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JOHN CLARK SHEEHAN September 23, 1915-March 21, 1992 BY E. J. COREY AND JOHN D . ROBERTS JOHN C. SHEEHAN WILL Tong be remembered for having solved one of the most formidable and prominent problems in synthetic chemistry of the twentieth century, the chemical synthesis of the penicillins, en c! for helping to lead organic chemistry to new heights in the post-WorIc} War II era. He macle major contributions to the Massachusetts Institute of Technology, his academic home for four cleca(les. His teaching and research were instrumental in rejuvenating chemistry anct maintaining its excellence at the institute, which also received enormous financial returns from his successful work on synthetic penicillins. His fundamental research provided the chemical base for the clevelopment of modern semisyn- thetic penicillins, which have saved countless human lives. John C. Sheehan was born on September 23, 1915, in Battle Creek, Michigan. His father, Leo C. Sheehan, then sports editor and police reporter for The Battle Creek Enquirer, and his mother, Florence, were clescribed in the news ar- ticle marking the birth as "prominent in the younger soci- ety circles of Battle Creek." In abolition to Irish forebears, the family hac! a substantial Yankee background; some six- teen known ancestors clatecl from revolutionary times. Flo- rence Sheehan was a brilliant woman and skilled genealo- 291

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292 BIOGRAPHICAL MEMOIRS gist who did professional work in the field and later be- came the Michigan registrar for the Daughters of the Ameri- can Revolution. John's father left home at fifteen with only an eighth-grade education to "see the world" and found work as a reporter in San Francisco, where he witnessed the 1906 earthquake. Leo Sheehan was a skilled writer and pro- gressed with The Battle Creek Enquirer to city editor and then to managing editor. He later functioned as a ghostwriter for Frank Murphy, once governor of Michigan and a Su- preme Court justice. {ohn's grandfather, John W. Sheehan, was an outstand- ina lawyer who had business dealings with William Jennings lo, , ~ _ _ _ ~ _ . . _ _ _ _ , _ _ _ _ w _ _ _ J _ A A A A A ~ ~ t~ ~ Bryan, the famous political leader and orator. His maternal grandfather, Nathaniel Y. Green, was a bank manager and maintained an interest in nature and learning. A skilled amateur taxidermist, he had a large collection of birds. He greatly stimulated iohn's interest in science bv giving him a J ~ ~ Zeiss microscope with an oil-immersion lens and also intro- duced John to the curator of the local museum who helped him with several small science projects. founts grandfather had a telescope for astronomical observations and took John to meetings with the local group of astronomy buffs. As with many future chemists in their early years, John progressed from a chemistry set to a basement laboratory and was fascinated by explosives and rocketry. He was a natural experimentalist with skillful hands. He also built model airplanes, and one with a delta wing won a first prize for longest flight time in the self-design class. He was also a zealous competitor in other activities. The Battle Creek news- paper reported him as the premier marble shooter of his grade school, representing the school in the city champion- ships; as winner of the city yo-yo championship with a per- fect score, as judged by the world's champion yo-yo player of the time; as a finalist in a Boy Scout election picking a mayor for a day; as having been injured in a high school

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J{OHN CLARK SHEEHAN 293 football game; and as Battle Creek College's No. 1 tennis player, as well as a participant with his brother Joseph in numerous tennis doubles tournaments. However, not all was rosy in John's younger years. His father had a long struggle with cancer and died at age fifty. John's brother, Joseph, most often known as Joe, later had a distinguished career as a professor of psychology at the University of California. As an adolescent and young adult' Joe suffered intensely from stuttering and with his wife, Vivian, herself an eminent speech pathologist, devoted their lives to developing and implementing very successful training programs for relieving speech defects. John and how's younger brother, David, now retired, was engaged in manufacturing in Battle Creek. John was raised as a Catholic and attended Catholic grade schools. However, in later life, both he and Joe were not particularly religious. John attended Battle Creek College with a double major in chemistry and political science. He graduated with honors as valedictorian of his class and won a state college scholarship for graduate work in any field of his choice. He elected to study chemistry at the University of Michigan. John received the Ph.D. degree in 1941. His thesis super- visor was Werner E. Bachmann, then engaged in the his- toric first total syntheses of the steroid hormones equilenin and estrone. John's research, on the synthesis of phenan- threne derivatives, was in Bachmann's other major field of this period, the investigation of potential carcinogenic hy- 1 ~ , drocarbons following along the lines of T. W. Cook with . _ ~ ~ ~ ~ ~ whom Bachmann had worked earlier. John became a su- perbly trained experimentalist in the grand tradition of Bachmann and Bachmann's illustrious teacher, Moses Gomberg, the founder of the field of stable carbon free radicals. Shortly after receiving his Ph.D., John married Marion

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294 BIOGRAPHICAL MEMOIRS Jennings, who had gracluatecl with him from St. Philips High School in Battle Creek. Earlier in 1941, Bachmann asked John to work with him as a postcloctoral fellow but clic! not specify the area of research. After John finished writing his thesis, Bachmann informecl him that it wouIc! be national defense research on the synthesis of cyclotrimethylenetrinitro- amine, cocle named RDX. This substance was known to be a very brisant explosive, but no commercial or large-scale synthesis was available for its preparation. Bachmann ant! Sheehan (levelopecl a procedure for synthesis of RDX by nitration of hexamethylenetetramine that they ran in the Michigan laboratories on a scale of more than a kilogram. One wonders whether the university administrators were aware of the substantial hazarc! involves] in this project. John displayer! a mixture of courage anct prudence, wearing not only the usual safety glasses ant! laboratory coat but also a heavy towel wrapper! arounc! his neck as protection from flying glass. While purifying the reaction product, John isolated cyclo- tetramethylenetetranitroamine, an excellent explosive in its own right. The Bachmann-Sheehan process was scaled up by Tennessee Eastman, and the RDX so proclucec! was used with great success by the United States for the remainder of the war (often in mixtures with TNT). The rapic! comple- tion of his part of the RDX project enabled Sheehan to accept a position as a research chemist at Merck and Co. in Rahway, New Jersey, starting in October lL941 uncler the direction of Max Tishier. John participated in several key synthetic projects, where research was needed for scale-up to the pilot plant and beyond. One was a new preparation of calcium pantothenate; another was removal of immuno- genic materials formed as by-proclucts in fermentation broths for the production of streptomycin; and a thirc! was isola- tion and purification of penicillin. Out of the latter came

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fOHN CLARK SHEEHAN 295 processes for the separation of penicillin G from other peni- cillins by formation of a crystalline salt with N-ethy~piperidine and subsequent exchange to the sodium salt with sodium 2- ethy~hexanoate. One of his laboratory associates at Merck was Donald I. Cram, who later shared with C. I. Peclersen and ~ean-Marie Lehn a Nobel Prize in chemistry for work on inclusion compounds. John's work at Merck strew very favorable attention from Homer Adkins, a consultant to the company and renowned! professor of chemistry at the University of Wisconsin. Adkins recommended John to Arthur C. Cope, who had been ap- pointecl heat! of the Department of Chemistry in 1945 by the president of MTT, Karl T. Compton, on the advice of a friend and wartime associate, Roger Adams of the Univer- sity of Illinois. John joiner! the MIT faculty as an assistant professor in 1946, at a salary he said was half his compensa- tion at Merck. At the same time, John D. Roberts and C. Gardner Swain were brought on board by Cope, and in the next few years MTT under Cope's vigorous leadership was propellecl into the front ranks of U.S. chemistry.) Within just four years at MTT John Sheehan became known as one of the most creative and dynamic synthetic organic chemists in the worIcl by his clevelopment of new methods of synthesis of peptides (carbodiimicle coupling and phthaloy! N-protection), three new syntheses of B-lactams, the first synthesis of the penicillin ring system, and isolation and iclentif~cation of a number of important new natural prod- ucts. His research on penicillins, initiated in 194S, was remark- able for several reasons. It came on the heels of the large wartime U.S.-British project of research on penicillins (in- volving more than a thousand chemists), which failed to develop a chemical synthesis and proclucecl instead an omi- nous summary of a great many failecl attempts. By 1948

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296 BIOGRAPHICAL MEMOIRS penicillin G was produced in abundance commercially by fermentation, and no other leading chemist saw any reason to take on the apparently hopeless task of synthesizing such an unstable molecule. In Johns own colorful language, the chemical synthesis of penicillin was like "placing an anvil on top of a house of cards." Years of determined and skill- ful effort were rewarded by success in 1957 when John and his group completed the first synthesis of penicillin V. One of the intermediates in the synthesis was 6-aminopenicillanic acid, a substance that Sheehan recognized could be used to prepare a variety of penicillins other than naturally occur- ring ones. This prescient conception turned out to have great medical value because it made possible variations in the penicillin structure that could be used to combat the tolerance developed by bacteria to particular forms of the antibiotic. The Sheehan synthesis of 6-aminopenicillanic acid is impractical for making these superpenicillins, but the amino acic! is available in quantity by fermentation. John later told of his involvement with penicillins in his book, The Enchanted Ring The Untold Story of Penicillin,2 which also includes an account of the complex legal skirmish over the Sheehan-MIT patents on penicillin synthesis. Although the legal battle was protracted MTT eventually received al- most $30 million in royalties from the Sheehan patent. MIT established the John C. Sheehan Professorship of Chemis- try in October 1992. Sheehan retired in 1977 and was named professor of chem- istry emeritus and senior lecturer. John Sheehan's major research achievements are described in some 150 synthetic papers and forty patents that cover not only penicillin but also peptides, antibiotics, alkaloids, and steroids. For his scientific contributions, John received several high honors, including the American Chemical So- ciety Award in Pure Chemistry (1951), election to the Na-

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JOHN CLARK SHEEHAN 297 tional Academy of Sciences (1957), the American Chemical Society Award for Creative Work in Synthetic Organic Chem- istry (1959), the John Scott Award for inventors benefiting mankind (1964), the Outstanding Achievement Award of the University of Michigan (1971), en cl honorary ctoctor- ates from Notre Dame (1953) and the Stevens Institute of Technology (1980). Sheehan spent ~ 953-54 in London as scientific liaison officer for the Office of Naval Research. From 1961 to 1965, he served the President's Science Advisory Committee as consultant, member of the limited war panel, and chair- man of the committee on chemistry ant! biology. In the latter capacity he was involved in technology transfer nego- tiations with the Japanese government. He later hack a close association with H. Umezawa, director of the Institute of Microbial Chemistry, and made many trips to Japan in con- nection with his interests in antibiotics anct other pharma- ccuticals. Sheehan played an active role in Organic Synthe- ses, Tnc., by serving as editor-in-chief of volume 38 and then for many years as a member of the Advisory Board and Board of Directors. He was also engaged in the affairs of the American Chemical Society and, among other activi- ties, server! on its Board of Directors for eight years. Sheehan was a member of the National Research CounciT's Commit- tee on Protection Against Mycotoxins (1982-84) and the Committee on Commercial Airport Security ~1988-92). Troni- cally, in the latter activity he was concerned with the cletec- tion of explosives, such as RDX, on airplanes and in lug- gage and shipments. Besides his work at MIT, Sheehan was involved in two rather unusual research activities of possible interest to those seeking alternative research support mechanisms. Thus, in 195S, the Schering Corporation set up the Research Insti- tute for Medicine and Chemistry in Cambridge close to

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298 BIOGRAPHICAL MEMOIRS M]:T in appreciation of the contributions of M. M. Pechet to the company's clinical work. As director, Pechet invited D. H. R. Barton, then at Imperial College, London, to su- pervise a small research group. At Barton's suggestion, Sheehan also spent several years in a similar capacity. The first project of the institute was to achieve a synthesis of alclosterone, a goal that Sheehan hoped to reach by degra- dation of a steroicial alkaloid, but was better prepared by a nitrite-photolysis procedure developer! by Barton. Subse- quently, Sheehan extended his research on water-soluble carbocliimicles at the institute for several years. Later in 1970 he was able to builcl on the results of a government- supportec! research program at Arthur D. Little Co. on can- nabinoic! derivatives as potential chemical warfare agents to set up a program aimed at the use of such derivatives in the treatment of nausea resulting from cancer chemotherapy. This work was carried out at a for-profit company called SHARPS Associates and the nonprofit John C. Sheehan Re- search Institute. The former was supported by contracts with pharmaceutical companies ant] the latter by research grants, as from the National Institutes of Health. The com- binec! operation got off to an excellent start, but Sheehan was later greatly clisappointecI by subsequent management problems. The present authors, one as a graduate student in the Sheehan research group and the other a professorial col- league, were greatly impressed by {ohn's ingrained! cheer- fuIness, optimism, and humor, as well as his broac! chemical expertise. His lL948-50 research group inclucled GeraTcl D. L~aubach (later president of Pfizer, Tnc.), Robert T. O'Neill (later a successful research chemist at Merck and a private businessman), Barry M. Bloom (president of Pfizer Research), Ajay K. Bose (professor of chemistry at Stevens Institute of Technology), David Johnson (research director at Bristol

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JOHN CLARK SHEEHAN 299 Myers), E. J. Corey (later professor of chemistry at Harvard), and Kenneth Henery-Logan (who later participated in the successful synthesis of penicillin). This was no collection of shrinking violets, and they all fount! as much enjoyment in exchanges with John as in the research adventure itself. John Sheehan was a man who made friencis easily and tract many close friends at home as well as abroad the re- sults of his extensive international travels. He was an avic! competitor in all things, a trait that was particularly evident to those who played tennis with him. He enjoyed boating, was a close follower of politics and sports, a marvelous ra- conteur, and a lover of goocI stories toIc! by others, as well as an entertaining clinner companion. John is survives! by Marion, his lovely and devotecl wife of more than fifty years; a brother, David Sheehan of Battle Creek, Michigan; three children, John C., Jr., of Denver, David E. of Key Biscayne, and Elizabeth (Betsy) S. Watkins of Sauderstown, Rhode TslancI; and six grancichiTciren. Sheehan's career was multifaceted, with achievements that clemonstrated an unusual ability to focus on chemical prob- lems of great practical importance, the courage to pioneer against strong Osiris, and an unflagging determination to succeed. THE AUTHORS ARE VERY GRATEFUL to Marion Sheehan; her sister-in-law, Vivian; Professor Ajay K. Bose; and Sir Derek Barton for providing valuable background material for this biography. NOTES 1. For more on the Cope era at MIT, see I. D. Roberts, The Right Place at the Right Time, pp. 53-59. (Washington, D.C.: American Chemical Society, 1990), and I. D. Roberts and l. C. Sheehan, "Arthur C. Cope," Biographical Memoirs, vol. 60, pp. 17-30 (Washington, D.C.: National Academy Press, 1991 ~ . 2. I. C. Sheehan, The Enchanted Ring The Untold Story of Penicil- lin (Cambridge, Mass.: MIT Press, 1982~.

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300 BIOGRAPHICAL MEMOIRS SELECTED BIBLIOGRAPHY Selection of the twenty-five papers cited here was arbitrary, in ne- cessity made by the biographers. A complete list of the publications of John C. Sheehan is available from the Archives of the National Academy of Sciences. 1946 With W. J. Mader and D. }. Cram. A chemical assay method for penicillin G. [. Am. Chem. Soc. 68:2407. 1948 With P. T. Izzo. A novel synthesis of a B-lactam. /. Am. Chem. So c. 70:1985. 1949 With W. E. Bachmann. A new method of preparing the high explo- sive RDX. [. Am. Chem. Soc. 71:1842. With V. S. Frank. A new synthetic route to peptides. [. Am. Chem. Soc. 71:1855. 1950 With E. I. Corey, G. Laubach, and I. I. Ryan. The total synthesis of a 5-phenyl penicillin; methyl-5-phenyl (2-carbomethoxyethyl)- penicillinate. [. Am. Chem. Soc. 72:3828. With A. K. Bose. A new synthesis of B-lactams. [. Am. Chem. Soc. 72:5158. 1951 With I. I. Ryan. The synthesis of substituted penicillins and simpler structural analogs. II. a-acylamino B-lactam-thiazolidines. i. Am. Chem. Soc. 73:4367. With E. J. Corey. The synthesis of substituted penicillins and sim- pler structural analogs. VI. The synthesis of a 6-phenylacetylamino- B-lactam-thiazolidine. J. Am. Chem. Soc. 73:4756. 1952 With B. M. Bloom. The synthesis of teloidinone and 6-hydroxy- tropionone. J. Am. Chem. Soc. 74:3825.

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JOHN CLARK SHEEHAN 1953 301 With R. C. Coderre and P. A. Cruickshank. The formation of five- and six-membered rings by the acyloin condensation. IV. The natural estrogenic steroids. [. A m. Chem. Soc. 75:6231. 1955 With G. P. Hess. A new method of forming peptide bonds. I. A m. Chem. So c. 77:1067. 1956 With }. I. Hlavka. The use of water-soluble and basic carbodiimides in peptides synthesis. [. Org. Chem. 21:439. 1957 With K. R. Henery-Logan. The total synthesis of penicillin V. [. A m. Chem. Soc. 79:1262. With H. G. Zachau and W. B. Lawson. The structure of etamycin. /. A m. Chem. Soc. 79:3933. With I. I. Hlavka. The cross-linking of gelatin using a water-soluble carbodiimide. [. A m. Chem. Soc. 79:4528. 1959 With K. R. Henery-Logan. The total synthesis of penicillin V. J. A m. Chem. Soc.81: 3089. 1961 With P. A. Cruickshank and G. L. Boshart. A convenient synthesis of water-soluble carbodiimides. J. Org. Chem. 26:2525. 1962 With K. R. Henery-Logan. The total and partial general syntheses of the penicillins. /. A m. Chem. Soc. 84:2983. 1963 Peptide-type antibiotics. Pure Appl. Chem. 6:297. 1964 With P. A. Cruickshank. Synthetic peptide models of enzyme active

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302 BIOGRAPHICAL MEMOIRS sites. II. L-threonyl-L-alanyl-L-seryl-L-histidyl-L-aspartic acid, an active esterase model. [. Am. Chem. Soc. 86:2070. 1968 With I. Lengyel. oc-lactams (aziridinones). Angew. Chem. 80:27. With D. Mania, S. Nakamura, I. A. Stock, and K. Maeda. The struc- ture of telomycin. [. Am. Chem. Soc. 90:462-70. 1973 With S. L. Ledis. Total synthesis of a monocyclic peptide lactone antibiotic, etamycin. {. Am. Chem. Soc. 95:875. 1974 With Y. S. Lo. Total synthesis and resolution of terreic acid. [. Med. Chem. 17:371. 1981 ,8-Lactam Antibiotics Historical Perspective. New York: Academic Press.

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