Percy Julian's Science
When Percy Julian returned to the DePauw University campus in 1932, he embarked on the project that would forever secure his reputation as a world-class researcher the first total synthesis of the anti-glaucoma drug physostigmine, an alkaloid found in the Calabar bean. Glaucoma, a disorder in which the pressure in the eyeball increases when the aqueous humor does not drain normally, can cause damage to the optic nerve and a loss of vision. Physostigmine promotes drainage of this fluid by easing the constriction of outflow channels. 65 years later, Julian's achievement still remains important as derivatives and optically pure forms of physostigmine continue to show therapeutic promise for the treatment of Alzheimer's disease and for combating the effects of chemical weapons.

Starting from phenacetin, Julian and Josef Pikl, who was working as an assistant in chemistry, assembled physostigmine in 11 synthetic steps. The project, which took three years to complete, was reported in a series of papers in the Journal of the American Chemical Society. During the project, while the two chemists were working toward the synthesis of d,l-eserethole (a key intermediate compound two steps removed from physostigmine), a group of chemists, also working to synthesize physostigmine, under the direction of Sir Robert Robinson at Oxford University in England, reported their synthesis of d,l-eserethole. Unlike today, when chemists can rely on modern analytical methods such as nuclear magnetic resonance spectroscopy, mass spectrometry, and X-ray crystallography to determine unequivocally the composition and structure of a compound, chemists in the 1930s relied on simpler, indirect, physicochemical methods for their analysis. As it happened in the case of d,l-eserethole, the physicochemical parameters of Robinson's d,l-eserethole were not in agreement with those of Julian and Pikl. Firm in his conviction that his synthetic strategy was sound, Julian risked his yet-unproven reputation and boldly wrote in the fourth paper in the series that the work of Robinson was in error.

Subsequently, in the much celebrated fifth paper in the series, "Studies in the Indole Series V. The Complete Synthesis of Physostigmine (Eserine)," Julian summarized his and Pikl's work on the most challenging total synthesis project of its time with the following:

"Physostigmine, the principal alkaloid of the Calabar bean, and long used as a drug, has, since its isolation by Jobst and Hesse 70 years ago, been the subject of numerous investigations. The determination of its constitution was rendered particularly difficult since its peculiar chemical structure found no analog in other plant products of known compositionæ.

Shortly after promising experiments in the direction of (its synthesis) were underway (in our laboratory) the work had to be interrupted and could only be resumed recently. In the meantime, the first of a series of ten papers dealing with the synthesis of physostigmine, by Robinson and his collaborators, appeared and seemingly proved convincingly that the (course) suggested in our formulas could not be realized in practice. Our experiments, nevertheless, were continued and ... led to the successful synthesis of d,l-eserethole.

To our surprise, our d,l-eserethole exhibited entirely different properties than those of a compound synthesized by Robinson and his coworkers and called d,l-eserethole. Likewise were all derivatives different. Inasmuch as our (optically) inactive material subjected to characteristic reactions of eserethole of natural origin yielded perfectly analogous results, we expressed the belief that our product was the real d,l-eserethole and that of the English chemists must be assigned another constitution.

This is now proved conclusively by synthesis of l-eserethole, identical with the product of natural origin."

Following the total synthesis of physostigmine and the separation of physostigmine into its optical isomers, Julian was to make another discovery at DePauw that not only would enhance his stature as a chemist but also greatly improve the lives of many. It was in the course of isolating geneserin, a companion alkaloid of physostigmine from the Calabar bean, that Julian discovered small crystals of the hydrate of stigmasterol in the acid-washed oil extracted from the beans. Molecules such as stigmasterol possess a central structural unit composed of 17 carbon atoms arranged into four fused rings that is also found in many biologically significant compounds such as cholesterol and the sex hormones, estradiol and testosterone. More generally known as steroids, these compounds cover a broad range of form and function and in many cases are of great value as therapeutic agents.

It was four years after this serendipitous discovery of the stigmasterol crystals that Percy Julian, then the director of research in the Soya Products Division of the Glidden Co., was summoned to a 100,000 gallon soybean oil storage container. Water seeping into the oil had resulted in the formation of a white solid material that had collected at the bottom of the tank. Remembering his DePauw experience, Julian realized that the extremely small amounts of sterols contained in soybean oil had been concentrated and isolated in the white solid. Subsequent modification of this "accidental procedure" led to the daily production of 100 pounds of mixed soya sterols worth more than $3.6 million annually. These sterols were then easily converted using methods and equipment designed by Julian to produce commercial quantities of a variety of sex hormones, including progesterone, all at a greatly reduced cost to the public but still with a healthy profit for Glidden.

Later in his career at Glidden and at his own research institute, the Julian Laboratories, Percy Julian continued to make important contributions to the field of medicinal chemistry. His 1948 synthesis of Reichstein's Substance S is still the most widely used route to the production of hydrocortisone and its derivatives, which are used in the treatment of rheumatoid arthritis. He developed efficient syntheses for whole families of steroids including 4,5-epoxy steroids, 16,17-epoxy steroids, 21- iodo steroids, 17-hydroxy steroids, 4-halo steroids, and numerous steroids containing the diosphenol structure. In later years, he worked on the synthesis of the yohimbine alkaloids and in uncovering the metabolism of tryptophan, one of the nine amino acids essential for healthy living.