Ralph F. Hirschmann

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1922 – 2009

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Ralph F. Hirschmann, one of our most distinguished scientists, passed away peacefully on June 20, 2009. Born on May 6, 1922, in Fu ̈rth, Barvaria, Germany, the youngest son of Carl and Alice Hirschmann, he attended the Gymnasium in Fürth until December 1936 when, due to the rise of Nazi Germany, he convinced his parents to leave Germany for the United States. Settling in Kansas City, Missouri, Ralph completed high school and in 1939 entered Oberlin College in Ohio, graduating in 1943 with a degree in Chemistry. He immediately enlisted in the U.S. Army, became a naturalized citizen in 1944, and then served for three years in the Pacific theater, stationed primarily in Guadalcanal and Okinawa.

After World War II, Ralph was admitted to the University of Wisconsin, where in 1950 he completed his Ph.D. degree in Chemistry under the mentorship of Professor W. S. Johnson. During a visit to the University by Dr. Max Tishler of Merck and Co., Ralph was persuaded to join the Merck Process Laboratories in Rahway, New Jersey. There he initiated what was to become a stellar career in both Medicinal and Bioorganic Chemistry, and Management in the Pharmaceutical Industry. Shortly after joining Merck, Ralph met and married fellow Merck chemist, Lucy Aliminosa.

The early days at Merck were principally concerned with steroid and vitamin K synthesis, the chemical frontiers of that time. Ralph’s interests, however, were not confined to organic chemistry! He quickly recognized the power of organic in the best traditions of W.S. Johnson and Max Tishler, to explore relevant biomedical issues.

With the steroid field maturing in the early 1960s, the powers at Merck asked Ralph to initiate a program in peptide/protein synthesis. This proved to be a brilliant change in direction, and in 1969, in collaboration with Dr. Robert Denkewalter, Ralph led the Merck team to achieve the first total synthesis of an enzyme, ribonuclease A, simultaneously with the Merrifield synthesis at Rockefeller University. The Hirschmann approach entailed the tactic of fragment coupling, while the Merrifield approach exploited their recently introduced step-wise solid-phase synthetic method. Nearly every major newspaper in the western world reported their achievements as front-page news.

Although Ralph maintained a strong interest in basic biomedical research at Merck during the 1970s and 1980s, with a particular focus on the mechanism of action and bioactive conformation of somatostatin, a neuropeptide hormone, his administrative duties increasingly removed him from the laboratory. Indeed, at the time of his retirement in 1987 as Senior Vice-President for Basic Research, Ralph had responsibilities for much of the company’s basic research, including the sites at Rahway, New Jersey, West Point, Pennsylvania, Terlings Park, UK, and Merck Frosst, Canada. During this time, under Ralph’s leadership, Merck developed Vasotec, Lisinopril, Primaxin, Mevacore, Proscar and Ivomec. It was also during this period, that Ralph championed, and was a major benefactor to, many young academic chemists at the outset of their academic careers.

Upon retirement from Merck in 1987, Ralph was invited to join the faculty of the University of Pennsylvania, first as a Research Professor and later as the Rao Makineni Professor of Bioorganic Chemistry. He also held a concurrent appointment at the Medical University of South Carolina between 1987 and 1999. At Penn he presented a yearly graduate course on Bioorganic and Medicinal Chemistry and he served as research mentor to 56 graduate students and postdoctoral fellows. His research at Penn focused initially on two areas. With the Nicolaou group he focused on the design and synthesis of small mimics of the neuropeptide hormone somatostatin, introducing β-D-glucose as a privileged scaffold, and with the Smith group, the design, synthesis and evaluation of what are now known as nonpeptide foldamers and inhibitors of the aspartic acid proteases, specifically renin and HIV-1. In 1989, a third major program would evolve that joined the forces of Professor Stephen Benkovic, a biochemist at The Pennsylvania State University, and the synthetic chemistry of the Smith laboratory to develop a transition state analog that would hold the promise of eliciting catalytic antibodies capable of peptide and protein ligation. Ralph knew only too well the potential that such an antibody would hold for protein synthesis, having achieved the total synthesis of ribonuclease, employing the tactic of fragment coupling. Each of these programs proved highly successful. Some 59 joint publications emanated from these efforts. Moreover, during this period, Ralph presented more than 100 plenary lectures both in this country and abroad about the Penn research.

Ralph served as a member of the Board of Editors for Organic Reactions for Volumes 24–33, and was a member of the Organic Reactions Board of Directors from 1982 – 1987.

For his many scholarly achievements both in medicinal and bioorganic chemistry, Ralph received numerous prestigious honors, including three honorary Doctor of Science Degrees: Oberlin College (1969), University of Wisconsin, Madison (1996), and the Medical College of South Carolina (1997). He was elected a member of the American Academy of Arts and Sciences, the National Academy of Sciences, and a Senior Fellow of the Institute of Medicine. His awards included the Intra-Science Research Foundation Award, the Merck Board of Director’s Award, the Nichols Medal, the Chemical Pioneer Award of the American Institute of Chemists, the Max Bergmann Kreis Award, the Carothers Award, the Guthikonda Memorial Award from Columbia University, the Joseph Rudiger Award of the European Peptide Society, and the Edward E. Smissman-Bristol Myers Award, and he was the only person to receive both the Alfred Burger Award in Medicinal Chemistry and the ACS Award in Medicinal Chemistry. In addition, he received the Williard Gibbs Medal, National Academy of Sciences Award for Industrial Application of Sciences, Arthur C. Cope Award, one of the highest awards of the American Chemical Society, and the National Medal of Sciences from President Clinton. Finally, the ACS-administered Award in Peptide Research and the Hirschmann-Makineni Professor in Chemistry at the University of Pennsylvania were established in his honor.

Ralph is survived by his wife, Lucy Hirschmann; his son, Ralph Frederick Hirschmann of Pasadena, California, and his daughter, Carla Hummel, MD, of Las Vegas, Nevada; his daughter-in-law, Karen Montle Hirschmann, and his son-in-law, Paul Hummel, MD; and his grandchildren, Brian, Lisa, Brendan, and Lauren Hirschmann, and Patrick and Christina Hummel.

Amos B. Smith III

University of Pennsylvania

August 11, 2009