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John Clark Sheehan (23 September 1915 – 21 March 1992) was an American organic chemist whose work on synthetic penicillin led to tailor-made forms of the drug. After nine years of hard work at the Massachusetts Institute of Technology (M.I.T.), he became the first to discover a practical method for synthesizing penicillin V. While achieving total synthesis, Sheehan also produced an intermediate compound, 6-aminopenicillanic acid, which turned out to be the foundation of hundreds of kinds of synthetic penicillin. Dr. Sheehan's research on synthetic penicillin paved the way for the development of customized forms of the lifesaving antibiotic that target specific bacteria. Over the four decades he worked at M.I.T., Sheehan came to hold over 30 patents, including the invention of ampicillin, a commonly used semi-synthetic penicillin that is taken orally rather than by injection. His research covered not only penicillin, but also peptides, other antibiotics, alkaloids, and steroids.

He studied chemistry and political science at Battle Creek College. In 1937, Sheehan graduated as the valedictorian of his class and won a scholarship for graduate studies in any subject of his choice. He decided to study organic chemistry at the University of Michigan, receiving his Master's in 1938 and his PhD in 1941. His doctorate advisor, Werner E. Bachmann, was involved in the synthesis of steroid hormones. As a post-doctoral fellow, Sheehan collaborated with Bachmann on the commercially feasible production of RDX also known as cyclonite, which turned out to give the Allies a huge advantage at sea during World War II.

For three decades after the discovery of natural penicillin by Sir Alexander Fleming, the source of the antibiotic hardly changed. Scientists made the drug by natural fermentation of Penicillium mold. However, during World War II, the United States government undertook a massive effort to determine the chemical structure of penicillin and to chemically synthesize it in large quantities. The scale of this project was compared to the development of the atomic bomb. This stemmed from the dire need for the antibiotic to treat soldiers on the battlefield. More than a thousand chemists working at thirty-nine laboratories were involved in the project. Despite the huge investment by the government, none proved to be successful in solving this elusive problem.

As John Sheehan described in his book The Enchanted Ring: The Untold Story of Penicillin, after the war, most other synthetic chemists abandoned attempting penicillin synthesis, and were convinced that such synthesis was impossible. For the nine years that he worked on penicillin synthesis, there were practically no competitors, leaving Sheehan on a lonely search for a way to synthesize the antibiotic. Most young academic chemists chose not to undertake projects that they perceived to be painfully slow because they wanted to impress faculty tenure committees with many experiments and publications. Even though many of his friends openly questioned his decision of getting involved with the drug, Sheehan was determined to work on the chemical synthesis of penicillin at M.I.T. Once he decided that penicillin was an important problem, and one that had a solution, Sheehan never re-evaluated his position. He explained that one of the reasons he decided to switch from his job at Merck to M.I.T. was because "At M.I.T, I was a research committee of one. I could make the decision to spend the rest of my life on the penicillin problem; it was only my career that was on the line."

At the time, it was known that the molecular weight of penicillin was around 350 g/mol, which was within the range of molecules that had already been chemically synthesized. The problem was the making the chemically unstable beta-lactam ring that was crucial to the antibiotic properties of the molecule. Beta-lactam antibiotics inhibit the formation of the peptidoglycan layer of the cell walls of Gram-positive bacteria. Most of the scientists experienced failure after failure because "the appropriate techniques and reactions for putting together the penicillin molecule simply had not yet been discovered." In the words of Sheehan, using traditional methods at the time was like "placing an anvil on top of a house of cards."[3] After nine years of dogged work in the M.I.T. laboratories, this persistent organic chemist finally solved one of chemistry's most baffling problems at the time.[4] In 1957, John C. Sheehan announced that his group had completed the first synthesis of penicillin V (one of the two most useful forms of the antibiotic). During the process, he had also produced an intermediate, 6-aminopenicillanic acid, which was later used as a foundation for preparing a variety of penicillins.[5] This allowed researchers to combat the resistance that certain bacteria had developed to particular forms of the drug. Sheehan later published his involvement in the synthesis of penicillins in The Enchanted Ring: The Untold Story of Penicillin, which noted a complex legal skirmish over his patents on penicillin synthesis involving M.I.T. and Beecham, a British industrial research laboratory that was also working on penicillins.

John Clark Sheehan