discovery ending the cortisone shortage. Since Dr. Julian’s Substance S was available in such large quantities, it was used as the starting material initially to create cortisone on a large scale. Hydrocortisone is still widely produced today from Substance S using methodologies similar to those developed by Dr. Julian and his coworkers.

While at Glidden, Dr. Julian also helped in the synthesis of several additional products made from soybeans found to be useful in a number of industrial applications. One such product included the fire retardant Aero-Foam, which was used to put out gasoline fires and attributed to saving many lives in World War II. Other soy proteins were found to be useful in latex house paints. Despite Dr. Julian’s success in synthesizing steroids, Glidden wanted Dr. Julian to concentrate on products related to paints. Given this environment and his competing interests, Dr. Julian decided to leave Glidden and form Julian Laboratories, where he could continue his work making hormones cheaply and in bulk quantities. In addition, he went on to establish Laboratorios Julian de Mexico in Mexico City and became founder and president of Empress Agro-Quimica Guatemaleca in Guatemala. His interest in establishing companies in both Mexico and Guatemala stemmed from the fact that wild yams found in these countries contained even more steroids (eg, Substance S) than soybeans to be used for the synthesis of cortisone. In 1961, Dr. Julian sold all of his companies for $2.3 million to the Smith Kline and Upjohn pharmaceutical companies. In 1964, he organized the Julian Research Institute and Julian Associates, Inc., where he continued his experimental work and provided consultation to outside chemical companies until he died in 1975.

Chicago circa 1950. In 1950, the Julian family moved to Oak Park, an upscale area in Chicago. On Thanksgiving Day that year, arsonists attempted to burn down the home of the first African American to live in this all white neighborhood. Despite outrage published in the Chicago Sun Times, a bomb was tossed at the home the following year (June 12, 1951) into the children’s room while Dr. Julian and his wife were away from the house. Later that same summer at a national meeting of scientists, the Union League Club prohibited his attendance because of their prohibition of African Americans.11

In 1973, Dr. Julian was inducted into the National Academy of Sciences, as only the second African American to achieve this honor. Dr. Julian overcame many obstacles in his pursuit to become a scientist and entrepreneur during an era of particularly intense racial inequity in the United States. His imagination, love, and passion for science flourished throughout his life and led to significant contributions to public health and medicinal chemistry through his valuable discoveries in plant chemistry (Figure 2). While his determination to succeed was laudable, it was his determination (and success) in making important, clinically useful drugs available that was most meritorious.

Figure 2

Synthetic pharmacological agents industrially produced by use of the syntheses generated by Dr. Julian. Corydaline and physostigmine are plant alkaloids Dr. Julian derived from the Austrian Corydalis cava and the West African Calabar bean Physostigma venenosum, respectively. Corydaline has been used to treat pain, while physostigmine was developed to treat glaucoma. Physostigmine’s parasympathomimetic activity inhibits the metabolism of acetylcholine, thereby promoting the drainage of ocular fluid. Dr. Julian subsequently developed the chemistry to synthesize progesterone from soybeans on an industrial scale, making his company the first to make sex hormones commercially available in the United States. Its wide application in medicine has been significant in many fields. Dr. Julian also helped develop the first mass production of cortisone from soybeans, a steroid hormone used to suppress the immune system in autoimmune diseases.

Dr. Julian placed a high priority on seeking to advance conditions for African Americans.

“The right of a people to live where they want to, without fear, is more important than science.”12

He helped found the Legal Defense and Educational Fund of Chicago, while additionally serving on many organization and university boards.11

“Science should not be assessed on the basis of its contribution of mere material things. Our contribution should be found instead in our devotion to the concept of an ordered natural world in which we live.”10

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