A NATIONAL HISTORICCHEMICAL LANDMARK

SYNTHESIS OFPHYSOSTIGMINEDEPAUWUNIVERSITYGREENCASTLE, INDIANAAPRIL 23, 1999

AMERICAN CHEMICAL SOCIETYDivision of the History of Chemistry andThe Office of Public Outreach

On the Cover: Percy L. Julian, workingin Minshall Laboratory.

Acknowledgments:The American Chemical Society gratefully acknowledges the assistance of those

who helped prepare this booklet, including: Theresa F. Bryant, Vice President forPublic Affairs, Donald J. Cook, Chemistry Professor Emeritus, and Jeffrey A.Hansen, Assistant Professor of Chemistry, of DePauw University; John J. Breen,Assistant Professor of Chemistry, IUPUI; and Ned D. Heindel, Professor ofChemistry, Lehigh University, the NHCLP Advisory Committee liaison.

This booklet was produced by the ACS Office of Communications.Design: Dahlman/Middour Design. Photographs courtesy of Donald J. Cook, theDePauw University Archives, and Faith R. Julian.

Copyright © 1999 American Chemical Society

This booklet commemorates Percy L. Julian’s1935 synthesis of the glaucoma drugphysostigmine as a National HistoricChemical Landmark. The designation was

conferred by the American Chemical Society, a not-for-profit scientific research and educational organization ofmore than 159,000 chemists and chemical engineers.A plaque marking the event was presented to DePauw

University on April 23, 1999, during the university’s cele-bration of the centennial anniversary of Percy Julian’sbirth. The inscription reads:

In 1935, in Minshall Laboratory, DePauw alumnusPercy L. Julian (1899–1975) first synthesized thedrug physostigmine, previously only available fromits natural source, the Calabar bean. His pioneeringresearch led to the process that made physostigminereadily available for the treatment of glaucoma. Itwas the first of Julian’s lifetime of achievements inthe chemical synthesis of commercially importantnatural products.

Minshall Laboratory, DePauw University.

PERCY L. JULIAN AND CHEMISTRYAT DEPAUWUNIVERSITY

1

The early 1930s was a time of greatchemical research productivity atDePauw. It was in this decade

that William M. Blanchard, Dean ofthe University, hired Percy Julian as aresearch fellow. Blanchard, who alsoserved as head of the chemistrydepartment, had been Julian’s mentorduring his undergraduate years atDePauw. Julian had received a Ph.D.degree in Vienna in 1931 and was inneed of a position in which he could con-tinue his research career. The DePauwchemistry program he joined in 1933 hadroots that extended back to 1839 when theuniversity was Asbury College and chemistry wasoffered as a natural science course taught by thepresident, Matthew Simpson. Chemistry became adistinct department in 1881 under the direction ofPhillip S. Baker. The department prospered and achemistry major was established in 1896. PercyJulian graduated from this program in 1920.

As a research fellow from 1932 to1935, Julian, working with his colleaguefrom Vienna, Josef Pikl, and severalDePauw students, produced a phenome-nal number of high-quality researchpapers. One such paper appeared in theApril 1935 issue of the Journal of theAmerican Chemical Society. This paper,entitled “Studies in the Indole Series V.The Complete Synthesis ofPhysostigmine (Eserine),” whichexplained how Julian synthesized

physostigmine, is undoubtedly the most sig-nificant chemical research publication tocome from DePauw. The student and fac-

ulty collaborative approach, promoted by Julian, hascontinued to the present, and today most of theresearch at DePauw is done in collaboration withstudents.

After the grant funding Julian’s positionexpired, Blanchard wanted to appoint Julian to theteaching staff. Despite Julian’s achievements, the

Board of Trustees did notallow it. Julian left DePauwto pursue a distinguishedcareer in industry.

In 1967, Julian wasappointed to the DePauwUniversity Board of Trustees.Also that year, planningbegan for a new sciencebuilding, which wouldreplace the 65-year-oldMinshall Laboratory, andconstruction commenced in1968. The Science andMathematics Center wasdedicated in September1972, with Percy Julian giv-ing the dedication address,“Science and the Good Lifeof Man.” Following Julian’sdeath, DePauw Universitynamed the Percy L. JulianScience and MathematicsCenter in his honor.

Percy Julian (top left) pictured with the DePauw University Science Club, circa 1920. William MartinBlanchard (third from the left), the Science Club advisor, was the first Ph.D. in chemistry to be hired byDePauw.

DePauw graduatePercy Julian, 1920.

WhenPercy Julian returned to the DePauwUniversity campus in 1932, he embarkedon the project that would forever secure

his reputation as a world-class researcher—the firsttotal synthesis of the anti-glaucoma drug physostig-mine, an alkaloid found in the Calabar bean.Glaucoma, a disorder in which the pressure in theeyeball increases when the aqueous humor does notdrain normally, can cause damage to the optic nerveand a loss of vision. Physostigmine promotesdrainage of this fluid by easing the constriction ofoutflow channels. Sixty-five years later, Julian’sachievement still remains important as derivativesand optically pure forms of physostigmine continueto show therapeutic promise for the treatment ofAlzheimer’s disease and for combating the effects ofchemical weapons.

Starting from phenacetin, Julian and JosefPikl, who was working as an assistant in chemistry,assembled physostigmine in 11 synthetic steps. Theproject, which took three years to complete, wasreported in a series of papers in the Journal of theAmerican Chemical Society. During the project, whilethe two chemists were working toward the synthesisof d,l-eserethole (a key intermediate compound two

steps removed from physostigmine), a group ofchemists, also working to synthesize physostigmine,under the direction of Sir Robert Robinson atOxford University in England, reported their syn-thesis of d,l-eserethole. Unlike today, when chemistscan rely on modern analytical methods such asnuclear magnetic resonance spectroscopy, mass spec-trometry, and X-ray crystallography to determineunequivocally the composition and structure of acompound, chemists in the 1930s relied on simpler,indirect, physicochemical methods for their analysis.As it happened in the case of d,l-eserethole, thephysicochemical parameters of Robinson’s d,l-eserethole were not in agreement with those ofJulian and Pikl. Firm in his conviction that his syn-thetic strategy was sound, Julian risked his yet-unproven reputation and boldly wrote in the fourthpaper in the series that the work of Robinson was inerror.

Subsequently, in the much celebrated fifthpaper in the series, “Studies in the Indole Series V.The Complete Synthesis of Physostigmine(Eserine),” Julian summarized his and Pikl’s work onthe most challenging total synthesis project of itstime with the following:

“Physostigmine, the principal alkaloid of theCalabar bean, and long used as a drug, has, since itsisolation by Jobst and Hesse 70 years ago, been thesubject of numerous investigations. The determina-tion of its constitution was rendered particularly dif-ficult since its peculiar chemical structure found noanalog in other plant products of knowncomposition….Shortly after promising experiments in the direction

of (its synthesis) were underway (in our laboratory)the work had to be interrupted and could only beresumed recently. In the meantime, the first of a seriesof ten papers dealing with the synthesis of physostig-mine, by Robinson and his collaborators, appearedand seemingly proved convincingly that the (course)suggested in our formulas could not be realized inpractice. Our experiments, nevertheless, were contin-ued 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 synthe-sized by Robinson and his coworkers and called d,l-eserethole. Likewise were all derivatives different.Inasmuch as our (optically) inactive material sub-

2

Percy Julian in the laboratory at DePauw during his tenure as a research fellow. Juliandirected qualified DePauw chemistry seniors in fundamental research. In a span of 4years, 11 senior papers from DePauw students were published in the Journal of theAmerican Chemical Society.

PERCY JULIAN’S SCIENCE

jected to characteristic reactions of eserethole of nat-ural origin yielded perfectly analogous results, weexpressed the belief that our product was the real d,l-eserethole and that of the English chemists must beassigned another constitution.This is now proved conclusively by synthesis of l-

eserethole, identical with the product of natural origin.”

Following the total synthesis of physostigmineand the separation of physostigmine into its opticalisomers, Julian was to make another discovery atDePauw that not only would enhance his stature asa chemist but also greatly improve the lives of many.It was in the course of isolating geneserin, a com-panion alkaloid of physostigmine from the Calabarbean, that Julian discovered small crystals of thehydrate of stigmasterol in the acid-washed oilextracted from the beans. Molecules such as stigmas-terol possess a central structural unit composed of 17carbon atoms arranged into 4 fused rings that is alsofound in many biologically significant compoundssuch as cholesterol and the sex hormones, estradioland testosterone. More generally known as steroids,these compounds cover a broad range of form andfunction and in many cases are of great value astherapeutic agents.

It was four years after this serendipitous discov-ery of the stigmasterol crystals that Percy Julian,then the director of research in the Soya Products

Division of the Glidden Co., was sum-moned to a 100,000 gallon soybean oilstorage container. Water seeping into theoil had resulted in the formation of awhite solid material that had collected atthe bottom of the tank. Remembering hisDePauw experience, Julian realized thatthe extremely small amounts of sterolscontained in soybean oil had been con-centrated and isolated in the white solid.Subsequent modification of this “acci-dental procedure” led to the daily produc-tion of 100 pounds of mixed soya sterolsworth more than $3.6 million annually.These sterols were then easily convertedusing methods and equipment designedby Julian to produce commercial quanti-ties of a variety of sex hormones, includ-ing progesterone, all at a greatly reducedcost to the public but still with a healthyprofit for Glidden.

Later in his career at Glidden and athis own research institute, the Julian Laboratories,Percy Julian continued to make important contribu-tions to the field of medicinal chemistry. His 1948synthesis of Reichstein’s Substance S is still the mostwidely used route to the pro-duction of hydrocortisoneand its derivatives, which areused in the treatment ofrheumatoid arthritis. Hedeveloped efficient synthesesfor whole families of steroidsincluding 4,5-epoxy steroids,16,17-epoxy steroids, 21-iodo steroids, 17-hydroxysteroids, 4-halo steroids, andnumerous steroids contain-ing the diosphenol structure.In later years, he worked onthe synthesis of the yohim-bine alkaloids and in uncov-ering the metabolism oftryptophan, one of the nineamino acids essential forhealthy living.

3

The Percy Lavon Julian commemorativestamp was issued in January 1993 as partof the U.S. Postal Service’s Black HeritageSeries.

In 1901, DePauw University received a gift of $25,000 from D. W. Minshall to constructa new science laboratory. Phillip S. Baker, the first DePauw Professor of Chemistry, didmuch of the planning for this building. Minshall Laboratory was completed in the springof 1902. It was demolished in 1973.

4

In a lifetime of continual striving, Percy L. Juliansucceeded against the prejudices and discrimina-tion of his time to become a pathbreaking syn-

thetic chemist, a successful industrial researchdirector, and a wealthy businessman. He was born in

Montgomery, AL,on April 11, 1899,the son of a railwayclerk and thegrandson ofslaves. From thebeginning, he didwell in school, butthere was no publichigh school forAfrican Americansin Montgomery.Julian graduatedfrom an all-Blacknormal schoolinadequately pre-pared for college.Even so, in the fall

of 1916, at the age of 17, he was accepted as a sub-freshman at DePauw. This meant that in addition tohis regular college courses he took classes at a nearbyhigh school. He also had to work in order to pay hiscollege expenses. Nevertheless, he excelled. Julianwas elected to Phi Beta Kappa and graduated with aB.A. degree in 1920 as valedictorian of his class. Hischosen path of chemistry would prove to be a rockyone. With no encouragement to continue his educa-tion, based on the lack of future job opportunities,Julian found a position as instructor in chemistry atFisk University, in Nashville, TN.

After two years at Fisk, Julian won an AustinFellowship to Harvard and received his M.A. degreein 1923. Again, he faced disappointment when nojob offer was forthcoming. In succeeding years, heserved on the staff of predominantly Black institu-tions—first at West Virginia State College, and in1928, as head of the department of chemistry atHoward University, Washington, DC. In 1929,Julian received a Rockefeller Foundation grant andthe chance to earn his doctorate in chemistry. Heelected to study natural products chemistry with

Ernst Späth at the University of Vienna. Hereceived his Ph.D. in 1931 and returned to Howard,accompanied by his friend, Josef Pikl. After twoyears there, internal politics forced them to leave. In1933, through the efforts of his former professorWilliam Blanchard, Julian returned to DePauwUniversity as a research fellow. He directed researchprojects for senior and graduate students. It was herein Minshall Laboratory in 1935, in collaborationwith Pikl, that he completed the research thatwould result in the total synthesis of physostigmine.This work established Julian’s reputation as a world-renowned chemist at the age of 36.

Despite his accomplishments as a recognizedand published researcher, Percy Julian was denied afaculty position at DePauw. Frustrated in his effortsto gain an academic post, Julian turned to industry.One research job fell through because of a town lawforbidding “housing of a Negro overnight.” Then,in 1936, a door opened when Julian was offered aposition as director of research for soya products forGlidden in Chicago. Over the next 18 years, theresults of his soybean protein research producednumerous patents and successful products forGlidden, among them a paper coating and a fire-retardant foam used widely in WWII to extinguishgasoline fires. His biomedical research made it possi-ble to produce large quantities of synthetic proges-terone and hydrocortisone at low cost.

In 1953, he established the Julian Laboratories,a successful enterprise that he sold for more than $2million in 1961. He later formed the JulianResearch Institute, a nonprofit research organiza-tion. Among his many lifetime honors was election,in 1973, to the National Academy of Sciences. Hewas also widely recognized as a steadfast advocate forhuman rights. Julian continued his private researchstudies and served as a consultant to major pharma-ceutical companies until his death on April 19, 1975.

PERCY LAVON JULIAN (1899–1975)

Percy L. Julian, ca. 1950.

Stu Borman, “Black Chemist Percy Julian Commemoratedon Postage Stamp,” Chemical & Engineering News, 71 (5)(Feb. 1, 1993): 9-12.

Mary Ellen Bowden, “Percy Lavon Julian (1899–1975) andCarl Djerassi (1923–).” In Chemical Achievers: The HumanFace of the Chemical Sciences. (Chemical HeritageFoundation: Philadelphia, PA, 1997): 109-113.

W. Montague Cobb, “Percy Lavon Julian,” Journal of theNational Medical Association, 63 (2), (March 1971): 143.

Donald J. Cook, Chemistry At DePauw University,1837–1987. (DePauw Association of Chemists: Greencastle,IN, 1987).

Paul DeKruif, “The ManWhoWouldn’t Give Up.” Reader’sDigest Magazine, (August 1946): 113-118.

P. L. Julian and J. Pikl, “Studies in the Indole Series. IV.The Synthesis of d,l- Eserethole.” Journal of the AmericanChemical Society, 57 (March 1935): 563-566.

P. L. Julian and J. Pikl, “Studies of the Indole Series. V.The Complete Synthesis of Physostigmine (Eserine).”Journal of the American Chemical Society, 57 (April 1935):755-757.

Bernard Witkop, “Percy Lavon Julian (1899–1975), ABiographical Memoir” in Biographical Memoirs, vol. 52,(The National Academy Press: Washington, DC, 1980),223.

Bernard Witkop, “From the ‘Ordeal Bean’ (PhysostigasVenenosum) to the Ordeal of Alzheimer’s Disease, Some ofthe Legacy of Percy Lavon Julian (1899–1975),”Heterocycles,49 (1998): 9-27.

FURTHER READING

THE NATIONAL HISTORIC CHEMICAL LANDMARKSPROGRAMOF THE AMERICAN CHEMICAL SOCIETY

The ACS National Historic Chemical Landmarks Program recognizesour scientific and technical heritage and encourages the preservation of his-torically important achievements and artifacts in chemistry, chemical engi-neering, and the chemical process industries. It provides an annotated rosterto remind chemists, chemical engineers, students, educators, historians, andtravelers of an inspiring heritage that illuminates where we have been andwhere we might go when traveling the diverse paths todiscovery.

An ACS historic chemical landmark represents a distinctive step inthe evolution of the chemical sciences and technologies. Designations ofsites and artifacts note events or developments of clear historical impor-tance to chemists and chemical engineers. Collections mark the contribu-tions of a number of objects with special significance to the historicaldevelopment of chemistry and chemical engineering.

This program began in 1992, when the Division of the History ofChemistry of the ACS formed an international Advisory Committee. The committee, composed of chemists,chemical engineers, and historians of science and technology, works with the ACS Office of Communications andis assisted by the Chemical Heritage Foundation. Together, these organizations provide a public service by exam-ining, noting, recording, and acknowledging particularly significant achievements in chemistry and chemicalengineering. For further information, please contact the ACS Office of Communications, 1155 Sixteenth Street,N.W., Washington, DC 20036; 800-ACS-5558, ext. 6274.

NATIONAL HISTORICCHEMICAL LANDMARK

SYNTHESIS OFPHYSOSTIGMINESYNTHESIS OF

PHYSOSTIGMINEDePauw UniversityGreencastle, Indiana

1935

In 1935, in Minsha l l Laboratory , DePauw alumnusPercy L . Ju l i an (1899–1975 ) f i r s t s yn the s i zed thedrug physostigmine, previously only available from itsna tu ra l sou rce , the Ca laba r bean . H i s p ionee r ingresearch led to the process that made physostigminer e a d i l y a v a i l a b l e f o r t h e t r e a t m e n t o f g l a u c o m a .It was the first of Julian’s lifetime of achievements in thec h e m i c a l s y n t h e s i s o f c o m m e r c i a l l y i m p o r t a n tnatural products.

Amer ican Chemica l Soc ie ty Apr i l 23 , 1999

The American Chemical SocietyEdel Wasserman, PresidentDaryle H. Busch, President-ElectHenry F. Whalen, Jr., Board ChairJohn K Crum, Executive DirectorDenise Graveline, Director of Communications

ACS Division of the History of ChemistryStephen J. Weininger, ChairRichard E. Rice, Chair-ElectVera V. Mainz, Secretary-Treasurer

ACS Indiana SectionSamuel R. Wendel, ChairJohn J. Breen, Immediate Past ChairChristina C. Bodurow, Chair-ElectRobert L. McClain, SecretaryPatrick N. Walsh, Treasurer

Historical Site CommitteeNeal B. Abraham, DePauw UniversityRobert G. Bottoms, DePauw UniversityJohn J. Breen, Indiana SectionTheresa F. Bryant, DePauw UniversityDonald J. Cook, DePauw UniversityJeffrey A. Hansen, DePauw UniversityEdwin T. Harper, Indiana SectionPatrick N. Walsh, Indiana SectionSamuel R. Wendel, Indiana Section

DePauw UniversityTimothy H. Ubben, Chairman, Board of TrusteesRobert G. Bottoms, PresidentNeal B. Abraham, Vice President for AcademicAffairsTheresa F. Bryant, Vice President for Public AffairsThomas E. Dixon, Vice President for Financeand AdministrationMadeleine R. Eagon, Vice President forAdmission and Financial AidPaul Hartman, Vice President for Developmentand Alumni RelationsJames L. Lincoln, Vice President for StudentServices

ACS Advisory Committee on National HistoricChemical LandmarksNed D. Heindel, Lehigh University, ChairJames J. Bohning, Wilkes UniversityJon B. Eklund, National Museum of AmericanHistoryYasu Furukawa, Tokyo Denki UniversityLeon Gortler, Brooklyn CollegePaul R. Jones, University of MichiganJames W. Long, University of OregonPeter J. T. Morris, Science Museum, LondonMary Virginia Orna, Chemical HeritageFoundationStanley Proctor, Jr., Proctor Consulting ServicesJeffrey L. Sturchio, Merck & Co., Inc.Frankie K. Wood-Black, Phillips PetroleumAnn C. Higgins, ACS Staff Liaison

American Chemical Society1155 Sixteenth Street, N.W.Washington, DC 20036